Title: WHO / Neuro
Tags: Neuro::Tumor::Glioneuronal_Neuronal Neuro::Tumor::Ependymal Neuro::Tumor::Mesenchymal Neuro::Heme::Lymphoma Neuro::Tumor::Diffuse_Glioma Neuro::Tumor::Embryonal Neuro::Tumor::Astrocytic_Circumscribed Neuro::Tumor::Nerve Neuro::Tumor::Sellar Neuro::Heme::Histiocytic Neuro::Tumor::Pineal Neuro::Tumor::Choroid_Plexus Neuro::Tumor::Familial_Tumor_Predisposition_Syndromes Neuro::Genetic_Syndrome::Tuberous_Sclerosis_Complex Neuro::Tumor::Adult_Type_Diffuse_Gliomas Neuro::Tumor::Melanocytic

Q: In Constitutional mismatch repair deficiency syndrome, a pathognomonic immunohistochemical finding in associated glioblastomas is the loss of mismatch repair protein (e.g., PMS2) expression in [...].
Glioblastoma in a child with CMMRD demonstrating a complete absence of PMS2 protein in both tumour cells and background normal cells, indicative of biallelic germline inactivation.
Glioblastoma arising in the setting of CMMRD showing severe nuclear pleomorphism and multinucleated giant cells.
A: both neoplastic and normal background cells
Back Extra: Constitutional mismatch repair deficiency syndrome
- Clinical: Autosomal recessive syndrome caused by biallelic germline mutations in mismatch repair genes (MLH1, PMS2, MSH2, or MSH6); features include café-au-lait macules, childhood-onset glioblastomas, hematological malignancies, and gastrointestinal polyposis.
- Microscopic: Glioblastomas often exhibit severe nuclear pleomorphism or bizarre multinucleated giant cells; a pathognomonic finding is the loss of MMR protein expression in both neoplastic and normal (non-neoplastic) background cells.
- Ancillary: Tumors are characterized by "ultrahypermutation" (> 100 mutations/Mb) and frequently harbor secondary somatic mutations in the proofreading domains of POLE or POLD1.
- Prognosis: While inherently resistant to temozolomide, the high neoantigen burden associated with ultrahypermutation makes these tumors potential candidates for immune checkpoint blockade.
Reference Gallery:
Glioblastoma in a child with CMMRD demonstrating a complete absence of PMS2 protein in both tumour cells and background normal cells, indicative of biallelic germline inactivation.
Glioblastoma arising in the setting of CMMRD showing severe nuclear pleomorphism and multinucleated giant cells.
T1-weighted postcontrast MRI of a patient with CMMRD and a homozygous MSH2 variant, demonstrating synchronous glioblastomas.
A model of replication repair deficiency leading to hypermutation and ultrahypermutation through combined mismatch repair and polymerase defects.

Q: Tumors associated with Constitutional mismatch repair deficiency syndrome frequently harbor secondary somatic mutations in the proofreading domains of POLE or POLD1, leading to a characteristic state of [...] (> 100 mutations/Mb).
Glioblastoma arising in the setting of CMMRD showing severe nuclear pleomorphism and multinucleated giant cells.
A model of replication repair deficiency leading to hypermutation and ultrahypermutation through combined mismatch repair and polymerase defects.
A: ultrahypermutation
Back Extra: Constitutional mismatch repair deficiency syndrome
- Clinical: Autosomal recessive syndrome caused by biallelic germline mutations in mismatch repair genes (MLH1, PMS2, MSH2, or MSH6); features include café-au-lait macules, childhood-onset glioblastomas, hematological malignancies, and gastrointestinal polyposis.
- Microscopic: Glioblastomas often exhibit severe nuclear pleomorphism or bizarre multinucleated giant cells; a pathognomonic finding is the loss of MMR protein expression in both neoplastic and normal (non-neoplastic) background cells.
- Ancillary: Tumors are characterized by "ultrahypermutation" (> 100 mutations/Mb) and frequently harbor secondary somatic mutations in the proofreading domains of POLE or POLD1.
- Prognosis: While inherently resistant to temozolomide, the high neoantigen burden associated with ultrahypermutation makes these tumors potential candidates for immune checkpoint blockade.
Reference Gallery:
Glioblastoma in a child with CMMRD demonstrating a complete absence of PMS2 protein in both tumour cells and background normal cells, indicative of biallelic germline inactivation.
Glioblastoma arising in the setting of CMMRD showing severe nuclear pleomorphism and multinucleated giant cells.
T1-weighted postcontrast MRI of a patient with CMMRD and a homozygous MSH2 variant, demonstrating synchronous glioblastomas.
A model of replication repair deficiency leading to hypermutation and ultrahypermutation through combined mismatch repair and polymerase defects.

Q: Familial adenomatous polyposis 1 is an autosomal dominant syndrome caused by germline inactivation of the [...] gene; when associated with medulloblastoma, it is termed Brain tumor polyposis syndrome 2.
Medulloblastoma in brain tumour polyposis syndrome 2. Classic medulloblastoma with Homer Wright rosettes.
A: APC
Back Extra: Familial adenomatous polyposis 1
- Clinical: Familial adenomatous polyposis 1 (FAP1) is an autosomal dominant syndrome caused by germline APC inactivation; the subtype involving medulloblastoma is termed Brain tumour polyposis syndrome 2 (BTP2).
- Microscopic: Medulloblastomas in this setting show classic histology, frequently featuring "Homer Wright rosettes" and lacking nodular or anaplastic features.
- Ancillary: Tumors show strong nuclear accumulation of beta-catenin (WNT pathway activation) but are characteristically wildtype for CTNNB1.
- Prognosis: Survival for FAP1-associated WNT-activated medulloblastoma is excellent, similar to sporadic counterparts.
Reference Gallery:
Medulloblastoma in brain tumour polyposis syndrome 2. Classic medulloblastoma with Homer Wright rosettes.

Q: Patients with Familial adenomatous polyposis 1 can develop medulloblastomas (Brain tumor polyposis syndrome 2), which typically demonstrate classic histology featuring [...].
Medulloblastoma in brain tumour polyposis syndrome 2. Classic medulloblastoma with Homer Wright rosettes.
A: Homer Wright rosettes
Back Extra: Familial adenomatous polyposis 1
- Clinical: Familial adenomatous polyposis 1 (FAP1) is an autosomal dominant syndrome caused by germline APC inactivation; the subtype involving medulloblastoma is termed Brain tumour polyposis syndrome 2 (BTP2).
- Microscopic: Medulloblastomas in this setting show classic histology, frequently featuring "Homer Wright rosettes" and lacking nodular or anaplastic features.
- Ancillary: Tumors show strong nuclear accumulation of beta-catenin (WNT pathway activation) but are characteristically wildtype for CTNNB1.
- Prognosis: Survival for FAP1-associated WNT-activated medulloblastoma is excellent, similar to sporadic counterparts.
Reference Gallery:
Medulloblastoma in brain tumour polyposis syndrome 2. Classic medulloblastoma with Homer Wright rosettes.

Q: In Familial Retinoblastoma, microscopic examination classically reveals a mitotically active small blue cell tumor featuring photoreceptor differentiation known as fleurettes and [...].
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.
A: Flexner-Wintersteiner rosettes
Back Extra: Familial Retinoblastoma
- Clinical: Familial cases result from germline RB1 mutations, typically presenting early (~12 months), often bilaterally (60%), and with risks for secondary malignancies such as osteosarcoma.
- Trilateral Disease: Germline carriers are predisposed to 'trilateral retinoblastoma,' involving intraocular tumors plus an intracranial tumor, most frequently in the pineal gland.
- Microscopic: Characterized as a mitotically active small blue cell tumor featuring Flexner–Wintersteiner rosettes (central lumen) and photoreceptor differentiation ('fleurettes').
- Risk Factors: Significant predictors of recurrence and mortality include retrolaminar optic nerve invasion and massive (>3 mm) choroidal invasion.
- Genetics: Primarily driven by RB1 inactivation (13q14.2); however, a small subset (2%) of sporadic cases is driven by MYCN amplification.
Reference Gallery:
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.

Q: Patients with Familial Retinoblastoma are predisposed to developing [...] disease, which is characterized by bilateral intraocular tumors along with an intracranial tumor (most frequently located in the pineal gland).
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.
A: trilateral
Back Extra: Familial Retinoblastoma
- Clinical: Familial cases result from germline RB1 mutations, typically presenting early (~12 months), often bilaterally (60%), and with risks for secondary malignancies such as osteosarcoma.
- Trilateral Disease: Germline carriers are predisposed to 'trilateral retinoblastoma,' involving intraocular tumors plus an intracranial tumor, most frequently in the pineal gland.
- Microscopic: Characterized as a mitotically active small blue cell tumor featuring Flexner–Wintersteiner rosettes (central lumen) and photoreceptor differentiation ('fleurettes').
- Risk Factors: Significant predictors of recurrence and mortality include retrolaminar optic nerve invasion and massive (>3 mm) choroidal invasion.
- Genetics: Primarily driven by RB1 inactivation (13q14.2); however, a small subset (2%) of sporadic cases is driven by MYCN amplification.
Reference Gallery:
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.

Q: The germline RB1 mutations responsible for Familial Retinoblastoma significantly increase the patient's risk of developing secondary malignancies, most notably [...].
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.
A: osteosarcoma
Back Extra: Familial Retinoblastoma
- Clinical: Familial cases result from germline RB1 mutations, typically presenting early (~12 months), often bilaterally (60%), and with risks for secondary malignancies such as osteosarcoma.
- Trilateral Disease: Germline carriers are predisposed to 'trilateral retinoblastoma,' involving intraocular tumors plus an intracranial tumor, most frequently in the pineal gland.
- Microscopic: Characterized as a mitotically active small blue cell tumor featuring Flexner–Wintersteiner rosettes (central lumen) and photoreceptor differentiation ('fleurettes').
- Risk Factors: Significant predictors of recurrence and mortality include retrolaminar optic nerve invasion and massive (>3 mm) choroidal invasion.
- Genetics: Primarily driven by RB1 inactivation (13q14.2); however, a small subset (2%) of sporadic cases is driven by MYCN amplification.
Reference Gallery:
Retinoblastoma. Low-power view showing replacement of the retina by retinoblastoma.

Q: High-grade gliomas associated with Neurofibromatosis type 1 frequently demonstrate loss of [...] expression by immunohistochemistry.
Neurofibromatosis type 1 (NF1). Loss of ATRX staining in an NF1-associated high-grade glioma. ATRX mutations lead to protein loss shown by immunohistochemistry, with preservation in blood vessels and other non-neoplastic cells.
A: ATRX
Back Extra: Neurofibromatosis type 1
- Clinical: Autosomal dominant syndrome caused by biallelic inactivation of the NF1 gene (17q11.2); classic features include café-au-lait spots, axillary/inguinal freckling, Lisch nodules, and osseous lesions like sphenoid wing dysplasia.
- Neoplasms: Predisposes to cutaneous and plexiform neurofibromas, optic pathway gliomas (predominantly pilocytic astrocytoma), malignant peripheral nerve sheath tumours (MPNST), and high-grade gliomas in adults.
- Microscopic: MPNST presents as high-grade spindle cell neoplasms with brisk mitosis and necrosis; ANNUBP is a precursor lesion defined by cytological atypia, hypercellularity, and mitotic counts between 0.2 and 1.5/mm².
- Ancillary: MPNSTs often show loss of H3K27me3 and p16 by IHC, while NF1-associated high-grade gliomas frequently demonstrate loss of ATRX expression.
Reference Gallery:
Neurofibromatosis type 1 (NF1). Multiple café-au-lait spots on the back in a child with NF1.
Neurofibromatosis type 1 (NF1). Cutaneous neurofibromas on the left arm of an adult with NF1.
Neurofibromatosis type 1 (NF1). Pilocytic astrocytoma. The most common brain tumour in patients with NF1 is pilocytic astrocytoma, which is frequently located in the optic nerve (asterisks).
Neurofibromatosis type 1 (NF1). Low-grade astrocytoma with subependymal giant cell astrocytoma (SEGA)-like morphology. A variety of gliomas may also affect patients with NF1, including low-grade astrocytomas that are difficult to classify, occasionally demonstrating SEGA-like morphology.
Neurofibromatosis type 1. High-grade glioma tumours usually afflict adult patients and may show infiltration, mitotic activity, and palisading necrosis, similar to glioblastoma.
Neurofibromatosis type 1 (NF1). Loss of ATRX staining in an NF1-associated high-grade glioma. ATRX mutations lead to protein loss shown by immunohistochemistry, with preservation in blood vessels and other non-neoplastic cells.

Q: High-grade glioma tumors affecting adult patients with Neurofibromatosis type 1 often exhibit infiltration, brisk mitotic activity, and [...].
Neurofibromatosis type 1. High-grade glioma tumours usually afflict adult patients and may show infiltration, mitotic activity, and palisading necrosis, similar to glioblastoma.
A: palisading necrosis
Back Extra: Neurofibromatosis type 1
- Clinical: Autosomal dominant syndrome caused by biallelic inactivation of the NF1 gene (17q11.2); classic features include café-au-lait spots, axillary/inguinal freckling, Lisch nodules, and osseous lesions like sphenoid wing dysplasia.
- Neoplasms: Predisposes to cutaneous and plexiform neurofibromas, optic pathway gliomas (predominantly pilocytic astrocytoma), malignant peripheral nerve sheath tumours (MPNST), and high-grade gliomas in adults.
- Microscopic: MPNST presents as high-grade spindle cell neoplasms with brisk mitosis and necrosis; ANNUBP is a precursor lesion defined by cytological atypia, hypercellularity, and mitotic counts between 0.2 and 1.5/mm².
- Ancillary: MPNSTs often show loss of H3K27me3 and p16 by IHC, while NF1-associated high-grade gliomas frequently demonstrate loss of ATRX expression.
Reference Gallery:
Neurofibromatosis type 1 (NF1). Multiple café-au-lait spots on the back in a child with NF1.
Neurofibromatosis type 1 (NF1). Cutaneous neurofibromas on the left arm of an adult with NF1.
Neurofibromatosis type 1 (NF1). Pilocytic astrocytoma. The most common brain tumour in patients with NF1 is pilocytic astrocytoma, which is frequently located in the optic nerve (asterisks).
Neurofibromatosis type 1 (NF1). Low-grade astrocytoma with subependymal giant cell astrocytoma (SEGA)-like morphology. A variety of gliomas may also affect patients with NF1, including low-grade astrocytomas that are difficult to classify, occasionally demonstrating SEGA-like morphology.
Neurofibromatosis type 1. High-grade glioma tumours usually afflict adult patients and may show infiltration, mitotic activity, and palisading necrosis, similar to glioblastoma.
Neurofibromatosis type 1 (NF1). Loss of ATRX staining in an NF1-associated high-grade glioma. ATRX mutations lead to protein loss shown by immunohistochemistry, with preservation in blood vessels and other non-neoplastic cells.

Q: Low-grade astrocytomas in patients with Neurofibromatosis type 1 can occasionally demonstrate unusual features, such as [...]-like morphology.
Neurofibromatosis type 1 (NF1). Low-grade astrocytoma with subependymal giant cell astrocytoma (SEGA)-like morphology. A variety of gliomas may also affect patients with NF1, including low-grade astrocytomas that are difficult to classify, occasionally demonstrating SEGA-like morphology.
A: subependymal giant cell astrocytoma (SEGA)
Back Extra: Neurofibromatosis type 1
- Clinical: Autosomal dominant syndrome caused by biallelic inactivation of the NF1 gene (17q11.2); classic features include café-au-lait spots, axillary/inguinal freckling, Lisch nodules, and osseous lesions like sphenoid wing dysplasia.
- Neoplasms: Predisposes to cutaneous and plexiform neurofibromas, optic pathway gliomas (predominantly pilocytic astrocytoma), malignant peripheral nerve sheath tumours (MPNST), and high-grade gliomas in adults.
- Microscopic: MPNST presents as high-grade spindle cell neoplasms with brisk mitosis and necrosis; ANNUBP is a precursor lesion defined by cytological atypia, hypercellularity, and mitotic counts between 0.2 and 1.5/mm².
- Ancillary: MPNSTs often show loss of H3K27me3 and p16 by IHC, while NF1-associated high-grade gliomas frequently demonstrate loss of ATRX expression.
Reference Gallery:
Neurofibromatosis type 1 (NF1). Multiple café-au-lait spots on the back in a child with NF1.
Neurofibromatosis type 1 (NF1). Cutaneous neurofibromas on the left arm of an adult with NF1.
Neurofibromatosis type 1 (NF1). Pilocytic astrocytoma. The most common brain tumour in patients with NF1 is pilocytic astrocytoma, which is frequently located in the optic nerve (asterisks).
Neurofibromatosis type 1 (NF1). Low-grade astrocytoma with subependymal giant cell astrocytoma (SEGA)-like morphology. A variety of gliomas may also affect patients with NF1, including low-grade astrocytomas that are difficult to classify, occasionally demonstrating SEGA-like morphology.
Neurofibromatosis type 1. High-grade glioma tumours usually afflict adult patients and may show infiltration, mitotic activity, and palisading necrosis, similar to glioblastoma.
Neurofibromatosis type 1 (NF1). Loss of ATRX staining in an NF1-associated high-grade glioma. ATRX mutations lead to protein loss shown by immunohistochemistry, with preservation in blood vessels and other non-neoplastic cells.

Q: In patients with Neurofibromatosis type 2, the presence of asymptomatic intracortical clusters of atypical large cells, known as [...], is considered histologically pathognomonic.
Other lesions in neurofibromatosis type 2. Small clusters of atypical large cells, known as glial microhamartomas, are asymptomatic and pathognomonic of neurofibromatosis type 2.
A: glial microhamartomas
Back Extra: Neurofibromatosis type 2
- Clinical: Autosomal dominant syndrome caused by mutations in the NF2 gene (22q12.1); hallmark presentation includes bilateral vestibular schwannomas, meningiomas, and spinal ependymomas.
- Microscopic: Characterized by a constellation of lesions including glial microhamartomas (pathognomonic atypical cells in the neocortex), meningioangiomatosis, and multinodular/plexiform schwannomas.
- Ancillary: Often demonstrates a patchy/mosaic pattern of SMARCB1 (INI1) loss in schwannomas; collision tumors can be differentiated using PR (meningioma component) and S100 (schwannoma component).
- Prognosis: Clinical course is divided into the severe Wishart phenotype (early onset, high tumor burden) and the milder Gardner phenotype (late onset, primarily vestibular tumors).
Reference Gallery:
Neurofibromatosis type 2 (NF2) schwannomas. Postcontrast T1-weighted MRI of bilateral vestibular schwannomas, the hallmark of NF2. When large, vestibular schwannomas may compress the brainstem.
Schwannoma/meningioma. A collision tumour of schwannoma (lower half) and meningioma (upper half) is characteristic of neurofibromatosis type 2.
Schwannoma/meningioma. The meningioma component is highlighted with PR immunostaining.
Schwannoma/meningioma. The schwannoma component is highlighted with S100 immunostaining.
Other lesions in neurofibromatosis type 2. Small clusters of atypical large cells, known as glial microhamartomas, are asymptomatic and pathognomonic of neurofibromatosis type 2.
Neurofibromatosis type 2 schwannoma. A mosaic pattern of SMARCB1 (INI1) staining is common in syndromic (neurofibromatosis type 2 and schwannomatosis) schwannomas.
Cutaneous schwannoma. Cutaneous schwannoma is a common manifestation in children with neurofibromatosis type 2, and it is often associated with a raised pigmented lesion of the skin (plaque).
Other lesions in neurofibromatosis type 2. Meningioangiomatosis histologically consists of an intracortical proliferation of small capillaries with a cuff of perivascular meningothelial cells separated by brain parenchyma.
Plexiform schwannoma. Multiple nerve fascicles are expanded and replaced by tumour, a pattern similar to that of a plexiform neurofibroma.
Plexiform schwannoma. High-power view shows the typical histological features of a schwannoma, including Verocay bodies.
Other lesions in neurofibromatosis type 2. Schwann cell tumourlet embedded in a peripheral nerve.
Cutaneous schwannoma. S100 immunostaining highlights a cutaneous plexiform schwannoma.

Q: Schwannomas associated with Neurofibromatosis type 2 frequently demonstrate a characteristic patchy or mosaic loss of [...] expression on immunohistochemistry.
Neurofibromatosis type 2 schwannoma. A mosaic pattern of SMARCB1 (INI1) staining is common in syndromic (neurofibromatosis type 2 and schwannomatosis) schwannomas.
A: SMARCB1 (INI1)
Back Extra: Neurofibromatosis type 2
- Clinical: Autosomal dominant syndrome caused by mutations in the NF2 gene (22q12.1); hallmark presentation includes bilateral vestibular schwannomas, meningiomas, and spinal ependymomas.
- Microscopic: Characterized by a constellation of lesions including glial microhamartomas (pathognomonic atypical cells in the neocortex), meningioangiomatosis, and multinodular/plexiform schwannomas.
- Ancillary: Often demonstrates a patchy/mosaic pattern of SMARCB1 (INI1) loss in schwannomas; collision tumors can be differentiated using PR (meningioma component) and S100 (schwannoma component).
- Prognosis: Clinical course is divided into the severe Wishart phenotype (early onset, high tumor burden) and the milder Gardner phenotype (late onset, primarily vestibular tumors).
Reference Gallery:
Neurofibromatosis type 2 (NF2) schwannomas. Postcontrast T1-weighted MRI of bilateral vestibular schwannomas, the hallmark of NF2. When large, vestibular schwannomas may compress the brainstem.
Schwannoma/meningioma. A collision tumour of schwannoma (lower half) and meningioma (upper half) is characteristic of neurofibromatosis type 2.
Schwannoma/meningioma. The meningioma component is highlighted with PR immunostaining.
Schwannoma/meningioma. The schwannoma component is highlighted with S100 immunostaining.
Other lesions in neurofibromatosis type 2. Small clusters of atypical large cells, known as glial microhamartomas, are asymptomatic and pathognomonic of neurofibromatosis type 2.
Neurofibromatosis type 2 schwannoma. A mosaic pattern of SMARCB1 (INI1) staining is common in syndromic (neurofibromatosis type 2 and schwannomatosis) schwannomas.
Cutaneous schwannoma. Cutaneous schwannoma is a common manifestation in children with neurofibromatosis type 2, and it is often associated with a raised pigmented lesion of the skin (plaque).
Other lesions in neurofibromatosis type 2. Meningioangiomatosis histologically consists of an intracortical proliferation of small capillaries with a cuff of perivascular meningothelial cells separated by brain parenchyma.
Plexiform schwannoma. Multiple nerve fascicles are expanded and replaced by tumour, a pattern similar to that of a plexiform neurofibroma.
Plexiform schwannoma. High-power view shows the typical histological features of a schwannoma, including Verocay bodies.
Other lesions in neurofibromatosis type 2. Schwann cell tumourlet embedded in a peripheral nerve.
Cutaneous schwannoma. S100 immunostaining highlights a cutaneous plexiform schwannoma.

Q: Neurofibromatosis type 2 uniquely features distinct [...] composed of intimately associated schwannoma (S100-positive) and meningioma (PR-positive) components.
Schwannoma/meningioma. A collision tumour of schwannoma (lower half) and meningioma (upper half) is characteristic of neurofibromatosis type 2.
Schwannoma/meningioma. The meningioma component is highlighted with PR immunostaining.
Schwannoma/meningioma. The schwannoma component is highlighted with S100 immunostaining.
A: collision tumors
Back Extra: Neurofibromatosis type 2
- Clinical: Autosomal dominant syndrome caused by mutations in the NF2 gene (22q12.1); hallmark presentation includes bilateral vestibular schwannomas, meningiomas, and spinal ependymomas.
- Microscopic: Characterized by a constellation of lesions including glial microhamartomas (pathognomonic atypical cells in the neocortex), meningioangiomatosis, and multinodular/plexiform schwannomas.
- Ancillary: Often demonstrates a patchy/mosaic pattern of SMARCB1 (INI1) loss in schwannomas; collision tumors can be differentiated using PR (meningioma component) and S100 (schwannoma component).
- Prognosis: Clinical course is divided into the severe Wishart phenotype (early onset, high tumor burden) and the milder Gardner phenotype (late onset, primarily vestibular tumors).
Reference Gallery:
Neurofibromatosis type 2 (NF2) schwannomas. Postcontrast T1-weighted MRI of bilateral vestibular schwannomas, the hallmark of NF2. When large, vestibular schwannomas may compress the brainstem.
Schwannoma/meningioma. A collision tumour of schwannoma (lower half) and meningioma (upper half) is characteristic of neurofibromatosis type 2.
Schwannoma/meningioma. The meningioma component is highlighted with PR immunostaining.
Schwannoma/meningioma. The schwannoma component is highlighted with S100 immunostaining.
Other lesions in neurofibromatosis type 2. Small clusters of atypical large cells, known as glial microhamartomas, are asymptomatic and pathognomonic of neurofibromatosis type 2.
Neurofibromatosis type 2 schwannoma. A mosaic pattern of SMARCB1 (INI1) staining is common in syndromic (neurofibromatosis type 2 and schwannomatosis) schwannomas.
Cutaneous schwannoma. Cutaneous schwannoma is a common manifestation in children with neurofibromatosis type 2, and it is often associated with a raised pigmented lesion of the skin (plaque).
Other lesions in neurofibromatosis type 2. Meningioangiomatosis histologically consists of an intracortical proliferation of small capillaries with a cuff of perivascular meningothelial cells separated by brain parenchyma.
Plexiform schwannoma. Multiple nerve fascicles are expanded and replaced by tumour, a pattern similar to that of a plexiform neurofibroma.
Plexiform schwannoma. High-power view shows the typical histological features of a schwannoma, including Verocay bodies.
Other lesions in neurofibromatosis type 2. Schwann cell tumourlet embedded in a peripheral nerve.
Cutaneous schwannoma. S100 immunostaining highlights a cutaneous plexiform schwannoma.

Q: In Tuberous Sclerosis Complex, the cortical tubers are microscopically characterized by disorganized lamination, dysmorphic enlarged neurons, and pathognomonic large [...] with glassy eosinophilic cytoplasm.
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
A: balloon cells
Back Extra: Tuberous Sclerosis Complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), presenting with epilepsy (80–90%), cognitive impairment, and multi-organ hamartomas (cardiac rhabdomyomas, renal angiomyolipomas).
- Microscopic: Characterized by cortical tubers containing disorganized lamination, dysmorphic enlarged neurons, and large "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal expression (positive for GFAP, S100, nestin, and neuronal markers like MAP2); dysmorphic neurons are highlighted by NeuN.
- Pathogenesis: Loss of function in the hamartin-tuberin complex leads to constitutive activation of the mTOR pathway, making mTOR inhibitors (e.g., everolimus) an effective therapy for associated tumors.
- Differential: Cortical tubers are morphologically indistinguishable from Focal Cortical Dysplasia (FCD) type 2b, which occurs sporadically without the systemic features of TSC.
Reference Gallery:
Gross autopsy section from a patient with tuberous sclerosis illustrates axially cut cerebral hemispheric parenchyma with multiple subependymal nodules in the lateral and third ventricles (arrows).
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.

Q: Ancillary studies of cortical tubers in [...] reveal a mixed glioneuronal population: the characteristic balloon cells are strongly immunoreactive for S100, while the dysmorphic neurons are highlighted by NeuN.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
A: Tuberous Sclerosis Complex
Back Extra: Tuberous Sclerosis Complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), presenting with epilepsy (80–90%), cognitive impairment, and multi-organ hamartomas (cardiac rhabdomyomas, renal angiomyolipomas).
- Microscopic: Characterized by cortical tubers containing disorganized lamination, dysmorphic enlarged neurons, and large "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal expression (positive for GFAP, S100, nestin, and neuronal markers like MAP2); dysmorphic neurons are highlighted by NeuN.
- Pathogenesis: Loss of function in the hamartin-tuberin complex leads to constitutive activation of the mTOR pathway, making mTOR inhibitors (e.g., everolimus) an effective therapy for associated tumors.
- Differential: Cortical tubers are morphologically indistinguishable from Focal Cortical Dysplasia (FCD) type 2b, which occurs sporadically without the systemic features of TSC.
Reference Gallery:
Gross autopsy section from a patient with tuberous sclerosis illustrates axially cut cerebral hemispheric parenchyma with multiple subependymal nodules in the lateral and third ventricles (arrows).
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.

Q: Genetically, Tuberous Sclerosis Complex is caused by TSC1 or TSC2 mutations, leading to loss of the hamartin-tuberin complex and constitutive activation of the [...] pathway.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
A: mTOR
Back Extra: Tuberous Sclerosis Complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), presenting with epilepsy (80–90%), cognitive impairment, and multi-organ hamartomas (cardiac rhabdomyomas, renal angiomyolipomas).
- Microscopic: Characterized by cortical tubers containing disorganized lamination, dysmorphic enlarged neurons, and large "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal expression (positive for GFAP, S100, nestin, and neuronal markers like MAP2); dysmorphic neurons are highlighted by NeuN.
- Pathogenesis: Loss of function in the hamartin-tuberin complex leads to constitutive activation of the mTOR pathway, making mTOR inhibitors (e.g., everolimus) an effective therapy for associated tumors.
- Differential: Cortical tubers are morphologically indistinguishable from Focal Cortical Dysplasia (FCD) type 2b, which occurs sporadically without the systemic features of TSC.
Reference Gallery:
Gross autopsy section from a patient with tuberous sclerosis illustrates axially cut cerebral hemispheric parenchyma with multiple subependymal nodules in the lateral and third ventricles (arrows).
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.

Q: Microscopically, the characteristic cortical tubers seen in Tuberous sclerosis complex feature dysmorphic neurons and distinct [...], which are characterized by abundant glassy eosinophilic cytoplasm and eccentric nuclei.
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
A: balloon cells
Back Extra: Tuberous sclerosis complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), featuring cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), epilepsy, and multi-organ hamartomas.
- Microscopic: Characterized by cortical lamination disruption, dysmorphic neurons with aberrant orientation, and characteristic "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal immunoreactivity (GFAP, S100, Nestin, and neuronal markers); dysmorphic neurons express NeuN.
- Pathogenesis: Loss of function in the TSC1/TSC2 complex leads to constitutive upregulation of the mTOR pathway, driving excessive cell growth and proliferation.
- Differential: Focal Cortical Dysplasia (FCD) Type 2b is morphologically identical but occurs sporadically without systemic features or germline mutations.
Reference Gallery:
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.

Q: In Tuberous sclerosis complex, the dysmorphic enlarged neurons highlight with the neuronal marker [...], while the characteristic balloon cells demonstrate mixed glioneuronal immunoreactivity, frequently showing strong positivity for S100.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
A: NeuN
Back Extra: Tuberous sclerosis complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), featuring cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), epilepsy, and multi-organ hamartomas.
- Microscopic: Characterized by cortical lamination disruption, dysmorphic neurons with aberrant orientation, and characteristic "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal immunoreactivity (GFAP, S100, Nestin, and neuronal markers); dysmorphic neurons express NeuN.
- Pathogenesis: Loss of function in the TSC1/TSC2 complex leads to constitutive upregulation of the mTOR pathway, driving excessive cell growth and proliferation.
- Differential: Focal Cortical Dysplasia (FCD) Type 2b is morphologically identical but occurs sporadically without systemic features or germline mutations.
Reference Gallery:
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.

Q: A hallmark MRI finding in Tuberous sclerosis complex includes hyperintense cortical tubers and enhancing [...] (SENs), which can occasionally progress to subependymal giant cell astrocytomas (SEGAs).
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
A: subependymal nodules
Back Extra: Tuberous sclerosis complex
- Clinical: Autosomal dominant syndrome caused by mutations in TSC1 (9q) or TSC2 (16p), featuring cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytomas (SEGAs), epilepsy, and multi-organ hamartomas.
- Microscopic: Characterized by cortical lamination disruption, dysmorphic neurons with aberrant orientation, and characteristic "balloon cells" with glassy eosinophilic cytoplasm and eccentric nuclei.
- Ancillary: Balloon cells show mixed glioneuronal immunoreactivity (GFAP, S100, Nestin, and neuronal markers); dysmorphic neurons express NeuN.
- Pathogenesis: Loss of function in the TSC1/TSC2 complex leads to constitutive upregulation of the mTOR pathway, driving excessive cell growth and proliferation.
- Differential: Focal Cortical Dysplasia (FCD) Type 2b is morphologically identical but occurs sporadically without systemic features or germline mutations.
Reference Gallery:
Tuberous sclerosis. Gross image of a brain from a 57-year-old man showing an unusual tuber in the cerebellar hemisphere with extensive calcification.
Tuberous sclerosis. T1-weighted postcontrast axial MRI demonstrates two small enhancing subependymal nodules along the right caudate nucleus (arrows).
Tuberous sclerosis. T2-weighted coronal MRI demonstrates a minimally expansile hyperintense lesion in the left frontal white matter compatible with a cortical/subcortical tuber (arrow).
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.
Tuberous sclerosis. Cortical tuber with large neuronal cells highlighted by NeuN.
Tuberous sclerosis. Balloon cell (with eosinophilic cytoplasm, large nucleus, and prominent nucleolus) in the white matter.
Tuberous sclerosis. Cortical tuber showing a balloon cell with a ganglion-like nucleus and strong immunoreactivity for S100.
Tuberous sclerosis. Cortical tuber with dysmorphic enlarged neurons embedded in a densely fibrillary background.

Q: In Von Hippel-Lindau syndrome, endolymphatic sac tumors (ELSTs) can be distinguished from morphologically similar choroid plexus papillomas on histology and CT imaging by the presence of [...].
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma, but the bone invasion essentially excludes that diagnosis.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. A CT of this same tumour shows destruction of the temporal bone, essentially excluding the diagnostic consideration of choroid plexus papilloma.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma.
A: bone invasion
Back Extra: Von Hippel-Lindau syndrome
- Clinical: Autosomal dominant disorder characterized by multisystem neoplasms including CNS/retinal haemangioblastomas, clear cell renal cell carcinoma (RCC), phaeochromocytoma, and endolymphatic sac tumours (ELST).
- Genetics: Caused by pathogenic germline variants of the VHL tumour suppressor gene on chromosome 3p25.3.
- Micro: CNS haemangioblastomas consist of vacuolated "stromal cells" with a clear cell phenotype (due to lipid accumulation) and a dense capillary network.
- Ancillary: Loss of pVHL leads to the accumulation of HIF1α and HIF2α, which upregulates VEGF-A and causes high vascularization and cyst formation.
- Differential: ELSTs are distinguished from choroid plexus papillomas by the presence of bone invasion and destruction of the temporal bone.
Reference Gallery:
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. This contrast-enhancing tumour (T1-weighted postcontrast MRI) occurred in the cerebellopontine angle.
Von Hippel–Lindau syndrome. Transverse MRI of a cystic cerebellar haemangioblastoma; solid tumour shows contrast enhancement.
Pathogenesis of von Hippel–Lindau syndrome. The β domain of VHL protein interacts with HIF1α, whereas the α domain interacts with other partners of the VHL protein complex.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing multiple renal cell carcinomas (arrows) and renal cysts.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma, but the bone invasion essentially excludes that diagnosis.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. A CT of this same tumour shows destruction of the temporal bone, essentially excluding the diagnostic consideration of choroid plexus papilloma.
Von Hippel–Lindau syndrome. Sagittal MRI of a cystic brain stem haemangioblastoma; solid tumour shows contrast enhancement.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI of a spinal haemangioblastoma.
Von Hippel–Lindau syndrome. Retinal haemangioblastoma. Angiography shows the tumour (arrow) with a pair of feeder vessels.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing right adrenal phaeochromocytoma (arrow).
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing thoracic phaeochromocytoma (paraganglioma) (arrow).
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma.

Q: Von Hippel-Lindau syndrome is caused by variants in the VHL tumor suppressor gene on chromosome 3p25.3, leading to the pathogenic accumulation of [...] and HIF2α, which upregulates VEGF-A.
Pathogenesis of von Hippel–Lindau syndrome. The β domain of VHL protein interacts with HIF1α, whereas the α domain interacts with other partners of the VHL protein complex.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma.
A: HIF1α
Back Extra: Von Hippel-Lindau syndrome
- Clinical: Autosomal dominant disorder characterized by multisystem neoplasms including CNS/retinal haemangioblastomas, clear cell renal cell carcinoma (RCC), phaeochromocytoma, and endolymphatic sac tumours (ELST).
- Genetics: Caused by pathogenic germline variants of the VHL tumour suppressor gene on chromosome 3p25.3.
- Micro: CNS haemangioblastomas consist of vacuolated "stromal cells" with a clear cell phenotype (due to lipid accumulation) and a dense capillary network.
- Ancillary: Loss of pVHL leads to the accumulation of HIF1α and HIF2α, which upregulates VEGF-A and causes high vascularization and cyst formation.
- Differential: ELSTs are distinguished from choroid plexus papillomas by the presence of bone invasion and destruction of the temporal bone.
Reference Gallery:
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. This contrast-enhancing tumour (T1-weighted postcontrast MRI) occurred in the cerebellopontine angle.
Von Hippel–Lindau syndrome. Transverse MRI of a cystic cerebellar haemangioblastoma; solid tumour shows contrast enhancement.
Pathogenesis of von Hippel–Lindau syndrome. The β domain of VHL protein interacts with HIF1α, whereas the α domain interacts with other partners of the VHL protein complex.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing multiple renal cell carcinomas (arrows) and renal cysts.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma, but the bone invasion essentially excludes that diagnosis.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. A CT of this same tumour shows destruction of the temporal bone, essentially excluding the diagnostic consideration of choroid plexus papilloma.
Von Hippel–Lindau syndrome. Sagittal MRI of a cystic brain stem haemangioblastoma; solid tumour shows contrast enhancement.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI of a spinal haemangioblastoma.
Von Hippel–Lindau syndrome. Retinal haemangioblastoma. Angiography shows the tumour (arrow) with a pair of feeder vessels.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing right adrenal phaeochromocytoma (arrow).
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing thoracic phaeochromocytoma (paraganglioma) (arrow).
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma.

Q: A hallmark CNS manifestation of Von Hippel-Lindau syndrome is the development of [...], which classically present on MRI as cystic lesions with a highly vascular, contrast-enhancing solid component.
Von Hippel–Lindau syndrome. Transverse MRI of a cystic cerebellar haemangioblastoma; solid tumour shows contrast enhancement.
Von Hippel–Lindau syndrome. Sagittal MRI of a cystic brain stem haemangioblastoma; solid tumour shows contrast enhancement.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI of a spinal haemangioblastoma.
A: hemangioblastomas
Back Extra: Von Hippel-Lindau syndrome
- Clinical: Autosomal dominant disorder characterized by multisystem neoplasms including CNS/retinal haemangioblastomas, clear cell renal cell carcinoma (RCC), phaeochromocytoma, and endolymphatic sac tumours (ELST).
- Genetics: Caused by pathogenic germline variants of the VHL tumour suppressor gene on chromosome 3p25.3.
- Micro: CNS haemangioblastomas consist of vacuolated "stromal cells" with a clear cell phenotype (due to lipid accumulation) and a dense capillary network.
- Ancillary: Loss of pVHL leads to the accumulation of HIF1α and HIF2α, which upregulates VEGF-A and causes high vascularization and cyst formation.
- Differential: ELSTs are distinguished from choroid plexus papillomas by the presence of bone invasion and destruction of the temporal bone.
Reference Gallery:
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. This contrast-enhancing tumour (T1-weighted postcontrast MRI) occurred in the cerebellopontine angle.
Von Hippel–Lindau syndrome. Transverse MRI of a cystic cerebellar haemangioblastoma; solid tumour shows contrast enhancement.
Pathogenesis of von Hippel–Lindau syndrome. The β domain of VHL protein interacts with HIF1α, whereas the α domain interacts with other partners of the VHL protein complex.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing multiple renal cell carcinomas (arrows) and renal cysts.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma, but the bone invasion essentially excludes that diagnosis.
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. A CT of this same tumour shows destruction of the temporal bone, essentially excluding the diagnostic consideration of choroid plexus papilloma.
Von Hippel–Lindau syndrome. Sagittal MRI of a cystic brain stem haemangioblastoma; solid tumour shows contrast enhancement.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI of a spinal haemangioblastoma.
Von Hippel–Lindau syndrome. Retinal haemangioblastoma. Angiography shows the tumour (arrow) with a pair of feeder vessels.
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing right adrenal phaeochromocytoma (arrow).
Von Hippel–Lindau syndrome. Contrast-enhanced MRI showing thoracic phaeochromocytoma (paraganglioma) (arrow).
Endolymphatic sac tumour in a patient with von Hippel–Lindau syndrome. The histopathology is reminiscent of choroid plexus papilloma.

Q: Histologically, Erdheim–Chester disease features an infiltrate of foamy to epithelioid histiocytes mixed with occasional multinucleated giant cells of the [...] type.
Erdheim–Chester disease. Sheets of large foamy histiocytes are seen, along with a lymphoid infiltrate, but no obvious emperipolesis.
Erdheim–Chester disease. Sheets of epithelioid histiocytes.
A: Touton
Back Extra: Erdheim–Chester disease
- Clinical: Neurological complications occur in 30–50% of patients, predominantly men around age 50. Clinical presentation depends on lesion location: - Tumour-like lesions: Symptoms of increased intracranial pressure, focal neu…
- Micro: The infiltrates are composed of: - Histiocytes: Foamy to epithelioid histiocytes with small nuclei. - Giant Cells: Occasional Touton-type multinucleated giant cells. - Background: Scant lymphocytes, rare eosi…
- Cyto: Cytology is generally not considered clinically relevant for the diagnosis of Erdheim–Chester disease in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Positive: CD68, CD163, CD14, and factor XIIIa. - Variable: S100; BRAF p.V600E (positive in ~50%). - Negative: CD1a (distinguishes from Langerhans cell histiocytosis). Mole…
Reference Gallery:
Erdheim–Chester disease. Sheets of large foamy histiocytes are seen, along with a lymphoid infiltrate, but no obvious emperipolesis.
Erdheim–Chester disease. Sheets of epithelioid histiocytes.
Erdheim–Chester disease. Strong CD163 immunoreactivity.
Erdheim–Chester disease. Extensive factor XIIIa positivity.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast axial MRI shows severe proptosis with intensely enhancing intraconal retrobulbar masses in both orbits. The cavernous sinus and pituitary gland are infiltrated and intensely enhancing. There is an additional enhancing mass along the tentorium and posteroinferior falx.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast sagittal MRI shows a mass infiltrating the pituitary gland and hypothalamus, extending inferiorly along the clivus. Multiple lobulated masses are present along the falx and tentorium. This is an important image because it shows patchy enhancing lesions in the pons, indicating parenchymal involvement.

Q: Immunohistochemistry in Erdheim–Chester disease characteristically demonstrates diffuse positivity for macrophage markers such as CD163 and [...].
Erdheim–Chester disease. Strong CD163 immunoreactivity.
Erdheim–Chester disease. Extensive factor XIIIa positivity.
A: factor XIIIa
Back Extra: Erdheim–Chester disease
- Clinical: Neurological complications occur in 30–50% of patients, predominantly men around age 50. Clinical presentation depends on lesion location: - Tumour-like lesions: Symptoms of increased intracranial pressure, focal neu…
- Micro: The infiltrates are composed of: - Histiocytes: Foamy to epithelioid histiocytes with small nuclei. - Giant Cells: Occasional Touton-type multinucleated giant cells. - Background: Scant lymphocytes, rare eosi…
- Cyto: Cytology is generally not considered clinically relevant for the diagnosis of Erdheim–Chester disease in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Positive: CD68, CD163, CD14, and factor XIIIa. - Variable: S100; BRAF p.V600E (positive in ~50%). - Negative: CD1a (distinguishes from Langerhans cell histiocytosis). Mole…
Reference Gallery:
Erdheim–Chester disease. Sheets of large foamy histiocytes are seen, along with a lymphoid infiltrate, but no obvious emperipolesis.
Erdheim–Chester disease. Sheets of epithelioid histiocytes.
Erdheim–Chester disease. Strong CD163 immunoreactivity.
Erdheim–Chester disease. Extensive factor XIIIa positivity.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast axial MRI shows severe proptosis with intensely enhancing intraconal retrobulbar masses in both orbits. The cavernous sinus and pituitary gland are infiltrated and intensely enhancing. There is an additional enhancing mass along the tentorium and posteroinferior falx.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast sagittal MRI shows a mass infiltrating the pituitary gland and hypothalamus, extending inferiorly along the clivus. Multiple lobulated masses are present along the falx and tentorium. This is an important image because it shows patchy enhancing lesions in the pons, indicating parenchymal involvement.

Q: In patients with Erdheim–Chester disease presenting with severe proptosis, T1-weighted postcontrast MRI frequently demonstrates intensely enhancing bilateral intraconal [...].
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast axial MRI shows severe proptosis with intensely enhancing intraconal retrobulbar masses in both orbits. The cavernous sinus and pituitary gland are infiltrated and intensely enhancing. There is an additional enhancing mass along the tentorium and posteroinferior falx.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast sagittal MRI shows a mass infiltrating the pituitary gland and hypothalamus, extending inferiorly along the clivus. Multiple lobulated masses are present along the falx and tentorium. This is an important image because it shows patchy enhancing lesions in the pons, indicating parenchymal involvement.
A: retrobulbar masses
Back Extra: Erdheim–Chester disease
- Clinical: Neurological complications occur in 30–50% of patients, predominantly men around age 50. Clinical presentation depends on lesion location: - Tumour-like lesions: Symptoms of increased intracranial pressure, focal neu…
- Micro: The infiltrates are composed of: - Histiocytes: Foamy to epithelioid histiocytes with small nuclei. - Giant Cells: Occasional Touton-type multinucleated giant cells. - Background: Scant lymphocytes, rare eosi…
- Cyto: Cytology is generally not considered clinically relevant for the diagnosis of Erdheim–Chester disease in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Positive: CD68, CD163, CD14, and factor XIIIa. - Variable: S100; BRAF p.V600E (positive in ~50%). - Negative: CD1a (distinguishes from Langerhans cell histiocytosis). Mole…
Reference Gallery:
Erdheim–Chester disease. Sheets of large foamy histiocytes are seen, along with a lymphoid infiltrate, but no obvious emperipolesis.
Erdheim–Chester disease. Sheets of epithelioid histiocytes.
Erdheim–Chester disease. Strong CD163 immunoreactivity.
Erdheim–Chester disease. Extensive factor XIIIa positivity.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast axial MRI shows severe proptosis with intensely enhancing intraconal retrobulbar masses in both orbits. The cavernous sinus and pituitary gland are infiltrated and intensely enhancing. There is an additional enhancing mass along the tentorium and posteroinferior falx.
Erdheim–Chester disease. This 39-year-old man presented with headaches and severe proptosis. T1-weighted postcontrast sagittal MRI shows a mass infiltrating the pituitary gland and hypothalamus, extending inferiorly along the clivus. Multiple lobulated masses are present along the falx and tentorium. This is an important image because it shows patchy enhancing lesions in the pons, indicating parenchymal involvement.

Q: Microscopically, Histiocytic sarcoma features non-cohesive infiltrates of large, pleomorphic histiocytes with abundant eosinophilic cytoplasm and indented or reniform nuclei, frequently accompanied by a prominent background of reactive [...] (suppuration).
Histiocytic sarcoma of brain. This example of histiocytic sarcoma is accompanied by a prominent infiltrate of neutrophils, with areas of suppuration.
Histiocytic sarcoma of brain. The large tumour cells have oval or reniform nuclei and abundant eosinophilic cytoplasm.
A: neutrophils
Back Extra: Histiocytic sarcoma
- Clinical: An exceptionally rare, high-grade malignancy (fewer than 100 CNS cases) typically presenting in adults with poor prognosis (survival <12 months).
- Microscopic: Characterized by non-cohesive infiltrates of large, pleomorphic histiocytes with abundant eosinophilic cytoplasm, indented or reniform nuclei, and a frequent background of reactive neutrophils/suppuration.
- Ancillary (IHC): Positive for CD68, CD163, CD14, and lysozyme; crucially negative for follicular dendritic markers CD23 and CD35.
- Genetics: High frequency of RAS/MAPK pathway alterations (57%, e.g., MAP2K1, KRAS, BRAF) and CDKN2A/B deletions (46%).
Reference Gallery:
Histiocytic sarcoma of brain. The lineage-specific marker CD163 was diagnostic in this high-grade neoplasm.
Histiocytic sarcoma of brain. This example of histiocytic sarcoma is accompanied by a prominent infiltrate of neutrophils, with areas of suppuration.
Histiocytic sarcoma of brain. The large tumour cells have oval or reniform nuclei and abundant eosinophilic cytoplasm.
Histiocytic sarcoma of brain. Positive immunostaining for S100 in a proportion of tumour cells is common.

Q: In Histiocytic sarcoma, the neoplastic cells are crucially negative for follicular dendritic markers (CD23, CD35) but are characteristically positive for lineage-specific markers such as CD68, CD14, and [...].
Histiocytic sarcoma of brain. The lineage-specific marker CD163 was diagnostic in this high-grade neoplasm.
Histiocytic sarcoma of brain. The large tumour cells have oval or reniform nuclei and abundant eosinophilic cytoplasm.
A: CD163
Back Extra: Histiocytic sarcoma
- Clinical: An exceptionally rare, high-grade malignancy (fewer than 100 CNS cases) typically presenting in adults with poor prognosis (survival <12 months).
- Microscopic: Characterized by non-cohesive infiltrates of large, pleomorphic histiocytes with abundant eosinophilic cytoplasm, indented or reniform nuclei, and a frequent background of reactive neutrophils/suppuration.
- Ancillary (IHC): Positive for CD68, CD163, CD14, and lysozyme; crucially negative for follicular dendritic markers CD23 and CD35.
- Genetics: High frequency of RAS/MAPK pathway alterations (57%, e.g., MAP2K1, KRAS, BRAF) and CDKN2A/B deletions (46%).
Reference Gallery:
Histiocytic sarcoma of brain. The lineage-specific marker CD163 was diagnostic in this high-grade neoplasm.
Histiocytic sarcoma of brain. This example of histiocytic sarcoma is accompanied by a prominent infiltrate of neutrophils, with areas of suppuration.
Histiocytic sarcoma of brain. The large tumour cells have oval or reniform nuclei and abundant eosinophilic cytoplasm.
Histiocytic sarcoma of brain. Positive immunostaining for S100 in a proportion of tumour cells is common.

Q: In Juvenile xanthogranuloma, the microscopic examination typically reveals foamy histiocytes alongside pathognomonic [...], which feature a ring of nuclei surrounding central eosinophilic cytoplasm.
Juvenile xanthogranuloma. Numerous foamy histiocytes and two large multinucleated Touton cells.
A: Touton giant cells
Back Extra: Juvenile xanthogranuloma
- Clinical: A predominantly pediatric non-Langerhans cell histiocytosis; while primarily cutaneous, CNS involvement can occur in <5% of cases, often presenting with dural or choroid plexus masses.
- Microscopic: Characterized by vacuolated (foamy) histiocytes and pathognomonic "Touton giant cells" (a ring of nuclei surrounding eosinophilic cytoplasm with peripheral xanthomatous change).
- Ancillary: Neoplastic cells are positive for CD68, CD163, and factor XIIIa, but characteristically negative for CD1a and S100 (distinguishing it from Langerhans cell histiocytosis).
- Molecular: Frequently driven by mutations in the MAPK signaling pathway, specifically ARAF, KRAS, NRAS, and occasionally BRAF V600E; NTRK fusions have also been reported.
Reference Gallery:
Juvenile xanthogranuloma. Numerous foamy histiocytes and two large multinucleated Touton cells.
Juvenile xanthogranuloma. T2-weighted axial MRI showing orbital infiltration and hypointense soft tissue masses involving the tentorium and straight sinus.
Juvenile xanthogranuloma. T2-weighted coronal MRI showing symmetrical hypointense masses along the tentorium and enlarged choroid plexus glomi.
Juvenile xanthogranuloma. T1-weighted, contrast-enhanced axial MRI showing intense enhancement of orbital masses and the straight sinus/tentorium mass.
Juvenile xanthogranuloma. T1-weighted postcontrast MRI showing intensely and uniformly enhancing dural-based lobulated masses and choroid plexus involvement.

Q: When Juvenile xanthogranuloma involves the central nervous system, it characteristically presents on MRI as lobulated, intensely enhancing masses along the dura or within the [...].
Juvenile xanthogranuloma. T2-weighted coronal MRI showing symmetrical hypointense masses along the tentorium and enlarged choroid plexus glomi.
Juvenile xanthogranuloma. T1-weighted postcontrast MRI showing intensely and uniformly enhancing dural-based lobulated masses and choroid plexus involvement.
A: choroid plexus
Back Extra: Juvenile xanthogranuloma
- Clinical: A predominantly pediatric non-Langerhans cell histiocytosis; while primarily cutaneous, CNS involvement can occur in <5% of cases, often presenting with dural or choroid plexus masses.
- Microscopic: Characterized by vacuolated (foamy) histiocytes and pathognomonic "Touton giant cells" (a ring of nuclei surrounding eosinophilic cytoplasm with peripheral xanthomatous change).
- Ancillary: Neoplastic cells are positive for CD68, CD163, and factor XIIIa, but characteristically negative for CD1a and S100 (distinguishing it from Langerhans cell histiocytosis).
- Molecular: Frequently driven by mutations in the MAPK signaling pathway, specifically ARAF, KRAS, NRAS, and occasionally BRAF V600E; NTRK fusions have also been reported.
Reference Gallery:
Juvenile xanthogranuloma. Numerous foamy histiocytes and two large multinucleated Touton cells.
Juvenile xanthogranuloma. T2-weighted axial MRI showing orbital infiltration and hypointense soft tissue masses involving the tentorium and straight sinus.
Juvenile xanthogranuloma. T2-weighted coronal MRI showing symmetrical hypointense masses along the tentorium and enlarged choroid plexus glomi.
Juvenile xanthogranuloma. T1-weighted, contrast-enhanced axial MRI showing intense enhancement of orbital masses and the straight sinus/tentorium mass.
Juvenile xanthogranuloma. T1-weighted postcontrast MRI showing intensely and uniformly enhancing dural-based lobulated masses and choroid plexus involvement.

Q: In Langerhans cell histiocytosis, the neoplastic cells typically display deeply grooved nuclei and are characteristically admixed with numerous [...].
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
A: eosinophils
Back Extra: Langerhans cell histiocytosis
- Clinical: Langerhans cell histiocytosis (LCH) primarily affects children (annual incidence 0.5 cases per 100,000 in those < 15 years) with an M:F ratio of approximately 1:2. Symptoms: * Circumscribed tumour lesions: Ac…
- Micro: The histopathology of CNS LCH varies by lesion type: Circumscribed Lesions: * Architecture: Infiltrates consisting of neoplastic cells in a variable background of reactive macrophages, lymphocytes, plasma cell…
- Cyto: Not relevant for the diagnostic standard in CNS LCH, though electron microscopy may show characteristic rod-shaped Birbeck granules.
- Ancillary: Immunohistochemistry (IHC): * Positive Markers: Neoplastic cells consistently express CD1a (surface), CD207 (langerin; granular cytoplasmic), S100 (nuclear and cytoplasmic), and CD68 (Golgi dot-like staining, o…
Reference Gallery:
Langerhans cell histiocytosis. X-ray showing bone lucency at site of disease.
Langerhans cell histiocytosis. CD1a expression by neoplastic Langerhans cells.
Langerhans cell histiocytosis. Electron microscopy showing characteristic rod-shaped structures (Birbeck granules).
Langerhans cell histiocytosis. BRAF p.V600E expression in neoplastic Langerhans cells.
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
Langerhans cell histiocytosis. Langerhans cells are immunoreactive for CD207 (langerin).
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI at a more cephalad level than in Fig. #20027 shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.

Q: The neoplastic cells of Langerhans cell histiocytosis are consistently immunoreactive for S100, CD1a, and the highly specific marker [...] (langerin).
Langerhans cell histiocytosis. CD1a expression by neoplastic Langerhans cells.
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
Langerhans cell histiocytosis. Langerhans cells are immunoreactive for CD207 (langerin).
A: CD207
Back Extra: Langerhans cell histiocytosis
- Clinical: Langerhans cell histiocytosis (LCH) primarily affects children (annual incidence 0.5 cases per 100,000 in those < 15 years) with an M:F ratio of approximately 1:2. Symptoms: * Circumscribed tumour lesions: Ac…
- Micro: The histopathology of CNS LCH varies by lesion type: Circumscribed Lesions: * Architecture: Infiltrates consisting of neoplastic cells in a variable background of reactive macrophages, lymphocytes, plasma cell…
- Cyto: Not relevant for the diagnostic standard in CNS LCH, though electron microscopy may show characteristic rod-shaped Birbeck granules.
- Ancillary: Immunohistochemistry (IHC): * Positive Markers: Neoplastic cells consistently express CD1a (surface), CD207 (langerin; granular cytoplasmic), S100 (nuclear and cytoplasmic), and CD68 (Golgi dot-like staining, o…
Reference Gallery:
Langerhans cell histiocytosis. X-ray showing bone lucency at site of disease.
Langerhans cell histiocytosis. CD1a expression by neoplastic Langerhans cells.
Langerhans cell histiocytosis. Electron microscopy showing characteristic rod-shaped structures (Birbeck granules).
Langerhans cell histiocytosis. BRAF p.V600E expression in neoplastic Langerhans cells.
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
Langerhans cell histiocytosis. Langerhans cells are immunoreactive for CD207 (langerin).
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI at a more cephalad level than in Fig. #20027 shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.

Q: On electron microscopy, Langerhans cell histiocytosis is classically identified by the presence of rod-shaped, pentalaminar structures known as [...].
Langerhans cell histiocytosis. Electron microscopy showing characteristic rod-shaped structures (Birbeck granules).
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
A: Birbeck granules
Back Extra: Langerhans cell histiocytosis
- Clinical: Langerhans cell histiocytosis (LCH) primarily affects children (annual incidence 0.5 cases per 100,000 in those < 15 years) with an M:F ratio of approximately 1:2. Symptoms: * Circumscribed tumour lesions: Ac…
- Micro: The histopathology of CNS LCH varies by lesion type: Circumscribed Lesions: * Architecture: Infiltrates consisting of neoplastic cells in a variable background of reactive macrophages, lymphocytes, plasma cell…
- Cyto: Not relevant for the diagnostic standard in CNS LCH, though electron microscopy may show characteristic rod-shaped Birbeck granules.
- Ancillary: Immunohistochemistry (IHC): * Positive Markers: Neoplastic cells consistently express CD1a (surface), CD207 (langerin; granular cytoplasmic), S100 (nuclear and cytoplasmic), and CD68 (Golgi dot-like staining, o…
Reference Gallery:
Langerhans cell histiocytosis. X-ray showing bone lucency at site of disease.
Langerhans cell histiocytosis. CD1a expression by neoplastic Langerhans cells.
Langerhans cell histiocytosis. Electron microscopy showing characteristic rod-shaped structures (Birbeck granules).
Langerhans cell histiocytosis. BRAF p.V600E expression in neoplastic Langerhans cells.
Langerhans cell histiocytosis. In this lesion involving the skull bone and dura, Langerhans cells have typically oval, deeply grooved to contorted nuclei, delicate nuclear membranes, fine chromatin, and ample lightly eosinophilic cytoplasm. There are admixed eosinophils.
Langerhans cell histiocytosis. Langerhans cells are immunoreactive for CD207 (langerin).
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.
Langerhans cell histiocytosis. T1-weighted postcontrast axial MRI at a more cephalad level than in Fig. #20027 shows a thickened, enhancing infundibulum with multiple patchy enhancing lesions in the pons and both temporal lobes in a 46-year-old man with multiple cranial nerve palsies.

Q: The hallmark microscopic feature of Rosai-Dorfman disease is the presence of large, pale histiocytes that engulf intact inflammatory cells (such as lymphocytes and plasma cells), a phenomenon known as [...].
Rosai–Dorfman disease. Multinodular mass composed of a mixed inflammatory infiltrate, including large pale histiocytes, numerous lymphocytes, and plasma cells.
Rosai–Dorfman disease. Emperipolesis with histiocytic engulfment of intact lymphocytes, plasma cells, neutrophils, and eosinophils.
A: emperipolesis
Q: Rosai-Dorfman disease
- Clinical: Typically presents as solitary or multiple dural masses mimicking meningioma, though often distinguished by T2-hypointensity; systemic symptoms like cervical lymphadenopathy are absent in 70% of CNS-isolated cases.
- Microscopic: Characterized by a multinodular inflammatory infiltrate containing large, pale histiocytes that demonstrate [...] (engulfment of intact inflammatory cells like lymphocytes and plasma cells).
- Ancillary: Histiocytes are characteristically positive for [...], CD68, and CD163, but negative for CD1a and CD207 (langerin).
- Genetics: Clonal histiocytic proliferation frequently involving the MAPK signaling pathway, with mutations in KRAS, NRAS, or BRAF (BRAF p.V600E in ~12.5% of cases).
Reference Gallery:
Rosai–Dorfman disease. Dural mass, mimicking a meningioma.
Rosai–Dorfman disease. Multinodular mass composed of a mixed inflammatory infiltrate, including large pale histiocytes, numerous lymphocytes, and plasma cells.
Rosai–Dorfman disease. Emperipolesis with histiocytic engulfment of intact lymphocytes, plasma cells, neutrophils, and eosinophils.
Rosai–Dorfman disease. CD45 expression by phagocytosed haematopoietic cells.
Rosai–Dorfman disease. This mass involved the dura. Some large histiocytes contain plasma cells or lymphocytes in the cytoplasm (emperipolesis).
Rosai–Dorfman disease. T2-weighted axial MRI shows a lobulated, nearly isointense dural-based mass along the anterior falx cerebri. The adjacent frontal white matter is severely oedematous.
Rosai–Dorfman disease. T1-weighted, postcontrast axial MRI shows that the dural-based bifrontal lobulated mass enhances intensely and uniformly.
Rosai–Dorfman disease. Coronal postcontrast T1-weighted image shows another lobulated, intensely enhancing mass along the posterior falx cerebri.
A: "emperipolesis"; S100

Q: In the central nervous system, Rosai-Dorfman disease characteristically presents as solitary or multiple dural-based masses with surrounding white matter edema, frequently mimicking a [...] radiologically.
Rosai–Dorfman disease. T2-weighted axial MRI shows a lobulated, nearly isointense dural-based mass along the anterior falx cerebri. The adjacent frontal white matter is severely oedematous.
Rosai–Dorfman disease. T1-weighted, postcontrast axial MRI shows that the dural-based bifrontal lobulated mass enhances intensely and uniformly.
A: meningioma
Q: Rosai-Dorfman disease
- Clinical: Typically presents as solitary or multiple dural masses mimicking meningioma, though often distinguished by T2-hypointensity; systemic symptoms like cervical lymphadenopathy are absent in 70% of CNS-isolated cases.
- Microscopic: Characterized by a multinodular inflammatory infiltrate containing large, pale histiocytes that demonstrate [...] (engulfment of intact inflammatory cells like lymphocytes and plasma cells).
- Ancillary: Histiocytes are characteristically positive for [...], CD68, and CD163, but negative for CD1a and CD207 (langerin).
- Genetics: Clonal histiocytic proliferation frequently involving the MAPK signaling pathway, with mutations in KRAS, NRAS, or BRAF (BRAF p.V600E in ~12.5% of cases).
Reference Gallery:
Rosai–Dorfman disease. Dural mass, mimicking a meningioma.
Rosai–Dorfman disease. Multinodular mass composed of a mixed inflammatory infiltrate, including large pale histiocytes, numerous lymphocytes, and plasma cells.
Rosai–Dorfman disease. Emperipolesis with histiocytic engulfment of intact lymphocytes, plasma cells, neutrophils, and eosinophils.
Rosai–Dorfman disease. CD45 expression by phagocytosed haematopoietic cells.
Rosai–Dorfman disease. This mass involved the dura. Some large histiocytes contain plasma cells or lymphocytes in the cytoplasm (emperipolesis).
Rosai–Dorfman disease. T2-weighted axial MRI shows a lobulated, nearly isointense dural-based mass along the anterior falx cerebri. The adjacent frontal white matter is severely oedematous.
Rosai–Dorfman disease. T1-weighted, postcontrast axial MRI shows that the dural-based bifrontal lobulated mass enhances intensely and uniformly.
Rosai–Dorfman disease. Coronal postcontrast T1-weighted image shows another lobulated, intensely enhancing mass along the posterior falx cerebri.
A: "emperipolesis"; S100

Q: In Rosai-Dorfman disease, immunohistochemistry for [...] can uniquely highlight the intact, engulfed hematopoietic cells to prominently demonstrate the characteristic finding of emperipolesis.
Rosai–Dorfman disease. CD45 expression by phagocytosed haematopoietic cells.
A: CD45
Q: Rosai-Dorfman disease
- Clinical: Typically presents as solitary or multiple dural masses mimicking meningioma, though often distinguished by T2-hypointensity; systemic symptoms like cervical lymphadenopathy are absent in 70% of CNS-isolated cases.
- Microscopic: Characterized by a multinodular inflammatory infiltrate containing large, pale histiocytes that demonstrate [...] (engulfment of intact inflammatory cells like lymphocytes and plasma cells).
- Ancillary: Histiocytes are characteristically positive for [...], CD68, and CD163, but negative for CD1a and CD207 (langerin).
- Genetics: Clonal histiocytic proliferation frequently involving the MAPK signaling pathway, with mutations in KRAS, NRAS, or BRAF (BRAF p.V600E in ~12.5% of cases).
Reference Gallery:
Rosai–Dorfman disease. Dural mass, mimicking a meningioma.
Rosai–Dorfman disease. Multinodular mass composed of a mixed inflammatory infiltrate, including large pale histiocytes, numerous lymphocytes, and plasma cells.
Rosai–Dorfman disease. Emperipolesis with histiocytic engulfment of intact lymphocytes, plasma cells, neutrophils, and eosinophils.
Rosai–Dorfman disease. CD45 expression by phagocytosed haematopoietic cells.
Rosai–Dorfman disease. This mass involved the dura. Some large histiocytes contain plasma cells or lymphocytes in the cytoplasm (emperipolesis).
Rosai–Dorfman disease. T2-weighted axial MRI shows a lobulated, nearly isointense dural-based mass along the anterior falx cerebri. The adjacent frontal white matter is severely oedematous.
Rosai–Dorfman disease. T1-weighted, postcontrast axial MRI shows that the dural-based bifrontal lobulated mass enhances intensely and uniformly.
Rosai–Dorfman disease. Coronal postcontrast T1-weighted image shows another lobulated, intensely enhancing mass along the posterior falx cerebri.
A: "emperipolesis"; S100

Q: In Anaplastic large cell lymphoma (ALK+/ALK−), the characteristic microscopic finding is the presence of large atypical cells known as [...], which feature kidney-shaped or bean-shaped nuclei and an eosinophilic paranuclear area.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: hallmark cells
Q: Anaplastic large cell lymphoma (ALK+/ALK−)
- Clinical: Rare CNS peripheral T-cell lymphoma; ALK+ typically presents in children/young adults (median ~17 years), whereas ALK− occurs in older adults (median ~65 years).
- Micro: Characterized by large atypical cells, most notably the [...], which features a kidney-shaped or bean-shaped nucleus and an eosinophilic paranuclear area.
- Ancillary (IHC): Requires strong, uniform expression of CD30; ALK expression is positive in the ALK+ subtype and negative in ALK−.
- Genetics: Most ALK+ cases (>80%) are driven by the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion.
- Differential: Distinguished from DLBCL by T-cell lineage and CD30 positivity, and from classic Hodgkin lymphoma by strong CD30/EMA positivity and lack of PAX5/CD15 expression.
Reference Gallery:
ALK+ anaplastic large cell lymphoma. Neoplastic large tumour cells with round nuclei and prominent nucleoli show cytoplasmic expression of ALK.
ALK+ anaplastic large cell lymphoma. The lymphoma cells strongly express the CD30 antigen.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: "hallmark cell"

Q: The diagnosis of Anaplastic large cell lymphoma (ALK+/ALK−) requires strong, uniform immunohistochemical expression of the [...] antigen by the neoplastic cells.
ALK+ anaplastic large cell lymphoma. The lymphoma cells strongly express the CD30 antigen.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: CD30
Q: Anaplastic large cell lymphoma (ALK+/ALK−)
- Clinical: Rare CNS peripheral T-cell lymphoma; ALK+ typically presents in children/young adults (median ~17 years), whereas ALK− occurs in older adults (median ~65 years).
- Micro: Characterized by large atypical cells, most notably the [...], which features a kidney-shaped or bean-shaped nucleus and an eosinophilic paranuclear area.
- Ancillary (IHC): Requires strong, uniform expression of CD30; ALK expression is positive in the ALK+ subtype and negative in ALK−.
- Genetics: Most ALK+ cases (>80%) are driven by the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion.
- Differential: Distinguished from DLBCL by T-cell lineage and CD30 positivity, and from classic Hodgkin lymphoma by strong CD30/EMA positivity and lack of PAX5/CD15 expression.
Reference Gallery:
ALK+ anaplastic large cell lymphoma. Neoplastic large tumour cells with round nuclei and prominent nucleoli show cytoplasmic expression of ALK.
ALK+ anaplastic large cell lymphoma. The lymphoma cells strongly express the CD30 antigen.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: "hallmark cell"

Q: In the ALK+ subtype of Anaplastic large cell lymphoma (ALK+/ALK−), the neoplastic cells demonstrate expression of the [...] protein by immunohistochemistry, most commonly driven by the t(2;5)(p23;q35) translocation.
ALK+ anaplastic large cell lymphoma. Neoplastic large tumour cells with round nuclei and prominent nucleoli show cytoplasmic expression of ALK.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: ALK
Q: Anaplastic large cell lymphoma (ALK+/ALK−)
- Clinical: Rare CNS peripheral T-cell lymphoma; ALK+ typically presents in children/young adults (median ~17 years), whereas ALK− occurs in older adults (median ~65 years).
- Micro: Characterized by large atypical cells, most notably the [...], which features a kidney-shaped or bean-shaped nucleus and an eosinophilic paranuclear area.
- Ancillary (IHC): Requires strong, uniform expression of CD30; ALK expression is positive in the ALK+ subtype and negative in ALK−.
- Genetics: Most ALK+ cases (>80%) are driven by the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion.
- Differential: Distinguished from DLBCL by T-cell lineage and CD30 positivity, and from classic Hodgkin lymphoma by strong CD30/EMA positivity and lack of PAX5/CD15 expression.
Reference Gallery:
ALK+ anaplastic large cell lymphoma. Neoplastic large tumour cells with round nuclei and prominent nucleoli show cytoplasmic expression of ALK.
ALK+ anaplastic large cell lymphoma. The lymphoma cells strongly express the CD30 antigen.
CNS anaplastic large cell lymphoma. There is a polymorphic lymphomatous infiltrate with occasional markedly atypical hallmark cells.
A: "hallmark cell"

Q: The majority of Immunodeficiency-associated CNS lymphoma cases are driven by Epstein-Barr virus (EBV) and will demonstrate strong nuclear positivity for [...] via in situ hybridization.
EBV+ diffuse large B-cell lymphoma of the CNS. There is strong expression of EBV-encoded small RNA (EBER) in the nuclei of the tumour cells.
A: EBER
Back Extra: Immunodeficiency-associated CNS lymphoma
- Clinical: This family of CNS lymphomas arises in patients with inherited or acquired immunodeficiencies (e.g., AIDS, iatrogenic suppression, immunosenescence) and frequently presents with multifocal, necrotic parenchymal lesions.
- Microscopic: Findings typically mirror diffuse large B-cell lymphoma (DLBCL), often exhibiting a characteristic perivascular distribution of large malignant B-cells.
- Ancillary: Most cases are driven by EBV and demonstrate strong nuclear expression of EBV-encoded small RNAs (EBER) via in situ hybridization.
- Immunoprofile: Tumor cells express pan-B-cell markers (CD19, CD20, CD79a) and often express EBV-associated proteins such as LMP1.
Reference Gallery:
EBV+ diffuse large B-cell lymphoma of the CNS. Large tumour cells clustering around a blood vessel are stained by the pan–B-cell marker CD20.
EBV+ diffuse large B-cell lymphoma of the CNS. There is strong expression of EBV-encoded small RNA (EBER) in the nuclei of the tumour cells.
HIV-associated primary diffuse large B-cell lymphoma of the CNS. This case was in an HIV-infected patient. In addition to the large tumour in the basal ganglia, there are further foci in the contralateral insular region (arrowheads).
HIV-associated primary diffuse large B-cell lymphoma of the CNS. Tumour in an HIV-infected patient.

Q: The malignant cells in Immunodeficiency-associated CNS lymphoma frequently exhibit a characteristic perivascular distribution and will strongly express the pan-B-cell marker [...].
EBV+ diffuse large B-cell lymphoma of the CNS. Large tumour cells clustering around a blood vessel are stained by the pan–B-cell marker CD20.
A: CD20
Back Extra: Immunodeficiency-associated CNS lymphoma
- Clinical: This family of CNS lymphomas arises in patients with inherited or acquired immunodeficiencies (e.g., AIDS, iatrogenic suppression, immunosenescence) and frequently presents with multifocal, necrotic parenchymal lesions.
- Microscopic: Findings typically mirror diffuse large B-cell lymphoma (DLBCL), often exhibiting a characteristic perivascular distribution of large malignant B-cells.
- Ancillary: Most cases are driven by EBV and demonstrate strong nuclear expression of EBV-encoded small RNAs (EBER) via in situ hybridization.
- Immunoprofile: Tumor cells express pan-B-cell markers (CD19, CD20, CD79a) and often express EBV-associated proteins such as LMP1.
Reference Gallery:
EBV+ diffuse large B-cell lymphoma of the CNS. Large tumour cells clustering around a blood vessel are stained by the pan–B-cell marker CD20.
EBV+ diffuse large B-cell lymphoma of the CNS. There is strong expression of EBV-encoded small RNA (EBER) in the nuclei of the tumour cells.
HIV-associated primary diffuse large B-cell lymphoma of the CNS. This case was in an HIV-infected patient. In addition to the large tumour in the basal ganglia, there are further foci in the contralateral insular region (arrowheads).
HIV-associated primary diffuse large B-cell lymphoma of the CNS. Tumour in an HIV-infected patient.

Q: Microscopically, Intravascular large B-cell lymphoma is characterized by large atypical B cells confined exclusively to the [...].
Intravascular large B-cell lymphoma. Neoplastic lymphoma cells are confined to the vessel lumen.
A: lumina of blood vessels
Back Extra: Intravascular large B-cell lymphoma
- Clinical: Rare, aggressive B-cell lymphoma primarily affecting adults (median age 70) and frequently involving the CNS (75–85%), often mimicking cerebral infarction or subacute encephalopathy.
- Microscopic: Characterized by large atypical B cells confined exclusively to the lumina of blood vessels with virtually no invasion into the brain parenchyma.
- Ancillary IHC: Neoplastic cells express B-cell markers (CD20, CD79a, PAX5); CD34 immunostaining is useful to highlight the vascular endothelium and confirm the restricted location.
- Pathophysiology: The inability to migrate transvascularly is linked to the absence of migration and adhesion markers including CD29, CD54 (ICAM1), MMP2, and MMP9.
Reference Gallery:
Intravascular large B-cell lymphoma. Neoplastic lymphoma cells are confined to the vessel lumen.
Intravascular large B-cell lymphoma. Immunostaining of vascular endothelium for CD34 highlights the intravascular location of the lymphoma cells.
Intravascular large B-cell lymphoma. There is intravascular accumulation of CD20+ lymphoma cells.

Q: To confirm the restricted location of neoplastic cells in Intravascular large B-cell lymphoma, [...] immunostaining is useful to highlight the surrounding vascular endothelium.
Intravascular large B-cell lymphoma. Immunostaining of vascular endothelium for CD34 highlights the intravascular location of the lymphoma cells.
A: CD34
Back Extra: Intravascular large B-cell lymphoma
- Clinical: Rare, aggressive B-cell lymphoma primarily affecting adults (median age 70) and frequently involving the CNS (75–85%), often mimicking cerebral infarction or subacute encephalopathy.
- Microscopic: Characterized by large atypical B cells confined exclusively to the lumina of blood vessels with virtually no invasion into the brain parenchyma.
- Ancillary IHC: Neoplastic cells express B-cell markers (CD20, CD79a, PAX5); CD34 immunostaining is useful to highlight the vascular endothelium and confirm the restricted location.
- Pathophysiology: The inability to migrate transvascularly is linked to the absence of migration and adhesion markers including CD29, CD54 (ICAM1), MMP2, and MMP9.
Reference Gallery:
Intravascular large B-cell lymphoma. Neoplastic lymphoma cells are confined to the vessel lumen.
Intravascular large B-cell lymphoma. Immunostaining of vascular endothelium for CD34 highlights the intravascular location of the lymphoma cells.
Intravascular large B-cell lymphoma. There is intravascular accumulation of CD20+ lymphoma cells.

Q: In Intravascular large B-cell lymphoma, the neoplastic cells characteristically accumulate within vessels and strongly express B-cell markers such as [...].
Intravascular large B-cell lymphoma. There is intravascular accumulation of CD20+ lymphoma cells.
A: CD20
Back Extra: Intravascular large B-cell lymphoma
- Clinical: Rare, aggressive B-cell lymphoma primarily affecting adults (median age 70) and frequently involving the CNS (75–85%), often mimicking cerebral infarction or subacute encephalopathy.
- Microscopic: Characterized by large atypical B cells confined exclusively to the lumina of blood vessels with virtually no invasion into the brain parenchyma.
- Ancillary IHC: Neoplastic cells express B-cell markers (CD20, CD79a, PAX5); CD34 immunostaining is useful to highlight the vascular endothelium and confirm the restricted location.
- Pathophysiology: The inability to migrate transvascularly is linked to the absence of migration and adhesion markers including CD29, CD54 (ICAM1), MMP2, and MMP9.
Reference Gallery:
Intravascular large B-cell lymphoma. Neoplastic lymphoma cells are confined to the vessel lumen.
Intravascular large B-cell lymphoma. Immunostaining of vascular endothelium for CD34 highlights the intravascular location of the lymphoma cells.
Intravascular large B-cell lymphoma. There is intravascular accumulation of CD20+ lymphoma cells.

Q: The classic histopathologic finding in Lymphomatoid granulomatosis is a polymorphous lymphoid infiltrate with a characteristic [...] (or angiotropic) growth pattern and frequent tissue necrosis.
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis. Angiocentric lymphoid lesion harbouring some large cells with prominent nucleoli.
Lymphomatoid granulomatosis. Polymorphous lymphoid infiltrate in the CNS parenchyma. Lymphocytes predominate, admixed with histiocytes and some plasma cells.
A: angiocentric
Back Extra: Lymphomatoid granulomatosis
- Clinical: Lymphomatoid granulomatosis involves the brain in approximately 26% of patients. Clinical presentations include focal neurological symptoms, headache, or cognitive impairment. Imaging (MRI) frequently reveals multiple fo…
- Micro: The lesions show a characteristic polymorphous lymphoid infiltrate consisting of small T lymphocytes (both CD4+ and CD8+), plasma cells, and histiocytes, admixed with varying numbers of atypical, large neoplastic B cells…
- Cyto: Not relevant for the diagnosis of this entity in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Neoplastic B cells: CD20+, CD30+/−, and CD15−. - EBV Status: Positive for EBV-encoded small RNA (EBER) by in situ hybridization or EBV markers by IHC. - Background Infiltrate:*…
Reference Gallery:
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the pan–B-cell marker CD20.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the CD30 antigen.
Lymphomatoid granulomatosis, CNS WHO grade 3. Note the high number of EBV-encoded small RNA (EBER)-positive cells.
Lymphomatoid granulomatosis. Angiocentric lymphoid lesion harbouring some large cells with prominent nucleoli.
Lymphomatoid granulomatosis. Polymorphous lymphoid infiltrate in the CNS parenchyma. Lymphocytes predominate, admixed with histiocytes and some plasma cells.
Lymphomatoid granulomatosis. Enlarged CD20+ B cells as part of a lymphoid infiltrate within a blood vessel wall.

Q: The atypical, large neoplastic B cells in Lymphomatoid granulomatosis are consistently driven by [...], which is typically confirmed by EBER in situ hybridization.
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis, CNS WHO grade 3. Note the high number of EBV-encoded small RNA (EBER)-positive cells.
A: Epstein-Barr virus (EBV)
Back Extra: Lymphomatoid granulomatosis
- Clinical: Lymphomatoid granulomatosis involves the brain in approximately 26% of patients. Clinical presentations include focal neurological symptoms, headache, or cognitive impairment. Imaging (MRI) frequently reveals multiple fo…
- Micro: The lesions show a characteristic polymorphous lymphoid infiltrate consisting of small T lymphocytes (both CD4+ and CD8+), plasma cells, and histiocytes, admixed with varying numbers of atypical, large neoplastic B cells…
- Cyto: Not relevant for the diagnosis of this entity in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Neoplastic B cells: CD20+, CD30+/−, and CD15−. - EBV Status: Positive for EBV-encoded small RNA (EBER) by in situ hybridization or EBV markers by IHC. - Background Infiltrate:*…
Reference Gallery:
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the pan–B-cell marker CD20.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the CD30 antigen.
Lymphomatoid granulomatosis, CNS WHO grade 3. Note the high number of EBV-encoded small RNA (EBER)-positive cells.
Lymphomatoid granulomatosis. Angiocentric lymphoid lesion harbouring some large cells with prominent nucleoli.
Lymphomatoid granulomatosis. Polymorphous lymphoid infiltrate in the CNS parenchyma. Lymphocytes predominate, admixed with histiocytes and some plasma cells.
Lymphomatoid granulomatosis. Enlarged CD20+ B cells as part of a lymphoid infiltrate within a blood vessel wall.

Q: Immunohistochemistry in Lymphomatoid granulomatosis reveals that the large neoplastic cells typically express the pan-B-cell marker CD20 and frequently the activation marker [...].
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the pan–B-cell marker CD20.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the CD30 antigen.
A: CD30
Back Extra: Lymphomatoid granulomatosis
- Clinical: Lymphomatoid granulomatosis involves the brain in approximately 26% of patients. Clinical presentations include focal neurological symptoms, headache, or cognitive impairment. Imaging (MRI) frequently reveals multiple fo…
- Micro: The lesions show a characteristic polymorphous lymphoid infiltrate consisting of small T lymphocytes (both CD4+ and CD8+), plasma cells, and histiocytes, admixed with varying numbers of atypical, large neoplastic B cells…
- Cyto: Not relevant for the diagnosis of this entity in the CNS context.
- Ancillary: Immunohistochemistry (IHC): - Neoplastic B cells: CD20+, CD30+/−, and CD15−. - EBV Status: Positive for EBV-encoded small RNA (EBER) by in situ hybridization or EBV markers by IHC. - Background Infiltrate:*…
Reference Gallery:
Lymphomatoid granulomatosis, CNS WHO grade 3. An angiotropic lymphoma with infiltration of the blood vessel walls by blasts, lymphocytes, and histiocytes. Blasts also invade the perivascular brain tissue, which is largely necrotic.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the pan–B-cell marker CD20.
Lymphomatoid granulomatosis, CNS WHO grade 3. Tumour cells express the CD30 antigen.
Lymphomatoid granulomatosis, CNS WHO grade 3. Note the high number of EBV-encoded small RNA (EBER)-positive cells.
Lymphomatoid granulomatosis. Angiocentric lymphoid lesion harbouring some large cells with prominent nucleoli.
Lymphomatoid granulomatosis. Polymorphous lymphoid infiltrate in the CNS parenchyma. Lymphocytes predominate, admixed with histiocytes and some plasma cells.
Lymphomatoid granulomatosis. Enlarged CD20+ B cells as part of a lymphoid infiltrate within a blood vessel wall.

Q: In MALT lymphoma of the dura, the dense lymphoid infiltrate frequently features reactive germinal centers with [...] by neoplastic small marginal zone B cells, which often display a "monocytoid" (clear cytoplasm) or plasmacytoid appearance.
MALT lymphoma. Lymphoma cells are small or of medium size and have colonized follicles.
MALT lymphoma. Low-power view of a dense lymphoid infiltrate with residual follicles visible.
A: follicular colonization
Back Extra: MALT lymphoma of the dura
- Clinical: Affects adults (median 6th decade) with a marked female predominance (M:F ratio 1:5–7); frequently mimics meningioma on imaging.
- Microscopic: Composed of small lymphocytes and marginal zone B cells, often with plasmacytic differentiation or "monocytoid" morphology (clear cytoplasm).
- Architecture: Presents as a solitary mass or plaque-like thickening, often showing reactive follicles with follicular colonization.
- Ancillary: Neoplastic cells are CD20+, CD79a+, and BCL2+, but typically negative for CD5, CD10, and BCL6; clonal IG genes are rearranged.
- Prognosis: Very good prognosis with high 3-year progression-free survival (approx. 89%) following surgery, radiation, or chemotherapy.
Reference Gallery:
MALT lymphoma. Lymphoma cells are small or of medium size and have colonized follicles.
MALT lymphoma. Low-power view of a dense lymphoid infiltrate with residual follicles visible.
MALT lymphoma. High-power view of the plasmacytoid infiltrate that may be present in MALT lymphomas.
MALT lymphoma. Staining for kappa light chains is positive.
MALT lymphoma. Staining for lambda light chains is negative.

Q: The neoplastic cells in MALT lymphoma of the dura frequently show plasmacytoid differentiation; clonality is definitively confirmed by demonstrating [...] (e.g., strong positivity for kappa and negativity for lambda) on immunohistochemistry.
MALT lymphoma. High-power view of the plasmacytoid infiltrate that may be present in MALT lymphomas.
MALT lymphoma. Staining for kappa light chains is positive.
MALT lymphoma. Staining for lambda light chains is negative.
A: light chain restriction
Back Extra: MALT lymphoma of the dura
- Clinical: Affects adults (median 6th decade) with a marked female predominance (M:F ratio 1:5–7); frequently mimics meningioma on imaging.
- Microscopic: Composed of small lymphocytes and marginal zone B cells, often with plasmacytic differentiation or "monocytoid" morphology (clear cytoplasm).
- Architecture: Presents as a solitary mass or plaque-like thickening, often showing reactive follicles with follicular colonization.
- Ancillary: Neoplastic cells are CD20+, CD79a+, and BCL2+, but typically negative for CD5, CD10, and BCL6; clonal IG genes are rearranged.
- Prognosis: Very good prognosis with high 3-year progression-free survival (approx. 89%) following surgery, radiation, or chemotherapy.
Reference Gallery:
MALT lymphoma. Lymphoma cells are small or of medium size and have colonized follicles.
MALT lymphoma. Low-power view of a dense lymphoid infiltrate with residual follicles visible.
MALT lymphoma. High-power view of the plasmacytoid infiltrate that may be present in MALT lymphomas.
MALT lymphoma. Staining for kappa light chains is positive.
MALT lymphoma. Staining for lambda light chains is negative.

Q: In Other low-grade B-cell lymphomas of the CNS, the characteristic microscopic pattern consists of small to medium-sized, monomorphic lymphoid cells forming [...].
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.
A: perivascular cuffs
Back Extra: Other low-grade B-cell lymphomas of the CNS
- Clinical: Affects middle-aged adults (median age 49) with a significantly better prognosis and less aggressive course compared to primary diffuse large B-cell lymphoma (PCNSL).
- Microscopic: Characterized by perivascular cuffs of small to medium-sized monomorphic lymphoid cells that infiltrate the parenchyma with a low proliferation index (Ki-67 < 10%).
- Ancillary: Tumors are typically CD20+ and BCL2+ but negative for CD3, CD5, CD10, and cyclin D1.
- Molecular: Clonal rearrangements of IGH and/or IGK genes are common, while the MYD88 p.L265P mutation is generally absent.
- Differential: Distinguished from demyelinating disease by the lack of macrophage-rich infiltrates and the presence of a monomorphic B-cell population.
Reference Gallery:
Low-grade B-cell lymphoma. Perivascular cuffs of medium-sized, monomorphic lymphoma cells, which express the pan–B-cell marker CD20.
Low-grade B-cell lymphoma. Admixed with the lymphoma cells are some reactive CD3 T cells.
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.

Q: Immunohistochemical analysis of Other low-grade B-cell lymphomas of the CNS reveals that the neoplastic monomorphic cells are strongly positive for the pan-B-cell marker [...].
Low-grade B-cell lymphoma. Perivascular cuffs of medium-sized, monomorphic lymphoma cells, which express the pan–B-cell marker CD20.
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.
A: CD20
Back Extra: Other low-grade B-cell lymphomas of the CNS
- Clinical: Affects middle-aged adults (median age 49) with a significantly better prognosis and less aggressive course compared to primary diffuse large B-cell lymphoma (PCNSL).
- Microscopic: Characterized by perivascular cuffs of small to medium-sized monomorphic lymphoid cells that infiltrate the parenchyma with a low proliferation index (Ki-67 < 10%).
- Ancillary: Tumors are typically CD20+ and BCL2+ but negative for CD3, CD5, CD10, and cyclin D1.
- Molecular: Clonal rearrangements of IGH and/or IGK genes are common, while the MYD88 p.L265P mutation is generally absent.
- Differential: Distinguished from demyelinating disease by the lack of macrophage-rich infiltrates and the presence of a monomorphic B-cell population.
Reference Gallery:
Low-grade B-cell lymphoma. Perivascular cuffs of medium-sized, monomorphic lymphoma cells, which express the pan–B-cell marker CD20.
Low-grade B-cell lymphoma. Admixed with the lymphoma cells are some reactive CD3 T cells.
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.

Q: Although Other low-grade B-cell lymphomas of the CNS are composed of neoplastic B-cells, they often contain an admixed population of reactive T-cells that can be highlighted by the [...] immunostain.
Low-grade B-cell lymphoma. Admixed with the lymphoma cells are some reactive CD3 T cells.
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.
A: CD3
Back Extra: Other low-grade B-cell lymphomas of the CNS
- Clinical: Affects middle-aged adults (median age 49) with a significantly better prognosis and less aggressive course compared to primary diffuse large B-cell lymphoma (PCNSL).
- Microscopic: Characterized by perivascular cuffs of small to medium-sized monomorphic lymphoid cells that infiltrate the parenchyma with a low proliferation index (Ki-67 < 10%).
- Ancillary: Tumors are typically CD20+ and BCL2+ but negative for CD3, CD5, CD10, and cyclin D1.
- Molecular: Clonal rearrangements of IGH and/or IGK genes are common, while the MYD88 p.L265P mutation is generally absent.
- Differential: Distinguished from demyelinating disease by the lack of macrophage-rich infiltrates and the presence of a monomorphic B-cell population.
Reference Gallery:
Low-grade B-cell lymphoma. Perivascular cuffs of medium-sized, monomorphic lymphoma cells, which express the pan–B-cell marker CD20.
Low-grade B-cell lymphoma. Admixed with the lymphoma cells are some reactive CD3 T cells.
Low-grade B-cell lymphoma. Perivascular cuffs of small, monomorphic-appearing lymphoid cells.

Q: Microscopically, Primary diffuse large B-cell lymphoma of the CNS features discohesive, large atypical cells with a characteristic [...] infiltration pattern, often invading and splitting the reticulin fibers of cerebral blood vessels.
Primary diffuse large B-cell lymphoma of the CNS. The lymphoma cells infiltrate around blood vessels (left) and also into their walls (right).
Primary diffuse large B-cell lymphoma of the CNS. Large cells with vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm.
A: angiocentric
Back Extra: Primary diffuse large B-cell lymphoma of the CNS
- Clinical: Patients typically present with cognitive dysfunction, psychomotor slowing, and focal neurological symptoms. MRI is the primary modality, showing lesions that are hypointense on T1, iso- to hyperintense on T2, and show d…
- Micro: Architecture: Highly cellular, patternless growth with a characteristic angiocentric infiltration pattern. Tumour cells frequently cause splitting of the argyrophilic fiber network of cerebral blood vessels. Central …
- Cyto: Intraoperative Smear: Shows enlarged, highly atypical, and discohesive neoplastic cells with minimal detectable cytoplasm, which helps distinguish it from the cohesive clusters seen in metastatic carcinoma. CSF Cyt…
- Ancillary: Immunohistochemistry (IHC): - Positive: Pan-B-cell markers (CD19, CD20, CD22, CD79a, PAX5), BCL6 (60–80%), MUM1/IRF4 (90%), BCL2, and often IgM/IgD. - Negative: Plasma cell markers (CD38, CD138), CD10 (usuall…
Reference Gallery:
Diffuse large B-cell lymphoma of the CNS. Copy-number profile. Note losses of chromosome arm 6q and homozygous deletion of CDKN2A on chromosome arm 9p.
Primary diffuse large B-cell lymphoma of the CNS. Single homogeneously enhancing lesion on postcontrast T1-weighted axial MRI.
Primary diffuse large B-cell lymphoma of the CNS. Multiple enhancing lesions with periventricular and subependymal location on postcontrast T1-weighted axial MRI.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The tumour cells express the pan–B-cell marker CD20.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The majority of the tumour cells show nuclear expression of BCL6.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. High proliferative activity evidenced by Ki-67 expression.
Primary diffuse large B-cell lymphoma of the CNS. The lymphoma cells infiltrate around blood vessels (left) and also into their walls (right).
Primary diffuse large B-cell lymphoma of the CNS. Large cells with vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm.
Pathogenesis of primary CNS-DLBCL, illustrating ASHM, BCR, TLR, and NF-κB pathway alterations.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear staining of the tumour cells for IRF4 (MUM1).
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Expression of BCL2.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear expression of MYC protein in the majority of the tumour cells in the absence of a MYC rearrangement.

Q: Immunohistochemical profiling of Primary diffuse large B-cell lymphoma of the CNS typically demonstrates a non-germinal center B-cell phenotype, showing diffuse positivity for pan-B-cell markers (e.g., CD20) and the post-germinal center marker [...] (IRF4).
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The tumour cells express the pan–B-cell marker CD20.
Primary diffuse large B-cell lymphoma of the CNS. Large cells with vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear staining of the tumour cells for IRF4 (MUM1).
A: MUM1
Back Extra: Primary diffuse large B-cell lymphoma of the CNS
- Clinical: Patients typically present with cognitive dysfunction, psychomotor slowing, and focal neurological symptoms. MRI is the primary modality, showing lesions that are hypointense on T1, iso- to hyperintense on T2, and show d…
- Micro: Architecture: Highly cellular, patternless growth with a characteristic angiocentric infiltration pattern. Tumour cells frequently cause splitting of the argyrophilic fiber network of cerebral blood vessels. Central …
- Cyto: Intraoperative Smear: Shows enlarged, highly atypical, and discohesive neoplastic cells with minimal detectable cytoplasm, which helps distinguish it from the cohesive clusters seen in metastatic carcinoma. CSF Cyt…
- Ancillary: Immunohistochemistry (IHC): - Positive: Pan-B-cell markers (CD19, CD20, CD22, CD79a, PAX5), BCL6 (60–80%), MUM1/IRF4 (90%), BCL2, and often IgM/IgD. - Negative: Plasma cell markers (CD38, CD138), CD10 (usuall…
Reference Gallery:
Diffuse large B-cell lymphoma of the CNS. Copy-number profile. Note losses of chromosome arm 6q and homozygous deletion of CDKN2A on chromosome arm 9p.
Primary diffuse large B-cell lymphoma of the CNS. Single homogeneously enhancing lesion on postcontrast T1-weighted axial MRI.
Primary diffuse large B-cell lymphoma of the CNS. Multiple enhancing lesions with periventricular and subependymal location on postcontrast T1-weighted axial MRI.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The tumour cells express the pan–B-cell marker CD20.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The majority of the tumour cells show nuclear expression of BCL6.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. High proliferative activity evidenced by Ki-67 expression.
Primary diffuse large B-cell lymphoma of the CNS. The lymphoma cells infiltrate around blood vessels (left) and also into their walls (right).
Primary diffuse large B-cell lymphoma of the CNS. Large cells with vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm.
Pathogenesis of primary CNS-DLBCL, illustrating ASHM, BCR, TLR, and NF-κB pathway alterations.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear staining of the tumour cells for IRF4 (MUM1).
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Expression of BCL2.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear expression of MYC protein in the majority of the tumour cells in the absence of a MYC rearrangement.

Q: On postcontrast T1-weighted MRI, Primary diffuse large B-cell lymphoma of the CNS classically presents as single or multiple homogeneously enhancing lesions that strongly favor a [...] and subependymal location.
Primary diffuse large B-cell lymphoma of the CNS. Single homogeneously enhancing lesion on postcontrast T1-weighted axial MRI.
Primary diffuse large B-cell lymphoma of the CNS. Multiple enhancing lesions with periventricular and subependymal location on postcontrast T1-weighted axial MRI.
A: periventricular
Back Extra: Primary diffuse large B-cell lymphoma of the CNS
- Clinical: Patients typically present with cognitive dysfunction, psychomotor slowing, and focal neurological symptoms. MRI is the primary modality, showing lesions that are hypointense on T1, iso- to hyperintense on T2, and show d…
- Micro: Architecture: Highly cellular, patternless growth with a characteristic angiocentric infiltration pattern. Tumour cells frequently cause splitting of the argyrophilic fiber network of cerebral blood vessels. Central …
- Cyto: Intraoperative Smear: Shows enlarged, highly atypical, and discohesive neoplastic cells with minimal detectable cytoplasm, which helps distinguish it from the cohesive clusters seen in metastatic carcinoma. CSF Cyt…
- Ancillary: Immunohistochemistry (IHC): - Positive: Pan-B-cell markers (CD19, CD20, CD22, CD79a, PAX5), BCL6 (60–80%), MUM1/IRF4 (90%), BCL2, and often IgM/IgD. - Negative: Plasma cell markers (CD38, CD138), CD10 (usuall…
Reference Gallery:
Diffuse large B-cell lymphoma of the CNS. Copy-number profile. Note losses of chromosome arm 6q and homozygous deletion of CDKN2A on chromosome arm 9p.
Primary diffuse large B-cell lymphoma of the CNS. Single homogeneously enhancing lesion on postcontrast T1-weighted axial MRI.
Primary diffuse large B-cell lymphoma of the CNS. Multiple enhancing lesions with periventricular and subependymal location on postcontrast T1-weighted axial MRI.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The tumour cells express the pan–B-cell marker CD20.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. The majority of the tumour cells show nuclear expression of BCL6.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. High proliferative activity evidenced by Ki-67 expression.
Primary diffuse large B-cell lymphoma of the CNS. The lymphoma cells infiltrate around blood vessels (left) and also into their walls (right).
Primary diffuse large B-cell lymphoma of the CNS. Large cells with vesicular nuclei, prominent nucleoli, and amphophilic cytoplasm.
Pathogenesis of primary CNS-DLBCL, illustrating ASHM, BCR, TLR, and NF-κB pathway alterations.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear staining of the tumour cells for IRF4 (MUM1).
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Expression of BCL2.
Immunophenotype of primary diffuse large B-cell lymphoma of the CNS. Strong nuclear expression of MYC protein in the majority of the tumour cells in the absence of a MYC rearrangement.

Q: In T-cell and NK/T-cell lymphomas involving the CNS, the atypical lymphoid cells frequently demonstrate a prominent perivascular growth pattern, expressing pan-T-cell markers like CD3, and are notably more commonly positive for [...] than CD4.
Peripheral T-cell lymphoma. Highly cellular lymphoma of medium-sized to large tumour cells with frequent mitoses diffusely infiltrates the brain tissue.
Peripheral T-cell lymphoma. Lymphoblastic and moderately sized lymphoma cells express the pan–T-cell marker CD3.
Peripheral T-cell lymphoma. The tumour cells show a sheet-like growth pattern and have invaded the wall of a cerebral blood vessel. They strongly express the CD8 antigen.
A: CD8
T-cell and NK/T-cell lymphomas
- Clinical: These rare CNS lymphomas primarily affect adults (5th–6th decade) and present with focal neurological deficits or seizures, often appearing as multifocal lesions in the frontal/temporal lobes.
- Microscopic: Features include highly cellular infiltrates of medium-sized to large atypical lymphoid cells, frequently displaying a prominent perivascular growth pattern and necrosis.
- Ancillary (PTCL): Tumour cells typically express pan-T-cell markers (CD3, CD2) and cytotoxic granules (TIA1, granzyme B); they are more commonly CD8+ than CD4+ in the CNS.
- Ancillary (NK/T-cell): Characterized by an angiocentric growth pattern, expression of CD56, and mandatory positivity for EBV-encoded small RNA (EBER).
- Molecular: Most cases of CNS T-cell lymphoma demonstrate clonal rearrangement of the T-cell receptor (TR) genes.
Reference Gallery:
Peripheral T-cell lymphoma. Highly cellular lymphoma of medium-sized to large tumour cells with frequent mitoses diffusely infiltrates the brain tissue.
Peripheral T-cell lymphoma. Lymphoblastic and moderately sized lymphoma cells express the pan–T-cell marker CD3.
Peripheral T-cell lymphoma. The tumour cells show a sheet-like growth pattern and have invaded the wall of a cerebral blood vessel. They strongly express the CD8 antigen.
Peripheral T-cell lymphoma. Many tumour cells express granzyme B, a cytotoxic granule, in their cytoplasm.

Q: A characteristic ancillary feature of T-cell and NK/T-cell lymphomas is the presence of tumor cells expressing cytoplasmic cytotoxic granules, such as TIA1 and [...].
Peripheral T-cell lymphoma. Highly cellular lymphoma of medium-sized to large tumour cells with frequent mitoses diffusely infiltrates the brain tissue.
Peripheral T-cell lymphoma. Many tumour cells express granzyme B, a cytotoxic granule, in their cytoplasm.
A: granzyme B
T-cell and NK/T-cell lymphomas
- Clinical: These rare CNS lymphomas primarily affect adults (5th–6th decade) and present with focal neurological deficits or seizures, often appearing as multifocal lesions in the frontal/temporal lobes.
- Microscopic: Features include highly cellular infiltrates of medium-sized to large atypical lymphoid cells, frequently displaying a prominent perivascular growth pattern and necrosis.
- Ancillary (PTCL): Tumour cells typically express pan-T-cell markers (CD3, CD2) and cytotoxic granules (TIA1, granzyme B); they are more commonly CD8+ than CD4+ in the CNS.
- Ancillary (NK/T-cell): Characterized by an angiocentric growth pattern, expression of CD56, and mandatory positivity for EBV-encoded small RNA (EBER).
- Molecular: Most cases of CNS T-cell lymphoma demonstrate clonal rearrangement of the T-cell receptor (TR) genes.
Reference Gallery:
Peripheral T-cell lymphoma. Highly cellular lymphoma of medium-sized to large tumour cells with frequent mitoses diffusely infiltrates the brain tissue.
Peripheral T-cell lymphoma. Lymphoblastic and moderately sized lymphoma cells express the pan–T-cell marker CD3.
Peripheral T-cell lymphoma. The tumour cells show a sheet-like growth pattern and have invaded the wall of a cerebral blood vessel. They strongly express the CD8 antigen.
Peripheral T-cell lymphoma. Many tumour cells express granzyme B, a cytotoxic granule, in their cytoplasm.

Q: Approximately 70% of tumors in Schwannomatosis exhibit characteristic histologic features of a [...].
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
A: hybrid schwannoma/neurofibroma
Back Extra: Schwannomatosis
- Clinical: Patients typically present in their second or third decade with severe chronic pain, a palpable mass, or both. Unlike NF2, severe pain is a hallmark feature, while neurological deficits and polyneuropathy are uncommon. T…
- Micro: The tumors associated with schwannomatosis are histologically similar to sporadic schwannomas. However, approximately 70% of tumors in this syndrome exhibit features of hybrid schwannoma/neurofibroma, characterized by a …
- Cyto: Not relevant.
- Ancillary: 1) Immunohistochemistry (IHC): - SMARCB1 (INI1): A characteristic mosaic pattern of nuclear staining (intermingled positive and negative nuclei) is seen in almost all familial and 55–100% of sporadic cases. This…
Reference Gallery:
Schwannomas in schwannomatosis. T1-weighted coronal MRI showing multiple bright, discrete peripheral tumours in a patient with schwannomatosis.
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
Schwannoma/neurofibroma hybrid tumour. SOX10 is diffusely positive in the schwannoma component of the tumour and shows patchy positivity in the neurofibroma component.
Schwannoma/neurofibroma hybrid tumour. This CD34 immunostain highlights a lattice-like pattern in the neurofibroma component but not the schwannoma component.

Q: In the characteristic hybrid tumors of Schwannomatosis, the schwannoma component is diffusely positive for SOX10, while the neurofibroma component uniquely exhibits a lattice-like network on a [...] immunostain.
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
Schwannoma/neurofibroma hybrid tumour. SOX10 is diffusely positive in the schwannoma component of the tumour and shows patchy positivity in the neurofibroma component.
Schwannoma/neurofibroma hybrid tumour. This CD34 immunostain highlights a lattice-like pattern in the neurofibroma component but not the schwannoma component.
A: CD34
Back Extra: Schwannomatosis
- Clinical: Patients typically present in their second or third decade with severe chronic pain, a palpable mass, or both. Unlike NF2, severe pain is a hallmark feature, while neurological deficits and polyneuropathy are uncommon. T…
- Micro: The tumors associated with schwannomatosis are histologically similar to sporadic schwannomas. However, approximately 70% of tumors in this syndrome exhibit features of hybrid schwannoma/neurofibroma, characterized by a …
- Cyto: Not relevant.
- Ancillary: 1) Immunohistochemistry (IHC): - SMARCB1 (INI1): A characteristic mosaic pattern of nuclear staining (intermingled positive and negative nuclei) is seen in almost all familial and 55–100% of sporadic cases. This…
Reference Gallery:
Schwannomas in schwannomatosis. T1-weighted coronal MRI showing multiple bright, discrete peripheral tumours in a patient with schwannomatosis.
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
Schwannoma/neurofibroma hybrid tumour. SOX10 is diffusely positive in the schwannoma component of the tumour and shows patchy positivity in the neurofibroma component.
Schwannoma/neurofibroma hybrid tumour. This CD34 immunostain highlights a lattice-like pattern in the neurofibroma component but not the schwannoma component.

Q: A hallmark clinical presentation of Schwannomatosis that helps distinguish it from neurofibromatosis type 2 (NF2) is the presence of [...] alongside multiple peripheral nerve tumors.
Schwannomas in schwannomatosis. T1-weighted coronal MRI showing multiple bright, discrete peripheral tumours in a patient with schwannomatosis.
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
A: severe chronic pain
Back Extra: Schwannomatosis
- Clinical: Patients typically present in their second or third decade with severe chronic pain, a palpable mass, or both. Unlike NF2, severe pain is a hallmark feature, while neurological deficits and polyneuropathy are uncommon. T…
- Micro: The tumors associated with schwannomatosis are histologically similar to sporadic schwannomas. However, approximately 70% of tumors in this syndrome exhibit features of hybrid schwannoma/neurofibroma, characterized by a …
- Cyto: Not relevant.
- Ancillary: 1) Immunohistochemistry (IHC): - SMARCB1 (INI1): A characteristic mosaic pattern of nuclear staining (intermingled positive and negative nuclei) is seen in almost all familial and 55–100% of sporadic cases. This…
Reference Gallery:
Schwannomas in schwannomatosis. T1-weighted coronal MRI showing multiple bright, discrete peripheral tumours in a patient with schwannomatosis.
Schwannoma/neurofibroma hybrid tumour. Tumours with hybrid features of schwannoma (left) and neurofibroma (right) are common in schwannomatosis and neurofibromatosis type 2.
Schwannoma/neurofibroma hybrid tumour. SOX10 is diffusely positive in the schwannoma component of the tumour and shows patchy positivity in the neurofibroma component.
Schwannoma/neurofibroma hybrid tumour. This CD34 immunostain highlights a lattice-like pattern in the neurofibroma component but not the schwannoma component.

Q: The defining immunohistochemical profile of an Astrocytoma, IDH-mutant includes diffuse cytoplasmic positivity for IDH1 p.R132H, strong nuclear staining for p53, and a characteristic loss of nuclear expression for [...].
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for IDH1 p.R132H demonstrates strong cytoplasmic reactivity in all neoplastic cells.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for ATRX reveals loss of nuclear staining in neoplastic cells.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. The nuclei of IDH-mutant astrocytomas are elongated, irregular, and hyperchromatic.
A: ATRX
Back Extra: Astrocytoma, IDH-mutant
- Clinical: The majority of patients present in their thirties or forties (median age: 38 years). Seizures are the most common presenting sign. Higher-grade tumours are associated with shorter clinical histories. Neurocognitive func…
- Micro: The tumor shows a spectrum of differentiation across three CNS WHO grades: - CNS WHO grade 2: Well-differentiated fibrillary glial cells with mild nuclear atypia infiltrating parenchyma; often shows a microcystic ma…
- Cyto: Cytological/Smear preparations show enlarged, angulated, and hyperchromatic nuclei with elongated eosinophilic cellular processes forming a loose fibrillar background. High-grade (Grade 4) lesions may demonstrate necroti…
- Ancillary: Immunohistochemistry (IHC): - IDH1 p.R132H: Positive (diffuse cytoplasmic staining) in ~90% of cases. - ATRX: Loss of nuclear expression in neoplastic cells (with internal positive control in vessels/neurons…
Reference Gallery:
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. An infiltrating astrocytic glioma of low cell density, showing mild nuclear atypia of tumour cells and a dense fibrillar background with mild oedema.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for IDH1 p.R132H demonstrates strong cytoplasmic reactivity in all neoplastic cells.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for ATRX reveals loss of nuclear staining in neoplastic cells.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Palisading cells around a central focus of necrosis.
T2-weighted MRI and FLAIR mismatch characteristic of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. Postcontrast T1-weighted MRI demonstrating an infiltrative mass involving the left frontal and parietal lobes that is T1-hypointense and without contrast enhancement, a pattern typical of grade 2 and 3 IDH-mutant astrocytomas.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Postcontrast T1-weighted MRI showing a mass centred in the right frontoparietal region demonstrating rim enhancement surrounding central necrosis with adjacent T1 hypointensity, typical of a grade 4 IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. Microcystic change / microcyst formation in the tumour stroma is a frequent feature.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. The nuclei of IDH-mutant astrocytomas are elongated, irregular, and hyperchromatic.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. CNS WHO grade 3 IDH-mutant astrocytomas show greater cellularity and nuclear atypia than do CNS WHO grade 2 tumours, as well as increased mitotic activity.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for p53 shows strong nuclear staining in a large percentage of neoplastic cells, which correlates well with TP53 mutation in the setting of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Smear preparation shows IDH-mutant astrocytoma cells with enlarged, hyperchromatic, and irregular nuclei within a background of extensive fibrillarity created by the elongated fibrillar processes emanating from tumour cell bodies.

Q: Histologically, a low-grade (CNS WHO grade 2) Astrocytoma, IDH-mutant typically exhibits infiltrating fibrillary glial cells with elongated, hyperchromatic nuclei and frequent formation of [...] within the tumor stroma.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. An infiltrating astrocytic glioma of low cell density, showing mild nuclear atypia of tumour cells and a dense fibrillar background with mild oedema.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. Microcystic change / microcyst formation in the tumour stroma is a frequent feature.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. The nuclei of IDH-mutant astrocytomas are elongated, irregular, and hyperchromatic.
A: microcysts
Back Extra: Astrocytoma, IDH-mutant
- Clinical: The majority of patients present in their thirties or forties (median age: 38 years). Seizures are the most common presenting sign. Higher-grade tumours are associated with shorter clinical histories. Neurocognitive func…
- Micro: The tumor shows a spectrum of differentiation across three CNS WHO grades: - CNS WHO grade 2: Well-differentiated fibrillary glial cells with mild nuclear atypia infiltrating parenchyma; often shows a microcystic ma…
- Cyto: Cytological/Smear preparations show enlarged, angulated, and hyperchromatic nuclei with elongated eosinophilic cellular processes forming a loose fibrillar background. High-grade (Grade 4) lesions may demonstrate necroti…
- Ancillary: Immunohistochemistry (IHC): - IDH1 p.R132H: Positive (diffuse cytoplasmic staining) in ~90% of cases. - ATRX: Loss of nuclear expression in neoplastic cells (with internal positive control in vessels/neurons…
Reference Gallery:
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. An infiltrating astrocytic glioma of low cell density, showing mild nuclear atypia of tumour cells and a dense fibrillar background with mild oedema.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for IDH1 p.R132H demonstrates strong cytoplasmic reactivity in all neoplastic cells.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for ATRX reveals loss of nuclear staining in neoplastic cells.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Palisading cells around a central focus of necrosis.
T2-weighted MRI and FLAIR mismatch characteristic of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. Postcontrast T1-weighted MRI demonstrating an infiltrative mass involving the left frontal and parietal lobes that is T1-hypointense and without contrast enhancement, a pattern typical of grade 2 and 3 IDH-mutant astrocytomas.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Postcontrast T1-weighted MRI showing a mass centred in the right frontoparietal region demonstrating rim enhancement surrounding central necrosis with adjacent T1 hypointensity, typical of a grade 4 IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. Microcystic change / microcyst formation in the tumour stroma is a frequent feature.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. The nuclei of IDH-mutant astrocytomas are elongated, irregular, and hyperchromatic.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. CNS WHO grade 3 IDH-mutant astrocytomas show greater cellularity and nuclear atypia than do CNS WHO grade 2 tumours, as well as increased mitotic activity.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for p53 shows strong nuclear staining in a large percentage of neoplastic cells, which correlates well with TP53 mutation in the setting of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Smear preparation shows IDH-mutant astrocytoma cells with enlarged, hyperchromatic, and irregular nuclei within a background of extensive fibrillarity created by the elongated fibrillar processes emanating from tumour cell bodies.

Q: On neuroimaging, a highly specific radiological feature often observed in non-enhancing, lower-grade Astrocytoma, IDH-mutant is the T2-weighted and [...] mismatch sign.
T2-weighted MRI and FLAIR mismatch characteristic of IDH-mutant astrocytoma.
A: FLAIR
Back Extra: Astrocytoma, IDH-mutant
- Clinical: The majority of patients present in their thirties or forties (median age: 38 years). Seizures are the most common presenting sign. Higher-grade tumours are associated with shorter clinical histories. Neurocognitive func…
- Micro: The tumor shows a spectrum of differentiation across three CNS WHO grades: - CNS WHO grade 2: Well-differentiated fibrillary glial cells with mild nuclear atypia infiltrating parenchyma; often shows a microcystic ma…
- Cyto: Cytological/Smear preparations show enlarged, angulated, and hyperchromatic nuclei with elongated eosinophilic cellular processes forming a loose fibrillar background. High-grade (Grade 4) lesions may demonstrate necroti…
- Ancillary: Immunohistochemistry (IHC): - IDH1 p.R132H: Positive (diffuse cytoplasmic staining) in ~90% of cases. - ATRX: Loss of nuclear expression in neoplastic cells (with internal positive control in vessels/neurons…
Reference Gallery:
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. An infiltrating astrocytic glioma of low cell density, showing mild nuclear atypia of tumour cells and a dense fibrillar background with mild oedema.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for IDH1 p.R132H demonstrates strong cytoplasmic reactivity in all neoplastic cells.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for ATRX reveals loss of nuclear staining in neoplastic cells.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Palisading cells around a central focus of necrosis.
T2-weighted MRI and FLAIR mismatch characteristic of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. Postcontrast T1-weighted MRI demonstrating an infiltrative mass involving the left frontal and parietal lobes that is T1-hypointense and without contrast enhancement, a pattern typical of grade 2 and 3 IDH-mutant astrocytomas.
Astrocytoma, IDH-mutant. CNS WHO grade 4 tumour. Postcontrast T1-weighted MRI showing a mass centred in the right frontoparietal region demonstrating rim enhancement surrounding central necrosis with adjacent T1 hypointensity, typical of a grade 4 IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. Microcystic change / microcyst formation in the tumour stroma is a frequent feature.
Astrocytoma, IDH-mutant. CNS WHO grade 2 tumour. The nuclei of IDH-mutant astrocytomas are elongated, irregular, and hyperchromatic.
Astrocytoma, IDH-mutant. CNS WHO grade 3 tumour. CNS WHO grade 3 IDH-mutant astrocytomas show greater cellularity and nuclear atypia than do CNS WHO grade 2 tumours, as well as increased mitotic activity.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Immunohistochemistry for p53 shows strong nuclear staining in a large percentage of neoplastic cells, which correlates well with TP53 mutation in the setting of IDH-mutant astrocytoma.
Astrocytoma, IDH-mutant, CNS WHO grade 3. Smear preparation shows IDH-mutant astrocytoma cells with enlarged, hyperchromatic, and irregular nuclei within a background of extensive fibrillarity created by the elongated fibrillar processes emanating from tumour cell bodies.

Q: Microscopically, Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is classically characterized by an artefactual clear cytoplasm creating a [...] appearance, along with a dense network of branching "chicken-wire" capillaries.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Typical image of a cellular glioma with 'honeycomb' cells and mitotic activity.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Intraoperative smear section showing tumour cells in a fibrillary background with delicate vasculature.
A: "fried-egg" or "honeycomb"
Back Extra: Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
- Clinical: Strong predilection for the frontal lobes; seizures are the presenting symptom in approximately two-thirds of patients.
- Microscopic: Characterized by a 'honeycomb' or 'fried-egg' appearance (artefactual clear cytoplasm), a dense network of branching 'chicken-wire' capillaries, and secondary structures like perineuronal satellitosis.
- Grading: CNS WHO grade 3 is distinguished from grade 2 by high cellularity, cytologic atypia, microvascular proliferation, necrosis, and high mitotic counts (often ≥ 2.5 mitoses/mm²).
- Ancillary: Integrated diagnosis requires detection of both an IDH1 or IDH2 mutation and 1p/19q whole-arm codeletion; nuclear ATRX expression is typically retained (unlike IDH-mutant astrocytoma).
- Molecular: Canonical molecular features include TERT promoter hotspot mutations and G-CIMP phenotype; homozygous CDKN2A/B deletion is a marker of grade 3.
Reference Gallery:
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Typical image of a cellular glioma with 'honeycomb' cells and mitotic activity.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Oligodendrogliomas often infiltrate the cortex, with individual tumour cells showing perineuronal satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Intraoperative smear section showing tumour cells in a fibrillary background with delicate vasculature.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Strong, diffuse immunoreactivity for IDH1 p.R132H.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Retained ATRX immunoreactivity within tumour cell nuclei.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. FISH demonstrates 1p/19q codeletion.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. CT without contrast showing calcification in a hypodense region.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Marked microvascular proliferation.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Focal necrosis with palisading tumour cells.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Cells embedded within a light-blue mucinous matrix.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Extensive perineuronal and perivascular satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. An elevated Ki-67 labelling index is typical.

Q: To help distinguish Oligodendroglioma, IDH-mutant and 1p/19q-codeleted from an IDH-mutant astrocytoma, immunohistochemistry typically demonstrates that nuclear expression of [...] is retained (rather than lost) within the tumor cells.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Typical image of a cellular glioma with 'honeycomb' cells and mitotic activity.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Retained ATRX immunoreactivity within tumour cell nuclei.
A: ATRX
Back Extra: Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
- Clinical: Strong predilection for the frontal lobes; seizures are the presenting symptom in approximately two-thirds of patients.
- Microscopic: Characterized by a 'honeycomb' or 'fried-egg' appearance (artefactual clear cytoplasm), a dense network of branching 'chicken-wire' capillaries, and secondary structures like perineuronal satellitosis.
- Grading: CNS WHO grade 3 is distinguished from grade 2 by high cellularity, cytologic atypia, microvascular proliferation, necrosis, and high mitotic counts (often ≥ 2.5 mitoses/mm²).
- Ancillary: Integrated diagnosis requires detection of both an IDH1 or IDH2 mutation and 1p/19q whole-arm codeletion; nuclear ATRX expression is typically retained (unlike IDH-mutant astrocytoma).
- Molecular: Canonical molecular features include TERT promoter hotspot mutations and G-CIMP phenotype; homozygous CDKN2A/B deletion is a marker of grade 3.
Reference Gallery:
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Typical image of a cellular glioma with 'honeycomb' cells and mitotic activity.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Oligodendrogliomas often infiltrate the cortex, with individual tumour cells showing perineuronal satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Intraoperative smear section showing tumour cells in a fibrillary background with delicate vasculature.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Strong, diffuse immunoreactivity for IDH1 p.R132H.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Retained ATRX immunoreactivity within tumour cell nuclei.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. FISH demonstrates 1p/19q codeletion.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. CT without contrast showing calcification in a hypodense region.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Marked microvascular proliferation.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Focal necrosis with palisading tumour cells.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Cells embedded within a light-blue mucinous matrix.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Extensive perineuronal and perivascular satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. An elevated Ki-67 labelling index is typical.

Q: On imaging, Oligodendroglioma, IDH-mutant and 1p/19q-codeleted frequently localizes to the frontal lobes and classically demonstrates prominent [...] on a non-contrast CT scan.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Oligodendrogliomas often infiltrate the cortex, with individual tumour cells showing perineuronal satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. CT without contrast showing calcification in a hypodense region.
A: calcification
Back Extra: Oligodendroglioma, IDH-mutant and 1p/19q-codeleted
- Clinical: Strong predilection for the frontal lobes; seizures are the presenting symptom in approximately two-thirds of patients.
- Microscopic: Characterized by a 'honeycomb' or 'fried-egg' appearance (artefactual clear cytoplasm), a dense network of branching 'chicken-wire' capillaries, and secondary structures like perineuronal satellitosis.
- Grading: CNS WHO grade 3 is distinguished from grade 2 by high cellularity, cytologic atypia, microvascular proliferation, necrosis, and high mitotic counts (often ≥ 2.5 mitoses/mm²).
- Ancillary: Integrated diagnosis requires detection of both an IDH1 or IDH2 mutation and 1p/19q whole-arm codeletion; nuclear ATRX expression is typically retained (unlike IDH-mutant astrocytoma).
- Molecular: Canonical molecular features include TERT promoter hotspot mutations and G-CIMP phenotype; homozygous CDKN2A/B deletion is a marker of grade 3.
Reference Gallery:
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Typical image of a cellular glioma with 'honeycomb' cells and mitotic activity.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Oligodendrogliomas often infiltrate the cortex, with individual tumour cells showing perineuronal satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Intraoperative smear section showing tumour cells in a fibrillary background with delicate vasculature.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Strong, diffuse immunoreactivity for IDH1 p.R132H.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. Retained ATRX immunoreactivity within tumour cell nuclei.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. FISH demonstrates 1p/19q codeletion.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. CT without contrast showing calcification in a hypodense region.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Marked microvascular proliferation.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Focal necrosis with palisading tumour cells.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2. Cells embedded within a light-blue mucinous matrix.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3. Extensive perineuronal and perivascular satellitosis.
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted CNS WHO grade 3. An elevated Ki-67 labelling index is typical.

Q: In Astroblastoma, MN1-altered, the histological hallmark is the [...], formed by radially oriented tumor cells anchored to central blood vessels by stout, eosinophilic processes.
Astroblastoma, MN1-altered. The histological hallmark is the astroblastic rosette, characterized by radially oriented tumour cells with elongate, stout processes and distally located nuclei extending to a central vascular structure.
Astroblastoma, MN1-altered. A ribbon-like or trabecular pattern is noted when elongated tumour cells oriented to central blood vessels are seen in cross-section.
A: astroblastic pseudorosette
Back Extra: Astroblastoma, MN1-altered
- Clinical: Clinical Presentation: Symptoms include headache, seizures, paralysis, nausea, and vomiting. Epidemiology: Predominantly affects children and young adults (range: 3 months to 40 years; median: 15 years) with a …
- Micro: The histological hallmark is the astroblastic pseudorosette, where neoplastic cells are radially arrayed around central blood vessels, anchored by stout, eosinophilic cytoplasmic processes. These cells often form pap…
- Cyto: The intraoperative smear/squash preparation cytology of MN1-altered astroblastomas has not been described.
- Ancillary: Immunohistochemistry (IHC): - GFAP: Characteristic cytoplasmic immunoreactivity (extent varies). - OLIG2: Focal nuclear expression in the large majority. - EMA: Regularly positive; distribution can be dif…
Reference Gallery:
Astroblastoma, MN1-altered. The histological hallmark is the astroblastic rosette, characterized by radially oriented tumour cells with elongate, stout processes and distally located nuclei extending to a central vascular structure.
Astroblastoma, MN1-altered. A ribbon-like or trabecular pattern is noted when elongated tumour cells oriented to central blood vessels are seen in cross-section.
Astroblastoma, MN1-altered. Perivascular and pericellular hyalinization is typical but varies considerably in its severity and extent.
Astroblastoma, MN1-altered. Immunohistochemistry for GFAP often shows strong, diffuse immunoreactivity in astroblastoma, MN1-altered.
Astroblastoma, MN1-altered. Note the sharp demarcation from adjacent brain parenchyma.
Astroblastoma, MN1-altered. This tumour included focal rhabdoid cytological features.
Astroblastoma with primitive cytology. Other areas of this tumour featured perivascular and stromal sclerosis, more typical of astroblastoma.
Astroblastoma, MN1-altered. Patchy membranous and cytoplasmic dot-like immunostaining for EMA.
Astroblastoma, MN1-altered. Membranous and cytoplasmic dot-like D2-40 (podoplanin) staining.
Astroblastoma with primitive cytology. The high cellularity, small round cell cytology, and geographical necrosis in this astroblastoma mimicked an embryonal neoplasm. Molecular testing revealed an MN1::BEND2 fusion.
Astroblastoma, MN1-altered. Postcontrast, T1-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.
Astroblastoma, MN1-altered. T2-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.

Q: Immunohistochemistry in Astroblastoma, MN1-altered typically demonstrates diffuse positivity for GFAP, along with characteristic focal membranous and cytoplasmic dot-like staining for D2-40 (podoplanin) and [...].
Astroblastoma, MN1-altered. Immunohistochemistry for GFAP often shows strong, diffuse immunoreactivity in astroblastoma, MN1-altered.
Astroblastoma, MN1-altered. Patchy membranous and cytoplasmic dot-like immunostaining for EMA.
Astroblastoma, MN1-altered. Membranous and cytoplasmic dot-like D2-40 (podoplanin) staining.
A: EMA
Back Extra: Astroblastoma, MN1-altered
- Clinical: Clinical Presentation: Symptoms include headache, seizures, paralysis, nausea, and vomiting. Epidemiology: Predominantly affects children and young adults (range: 3 months to 40 years; median: 15 years) with a …
- Micro: The histological hallmark is the astroblastic pseudorosette, where neoplastic cells are radially arrayed around central blood vessels, anchored by stout, eosinophilic cytoplasmic processes. These cells often form pap…
- Cyto: The intraoperative smear/squash preparation cytology of MN1-altered astroblastomas has not been described.
- Ancillary: Immunohistochemistry (IHC): - GFAP: Characteristic cytoplasmic immunoreactivity (extent varies). - OLIG2: Focal nuclear expression in the large majority. - EMA: Regularly positive; distribution can be dif…
Reference Gallery:
Astroblastoma, MN1-altered. The histological hallmark is the astroblastic rosette, characterized by radially oriented tumour cells with elongate, stout processes and distally located nuclei extending to a central vascular structure.
Astroblastoma, MN1-altered. A ribbon-like or trabecular pattern is noted when elongated tumour cells oriented to central blood vessels are seen in cross-section.
Astroblastoma, MN1-altered. Perivascular and pericellular hyalinization is typical but varies considerably in its severity and extent.
Astroblastoma, MN1-altered. Immunohistochemistry for GFAP often shows strong, diffuse immunoreactivity in astroblastoma, MN1-altered.
Astroblastoma, MN1-altered. Note the sharp demarcation from adjacent brain parenchyma.
Astroblastoma, MN1-altered. This tumour included focal rhabdoid cytological features.
Astroblastoma with primitive cytology. Other areas of this tumour featured perivascular and stromal sclerosis, more typical of astroblastoma.
Astroblastoma, MN1-altered. Patchy membranous and cytoplasmic dot-like immunostaining for EMA.
Astroblastoma, MN1-altered. Membranous and cytoplasmic dot-like D2-40 (podoplanin) staining.
Astroblastoma with primitive cytology. The high cellularity, small round cell cytology, and geographical necrosis in this astroblastoma mimicked an embryonal neoplasm. Molecular testing revealed an MN1::BEND2 fusion.
Astroblastoma, MN1-altered. Postcontrast, T1-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.
Astroblastoma, MN1-altered. T2-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.

Q: In addition to characteristic cellular arrangements, Astroblastoma, MN1-altered frequently exhibits striking [...] and is morphologically known for its sharp demarcation from adjacent brain parenchyma.
Astroblastoma, MN1-altered. Perivascular and pericellular hyalinization is typical but varies considerably in its severity and extent.
Astroblastoma, MN1-altered. Note the sharp demarcation from adjacent brain parenchyma.
A: perivascular hyalinization
Back Extra: Astroblastoma, MN1-altered
- Clinical: Clinical Presentation: Symptoms include headache, seizures, paralysis, nausea, and vomiting. Epidemiology: Predominantly affects children and young adults (range: 3 months to 40 years; median: 15 years) with a …
- Micro: The histological hallmark is the astroblastic pseudorosette, where neoplastic cells are radially arrayed around central blood vessels, anchored by stout, eosinophilic cytoplasmic processes. These cells often form pap…
- Cyto: The intraoperative smear/squash preparation cytology of MN1-altered astroblastomas has not been described.
- Ancillary: Immunohistochemistry (IHC): - GFAP: Characteristic cytoplasmic immunoreactivity (extent varies). - OLIG2: Focal nuclear expression in the large majority. - EMA: Regularly positive; distribution can be dif…
Reference Gallery:
Astroblastoma, MN1-altered. The histological hallmark is the astroblastic rosette, characterized by radially oriented tumour cells with elongate, stout processes and distally located nuclei extending to a central vascular structure.
Astroblastoma, MN1-altered. A ribbon-like or trabecular pattern is noted when elongated tumour cells oriented to central blood vessels are seen in cross-section.
Astroblastoma, MN1-altered. Perivascular and pericellular hyalinization is typical but varies considerably in its severity and extent.
Astroblastoma, MN1-altered. Immunohistochemistry for GFAP often shows strong, diffuse immunoreactivity in astroblastoma, MN1-altered.
Astroblastoma, MN1-altered. Note the sharp demarcation from adjacent brain parenchyma.
Astroblastoma, MN1-altered. This tumour included focal rhabdoid cytological features.
Astroblastoma with primitive cytology. Other areas of this tumour featured perivascular and stromal sclerosis, more typical of astroblastoma.
Astroblastoma, MN1-altered. Patchy membranous and cytoplasmic dot-like immunostaining for EMA.
Astroblastoma, MN1-altered. Membranous and cytoplasmic dot-like D2-40 (podoplanin) staining.
Astroblastoma with primitive cytology. The high cellularity, small round cell cytology, and geographical necrosis in this astroblastoma mimicked an embryonal neoplasm. Molecular testing revealed an MN1::BEND2 fusion.
Astroblastoma, MN1-altered. Postcontrast, T1-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.
Astroblastoma, MN1-altered. T2-weighted MRI shows a large, well-demarcated, contrast-enhancing, solid and cystic right temporoparietal mass.

Q: A well-demarcated brain tumor characteristically located in the anterior third ventricle, composed of cords of epithelioid cells in a myxoid stroma, is diagnostic of a(n) [...].
Chordoid glioma. Sagittal MRI from a chordoid glioma in a 67-year-old man shows the tumour located in the anterior third ventricle. Note the lack of involvement of the pituitary gland, lateral ventricle, and corpus callosum.
Chordoid glioma. Typical histological appearance of a chordoid glioma composed of cords and clusters of epithelioid tumour cells in a myxoid stroma, resembling the notochordal tumour chordoma.
A: Chordoid glioma
Back Extra: Chordoid glioma
- Clinical: Chordoid gliomas are rare (< 0.1% of primary brain tumours), typically presenting in adults (median age 45 years) with a 2:1 female predominance. Clinical features include symptoms of obstructive hydrocephalus (headache,…
- Micro: Chordoid gliomas are well-demarcated, solid neoplasms. Architecture typically consists of clusters and cords of epithelioid cells within a variably mucinous (myxoid) stroma. Three variants are described: a solid pattern …
- Cyto: Not clinically relevant for this entity.
- Ancillary: Immunohistochemistry (IHC): - Positive: GFAP (strong, diffuse), TTF1 (NKX2-1; nuclear positivity is consistent), CD34 (strong, diffuse), Vimentin, and S100/EMA (variable). - Negative: Neuronal and neuroendocr…
Reference Gallery:
Chordoid glioma. All tumours show diffuse cytoplasmic immunoreactivity for GFAP, as shown here. Note the lymphoplasmacytic infiltrates that are GFAP-immunonegative, shown in the lower right of this image.
Chordoid glioma. Axial MRI from a tumour in a 67-year-old man shows the typical imaging features of chordoid glioma, including sharp circumscription, large size, contrast enhancement, and compression of nearby structures.
Chordoid glioma. Sagittal MRI from a chordoid glioma in a 67-year-old man shows the tumour located in the anterior third ventricle. Note the lack of involvement of the pituitary gland, lateral ventricle, and corpus callosum.
Chordoid glioma. Strong diffuse cytoplasmic immunostaining for CD34 is typically seen in chordoid glioma.
Chordoid glioma. The lymphoplasmacytic infiltrates in these tumours can have plasma cells containing eosinophilic small globular Russell bodies.
Chordoid glioma. The demarcation between the tumour and adjacent brain tissue is often sharp; individual cell infiltration is not seen. The adjacent brain tissue in this example shows chronic inflammation and numerous Rosenthal fibres.
Chordoid glioma. Chordoid glioma demonstrating a dense rim of lymphoplasmacytic inflammation at the periphery of the tumour.
Chordoid glioma. This chordoid glioma is composed of bipolar spindled cells in a prominent myxoid stroma.
Chordoid glioma. This chordoid glioma is composed of plump epithelioid cells in a prominent myxoid stroma.
Chordoid glioma. Typical histological appearance of a chordoid glioma composed of cords and clusters of epithelioid tumour cells in a myxoid stroma, resembling the notochordal tumour chordoma.
Chordoid glioma. Nuclear positivity for thyroid transcription factor 1 (TTF1, a homeobox transcription factor encoded by the gene NKX2-1) is typical of chordoid gliomas.

Q: Immunohistochemically, Chordoid glioma typically shows strong expression of GFAP and CD34, along with characteristic nuclear positivity for [...] (NKX2-1).
Chordoid glioma. All tumours show diffuse cytoplasmic immunoreactivity for GFAP, as shown here. Note the lymphoplasmacytic infiltrates that are GFAP-immunonegative, shown in the lower right of this image.
Chordoid glioma. Strong diffuse cytoplasmic immunostaining for CD34 is typically seen in chordoid glioma.
Chordoid glioma. Typical histological appearance of a chordoid glioma composed of cords and clusters of epithelioid tumour cells in a myxoid stroma, resembling the notochordal tumour chordoma.
A: TTF1
Back Extra: Chordoid glioma
- Clinical: Chordoid gliomas are rare (< 0.1% of primary brain tumours), typically presenting in adults (median age 45 years) with a 2:1 female predominance. Clinical features include symptoms of obstructive hydrocephalus (headache,…
- Micro: Chordoid gliomas are well-demarcated, solid neoplasms. Architecture typically consists of clusters and cords of epithelioid cells within a variably mucinous (myxoid) stroma. Three variants are described: a solid pattern …
- Cyto: Not clinically relevant for this entity.
- Ancillary: Immunohistochemistry (IHC): - Positive: GFAP (strong, diffuse), TTF1 (NKX2-1; nuclear positivity is consistent), CD34 (strong, diffuse), Vimentin, and S100/EMA (variable). - Negative: Neuronal and neuroendocr…
Reference Gallery:
Chordoid glioma. All tumours show diffuse cytoplasmic immunoreactivity for GFAP, as shown here. Note the lymphoplasmacytic infiltrates that are GFAP-immunonegative, shown in the lower right of this image.
Chordoid glioma. Axial MRI from a tumour in a 67-year-old man shows the typical imaging features of chordoid glioma, including sharp circumscription, large size, contrast enhancement, and compression of nearby structures.
Chordoid glioma. Sagittal MRI from a chordoid glioma in a 67-year-old man shows the tumour located in the anterior third ventricle. Note the lack of involvement of the pituitary gland, lateral ventricle, and corpus callosum.
Chordoid glioma. Strong diffuse cytoplasmic immunostaining for CD34 is typically seen in chordoid glioma.
Chordoid glioma. The lymphoplasmacytic infiltrates in these tumours can have plasma cells containing eosinophilic small globular Russell bodies.
Chordoid glioma. The demarcation between the tumour and adjacent brain tissue is often sharp; individual cell infiltration is not seen. The adjacent brain tissue in this example shows chronic inflammation and numerous Rosenthal fibres.
Chordoid glioma. Chordoid glioma demonstrating a dense rim of lymphoplasmacytic inflammation at the periphery of the tumour.
Chordoid glioma. This chordoid glioma is composed of bipolar spindled cells in a prominent myxoid stroma.
Chordoid glioma. This chordoid glioma is composed of plump epithelioid cells in a prominent myxoid stroma.
Chordoid glioma. Typical histological appearance of a chordoid glioma composed of cords and clusters of epithelioid tumour cells in a myxoid stroma, resembling the notochordal tumour chordoma.
Chordoid glioma. Nuclear positivity for thyroid transcription factor 1 (TTF1, a homeobox transcription factor encoded by the gene NKX2-1) is typical of chordoid gliomas.

Q: Histologically, Chordoid glioma often exhibits a sharp border with adjacent brain tissue and a prominent peripheral rim of [...] inflammation, which may contain eosinophilic Russell bodies.
Chordoid glioma. The lymphoplasmacytic infiltrates in these tumours can have plasma cells containing eosinophilic small globular Russell bodies.
Chordoid glioma. The demarcation between the tumour and adjacent brain tissue is often sharp; individual cell infiltration is not seen. The adjacent brain tissue in this example shows chronic inflammation and numerous Rosenthal fibres.
Chordoid glioma. Chordoid glioma demonstrating a dense rim of lymphoplasmacytic inflammation at the periphery of the tumour.
A: lymphoplasmacytic
Back Extra: Chordoid glioma
- Clinical: Chordoid gliomas are rare (< 0.1% of primary brain tumours), typically presenting in adults (median age 45 years) with a 2:1 female predominance. Clinical features include symptoms of obstructive hydrocephalus (headache,…
- Micro: Chordoid gliomas are well-demarcated, solid neoplasms. Architecture typically consists of clusters and cords of epithelioid cells within a variably mucinous (myxoid) stroma. Three variants are described: a solid pattern …
- Cyto: Not clinically relevant for this entity.
- Ancillary: Immunohistochemistry (IHC): - Positive: GFAP (strong, diffuse), TTF1 (NKX2-1; nuclear positivity is consistent), CD34 (strong, diffuse), Vimentin, and S100/EMA (variable). - Negative: Neuronal and neuroendocr…
Reference Gallery:
Chordoid glioma. All tumours show diffuse cytoplasmic immunoreactivity for GFAP, as shown here. Note the lymphoplasmacytic infiltrates that are GFAP-immunonegative, shown in the lower right of this image.
Chordoid glioma. Axial MRI from a tumour in a 67-year-old man shows the typical imaging features of chordoid glioma, including sharp circumscription, large size, contrast enhancement, and compression of nearby structures.
Chordoid glioma. Sagittal MRI from a chordoid glioma in a 67-year-old man shows the tumour located in the anterior third ventricle. Note the lack of involvement of the pituitary gland, lateral ventricle, and corpus callosum.
Chordoid glioma. Strong diffuse cytoplasmic immunostaining for CD34 is typically seen in chordoid glioma.
Chordoid glioma. The lymphoplasmacytic infiltrates in these tumours can have plasma cells containing eosinophilic small globular Russell bodies.
Chordoid glioma. The demarcation between the tumour and adjacent brain tissue is often sharp; individual cell infiltration is not seen. The adjacent brain tissue in this example shows chronic inflammation and numerous Rosenthal fibres.
Chordoid glioma. Chordoid glioma demonstrating a dense rim of lymphoplasmacytic inflammation at the periphery of the tumour.
Chordoid glioma. This chordoid glioma is composed of bipolar spindled cells in a prominent myxoid stroma.
Chordoid glioma. This chordoid glioma is composed of plump epithelioid cells in a prominent myxoid stroma.
Chordoid glioma. Typical histological appearance of a chordoid glioma composed of cords and clusters of epithelioid tumour cells in a myxoid stroma, resembling the notochordal tumour chordoma.
Chordoid glioma. Nuclear positivity for thyroid transcription factor 1 (TTF1, a homeobox transcription factor encoded by the gene NKX2-1) is typical of chordoid gliomas.

Q: High-grade astrocytoma with piloid features demonstrates a wide range of morphologies, with a subset showing a mainly piloid appearance that can contain numerous eosinophilic [...].
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 40% of cases have a mainly piloid morphology, sometimes with numerous Rosenthal fibres.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 45% of cases show a mainly glioblastoma-like morphology.
A: Rosenthal fibers
Back Extra: High-grade astrocytoma with piloid features
- Clinical: HGAP occurs throughout the entire CNS but most frequently originates in the posterior fossa (cerebellum, 74%). It primarily affects adults (median age 40 years) and is very rare in the pediatric population. Clinically, i…
- Micro: The histological appearance is variable and not sufficient for diagnosis without molecular testing. Features include: - Architecture: Moderately cell-dense and moderately pleomorphic astrocytic glioma. Growth patter…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): - ATRX: Nuclear loss of expression in tumour cells (approx. 40% of cases). - IDH1 p.R132H: Negative. - H3 p.K28M (K27M): Very rare cases show expression, though their classific…
Reference Gallery:
High-grade astrocytoma with piloid features. T2-weighted MRI shows a hyperintense lesion without sharp tumour margins in the dorsal pons and right cerebellar peduncle.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 40% of cases have a mainly piloid morphology, sometimes with numerous Rosenthal fibres.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 45% of cases show a mainly glioblastoma-like morphology.
High-grade astrocytoma with piloid features. ATRX immunohistochemistry of the same case as in Fig. <<#22363>>, with nuclear ATRX loss in tumour cells but retained staining in pre-existent cells.
High-grade astrocytoma with piloid features. The DNA copy-number profile of this case shows, among other changes, several chromosomal alterations that recurrently occur in this tumour type: homozygous deletion of CDKN2A and/or CDKN2B (observed in close to 80%), partial gain of 12q and 17q (each in ∼30%), and 1p loss (in ∼20%).
High-grade astrocytoma with piloid features (HGAP) is defined by a specific DNA methylation profile. t-distributed stochastic neighbour embedding (t-SNE) of DNA methylation data of HGAP and several relevant differential diagnoses. HGAP forms a distinct molecular group.
High-grade astrocytoma with piloid features. FET PET indicates highly increased amino acid metabolism in the tumour.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 10% of cases have features reminiscent of pleomorphic xanthoastrocytoma.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. Tumours may rarely resemble epithelioid glioblastoma.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the granular layer of the cerebellar cortex.
High-grade astrocytoma with piloid features. Sparse infiltration of cerebellar white matter. Note the single pleomorphic cells.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the pons, with residual pigmented neurons of the locus coeruleus.

Q: In High-grade astrocytoma with piloid features, roughly 40% of cases exhibit a nuclear loss of expression for [...] on immunohistochemistry.
High-grade astrocytoma with piloid features. ATRX immunohistochemistry of the same case as in Fig. <<#22363>>, with nuclear ATRX loss in tumour cells but retained staining in pre-existent cells.
A: ATRX
Back Extra: High-grade astrocytoma with piloid features
- Clinical: HGAP occurs throughout the entire CNS but most frequently originates in the posterior fossa (cerebellum, 74%). It primarily affects adults (median age 40 years) and is very rare in the pediatric population. Clinically, i…
- Micro: The histological appearance is variable and not sufficient for diagnosis without molecular testing. Features include: - Architecture: Moderately cell-dense and moderately pleomorphic astrocytic glioma. Growth patter…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): - ATRX: Nuclear loss of expression in tumour cells (approx. 40% of cases). - IDH1 p.R132H: Negative. - H3 p.K28M (K27M): Very rare cases show expression, though their classific…
Reference Gallery:
High-grade astrocytoma with piloid features. T2-weighted MRI shows a hyperintense lesion without sharp tumour margins in the dorsal pons and right cerebellar peduncle.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 40% of cases have a mainly piloid morphology, sometimes with numerous Rosenthal fibres.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 45% of cases show a mainly glioblastoma-like morphology.
High-grade astrocytoma with piloid features. ATRX immunohistochemistry of the same case as in Fig. <<#22363>>, with nuclear ATRX loss in tumour cells but retained staining in pre-existent cells.
High-grade astrocytoma with piloid features. The DNA copy-number profile of this case shows, among other changes, several chromosomal alterations that recurrently occur in this tumour type: homozygous deletion of CDKN2A and/or CDKN2B (observed in close to 80%), partial gain of 12q and 17q (each in ∼30%), and 1p loss (in ∼20%).
High-grade astrocytoma with piloid features (HGAP) is defined by a specific DNA methylation profile. t-distributed stochastic neighbour embedding (t-SNE) of DNA methylation data of HGAP and several relevant differential diagnoses. HGAP forms a distinct molecular group.
High-grade astrocytoma with piloid features. FET PET indicates highly increased amino acid metabolism in the tumour.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 10% of cases have features reminiscent of pleomorphic xanthoastrocytoma.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. Tumours may rarely resemble epithelioid glioblastoma.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the granular layer of the cerebellar cortex.
High-grade astrocytoma with piloid features. Sparse infiltration of cerebellar white matter. Note the single pleomorphic cells.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the pons, with residual pigmented neurons of the locus coeruleus.

Q: The DNA copy-number profile of High-grade astrocytoma with piloid features is characterized by recurrent chromosomal alterations, most notably the homozygous deletion of [...] in nearly 80% of cases.
High-grade astrocytoma with piloid features. The DNA copy-number profile of this case shows, among other changes, several chromosomal alterations that recurrently occur in this tumour type: homozygous deletion of CDKN2A and/or CDKN2B (observed in close to 80%), partial gain of 12q and 17q (each in ∼30%), and 1p loss (in ∼20%).
High-grade astrocytoma with piloid features (HGAP) is defined by a specific DNA methylation profile. t-distributed stochastic neighbour embedding (t-SNE) of DNA methylation data of HGAP and several relevant differential diagnoses. HGAP forms a distinct molecular group.
A: CDKN2A and/or CDKN2B
Back Extra: High-grade astrocytoma with piloid features
- Clinical: HGAP occurs throughout the entire CNS but most frequently originates in the posterior fossa (cerebellum, 74%). It primarily affects adults (median age 40 years) and is very rare in the pediatric population. Clinically, i…
- Micro: The histological appearance is variable and not sufficient for diagnosis without molecular testing. Features include: - Architecture: Moderately cell-dense and moderately pleomorphic astrocytic glioma. Growth patter…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): - ATRX: Nuclear loss of expression in tumour cells (approx. 40% of cases). - IDH1 p.R132H: Negative. - H3 p.K28M (K27M): Very rare cases show expression, though their classific…
Reference Gallery:
High-grade astrocytoma with piloid features. T2-weighted MRI shows a hyperintense lesion without sharp tumour margins in the dorsal pons and right cerebellar peduncle.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 40% of cases have a mainly piloid morphology, sometimes with numerous Rosenthal fibres.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 45% of cases show a mainly glioblastoma-like morphology.
High-grade astrocytoma with piloid features. ATRX immunohistochemistry of the same case as in Fig. <<#22363>>, with nuclear ATRX loss in tumour cells but retained staining in pre-existent cells.
High-grade astrocytoma with piloid features. The DNA copy-number profile of this case shows, among other changes, several chromosomal alterations that recurrently occur in this tumour type: homozygous deletion of CDKN2A and/or CDKN2B (observed in close to 80%), partial gain of 12q and 17q (each in ∼30%), and 1p loss (in ∼20%).
High-grade astrocytoma with piloid features (HGAP) is defined by a specific DNA methylation profile. t-distributed stochastic neighbour embedding (t-SNE) of DNA methylation data of HGAP and several relevant differential diagnoses. HGAP forms a distinct molecular group.
High-grade astrocytoma with piloid features. FET PET indicates highly increased amino acid metabolism in the tumour.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. About 10% of cases have features reminiscent of pleomorphic xanthoastrocytoma.
High-grade astrocytoma with piloid features. This tumour type has a wide range of morphologies. Tumours may rarely resemble epithelioid glioblastoma.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the granular layer of the cerebellar cortex.
High-grade astrocytoma with piloid features. Sparse infiltration of cerebellar white matter. Note the single pleomorphic cells.
High-grade astrocytoma with piloid features. Diffuse infiltration of the tumour into the pons, with residual pigmented neurons of the locus coeruleus.

Q: Histologically, Pilocytic astrocytoma demonstrates a biphasic pattern with compact areas containing strongly eosinophilic Rosenthal fibers and loose myxoid areas containing eosinophilic [...].
Pilocytic astrocytoma. Typical biphasic appearance of pilocytic astrocytoma. Compact areas that often harbour Rosenthal fibres alternate with loose and somewhat myxoid regions.
Pilocytic astrocytoma. Rosenthal fibres and eosinophilic granular bodies. Typically, Rosenthal fibres are more abundant than eosinophilic granular bodies in pilocytic astrocytomas, but both can be observed, as in this case.
A: granular bodies
Q: Pilocytic astrocytoma
- Clinical: Most common childhood glioma (CNS WHO grade 1), classically presenting as a cystic lesion with an enhancing mural nodule in the cerebellum.
- Microscopic: Characterized by a biphasic pattern of compact areas containing Rosenthal fibers and loose myxoid areas containing eosinophilic granular bodies (EGBs).
- Microscopic: Diagnostic features include hyalinized thick-walled vessels, glomeruloid vascular proliferation (benign in this context), and multinucleated cells with a "pennies-on-a-plate" arrangement.
- Ancillary: Driven by MAPK pathway activation, most frequently via the [BRAF] gene fusion resulting from a 7q34 tandem duplication.
Reference Gallery:
Pilocytic astrocytoma. Typical biphasic appearance of pilocytic astrocytoma. Compact areas that often harbour Rosenthal fibres alternate with loose and somewhat myxoid regions.
Pilocytic astrocytoma. Hyaline vessels and Rosenthal fibres. In most pilocytic astrocytomas, vascular structures within the tumour demonstrate brisk hyalinization. Numerous Rosenthal fibres are also observed.
Pilocytic astrocytoma. Rosenthal fibres and eosinophilic granular bodies. Typically, Rosenthal fibres are more abundant than eosinophilic granular bodies in pilocytic astrocytomas, but both can be observed, as in this case.
Pilocytic astrocytoma. Pilocytic astrocytomas often harbour large cells with multiple nuclei (the pennies-on-a-plate appearance).
Pilomyxoid astrocytoma. Pilomyxoid astrocytoma in a 10-month-old boy, located in the hypothalamic region. The typical angiocentric and markedly myxoid pattern is seen throughout the tumour. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion.
Pilocytic astrocytoma. Interphase break-apart dual-colour FISH for the BRAF gene (red signal, 3′ end; green signal, 5′ end). The type of alteration to suggest fusion is duplication and splitting of the two probes.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. T2-weighted image.
Pilocytic astrocytoma. Infiltrative edge. In many pilocytic astrocytomas, infiltrative-appearing regions can be recognized. In small biopsies, these areas may evoke the impression of a diffuse astrocytoma.
Pilocytic astrocytoma. Pilocytic astrocytomas typically show strong and diffusely positive GFAP staining.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features, including increased cellularity and palisading necrosis.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features including increased mitotic activity.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion. Contrast-enhanced T1-weighted image.
A: KIAA1549

Q: Pilocytic astrocytoma often displays hyalinized thick-walled vessels, glomeruloid vascular proliferation, and characteristic multinucleated cells with a "[...]" arrangement.
Pilocytic astrocytoma. Hyaline vessels and Rosenthal fibres. In most pilocytic astrocytomas, vascular structures within the tumour demonstrate brisk hyalinization. Numerous Rosenthal fibres are also observed.
Pilocytic astrocytoma. Pilocytic astrocytomas often harbour large cells with multiple nuclei (the pennies-on-a-plate appearance).
A: pennies-on-a-plate
Q: Pilocytic astrocytoma
- Clinical: Most common childhood glioma (CNS WHO grade 1), classically presenting as a cystic lesion with an enhancing mural nodule in the cerebellum.
- Microscopic: Characterized by a biphasic pattern of compact areas containing Rosenthal fibers and loose myxoid areas containing eosinophilic granular bodies (EGBs).
- Microscopic: Diagnostic features include hyalinized thick-walled vessels, glomeruloid vascular proliferation (benign in this context), and multinucleated cells with a "pennies-on-a-plate" arrangement.
- Ancillary: Driven by MAPK pathway activation, most frequently via the [BRAF] gene fusion resulting from a 7q34 tandem duplication.
Reference Gallery:
Pilocytic astrocytoma. Typical biphasic appearance of pilocytic astrocytoma. Compact areas that often harbour Rosenthal fibres alternate with loose and somewhat myxoid regions.
Pilocytic astrocytoma. Hyaline vessels and Rosenthal fibres. In most pilocytic astrocytomas, vascular structures within the tumour demonstrate brisk hyalinization. Numerous Rosenthal fibres are also observed.
Pilocytic astrocytoma. Rosenthal fibres and eosinophilic granular bodies. Typically, Rosenthal fibres are more abundant than eosinophilic granular bodies in pilocytic astrocytomas, but both can be observed, as in this case.
Pilocytic astrocytoma. Pilocytic astrocytomas often harbour large cells with multiple nuclei (the pennies-on-a-plate appearance).
Pilomyxoid astrocytoma. Pilomyxoid astrocytoma in a 10-month-old boy, located in the hypothalamic region. The typical angiocentric and markedly myxoid pattern is seen throughout the tumour. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion.
Pilocytic astrocytoma. Interphase break-apart dual-colour FISH for the BRAF gene (red signal, 3′ end; green signal, 5′ end). The type of alteration to suggest fusion is duplication and splitting of the two probes.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. T2-weighted image.
Pilocytic astrocytoma. Infiltrative edge. In many pilocytic astrocytomas, infiltrative-appearing regions can be recognized. In small biopsies, these areas may evoke the impression of a diffuse astrocytoma.
Pilocytic astrocytoma. Pilocytic astrocytomas typically show strong and diffusely positive GFAP staining.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features, including increased cellularity and palisading necrosis.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features including increased mitotic activity.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion. Contrast-enhanced T1-weighted image.
A: KIAA1549

Q: Molecularly, Pilocytic astrocytoma is classically driven by MAPK pathway activation, most frequently due to a [BRAF] gene fusion resulting from a tandem duplication at 7q34.
Pilocytic astrocytoma. Typical biphasic appearance of pilocytic astrocytoma. Compact areas that often harbour Rosenthal fibres alternate with loose and somewhat myxoid regions.
Pilocytic astrocytoma. Interphase break-apart dual-colour FISH for the BRAF gene (red signal, 3′ end; green signal, 5′ end). The type of alteration to suggest fusion is duplication and splitting of the two probes.
A: KIAA1549
Q: Pilocytic astrocytoma
- Clinical: Most common childhood glioma (CNS WHO grade 1), classically presenting as a cystic lesion with an enhancing mural nodule in the cerebellum.
- Microscopic: Characterized by a biphasic pattern of compact areas containing Rosenthal fibers and loose myxoid areas containing eosinophilic granular bodies (EGBs).
- Microscopic: Diagnostic features include hyalinized thick-walled vessels, glomeruloid vascular proliferation (benign in this context), and multinucleated cells with a "pennies-on-a-plate" arrangement.
- Ancillary: Driven by MAPK pathway activation, most frequently via the [BRAF] gene fusion resulting from a 7q34 tandem duplication.
Reference Gallery:
Pilocytic astrocytoma. Typical biphasic appearance of pilocytic astrocytoma. Compact areas that often harbour Rosenthal fibres alternate with loose and somewhat myxoid regions.
Pilocytic astrocytoma. Hyaline vessels and Rosenthal fibres. In most pilocytic astrocytomas, vascular structures within the tumour demonstrate brisk hyalinization. Numerous Rosenthal fibres are also observed.
Pilocytic astrocytoma. Rosenthal fibres and eosinophilic granular bodies. Typically, Rosenthal fibres are more abundant than eosinophilic granular bodies in pilocytic astrocytomas, but both can be observed, as in this case.
Pilocytic astrocytoma. Pilocytic astrocytomas often harbour large cells with multiple nuclei (the pennies-on-a-plate appearance).
Pilomyxoid astrocytoma. Pilomyxoid astrocytoma in a 10-month-old boy, located in the hypothalamic region. The typical angiocentric and markedly myxoid pattern is seen throughout the tumour. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion.
Pilocytic astrocytoma. Interphase break-apart dual-colour FISH for the BRAF gene (red signal, 3′ end; green signal, 5′ end). The type of alteration to suggest fusion is duplication and splitting of the two probes.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. T2-weighted image.
Pilocytic astrocytoma. Infiltrative edge. In many pilocytic astrocytomas, infiltrative-appearing regions can be recognized. In small biopsies, these areas may evoke the impression of a diffuse astrocytoma.
Pilocytic astrocytoma. Pilocytic astrocytomas typically show strong and diffusely positive GFAP staining.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features, including increased cellularity and palisading necrosis.
Pilocytic astrocytoma with anaplastic features. Region of tumour with anaplastic features including increased mitotic activity.
Pilocytic astrocytoma. Typical MRI appearance of pilocytic astrocytoma in the posterior fossa of a 5-year-old boy, showing a large cystic lesion with an enhancing mural nodule. The tumour has BRAF kinase domain duplication with KIAA1549::BRAF gene fusion. Contrast-enhanced T1-weighted image.
A: KIAA1549

Q: Histologically, Pleomorphic xanthoastrocytoma is characterized by markedly pleomorphic cells, lipid-laden (xanthomatous) cells, and numerous characteristic proteinaceous structures known as eosinophilic [...].
Pleomorphic xanthoastrocytoma, classic histology. Tumour cells show marked cytoplasmic and nuclear pleomorphism with frequent intensely eosinophilic granular bodies (arrow).
Pleomorphic xanthoastrocytoma, classic histology. There are frequent pale granular bodies (arrow) and cytoplasmic vacuolation with xanthomatous cells.
A: granular bodies
Q: Pleomorphic xanthoastrocytoma
- Clinical: Typically presents in children and young adults (median age 20.5) with a long history of seizures; most common in the temporal lobe as a cystic mass with an enhancing mural nodule.
- Microscopic: Characterized by a solid growth of pleomorphic/multinucleated astrocytes, spindle cells, and lipidized (xanthomatous) cells, along with characteristic eosinophilic granular bodies (EGBs).
- Grading: CNS WHO grade 2 or 3; grade 3 (anaplastic) is defined by a mitotic threshold of ≥ [...] mitoses/mm².
- Ancillary: Molecular hallmarks include the BRAF p.V600E mutation (60–80%) and the near-defining homozygous deletion of [...].
- IHC: Usually positive for S100, GFAP (focal/diffuse), and frequently CD34; focal expression of neuronal markers (e.g., synaptophysin) is common.
Reference Gallery:
Pleomorphic xanthoastrocytoma. T1-weighted postcontrast MRI of a CNS WHO grade 2 tumour forming a right temporal superficial enhancing nodule with a small cystic component and scalloping of the bone.
Pleomorphic xanthoastrocytoma, classic histology. Pleomorphic xanthoastrocytoma is a cellular tumour with marked cellular pleomorphism that is apparent even at low power.
Pleomorphic xanthoastrocytoma, classic histology. Tumour cells show marked cytoplasmic and nuclear pleomorphism with frequent intensely eosinophilic granular bodies (arrow).
Pleomorphic xanthoastrocytoma, classic histology. There are frequent pale granular bodies (arrow) and cytoplasmic vacuolation with xanthomatous cells.
Pleomorphic xanthoastrocytoma, classic histology. Perivascular lymphocytic cuffing is common.
Pleomorphic xanthoastrocytoma, spindle cell histology. Some tumours have a predominant cellular and spindle appearance with relative monomorphism.
Pleomorphic xanthoastrocytoma. CNS WHO grade 3. This tumour shows classic features, with pleomorphic and xanthomatous cells and brisk mitotic activity (arrows).
Pleomorphic xanthoastrocytoma. Reticulin deposition is present in approximately 60% of cases.
Pleomorphic xanthoastrocytoma. BRAF p.V600E mutation can be detected by immunostaining.
Pleomorphic xanthoastrocytoma. CD34 positivity is frequent but variable.
Pleomorphic xanthoastrocytoma. Neuronal markers are often expressed, in particular synaptophysin, shown here in a large pleomorphic and vacuolated tumour cell.
Pleomorphic xanthoastrocytoma. Chromosomal microarray demonstrating homozygous deletion of CDKN2A and/or CDKN2B.
A: 2.5; CDKN2A/B

Q: The major molecular hallmarks of Pleomorphic xanthoastrocytoma include the BRAF p.V600E mutation (present in 60–80% of cases) and the near-defining homozygous deletion of [...].
Pleomorphic xanthoastrocytoma, classic histology. Pleomorphic xanthoastrocytoma is a cellular tumour with marked cellular pleomorphism that is apparent even at low power.
Pleomorphic xanthoastrocytoma. BRAF p.V600E mutation can be detected by immunostaining.
Pleomorphic xanthoastrocytoma. Chromosomal microarray demonstrating homozygous deletion of CDKN2A and/or CDKN2B.
A: CDKN2A/B
Q: Pleomorphic xanthoastrocytoma
- Clinical: Typically presents in children and young adults (median age 20.5) with a long history of seizures; most common in the temporal lobe as a cystic mass with an enhancing mural nodule.
- Microscopic: Characterized by a solid growth of pleomorphic/multinucleated astrocytes, spindle cells, and lipidized (xanthomatous) cells, along with characteristic eosinophilic granular bodies (EGBs).
- Grading: CNS WHO grade 2 or 3; grade 3 (anaplastic) is defined by a mitotic threshold of ≥ [...] mitoses/mm².
- Ancillary: Molecular hallmarks include the BRAF p.V600E mutation (60–80%) and the near-defining homozygous deletion of [...].
- IHC: Usually positive for S100, GFAP (focal/diffuse), and frequently CD34; focal expression of neuronal markers (e.g., synaptophysin) is common.
Reference Gallery:
Pleomorphic xanthoastrocytoma. T1-weighted postcontrast MRI of a CNS WHO grade 2 tumour forming a right temporal superficial enhancing nodule with a small cystic component and scalloping of the bone.
Pleomorphic xanthoastrocytoma, classic histology. Pleomorphic xanthoastrocytoma is a cellular tumour with marked cellular pleomorphism that is apparent even at low power.
Pleomorphic xanthoastrocytoma, classic histology. Tumour cells show marked cytoplasmic and nuclear pleomorphism with frequent intensely eosinophilic granular bodies (arrow).
Pleomorphic xanthoastrocytoma, classic histology. There are frequent pale granular bodies (arrow) and cytoplasmic vacuolation with xanthomatous cells.
Pleomorphic xanthoastrocytoma, classic histology. Perivascular lymphocytic cuffing is common.
Pleomorphic xanthoastrocytoma, spindle cell histology. Some tumours have a predominant cellular and spindle appearance with relative monomorphism.
Pleomorphic xanthoastrocytoma. CNS WHO grade 3. This tumour shows classic features, with pleomorphic and xanthomatous cells and brisk mitotic activity (arrows).
Pleomorphic xanthoastrocytoma. Reticulin deposition is present in approximately 60% of cases.
Pleomorphic xanthoastrocytoma. BRAF p.V600E mutation can be detected by immunostaining.
Pleomorphic xanthoastrocytoma. CD34 positivity is frequent but variable.
Pleomorphic xanthoastrocytoma. Neuronal markers are often expressed, in particular synaptophysin, shown here in a large pleomorphic and vacuolated tumour cell.
Pleomorphic xanthoastrocytoma. Chromosomal microarray demonstrating homozygous deletion of CDKN2A and/or CDKN2B.
A: 2.5; CDKN2A/B

Q: Unlike many other astrocytic tumors, Pleomorphic xanthoastrocytoma frequently demonstrates immunohistochemical positivity for the progenitor and vascular marker [...], in addition to typical glial markers like GFAP and S100.
Pleomorphic xanthoastrocytoma, classic histology. Pleomorphic xanthoastrocytoma is a cellular tumour with marked cellular pleomorphism that is apparent even at low power.
Pleomorphic xanthoastrocytoma. CD34 positivity is frequent but variable.
A: CD34
Q: Pleomorphic xanthoastrocytoma
- Clinical: Typically presents in children and young adults (median age 20.5) with a long history of seizures; most common in the temporal lobe as a cystic mass with an enhancing mural nodule.
- Microscopic: Characterized by a solid growth of pleomorphic/multinucleated astrocytes, spindle cells, and lipidized (xanthomatous) cells, along with characteristic eosinophilic granular bodies (EGBs).
- Grading: CNS WHO grade 2 or 3; grade 3 (anaplastic) is defined by a mitotic threshold of ≥ [...] mitoses/mm².
- Ancillary: Molecular hallmarks include the BRAF p.V600E mutation (60–80%) and the near-defining homozygous deletion of [...].
- IHC: Usually positive for S100, GFAP (focal/diffuse), and frequently CD34; focal expression of neuronal markers (e.g., synaptophysin) is common.
Reference Gallery:
Pleomorphic xanthoastrocytoma. T1-weighted postcontrast MRI of a CNS WHO grade 2 tumour forming a right temporal superficial enhancing nodule with a small cystic component and scalloping of the bone.
Pleomorphic xanthoastrocytoma, classic histology. Pleomorphic xanthoastrocytoma is a cellular tumour with marked cellular pleomorphism that is apparent even at low power.
Pleomorphic xanthoastrocytoma, classic histology. Tumour cells show marked cytoplasmic and nuclear pleomorphism with frequent intensely eosinophilic granular bodies (arrow).
Pleomorphic xanthoastrocytoma, classic histology. There are frequent pale granular bodies (arrow) and cytoplasmic vacuolation with xanthomatous cells.
Pleomorphic xanthoastrocytoma, classic histology. Perivascular lymphocytic cuffing is common.
Pleomorphic xanthoastrocytoma, spindle cell histology. Some tumours have a predominant cellular and spindle appearance with relative monomorphism.
Pleomorphic xanthoastrocytoma. CNS WHO grade 3. This tumour shows classic features, with pleomorphic and xanthomatous cells and brisk mitotic activity (arrows).
Pleomorphic xanthoastrocytoma. Reticulin deposition is present in approximately 60% of cases.
Pleomorphic xanthoastrocytoma. BRAF p.V600E mutation can be detected by immunostaining.
Pleomorphic xanthoastrocytoma. CD34 positivity is frequent but variable.
Pleomorphic xanthoastrocytoma. Neuronal markers are often expressed, in particular synaptophysin, shown here in a large pleomorphic and vacuolated tumour cell.
Pleomorphic xanthoastrocytoma. Chromosomal microarray demonstrating homozygous deletion of CDKN2A and/or CDKN2B.
A: 2.5; CDKN2A/B

Q: Composed of large cells with voluminous, glassy cytoplasm and ganglioid features, the classically enhancing tumor arising near the foramen of Monro is the [...].
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI showing a right subependymal giant cell astrocytoma near the foramen of Monro, with avid enhancement.
Subependymal giant cell astrocytoma. Large cells with voluminous cytoplasm and well-delineated borders may be present.
Subependymal giant cell astrocytoma. Elongated cytoplasmic profiles and a more ganglioid appearance may be a feature.
A: Subependymal giant cell astrocytoma
Back Extra: Subependymal giant cell astrocytoma
- Clinical: Most patients present with symptoms of increased intracranial pressure due to obstructive hydrocephalus caused by tumour growth at the foramen of Monro. Spontaneous massive haemorrhage may occur. The tumour is strongly a…
- Micro: SEGAs are well-circumscribed, moderately cellular tumours. They exhibit a spectrum of glial phenotypes including polygonal cells with glassy cytoplasm, small spindle cells, and gemistocyte-like cells arranged in fascicle…
- Cyto: Cytology shows diverse elements including elongated spindle-shaped cells, strap cells with thick processes, and pleomorphic binucleated or multinucleated giant cells.
- Ancillary: Immunohistochemistry (IHC): * Glial/Neuronal Markers: Uniform and intense S100 immunoreactivity; variable GFAP expression. Neuronal markers like class III β-tubulin (widespread), synaptophysin (variable), NeuN (v…
Reference Gallery:
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI showing a right subependymal giant cell astrocytoma near the foramen of Monro, with avid enhancement.
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI of the case in <<#16748>>Fig. #16748 after 3 months of treatment with an mTOR inhibitor. The tumour shows decreased size and enhancement.
Subependymal giant cell astrocytoma. Class III β-tubulin (as recognized by TUJ1) is the most ubiquitous neuronal marker in these tumours.
Subependymal giant cell astrocytoma. Large cells with voluminous cytoplasm and well-delineated borders may be present.
Subependymal giant cell astrocytoma. Elongated cytoplasmic profiles and a more ganglioid appearance may be a feature.
Subependymal giant cell astrocytoma. Tumours uniformly express S100.
Subependymal giant cell astrocytoma. GFAP expression is more variable than S100, and absent in individual cells, but it is usually present at least focally.
Subependymal giant cell astrocytoma. Markers of neuronal differentiation, including synaptophysin, are frequently positive in these tumours.
Subependymal giant cell astrocytoma. Mitotic activity does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of microvascular proliferation does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of necrosis (even if palisading) does not change the CNS WHO grade 1 designation.

Q: Despite potentially displaying alarming histologic features like mitotic activity, microvascular proliferation, and palisading necrosis, [...] always remains designated as a CNS WHO grade 1 tumor.
Subependymal giant cell astrocytoma. Mitotic activity does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of microvascular proliferation does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of necrosis (even if palisading) does not change the CNS WHO grade 1 designation.
A: Subependymal giant cell astrocytoma
Back Extra: Subependymal giant cell astrocytoma
- Clinical: Most patients present with symptoms of increased intracranial pressure due to obstructive hydrocephalus caused by tumour growth at the foramen of Monro. Spontaneous massive haemorrhage may occur. The tumour is strongly a…
- Micro: SEGAs are well-circumscribed, moderately cellular tumours. They exhibit a spectrum of glial phenotypes including polygonal cells with glassy cytoplasm, small spindle cells, and gemistocyte-like cells arranged in fascicle…
- Cyto: Cytology shows diverse elements including elongated spindle-shaped cells, strap cells with thick processes, and pleomorphic binucleated or multinucleated giant cells.
- Ancillary: Immunohistochemistry (IHC): * Glial/Neuronal Markers: Uniform and intense S100 immunoreactivity; variable GFAP expression. Neuronal markers like class III β-tubulin (widespread), synaptophysin (variable), NeuN (v…
Reference Gallery:
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI showing a right subependymal giant cell astrocytoma near the foramen of Monro, with avid enhancement.
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI of the case in <<#16748>>Fig. #16748 after 3 months of treatment with an mTOR inhibitor. The tumour shows decreased size and enhancement.
Subependymal giant cell astrocytoma. Class III β-tubulin (as recognized by TUJ1) is the most ubiquitous neuronal marker in these tumours.
Subependymal giant cell astrocytoma. Large cells with voluminous cytoplasm and well-delineated borders may be present.
Subependymal giant cell astrocytoma. Elongated cytoplasmic profiles and a more ganglioid appearance may be a feature.
Subependymal giant cell astrocytoma. Tumours uniformly express S100.
Subependymal giant cell astrocytoma. GFAP expression is more variable than S100, and absent in individual cells, but it is usually present at least focally.
Subependymal giant cell astrocytoma. Markers of neuronal differentiation, including synaptophysin, are frequently positive in these tumours.
Subependymal giant cell astrocytoma. Mitotic activity does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of microvascular proliferation does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of necrosis (even if palisading) does not change the CNS WHO grade 1 designation.

Q: Immunohistochemistry for Subependymal giant cell astrocytoma typically shows uniform expression of S100 and ubiquitous neuronal markers like class III β-tubulin, while the expression of the classic glial marker [...] is notoriously variable or locally absent.
Subependymal giant cell astrocytoma. Class III β-tubulin (as recognized by TUJ1) is the most ubiquitous neuronal marker in these tumours.
Subependymal giant cell astrocytoma. Tumours uniformly express S100.
Subependymal giant cell astrocytoma. GFAP expression is more variable than S100, and absent in individual cells, but it is usually present at least focally.
A: GFAP
Back Extra: Subependymal giant cell astrocytoma
- Clinical: Most patients present with symptoms of increased intracranial pressure due to obstructive hydrocephalus caused by tumour growth at the foramen of Monro. Spontaneous massive haemorrhage may occur. The tumour is strongly a…
- Micro: SEGAs are well-circumscribed, moderately cellular tumours. They exhibit a spectrum of glial phenotypes including polygonal cells with glassy cytoplasm, small spindle cells, and gemistocyte-like cells arranged in fascicle…
- Cyto: Cytology shows diverse elements including elongated spindle-shaped cells, strap cells with thick processes, and pleomorphic binucleated or multinucleated giant cells.
- Ancillary: Immunohistochemistry (IHC): * Glial/Neuronal Markers: Uniform and intense S100 immunoreactivity; variable GFAP expression. Neuronal markers like class III β-tubulin (widespread), synaptophysin (variable), NeuN (v…
Reference Gallery:
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI showing a right subependymal giant cell astrocytoma near the foramen of Monro, with avid enhancement.
Subependymal giant cell astrocytoma. Postcontrast axial T1-weighted MRI of the case in <<#16748>>Fig. #16748 after 3 months of treatment with an mTOR inhibitor. The tumour shows decreased size and enhancement.
Subependymal giant cell astrocytoma. Class III β-tubulin (as recognized by TUJ1) is the most ubiquitous neuronal marker in these tumours.
Subependymal giant cell astrocytoma. Large cells with voluminous cytoplasm and well-delineated borders may be present.
Subependymal giant cell astrocytoma. Elongated cytoplasmic profiles and a more ganglioid appearance may be a feature.
Subependymal giant cell astrocytoma. Tumours uniformly express S100.
Subependymal giant cell astrocytoma. GFAP expression is more variable than S100, and absent in individual cells, but it is usually present at least focally.
Subependymal giant cell astrocytoma. Markers of neuronal differentiation, including synaptophysin, are frequently positive in these tumours.
Subependymal giant cell astrocytoma. Mitotic activity does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of microvascular proliferation does not change the CNS WHO grade 1 designation.
Subependymal giant cell astrocytoma. The rare presence of necrosis (even if palisading) does not change the CNS WHO grade 1 designation.

Q: The defining histological feature required for the diagnosis of Atypical choroid plexus papilloma is a mitotic count of [...] (equating to ≥ 2 mitoses/10 HPF) in a tumor otherwise resembling a standard choroid plexus papilloma.
Atypical choroid plexus papilloma. Increased mitotic activity in an otherwise well-differentiated papillary tumour.
A: ≥ 1 mitosis/mm²
Back Extra: Atypical choroid plexus papilloma
- Clinical: Patients typically present with symptoms of hydrocephalus and raised intracranial pressure resulting from the blockage of cerebrospinal fluid pathways. While choroid plexus papillomas (CNS WHO grade 1) occur in supratent…
- Micro: The defining feature is increased mitotic activity within a tumour otherwise resembling a choroid plexus papilloma. A mitotic count of ≥ 1 mitosis/mm² (equating to ≥ 2 mitoses/10 HPF of 0.23 mm²) is required for diagnosi…
- Cyto: Cytological features are similar to those of choroid plexus papillomas (CNS WHO grade 1).
- Ancillary: 1) Immunohistochemistry (IHC): Expression: Similar to choroid plexus papilloma (S100, transthyretin, and CD44 are expressed, but not helpful for grading). Ki-67: The median Ki-67 index is 9.1%. 2) …
Reference Gallery:
Atypical choroid plexus papilloma. Increased mitotic activity in an otherwise well-differentiated papillary tumour.
Atypical choroid plexus papilloma. Increased proliferative activity (Ki-67 immunohistochemistry).

Q: In Atypical choroid plexus papilloma, assessing the increased proliferative activity with a [...] immunostain often reveals an elevated labeling index (median ~9.1%) compared to grade 1 tumors.
Atypical choroid plexus papilloma. Increased mitotic activity in an otherwise well-differentiated papillary tumour.
Atypical choroid plexus papilloma. Increased proliferative activity (Ki-67 immunohistochemistry).
A: Ki-67
Back Extra: Atypical choroid plexus papilloma
- Clinical: Patients typically present with symptoms of hydrocephalus and raised intracranial pressure resulting from the blockage of cerebrospinal fluid pathways. While choroid plexus papillomas (CNS WHO grade 1) occur in supratent…
- Micro: The defining feature is increased mitotic activity within a tumour otherwise resembling a choroid plexus papilloma. A mitotic count of ≥ 1 mitosis/mm² (equating to ≥ 2 mitoses/10 HPF of 0.23 mm²) is required for diagnosi…
- Cyto: Cytological features are similar to those of choroid plexus papillomas (CNS WHO grade 1).
- Ancillary: 1) Immunohistochemistry (IHC): Expression: Similar to choroid plexus papilloma (S100, transthyretin, and CD44 are expressed, but not helpful for grading). Ki-67: The median Ki-67 index is 9.1%. 2) …
Reference Gallery:
Atypical choroid plexus papilloma. Increased mitotic activity in an otherwise well-differentiated papillary tumour.
Atypical choroid plexus papilloma. Increased proliferative activity (Ki-67 immunohistochemistry).

Q: A pediatric brain tumor showing malignant features is diagnosed as Choroid plexus carcinoma. This WHO grade 3 neoplasm is highly associated with [...] mutations, often seen in the context of Li-Fraumeni syndrome.
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
Choroid plexus carcinoma. Increased cellularity, nuclear pleomorphism, and mitotic activity.
A: TP53
Back Extra: Choroid plexus carcinoma
- Clinical: Predominantly a pediatric tumor (80% of cases) typically located in the lateral ventricles; patients often present with symptoms of hydrocephalus and increased intracranial pressure.
- Microscopic: Malignant CNS WHO grade 3 neoplasm requiring 4 of 5 features: increased cellularity, nuclear pleomorphism, blurring of papillary pattern (solid sheets), necrosis, and frequent mitoses (>5 per 10 HPF).
- Ancillary: Highly associated with TP53 mutations (50%), often in the context of Li–Fraumeni syndrome; immunohistochemistry shows positive cytokeratins but typically lacks EMA expression.
- Prognosis: Generally poor outcome with potential for CSF dissemination; prognosis is influenced by the extent of surgical resection and TP53 status.
Reference Gallery:
Choroid plexus carcinoma. A large choroid plexus carcinoma in the lateral ventricle with extensive invasion of brain tissue.
Choroid plexus carcinoma. This T1-weighted coronal MRI of a 5-year-old girl shows a contrast-enhancing tumour related to the lateral ventricle.
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
Choroid plexus carcinoma. Touch preparation shows epithelioid cells with pleomorphism.
Choroid plexus carcinoma. Increased cellularity, nuclear pleomorphism, and mitotic activity.
Choroid plexus carcinoma. Immunohistochemistry for cytokeratin is positive.
Choroid plexus carcinoma. Immunohistochemistry demonstrates a lack of expression of epithelial membrane antigen (EMA).
Choroid plexus carcinoma. Ki-67 immunohistochemical staining shows high proliferative activity.
Choroid plexus carcinoma. Immunohistochemistry for transthyretin highlights infiltration of surrounding brain tissue.

Q: Immunohistochemistry for Choroid plexus carcinoma typically shows strong positivity for cytokeratins but characteristically lacks expression of [...].
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
Choroid plexus carcinoma. Immunohistochemistry for cytokeratin is positive.
Choroid plexus carcinoma. Immunohistochemistry demonstrates a lack of expression of epithelial membrane antigen (EMA).
A: epithelial membrane antigen (EMA)
Back Extra: Choroid plexus carcinoma
- Clinical: Predominantly a pediatric tumor (80% of cases) typically located in the lateral ventricles; patients often present with symptoms of hydrocephalus and increased intracranial pressure.
- Microscopic: Malignant CNS WHO grade 3 neoplasm requiring 4 of 5 features: increased cellularity, nuclear pleomorphism, blurring of papillary pattern (solid sheets), necrosis, and frequent mitoses (>5 per 10 HPF).
- Ancillary: Highly associated with TP53 mutations (50%), often in the context of Li–Fraumeni syndrome; immunohistochemistry shows positive cytokeratins but typically lacks EMA expression.
- Prognosis: Generally poor outcome with potential for CSF dissemination; prognosis is influenced by the extent of surgical resection and TP53 status.
Reference Gallery:
Choroid plexus carcinoma. A large choroid plexus carcinoma in the lateral ventricle with extensive invasion of brain tissue.
Choroid plexus carcinoma. This T1-weighted coronal MRI of a 5-year-old girl shows a contrast-enhancing tumour related to the lateral ventricle.
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
Choroid plexus carcinoma. Touch preparation shows epithelioid cells with pleomorphism.
Choroid plexus carcinoma. Increased cellularity, nuclear pleomorphism, and mitotic activity.
Choroid plexus carcinoma. Immunohistochemistry for cytokeratin is positive.
Choroid plexus carcinoma. Immunohistochemistry demonstrates a lack of expression of epithelial membrane antigen (EMA).
Choroid plexus carcinoma. Ki-67 immunohistochemical staining shows high proliferative activity.
Choroid plexus carcinoma. Immunohistochemistry for transthyretin highlights infiltration of surrounding brain tissue.

Q: A pediatric patient with Choroid plexus carcinoma often presents with hydrocephalus due to a large, contrast-enhancing tumor characteristically located in the [...].
Choroid plexus carcinoma. This T1-weighted coronal MRI of a 5-year-old girl shows a contrast-enhancing tumour related to the lateral ventricle.
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
A: lateral ventricles
Back Extra: Choroid plexus carcinoma
- Clinical: Predominantly a pediatric tumor (80% of cases) typically located in the lateral ventricles; patients often present with symptoms of hydrocephalus and increased intracranial pressure.
- Microscopic: Malignant CNS WHO grade 3 neoplasm requiring 4 of 5 features: increased cellularity, nuclear pleomorphism, blurring of papillary pattern (solid sheets), necrosis, and frequent mitoses (>5 per 10 HPF).
- Ancillary: Highly associated with TP53 mutations (50%), often in the context of Li–Fraumeni syndrome; immunohistochemistry shows positive cytokeratins but typically lacks EMA expression.
- Prognosis: Generally poor outcome with potential for CSF dissemination; prognosis is influenced by the extent of surgical resection and TP53 status.
Reference Gallery:
Choroid plexus carcinoma. A large choroid plexus carcinoma in the lateral ventricle with extensive invasion of brain tissue.
Choroid plexus carcinoma. This T1-weighted coronal MRI of a 5-year-old girl shows a contrast-enhancing tumour related to the lateral ventricle.
Choroid plexus carcinoma. Increased cellularity, blurring of the papillary pattern, and necrosis.
Choroid plexus carcinoma. Touch preparation shows epithelioid cells with pleomorphism.
Choroid plexus carcinoma. Increased cellularity, nuclear pleomorphism, and mitotic activity.
Choroid plexus carcinoma. Immunohistochemistry for cytokeratin is positive.
Choroid plexus carcinoma. Immunohistochemistry demonstrates a lack of expression of epithelial membrane antigen (EMA).
Choroid plexus carcinoma. Ki-67 immunohistochemical staining shows high proliferative activity.
Choroid plexus carcinoma. Immunohistochemistry for transthyretin highlights infiltration of surrounding brain tissue.

Q: Microscopically, Choroid plexus papilloma is a CNS WHO grade 1 tumor characterized by fibrovascular fronds lined by a single layer of uniform, monomorphic [...] epithelium.
Choroid plexus papilloma. Papillary pattern with a single layer of monomorphic cuboidal cells.
A: cuboidal to columnar
Back Extra: Choroid plexus papilloma
- Clinical: Typically presents as a well-delineated, "cauliflower-like" intraventricular mass causing hydrocephalus; most common in lateral ventricles (children) or fourth ventricle (adults).
- Microscopic: CNS WHO grade 1 tumor characterized by fibrovascular fronds lined by a single layer of uniform, monomorphic cuboidal to columnar epithelium with minimal to no mitotic activity.
- Ancillary: Strongly positive for S100, Cytokeratins (usually CK7+/CK20-), and Kir7.1; Kir7.1 shows characteristic apical membranous staining.
- Molecular: Often hyperdiploid (e.g., gain of 9p) and associated with Aicardi syndrome; distinct methylation profiles separate it from choroid plexus carcinoma.
Reference Gallery:
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a choroid plexus papilloma in the fourth ventricle of a 38-year-old man.
Choroid plexus papilloma. Papillary pattern with a single layer of monomorphic cuboidal cells.
Choroid plexus papilloma. Immunohistochemistry for S100.
Choroid plexus papilloma. Immunohistochemistry for transthyretin (prealbumin).
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a strongly enhancing, cauliflower-like mass in the third ventricle of a 22-month-old girl.
Choroid plexus papilloma. Intraoperative endoscopic view of a choroid plexus papilloma.
Choroid plexus papilloma cells in cerebrospinal fluid. Immunohistochemistry for the potassium channel Kir7.1.
Choroid plexus papilloma. Immunohistochemistry for the potassium channel Kir7.1 shows typical membranous labelling of the apical surface of tumour cells.

Q: Immunohistochemistry for Choroid plexus papilloma characteristically shows positive apical membranous staining for the potassium channel [...].
Choroid plexus papilloma. Papillary pattern with a single layer of monomorphic cuboidal cells.
Choroid plexus papilloma. Immunohistochemistry for the potassium channel Kir7.1 shows typical membranous labelling of the apical surface of tumour cells.
A: Kir7.1
Back Extra: Choroid plexus papilloma
- Clinical: Typically presents as a well-delineated, "cauliflower-like" intraventricular mass causing hydrocephalus; most common in lateral ventricles (children) or fourth ventricle (adults).
- Microscopic: CNS WHO grade 1 tumor characterized by fibrovascular fronds lined by a single layer of uniform, monomorphic cuboidal to columnar epithelium with minimal to no mitotic activity.
- Ancillary: Strongly positive for S100, Cytokeratins (usually CK7+/CK20-), and Kir7.1; Kir7.1 shows characteristic apical membranous staining.
- Molecular: Often hyperdiploid (e.g., gain of 9p) and associated with Aicardi syndrome; distinct methylation profiles separate it from choroid plexus carcinoma.
Reference Gallery:
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a choroid plexus papilloma in the fourth ventricle of a 38-year-old man.
Choroid plexus papilloma. Papillary pattern with a single layer of monomorphic cuboidal cells.
Choroid plexus papilloma. Immunohistochemistry for S100.
Choroid plexus papilloma. Immunohistochemistry for transthyretin (prealbumin).
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a strongly enhancing, cauliflower-like mass in the third ventricle of a 22-month-old girl.
Choroid plexus papilloma. Intraoperative endoscopic view of a choroid plexus papilloma.
Choroid plexus papilloma cells in cerebrospinal fluid. Immunohistochemistry for the potassium channel Kir7.1.
Choroid plexus papilloma. Immunohistochemistry for the potassium channel Kir7.1 shows typical membranous labelling of the apical surface of tumour cells.

Q: On MRI, Choroid plexus papilloma typically presents as a well-delineated, "cauliflower-like" enhancing mass that most commonly arises in the lateral ventricles of children and the [...] of adults.
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a choroid plexus papilloma in the fourth ventricle of a 38-year-old man.
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a strongly enhancing, cauliflower-like mass in the third ventricle of a 22-month-old girl.
A: fourth ventricle
Back Extra: Choroid plexus papilloma
- Clinical: Typically presents as a well-delineated, "cauliflower-like" intraventricular mass causing hydrocephalus; most common in lateral ventricles (children) or fourth ventricle (adults).
- Microscopic: CNS WHO grade 1 tumor characterized by fibrovascular fronds lined by a single layer of uniform, monomorphic cuboidal to columnar epithelium with minimal to no mitotic activity.
- Ancillary: Strongly positive for S100, Cytokeratins (usually CK7+/CK20-), and Kir7.1; Kir7.1 shows characteristic apical membranous staining.
- Molecular: Often hyperdiploid (e.g., gain of 9p) and associated with Aicardi syndrome; distinct methylation profiles separate it from choroid plexus carcinoma.
Reference Gallery:
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a choroid plexus papilloma in the fourth ventricle of a 38-year-old man.
Choroid plexus papilloma. Papillary pattern with a single layer of monomorphic cuboidal cells.
Choroid plexus papilloma. Immunohistochemistry for S100.
Choroid plexus papilloma. Immunohistochemistry for transthyretin (prealbumin).
Choroid plexus papilloma. Sagittal, contrast-enhanced, T1-weighted MRI shows a strongly enhancing, cauliflower-like mass in the third ventricle of a 22-month-old girl.
Choroid plexus papilloma. Intraoperative endoscopic view of a choroid plexus papilloma.
Choroid plexus papilloma cells in cerebrospinal fluid. Immunohistochemistry for the potassium channel Kir7.1.
Choroid plexus papilloma. Immunohistochemistry for the potassium channel Kir7.1 shows typical membranous labelling of the apical surface of tumour cells.

Q: In a cerebral hemisphere tumor of a young adult with palisading necrosis, testing reveals a missense mutation at position G34 of the H3-3A gene. This defines the entity [...].
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
A: Diffuse hemispheric glioma, H3 G34-mutant
Back Extra: Diffuse hemispheric glioma, H3 G34-mutant
- Clinical: Typically involves the cerebral hemispheres (parietal/temporal lobes) of adolescents and young adults (median age 15–19 years).
- Microscopic: Features range from a glioblastoma-like pattern (with necrosis and microvascular proliferation) to an embryonal-like pattern with monomorphic cells.
- Genetics: Defined by a missense mutation in the H3-3A gene at position G34 (most commonly G34R), often co-occurring with TP53 and ATRX mutations.
- Ancillary: Characteristically demonstrates loss of nuclear ATRX (~95%) and lack of OLIG2 expression, which helps distinguish it from IDH-wildtype glioblastoma.
- Prognosis: Aggressive clinical course (CNS WHO grade 4) with a median overall survival of 18–22 months.
Reference Gallery:
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
Diffuse hemispheric glioma, H3 G34–mutant with variable GFAP immunoreactivity.
Diffuse hemispheric glioma, H3 G34–mutant characteristically lacking nuclear OLIG2 expression.
Diffuse hemispheric glioma, H3 G34–mutant showing nuclear accumulation of p53.
Diffuse hemispheric glioma, H3 G34–mutant demonstrating lack of nuclear ATRX expression.

Q: Immunohistochemically, Diffuse hemispheric glioma, H3 G34-mutant characteristically demonstrates a lack of nuclear [...] expression alongside loss of nuclear ATRX, helping distinguish it from IDH-wildtype glioblastoma.
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
Diffuse hemispheric glioma, H3 G34–mutant characteristically lacking nuclear OLIG2 expression.
Diffuse hemispheric glioma, H3 G34–mutant demonstrating lack of nuclear ATRX expression.
A: OLIG2
Back Extra: Diffuse hemispheric glioma, H3 G34-mutant
- Clinical: Typically involves the cerebral hemispheres (parietal/temporal lobes) of adolescents and young adults (median age 15–19 years).
- Microscopic: Features range from a glioblastoma-like pattern (with necrosis and microvascular proliferation) to an embryonal-like pattern with monomorphic cells.
- Genetics: Defined by a missense mutation in the H3-3A gene at position G34 (most commonly G34R), often co-occurring with TP53 and ATRX mutations.
- Ancillary: Characteristically demonstrates loss of nuclear ATRX (~95%) and lack of OLIG2 expression, which helps distinguish it from IDH-wildtype glioblastoma.
- Prognosis: Aggressive clinical course (CNS WHO grade 4) with a median overall survival of 18–22 months.
Reference Gallery:
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
Diffuse hemispheric glioma, H3 G34–mutant with variable GFAP immunoreactivity.
Diffuse hemispheric glioma, H3 G34–mutant characteristically lacking nuclear OLIG2 expression.
Diffuse hemispheric glioma, H3 G34–mutant showing nuclear accumulation of p53.
Diffuse hemispheric glioma, H3 G34–mutant demonstrating lack of nuclear ATRX expression.

Q: Diffuse hemispheric glioma, H3 G34-mutant is a high-grade tumor (CNS WHO grade 4) that frequently shows nuclear accumulation of [...] and loss of nuclear ATRX due to characteristic co-mutations.
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
Diffuse hemispheric glioma, H3 G34–mutant showing nuclear accumulation of p53.
Diffuse hemispheric glioma, H3 G34–mutant demonstrating lack of nuclear ATRX expression.
A: p53
Back Extra: Diffuse hemispheric glioma, H3 G34-mutant
- Clinical: Typically involves the cerebral hemispheres (parietal/temporal lobes) of adolescents and young adults (median age 15–19 years).
- Microscopic: Features range from a glioblastoma-like pattern (with necrosis and microvascular proliferation) to an embryonal-like pattern with monomorphic cells.
- Genetics: Defined by a missense mutation in the H3-3A gene at position G34 (most commonly G34R), often co-occurring with TP53 and ATRX mutations.
- Ancillary: Characteristically demonstrates loss of nuclear ATRX (~95%) and lack of OLIG2 expression, which helps distinguish it from IDH-wildtype glioblastoma.
- Prognosis: Aggressive clinical course (CNS WHO grade 4) with a median overall survival of 18–22 months.
Reference Gallery:
Diffuse hemispheric glioma, H3 G34–mutant showing palisading necrosis.
Diffuse hemispheric glioma, H3 G34–mutant with variable GFAP immunoreactivity.
Diffuse hemispheric glioma, H3 G34–mutant characteristically lacking nuclear OLIG2 expression.
Diffuse hemispheric glioma, H3 G34–mutant showing nuclear accumulation of p53.
Diffuse hemispheric glioma, H3 G34–mutant demonstrating lack of nuclear ATRX expression.

Q: In Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, the [...] molecular subtype frequently demonstrates a primitive, highly cellular embryonal-like morphology and tends to form circumscribed nodules.
Highly cellular tumor showing an embryonal morphology and sharp demarcation from brain tissue, characteristic of the MYCN subtype.
The tumor may exhibit a prominent embryonal appearance alongside more conventional glial areas.
A: MYCN
Q: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
- Definition: A CNS WHO grade 4 diffuse glioma occurring primarily in children and young adults, defined by the absence of histone H3 and IDH1/2 mutations.
- Histopathology: Typically shows glioblastoma-like features (necrosis, vascular proliferation) or a primitive, highly cellular embryonal-like morphology; the MYCN subtype often demonstrates circumscribed nodules.
- Molecular Subgroups: Three main subtypes are identified via DNA methylation profiling: RTK1 (often PDGFRA-amplified), RTK2 (often EGFR-amplified), and MYCN (MYCN-amplified).
- Ancillary Testing: H3K27me3 nuclear expression is [...] (unlike H3 K27-altered diffuse midline gliomas), and tumors lack the +7/-10 chromosomal pattern typical of adult-type glioblastoma.
- Clinical Associations: The RTK1 subtype is frequently associated with germline mismatch repair deficiencies (CMMRD) or Lynch syndrome (MSH2/MSH6/MLH1/PMS2 loss).
Reference Gallery:
Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype. Axial T1-weighted MRI demonstrating a well-circumscribed lesion in the left insular/temporal region with relatively homogeneous contrast enhancement.
Highly cellular tumor showing an embryonal morphology and sharp demarcation from brain tissue, characteristic of the MYCN subtype.
The tumor may exhibit a prominent embryonal appearance alongside more conventional glial areas.
In the MYCN subtype, GFAP expression may be limited to only scattered cells.
RTK1 subtype showing pleomorphic giant cells in a child with Lynch syndrome (MSH2/MSH6 loss).
Radiation-induced RTK1 subtype demonstrating extensive myxoid change.
DNA methylation-derived copy-number profile showing MYCN amplification; note the absence of the adult-type +7/−10 pattern.
A: retained

Q: The RTK1 subtype of Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (which often features pleomorphic giant cells) is frequently associated with germline [...] (e.g., Lynch syndrome).
RTK1 subtype showing pleomorphic giant cells in a child with Lynch syndrome (MSH2/MSH6 loss).
A: mismatch repair deficiencies
Q: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
- Definition: A CNS WHO grade 4 diffuse glioma occurring primarily in children and young adults, defined by the absence of histone H3 and IDH1/2 mutations.
- Histopathology: Typically shows glioblastoma-like features (necrosis, vascular proliferation) or a primitive, highly cellular embryonal-like morphology; the MYCN subtype often demonstrates circumscribed nodules.
- Molecular Subgroups: Three main subtypes are identified via DNA methylation profiling: RTK1 (often PDGFRA-amplified), RTK2 (often EGFR-amplified), and MYCN (MYCN-amplified).
- Ancillary Testing: H3K27me3 nuclear expression is [...] (unlike H3 K27-altered diffuse midline gliomas), and tumors lack the +7/-10 chromosomal pattern typical of adult-type glioblastoma.
- Clinical Associations: The RTK1 subtype is frequently associated with germline mismatch repair deficiencies (CMMRD) or Lynch syndrome (MSH2/MSH6/MLH1/PMS2 loss).
Reference Gallery:
Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype. Axial T1-weighted MRI demonstrating a well-circumscribed lesion in the left insular/temporal region with relatively homogeneous contrast enhancement.
Highly cellular tumor showing an embryonal morphology and sharp demarcation from brain tissue, characteristic of the MYCN subtype.
The tumor may exhibit a prominent embryonal appearance alongside more conventional glial areas.
In the MYCN subtype, GFAP expression may be limited to only scattered cells.
RTK1 subtype showing pleomorphic giant cells in a child with Lynch syndrome (MSH2/MSH6 loss).
Radiation-induced RTK1 subtype demonstrating extensive myxoid change.
DNA methylation-derived copy-number profile showing MYCN amplification; note the absence of the adult-type +7/−10 pattern.
A: retained

Q: In the primitive MYCN subtype of Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, immunohistochemical staining for [...] is typically very limited and may only highlight scattered cells.
In the MYCN subtype, GFAP expression may be limited to only scattered cells.
A: GFAP
Q: Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
- Definition: A CNS WHO grade 4 diffuse glioma occurring primarily in children and young adults, defined by the absence of histone H3 and IDH1/2 mutations.
- Histopathology: Typically shows glioblastoma-like features (necrosis, vascular proliferation) or a primitive, highly cellular embryonal-like morphology; the MYCN subtype often demonstrates circumscribed nodules.
- Molecular Subgroups: Three main subtypes are identified via DNA methylation profiling: RTK1 (often PDGFRA-amplified), RTK2 (often EGFR-amplified), and MYCN (MYCN-amplified).
- Ancillary Testing: H3K27me3 nuclear expression is [...] (unlike H3 K27-altered diffuse midline gliomas), and tumors lack the +7/-10 chromosomal pattern typical of adult-type glioblastoma.
- Clinical Associations: The RTK1 subtype is frequently associated with germline mismatch repair deficiencies (CMMRD) or Lynch syndrome (MSH2/MSH6/MLH1/PMS2 loss).
Reference Gallery:
Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype. Axial T1-weighted MRI demonstrating a well-circumscribed lesion in the left insular/temporal region with relatively homogeneous contrast enhancement.
Highly cellular tumor showing an embryonal morphology and sharp demarcation from brain tissue, characteristic of the MYCN subtype.
The tumor may exhibit a prominent embryonal appearance alongside more conventional glial areas.
In the MYCN subtype, GFAP expression may be limited to only scattered cells.
RTK1 subtype showing pleomorphic giant cells in a child with Lynch syndrome (MSH2/MSH6 loss).
Radiation-induced RTK1 subtype demonstrating extensive myxoid change.
DNA methylation-derived copy-number profile showing MYCN amplification; note the absence of the adult-type +7/−10 pattern.
A: retained

Q: Genetically, Infant-type hemispheric glioma is defined by receptor tyrosine kinase (RTK) fusions, specifically involving the genes [...].
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
Infant-type hemispheric glioma. An infant-type hemispheric glioma with a CLIP2::MET fusion showing a cellular glioma with several clusters of more primitive-appearing cells.
A: NTRK, ALK, ROS1, or MET
Infant-type hemispheric glioma
- Clinical: Typically presents in the first year of life (median age 2.8 months) with acute symptoms and increased head circumference; despite high-grade features, the prognosis is generally better than in older children.
- Microscopic: Cellular astrocytic tumor, often well-demarcated, showing fascicles or sheets of spindle-shaped cells; high-grade features like palisading necrosis and microvascular proliferation are common.
- Genetics: Defined by receptor tyrosine kinase (RTK) fusions, specifically involving NTRK1/2/3, ALK, ROS1, or MET.
- Ancillary: Forms a distinct subgroup on DNA methylation profiling; IHC for ALK can be positive in relevant fusion cases, while NTRK IHC is unreliable due to high background expression in normal brain.
Reference Gallery:
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
Infant-type hemispheric glioma. An infant-type hemispheric glioma with a CLIP2::MET fusion showing a cellular glioma with several clusters of more primitive-appearing cells.
Infant-type hemispheric glioma. GFAP immunostaining.
Infant-type hemispheric glioma. OLIG2 immunostaining.
Infant-type hemispheric glioma. Immunostaining showing elevated Ki-67 (MIB1) proliferation index.

Q: An infant presents with a massive cerebral tumor showing high-grade histologic features, elevated Ki-67, and strong positivity for GFAP and OLIG2. Molecular testing reveals an ALK fusion. This distinct entity, which typically has a better prognosis than similar-appearing tumors in older children, is [...].
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
Infant-type hemispheric glioma. GFAP immunostaining.
Infant-type hemispheric glioma. OLIG2 immunostaining.
A: Infant-type hemispheric glioma
Infant-type hemispheric glioma
- Clinical: Typically presents in the first year of life (median age 2.8 months) with acute symptoms and increased head circumference; despite high-grade features, the prognosis is generally better than in older children.
- Microscopic: Cellular astrocytic tumor, often well-demarcated, showing fascicles or sheets of spindle-shaped cells; high-grade features like palisading necrosis and microvascular proliferation are common.
- Genetics: Defined by receptor tyrosine kinase (RTK) fusions, specifically involving NTRK1/2/3, ALK, ROS1, or MET.
- Ancillary: Forms a distinct subgroup on DNA methylation profiling; IHC for ALK can be positive in relevant fusion cases, while NTRK IHC is unreliable due to high background expression in normal brain.
Reference Gallery:
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
Infant-type hemispheric glioma. An infant-type hemispheric glioma with a CLIP2::MET fusion showing a cellular glioma with several clusters of more primitive-appearing cells.
Infant-type hemispheric glioma. GFAP immunostaining.
Infant-type hemispheric glioma. OLIG2 immunostaining.
Infant-type hemispheric glioma. Immunostaining showing elevated Ki-67 (MIB1) proliferation index.

Q: Despite a generally better prognosis than in older children, the microscopic features of Infant-type hemispheric glioma commonly include a cellular spindle-cell proliferation with high-grade features such as endothelial proliferation and [...].
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
A: palisading necrosis
Infant-type hemispheric glioma
- Clinical: Typically presents in the first year of life (median age 2.8 months) with acute symptoms and increased head circumference; despite high-grade features, the prognosis is generally better than in older children.
- Microscopic: Cellular astrocytic tumor, often well-demarcated, showing fascicles or sheets of spindle-shaped cells; high-grade features like palisading necrosis and microvascular proliferation are common.
- Genetics: Defined by receptor tyrosine kinase (RTK) fusions, specifically involving NTRK1/2/3, ALK, ROS1, or MET.
- Ancillary: Forms a distinct subgroup on DNA methylation profiling; IHC for ALK can be positive in relevant fusion cases, while NTRK IHC is unreliable due to high background expression in normal brain.
Reference Gallery:
Infant-type hemispheric glioma. An infant-type hemispheric glioma showing classic features of a high-grade glioma including palisading necrosis and endothelial proliferation.
Infant-type hemispheric glioma. An infant-type hemispheric glioma with a CLIP2::MET fusion showing a cellular glioma with several clusters of more primitive-appearing cells.
Infant-type hemispheric glioma. GFAP immunostaining.
Infant-type hemispheric glioma. OLIG2 immunostaining.
Infant-type hemispheric glioma. Immunostaining showing elevated Ki-67 (MIB1) proliferation index.

Q: A child presenting with chronic, intractable partial epilepsy is found to have a cortical lesion on MRI. Histology reveals monomorphous, bipolar spindle cells forming perivascular sleeves and rosette-like patterns. This describes an [...].
Angiocentric glioma showing a pronounced angiocentric pattern and entrapped neurons.
High-power view showing elongated cells with bipolar cytoplasmic processes.
T2-weighted MRI showing a cortical parietal lesion with minimal mass effect.
A: Angiocentric glioma
Q: Angiocentric glioma
- Clinical: Typically affects children and young adults (median age 13) presenting with chronic, intractable partial epilepsy; most common in the temporal or frontal cortex.
- Microscopic: Characterized by monomorphous, bipolar spindle cells forming perivascular sleeves or rosette-like patterns around blood vessels.
- Ancillary (IHC): Tumor cells are GFAP positive, OLIG2 negative (distinguishing it from other astrocytomas), and show characteristic "dot-like" or ring-like EMA positivity.
- Molecular: Nearly all cases harbor MYB rearrangements, most commonly the [QKI] gene fusion (~87%).
- Prognosis: CNS WHO grade 1; behavior is generally indolent with gross total resection often being curative.
Reference Gallery:
Angiocentric glioma showing a pronounced angiocentric pattern and entrapped neurons.
High-power view showing elongated cells with bipolar cytoplasmic processes.
Dot-like or ring-like immunoreactivity for EMA is characteristically present.
Angiocentric glioma with entrapped neurons within a syncytial pattern of tumor cells.
Perivascular tumor cells demonstrating GFAP immunoreactivity.
Tumor cells are predominantly OLIG2-negative, though entrapped oligodendrocytes may be positive.
NFP staining highlighting entrapped axons, illustrating the infiltrative growth pattern.
T2-weighted MRI showing a cortical parietal lesion with minimal mass effect.
A: MYB

Q: In Angiocentric glioma, tumor cells typically display a characteristic [...] pattern of EMA immunoreactivity.
Angiocentric glioma showing a pronounced angiocentric pattern and entrapped neurons.
Dot-like or ring-like immunoreactivity for EMA is characteristically present.
A: dot-like or ring-like
Q: Angiocentric glioma
- Clinical: Typically affects children and young adults (median age 13) presenting with chronic, intractable partial epilepsy; most common in the temporal or frontal cortex.
- Microscopic: Characterized by monomorphous, bipolar spindle cells forming perivascular sleeves or rosette-like patterns around blood vessels.
- Ancillary (IHC): Tumor cells are GFAP positive, OLIG2 negative (distinguishing it from other astrocytomas), and show characteristic "dot-like" or ring-like EMA positivity.
- Molecular: Nearly all cases harbor MYB rearrangements, most commonly the [QKI] gene fusion (~87%).
- Prognosis: CNS WHO grade 1; behavior is generally indolent with gross total resection often being curative.
Reference Gallery:
Angiocentric glioma showing a pronounced angiocentric pattern and entrapped neurons.
High-power view showing elongated cells with bipolar cytoplasmic processes.
Dot-like or ring-like immunoreactivity for EMA is characteristically present.
Angiocentric glioma with entrapped neurons within a syncytial pattern of tumor cells.
Perivascular tumor cells demonstrating GFAP immunoreactivity.
Tumor cells are predominantly OLIG2-negative, though entrapped oligodendrocytes may be positive.
NFP staining highlighting entrapped axons, illustrating the infiltrative growth pattern.
T2-weighted MRI showing a cortical parietal lesion with minimal mass effect.
A: MYB

Q: Nearly all cases of Angiocentric glioma harbor structural rearrangements of the MYB gene, most commonly resulting in the [QKI] gene fusion.
Angiocentric glioma with entrapped neurons within a syncytial pattern of tumor cells.
A: MYB
Q: Angiocentric glioma
- Clinical: Typically affects children and young adults (median age 13) presenting with chronic, intractable partial epilepsy; most common in the temporal or frontal cortex.
- Microscopic: Characterized by monomorphous, bipolar spindle cells forming perivascular sleeves or rosette-like patterns around blood vessels.
- Ancillary (IHC): Tumor cells are GFAP positive, OLIG2 negative (distinguishing it from other astrocytomas), and show characteristic "dot-like" or ring-like EMA positivity.
- Molecular: Nearly all cases harbor MYB rearrangements, most commonly the [QKI] gene fusion (~87%).
- Prognosis: CNS WHO grade 1; behavior is generally indolent with gross total resection often being curative.
Reference Gallery:
Angiocentric glioma showing a pronounced angiocentric pattern and entrapped neurons.
High-power view showing elongated cells with bipolar cytoplasmic processes.
Dot-like or ring-like immunoreactivity for EMA is characteristically present.
Angiocentric glioma with entrapped neurons within a syncytial pattern of tumor cells.
Perivascular tumor cells demonstrating GFAP immunoreactivity.
Tumor cells are predominantly OLIG2-negative, though entrapped oligodendrocytes may be positive.
NFP staining highlighting entrapped axons, illustrating the infiltrative growth pattern.
T2-weighted MRI showing a cortical parietal lesion with minimal mass effect.
A: MYB

Q: A pediatric low-grade glioma that frequently presents as a long-term epilepsy-associated tumor (LEAT) and characteristically shows an absence of both OLIG2 and SOX10 expression is diagnosed as [...].
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade glioma subtypes, this tumour is mostly negative for OLIG2.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade astrocytic neoplasms, this tumour is mostly negative for SOX10.
A: Diffuse astrocytoma, MYB- or MYBL1-altered
Diffuse astrocytoma, MYB- or MYBL1-altered
- Clinical: Typically presents in children and young adults (median age 10 years) with drug-resistant epilepsy; it is classified as a long-term epilepsy-associated tumour (LEAT).
- Microscopic: Characterized by a diffusely infiltrative proliferation of monomorphic glial cells with bland nuclei; often exhibits low cellularity and entrapped neurons.
- Ancillary (IHC): Tumour cells are GFAP-positive but uniquely negative for OLIG2 and SOX10, distinguishing it from many other low-grade gliomas.
- Genetics: Defined by structural rearrangements/fusions involving either the MYB or MYBL1 genes; tumors are IDH-wildtype and H3-wildtype.
Reference Gallery:
Diffuse astrocytoma, MYB- or MYBL1-altered. MRI of a MYBL1-altered diffuse astrocytoma located in the inferior frontal gyrus in a 39-year-old patient with epilepsy since the age of 3 years. The tumour (white arrow) is T1-hypointense (left), T2-hyperintense (middle), and FLAIR-hyperintense (right).
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYB- or MYBL1-altered. GFAP-immunostained section showing diffuse immunopositivity both of tumour cells and of the background neuropil.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.
Diffuse astrocytoma, MYBL1-altered. Neurofilament immunostaining highlights numerous entrapped axons.
Diffuse astrocytoma, MYBL1-altered. MAP2 immunostaining highlights entrapped ganglion cells and their processes, but most tumour cells are negative, unlike in most other low-grade astrocytic neoplasms.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade glioma subtypes, this tumour is mostly negative for OLIG2.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade astrocytic neoplasms, this tumour is mostly negative for SOX10.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.

Q: In Diffuse astrocytoma, MYB- or MYBL1-altered, the tumor cells are typically positive for GFAP but uniquely lack expression of the key glial markers [...].
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYB- or MYBL1-altered. GFAP-immunostained section showing diffuse immunopositivity both of tumour cells and of the background neuropil.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade glioma subtypes, this tumour is mostly negative for OLIG2.
A: OLIG2 and SOX10
Diffuse astrocytoma, MYB- or MYBL1-altered
- Clinical: Typically presents in children and young adults (median age 10 years) with drug-resistant epilepsy; it is classified as a long-term epilepsy-associated tumour (LEAT).
- Microscopic: Characterized by a diffusely infiltrative proliferation of monomorphic glial cells with bland nuclei; often exhibits low cellularity and entrapped neurons.
- Ancillary (IHC): Tumour cells are GFAP-positive but uniquely negative for OLIG2 and SOX10, distinguishing it from many other low-grade gliomas.
- Genetics: Defined by structural rearrangements/fusions involving either the MYB or MYBL1 genes; tumors are IDH-wildtype and H3-wildtype.
Reference Gallery:
Diffuse astrocytoma, MYB- or MYBL1-altered. MRI of a MYBL1-altered diffuse astrocytoma located in the inferior frontal gyrus in a 39-year-old patient with epilepsy since the age of 3 years. The tumour (white arrow) is T1-hypointense (left), T2-hyperintense (middle), and FLAIR-hyperintense (right).
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYB- or MYBL1-altered. GFAP-immunostained section showing diffuse immunopositivity both of tumour cells and of the background neuropil.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.
Diffuse astrocytoma, MYBL1-altered. Neurofilament immunostaining highlights numerous entrapped axons.
Diffuse astrocytoma, MYBL1-altered. MAP2 immunostaining highlights entrapped ganglion cells and their processes, but most tumour cells are negative, unlike in most other low-grade astrocytic neoplasms.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade glioma subtypes, this tumour is mostly negative for OLIG2.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade astrocytic neoplasms, this tumour is mostly negative for SOX10.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.

Q: Microscopically, Diffuse astrocytoma, MYB- or MYBL1-altered exhibits a diffusely infiltrative proliferation of monomorphic glial cells that frequently entrap normal [...] (which can be highlighted by neurofilament or MAP2 immunostains).
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYBL1-altered. Neurofilament immunostaining highlights numerous entrapped axons.
Diffuse astrocytoma, MYBL1-altered. MAP2 immunostaining highlights entrapped ganglion cells and their processes, but most tumour cells are negative, unlike in most other low-grade astrocytic neoplasms.
A: neurons
Diffuse astrocytoma, MYB- or MYBL1-altered
- Clinical: Typically presents in children and young adults (median age 10 years) with drug-resistant epilepsy; it is classified as a long-term epilepsy-associated tumour (LEAT).
- Microscopic: Characterized by a diffusely infiltrative proliferation of monomorphic glial cells with bland nuclei; often exhibits low cellularity and entrapped neurons.
- Ancillary (IHC): Tumour cells are GFAP-positive but uniquely negative for OLIG2 and SOX10, distinguishing it from many other low-grade gliomas.
- Genetics: Defined by structural rearrangements/fusions involving either the MYB or MYBL1 genes; tumors are IDH-wildtype and H3-wildtype.
Reference Gallery:
Diffuse astrocytoma, MYB- or MYBL1-altered. MRI of a MYBL1-altered diffuse astrocytoma located in the inferior frontal gyrus in a 39-year-old patient with epilepsy since the age of 3 years. The tumour (white arrow) is T1-hypointense (left), T2-hyperintense (middle), and FLAIR-hyperintense (right).
Diffuse astrocytoma, MYB- or MYBL1-altered. A typical MYB- or MYBL1-altered diffuse astrocytoma showing monomorphic glial cells with bland nuclei and diffusely permeating neuropil.
Diffuse astrocytoma, MYB- or MYBL1-altered. GFAP-immunostained section showing diffuse immunopositivity both of tumour cells and of the background neuropil.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.
Diffuse astrocytoma, MYBL1-altered. Neurofilament immunostaining highlights numerous entrapped axons.
Diffuse astrocytoma, MYBL1-altered. MAP2 immunostaining highlights entrapped ganglion cells and their processes, but most tumour cells are negative, unlike in most other low-grade astrocytic neoplasms.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade glioma subtypes, this tumour is mostly negative for OLIG2.
Diffuse astrocytoma, MYBL1-altered. In contrast to most other low-grade astrocytic neoplasms, this tumour is mostly negative for SOX10.
Diffuse astrocytoma, MYBL1-altered. Infiltrative glioma with mild hypercellularity and atypia.

Q: Immunohistochemistry for Diffuse low-grade glioma, MAPK pathway–altered can demonstrate the presence of an underlying MAPK pathway mutation, frequently highlighting the mutant protein [...].
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. Mildly atypical neoplastic glial cells with an astrocytic or oligodendrocytic morphology are diffusely distributed in cerebral cortex and underlying white matter. Nodule formation is rare. An FGFR1 tyrosine kinase domain (TKD) duplication was detected.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells express the mutant protein BRAF p.V600E.
A: BRAF p.V600E
Diffuse low-grade glioma, MAPK pathway–altered
- Clinical: Typically presents in children with epilepsy; although primarily pediatric, it can occur across the craniospinal axis, especially in the cerebral hemispheres.
- Microscopic: Composed of mildly atypical glial cells (astrocytic or oligodendroglial) at low density; lacks high-grade features like necrosis or microvascular proliferation.
- Ancillary (Molecular): Defined by pathogenic alterations in the MAPK pathway, most commonly FGFR1 (TKD duplication) or BRAF (p.V600E).
- Essential Criteria: Tumors must be IDH-wildtype, H3-wildtype, and must lack homozygous deletion of CDKN2A.
Reference Gallery:
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. Mildly atypical neoplastic glial cells with an astrocytic or oligodendrocytic morphology are diffusely distributed in cerebral cortex and underlying white matter. Nodule formation is rare. An FGFR1 tyrosine kinase domain (TKD) duplication was detected.
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. A fibrillary matrix is found in some regions.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity entrapping normal neurons. The tumour cells have a bland appearance and are mildly atypical.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity showing subpial aggregation typical of diffuse gliomas.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for GFAP.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for OLIG2.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells express the mutant protein BRAF p.V600E.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. Postcontrast T1-weighted MRI shows a heterogeneously enhancing mass, with a cystic element, within the medial aspect of the right temporal lobe.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with low T1 signal.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with high T2 signal.

Q: Histologically, Diffuse low-grade glioma, MAPK pathway–altered is characterized by bland to mildly atypical glial cells that infiltratively entrap normal neurons and frequently display [...].
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity entrapping normal neurons. The tumour cells have a bland appearance and are mildly atypical.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity showing subpial aggregation typical of diffuse gliomas.
A: subpial aggregation
Diffuse low-grade glioma, MAPK pathway–altered
- Clinical: Typically presents in children with epilepsy; although primarily pediatric, it can occur across the craniospinal axis, especially in the cerebral hemispheres.
- Microscopic: Composed of mildly atypical glial cells (astrocytic or oligodendroglial) at low density; lacks high-grade features like necrosis or microvascular proliferation.
- Ancillary (Molecular): Defined by pathogenic alterations in the MAPK pathway, most commonly FGFR1 (TKD duplication) or BRAF (p.V600E).
- Essential Criteria: Tumors must be IDH-wildtype, H3-wildtype, and must lack homozygous deletion of CDKN2A.
Reference Gallery:
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. Mildly atypical neoplastic glial cells with an astrocytic or oligodendrocytic morphology are diffusely distributed in cerebral cortex and underlying white matter. Nodule formation is rare. An FGFR1 tyrosine kinase domain (TKD) duplication was detected.
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. A fibrillary matrix is found in some regions.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity entrapping normal neurons. The tumour cells have a bland appearance and are mildly atypical.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity showing subpial aggregation typical of diffuse gliomas.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for GFAP.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for OLIG2.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells express the mutant protein BRAF p.V600E.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. Postcontrast T1-weighted MRI shows a heterogeneously enhancing mass, with a cystic element, within the medial aspect of the right temporal lobe.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with low T1 signal.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with high T2 signal.

Q: On magnetic resonance imaging (MRI), Diffuse low-grade glioma, MAPK pathway–altered typically presents as a heterogeneously enhancing mass (often with cystic components) that exhibits high signal intensity on [...]-weighted sequences.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. Postcontrast T1-weighted MRI shows a heterogeneously enhancing mass, with a cystic element, within the medial aspect of the right temporal lobe.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with high T2 signal.
A: T2
Diffuse low-grade glioma, MAPK pathway–altered
- Clinical: Typically presents in children with epilepsy; although primarily pediatric, it can occur across the craniospinal axis, especially in the cerebral hemispheres.
- Microscopic: Composed of mildly atypical glial cells (astrocytic or oligodendroglial) at low density; lacks high-grade features like necrosis or microvascular proliferation.
- Ancillary (Molecular): Defined by pathogenic alterations in the MAPK pathway, most commonly FGFR1 (TKD duplication) or BRAF (p.V600E).
- Essential Criteria: Tumors must be IDH-wildtype, H3-wildtype, and must lack homozygous deletion of CDKN2A.
Reference Gallery:
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. Mildly atypical neoplastic glial cells with an astrocytic or oligodendrocytic morphology are diffusely distributed in cerebral cortex and underlying white matter. Nodule formation is rare. An FGFR1 tyrosine kinase domain (TKD) duplication was detected.
Diffuse low-grade glioma, MAPK pathway–altered. Temporal lobe tumour in a 7-year-old patient. A fibrillary matrix is found in some regions.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity entrapping normal neurons. The tumour cells have a bland appearance and are mildly atypical.
Diffuse low-grade glioma, MAPK pathway–altered. A low-grade diffuse glioma of moderate cellularity showing subpial aggregation typical of diffuse gliomas.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for GFAP.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells show immunopositivity for OLIG2.
Diffuse low-grade glioma, MAPK pathway–altered. Neoplastic astrocytic glioma cells express the mutant protein BRAF p.V600E.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. Postcontrast T1-weighted MRI shows a heterogeneously enhancing mass, with a cystic element, within the medial aspect of the right temporal lobe.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with low T1 signal.
Diffuse low-grade glioma, MAPK pathway–altered. Diffuse low-grade glioma in a 1-year-old girl. MRI shows a mass within the medial aspect of the right temporal lobe, with high T2 signal.

Q: In Polymorphous low-grade neuroepithelial tumour of the young, immunohistochemistry typically exhibits characteristic intense, regional or diffuse positivity for [...].
Polymorphous low-grade neuroepithelial tumour of the young. Oligodendroglioma-like features include small round nuclei, perinuclear haloes, and delicate branching capillaries.
Polymorphous low-grade neuroepithelial tumour of the young. Intense regional immunoreactivity of the tumour matrix for CD34 is seen in the lower half of this field.
A: CD34
Back Extra: Polymorphous low-grade neuroepithelial tumour of the young
- Clinical: Typically presents in children and young adults (median age 16) with long-term refractory epilepsy, most commonly localized to the temporal lobe (80%).
- Microscopic: Characterized by a 'polymorphous' appearance with oligodendroglioma-like components (small round nuclei, haloes), astrocytic elements, and coarse, confluent calcifications.
- Ancillary (IHC): Exhibits characteristic intense, often regional or diffuse, immunoreactivity for CD34; OLIG2 and GFAP are also typically positive.
- Molecular: Driven by MAPK pathway–activating abnormalities, primarily BRAF p.V600E mutations or fusions involving FGFR2 or FGFR3.
- Prognosis: Behave indolently (CNS WHO grade 1) and are usually successfully managed with surgical resection for seizure control.
Reference Gallery:
Polymorphous low-grade neuroepithelial tumour of the young. FLAIR-hyperintense solid components, cystic changes, and the absence of mass effect are seen in this MRI.
Polymorphous low-grade neuroepithelial tumour of the young. A diffuse growth pattern and conspicuous calcification are seen.
Polymorphous low-grade neuroepithelial tumour of the young. Oligodendroglioma-like features include small round nuclei, perinuclear haloes, and delicate branching capillaries.
Polymorphous low-grade neuroepithelial tumour of the young. Mild nuclear pleomorphism and membrane irregularities are common.
Polymorphous low-grade neuroepithelial tumour of the young. Astroglial elements here exhibit spindling and more conspicuous atypia without mitotic activity.
Polymorphous low-grade neuroepithelial tumour of the young. Intense regional immunoreactivity of the tumour matrix for CD34 is seen in the lower half of this field.
Polymorphous low-grade neuroepithelial tumour of the young. Vascular mineralization was evident in this example.
Polymorphous low-grade neuroepithelial tumour of the young. Entrapped neurofilament-positive axons confirm that this tumour is at least partially infiltrative.
Polymorphous low-grade neuroepithelial tumour of the young. Extensive OLIG2 positivity in tumour cell nuclei.

Q: The pathogenesis of Polymorphous low-grade neuroepithelial tumour of the young is driven by MAPK pathway activation, most commonly involving FGFR2/FGFR3 fusions or [...] mutations.
Polymorphous low-grade neuroepithelial tumour of the young. Oligodendroglioma-like features include small round nuclei, perinuclear haloes, and delicate branching capillaries.
Polymorphous low-grade neuroepithelial tumour of the young. Astroglial elements here exhibit spindling and more conspicuous atypia without mitotic activity.
A: BRAF p.V600E
Back Extra: Polymorphous low-grade neuroepithelial tumour of the young
- Clinical: Typically presents in children and young adults (median age 16) with long-term refractory epilepsy, most commonly localized to the temporal lobe (80%).
- Microscopic: Characterized by a 'polymorphous' appearance with oligodendroglioma-like components (small round nuclei, haloes), astrocytic elements, and coarse, confluent calcifications.
- Ancillary (IHC): Exhibits characteristic intense, often regional or diffuse, immunoreactivity for CD34; OLIG2 and GFAP are also typically positive.
- Molecular: Driven by MAPK pathway–activating abnormalities, primarily BRAF p.V600E mutations or fusions involving FGFR2 or FGFR3.
- Prognosis: Behave indolently (CNS WHO grade 1) and are usually successfully managed with surgical resection for seizure control.
Reference Gallery:
Polymorphous low-grade neuroepithelial tumour of the young. FLAIR-hyperintense solid components, cystic changes, and the absence of mass effect are seen in this MRI.
Polymorphous low-grade neuroepithelial tumour of the young. A diffuse growth pattern and conspicuous calcification are seen.
Polymorphous low-grade neuroepithelial tumour of the young. Oligodendroglioma-like features include small round nuclei, perinuclear haloes, and delicate branching capillaries.
Polymorphous low-grade neuroepithelial tumour of the young. Mild nuclear pleomorphism and membrane irregularities are common.
Polymorphous low-grade neuroepithelial tumour of the young. Astroglial elements here exhibit spindling and more conspicuous atypia without mitotic activity.
Polymorphous low-grade neuroepithelial tumour of the young. Intense regional immunoreactivity of the tumour matrix for CD34 is seen in the lower half of this field.
Polymorphous low-grade neuroepithelial tumour of the young. Vascular mineralization was evident in this example.
Polymorphous low-grade neuroepithelial tumour of the young. Entrapped neurofilament-positive axons confirm that this tumour is at least partially infiltrative.
Polymorphous low-grade neuroepithelial tumour of the young. Extensive OLIG2 positivity in tumour cell nuclei.

Q: Clinically, Polymorphous low-grade neuroepithelial tumour of the young typically presents with refractory epilepsy, and on MRI, it often appears as a FLAIR-hyperintense mass predominantly localized to the [...].
Polymorphous low-grade neuroepithelial tumour of the young. FLAIR-hyperintense solid components, cystic changes, and the absence of mass effect are seen in this MRI.
Polymorphous low-grade neuroepithelial tumour of the young. A diffuse growth pattern and conspicuous calcification are seen.
A: temporal lobe
Back Extra: Polymorphous low-grade neuroepithelial tumour of the young
- Clinical: Typically presents in children and young adults (median age 16) with long-term refractory epilepsy, most commonly localized to the temporal lobe (80%).
- Microscopic: Characterized by a 'polymorphous' appearance with oligodendroglioma-like components (small round nuclei, haloes), astrocytic elements, and coarse, confluent calcifications.
- Ancillary (IHC): Exhibits characteristic intense, often regional or diffuse, immunoreactivity for CD34; OLIG2 and GFAP are also typically positive.
- Molecular: Driven by MAPK pathway–activating abnormalities, primarily BRAF p.V600E mutations or fusions involving FGFR2 or FGFR3.
- Prognosis: Behave indolently (CNS WHO grade 1) and are usually successfully managed with surgical resection for seizure control.
Reference Gallery:
Polymorphous low-grade neuroepithelial tumour of the young. FLAIR-hyperintense solid components, cystic changes, and the absence of mass effect are seen in this MRI.
Polymorphous low-grade neuroepithelial tumour of the young. A diffuse growth pattern and conspicuous calcification are seen.
Polymorphous low-grade neuroepithelial tumour of the young. Oligodendroglioma-like features include small round nuclei, perinuclear haloes, and delicate branching capillaries.
Polymorphous low-grade neuroepithelial tumour of the young. Mild nuclear pleomorphism and membrane irregularities are common.
Polymorphous low-grade neuroepithelial tumour of the young. Astroglial elements here exhibit spindling and more conspicuous atypia without mitotic activity.
Polymorphous low-grade neuroepithelial tumour of the young. Intense regional immunoreactivity of the tumour matrix for CD34 is seen in the lower half of this field.
Polymorphous low-grade neuroepithelial tumour of the young. Vascular mineralization was evident in this example.
Polymorphous low-grade neuroepithelial tumour of the young. Entrapped neurofilament-positive axons confirm that this tumour is at least partially infiltrative.
Polymorphous low-grade neuroepithelial tumour of the young. Extensive OLIG2 positivity in tumour cell nuclei.

Q: Histologically, Atypical teratoid/rhabdoid tumour is a highly malignant pediatric central nervous system tumor characterized by the presence of large [...] cells, which feature eccentric nuclei, prominent eosinophilic nucleoli, and abundant eosinophilic cytoplasm.
Atypical teratoid/rhabdoid tumour. Rhabdoid cells of varying size with vesicular nuclei, prominent nucleoli, and pale eosinophilic cytoplasm.
A: rhabdoid
Back Extra: Atypical teratoid/rhabdoid tumour
- Clinical: AT/RTs occur throughout the neuraxis, most commonly in the cerebral hemispheres (supratentorial) or cerebellopontine angle and brainstem (infratentorial). It predominantly affects children <2 years of age. Infants presen…
- Micro: AT/RT is histologically heterogeneous and characteristically contains: 1. Rhabdoid cells: Large cells with eccentric nuclei, vesicular chromatin, prominent eosinophilic nucleoli, and homogeneously eosinophilic cytopl…
- Cyto: Cytological preparations (including CSF for staging) are typically dominated by embryonal cells with hyperchromatic round/oval nuclei and minimal cytoplasm. Characteristic rhabdoid cells are larger, featuring eccentrical…
- Ancillary: Immunohistochemistry (IHC): SMARCB1 (INI1): Nuclear loss of expression is the diagnostic hallmark; endothelial cells serve as an internal positive control. SMARCA4 (BRG1): Nuclear loss is seen in the rare…
Reference Gallery:
Atypical teratoid/rhabdoid tumour. Rhabdoid cells of varying size with vesicular nuclei, prominent nucleoli, and pale eosinophilic cytoplasm.
Atypical teratoid/rhabdoid tumour. Loss of nuclear immunoreactivity for SMARCB1 in tumour cells, with retained expression in endothelial cells.
Atypical teratoid/rhabdoid tumour. Rare cases manifest loss of SMARCA4 (BRG1) immunoreactivity, as illustrated here, but retain expression of SMARCB1 (INI1).
Atypical teratoid/rhabdoid tumour. Leptomeningeal tumour spread. Cerebrospinal fluid cytology shows large tumour cells with rhabdoid features (extensive cytoplasm with eccentric nuclei).
Atypical teratoid/rhabdoid tumour (AT/RT) consensus subtypes. Summary of demographic and molecular features of AT/RT subtypes.
Atypical teratoid/rhabdoid tumour. Axial T2-weighted MRI demonstrating tumour heterogeneity.
Atypical teratoid/rhabdoid tumour. Axial T1-weighted MRI.
Atypical teratoid/rhabdoid tumour. Lesions composed of small embryonal cells without typical rhabdoid cells raise the diagnostic possibility of other CNS embryonal tumours.
Atypical teratoid/rhabdoid tumour. Mesenchymal area composed of loosely arranged elongated cells.
Atypical teratoid/rhabdoid tumour. Compact area with fascicular growth pattern.
Atypical teratoid/rhabdoid tumour. SMA positivity.
Atypical teratoid/rhabdoid tumour. Patchy expression of EMA.

Q: The diagnostic hallmark of Atypical teratoid/rhabdoid tumour is the immunohistochemical nuclear loss of expression of [...] (or, rarely, SMARCA4), while background endothelial cells serve as a retained internal positive control.
Atypical teratoid/rhabdoid tumour. Rhabdoid cells of varying size with vesicular nuclei, prominent nucleoli, and pale eosinophilic cytoplasm.
Atypical teratoid/rhabdoid tumour. Loss of nuclear immunoreactivity for SMARCB1 in tumour cells, with retained expression in endothelial cells.
Atypical teratoid/rhabdoid tumour. Rare cases manifest loss of SMARCA4 (BRG1) immunoreactivity, as illustrated here, but retain expression of SMARCB1 (INI1).
A: SMARCB1 (INI1)
Back Extra: Atypical teratoid/rhabdoid tumour
- Clinical: AT/RTs occur throughout the neuraxis, most commonly in the cerebral hemispheres (supratentorial) or cerebellopontine angle and brainstem (infratentorial). It predominantly affects children <2 years of age. Infants presen…
- Micro: AT/RT is histologically heterogeneous and characteristically contains: 1. Rhabdoid cells: Large cells with eccentric nuclei, vesicular chromatin, prominent eosinophilic nucleoli, and homogeneously eosinophilic cytopl…
- Cyto: Cytological preparations (including CSF for staging) are typically dominated by embryonal cells with hyperchromatic round/oval nuclei and minimal cytoplasm. Characteristic rhabdoid cells are larger, featuring eccentrical…
- Ancillary: Immunohistochemistry (IHC): SMARCB1 (INI1): Nuclear loss of expression is the diagnostic hallmark; endothelial cells serve as an internal positive control. SMARCA4 (BRG1): Nuclear loss is seen in the rare…
Reference Gallery:
Atypical teratoid/rhabdoid tumour. Rhabdoid cells of varying size with vesicular nuclei, prominent nucleoli, and pale eosinophilic cytoplasm.
Atypical teratoid/rhabdoid tumour. Loss of nuclear immunoreactivity for SMARCB1 in tumour cells, with retained expression in endothelial cells.
Atypical teratoid/rhabdoid tumour. Rare cases manifest loss of SMARCA4 (BRG1) immunoreactivity, as illustrated here, but retain expression of SMARCB1 (INI1).
Atypical teratoid/rhabdoid tumour. Leptomeningeal tumour spread. Cerebrospinal fluid cytology shows large tumour cells with rhabdoid features (extensive cytoplasm with eccentric nuclei).
Atypical teratoid/rhabdoid tumour (AT/RT) consensus subtypes. Summary of demographic and molecular features of AT/RT subtypes.
Atypical teratoid/rhabdoid tumour. Axial T2-weighted MRI demonstrating tumour heterogeneity.
Atypical teratoid/rhabdoid tumour. Axial T1-weighted MRI.
Atypical teratoid/rhabdoid tumour. Lesions composed of small embryonal cells without typical rhabdoid cells raise the diagnostic possibility of other CNS embryonal tumours.
Atypical teratoid/rhabdoid tumour. Mesenchymal area composed of loosely arranged elongated cells.
Atypical teratoid/rhabdoid tumour. Compact area with fascicular growth pattern.
Atypical teratoid/rhabdoid tumour. SMA positivity.
Atypical teratoid/rhabdoid tumour. Patchy expression of EMA.

Q: Histologic examination of a [...] reveals sheets of densely packed, small, poorly differentiated cells with high mitotic activity, and relies on molecular/methylation profiling to confirm the lack of a specific classifier match.
CNS embryonal tumour consisting of densely packed, small, poorly differentiated cells with a high mitotic count. RNA sequencing revealed a BRD4::CREBBP fusion gene. Methylation profiling did not result in a match using the brain tumour classifier.
The copy-number variation profile of the tumour (derived from genome-wide methylome analysis) did not reveal large chromosomal gains or losses. The tumour was classified as CNS embryonal tumour not elsewhere classified (NEC).
A: CNS embryonal tumor NEC/NOS
Back Extra: CNS embryonal tumour NEC/NOS
- Clinical: Patients typically present acutely with symptoms of raised intracranial pressure, epilepsy, or focal neurological deficits. Metastatic dissemination is common, occurring in 25–35% of cases at presentation. Imaging usuall…
- Micro: Histology shows sheets of densely packed, immature cells characterized by a high N:C ratio and hyperchromatic, angulated, round, or oval nuclei. High mitotic activity is typical. Foci of neurocytic or ganglion cell diffe…
- Cyto: Cerebrospinal fluid (CSF) cytology is mandatory for clinical staging to detect subarachnoid metastatic spread.
- Ancillary: Immunohistochemistry (IHC): - Positive: Variably positive for synaptophysin and OLIG2. Ki-67 proliferation index is typically very high. - Negative: GFAP and vimentin are generally absent in neoplastic cells …
Reference Gallery:
CNS embryonal tumour. Postcontrast, T1-weighted MRI showing a large, partly solid, partly cystic tumour in the left frontal lobe of an infant. This is the same patient of whom the histology and copy-number variation profile are shown in Fig. 19718 and Fig. 19719.
CNS embryonal tumour consisting of densely packed, small, poorly differentiated cells with a high mitotic count. RNA sequencing revealed a BRD4::CREBBP fusion gene. Methylation profiling did not result in a match using the brain tumour classifier.
The copy-number variation profile of the tumour (derived from genome-wide methylome analysis) did not reveal large chromosomal gains or losses. The tumour was classified as CNS embryonal tumour not elsewhere classified (NEC).

Q: On post-contrast T1-weighted MRI, a [...] often appears as a large, partly solid, and partly cystic mass; cerebrospinal fluid (CSF) cytologic analysis is mandatory for staging due to the high risk of early dissemination.
CNS embryonal tumour. Postcontrast, T1-weighted MRI showing a large, partly solid, partly cystic tumour in the left frontal lobe of an infant. This is the same patient of whom the histology and copy-number variation profile are shown in Fig. 19718 and Fig. 19719.
A: CNS embryonal tumor NEC/NOS
Back Extra: CNS embryonal tumour NEC/NOS
- Clinical: Patients typically present acutely with symptoms of raised intracranial pressure, epilepsy, or focal neurological deficits. Metastatic dissemination is common, occurring in 25–35% of cases at presentation. Imaging usuall…
- Micro: Histology shows sheets of densely packed, immature cells characterized by a high N:C ratio and hyperchromatic, angulated, round, or oval nuclei. High mitotic activity is typical. Foci of neurocytic or ganglion cell diffe…
- Cyto: Cerebrospinal fluid (CSF) cytology is mandatory for clinical staging to detect subarachnoid metastatic spread.
- Ancillary: Immunohistochemistry (IHC): - Positive: Variably positive for synaptophysin and OLIG2. Ki-67 proliferation index is typically very high. - Negative: GFAP and vimentin are generally absent in neoplastic cells …
Reference Gallery:
CNS embryonal tumour. Postcontrast, T1-weighted MRI showing a large, partly solid, partly cystic tumour in the left frontal lobe of an infant. This is the same patient of whom the histology and copy-number variation profile are shown in Fig. 19718 and Fig. 19719.
CNS embryonal tumour consisting of densely packed, small, poorly differentiated cells with a high mitotic count. RNA sequencing revealed a BRD4::CREBBP fusion gene. Methylation profiling did not result in a match using the brain tumour classifier.
The copy-number variation profile of the tumour (derived from genome-wide methylome analysis) did not reveal large chromosomal gains or losses. The tumour was classified as CNS embryonal tumour not elsewhere classified (NEC).

Q: Microscopically, CNS neuroblastoma, FOXR2-activated typically consists of neurocytic and neuroblastic cells in a neuropil-like matrix, and some tumors may demonstrate focal [...] formation (ganglioneuroblastoma phenotype).
CNS neuroblastoma, FOXR2-activated. Neurocytic and neuroblastic cells are set in a neuropil-like matrix.
CNS neuroblastoma, FOXR2-activated. Some tumours show focal ganglion cell formation (ganglioneuroblastoma phenotype).
A: ganglion cell
Back Extra: CNS neuroblastoma, FOXR2-activated
- Clinical: Typically occurs in childhood with a slight female preponderance. It usually presents as a demarcated mass in a cerebral hemisphere, sometimes with a prominent cystic component. Solid components often show moderate and h…
- Micro: The tumour typically consists of sheets of poorly differentiated cells with a high N:C ratio; round, oval, or angulated hyperchromatic nuclei; and abundant mitotic activity. Specific architectural features include: - R…
- Cyto: Evaluation of cerebrospinal fluid (CSF) for the presence of tumour cells is required for staging. Microscopic tumour cells found in the CSF are classified as M1 in the Chang staging system.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Strong nuclear expression in most cells. - Synaptophysin: Positive in embryonal cells, with accentuation in regions of neurocytic or ganglion cell differentiation. - …
Reference Gallery:
CNS neuroblastoma, FOXR2-activated. Neurocytic and neuroblastic cells are set in a neuropil-like matrix.
CNS neuroblastoma, FOXR2-activated. Typically, there is patchy immunoreactivity for synaptophysin, although expression is widespread in this example.
CNS neuroblastoma, FOXR2-activated. Extensive and strong OLIG2 immunolabelling is present in tumour cell nuclei.
CNS neuroblastoma, FOXR2-activated. The Ki-67 proliferation index is high.
CNS neuroblastoma, FOXR2-activated. Widespread and strong immunoreactivity for thyroid transcription factor 1 (TTF1, also called NKX2-1) may be found.
CNS neuroblastoma, FOXR2-activated. Some tumours show focal ganglion cell formation (ganglioneuroblastoma phenotype).
CNS neuroblastoma, FOXR2-activated. Axial T2-weighted image showing a large, partially cystic mass involving the right parietal lobe (left).
CNS neuroblastoma, FOXR2-activated. Postcontrast T1-weighted image showing thickening and enhancement of overlying meninges as well as inhomogeneous enhancement of solid tumour components.

Q: A characteristic immunohistochemical profile for CNS neuroblastoma, FOXR2-activated includes strong nuclear expression of OLIG2 along with widespread immunoreactivity for [...] (also known as NKX2-1).
CNS neuroblastoma, FOXR2-activated. Extensive and strong OLIG2 immunolabelling is present in tumour cell nuclei.
CNS neuroblastoma, FOXR2-activated. Widespread and strong immunoreactivity for thyroid transcription factor 1 (TTF1, also called NKX2-1) may be found.
A: TTF1
Back Extra: CNS neuroblastoma, FOXR2-activated
- Clinical: Typically occurs in childhood with a slight female preponderance. It usually presents as a demarcated mass in a cerebral hemisphere, sometimes with a prominent cystic component. Solid components often show moderate and h…
- Micro: The tumour typically consists of sheets of poorly differentiated cells with a high N:C ratio; round, oval, or angulated hyperchromatic nuclei; and abundant mitotic activity. Specific architectural features include: - R…
- Cyto: Evaluation of cerebrospinal fluid (CSF) for the presence of tumour cells is required for staging. Microscopic tumour cells found in the CSF are classified as M1 in the Chang staging system.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Strong nuclear expression in most cells. - Synaptophysin: Positive in embryonal cells, with accentuation in regions of neurocytic or ganglion cell differentiation. - …
Reference Gallery:
CNS neuroblastoma, FOXR2-activated. Neurocytic and neuroblastic cells are set in a neuropil-like matrix.
CNS neuroblastoma, FOXR2-activated. Typically, there is patchy immunoreactivity for synaptophysin, although expression is widespread in this example.
CNS neuroblastoma, FOXR2-activated. Extensive and strong OLIG2 immunolabelling is present in tumour cell nuclei.
CNS neuroblastoma, FOXR2-activated. The Ki-67 proliferation index is high.
CNS neuroblastoma, FOXR2-activated. Widespread and strong immunoreactivity for thyroid transcription factor 1 (TTF1, also called NKX2-1) may be found.
CNS neuroblastoma, FOXR2-activated. Some tumours show focal ganglion cell formation (ganglioneuroblastoma phenotype).
CNS neuroblastoma, FOXR2-activated. Axial T2-weighted image showing a large, partially cystic mass involving the right parietal lobe (left).
CNS neuroblastoma, FOXR2-activated. Postcontrast T1-weighted image showing thickening and enhancement of overlying meninges as well as inhomogeneous enhancement of solid tumour components.

Q: On MRI, CNS neuroblastoma, FOXR2-activated often presents as a large, demarcated mass in a cerebral hemisphere that frequently features a prominent [...] component.
CNS neuroblastoma, FOXR2-activated. Axial T2-weighted image showing a large, partially cystic mass involving the right parietal lobe (left).
A: cystic
Back Extra: CNS neuroblastoma, FOXR2-activated
- Clinical: Typically occurs in childhood with a slight female preponderance. It usually presents as a demarcated mass in a cerebral hemisphere, sometimes with a prominent cystic component. Solid components often show moderate and h…
- Micro: The tumour typically consists of sheets of poorly differentiated cells with a high N:C ratio; round, oval, or angulated hyperchromatic nuclei; and abundant mitotic activity. Specific architectural features include: - R…
- Cyto: Evaluation of cerebrospinal fluid (CSF) for the presence of tumour cells is required for staging. Microscopic tumour cells found in the CSF are classified as M1 in the Chang staging system.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Strong nuclear expression in most cells. - Synaptophysin: Positive in embryonal cells, with accentuation in regions of neurocytic or ganglion cell differentiation. - …
Reference Gallery:
CNS neuroblastoma, FOXR2-activated. Neurocytic and neuroblastic cells are set in a neuropil-like matrix.
CNS neuroblastoma, FOXR2-activated. Typically, there is patchy immunoreactivity for synaptophysin, although expression is widespread in this example.
CNS neuroblastoma, FOXR2-activated. Extensive and strong OLIG2 immunolabelling is present in tumour cell nuclei.
CNS neuroblastoma, FOXR2-activated. The Ki-67 proliferation index is high.
CNS neuroblastoma, FOXR2-activated. Widespread and strong immunoreactivity for thyroid transcription factor 1 (TTF1, also called NKX2-1) may be found.
CNS neuroblastoma, FOXR2-activated. Some tumours show focal ganglion cell formation (ganglioneuroblastoma phenotype).
CNS neuroblastoma, FOXR2-activated. Axial T2-weighted image showing a large, partially cystic mass involving the right parietal lobe (left).
CNS neuroblastoma, FOXR2-activated. Postcontrast T1-weighted image showing thickening and enhancement of overlying meninges as well as inhomogeneous enhancement of solid tumour components.

Q: In CNS tumor with BCOR internal tandem duplication, the histologic evaluation classically demonstrates uniform spindle-to-oval cells and GFAP-negative [...].
CNS tumour with BCOR internal tandem duplication. This tumour exhibits ependymoma-like pseudorosettes.
A: ependymoma-like perivascular pseudorosettes
Back Extra: CNS tumour with BCOR internal tandem duplication
- Clinical: Primarily affects children (median age 3.5 years), presenting as large, well-demarcated, often cystic masses involving multiple lobes or the basal ganglia.
- Microscopic: Features uniform spindle/oval cells, a dense branching capillary network, and ependymoma-like perivascular pseudorosettes that are GFAP-negative.
- Ancillary: The defining hallmark is a heterozygous internal tandem duplication (ITD) in exon 15 of the BCOR gene.
- Immunohistochemistry: Shows diffuse, strong nuclear BCOR expression and a significantly elevated Ki-67 labeling index (15–60%).
- Differential: Distinguished from ependymoma by the absence of widespread GFAP expression and the presence of BCOR ITD rather than ZFTA or YAP1 fusions.
Reference Gallery:
CNS tumour with BCOR internal tandem duplication. This tumour exhibits ependymoma-like pseudorosettes.
CNS tumour with BCOR internal tandem duplication. Strong nuclear expression of BCOR is present in all tumour cells.
CNS tumour with BCOR internal tandem duplication. Areas of necrosis with a palisading pattern can be present.
CNS tumour with BCOR internal tandem duplication. Some tumours demonstrate a glioma-like fibrillarity.
CNS tumour with BCOR internal tandem duplication. This field shows a high cell density and brisk mitotic activity.
CNS tumour with BCOR internal tandem duplication. Marked cytological pleomorphism may occasionally be found.
CNS tumour with BCOR internal tandem duplication. A collagenous stroma and rosette formation are occasionally seen.
CNS tumour with BCOR internal tandem duplication. Expression of OLIG2 is present in a subset of tumour cell nuclei.
CNS tumour with BCOR internal tandem duplication. Expression of NeuN is variable.
CNS tumour with BCOR internal tandem duplication. Weak, granular, cytoplasmic immunoreactivity for EMA is occasionally found.
CNS tumour with BCOR internal tandem duplication. Axial MRI/FLAIR image of a tumour in the basal ganglia.
CNS tumour with BCOR internal tandem duplication. Coronal T2-weighted MRI of a tumour located in the cerebellar hemisphere.

Q: The characteristic immunohistochemical feature of CNS tumor with BCOR internal tandem duplication is diffuse, strong nuclear expression of [...].
CNS tumour with BCOR internal tandem duplication. Strong nuclear expression of BCOR is present in all tumour cells.
CNS tumour with BCOR internal tandem duplication. This field shows a high cell density and brisk mitotic activity.
A: BCOR
Back Extra: CNS tumour with BCOR internal tandem duplication
- Clinical: Primarily affects children (median age 3.5 years), presenting as large, well-demarcated, often cystic masses involving multiple lobes or the basal ganglia.
- Microscopic: Features uniform spindle/oval cells, a dense branching capillary network, and ependymoma-like perivascular pseudorosettes that are GFAP-negative.
- Ancillary: The defining hallmark is a heterozygous internal tandem duplication (ITD) in exon 15 of the BCOR gene.
- Immunohistochemistry: Shows diffuse, strong nuclear BCOR expression and a significantly elevated Ki-67 labeling index (15–60%).
- Differential: Distinguished from ependymoma by the absence of widespread GFAP expression and the presence of BCOR ITD rather than ZFTA or YAP1 fusions.
Reference Gallery:
CNS tumour with BCOR internal tandem duplication. This tumour exhibits ependymoma-like pseudorosettes.
CNS tumour with BCOR internal tandem duplication. Strong nuclear expression of BCOR is present in all tumour cells.
CNS tumour with BCOR internal tandem duplication. Areas of necrosis with a palisading pattern can be present.
CNS tumour with BCOR internal tandem duplication. Some tumours demonstrate a glioma-like fibrillarity.
CNS tumour with BCOR internal tandem duplication. This field shows a high cell density and brisk mitotic activity.
CNS tumour with BCOR internal tandem duplication. Marked cytological pleomorphism may occasionally be found.
CNS tumour with BCOR internal tandem duplication. A collagenous stroma and rosette formation are occasionally seen.
CNS tumour with BCOR internal tandem duplication. Expression of OLIG2 is present in a subset of tumour cell nuclei.
CNS tumour with BCOR internal tandem duplication. Expression of NeuN is variable.
CNS tumour with BCOR internal tandem duplication. Weak, granular, cytoplasmic immunoreactivity for EMA is occasionally found.
CNS tumour with BCOR internal tandem duplication. Axial MRI/FLAIR image of a tumour in the basal ganglia.
CNS tumour with BCOR internal tandem duplication. Coronal T2-weighted MRI of a tumour located in the cerebellar hemisphere.

Q: The defining molecular hallmark of CNS tumor with BCOR internal tandem duplication is an internal tandem duplication (ITD) specifically occurring in exon 15 of the [...] gene.
CNS tumour with BCOR internal tandem duplication. This tumour exhibits ependymoma-like pseudorosettes.
CNS tumour with BCOR internal tandem duplication. This field shows a high cell density and brisk mitotic activity.
A: BCOR
Back Extra: CNS tumour with BCOR internal tandem duplication
- Clinical: Primarily affects children (median age 3.5 years), presenting as large, well-demarcated, often cystic masses involving multiple lobes or the basal ganglia.
- Microscopic: Features uniform spindle/oval cells, a dense branching capillary network, and ependymoma-like perivascular pseudorosettes that are GFAP-negative.
- Ancillary: The defining hallmark is a heterozygous internal tandem duplication (ITD) in exon 15 of the BCOR gene.
- Immunohistochemistry: Shows diffuse, strong nuclear BCOR expression and a significantly elevated Ki-67 labeling index (15–60%).
- Differential: Distinguished from ependymoma by the absence of widespread GFAP expression and the presence of BCOR ITD rather than ZFTA or YAP1 fusions.
Reference Gallery:
CNS tumour with BCOR internal tandem duplication. This tumour exhibits ependymoma-like pseudorosettes.
CNS tumour with BCOR internal tandem duplication. Strong nuclear expression of BCOR is present in all tumour cells.
CNS tumour with BCOR internal tandem duplication. Areas of necrosis with a palisading pattern can be present.
CNS tumour with BCOR internal tandem duplication. Some tumours demonstrate a glioma-like fibrillarity.
CNS tumour with BCOR internal tandem duplication. This field shows a high cell density and brisk mitotic activity.
CNS tumour with BCOR internal tandem duplication. Marked cytological pleomorphism may occasionally be found.
CNS tumour with BCOR internal tandem duplication. A collagenous stroma and rosette formation are occasionally seen.
CNS tumour with BCOR internal tandem duplication. Expression of OLIG2 is present in a subset of tumour cell nuclei.
CNS tumour with BCOR internal tandem duplication. Expression of NeuN is variable.
CNS tumour with BCOR internal tandem duplication. Weak, granular, cytoplasmic immunoreactivity for EMA is occasionally found.
CNS tumour with BCOR internal tandem duplication. Axial MRI/FLAIR image of a tumour in the basal ganglia.
CNS tumour with BCOR internal tandem duplication. Coronal T2-weighted MRI of a tumour located in the cerebellar hemisphere.

Q: Histologically, Cribriform neuroepithelial tumor is a highly cellular pediatric neoplasm characterized by cords, ribbons, and trabeculae that form a distinctive sieve-like or [...] pattern.
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
A: cribriform
Back Extra: Cribriform neuroepithelial tumour
- Clinical: CRINET is primarily seen in children, with a median age of 20 months (range 10–129 months) and a slight male predilection (M:F ratio 1.5:1). The tumours are typically located in the vicinity of the fourth, third, or late…
- Micro: CRINET is a highly cellular tumour with the following features: Architecture: Characterized by cribriform (sieve-like) strands, ribbons, and trabeculae of varying thickness. Patterns: In compact areas, s…
- Cyto: Cytology is not clinically relevant for this entity.
- Ancillary: 1) Immunohistochemistry (IHC): Diagnostic Markers: Loss of nuclear SMARCB1 (INI1) expression is a defining feature. Positive Expression: Frequent expression of EMA, tyrosinase, MAP2, synaptophysin, an…
Reference Gallery:
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
Cribriform neuroepithelial tumour. Strong EMA expression in the tumour cells.
Cribriform neuroepithelial tumour. Loss of nuclear SMARCB1 (INI1) expression in the tumour cells.

Q: A defining diagnostic feature of Cribriform neuroepithelial tumor is the characteristic immunohistochemical loss of nuclear expression for [...].
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
Cribriform neuroepithelial tumour. Loss of nuclear SMARCB1 (INI1) expression in the tumour cells.
A: SMARCB1 (INI1)
Back Extra: Cribriform neuroepithelial tumour
- Clinical: CRINET is primarily seen in children, with a median age of 20 months (range 10–129 months) and a slight male predilection (M:F ratio 1.5:1). The tumours are typically located in the vicinity of the fourth, third, or late…
- Micro: CRINET is a highly cellular tumour with the following features: Architecture: Characterized by cribriform (sieve-like) strands, ribbons, and trabeculae of varying thickness. Patterns: In compact areas, s…
- Cyto: Cytology is not clinically relevant for this entity.
- Ancillary: 1) Immunohistochemistry (IHC): Diagnostic Markers: Loss of nuclear SMARCB1 (INI1) expression is a defining feature. Positive Expression: Frequent expression of EMA, tyrosinase, MAP2, synaptophysin, an…
Reference Gallery:
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
Cribriform neuroepithelial tumour. Strong EMA expression in the tumour cells.
Cribriform neuroepithelial tumour. Loss of nuclear SMARCB1 (INI1) expression in the tumour cells.

Q: The neoplastic cells of a Cribriform neuroepithelial tumor frequently demonstrate strong immunohistochemical positivity for the epithelial marker [...].
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
Cribriform neuroepithelial tumour. Strong EMA expression in the tumour cells.
A: EMA
Back Extra: Cribriform neuroepithelial tumour
- Clinical: CRINET is primarily seen in children, with a median age of 20 months (range 10–129 months) and a slight male predilection (M:F ratio 1.5:1). The tumours are typically located in the vicinity of the fourth, third, or late…
- Micro: CRINET is a highly cellular tumour with the following features: Architecture: Characterized by cribriform (sieve-like) strands, ribbons, and trabeculae of varying thickness. Patterns: In compact areas, s…
- Cyto: Cytology is not clinically relevant for this entity.
- Ancillary: 1) Immunohistochemistry (IHC): Diagnostic Markers: Loss of nuclear SMARCB1 (INI1) expression is a defining feature. Positive Expression: Frequent expression of EMA, tyrosinase, MAP2, synaptophysin, an…
Reference Gallery:
Cribriform neuroepithelial tumour. A highly cellular tumour composed of relatively small cells arranged in cribriform strands, and trabeculae of varying thickness, forming well-defined surfaces.
Cribriform neuroepithelial tumour. Strong EMA expression in the tumour cells.
Cribriform neuroepithelial tumour. Loss of nuclear SMARCB1 (INI1) expression in the tumour cells.

Q: Strong and diffuse cytoplasmic immunoreactivity for [...] is a diagnostic hallmark found across all morphological patterns of Embryonal tumor with multilayered rosettes.
Embryonal tumour with multilayered rosettes. An embryonal tumour with abundant neuropil and true rosettes pattern. Groups of densely packed embryonal cells, some including multilayered rosettes, contrast with neuropil-like areas that typically contain neoplastic neurocytic cells.
Embryonal tumour with multilayered rosettes. Tumour cells are strongly immunopositive for LIN28A.
A: LIN28A
Q: Embryonal tumour with multilayered rosettes
- Clinical: Highly aggressive CNS WHO grade 4 tumor primarily affecting children under 4 years old, typically presenting in the cerebral hemispheres.
- Microscopic: Characterized by a spectrum of three patterns: ETANTR (biphasic neuropil/rosettes), ependymoblastoma (sheets of rosettes), and medulloepithelioma (neural tube-like structures).
- Ancillary (IHC): Strong and diffuse cytoplasmic immunoreactivity for [...] is a diagnostic hallmark found across all morphological patterns.
- Ancillary (Molecular): Approximately 90% of cases harbor amplification or fusion of the [...] microRNA cluster at 19q13.42; a small subset is associated with DICER1 mutations.
Reference Gallery:
Embryonal tumour with multilayered rosettes. An embryonal tumour with abundant neuropil and true rosettes pattern. Groups of densely packed embryonal cells, some including multilayered rosettes, contrast with neuropil-like areas that typically contain neoplastic neurocytic cells.
Embryonal tumour with multilayered rosettes (ETMR). Multilayered rosettes are a defining feature of EMTR.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with ependymoblastoma morphology. Multilayered rosettes are abundant.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with medulloepithelioma morphology. Tubular structures resemble embryonic neural tube or elongated multilayered rosettes.
Embryonal tumour with multilayered rosettes. Interphase FISH. Amplification (green signals) of the C19MC locus at 19q13.42.
Embryonal tumour with multilayered rosettes. Many cells are immunopositive for vimentin.
Embryonal tumour with multilayered rosettes (ETMR). The neuropil-like matrix of ETMRs with an abundant neuropil and true rosettes pattern is synaptophysin-immunopositive.
Embryonal tumour with multilayered rosettes. Tumour cells are strongly immunopositive for LIN28A.
Embryonal tumour with multilayered rosettes. Panchromosomal copy-number alterations shown by DNA methylation array. Amplification and rearrangement of the C19MC locus on chromosome 19q and gain of chromosome 2 are prominent.
A: LIN28A; C19MC

Q: Approximately 90% of cases of Embryonal tumor with multilayered rosettes harbor amplification or fusion of the [...] microRNA cluster at 19q13.42.
Embryonal tumour with multilayered rosettes (ETMR). Multilayered rosettes are a defining feature of EMTR.
Embryonal tumour with multilayered rosettes. Interphase FISH. Amplification (green signals) of the C19MC locus at 19q13.42.
A: C19MC
Q: Embryonal tumour with multilayered rosettes
- Clinical: Highly aggressive CNS WHO grade 4 tumor primarily affecting children under 4 years old, typically presenting in the cerebral hemispheres.
- Microscopic: Characterized by a spectrum of three patterns: ETANTR (biphasic neuropil/rosettes), ependymoblastoma (sheets of rosettes), and medulloepithelioma (neural tube-like structures).
- Ancillary (IHC): Strong and diffuse cytoplasmic immunoreactivity for [...] is a diagnostic hallmark found across all morphological patterns.
- Ancillary (Molecular): Approximately 90% of cases harbor amplification or fusion of the [...] microRNA cluster at 19q13.42; a small subset is associated with DICER1 mutations.
Reference Gallery:
Embryonal tumour with multilayered rosettes. An embryonal tumour with abundant neuropil and true rosettes pattern. Groups of densely packed embryonal cells, some including multilayered rosettes, contrast with neuropil-like areas that typically contain neoplastic neurocytic cells.
Embryonal tumour with multilayered rosettes (ETMR). Multilayered rosettes are a defining feature of EMTR.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with ependymoblastoma morphology. Multilayered rosettes are abundant.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with medulloepithelioma morphology. Tubular structures resemble embryonic neural tube or elongated multilayered rosettes.
Embryonal tumour with multilayered rosettes. Interphase FISH. Amplification (green signals) of the C19MC locus at 19q13.42.
Embryonal tumour with multilayered rosettes. Many cells are immunopositive for vimentin.
Embryonal tumour with multilayered rosettes (ETMR). The neuropil-like matrix of ETMRs with an abundant neuropil and true rosettes pattern is synaptophysin-immunopositive.
Embryonal tumour with multilayered rosettes. Tumour cells are strongly immunopositive for LIN28A.
Embryonal tumour with multilayered rosettes. Panchromosomal copy-number alterations shown by DNA methylation array. Amplification and rearrangement of the C19MC locus on chromosome 19q and gain of chromosome 2 are prominent.
A: LIN28A; C19MC

Q: Morphologically, Embryonal tumor with multilayered rosettes features a spectrum of patterns, including ETANTR (biphasic neuropil/rosettes), ependymoblastoma, and [...], which typically exhibits embryonic neural tube-like structures.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with ependymoblastoma morphology. Multilayered rosettes are abundant.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with medulloepithelioma morphology. Tubular structures resemble embryonic neural tube or elongated multilayered rosettes.
A: medulloepithelioma
Q: Embryonal tumour with multilayered rosettes
- Clinical: Highly aggressive CNS WHO grade 4 tumor primarily affecting children under 4 years old, typically presenting in the cerebral hemispheres.
- Microscopic: Characterized by a spectrum of three patterns: ETANTR (biphasic neuropil/rosettes), ependymoblastoma (sheets of rosettes), and medulloepithelioma (neural tube-like structures).
- Ancillary (IHC): Strong and diffuse cytoplasmic immunoreactivity for [...] is a diagnostic hallmark found across all morphological patterns.
- Ancillary (Molecular): Approximately 90% of cases harbor amplification or fusion of the [...] microRNA cluster at 19q13.42; a small subset is associated with DICER1 mutations.
Reference Gallery:
Embryonal tumour with multilayered rosettes. An embryonal tumour with abundant neuropil and true rosettes pattern. Groups of densely packed embryonal cells, some including multilayered rosettes, contrast with neuropil-like areas that typically contain neoplastic neurocytic cells.
Embryonal tumour with multilayered rosettes (ETMR). Multilayered rosettes are a defining feature of EMTR.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with ependymoblastoma morphology. Multilayered rosettes are abundant.
Embryonal tumour with multilayered rosettes (ETMR). ETMR with medulloepithelioma morphology. Tubular structures resemble embryonic neural tube or elongated multilayered rosettes.
Embryonal tumour with multilayered rosettes. Interphase FISH. Amplification (green signals) of the C19MC locus at 19q13.42.
Embryonal tumour with multilayered rosettes. Many cells are immunopositive for vimentin.
Embryonal tumour with multilayered rosettes (ETMR). The neuropil-like matrix of ETMRs with an abundant neuropil and true rosettes pattern is synaptophysin-immunopositive.
Embryonal tumour with multilayered rosettes. Tumour cells are strongly immunopositive for LIN28A.
Embryonal tumour with multilayered rosettes. Panchromosomal copy-number alterations shown by DNA methylation array. Amplification and rearrangement of the C19MC locus on chromosome 19q and gain of chromosome 2 are prominent.
A: LIN28A; C19MC

Q: The majority of cases of Medulloblastoma, SHH-activated and TP53-mutant demonstrate a [...] phenotype characterized by marked nuclear pleomorphism, high mitotic activity, and cell wrapping.
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
A: large cell / anaplastic
Back Extra: Medulloblastoma, SHH-activated and TP53-mutant
- Clinical: Predominantly affects children and adolescents (median age ~15 years) and carries a very poor prognosis; germline screening for Li–Fraumeni syndrome is recommended.
- Microscopic: The majority (70%) of cases demonstrate a "large cell / anaplastic" phenotype characterized by marked nuclear pleomorphism, high mitotic activity, and cell wrapping.
- Ancillary: Shows positivity for GAB1 and YAP1 (SHH pathway markers) and characteristically demonstrates widespread strong nuclear immunoreactivity for p53.
- Genetics: Defined by TP53 mutations often occurring in conjunction with MYCN amplification, GLI2 amplification, and chromothripsis.
Reference Gallery:
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
SHH-activated and TP53-mutant medulloblastoma. Widespread strong nuclear immunoreactivity for p53, reflecting the presence of a TP53 mutation.

Q: By immunohistochemistry, Medulloblastoma, SHH-activated and TP53-mutant characteristically demonstrates widespread strong nuclear immunoreactivity for [...], reflecting its underlying genetic driver.
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
SHH-activated and TP53-mutant medulloblastoma. Widespread strong nuclear immunoreactivity for p53, reflecting the presence of a TP53 mutation.
A: p53
Back Extra: Medulloblastoma, SHH-activated and TP53-mutant
- Clinical: Predominantly affects children and adolescents (median age ~15 years) and carries a very poor prognosis; germline screening for Li–Fraumeni syndrome is recommended.
- Microscopic: The majority (70%) of cases demonstrate a "large cell / anaplastic" phenotype characterized by marked nuclear pleomorphism, high mitotic activity, and cell wrapping.
- Ancillary: Shows positivity for GAB1 and YAP1 (SHH pathway markers) and characteristically demonstrates widespread strong nuclear immunoreactivity for p53.
- Genetics: Defined by TP53 mutations often occurring in conjunction with MYCN amplification, GLI2 amplification, and chromothripsis.
Reference Gallery:
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
SHH-activated and TP53-mutant medulloblastoma. Widespread strong nuclear immunoreactivity for p53, reflecting the presence of a TP53 mutation.

Q: Medulloblastoma, SHH-activated and TP53-mutant predominantly affects older children and adolescents and carries a very poor prognosis, prompting recommended germline screening for [...] syndrome.
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
A: Li-Fraumeni
Back Extra: Medulloblastoma, SHH-activated and TP53-mutant
- Clinical: Predominantly affects children and adolescents (median age ~15 years) and carries a very poor prognosis; germline screening for Li–Fraumeni syndrome is recommended.
- Microscopic: The majority (70%) of cases demonstrate a "large cell / anaplastic" phenotype characterized by marked nuclear pleomorphism, high mitotic activity, and cell wrapping.
- Ancillary: Shows positivity for GAB1 and YAP1 (SHH pathway markers) and characteristically demonstrates widespread strong nuclear immunoreactivity for p53.
- Genetics: Defined by TP53 mutations often occurring in conjunction with MYCN amplification, GLI2 amplification, and chromothripsis.
Reference Gallery:
SHH-activated and TP53-mutant medulloblastoma. Marked anaplasia and mitotic activity, consistent with large cell / anaplastic medulloblastoma.
SHH-activated and TP53-mutant medulloblastoma. Widespread strong nuclear immunoreactivity for p53, reflecting the presence of a TP53 mutation.

Q: The diagnostic hallmark of Medulloblastoma, WNT-activated is strong nuclear immunoreactivity for [...].
Medulloblastoma, WNT-activated. Diffuse nuclear immunoreactivity for β-catenin.
Medulloblastoma, WNT-activated. Patchy nuclear immunoreactivity for β-catenin.
A: β-catenin
Back Extra: Medulloblastoma, WNT-activated
- Clinical: Primarily affects older children (7–14 years) and adults; typically presents as a midline or cerebellopontine angle (CPA) mass contiguous with the brainstem.
- Microscopic: Almost all cases exhibit 'classic' morphology; desmoplastic/nodular variants are notably absent in this molecular group.
- Ancillary: Nuclear β-catenin immunoreactivity is the diagnostic hallmark; most cases harbor somatic exon 3 CTNNB1 mutations or germline APC mutations.
- Genetics: Monosomy 6 is the characteristic cytogenetic finding, present in approximately 83% of cases.
- Prognosis: Excellent outcomes in children (near 100% survival), and unlike SHH-activated tumors, TP53 mutations do not negatively impact prognosis.
Reference Gallery:
Medulloblastoma, WNT-activated. MRI of WNT-activated medulloblastoma arising in the cerebellopontine angle.
Medulloblastoma, WNT-activated. Diffuse nuclear immunoreactivity for β-catenin.
Medulloblastoma, WNT-activated. Patchy nuclear immunoreactivity for β-catenin.
Non-WNT/non-SHH medulloblastoma. Cytoplasmic, but not nuclear, immunoreactivity for β-catenin.

Q: On MRI, Medulloblastoma, WNT-activated typically presents as a midline mass or characteristically arises in the [...].
Medulloblastoma, WNT-activated. MRI of WNT-activated medulloblastoma arising in the cerebellopontine angle.
A: cerebellopontine angle
Back Extra: Medulloblastoma, WNT-activated
- Clinical: Primarily affects older children (7–14 years) and adults; typically presents as a midline or cerebellopontine angle (CPA) mass contiguous with the brainstem.
- Microscopic: Almost all cases exhibit 'classic' morphology; desmoplastic/nodular variants are notably absent in this molecular group.
- Ancillary: Nuclear β-catenin immunoreactivity is the diagnostic hallmark; most cases harbor somatic exon 3 CTNNB1 mutations or germline APC mutations.
- Genetics: Monosomy 6 is the characteristic cytogenetic finding, present in approximately 83% of cases.
- Prognosis: Excellent outcomes in children (near 100% survival), and unlike SHH-activated tumors, TP53 mutations do not negatively impact prognosis.
Reference Gallery:
Medulloblastoma, WNT-activated. MRI of WNT-activated medulloblastoma arising in the cerebellopontine angle.
Medulloblastoma, WNT-activated. Diffuse nuclear immunoreactivity for β-catenin.
Medulloblastoma, WNT-activated. Patchy nuclear immunoreactivity for β-catenin.
Non-WNT/non-SHH medulloblastoma. Cytoplasmic, but not nuclear, immunoreactivity for β-catenin.

Q: Myxopapillary ependymoma classically features tumor cells arranged radially around hyalinized fibrovascular cores with prominent perivascular [...].
Myxopapillary ependymoma. Epithelioid tumour cells are arranged around fibrovascular cores and microcysts containing myxoid material.
Myxopapillary ependymoma. Tapering tumour cell processes are oriented towards a fibrovascular core with collaring myxoid matrix.
Myxopapillary ependymoma. Papillary structure, perivascular myxoid change, and spindled tumour cells oriented towards fibromyxoid cores are evident in this smear preparation.
A: myxoid change
Back Extra: Myxopapillary ependymoma
- Clinical: Arises almost exclusively in the conus medullaris and filum terminale; presents as a CNS WHO grade 2 neoplasm with a high risk of CSF-borne seeding, especially in children.
- Microscopic: Characterized by a radial arrangement of cuboidal to elongated cells around hyalinized fibrovascular cores with prominent perivascular myxoid change.
- Ancillary: Demonstrates diffuse, strong GFAP, S100, and CD99 immunoreactivity; notably, AE1/AE3 pancytokeratin is often positive while EMA and OLIG2 are typically negative.
- Genetics: Recurrent chromosomal findings include gains of chromosome 16 and losses of chromosome 10, with a unique DNA methylation profile.
Reference Gallery:
Myxopapillary ependymoma. The well-circumscribed, contrast-enhancing primary tumour in the filum is associated with a drop metastasis in the low thecal sac.
Myxopapillary ependymoma. Epithelioid tumour cells are arranged around fibrovascular cores and microcysts containing myxoid material.
Myxopapillary ependymoma. Tapering tumour cell processes are oriented towards a fibrovascular core with collaring myxoid matrix.
Myxopapillary ependymoma. Tumour cells are diffusely and strongly GFAP-immunoreactive.
Myxopapillary ependymoma. Papillary structure, perivascular myxoid change, and spindled tumour cells oriented towards fibromyxoid cores are evident in this smear preparation.

Q: Myxopapillary ependymoma is a CNS WHO grade 2 neoplasm that almost exclusively arises in the lower spinal cord, specifically the [...].
Myxopapillary ependymoma. The well-circumscribed, contrast-enhancing primary tumour in the filum is associated with a drop metastasis in the low thecal sac.
Myxopapillary ependymoma. Epithelioid tumour cells are arranged around fibrovascular cores and microcysts containing myxoid material.
A: conus medullaris and filum terminale
Back Extra: Myxopapillary ependymoma
- Clinical: Arises almost exclusively in the conus medullaris and filum terminale; presents as a CNS WHO grade 2 neoplasm with a high risk of CSF-borne seeding, especially in children.
- Microscopic: Characterized by a radial arrangement of cuboidal to elongated cells around hyalinized fibrovascular cores with prominent perivascular myxoid change.
- Ancillary: Demonstrates diffuse, strong GFAP, S100, and CD99 immunoreactivity; notably, AE1/AE3 pancytokeratin is often positive while EMA and OLIG2 are typically negative.
- Genetics: Recurrent chromosomal findings include gains of chromosome 16 and losses of chromosome 10, with a unique DNA methylation profile.
Reference Gallery:
Myxopapillary ependymoma. The well-circumscribed, contrast-enhancing primary tumour in the filum is associated with a drop metastasis in the low thecal sac.
Myxopapillary ependymoma. Epithelioid tumour cells are arranged around fibrovascular cores and microcysts containing myxoid material.
Myxopapillary ependymoma. Tapering tumour cell processes are oriented towards a fibrovascular core with collaring myxoid matrix.
Myxopapillary ependymoma. Tumour cells are diffusely and strongly GFAP-immunoreactive.
Myxopapillary ependymoma. Papillary structure, perivascular myxoid change, and spindled tumour cells oriented towards fibromyxoid cores are evident in this smear preparation.

Q: Myxopapillary ependymoma typically demonstrates diffuse and strong immunohistochemical positivity for [...], as well as S100 and CD99.
Myxopapillary ependymoma. Tapering tumour cell processes are oriented towards a fibrovascular core with collaring myxoid matrix.
Myxopapillary ependymoma. Tumour cells are diffusely and strongly GFAP-immunoreactive.
A: GFAP
Back Extra: Myxopapillary ependymoma
- Clinical: Arises almost exclusively in the conus medullaris and filum terminale; presents as a CNS WHO grade 2 neoplasm with a high risk of CSF-borne seeding, especially in children.
- Microscopic: Characterized by a radial arrangement of cuboidal to elongated cells around hyalinized fibrovascular cores with prominent perivascular myxoid change.
- Ancillary: Demonstrates diffuse, strong GFAP, S100, and CD99 immunoreactivity; notably, AE1/AE3 pancytokeratin is often positive while EMA and OLIG2 are typically negative.
- Genetics: Recurrent chromosomal findings include gains of chromosome 16 and losses of chromosome 10, with a unique DNA methylation profile.
Reference Gallery:
Myxopapillary ependymoma. The well-circumscribed, contrast-enhancing primary tumour in the filum is associated with a drop metastasis in the low thecal sac.
Myxopapillary ependymoma. Epithelioid tumour cells are arranged around fibrovascular cores and microcysts containing myxoid material.
Myxopapillary ependymoma. Tapering tumour cell processes are oriented towards a fibrovascular core with collaring myxoid matrix.
Myxopapillary ependymoma. Tumour cells are diffusely and strongly GFAP-immunoreactive.
Myxopapillary ependymoma. Papillary structure, perivascular myxoid change, and spindled tumour cells oriented towards fibromyxoid cores are evident in this smear preparation.

Q: A classic architectural feature of Posterior fossa ependymoma is the presence of [...], characterized by tumor cells radially arranged around blood vessels with an intervening anucleate zone.
Posterior fossa ependymoma. Perivascular pseudorosettes are characterized by tumour cells radially arranged around blood vessels with an intervening anucleate zone.
Posterior fossa ependymoma. True ependymal rosettes characterized by periluminal cuboidal or columnar cells without a basement membrane.
A: perivascular pseudorosettes
Back Extra: Posterior fossa ependymoma
- Clinical: Commonly arises in the fourth ventricle (floor, roof, or lateral cerebellar peduncles) and can occur in the cerebellopontine angle. Symptoms involve mass effect and secondary hydrocephalus, including headache, vomiting, …
- Micro: The tumor is circumscribed and composed of uniform small cells with round nuclei and indistinct cytoplasmic borders. Architecture: - Perivascular pseudorosettes: Cells arranged radially around blood vessels with a…
- Cyto: Cytological preparations show uniform cells with round nuclei and sparse delicate cytoplasmic processes. Tumour cells often form clusters and palisades around vascular structures, reflecting the arrangement of perivascul…
- Ancillary: Immunohistochemistry (IHC): - S100/GFAP: Usually positive, particularly accentuated in perivascular pseudorosettes. - EMA: Paranuclear dot-like pattern or ring-like structures. - H3 p.K28me3 (K27me3): Los…
Reference Gallery:
Posterior fossa ependymoma. MRI shows a tumour in the fourth ventricle (arrows). Note that the aqueduct of Sylvius and the third ventricle are enlarged.
Posterior fossa ependymoma. Perivascular pseudorosettes are characterized by tumour cells radially arranged around blood vessels with an intervening anucleate zone.
Posterior fossa ependymoma. True ependymal rosettes characterized by periluminal cuboidal or columnar cells without a basement membrane.
Posterior fossa ependymoma. Immunoreactivity for EMA typically shows a paranuclear dot-like pattern and occurs along the luminal surface of true ependymal rosettes.
Posterior fossa ependymoma. CNS WHO grade 3 posterior fossa ependymoma showing plentiful mitotic activity but little nuclear pleomorphism.
Posterior fossa ependymoma. Microvascular proliferation typically characterized by multilayered endothelial cells.
Posterior fossa ependymoma. At the ultrastructural level, the cells of an ependymoma typically show cilia with a 9 + 2 microtubular pattern and microvilli at luminal surfaces.
Posterior fossa ependymoma. Immunoreactivity for GFAP is typically present in many (but not all) tumour cells. Note accentuation of staining in perivascular pseudorosettes.
Posterior fossa ependymoma. Immunoreactivity for NFP highlights axons in surrounding brain parenchyma and demonstrates the pushing border of the tumour.
Posterior fossa ependymoma. Palisading necrosis.
Posterior fossa ependymoma. Ependymoma in the fourth ventricle (arrows) displacing adjacent posterior fossa structures.
Posterior fossa ependymoma. A pseudopapillary pattern with finger-like projections lined by a single layer or multiple layers of cuboidal cells.

Q: In Posterior fossa ependymoma, immunohistochemical staining for EMA characteristically shows a [...] pattern, often located along the luminal surface of true rosettes.
Posterior fossa ependymoma. Immunoreactivity for EMA typically shows a paranuclear dot-like pattern and occurs along the luminal surface of true ependymal rosettes.
A: paranuclear dot-like
Back Extra: Posterior fossa ependymoma
- Clinical: Commonly arises in the fourth ventricle (floor, roof, or lateral cerebellar peduncles) and can occur in the cerebellopontine angle. Symptoms involve mass effect and secondary hydrocephalus, including headache, vomiting, …
- Micro: The tumor is circumscribed and composed of uniform small cells with round nuclei and indistinct cytoplasmic borders. Architecture: - Perivascular pseudorosettes: Cells arranged radially around blood vessels with a…
- Cyto: Cytological preparations show uniform cells with round nuclei and sparse delicate cytoplasmic processes. Tumour cells often form clusters and palisades around vascular structures, reflecting the arrangement of perivascul…
- Ancillary: Immunohistochemistry (IHC): - S100/GFAP: Usually positive, particularly accentuated in perivascular pseudorosettes. - EMA: Paranuclear dot-like pattern or ring-like structures. - H3 p.K28me3 (K27me3): Los…
Reference Gallery:
Posterior fossa ependymoma. MRI shows a tumour in the fourth ventricle (arrows). Note that the aqueduct of Sylvius and the third ventricle are enlarged.
Posterior fossa ependymoma. Perivascular pseudorosettes are characterized by tumour cells radially arranged around blood vessels with an intervening anucleate zone.
Posterior fossa ependymoma. True ependymal rosettes characterized by periluminal cuboidal or columnar cells without a basement membrane.
Posterior fossa ependymoma. Immunoreactivity for EMA typically shows a paranuclear dot-like pattern and occurs along the luminal surface of true ependymal rosettes.
Posterior fossa ependymoma. CNS WHO grade 3 posterior fossa ependymoma showing plentiful mitotic activity but little nuclear pleomorphism.
Posterior fossa ependymoma. Microvascular proliferation typically characterized by multilayered endothelial cells.
Posterior fossa ependymoma. At the ultrastructural level, the cells of an ependymoma typically show cilia with a 9 + 2 microtubular pattern and microvilli at luminal surfaces.
Posterior fossa ependymoma. Immunoreactivity for GFAP is typically present in many (but not all) tumour cells. Note accentuation of staining in perivascular pseudorosettes.
Posterior fossa ependymoma. Immunoreactivity for NFP highlights axons in surrounding brain parenchyma and demonstrates the pushing border of the tumour.
Posterior fossa ependymoma. Palisading necrosis.
Posterior fossa ependymoma. Ependymoma in the fourth ventricle (arrows) displacing adjacent posterior fossa structures.
Posterior fossa ependymoma. A pseudopapillary pattern with finger-like projections lined by a single layer or multiple layers of cuboidal cells.

Q: At the ultrastructural level, the cells of a Posterior fossa ependymoma typically demonstrate apical microvilli and [...] with a classic 9 + 2 microtubular pattern.
Posterior fossa ependymoma. At the ultrastructural level, the cells of an ependymoma typically show cilia with a 9 + 2 microtubular pattern and microvilli at luminal surfaces.
A: cilia
Back Extra: Posterior fossa ependymoma
- Clinical: Commonly arises in the fourth ventricle (floor, roof, or lateral cerebellar peduncles) and can occur in the cerebellopontine angle. Symptoms involve mass effect and secondary hydrocephalus, including headache, vomiting, …
- Micro: The tumor is circumscribed and composed of uniform small cells with round nuclei and indistinct cytoplasmic borders. Architecture: - Perivascular pseudorosettes: Cells arranged radially around blood vessels with a…
- Cyto: Cytological preparations show uniform cells with round nuclei and sparse delicate cytoplasmic processes. Tumour cells often form clusters and palisades around vascular structures, reflecting the arrangement of perivascul…
- Ancillary: Immunohistochemistry (IHC): - S100/GFAP: Usually positive, particularly accentuated in perivascular pseudorosettes. - EMA: Paranuclear dot-like pattern or ring-like structures. - H3 p.K28me3 (K27me3): Los…
Reference Gallery:
Posterior fossa ependymoma. MRI shows a tumour in the fourth ventricle (arrows). Note that the aqueduct of Sylvius and the third ventricle are enlarged.
Posterior fossa ependymoma. Perivascular pseudorosettes are characterized by tumour cells radially arranged around blood vessels with an intervening anucleate zone.
Posterior fossa ependymoma. True ependymal rosettes characterized by periluminal cuboidal or columnar cells without a basement membrane.
Posterior fossa ependymoma. Immunoreactivity for EMA typically shows a paranuclear dot-like pattern and occurs along the luminal surface of true ependymal rosettes.
Posterior fossa ependymoma. CNS WHO grade 3 posterior fossa ependymoma showing plentiful mitotic activity but little nuclear pleomorphism.
Posterior fossa ependymoma. Microvascular proliferation typically characterized by multilayered endothelial cells.
Posterior fossa ependymoma. At the ultrastructural level, the cells of an ependymoma typically show cilia with a 9 + 2 microtubular pattern and microvilli at luminal surfaces.
Posterior fossa ependymoma. Immunoreactivity for GFAP is typically present in many (but not all) tumour cells. Note accentuation of staining in perivascular pseudorosettes.
Posterior fossa ependymoma. Immunoreactivity for NFP highlights axons in surrounding brain parenchyma and demonstrates the pushing border of the tumour.
Posterior fossa ependymoma. Palisading necrosis.
Posterior fossa ependymoma. Ependymoma in the fourth ventricle (arrows) displacing adjacent posterior fossa structures.
Posterior fossa ependymoma. A pseudopapillary pattern with finger-like projections lined by a single layer or multiple layers of cuboidal cells.

Q: Immunohistochemically, Posterior fossa group A (PFA) ependymoma is characteristically defined by the global loss of nuclear [...] (with retained expression in internal endothelial controls).
Posterior fossa group A (PFA) ependymoma. In most examples of this tumour type, immunoreactivity for H3 p.K28me3 (K27me3) in tumour cells is lost.
Posterior fossa group A (PFA) ependymoma. Subtle pseudorosette formation and a high cell density characterize some PFA ependymomas.
A: H3 p.K28me3 (K27me3)
Back Extra: Posterior fossa group A (PFA) ependymoma
- Clinical: Predominantly occurs in infants and young children (median age 3 years), accounting for >95% of PF ependymomas in patients under age 6.
- Microscopic: Characterized by uniform small cells with round nuclei, fibrillary matrix, and ependymal or perivascular pseudorosettes; high-grade features (mitoses/necrosis) are common.
- Ancillary (IHC): Defined by global loss of nuclear H3 p.K28me3 (K27me3) immunoreactivity (with retained endothelial control) and EZHIP overexpression.
- Prognosis: Significantly worse prognosis than PFB ependymomas; chromosome 1q gain is a key adverse prognostic indicator.
Reference Gallery:
Posterior fossa ependymoma. PFA ependymoma (EPN-PFA), sometimes referred to as “infantile posterior fossa ependymoma”, predominantly occurs in infants and children.
Posterior fossa group A (PFA) ependymoma. In most examples of this tumour type, immunoreactivity for H3 p.K28me3 (K27me3) in tumour cells is lost.
Posterior fossa group A (PFA) ependymoma. Immunoreactivity for H3 p.K28me3 (K27me3) can sometimes be retained in a variable proportion of tumour cells.
Posterior fossa group A (PFA) ependymoma. Nodules of high cell density are common in PFA ependymomas.
Posterior fossa group A (PFA) ependymoma. Subtle pseudorosette formation and a high cell density characterize some PFA ependymomas.

Q: Histologically, Posterior fossa group A (PFA) ependymoma often demonstrates nodules of high cell density and classic ependymal or [...] within a fibrillary matrix.
Posterior fossa group A (PFA) ependymoma. Nodules of high cell density are common in PFA ependymomas.
Posterior fossa group A (PFA) ependymoma. Subtle pseudorosette formation and a high cell density characterize some PFA ependymomas.
A: perivascular pseudorosettes
Back Extra: Posterior fossa group A (PFA) ependymoma
- Clinical: Predominantly occurs in infants and young children (median age 3 years), accounting for >95% of PF ependymomas in patients under age 6.
- Microscopic: Characterized by uniform small cells with round nuclei, fibrillary matrix, and ependymal or perivascular pseudorosettes; high-grade features (mitoses/necrosis) are common.
- Ancillary (IHC): Defined by global loss of nuclear H3 p.K28me3 (K27me3) immunoreactivity (with retained endothelial control) and EZHIP overexpression.
- Prognosis: Significantly worse prognosis than PFB ependymomas; chromosome 1q gain is a key adverse prognostic indicator.
Reference Gallery:
Posterior fossa ependymoma. PFA ependymoma (EPN-PFA), sometimes referred to as “infantile posterior fossa ependymoma”, predominantly occurs in infants and children.
Posterior fossa group A (PFA) ependymoma. In most examples of this tumour type, immunoreactivity for H3 p.K28me3 (K27me3) in tumour cells is lost.
Posterior fossa group A (PFA) ependymoma. Immunoreactivity for H3 p.K28me3 (K27me3) can sometimes be retained in a variable proportion of tumour cells.
Posterior fossa group A (PFA) ependymoma. Nodules of high cell density are common in PFA ependymomas.
Posterior fossa group A (PFA) ependymoma. Subtle pseudorosette formation and a high cell density characterize some PFA ependymomas.

Q: In Posterior fossa group B (PFB) ependymoma, which often presents as a fourth ventricle mass on MRI, histology characteristically shows a pseudopapillary pattern with perivascular [...].
Posterior fossa group B (PFB) ependymoma. T1-weighted MRI shows a large tumour in the fourth ventricle of a 37-year-old man.
Posterior fossa group B (PFB) ependymoma. Pseudopapillary architectural pattern featuring finger-like projections and perivascular pseudorosettes.
A: pseudorosettes
Back Extra: Posterior fossa group B (PFB) ependymoma
- Clinical: PFB ependymomas occur predominantly in adults (median age: 30 years) and are more common in adolescents than in children; they represent < 5% of ependymomas in infants and young children (< 5 years). They arise in the fo…
- Micro: PFB ependymomas demonstrate the typical histopathological features of ependymomas: - Architecture: Circumscribed growth with perivascular pseudorosettes and/or ependymal rosettes. - Cytology: Uniform small cells …
- Cyto: Cytological preparations generally show: - Cellular Morphology: Uniform cells with round nuclei and sparse, delicate cytoplasmic processes. - Nuclear features: Mild pleomorphism, which is exaggerated in the rare …
- Ancillary: 1) Immunohistochemistry (IHC): - H3 p.K28me3 (K27me3): Retention of nuclear expression is observed in practically all PFB ependymomas. While required for diagnosis, this finding is not entirely specific. 2) Mo…
Reference Gallery:
Posterior fossa group B (PFB) ependymoma. T1-weighted MRI shows a large tumour in the fourth ventricle of a 37-year-old man.
Posterior fossa group B (PFB) ependymoma. Pseudopapillary architectural pattern featuring finger-like projections and perivascular pseudorosettes.
Posterior fossa group B (PFB) ependymoma. Expression of H3 p.K28me3 (K27me3) is present in all tumour cells.

Q: Unlike group A tumors, a defining immunohistochemical feature of Posterior fossa group B (PFB) ependymoma is the diffuse [...] of nuclear H3 p.K28me3 (K27me3) expression.
Posterior fossa group B (PFB) ependymoma. Pseudopapillary architectural pattern featuring finger-like projections and perivascular pseudorosettes.
Posterior fossa group B (PFB) ependymoma. Expression of H3 p.K28me3 (K27me3) is present in all tumour cells.
A: retention
Back Extra: Posterior fossa group B (PFB) ependymoma
- Clinical: PFB ependymomas occur predominantly in adults (median age: 30 years) and are more common in adolescents than in children; they represent < 5% of ependymomas in infants and young children (< 5 years). They arise in the fo…
- Micro: PFB ependymomas demonstrate the typical histopathological features of ependymomas: - Architecture: Circumscribed growth with perivascular pseudorosettes and/or ependymal rosettes. - Cytology: Uniform small cells …
- Cyto: Cytological preparations generally show: - Cellular Morphology: Uniform cells with round nuclei and sparse, delicate cytoplasmic processes. - Nuclear features: Mild pleomorphism, which is exaggerated in the rare …
- Ancillary: 1) Immunohistochemistry (IHC): - H3 p.K28me3 (K27me3): Retention of nuclear expression is observed in practically all PFB ependymomas. While required for diagnosis, this finding is not entirely specific. 2) Mo…
Reference Gallery:
Posterior fossa group B (PFB) ependymoma. T1-weighted MRI shows a large tumour in the fourth ventricle of a 37-year-old man.
Posterior fossa group B (PFB) ependymoma. Pseudopapillary architectural pattern featuring finger-like projections and perivascular pseudorosettes.
Posterior fossa group B (PFB) ependymoma. Expression of H3 p.K28me3 (K27me3) is present in all tumour cells.

Q: The hallmark microscopic feature of Spinal ependymoma consists of tumor cells arranged around blood vessels with an intervening anucleate zone, termed [...].
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
A: perivascular pseudorosettes
Back Extra: Spinal ependymoma
- Clinical: Typically presents as a contrast-enhancing intramedullary mass in the cervical or cervicothoracic spinal cord, often associated with syringomyelia (60%).
- Microscopic: Characterized by isomorphic glial cells with round/oval nuclei forming "perivascular pseudorosettes" (anucleate zones around vessels) and less common true ependymal rosettes.
- Ancillary: Shows diffuse GFAP and S100 expression, with a characteristic focal "dot-like" or ring-like EMA immunoreactivity pattern.
- Genetics: Often demonstrates chromosome 22q loss and somatic NF2 mutations; MYCN amplification is absent by definition for this entity.
- Prognosis: Generally favorable (CNS WHO grade 2), though recurrence can occur; extent of resection is the most critical prognostic factor.
Reference Gallery:
Spinal ependymoma, CNS WHO grade 2. Sagittal T1-weighted MRI of a spinal ependymoma showing gadolinium contrast enhancement.
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
Spinal ependymoma. Tumour showing characteristic GFAP immunoreactivity, enriched in perivascular areas.
Spinal ependymoma. Tumour showing intracytoplasmic dot-like EMA immunoreactivity corresponding to microlumina.

Q: Immunohistochemistry for Spinal ependymoma typically shows diffuse GFAP expression along with characteristic [...] or ring-like positivity for EMA.
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
Spinal ependymoma. Tumour showing characteristic GFAP immunoreactivity, enriched in perivascular areas.
Spinal ependymoma. Tumour showing intracytoplasmic dot-like EMA immunoreactivity corresponding to microlumina.
A: dot-like
Back Extra: Spinal ependymoma
- Clinical: Typically presents as a contrast-enhancing intramedullary mass in the cervical or cervicothoracic spinal cord, often associated with syringomyelia (60%).
- Microscopic: Characterized by isomorphic glial cells with round/oval nuclei forming "perivascular pseudorosettes" (anucleate zones around vessels) and less common true ependymal rosettes.
- Ancillary: Shows diffuse GFAP and S100 expression, with a characteristic focal "dot-like" or ring-like EMA immunoreactivity pattern.
- Genetics: Often demonstrates chromosome 22q loss and somatic NF2 mutations; MYCN amplification is absent by definition for this entity.
- Prognosis: Generally favorable (CNS WHO grade 2), though recurrence can occur; extent of resection is the most critical prognostic factor.
Reference Gallery:
Spinal ependymoma, CNS WHO grade 2. Sagittal T1-weighted MRI of a spinal ependymoma showing gadolinium contrast enhancement.
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
Spinal ependymoma. Tumour showing characteristic GFAP immunoreactivity, enriched in perivascular areas.
Spinal ependymoma. Tumour showing intracytoplasmic dot-like EMA immunoreactivity corresponding to microlumina.

Q: Genetically, Spinal ependymoma is frequently associated with chromosome 22q loss and somatic mutations in the [...] gene.
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
A: NF2
Back Extra: Spinal ependymoma
- Clinical: Typically presents as a contrast-enhancing intramedullary mass in the cervical or cervicothoracic spinal cord, often associated with syringomyelia (60%).
- Microscopic: Characterized by isomorphic glial cells with round/oval nuclei forming "perivascular pseudorosettes" (anucleate zones around vessels) and less common true ependymal rosettes.
- Ancillary: Shows diffuse GFAP and S100 expression, with a characteristic focal "dot-like" or ring-like EMA immunoreactivity pattern.
- Genetics: Often demonstrates chromosome 22q loss and somatic NF2 mutations; MYCN amplification is absent by definition for this entity.
- Prognosis: Generally favorable (CNS WHO grade 2), though recurrence can occur; extent of resection is the most critical prognostic factor.
Reference Gallery:
Spinal ependymoma, CNS WHO grade 2. Sagittal T1-weighted MRI of a spinal ependymoma showing gadolinium contrast enhancement.
Spinal ependymoma. Tumour showing characteristic perivascular anucleate areas (pseudorosettes).
Spinal ependymoma. Tumour showing characteristic GFAP immunoreactivity, enriched in perivascular areas.
Spinal ependymoma. Tumour showing intracytoplasmic dot-like EMA immunoreactivity corresponding to microlumina.

Q: An aggressive tumor of the cervical or thoracic spine that exhibits high cell density, vague pseudorosettes, and extensive nuclear expression of MYCN by immunohistochemistry is diagnostic of [...].
Spinal ependymoma, MYCN-amplified. High cell density, mitotic activity, and vague pseudorosette formation are present.
Spinal ependymoma, MYCN-amplified. Extensive nuclear expression of MYCN is detected by immunohistochemistry.
A: Spinal ependymoma, MYCN-amplified
Back Extra: Spinal ependymoma, MYCN-amplified
- Clinical: An aggressive tumor primarily affecting the cervical or thoracic spine (median age 31 years); frequent leptomeningeal dissemination is a hallmark of its clinical course.
- Microscopic: Characterized by high cell density, pseudorosettes, and frequent high-grade features including brisk mitotic activity, microvascular proliferation, and necrosis.
- Ancillary: Requires demonstration of high-level MYCN amplification; IHC often shows GFAP positivity and a focal cytoplasmic "dot-like" pattern of EMA expression.
- Differential: Must be distinguished from neuroblastoma and MYCN-amplified pediatric-type glioblastoma via DNA methylation profiling.
Reference Gallery:
Spinal ependymoma, MYCN-amplified. Tumour with a focal pseudopapillary architecture and densely packed cells.
Spinal ependymoma, MYCN-amplified. High cell density, mitotic activity, and vague pseudorosette formation are present.
Spinal ependymoma, MYCN-amplified. Immunohistochemistry shows many tumour cells expressing GFAP, which is typically present in perivascular radiating processes.
Spinal ependymoma, MYCN-amplified. Nuclear immunoreactivity for H3 p.K28me3 (K27me3) can be completely lost, partially lost (as shown here), or retained.
Spinal ependymoma, MYCN-amplified. Electron microscopy. Intercellular junctions end at a microlumen filled with microvilli, typical of ependymal differentiation. Cilia (black-and-white arrows) and basal bodies (black arrows) are also present.
Spinal ependymoma, MYCN-amplified. Chromosomal microarray showing amplification of 2p24.3-p24.2, including MYCN.
Spinal ependymoma, MYCN-amplified. Extensive nuclear expression of MYCN is detected by immunohistochemistry.

Q: By definition, the diagnosis of Spinal ependymoma, MYCN-amplified requires the demonstration of high-level [...] (e.g., via chromosomal microarray showing amplification at 2p24.3-p24.2).
Spinal ependymoma, MYCN-amplified. Tumour with a focal pseudopapillary architecture and densely packed cells.
Spinal ependymoma, MYCN-amplified. Chromosomal microarray showing amplification of 2p24.3-p24.2, including MYCN.
A: MYCN amplification
Back Extra: Spinal ependymoma, MYCN-amplified
- Clinical: An aggressive tumor primarily affecting the cervical or thoracic spine (median age 31 years); frequent leptomeningeal dissemination is a hallmark of its clinical course.
- Microscopic: Characterized by high cell density, pseudorosettes, and frequent high-grade features including brisk mitotic activity, microvascular proliferation, and necrosis.
- Ancillary: Requires demonstration of high-level MYCN amplification; IHC often shows GFAP positivity and a focal cytoplasmic "dot-like" pattern of EMA expression.
- Differential: Must be distinguished from neuroblastoma and MYCN-amplified pediatric-type glioblastoma via DNA methylation profiling.
Reference Gallery:
Spinal ependymoma, MYCN-amplified. Tumour with a focal pseudopapillary architecture and densely packed cells.
Spinal ependymoma, MYCN-amplified. High cell density, mitotic activity, and vague pseudorosette formation are present.
Spinal ependymoma, MYCN-amplified. Immunohistochemistry shows many tumour cells expressing GFAP, which is typically present in perivascular radiating processes.
Spinal ependymoma, MYCN-amplified. Nuclear immunoreactivity for H3 p.K28me3 (K27me3) can be completely lost, partially lost (as shown here), or retained.
Spinal ependymoma, MYCN-amplified. Electron microscopy. Intercellular junctions end at a microlumen filled with microvilli, typical of ependymal differentiation. Cilia (black-and-white arrows) and basal bodies (black arrows) are also present.
Spinal ependymoma, MYCN-amplified. Chromosomal microarray showing amplification of 2p24.3-p24.2, including MYCN.
Spinal ependymoma, MYCN-amplified. Extensive nuclear expression of MYCN is detected by immunohistochemistry.

Q: In addition to its defining molecular driver, Spinal ependymoma, MYCN-amplified may exhibit complete or partial loss of nuclear immunoreactivity for [...] by immunohistochemistry.
Spinal ependymoma, MYCN-amplified. High cell density, mitotic activity, and vague pseudorosette formation are present.
Spinal ependymoma, MYCN-amplified. Nuclear immunoreactivity for H3 p.K28me3 (K27me3) can be completely lost, partially lost (as shown here), or retained.
A: H3 K27me3
Back Extra: Spinal ependymoma, MYCN-amplified
- Clinical: An aggressive tumor primarily affecting the cervical or thoracic spine (median age 31 years); frequent leptomeningeal dissemination is a hallmark of its clinical course.
- Microscopic: Characterized by high cell density, pseudorosettes, and frequent high-grade features including brisk mitotic activity, microvascular proliferation, and necrosis.
- Ancillary: Requires demonstration of high-level MYCN amplification; IHC often shows GFAP positivity and a focal cytoplasmic "dot-like" pattern of EMA expression.
- Differential: Must be distinguished from neuroblastoma and MYCN-amplified pediatric-type glioblastoma via DNA methylation profiling.
Reference Gallery:
Spinal ependymoma, MYCN-amplified. Tumour with a focal pseudopapillary architecture and densely packed cells.
Spinal ependymoma, MYCN-amplified. High cell density, mitotic activity, and vague pseudorosette formation are present.
Spinal ependymoma, MYCN-amplified. Immunohistochemistry shows many tumour cells expressing GFAP, which is typically present in perivascular radiating processes.
Spinal ependymoma, MYCN-amplified. Nuclear immunoreactivity for H3 p.K28me3 (K27me3) can be completely lost, partially lost (as shown here), or retained.
Spinal ependymoma, MYCN-amplified. Electron microscopy. Intercellular junctions end at a microlumen filled with microvilli, typical of ependymal differentiation. Cilia (black-and-white arrows) and basal bodies (black arrows) are also present.
Spinal ependymoma, MYCN-amplified. Chromosomal microarray showing amplification of 2p24.3-p24.2, including MYCN.
Spinal ependymoma, MYCN-amplified. Extensive nuclear expression of MYCN is detected by immunohistochemistry.

Q: Histologically, a [...] is characterized by small, uniform cells exhibiting prominent nuclear clustering embedded in a voluminous fibrillary matrix, often with microcystic changes.
Subependymoma. Tumour cell nuclei cluster in a dense fibrillary matrix.
Subependymoma. Tumour cell nuclei are small, uniform, and without mitotic activity.
Subependymoma. Microcystic change in the fibrillary matrix is shown.
A: subependymoma
Back Extra: Subependymoma
- Clinical: Subependymomas are frequently asymptomatic and discovered incidentally. Symptomatic cases often present with ventricular obstruction or intracranial hypertension. On imaging, they are typically sharply demarcated, hypoin…
- Micro: The tumor is characterized by clusters of small, euchromatic, round to oval nuclei embedded in a voluminous fibrillary matrix of cytoplasmic processes. Common features include microcystic changes, calcifications, and scl…
- Cyto: Smear and squash preparations demonstrate uniform round or oval nuclei, nuclear clustering, and a fibrillary matrix. Myxoid and microcystic changes may also be present.
- Ancillary: Immunohistochemistry (IHC): - Positive: Diffuse GFAP reactivity; focal dot-like EMA expression (less frequent than in ependymoma). Expression of aquaporin-1, aquaporin-4, HIF1α, and phosphorylated STAT3 is report…
Reference Gallery:
Subependymoma. A sharply circumscribed, intraventricular mass with foci of wispy contrast enhancement is demonstrated in this T1-weighted MRI.
Subependymoma. Tumour cell nuclei cluster in a dense fibrillary matrix.
Subependymoma. Tumour cell nuclei are small, uniform, and without mitotic activity.
Subependymoma. Microcystic change in the fibrillary matrix is shown.

Q: On T1-weighted MRI, a [...] classically presents as a sharply circumscribed, intraventricular mass that may exhibit foci of wispy contrast enhancement.
Subependymoma. A sharply circumscribed, intraventricular mass with foci of wispy contrast enhancement is demonstrated in this T1-weighted MRI.
A: subependymoma
Back Extra: Subependymoma
- Clinical: Subependymomas are frequently asymptomatic and discovered incidentally. Symptomatic cases often present with ventricular obstruction or intracranial hypertension. On imaging, they are typically sharply demarcated, hypoin…
- Micro: The tumor is characterized by clusters of small, euchromatic, round to oval nuclei embedded in a voluminous fibrillary matrix of cytoplasmic processes. Common features include microcystic changes, calcifications, and scl…
- Cyto: Smear and squash preparations demonstrate uniform round or oval nuclei, nuclear clustering, and a fibrillary matrix. Myxoid and microcystic changes may also be present.
- Ancillary: Immunohistochemistry (IHC): - Positive: Diffuse GFAP reactivity; focal dot-like EMA expression (less frequent than in ependymoma). Expression of aquaporin-1, aquaporin-4, HIF1α, and phosphorylated STAT3 is report…
Reference Gallery:
Subependymoma. A sharply circumscribed, intraventricular mass with foci of wispy contrast enhancement is demonstrated in this T1-weighted MRI.
Subependymoma. Tumour cell nuclei cluster in a dense fibrillary matrix.
Subependymoma. Tumour cell nuclei are small, uniform, and without mitotic activity.
Subependymoma. Microcystic change in the fibrillary matrix is shown.

Q: In Supratentorial ependymoma, a frequently observed cytological feature is the [...] phenotype, which is often seen alongside a characteristic branching network of small blood vessels.
Supratentorial ependymoma. A branching network of small blood vessels is a frequent architectural feature of supratentorial ependymomas. Perivascular anucleate zones can be subtle.
Supratentorial ependymoma. Clear cell change is a frequent cytological feature of supratentorial ependymomas. Nuclear pleomorphism is mild in most cases, and the number of mitotic figures can be variable.
A: clear cell
Back Extra: Supratentorial ependymoma
- Clinical: Affects both children and adults, typically presenting with focal neurological deficits, seizures, or symptoms of raised intracranial pressure (hydrocephalus).
- Microscopic: Characterized by uniform small cells in a fibrillary matrix, perivascular pseudorosettes, and a characteristic "branching network of small blood vessels."
- Cytology: Frequently displays a "clear cell phenotype," which is more common in the supratentorial compartment than in posterior fossa or spinal ependymomas.
- Ancillary: Shows characteristic EMA "paranuclear dot-like" staining and variable GFAP expression; diagnosis requires excluding ZFTA and YAP1 fusions.
- Prognosis: Complete surgical resection is the most significant predictor of survival; approximately 15% of cases may develop cerebrospinal fluid spread.
Reference Gallery:
Supratentorial ependymoma. T2-weighted axial MRI showing a large circumscribed mass in the cerebral hemisphere.
Supratentorial ependymoma. A branching network of small blood vessels is a frequent architectural feature of supratentorial ependymomas. Perivascular anucleate zones can be subtle.
Supratentorial ependymoma. Ependymal rosettes are present in a minority of cases.
Supratentorial ependymoma. Clear cell change is a frequent cytological feature of supratentorial ependymomas. Nuclear pleomorphism is mild in most cases, and the number of mitotic figures can be variable.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.
Supratentorial ependymoma. OLIG2 is usually present in sparse tumour cells.
Supratentorial ependymoma. T1-weighted gadolinium-enhanced axial MRI in an adult, showing an intraventricular nodular lesion with heterogeneous contrast enhancement and solid and cystic components.
Supratentorial ependymoma. Immunoreactivity for EMA is present in a variable number of tumour cells and usually manifests as paranuclear dots or ring structures.
Supratentorial ependymoma. Nuclear pleomorphism is mild in most cases, but it can be marked in some cases.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.

Q: The characteristic EMA immunohistochemical staining pattern seen in Supratentorial ependymoma consists of [...] or ring structures.
Supratentorial ependymoma. Immunoreactivity for EMA is present in a variable number of tumour cells and usually manifests as paranuclear dots or ring structures.
A: paranuclear dots
Back Extra: Supratentorial ependymoma
- Clinical: Affects both children and adults, typically presenting with focal neurological deficits, seizures, or symptoms of raised intracranial pressure (hydrocephalus).
- Microscopic: Characterized by uniform small cells in a fibrillary matrix, perivascular pseudorosettes, and a characteristic "branching network of small blood vessels."
- Cytology: Frequently displays a "clear cell phenotype," which is more common in the supratentorial compartment than in posterior fossa or spinal ependymomas.
- Ancillary: Shows characteristic EMA "paranuclear dot-like" staining and variable GFAP expression; diagnosis requires excluding ZFTA and YAP1 fusions.
- Prognosis: Complete surgical resection is the most significant predictor of survival; approximately 15% of cases may develop cerebrospinal fluid spread.
Reference Gallery:
Supratentorial ependymoma. T2-weighted axial MRI showing a large circumscribed mass in the cerebral hemisphere.
Supratentorial ependymoma. A branching network of small blood vessels is a frequent architectural feature of supratentorial ependymomas. Perivascular anucleate zones can be subtle.
Supratentorial ependymoma. Ependymal rosettes are present in a minority of cases.
Supratentorial ependymoma. Clear cell change is a frequent cytological feature of supratentorial ependymomas. Nuclear pleomorphism is mild in most cases, and the number of mitotic figures can be variable.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.
Supratentorial ependymoma. OLIG2 is usually present in sparse tumour cells.
Supratentorial ependymoma. T1-weighted gadolinium-enhanced axial MRI in an adult, showing an intraventricular nodular lesion with heterogeneous contrast enhancement and solid and cystic components.
Supratentorial ependymoma. Immunoreactivity for EMA is present in a variable number of tumour cells and usually manifests as paranuclear dots or ring structures.
Supratentorial ependymoma. Nuclear pleomorphism is mild in most cases, but it can be marked in some cases.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.

Q: Histologically, Supratentorial ependymoma typically features uniform small cells in a fibrillary matrix that form subtle [...] and occasionally true ependymal rosettes.
Supratentorial ependymoma. A branching network of small blood vessels is a frequent architectural feature of supratentorial ependymomas. Perivascular anucleate zones can be subtle.
Supratentorial ependymoma. Ependymal rosettes are present in a minority of cases.
A: perivascular pseudorosettes
Back Extra: Supratentorial ependymoma
- Clinical: Affects both children and adults, typically presenting with focal neurological deficits, seizures, or symptoms of raised intracranial pressure (hydrocephalus).
- Microscopic: Characterized by uniform small cells in a fibrillary matrix, perivascular pseudorosettes, and a characteristic "branching network of small blood vessels."
- Cytology: Frequently displays a "clear cell phenotype," which is more common in the supratentorial compartment than in posterior fossa or spinal ependymomas.
- Ancillary: Shows characteristic EMA "paranuclear dot-like" staining and variable GFAP expression; diagnosis requires excluding ZFTA and YAP1 fusions.
- Prognosis: Complete surgical resection is the most significant predictor of survival; approximately 15% of cases may develop cerebrospinal fluid spread.
Reference Gallery:
Supratentorial ependymoma. T2-weighted axial MRI showing a large circumscribed mass in the cerebral hemisphere.
Supratentorial ependymoma. A branching network of small blood vessels is a frequent architectural feature of supratentorial ependymomas. Perivascular anucleate zones can be subtle.
Supratentorial ependymoma. Ependymal rosettes are present in a minority of cases.
Supratentorial ependymoma. Clear cell change is a frequent cytological feature of supratentorial ependymomas. Nuclear pleomorphism is mild in most cases, and the number of mitotic figures can be variable.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.
Supratentorial ependymoma. OLIG2 is usually present in sparse tumour cells.
Supratentorial ependymoma. T1-weighted gadolinium-enhanced axial MRI in an adult, showing an intraventricular nodular lesion with heterogeneous contrast enhancement and solid and cystic components.
Supratentorial ependymoma. Immunoreactivity for EMA is present in a variable number of tumour cells and usually manifests as paranuclear dots or ring structures.
Supratentorial ependymoma. Nuclear pleomorphism is mild in most cases, but it can be marked in some cases.
Supratentorial ependymoma. By immunohistochemistry, GFAP is variably expressed in supratentorial ependymomas.

Q: In Supratentorial ependymoma, YAP1 fusion-positive, immunohistochemistry typically reveals widespread, strong, dot-like positivity for [...].
Supratentorial ependymoma, YAP1 fusion–positive. Small, slightly angulated nuclei set against a fibrillary matrix.
Supratentorial ependymoma, YAP1 fusion–positive. Typical widespread and strong dot-like EMA immunoreactivity.
A: EMA
Back Extra: Supratentorial ependymoma, YAP1 fusion-positive
- Clinical: This tumor predominantly affects young children, with a female predilection (M:F ratio 0.3:1). Patients often present with symptoms of raised intracranial pressure, focal neurological deficits, or seizures due to large t…
- Micro: The tumor is well-demarcated from the surrounding brain parenchyma. It consists of uniform cells with small to medium-sized round or angulated nuclei. Key features include: - Architecture: Presence of ependymal roset…
- Cyto: Cytological preparations generally show uniform cells with round nuclei and sparse, delicate cytoplasmic processes. Nuclear pleomorphism is mild but can be exaggerated in the rare giant cell phenotype.
- Ancillary: 1) Immunohistochemistry (IHC): - EMA: Widespread and strong immunoreactivity (often dot-like). - L1CAM: Negative. - p65 (RELA): Nuclear expression is negative. - PAX6: Positive (suggestive of radial g…
Reference Gallery:
Supratentorial ependymoma, YAP1 fusion–positive. Small, slightly angulated nuclei set against a fibrillary matrix.
Supratentorial ependymoma, YAP1 fusion–positive. Typical widespread and strong dot-like EMA immunoreactivity.
Supratentorial ependymoma, YAP1 fusion–positive. T2-weighted coronal MRI showing a large cystic tumour.
Supratentorial ependymoma, YAP1 fusion–positive. Ependymoma with YAP1::MAMLD1 fusion. T1-weighted axial MRI showing a large cystic tumour with contrast enhancement of solid tumour parts.

Q: A young female patient presents with a large brain tumor that appears markedly cystic with solid enhancing components on MRI. Biopsy shows uniform cells with slightly angulated nuclei set against a fibrillary matrix. This clinico-radiologic and histologic presentation is highly characteristic of [...].
Supratentorial ependymoma, YAP1 fusion–positive. Small, slightly angulated nuclei set against a fibrillary matrix.
Supratentorial ependymoma, YAP1 fusion–positive. Ependymoma with YAP1::MAMLD1 fusion. T1-weighted axial MRI showing a large cystic tumour with contrast enhancement of solid tumour parts.
A: Supratentorial ependymoma, YAP1 fusion-positive
Back Extra: Supratentorial ependymoma, YAP1 fusion-positive
- Clinical: This tumor predominantly affects young children, with a female predilection (M:F ratio 0.3:1). Patients often present with symptoms of raised intracranial pressure, focal neurological deficits, or seizures due to large t…
- Micro: The tumor is well-demarcated from the surrounding brain parenchyma. It consists of uniform cells with small to medium-sized round or angulated nuclei. Key features include: - Architecture: Presence of ependymal roset…
- Cyto: Cytological preparations generally show uniform cells with round nuclei and sparse, delicate cytoplasmic processes. Nuclear pleomorphism is mild but can be exaggerated in the rare giant cell phenotype.
- Ancillary: 1) Immunohistochemistry (IHC): - EMA: Widespread and strong immunoreactivity (often dot-like). - L1CAM: Negative. - p65 (RELA): Nuclear expression is negative. - PAX6: Positive (suggestive of radial g…
Reference Gallery:
Supratentorial ependymoma, YAP1 fusion–positive. Small, slightly angulated nuclei set against a fibrillary matrix.
Supratentorial ependymoma, YAP1 fusion–positive. Typical widespread and strong dot-like EMA immunoreactivity.
Supratentorial ependymoma, YAP1 fusion–positive. T2-weighted coronal MRI showing a large cystic tumour.
Supratentorial ependymoma, YAP1 fusion–positive. Ependymoma with YAP1::MAMLD1 fusion. T1-weighted axial MRI showing a large cystic tumour with contrast enhancement of solid tumour parts.

Q: Immunohistochemistry for Supratentorial ependymoma, ZFTA fusion-positive characteristically demonstrates universal cytoplasmic expression of [...] and specific nuclear immunoreactivity for p65.
Supratentorial ependymoma, ZFTA fusion–positive. Universal cytoplasmic expression of L1CAM.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching blood vessels and dystrophic calcification can be seen.
Supratentorial ependymoma, ZFTA fusion–positive. Nuclear immunoreactivity for p65 (encoded by RELA).
A: L1CAM
Back Extra: Supratentorial ependymoma, ZFTA fusion-positive
- Clinical: Presents as well-demarcated lesions in the frontal or parietal lobes; symptoms include seizures, focal neurological deficits, and signs of increased intracranial pressure.
- Micro: Composed of cells with round uniform nuclei and speckled chromatin in a fibrillary matrix, frequently featuring a network of branching capillary blood vessels and dystrophic calcification.
- Ancillary (IHC): Characterized by universal cytoplasmic expression of L1CAM and specific nuclear immunoreactivity for p65 (encoded by RELA).
- Molecular: Driven by ZFTA (formerly C11orf95) fusions, most commonly ZFTA::RELA, often resulting from chromothriptic events on chromosome 11.
- Prognosis: Generally carries the poorest outcome among supratentorial ependymomas; homozygous deletion of CDKN2A/B is an independent predictor of poor overall survival.
Reference Gallery:
Supratentorial ependymoma, ZFTA fusion–positive. Universal cytoplasmic expression of L1CAM.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching blood vessels and dystrophic calcification can be seen.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix with branching capillary blood vessels.
Supratentorial ependymoma, ZFTA fusion–positive. Nuclear immunoreactivity for p65 (encoded by RELA).
Supratentorial ependymoma, ZFTA fusion–positive. T1-weighted axial MRI with gadolinium, showing a well-demarcated left frontal lesion with heterogeneous contrast enhancement and areas of necrosis.
Supratentorial ependymoma, ZFTA fusion–positive. Coronal FLAIR MRI showing conspicuous surrounding oedema.
Supratentorial ependymoma, ZFTA fusion–positive. Copy-number profile derived from Illumina 450K array data, showing chromothripsis on chromosome 11.

Q: The molecular driver in Supratentorial ependymoma, ZFTA fusion-positive is often a fusion (e.g., ZFTA::RELA) resulting from massive genomic rearrangements known as chromothripsis occurring on chromosome [...].
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix with branching capillary blood vessels.
Supratentorial ependymoma, ZFTA fusion–positive. Copy-number profile derived from Illumina 450K array data, showing chromothripsis on chromosome 11.
A: 11
Back Extra: Supratentorial ependymoma, ZFTA fusion-positive
- Clinical: Presents as well-demarcated lesions in the frontal or parietal lobes; symptoms include seizures, focal neurological deficits, and signs of increased intracranial pressure.
- Micro: Composed of cells with round uniform nuclei and speckled chromatin in a fibrillary matrix, frequently featuring a network of branching capillary blood vessels and dystrophic calcification.
- Ancillary (IHC): Characterized by universal cytoplasmic expression of L1CAM and specific nuclear immunoreactivity for p65 (encoded by RELA).
- Molecular: Driven by ZFTA (formerly C11orf95) fusions, most commonly ZFTA::RELA, often resulting from chromothriptic events on chromosome 11.
- Prognosis: Generally carries the poorest outcome among supratentorial ependymomas; homozygous deletion of CDKN2A/B is an independent predictor of poor overall survival.
Reference Gallery:
Supratentorial ependymoma, ZFTA fusion–positive. Universal cytoplasmic expression of L1CAM.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching blood vessels and dystrophic calcification can be seen.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix with branching capillary blood vessels.
Supratentorial ependymoma, ZFTA fusion–positive. Nuclear immunoreactivity for p65 (encoded by RELA).
Supratentorial ependymoma, ZFTA fusion–positive. T1-weighted axial MRI with gadolinium, showing a well-demarcated left frontal lesion with heterogeneous contrast enhancement and areas of necrosis.
Supratentorial ependymoma, ZFTA fusion–positive. Coronal FLAIR MRI showing conspicuous surrounding oedema.
Supratentorial ependymoma, ZFTA fusion–positive. Copy-number profile derived from Illumina 450K array data, showing chromothripsis on chromosome 11.

Q: In patients with Supratentorial ependymoma, ZFTA fusion-positive, an independent molecular predictor of poor overall survival is the homozygous deletion of [...].
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching blood vessels and dystrophic calcification can be seen.
A: CDKN2A/B
Back Extra: Supratentorial ependymoma, ZFTA fusion-positive
- Clinical: Presents as well-demarcated lesions in the frontal or parietal lobes; symptoms include seizures, focal neurological deficits, and signs of increased intracranial pressure.
- Micro: Composed of cells with round uniform nuclei and speckled chromatin in a fibrillary matrix, frequently featuring a network of branching capillary blood vessels and dystrophic calcification.
- Ancillary (IHC): Characterized by universal cytoplasmic expression of L1CAM and specific nuclear immunoreactivity for p65 (encoded by RELA).
- Molecular: Driven by ZFTA (formerly C11orf95) fusions, most commonly ZFTA::RELA, often resulting from chromothriptic events on chromosome 11.
- Prognosis: Generally carries the poorest outcome among supratentorial ependymomas; homozygous deletion of CDKN2A/B is an independent predictor of poor overall survival.
Reference Gallery:
Supratentorial ependymoma, ZFTA fusion–positive. Universal cytoplasmic expression of L1CAM.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix. Branching blood vessels and dystrophic calcification can be seen.
Supratentorial ependymoma, ZFTA fusion–positive. Tumour cells with round nuclei set in a fibrillary matrix with branching capillary blood vessels.
Supratentorial ependymoma, ZFTA fusion–positive. Nuclear immunoreactivity for p65 (encoded by RELA).
Supratentorial ependymoma, ZFTA fusion–positive. T1-weighted axial MRI with gadolinium, showing a well-demarcated left frontal lesion with heterogeneous contrast enhancement and areas of necrosis.
Supratentorial ependymoma, ZFTA fusion–positive. Coronal FLAIR MRI showing conspicuous surrounding oedema.
Supratentorial ependymoma, ZFTA fusion–positive. Copy-number profile derived from Illumina 450K array data, showing chromothripsis on chromosome 11.

Q: Meningiomas arising in the setting of BAP1 tumour predisposition syndrome often display aggressive behavior and characteristically exhibit papillary or [...] cytomorphology.
BAP1 meningioma showing mixed rhabdoid and papillary features in a patient with a germline BAP1 truncating mutation.
Meningioma with prominent rhabdoid features arising in the setting of BAP1 tumour predisposition syndrome.
A: rhabdoid
Back Extra: BAP1 tumour predisposition syndrome
- Clinical: Autosomal dominant syndrome caused by germline pathogenic variants in BAP1 (3p21.1), predisposing to uveal melanoma, mesothelioma, renal cell carcinoma, and cutaneous melanoma.
- Microscopic: Meningiomas in this syndrome are often aggressive and frequently display "rhabdoid" or "papillary" cytomorphology.
- Ancillary: Loss of nuclear BAP1 protein expression by immunohistochemistry (IHC) serves as a highly sensitive and specific surrogate for BAP1 gene inactivation.
- Clinical Indicator: Histologically distinctive BAP1-inactivated naevi (melanocytomas) occur in approximately 75% of germline carriers and are a key diagnostic clue.
Reference Gallery:
BAP1 meningioma showing mixed rhabdoid and papillary features in a patient with a germline BAP1 truncating mutation.
BAP1 immunohistochemistry: Nuclear expression is lost in neoplastic cells and retained in non-neoplastic internal control cells.
Meningioma with prominent rhabdoid features arising in the setting of BAP1 tumour predisposition syndrome.
High-power view of BAP1 IHC showing loss of nuclear reactivity in rhabdoid neoplastic cells.
Poorly differentiated region of a BAP1-deficient meningioma.
BAP1 expression is lost in poorly differentiated tumour cells while retained in associated non-neoplastic cells.

Q: In BAP1 tumour predisposition syndrome, immunohistochemistry serves as a highly sensitive surrogate for gene inactivation, characteristically demonstrating a loss of [...] BAP1 expression in neoplastic cells.
BAP1 immunohistochemistry: Nuclear expression is lost in neoplastic cells and retained in non-neoplastic internal control cells.
High-power view of BAP1 IHC showing loss of nuclear reactivity in rhabdoid neoplastic cells.
A: nuclear
Back Extra: BAP1 tumour predisposition syndrome
- Clinical: Autosomal dominant syndrome caused by germline pathogenic variants in BAP1 (3p21.1), predisposing to uveal melanoma, mesothelioma, renal cell carcinoma, and cutaneous melanoma.
- Microscopic: Meningiomas in this syndrome are often aggressive and frequently display "rhabdoid" or "papillary" cytomorphology.
- Ancillary: Loss of nuclear BAP1 protein expression by immunohistochemistry (IHC) serves as a highly sensitive and specific surrogate for BAP1 gene inactivation.
- Clinical Indicator: Histologically distinctive BAP1-inactivated naevi (melanocytomas) occur in approximately 75% of germline carriers and are a key diagnostic clue.
Reference Gallery:
BAP1 meningioma showing mixed rhabdoid and papillary features in a patient with a germline BAP1 truncating mutation.
BAP1 immunohistochemistry: Nuclear expression is lost in neoplastic cells and retained in non-neoplastic internal control cells.
Meningioma with prominent rhabdoid features arising in the setting of BAP1 tumour predisposition syndrome.
High-power view of BAP1 IHC showing loss of nuclear reactivity in rhabdoid neoplastic cells.
Poorly differentiated region of a BAP1-deficient meningioma.
BAP1 expression is lost in poorly differentiated tumour cells while retained in associated non-neoplastic cells.

Q: In ELP1-medulloblastoma syndrome, the tumor most frequently presents with a [...] histologic pattern, characterized by reticulin-free zones surrounded by a reticulin-positive collagenous network.
Histopathology of ELP1-associated medulloblastoma. Desmoplastic/nodular pattern characterized by nodular, reticulin-free zones and intervening densely packed, poorly differentiated cells that produce an intercellular network of reticulin-positive collagen fibres.
A: desmoplastic/nodular
Back Extra: ELP1-medulloblastoma syndrome
- Clinical: Autosomal dominant disorder typically presenting in children (median age 6 years) with SHH-activated, TP53-wildtype medulloblastoma.
- Microscopic: Most frequently (76%) presents with a desmoplastic/nodular pattern featuring reticulin-free nodular zones surrounded by a reticulin-positive collagenous network.
- Ancillary IHC: Absence of ELP1 protein expression in tumor cells is a sensitive and specific marker for identifying affected patients.
- Genetics: Characterized by pathogenic germline variants in ELP1 (9q31.3) followed by somatic biallelic inactivation through loss of chromosome arm 9q (100% of cases).
- Pathogenesis: Frequently involves subsequent somatic PTCH1 mutation or focal deletion (84% of cases) as a 'third hit' in the SHH pathway.
Reference Gallery:
Histopathology of ELP1-associated medulloblastoma. Desmoplastic/nodular pattern characterized by nodular, reticulin-free zones and intervening densely packed, poorly differentiated cells that produce an intercellular network of reticulin-positive collagen fibres.
Proposed three-step model of tumorigenesis in ELP1-medulloblastoma syndrome. Step 1: germline variant results in monoallelic inactivation of ELP1. Step 2: somatic deletion of chromosome 9q results in biallelic inactivation of ELP1 and concurrent monoallelic inactivation of PTCH1. Step 3: somatic PTCH1 mutation or focal deletion on 9q22.32 results in biallelic inactivation of PTCH1.

Q: The pathogenesis of ELP1-medulloblastoma syndrome typically follows a three-step model: a germline ELP1 variant, somatic loss of chromosome arm 9q, and a somatic "third hit" mutation or deletion in [...].
Histopathology of ELP1-associated medulloblastoma. Desmoplastic/nodular pattern characterized by nodular, reticulin-free zones and intervening densely packed, poorly differentiated cells that produce an intercellular network of reticulin-positive collagen fibres.
Proposed three-step model of tumorigenesis in ELP1-medulloblastoma syndrome. Step 1: germline variant results in monoallelic inactivation of ELP1. Step 2: somatic deletion of chromosome 9q results in biallelic inactivation of ELP1 and concurrent monoallelic inactivation of PTCH1. Step 3: somatic PTCH1 mutation or focal deletion on 9q22.32 results in biallelic inactivation of PTCH1.
A: PTCH1
Back Extra: ELP1-medulloblastoma syndrome
- Clinical: Autosomal dominant disorder typically presenting in children (median age 6 years) with SHH-activated, TP53-wildtype medulloblastoma.
- Microscopic: Most frequently (76%) presents with a desmoplastic/nodular pattern featuring reticulin-free nodular zones surrounded by a reticulin-positive collagenous network.
- Ancillary IHC: Absence of ELP1 protein expression in tumor cells is a sensitive and specific marker for identifying affected patients.
- Genetics: Characterized by pathogenic germline variants in ELP1 (9q31.3) followed by somatic biallelic inactivation through loss of chromosome arm 9q (100% of cases).
- Pathogenesis: Frequently involves subsequent somatic PTCH1 mutation or focal deletion (84% of cases) as a 'third hit' in the SHH pathway.
Reference Gallery:
Histopathology of ELP1-associated medulloblastoma. Desmoplastic/nodular pattern characterized by nodular, reticulin-free zones and intervening densely packed, poorly differentiated cells that produce an intercellular network of reticulin-positive collagen fibres.
Proposed three-step model of tumorigenesis in ELP1-medulloblastoma syndrome. Step 1: germline variant results in monoallelic inactivation of ELP1. Step 2: somatic deletion of chromosome 9q results in biallelic inactivation of ELP1 and concurrent monoallelic inactivation of PTCH1. Step 3: somatic PTCH1 mutation or focal deletion on 9q22.32 results in biallelic inactivation of PTCH1.

Q: CNS tumors arising in patients with Fanconi anaemia are typically SHH-activated, TP53-mutant medulloblastomas that predominantly demonstrate a [...] histological morphology.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma in a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations demonstrates severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. High power demonstrates the large cells with severe anaplasia.
A: large cell / anaplastic
Back Extra: Fanconi anaemia
- Clinical: Classic physical features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, abnormal facies (triangular face, microcephaly), abnormal kidneys, and decreased fertility. Clinical progression inv…
- Micro: CNS tumors arising in FA, specifically medulloblastomas, are typically of the large cell / anaplastic histological type. Alternatively, they may present as desmoplastic/nodular histology with superimposed anaplasia.
- Cyto: Not relevant.
- Ancillary: Immunohistochemistry (IHC): - GAB1: Typically positive, indicating SHH pathway activation in FA-associated medulloblastomas. - p53: Often shows strong nuclear staining in the majority of tumor cells, correspo…
Reference Gallery:
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma in a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations demonstrates severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. High power demonstrates the large cells with severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma demonstrates immunopositivity for GAB1, indicative of SHH pathway activation.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma also demonstrates strong nuclear staining for p53 protein in the majority of tumour cells, corresponding with the somatic TP53 mutation that is present.
Medulloblastoma arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. T1-weighted postcontrast coronal MRI demonstrating a medulloblastoma in the cerebellar hemisphere of a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations.
Medulloblastoma, SHH-activated and TP53-mutant, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. Genome-wide copy plot showing the aneuploid genome, with most chromosomes in the genome harbouring multiple intrachromosomal copy-number breakpoints, reflective of the defect in double-strand DNA break repair caused by the BRCA2 biallelic inactivation.

Q: Medulloblastomas arising in the setting of Fanconi anaemia typically demonstrate strong nuclear staining for p53 and immunopositivity for [...], indicative of SHH pathway activation.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. High power demonstrates the large cells with severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma demonstrates immunopositivity for GAB1, indicative of SHH pathway activation.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma also demonstrates strong nuclear staining for p53 protein in the majority of tumour cells, corresponding with the somatic TP53 mutation that is present.
A: GAB1
Back Extra: Fanconi anaemia
- Clinical: Classic physical features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, abnormal facies (triangular face, microcephaly), abnormal kidneys, and decreased fertility. Clinical progression inv…
- Micro: CNS tumors arising in FA, specifically medulloblastomas, are typically of the large cell / anaplastic histological type. Alternatively, they may present as desmoplastic/nodular histology with superimposed anaplasia.
- Cyto: Not relevant.
- Ancillary: Immunohistochemistry (IHC): - GAB1: Typically positive, indicating SHH pathway activation in FA-associated medulloblastomas. - p53: Often shows strong nuclear staining in the majority of tumor cells, correspo…
Reference Gallery:
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma in a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations demonstrates severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. High power demonstrates the large cells with severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma demonstrates immunopositivity for GAB1, indicative of SHH pathway activation.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma also demonstrates strong nuclear staining for p53 protein in the majority of tumour cells, corresponding with the somatic TP53 mutation that is present.
Medulloblastoma arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. T1-weighted postcontrast coronal MRI demonstrating a medulloblastoma in the cerebellar hemisphere of a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations.
Medulloblastoma, SHH-activated and TP53-mutant, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. Genome-wide copy plot showing the aneuploid genome, with most chromosomes in the genome harbouring multiple intrachromosomal copy-number breakpoints, reflective of the defect in double-strand DNA break repair caused by the BRCA2 biallelic inactivation.

Q: In a young child with Fanconi anaemia, a T1-weighted postcontrast MRI demonstrating an enhancing mass in the cerebellar hemisphere is highly suspicious for a [...].
Medulloblastoma arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. T1-weighted postcontrast coronal MRI demonstrating a medulloblastoma in the cerebellar hemisphere of a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations.
A: medulloblastoma
Back Extra: Fanconi anaemia
- Clinical: Classic physical features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, abnormal facies (triangular face, microcephaly), abnormal kidneys, and decreased fertility. Clinical progression inv…
- Micro: CNS tumors arising in FA, specifically medulloblastomas, are typically of the large cell / anaplastic histological type. Alternatively, they may present as desmoplastic/nodular histology with superimposed anaplasia.
- Cyto: Not relevant.
- Ancillary: Immunohistochemistry (IHC): - GAB1: Typically positive, indicating SHH pathway activation in FA-associated medulloblastomas. - p53: Often shows strong nuclear staining in the majority of tumor cells, correspo…
Reference Gallery:
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma in a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations demonstrates severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. High power demonstrates the large cells with severe anaplasia.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma demonstrates immunopositivity for GAB1, indicative of SHH pathway activation.
Medulloblastoma. Large cell / anaplastic histological type, SHH-activated and TP53-mutant molecular subtype, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. This medulloblastoma also demonstrates strong nuclear staining for p53 protein in the majority of tumour cells, corresponding with the somatic TP53 mutation that is present.
Medulloblastoma arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. T1-weighted postcontrast coronal MRI demonstrating a medulloblastoma in the cerebellar hemisphere of a young child with Fanconi anaemia due to biallelic germline BRCA2 mutations.
Medulloblastoma, SHH-activated and TP53-mutant, arising in the setting of Fanconi anaemia due to biallelic germline BRCA2 mutations. Genome-wide copy plot showing the aneuploid genome, with most chromosomes in the genome harbouring multiple intrachromosomal copy-number breakpoints, reflective of the defect in double-strand DNA break repair caused by the BRCA2 biallelic inactivation.

Q: Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline variants in the [...] tumor suppressor gene, with most mutations clustering in the sequence-specific core DNA-binding domain.
Li–Fraumeni syndrome. Mutation landscape of TP53 germline and somatic mutations in human cancer. ++, lysine-rich basic C-terminal domain; DBD, sequence-specific core DNA-binding domain; L, linker region; PP, proline domain; TAD, transcriptional activation domain; Tet, tetramerization domain.
A: TP53
Back Extra: Li-Fraumeni syndrome
- Clinical: Autosomal dominant disorder caused by germline variants in the TP53 tumor suppressor gene (17p13.1), characterized by multiple primary neoplasms including sarcomas, breast cancer, and CNS tumors.
- CNS Manifestations: Shows a bimodal age distribution; children frequently present with choroid plexus carcinomas, SHH-activated medulloblastomas, and IDH-wildtype glioblastomas.
- Microscopic: LFS-associated tumors generally resemble their sporadic counterparts, though LFS-associated medulloblastomas show a higher frequency of the large cell / anaplastic pattern.
- Immunohistochemistry: p53 IHC serves as a surrogate marker; missense mutations show strong/diffuse nuclear labeling, while truncating mutations (nonsense/frameshift) result in complete absence of staining.
- Molecular: Most germline mutations (>85%) are missense and clustered in exons 5-8, frequently involving the DNA-binding domain (DBD).
Reference Gallery:
Li–Fraumeni syndrome. Mutation landscape of TP53 germline and somatic mutations in human cancer. ++, lysine-rich basic C-terminal domain; DBD, sequence-specific core DNA-binding domain; L, linker region; PP, proline domain; TAD, transcriptional activation domain; Tet, tetramerization domain.

Q: The [...] subtype of Germ cell tumours of the CNS is histologically characterized by a classic 'bipartite' appearance consisting of large, clear tumor cells separated by delicate fibrovascular septa that are heavily infiltrated by lymphocytes.
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
A: germinoma
Back Extra: Germ cell tumours of the CNS
- Clinical: Approximately 80–90% arise in the midline, primarily the pineal region (causing hydrocephalus, intracranial hypertension, and Parinaud syndrome) and the suprasellar compartment (causing diabetes insipidus, visual disturb…
- Micro: ### Architecture and Cytology by Subtype - Germinoma: Large, undifferentiated cells in sheets or lobules, separated by fibrovascular septa infiltrated by T-lymphocytes. Cells have round, vesicular nuclei with promine…
- Cyto: ### Squash and Smear Preparations - Germinoma: Large tumour cells with delicate, vacuolated cytoplasm and prominent nucleoli; background often contains small lymphocytes and may show a 'tigroid' appearance on Giemsa …
- Ancillary: ### Immunohistochemistry (IHC) - Germinoma: KIT (CD117) positive (membranous and Golgi), D2-40 positive (membranous), OCT4 and SALL4 positive (nuclear). Unique loss of nuclear 5-methylcytosine (DNA hypomethylation). …
Reference Gallery:
Teratoma. Large immature teratoma of the cerebellum in a 4-week-old infant, with characteristic cysts and chondroid nodules.
Germinoma. Suprasellar tumour from a 7-year-old girl.
Germinoma. Sagittal MRI... T1-weighted image shows a contrast-enhancing tumour of the pineal region.
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
Germinoma. Immunohistochemistry for OCT4 shows nuclear expression in germinoma cells.
Germinoma. There is membranous and cytoplasmic expression of KIT.
Germinoma. Immunohistochemistry for 5-methylcytosine. In contrast to inflammatory cells, germinoma cells show unmethylated chromatin.
Yolk sac tumour. A Schiller–Duval body.
Choriocarcinoma. The tumour is composed of multinucleated syncytiotrophoblastic giant cells and cytotrophoblasts.
Germinoma. Sagittal MRI of a 21-year-old man who developed headache, nausea, and Parinaud syndrome. T2-weighted image of a germinoma in the pineal region.
Germinoma. This tumour shows granulomatous inflammation.
Germinoma. Syncytiotrophoblastic giant cells are sometimes present.

Q: Immunohistochemical evaluation of the germinoma subtype of Germ cell tumours of the CNS classically demonstrates strong membranous positivity for KIT (CD117) and nuclear expression of the stem-cell transcription factor [...].
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
Germinoma. Immunohistochemistry for OCT4 shows nuclear expression in germinoma cells.
Germinoma. There is membranous and cytoplasmic expression of KIT.
A: OCT4
Back Extra: Germ cell tumours of the CNS
- Clinical: Approximately 80–90% arise in the midline, primarily the pineal region (causing hydrocephalus, intracranial hypertension, and Parinaud syndrome) and the suprasellar compartment (causing diabetes insipidus, visual disturb…
- Micro: ### Architecture and Cytology by Subtype - Germinoma: Large, undifferentiated cells in sheets or lobules, separated by fibrovascular septa infiltrated by T-lymphocytes. Cells have round, vesicular nuclei with promine…
- Cyto: ### Squash and Smear Preparations - Germinoma: Large tumour cells with delicate, vacuolated cytoplasm and prominent nucleoli; background often contains small lymphocytes and may show a 'tigroid' appearance on Giemsa …
- Ancillary: ### Immunohistochemistry (IHC) - Germinoma: KIT (CD117) positive (membranous and Golgi), D2-40 positive (membranous), OCT4 and SALL4 positive (nuclear). Unique loss of nuclear 5-methylcytosine (DNA hypomethylation). …
Reference Gallery:
Teratoma. Large immature teratoma of the cerebellum in a 4-week-old infant, with characteristic cysts and chondroid nodules.
Germinoma. Suprasellar tumour from a 7-year-old girl.
Germinoma. Sagittal MRI... T1-weighted image shows a contrast-enhancing tumour of the pineal region.
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
Germinoma. Immunohistochemistry for OCT4 shows nuclear expression in germinoma cells.
Germinoma. There is membranous and cytoplasmic expression of KIT.
Germinoma. Immunohistochemistry for 5-methylcytosine. In contrast to inflammatory cells, germinoma cells show unmethylated chromatin.
Yolk sac tumour. A Schiller–Duval body.
Choriocarcinoma. The tumour is composed of multinucleated syncytiotrophoblastic giant cells and cytotrophoblasts.
Germinoma. Sagittal MRI of a 21-year-old man who developed headache, nausea, and Parinaud syndrome. T2-weighted image of a germinoma in the pineal region.
Germinoma. This tumour shows granulomatous inflammation.
Germinoma. Syncytiotrophoblastic giant cells are sometimes present.

Q: A unique epigenetic and immunohistochemical signature of the germinoma subtype of Germ cell tumours of the CNS is global DNA hypomethylation, visualized as a marked loss of nuclear [...].
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
Germinoma. Immunohistochemistry for 5-methylcytosine. In contrast to inflammatory cells, germinoma cells show unmethylated chromatin.
A: 5-methylcytosine
Back Extra: Germ cell tumours of the CNS
- Clinical: Approximately 80–90% arise in the midline, primarily the pineal region (causing hydrocephalus, intracranial hypertension, and Parinaud syndrome) and the suprasellar compartment (causing diabetes insipidus, visual disturb…
- Micro: ### Architecture and Cytology by Subtype - Germinoma: Large, undifferentiated cells in sheets or lobules, separated by fibrovascular septa infiltrated by T-lymphocytes. Cells have round, vesicular nuclei with promine…
- Cyto: ### Squash and Smear Preparations - Germinoma: Large tumour cells with delicate, vacuolated cytoplasm and prominent nucleoli; background often contains small lymphocytes and may show a 'tigroid' appearance on Giemsa …
- Ancillary: ### Immunohistochemistry (IHC) - Germinoma: KIT (CD117) positive (membranous and Golgi), D2-40 positive (membranous), OCT4 and SALL4 positive (nuclear). Unique loss of nuclear 5-methylcytosine (DNA hypomethylation). …
Reference Gallery:
Teratoma. Large immature teratoma of the cerebellum in a 4-week-old infant, with characteristic cysts and chondroid nodules.
Germinoma. Suprasellar tumour from a 7-year-old girl.
Germinoma. Sagittal MRI... T1-weighted image shows a contrast-enhancing tumour of the pineal region.
Germinoma. The cells show large round nuclei, prominent nucleoli, and clear cytoplasm with interspersed lymphoid infiltrates.
Germinoma. Immunohistochemistry for OCT4 shows nuclear expression in germinoma cells.
Germinoma. There is membranous and cytoplasmic expression of KIT.
Germinoma. Immunohistochemistry for 5-methylcytosine. In contrast to inflammatory cells, germinoma cells show unmethylated chromatin.
Yolk sac tumour. A Schiller–Duval body.
Choriocarcinoma. The tumour is composed of multinucleated syncytiotrophoblastic giant cells and cytotrophoblasts.
Germinoma. Sagittal MRI of a 21-year-old man who developed headache, nausea, and Parinaud syndrome. T2-weighted image of a germinoma in the pineal region.
Germinoma. This tumour shows granulomatous inflammation.
Germinoma. Syncytiotrophoblastic giant cells are sometimes present.

Q: The classic microscopic appearance of a Central Neurocytoma features monotonous round cells with prominent cytoplasmic clearing and speckled, [...] chromatin.
Central neurocytoma. Typical central neurocytoma shows a sheet of monotonous cells with round nuclei and salt-and-pepper chromatin patterns.
Central neurocytoma. Sometimes cytoplasmic clearing is prominent, mimicking oligodendroglioma.
A: salt-and-pepper
Back Extra: Central Neurocytoma
- Clinical: Typically presents in young adults (mean age 28) with symptoms of increased intracranial pressure; most commonly located in the lateral ventricles attached to the septum pellucidum.
- Microscopic: Characterized by monotonous sheets of uniform round cells with "salt-and-pepper" (speckled) chromatin and fibrillary neuropil-like areas; often exhibits an oligodendroglioma-like honeycomb pattern.
- Ancillary: Diffusely positive for synaptophysin (most reliable); often positive for NeuN and TTF1 (clone SPT24), while lacking 1p/19q codeletion and diffuse OLIG2 expression.
- Prognosis: CNS WHO grade 2 with a favorable outcome; "atypical" variants are defined by brisk mitoses, necrosis, or microvascular proliferation and carry a higher risk of recurrence.
Reference Gallery:
Central neurocytoma. Typical central neurocytoma shows a sheet of monotonous cells with round nuclei and salt-and-pepper chromatin patterns.
Central neurocytoma. Sometimes cytoplasmic clearing is prominent, mimicking oligodendroglioma.
Central neurocytoma. Dilated and hyalinized blood vessels are sometimes prominent.
Central neurocytoma. Numerous psammomatous calcifications may be present.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for NeuN.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for thyroid transcription factor 1 (TTF1).
Central neurocytoma. The cytoplasm of the tumour cells is positive for synaptophysin, the most reliable marker.
Central neurocytoma. MAP2 is strongly positive in the tumour cells.
Central neurocytoma. The cytoplasm of the tumour cells is positive for L1CAM.
Central neurocytoma. T1-weighted MRI reveals a soap bubble–like multicystic appearance. The tumour is attached to the septum pellucidum.
Central neurocytoma. CT reveals multifocal hyperattenuating calcifications within the tumour.
Central neurocytoma. OLIG2 stain reveals a few positive nuclei, distinguishing it from the diffuse staining in oligodendroglioma.

Q: To distinguish Central Neurocytoma from its morphologic mimic, oligodendroglioma, immunohistochemistry will demonstrate diffuse positivity for the reliable neuronal marker [...] alongside non-diffuse, minimal OLIG2 expression.
Central neurocytoma. Sometimes cytoplasmic clearing is prominent, mimicking oligodendroglioma.
Central neurocytoma. The cytoplasm of the tumour cells is positive for synaptophysin, the most reliable marker.
Central neurocytoma. OLIG2 stain reveals a few positive nuclei, distinguishing it from the diffuse staining in oligodendroglioma.
A: synaptophysin
Back Extra: Central Neurocytoma
- Clinical: Typically presents in young adults (mean age 28) with symptoms of increased intracranial pressure; most commonly located in the lateral ventricles attached to the septum pellucidum.
- Microscopic: Characterized by monotonous sheets of uniform round cells with "salt-and-pepper" (speckled) chromatin and fibrillary neuropil-like areas; often exhibits an oligodendroglioma-like honeycomb pattern.
- Ancillary: Diffusely positive for synaptophysin (most reliable); often positive for NeuN and TTF1 (clone SPT24), while lacking 1p/19q codeletion and diffuse OLIG2 expression.
- Prognosis: CNS WHO grade 2 with a favorable outcome; "atypical" variants are defined by brisk mitoses, necrosis, or microvascular proliferation and carry a higher risk of recurrence.
Reference Gallery:
Central neurocytoma. Typical central neurocytoma shows a sheet of monotonous cells with round nuclei and salt-and-pepper chromatin patterns.
Central neurocytoma. Sometimes cytoplasmic clearing is prominent, mimicking oligodendroglioma.
Central neurocytoma. Dilated and hyalinized blood vessels are sometimes prominent.
Central neurocytoma. Numerous psammomatous calcifications may be present.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for NeuN.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for thyroid transcription factor 1 (TTF1).
Central neurocytoma. The cytoplasm of the tumour cells is positive for synaptophysin, the most reliable marker.
Central neurocytoma. MAP2 is strongly positive in the tumour cells.
Central neurocytoma. The cytoplasm of the tumour cells is positive for L1CAM.
Central neurocytoma. T1-weighted MRI reveals a soap bubble–like multicystic appearance. The tumour is attached to the septum pellucidum.
Central neurocytoma. CT reveals multifocal hyperattenuating calcifications within the tumour.
Central neurocytoma. OLIG2 stain reveals a few positive nuclei, distinguishing it from the diffuse staining in oligodendroglioma.

Q: On MRI, Central Neurocytoma frequently presents as a "soap bubble" mass within the lateral ventricles that is characteristically attached to the [...].
Central neurocytoma. Typical central neurocytoma shows a sheet of monotonous cells with round nuclei and salt-and-pepper chromatin patterns.
Central neurocytoma. T1-weighted MRI reveals a soap bubble–like multicystic appearance. The tumour is attached to the septum pellucidum.
A: septum pellucidum
Back Extra: Central Neurocytoma
- Clinical: Typically presents in young adults (mean age 28) with symptoms of increased intracranial pressure; most commonly located in the lateral ventricles attached to the septum pellucidum.
- Microscopic: Characterized by monotonous sheets of uniform round cells with "salt-and-pepper" (speckled) chromatin and fibrillary neuropil-like areas; often exhibits an oligodendroglioma-like honeycomb pattern.
- Ancillary: Diffusely positive for synaptophysin (most reliable); often positive for NeuN and TTF1 (clone SPT24), while lacking 1p/19q codeletion and diffuse OLIG2 expression.
- Prognosis: CNS WHO grade 2 with a favorable outcome; "atypical" variants are defined by brisk mitoses, necrosis, or microvascular proliferation and carry a higher risk of recurrence.
Reference Gallery:
Central neurocytoma. Typical central neurocytoma shows a sheet of monotonous cells with round nuclei and salt-and-pepper chromatin patterns.
Central neurocytoma. Sometimes cytoplasmic clearing is prominent, mimicking oligodendroglioma.
Central neurocytoma. Dilated and hyalinized blood vessels are sometimes prominent.
Central neurocytoma. Numerous psammomatous calcifications may be present.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for NeuN.
Central neurocytoma. Immunohistochemically, the tumour cell nuclei in this particular case are robustly positive for thyroid transcription factor 1 (TTF1).
Central neurocytoma. The cytoplasm of the tumour cells is positive for synaptophysin, the most reliable marker.
Central neurocytoma. MAP2 is strongly positive in the tumour cells.
Central neurocytoma. The cytoplasm of the tumour cells is positive for L1CAM.
Central neurocytoma. T1-weighted MRI reveals a soap bubble–like multicystic appearance. The tumour is attached to the septum pellucidum.
Central neurocytoma. CT reveals multifocal hyperattenuating calcifications within the tumour.
Central neurocytoma. OLIG2 stain reveals a few positive nuclei, distinguishing it from the diffuse staining in oligodendroglioma.

Q: The hallmark microscopic finding in Cerebellar liponeurocytoma is the presence of uniform neurocytes interspersed with [...] resembling adipocytes.
Cerebellar liponeurocytoma. Classic histology showing neurocytes and lipidized tumour cells.
A: lipidized tumor cells
Back Extra: Cerebellar liponeurocytoma
- Definition: A CNS WHO grade 2 cerebellar neoplasm exhibiting advanced neuronal/neurocytic differentiation and hallmark focal "lipidized" neuroepithelial cells resembling adipocytes.
- Clinical/Imaging: Presents in adults with headache and ataxia; MRI shows T1-hyperintense areas that lose signal on fat-saturated sequences due to intrinsic lipid content.
- Microscopic: Composed of sheets/lobules of uniform neurocytes with regular nuclei and clear cytoplasm, interspersed with clusters of lipid-laden tumor cells; Ki-67 is typically low (1–4%).
- Ancillary: Consistently expresses neuronal markers (Synaptophysin, NeuN) and focal GFAP; molecularly distinct from medulloblastoma by the presence of focal losses of chromosomes 14 and 2p.
Reference Gallery:
Cerebellar liponeurocytoma. Intense immunoreactivity of neurocytes for synaptophysin.
Cerebellar liponeurocytoma. Liponeurocytomas also express NeuN.
Cerebellar liponeurocytoma. GFAP-positive neoplastic cells can be present.
Cerebellar liponeurocytoma. T2-weighted MRI depicts the mass as well circumscribed and mildly heterogeneous, with small cystic areas medially.
Cerebellar liponeurocytoma. Inherently bright signal on T1-weighted pre-contrast images corresponding to lipid within the tumour.
Cerebellar liponeurocytoma. Postgadolinium T1-weighted imaging with fat saturation depicts mild diffuse enhancement of the mass, while the bright signal in fat-rich areas is lost with fat saturation.
Cerebellar liponeurocytoma. Copy-number analysis showing focal losses of chromosomes 14p and 2p.
Cerebellar liponeurocytoma. Classic histology showing neurocytes and lipidized tumour cells.

Q: On MRI, Cerebellar liponeurocytoma characteristically exhibits T1-hyperintense areas that lose signal on [...] sequences due to intrinsic lipid content.
Cerebellar liponeurocytoma. Inherently bright signal on T1-weighted pre-contrast images corresponding to lipid within the tumour.
Cerebellar liponeurocytoma. Postgadolinium T1-weighted imaging with fat saturation depicts mild diffuse enhancement of the mass, while the bright signal in fat-rich areas is lost with fat saturation.
A: fat-saturated
Back Extra: Cerebellar liponeurocytoma
- Definition: A CNS WHO grade 2 cerebellar neoplasm exhibiting advanced neuronal/neurocytic differentiation and hallmark focal "lipidized" neuroepithelial cells resembling adipocytes.
- Clinical/Imaging: Presents in adults with headache and ataxia; MRI shows T1-hyperintense areas that lose signal on fat-saturated sequences due to intrinsic lipid content.
- Microscopic: Composed of sheets/lobules of uniform neurocytes with regular nuclei and clear cytoplasm, interspersed with clusters of lipid-laden tumor cells; Ki-67 is typically low (1–4%).
- Ancillary: Consistently expresses neuronal markers (Synaptophysin, NeuN) and focal GFAP; molecularly distinct from medulloblastoma by the presence of focal losses of chromosomes 14 and 2p.
Reference Gallery:
Cerebellar liponeurocytoma. Intense immunoreactivity of neurocytes for synaptophysin.
Cerebellar liponeurocytoma. Liponeurocytomas also express NeuN.
Cerebellar liponeurocytoma. GFAP-positive neoplastic cells can be present.
Cerebellar liponeurocytoma. T2-weighted MRI depicts the mass as well circumscribed and mildly heterogeneous, with small cystic areas medially.
Cerebellar liponeurocytoma. Inherently bright signal on T1-weighted pre-contrast images corresponding to lipid within the tumour.
Cerebellar liponeurocytoma. Postgadolinium T1-weighted imaging with fat saturation depicts mild diffuse enhancement of the mass, while the bright signal in fat-rich areas is lost with fat saturation.
Cerebellar liponeurocytoma. Copy-number analysis showing focal losses of chromosomes 14p and 2p.
Cerebellar liponeurocytoma. Classic histology showing neurocytes and lipidized tumour cells.

Q: In addition to consistent expression of neuronal markers (Synaptophysin, NeuN), Cerebellar liponeurocytoma typically shows focal positivity for [...] on immunohistochemistry.
Cerebellar liponeurocytoma. Intense immunoreactivity of neurocytes for synaptophysin.
Cerebellar liponeurocytoma. Liponeurocytomas also express NeuN.
Cerebellar liponeurocytoma. GFAP-positive neoplastic cells can be present.
A: GFAP
Back Extra: Cerebellar liponeurocytoma
- Definition: A CNS WHO grade 2 cerebellar neoplasm exhibiting advanced neuronal/neurocytic differentiation and hallmark focal "lipidized" neuroepithelial cells resembling adipocytes.
- Clinical/Imaging: Presents in adults with headache and ataxia; MRI shows T1-hyperintense areas that lose signal on fat-saturated sequences due to intrinsic lipid content.
- Microscopic: Composed of sheets/lobules of uniform neurocytes with regular nuclei and clear cytoplasm, interspersed with clusters of lipid-laden tumor cells; Ki-67 is typically low (1–4%).
- Ancillary: Consistently expresses neuronal markers (Synaptophysin, NeuN) and focal GFAP; molecularly distinct from medulloblastoma by the presence of focal losses of chromosomes 14 and 2p.
Reference Gallery:
Cerebellar liponeurocytoma. Intense immunoreactivity of neurocytes for synaptophysin.
Cerebellar liponeurocytoma. Liponeurocytomas also express NeuN.
Cerebellar liponeurocytoma. GFAP-positive neoplastic cells can be present.
Cerebellar liponeurocytoma. T2-weighted MRI depicts the mass as well circumscribed and mildly heterogeneous, with small cystic areas medially.
Cerebellar liponeurocytoma. Inherently bright signal on T1-weighted pre-contrast images corresponding to lipid within the tumour.
Cerebellar liponeurocytoma. Postgadolinium T1-weighted imaging with fat saturation depicts mild diffuse enhancement of the mass, while the bright signal in fat-rich areas is lost with fat saturation.
Cerebellar liponeurocytoma. Copy-number analysis showing focal losses of chromosomes 14p and 2p.
Cerebellar liponeurocytoma. Classic histology showing neurocytes and lipidized tumour cells.

Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma is a rare infant CNS tumor characterized by a biphasic architecture that includes a neuroepithelial component and a prominent, reticulin-rich [...] stroma.
Desmoplastic infantile ganglioglioma. The tumour shows a marked desmoplastic component, evidenced by reticulin staining, whereas the adjacent cortex is negative.
Desmoplastic infantile ganglioglioma. Neoplastic cells are arranged in streams in the desmoplastic component.
A: desmoplastic
Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma
- Clinical: Rare CNS WHO grade 1 tumors typically presenting in infants (<24 months) as large, superficial, cystic and solid hemispheric masses, often associated with the [...] and increased head circumference.
- Microscopic: Characterized by a biphasic architecture with a prominent desmoplastic stroma (spindle cells in a reticulin-rich matrix) and a neuroepithelial component; DIA contains astrocytes only, while DIG includes both astrocytic and neuronal components.
- Architecture: Often contains foci of primitive, [...] tumour cells which lack desmoplasia and may show higher mitotic activity than the surrounding desmoplastic areas.
- Ancillary: Driven by activation of the [...] pathway, frequently through BRAF mutations (e.g., p.V600E) or fusions; tumors are typically IDH-wildtype and Histone H3-wildtype.
- Prognosis: Excellent prognosis following total surgical resection; targeted therapy with BRAF inhibitors is an option for residual or progressive mutated cases.
Reference Gallery:
Desmoplastic infantile ganglioglioma. The tumour is superficial, with sharp demarcation from the cortex.
Desmoplastic infantile ganglioglioma. The tumour shows a marked desmoplastic component, evidenced by reticulin staining, whereas the adjacent cortex is negative.
Desmoplastic infantile ganglioglioma. Neoplastic cells are arranged in streams in the desmoplastic component.
Desmoplastic infantile ganglioglioma. Some cells express synaptophysin.
Desmoplastic infantile ganglioglioma. A few cells are GFAP-positive.
Desmoplastic infantile ganglioglioma. The Ki-67 labelling index is very low in desmoplastic areas.
Desmoplastic infantile ganglioglioma. Advanced neuronal differentiation is associated with poorly differentiated cells.
Desmoplastic infantile ganglioglioma. Neuronal cells strongly express synaptophysin.
Desmoplastic infantile ganglioglioma. Cells with advanced neuronal differentiation often express chromogranin.
Desmoplastic infantile ganglioglioma. Axial T2-weighted MRI shows multiple cystic components and a peripheral solid component.
Desmoplastic infantile ganglioglioma. Contrast-enhanced T1-weighted MRI shows intense enhancement of the solid component.
Desmoplastic infantile astrocytoma. Diffuse BRAF p.V600E immunoexpression.
A: sunset sign; embryonal-like; MAPK

Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma is frequently driven by MAPK pathway activation, most commonly due to [...] mutations, which can be visualized via targeted immunohistochemistry.
Desmoplastic infantile ganglioglioma. Neoplastic cells are arranged in streams in the desmoplastic component.
Desmoplastic infantile astrocytoma. Diffuse BRAF p.V600E immunoexpression.
A: BRAF p.V600E
Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma
- Clinical: Rare CNS WHO grade 1 tumors typically presenting in infants (<24 months) as large, superficial, cystic and solid hemispheric masses, often associated with the [...] and increased head circumference.
- Microscopic: Characterized by a biphasic architecture with a prominent desmoplastic stroma (spindle cells in a reticulin-rich matrix) and a neuroepithelial component; DIA contains astrocytes only, while DIG includes both astrocytic and neuronal components.
- Architecture: Often contains foci of primitive, [...] tumour cells which lack desmoplasia and may show higher mitotic activity than the surrounding desmoplastic areas.
- Ancillary: Driven by activation of the [...] pathway, frequently through BRAF mutations (e.g., p.V600E) or fusions; tumors are typically IDH-wildtype and Histone H3-wildtype.
- Prognosis: Excellent prognosis following total surgical resection; targeted therapy with BRAF inhibitors is an option for residual or progressive mutated cases.
Reference Gallery:
Desmoplastic infantile ganglioglioma. The tumour is superficial, with sharp demarcation from the cortex.
Desmoplastic infantile ganglioglioma. The tumour shows a marked desmoplastic component, evidenced by reticulin staining, whereas the adjacent cortex is negative.
Desmoplastic infantile ganglioglioma. Neoplastic cells are arranged in streams in the desmoplastic component.
Desmoplastic infantile ganglioglioma. Some cells express synaptophysin.
Desmoplastic infantile ganglioglioma. A few cells are GFAP-positive.
Desmoplastic infantile ganglioglioma. The Ki-67 labelling index is very low in desmoplastic areas.
Desmoplastic infantile ganglioglioma. Advanced neuronal differentiation is associated with poorly differentiated cells.
Desmoplastic infantile ganglioglioma. Neuronal cells strongly express synaptophysin.
Desmoplastic infantile ganglioglioma. Cells with advanced neuronal differentiation often express chromogranin.
Desmoplastic infantile ganglioglioma. Axial T2-weighted MRI shows multiple cystic components and a peripheral solid component.
Desmoplastic infantile ganglioglioma. Contrast-enhanced T1-weighted MRI shows intense enhancement of the solid component.
Desmoplastic infantile astrocytoma. Diffuse BRAF p.V600E immunoexpression.
A: sunset sign; embryonal-like; MAPK

Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma characteristically presents in infants on MRI as a large, superficial hemispheric tumor with an intensely enhancing peripheral solid component and prominent [...] spaces.
Desmoplastic infantile ganglioglioma. Axial T2-weighted MRI shows multiple cystic components and a peripheral solid component.
Desmoplastic infantile ganglioglioma. Contrast-enhanced T1-weighted MRI shows intense enhancement of the solid component.
A: cystic
Q: Desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma
- Clinical: Rare CNS WHO grade 1 tumors typically presenting in infants (<24 months) as large, superficial, cystic and solid hemispheric masses, often associated with the [...] and increased head circumference.
- Microscopic: Characterized by a biphasic architecture with a prominent desmoplastic stroma (spindle cells in a reticulin-rich matrix) and a neuroepithelial component; DIA contains astrocytes only, while DIG includes both astrocytic and neuronal components.
- Architecture: Often contains foci of primitive, [...] tumour cells which lack desmoplasia and may show higher mitotic activity than the surrounding desmoplastic areas.
- Ancillary: Driven by activation of the [...] pathway, frequently through BRAF mutations (e.g., p.V600E) or fusions; tumors are typically IDH-wildtype and Histone H3-wildtype.
- Prognosis: Excellent prognosis following total surgical resection; targeted therapy with BRAF inhibitors is an option for residual or progressive mutated cases.
Reference Gallery:
Desmoplastic infantile ganglioglioma. The tumour is superficial, with sharp demarcation from the cortex.
Desmoplastic infantile ganglioglioma. The tumour shows a marked desmoplastic component, evidenced by reticulin staining, whereas the adjacent cortex is negative.
Desmoplastic infantile ganglioglioma. Neoplastic cells are arranged in streams in the desmoplastic component.
Desmoplastic infantile ganglioglioma. Some cells express synaptophysin.
Desmoplastic infantile ganglioglioma. A few cells are GFAP-positive.
Desmoplastic infantile ganglioglioma. The Ki-67 labelling index is very low in desmoplastic areas.
Desmoplastic infantile ganglioglioma. Advanced neuronal differentiation is associated with poorly differentiated cells.
Desmoplastic infantile ganglioglioma. Neuronal cells strongly express synaptophysin.
Desmoplastic infantile ganglioglioma. Cells with advanced neuronal differentiation often express chromogranin.
Desmoplastic infantile ganglioglioma. Axial T2-weighted MRI shows multiple cystic components and a peripheral solid component.
Desmoplastic infantile ganglioglioma. Contrast-enhanced T1-weighted MRI shows intense enhancement of the solid component.
Desmoplastic infantile astrocytoma. Diffuse BRAF p.V600E immunoexpression.
A: sunset sign; embryonal-like; MAPK

Q: A key diagnostic histologic feature of Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, in addition to clear cells with perinuclear halos, is the presence of distinctive ring- or C-shaped [...].
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Several nuclear clusters (some indicated by arrows).
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with clear cell morphology and several ring- or C-shaped nuclear clusters.
A: nuclear clusters
Back Extra: Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters
- Clinical: The majority of cases occur in paediatric patients (median age 9 years), though the range extends to older adults (up to 75 years). There is an equal sex distribution. Patients typically present with symptoms related to …
- Micro: The tumours show variable cellularity (moderate to high) and are composed of small to medium-sized cells with scant cytoplasm and perinuclear haloes, mimicking oligodendroglioma. Key diagnostic features include scattered…
- Cyto: Insufficient data available, though the tumour is characterized by small to medium cells and large irregular pleomorphic nuclei.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Diffusely positive in most cases. - GFAP: Characteristically negative in tumour cells (reactive astrocytes will be positive). - Synaptophysin: Highlights the neurop…
Reference Gallery:
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC). DNA methylation profiling confirming the distinct nature of the DGONC entity compared to other CNS tumours.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Clear cell histology can resemble oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Several nuclear clusters (some indicated by arrows).
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Monomorphic clear cell morphology, resembling oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with clear cell morphology and several ring- or C-shaped nuclear clusters.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with oligodendroglioma-like perinuclear haloes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for GFAP is largely confined to reactive astrocytes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for OLIG2 is positive in the majority of tumour cells.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for synaptophysin shows variable staining.

Q: In Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, the neoplastic cells characteristically demonstrate diffuse immunohistochemical positivity for OLIG2 but are typically negative for [...] (which instead highlights interspersed reactive astrocytes).
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for GFAP is largely confined to reactive astrocytes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for OLIG2 is positive in the majority of tumour cells.
A: GFAP
Back Extra: Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters
- Clinical: The majority of cases occur in paediatric patients (median age 9 years), though the range extends to older adults (up to 75 years). There is an equal sex distribution. Patients typically present with symptoms related to …
- Micro: The tumours show variable cellularity (moderate to high) and are composed of small to medium-sized cells with scant cytoplasm and perinuclear haloes, mimicking oligodendroglioma. Key diagnostic features include scattered…
- Cyto: Insufficient data available, though the tumour is characterized by small to medium cells and large irregular pleomorphic nuclei.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Diffusely positive in most cases. - GFAP: Characteristically negative in tumour cells (reactive astrocytes will be positive). - Synaptophysin: Highlights the neurop…
Reference Gallery:
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC). DNA methylation profiling confirming the distinct nature of the DGONC entity compared to other CNS tumours.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Clear cell histology can resemble oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Several nuclear clusters (some indicated by arrows).
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Monomorphic clear cell morphology, resembling oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with clear cell morphology and several ring- or C-shaped nuclear clusters.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with oligodendroglioma-like perinuclear haloes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for GFAP is largely confined to reactive astrocytes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for OLIG2 is positive in the majority of tumour cells.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for synaptophysin shows variable staining.

Q: The characteristic morphology of Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters features monomorphic cells with scant cytoplasm and prominent [...], frequently mimicking an oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Clear cell histology can resemble oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with oligodendroglioma-like perinuclear haloes.
A: perinuclear halos
Back Extra: Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters
- Clinical: The majority of cases occur in paediatric patients (median age 9 years), though the range extends to older adults (up to 75 years). There is an equal sex distribution. Patients typically present with symptoms related to …
- Micro: The tumours show variable cellularity (moderate to high) and are composed of small to medium-sized cells with scant cytoplasm and perinuclear haloes, mimicking oligodendroglioma. Key diagnostic features include scattered…
- Cyto: Insufficient data available, though the tumour is characterized by small to medium cells and large irregular pleomorphic nuclei.
- Ancillary: 1) Immunohistochemistry (IHC): - OLIG2: Diffusely positive in most cases. - GFAP: Characteristically negative in tumour cells (reactive astrocytes will be positive). - Synaptophysin: Highlights the neurop…
Reference Gallery:
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC). DNA methylation profiling confirming the distinct nature of the DGONC entity compared to other CNS tumours.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Clear cell histology can resemble oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Several nuclear clusters (some indicated by arrows).
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Monomorphic clear cell morphology, resembling oligodendroglioma.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with clear cell morphology and several ring- or C-shaped nuclear clusters.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Tumour with oligodendroglioma-like perinuclear haloes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for GFAP is largely confined to reactive astrocytes.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for OLIG2 is positive in the majority of tumour cells.
Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters. Immunohistochemistry for synaptophysin shows variable staining.

Q: Microscopic examination of a Diffuse leptomeningeal glioneuronal tumor characteristically reveals monomorphic "oligodendrocyte-like" cells that expand the leptomeninges and extend into the adjacent brain parenchyma via the [...].
Diffuse leptomeningeal glioneuronal tumour. Marked expansion and hypercellularity of the leptomeninges.
Diffuse leptomeningeal glioneuronal tumour. Extension along the perivascular Virchow–Robin space is evident within the adjacent brain parenchyma of this tumour.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of neurocytic rosettes and perivascular pseudorosettes.
A: Virchow-Robin spaces
Back Extra: Diffuse leptomeningeal glioneuronal tumour
- Clinical: Typically presents in childhood (median age 5) with signs of increased intracranial pressure; MRI characteristically shows diffuse leptomeningeal enhancement/thickening and small T2-hyperintense subpial cysts.
- Microscopic: Composed of monomorphic "oligodendrocyte-like" cells involving the leptomeninges and Virchow-Robin spaces, often with areas of neuronal differentiation (rosettes, ganglion cells).
- Ancillary: Key molecular features include isolated chromosome arm 1p deletion and MAPK pathway alterations, most commonly the KIAA1549::BRAF fusion.
- Prognosis: Generally slow progression, but high-grade features (mitoses, microvascular proliferation) or chromosome 1q gain (DLGNT-MC-2 methylation subclass) predict a significantly worse outcome.
Reference Gallery:
Diffuse leptomeningeal glioneuronal tumour. Note the extensive intraventricular involvement, as well as the parenchymal cysts.
Diffuse leptomeningeal glioneuronal tumour. Extensive spinal leptomeningeal involvement.
Diffuse leptomeningeal glioneuronal tumour. Marked expansion and hypercellularity of the leptomeninges.
Diffuse leptomeningeal glioneuronal tumour. Extension along the perivascular Virchow–Robin space is evident within the adjacent brain parenchyma of this tumour.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of neurocytic rosettes and perivascular pseudorosettes.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of ganglion cells.
Diffuse leptomeningeal glioneuronal tumour. The tumour cells are GFAP-negative.
Diffuse leptomeningeal glioneuronal tumour. Tumour cells show extensive nuclear immunoreactivity for OLIG2.
FISH studies using BRAF (red) and KIAA1549 (green) probes show increased copy numbers and yellow fusion signals.
Diffuse leptomeningeal glioneuronal tumour with 1q gain. FISH studies using chromosome 1p (orange) and 1q (green) probes show simultaneous 1p loss (only 1 signal) and 1q gain (> 2 signals) in most tumour nuclei.

Q: A key molecular feature of Diffuse leptomeningeal glioneuronal tumor is an isolated chromosome arm 1p deletion combined with a MAPK pathway alteration, most frequently the [BRAF fusion].
Diffuse leptomeningeal glioneuronal tumour. Marked expansion and hypercellularity of the leptomeninges.
FISH studies using BRAF (red) and KIAA1549 (green) probes show increased copy numbers and yellow fusion signals.
A: KIAA1549
Back Extra: Diffuse leptomeningeal glioneuronal tumour
- Clinical: Typically presents in childhood (median age 5) with signs of increased intracranial pressure; MRI characteristically shows diffuse leptomeningeal enhancement/thickening and small T2-hyperintense subpial cysts.
- Microscopic: Composed of monomorphic "oligodendrocyte-like" cells involving the leptomeninges and Virchow-Robin spaces, often with areas of neuronal differentiation (rosettes, ganglion cells).
- Ancillary: Key molecular features include isolated chromosome arm 1p deletion and MAPK pathway alterations, most commonly the KIAA1549::BRAF fusion.
- Prognosis: Generally slow progression, but high-grade features (mitoses, microvascular proliferation) or chromosome 1q gain (DLGNT-MC-2 methylation subclass) predict a significantly worse outcome.
Reference Gallery:
Diffuse leptomeningeal glioneuronal tumour. Note the extensive intraventricular involvement, as well as the parenchymal cysts.
Diffuse leptomeningeal glioneuronal tumour. Extensive spinal leptomeningeal involvement.
Diffuse leptomeningeal glioneuronal tumour. Marked expansion and hypercellularity of the leptomeninges.
Diffuse leptomeningeal glioneuronal tumour. Extension along the perivascular Virchow–Robin space is evident within the adjacent brain parenchyma of this tumour.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of neurocytic rosettes and perivascular pseudorosettes.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of ganglion cells.
Diffuse leptomeningeal glioneuronal tumour. The tumour cells are GFAP-negative.
Diffuse leptomeningeal glioneuronal tumour. Tumour cells show extensive nuclear immunoreactivity for OLIG2.
FISH studies using BRAF (red) and KIAA1549 (green) probes show increased copy numbers and yellow fusion signals.
Diffuse leptomeningeal glioneuronal tumour with 1q gain. FISH studies using chromosome 1p (orange) and 1q (green) probes show simultaneous 1p loss (only 1 signal) and 1q gain (> 2 signals) in most tumour nuclei.

Q: Although a Diffuse leptomeningeal glioneuronal tumor generally progresses slowly, FISH or molecular analysis revealing a chromosome [...] predicts a significantly worse outcome.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of ganglion cells.
Diffuse leptomeningeal glioneuronal tumour with 1q gain. FISH studies using chromosome 1p (orange) and 1q (green) probes show simultaneous 1p loss (only 1 signal) and 1q gain (> 2 signals) in most tumour nuclei.
A: 1q gain
Back Extra: Diffuse leptomeningeal glioneuronal tumour
- Clinical: Typically presents in childhood (median age 5) with signs of increased intracranial pressure; MRI characteristically shows diffuse leptomeningeal enhancement/thickening and small T2-hyperintense subpial cysts.
- Microscopic: Composed of monomorphic "oligodendrocyte-like" cells involving the leptomeninges and Virchow-Robin spaces, often with areas of neuronal differentiation (rosettes, ganglion cells).
- Ancillary: Key molecular features include isolated chromosome arm 1p deletion and MAPK pathway alterations, most commonly the KIAA1549::BRAF fusion.
- Prognosis: Generally slow progression, but high-grade features (mitoses, microvascular proliferation) or chromosome 1q gain (DLGNT-MC-2 methylation subclass) predict a significantly worse outcome.
Reference Gallery:
Diffuse leptomeningeal glioneuronal tumour. Note the extensive intraventricular involvement, as well as the parenchymal cysts.
Diffuse leptomeningeal glioneuronal tumour. Extensive spinal leptomeningeal involvement.
Diffuse leptomeningeal glioneuronal tumour. Marked expansion and hypercellularity of the leptomeninges.
Diffuse leptomeningeal glioneuronal tumour. Extension along the perivascular Virchow–Robin space is evident within the adjacent brain parenchyma of this tumour.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of neurocytic rosettes and perivascular pseudorosettes.
Diffuse leptomeningeal glioneuronal tumour. Neuronal differentiation is evident in the form of ganglion cells.
Diffuse leptomeningeal glioneuronal tumour. The tumour cells are GFAP-negative.
Diffuse leptomeningeal glioneuronal tumour. Tumour cells show extensive nuclear immunoreactivity for OLIG2.
FISH studies using BRAF (red) and KIAA1549 (green) probes show increased copy numbers and yellow fusion signals.
Diffuse leptomeningeal glioneuronal tumour with 1q gain. FISH studies using chromosome 1p (orange) and 1q (green) probes show simultaneous 1p loss (only 1 signal) and 1q gain (> 2 signals) in most tumour nuclei.

Q: The hallmark histopathologic finding in a dysembryoplastic neuroepithelial tumor is a multinodular intracortical growth pattern with a specific glioneuronal element, featuring oligodendroglia-like cells and interspersed [...] within a mucoid matrix.
Dysembryoplastic neuroepithelial tumour. Specific glioneuronal element: bundles of axons lined by small oligodendroglia-like cells. Interspersed neurons appear to float in a mucoid matrix (floating neurons).
Dysembryoplastic neuroepithelial tumour. Low-power micrograph illustrating the multinodular intracortical growth pattern.
A: floating neurons
Back Extra: Dysembryoplastic neuroepithelial tumour
- Clinical: Patients typically present with drug-resistant focal epilepsy starting in childhood or young adulthood. Imaging (MRI) reveals a cortical-based, well-defined, lobulated mass that is T2/FLAIR hyperintensity. Key radiologic…
- Micro: The histopathological hallmark is the multinodular intracortical growth pattern and the specific glioneuronal element. - Architecture: Columns oriented perpendicularly to the cortex, composed of bundles of …
- Cyto: Smear/squash preparations reveal a uniform population of small, rounded cells with spherical nuclei and scant cytoplasm, set in a mucinous or fibrillary matrix. Mitotic activity is typically absent.
- Ancillary: Immunohistochemistry (IHC): - Oligodendroglia-like cells (OLCs): Positive for S100, OLIG2, and PDGFRA; Negative for GFAP and IDH1 p.R132H. - Floating Neurons: Positive for NeuN and Synaptophysin; Negative fo…
Reference Gallery:
Dysembryoplastic neuroepithelial tumour. Specific glioneuronal element: bundles of axons lined by small oligodendroglia-like cells. Interspersed neurons appear to float in a mucoid matrix (floating neurons).
Dysembryoplastic neuroepithelial tumour. Low-power micrograph illustrating the multinodular intracortical growth pattern.
Dysembryoplastic neuroepithelial tumour. Coronal T2-weighted MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Coronal FLAIR MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Large floating non-dysplastic neurons in an alcianophilic matrix (Alcian blue staining).
Dysembryoplastic neuroepithelial tumour. Large floating neuron (synaptophysin immunohistochemistry).
Dysembryoplastic neuroepithelial tumour. Floating neuron (NeuN immunohistochemistry).

Q: In a dysembryoplastic neuroepithelial tumor, the characteristic "floating neurons" are positive for mature neuronal immunohistochemical markers such as Synaptophysin and [...].
Dysembryoplastic neuroepithelial tumour. Large floating neuron (synaptophysin immunohistochemistry).
Dysembryoplastic neuroepithelial tumour. Floating neuron (NeuN immunohistochemistry).
A: NeuN
Back Extra: Dysembryoplastic neuroepithelial tumour
- Clinical: Patients typically present with drug-resistant focal epilepsy starting in childhood or young adulthood. Imaging (MRI) reveals a cortical-based, well-defined, lobulated mass that is T2/FLAIR hyperintensity. Key radiologic…
- Micro: The histopathological hallmark is the multinodular intracortical growth pattern and the specific glioneuronal element. - Architecture: Columns oriented perpendicularly to the cortex, composed of bundles of …
- Cyto: Smear/squash preparations reveal a uniform population of small, rounded cells with spherical nuclei and scant cytoplasm, set in a mucinous or fibrillary matrix. Mitotic activity is typically absent.
- Ancillary: Immunohistochemistry (IHC): - Oligodendroglia-like cells (OLCs): Positive for S100, OLIG2, and PDGFRA; Negative for GFAP and IDH1 p.R132H. - Floating Neurons: Positive for NeuN and Synaptophysin; Negative fo…
Reference Gallery:
Dysembryoplastic neuroepithelial tumour. Specific glioneuronal element: bundles of axons lined by small oligodendroglia-like cells. Interspersed neurons appear to float in a mucoid matrix (floating neurons).
Dysembryoplastic neuroepithelial tumour. Low-power micrograph illustrating the multinodular intracortical growth pattern.
Dysembryoplastic neuroepithelial tumour. Coronal T2-weighted MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Coronal FLAIR MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Large floating non-dysplastic neurons in an alcianophilic matrix (Alcian blue staining).
Dysembryoplastic neuroepithelial tumour. Large floating neuron (synaptophysin immunohistochemistry).
Dysembryoplastic neuroepithelial tumour. Floating neuron (NeuN immunohistochemistry).

Q: A dysembryoplastic neuroepithelial tumor typically presents with drug-resistant focal epilepsy and appears on MRI as a cortical-based, lobulated mass that is hyperintense on [...] sequences.
Dysembryoplastic neuroepithelial tumour. Coronal T2-weighted MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Coronal FLAIR MRI of a temporal tumour.
A: T2 and FLAIR
Back Extra: Dysembryoplastic neuroepithelial tumour
- Clinical: Patients typically present with drug-resistant focal epilepsy starting in childhood or young adulthood. Imaging (MRI) reveals a cortical-based, well-defined, lobulated mass that is T2/FLAIR hyperintensity. Key radiologic…
- Micro: The histopathological hallmark is the multinodular intracortical growth pattern and the specific glioneuronal element. - Architecture: Columns oriented perpendicularly to the cortex, composed of bundles of …
- Cyto: Smear/squash preparations reveal a uniform population of small, rounded cells with spherical nuclei and scant cytoplasm, set in a mucinous or fibrillary matrix. Mitotic activity is typically absent.
- Ancillary: Immunohistochemistry (IHC): - Oligodendroglia-like cells (OLCs): Positive for S100, OLIG2, and PDGFRA; Negative for GFAP and IDH1 p.R132H. - Floating Neurons: Positive for NeuN and Synaptophysin; Negative fo…
Reference Gallery:
Dysembryoplastic neuroepithelial tumour. Specific glioneuronal element: bundles of axons lined by small oligodendroglia-like cells. Interspersed neurons appear to float in a mucoid matrix (floating neurons).
Dysembryoplastic neuroepithelial tumour. Low-power micrograph illustrating the multinodular intracortical growth pattern.
Dysembryoplastic neuroepithelial tumour. Coronal T2-weighted MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Coronal FLAIR MRI of a temporal tumour.
Dysembryoplastic neuroepithelial tumour. Large floating non-dysplastic neurons in an alcianophilic matrix (Alcian blue staining).
Dysembryoplastic neuroepithelial tumour. Large floating neuron (synaptophysin immunohistochemistry).
Dysembryoplastic neuroepithelial tumour. Floating neuron (NeuN immunohistochemistry).

Q: Dysplastic cerebellar gangliocytoma typically presents on T2-weighted MRI as a mass with a characteristic [...] pattern of alternating hyperintense and hypointense layers.
Dysplastic cerebellar gangliocytoma. T2-weighted MRI shows a mass with the typical tiger-stripe pattern of alternating inner hyperintense and outer hypointense layers.
A: "tiger-stripe"
Back Extra: Dysplastic cerebellar gangliocytoma
- Clinical: Often presents as part of Cowden syndrome (PTEN hamartoma tumor syndrome) and exhibits a characteristic "tiger-stripe" pattern on T2-weighted MRI.
- Micro: Features an "inverted cerebellar cortex" where the internal granular layer is replaced by dysplastic ganglion cells and the molecular layer is thickened with abnormally myelinated axons.
- Ancillary: Typically shows loss of PTEN protein expression by IHC and increased activation of the mTOR pathway (e.g., phosphorylated S6 or mTOR).
- Prognosis: Assigned CNS WHO grade 1; however, its association with Cowden syndrome necessitates screening for extra-axial malignancies like breast and thyroid cancer.
Reference Gallery:
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Thickened cerebellar folium is replaced by large ganglion cells and disappearing inner granule cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Numerous large ganglion cells and abnormally myelinated axon bundles in the cerebellar cortex.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). NeuN immunohistochemistry reveals the abnormal arrangement of dysplastic ganglion cells, which are most densely present in the cerebellar molecular layer.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Some of the dysplastic ganglion cells are immunoreactive for phosphorylated mTOR.
Dysplastic cerebellar gangliocytoma. T2-weighted MRI shows a mass with the typical tiger-stripe pattern of alternating inner hyperintense and outer hypointense layers.
Dysplastic cerebellar gangliocytoma. Diffusion-weighted MRI reveals hyperintensity within the T2-hyperintense area of the tumour.
Dysplastic cerebellar gangliocytoma. Precontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.
Dysplastic cerebellar gangliocytoma. Postcontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.

Q: Dysplastic cerebellar gangliocytoma is microscopically characterized by an [...] cerebellar cortex, in which the normal internal granular layer is replaced by large, dysplastic ganglion cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Thickened cerebellar folium is replaced by large ganglion cells and disappearing inner granule cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Numerous large ganglion cells and abnormally myelinated axon bundles in the cerebellar cortex.
A: "inverted"
Back Extra: Dysplastic cerebellar gangliocytoma
- Clinical: Often presents as part of Cowden syndrome (PTEN hamartoma tumor syndrome) and exhibits a characteristic "tiger-stripe" pattern on T2-weighted MRI.
- Micro: Features an "inverted cerebellar cortex" where the internal granular layer is replaced by dysplastic ganglion cells and the molecular layer is thickened with abnormally myelinated axons.
- Ancillary: Typically shows loss of PTEN protein expression by IHC and increased activation of the mTOR pathway (e.g., phosphorylated S6 or mTOR).
- Prognosis: Assigned CNS WHO grade 1; however, its association with Cowden syndrome necessitates screening for extra-axial malignancies like breast and thyroid cancer.
Reference Gallery:
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Thickened cerebellar folium is replaced by large ganglion cells and disappearing inner granule cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Numerous large ganglion cells and abnormally myelinated axon bundles in the cerebellar cortex.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). NeuN immunohistochemistry reveals the abnormal arrangement of dysplastic ganglion cells, which are most densely present in the cerebellar molecular layer.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Some of the dysplastic ganglion cells are immunoreactive for phosphorylated mTOR.
Dysplastic cerebellar gangliocytoma. T2-weighted MRI shows a mass with the typical tiger-stripe pattern of alternating inner hyperintense and outer hypointense layers.
Dysplastic cerebellar gangliocytoma. Diffusion-weighted MRI reveals hyperintensity within the T2-hyperintense area of the tumour.
Dysplastic cerebellar gangliocytoma. Precontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.
Dysplastic cerebellar gangliocytoma. Postcontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.

Q: Dysplastic cerebellar gangliocytoma is a key manifestation of Cowden syndrome (PTEN hamartoma tumor syndrome) and exhibits aberrant signaling that can be highlighted by immunohistochemistry for [...].
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Thickened cerebellar folium is replaced by large ganglion cells and disappearing inner granule cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Some of the dysplastic ganglion cells are immunoreactive for phosphorylated mTOR.
A: phosphorylated mTOR
Back Extra: Dysplastic cerebellar gangliocytoma
- Clinical: Often presents as part of Cowden syndrome (PTEN hamartoma tumor syndrome) and exhibits a characteristic "tiger-stripe" pattern on T2-weighted MRI.
- Micro: Features an "inverted cerebellar cortex" where the internal granular layer is replaced by dysplastic ganglion cells and the molecular layer is thickened with abnormally myelinated axons.
- Ancillary: Typically shows loss of PTEN protein expression by IHC and increased activation of the mTOR pathway (e.g., phosphorylated S6 or mTOR).
- Prognosis: Assigned CNS WHO grade 1; however, its association with Cowden syndrome necessitates screening for extra-axial malignancies like breast and thyroid cancer.
Reference Gallery:
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Thickened cerebellar folium is replaced by large ganglion cells and disappearing inner granule cells.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Numerous large ganglion cells and abnormally myelinated axon bundles in the cerebellar cortex.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). NeuN immunohistochemistry reveals the abnormal arrangement of dysplastic ganglion cells, which are most densely present in the cerebellar molecular layer.
Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease). Some of the dysplastic ganglion cells are immunoreactive for phosphorylated mTOR.
Dysplastic cerebellar gangliocytoma. T2-weighted MRI shows a mass with the typical tiger-stripe pattern of alternating inner hyperintense and outer hypointense layers.
Dysplastic cerebellar gangliocytoma. Diffusion-weighted MRI reveals hyperintensity within the T2-hyperintense area of the tumour.
Dysplastic cerebellar gangliocytoma. Precontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.
Dysplastic cerebellar gangliocytoma. Postcontrast T1-weighted MRI shows the vascular pattern of enhancement between the folia.

Q: In Extraventricular neurocytoma, the tumor cells are characteristically monomorphic and oligodendroglia-like, but they can be distinguished by their diffuse cytoplasmic immunoreactivity for [...].
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Diffuse cytoplasmic immunoreactivity for synaptophysin is characteristic of extraventricular neurocytoma.
A: synaptophysin
Q: Extraventricular neurocytoma
- Clinical: CNS WHO grade 2 neuronal neoplasm arising outside the ventricular system (most commonly cerebral hemispheres); peak incidence is in the 3rd to 4th decades.
- Microscopic: Characterized by monomorphic "oligodendroglia-like" cells with clear perinuclear haloes, neuropil islands, and common features like microcalcifications and hyalinized vessels.
- Ancillary: Diffuse cytoplasmic synaptophysin expression is characteristic; NeuN/Chromogranin A may be focal, and tumors are IDH-wildtype.
- Molecular: The most frequent alteration is the [TACC1] fusion, occurring in approximately 60% of cases.
Reference Gallery:
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Neoplastic cells arranged in rows or ribbons.
Extraventricular neurocytoma. Microcalcifications may be present.
Extraventricular neurocytoma. Diffuse cytoplasmic immunoreactivity for synaptophysin is characteristic of extraventricular neurocytoma.
Extraventricular neurocytoma. Variable proportions of GFAP-positive cells may be present in some tumours.
A: FGFR1

Q: The most frequent molecular alteration driving Extraventricular neurocytoma is the [TACC1] fusion, which occurs in approximately 60% of cases.
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
A: FGFR1
Q: Extraventricular neurocytoma
- Clinical: CNS WHO grade 2 neuronal neoplasm arising outside the ventricular system (most commonly cerebral hemispheres); peak incidence is in the 3rd to 4th decades.
- Microscopic: Characterized by monomorphic "oligodendroglia-like" cells with clear perinuclear haloes, neuropil islands, and common features like microcalcifications and hyalinized vessels.
- Ancillary: Diffuse cytoplasmic synaptophysin expression is characteristic; NeuN/Chromogranin A may be focal, and tumors are IDH-wildtype.
- Molecular: The most frequent alteration is the [TACC1] fusion, occurring in approximately 60% of cases.
Reference Gallery:
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Neoplastic cells arranged in rows or ribbons.
Extraventricular neurocytoma. Microcalcifications may be present.
Extraventricular neurocytoma. Diffuse cytoplasmic immunoreactivity for synaptophysin is characteristic of extraventricular neurocytoma.
Extraventricular neurocytoma. Variable proportions of GFAP-positive cells may be present in some tumours.
A: FGFR1

Q: Histologically, Extraventricular neurocytoma can closely mimic oligodendroglioma due to its monomorphic cells with clear perinuclear haloes and frequent [...].
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Microcalcifications may be present.
A: microcalcifications
Q: Extraventricular neurocytoma
- Clinical: CNS WHO grade 2 neuronal neoplasm arising outside the ventricular system (most commonly cerebral hemispheres); peak incidence is in the 3rd to 4th decades.
- Microscopic: Characterized by monomorphic "oligodendroglia-like" cells with clear perinuclear haloes, neuropil islands, and common features like microcalcifications and hyalinized vessels.
- Ancillary: Diffuse cytoplasmic synaptophysin expression is characteristic; NeuN/Chromogranin A may be focal, and tumors are IDH-wildtype.
- Molecular: The most frequent alteration is the [TACC1] fusion, occurring in approximately 60% of cases.
Reference Gallery:
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Round, monomorphic, oligodendroglia-like tumour cells with small, uniform nuclei and sparse cytoplasm, frequently with clear perinuclear haloes.
Extraventricular neurocytoma. Neoplastic cells arranged in rows or ribbons.
Extraventricular neurocytoma. Microcalcifications may be present.
Extraventricular neurocytoma. Diffuse cytoplasmic immunoreactivity for synaptophysin is characteristic of extraventricular neurocytoma.
Extraventricular neurocytoma. Variable proportions of GFAP-positive cells may be present in some tumours.
A: FGFR1

Q: The classic histologic appearance of Gangliocytoma features irregular clusters of large, mature, but dysplastic [...] that often exhibit binucleation and cytoplasmic ballooning.
Gangliocytoma. Clusters of large ganglion cells in a matrix indistinguishable from normal neuropil. Microcalcifications are present.
Gangliocytoma. Large ganglion cells with cytoplasmic ballooning; one is binucleated.
A: ganglion cells
Back Extra: Gangliocytoma
- Clinical: Gangliocytomas are benign (CNS WHO grade 1) neuroepithelial neoplasms predominantly affecting children; over 80% are associated with temporal lobe epilepsy.
- Microscopic: Characterized by irregular clusters of large, mature, but dysplastic ganglion cells showing features like binucleation and cytoplasmic ballooning in a neuropil-like matrix.
- Glial Component: Glial elements are sparsely represented and strictly reactive; the presence of a neoplastic glial component would shift the diagnosis to ganglioglioma.
- Ancillary: Neoplastic cells are typically immunopositive for synaptophysin, chromogranin, and neurofilament protein (NFP), while NeuN expression is frequently diminished or lost.
Reference Gallery:
Gangliocytoma. Right frontal lobe. Relatively circumscribed lesion involving cortex and superficial white matter, T2-hyperintense on MRI.
Gangliocytoma. Relatively circumscribed lesion involving cortex and superficial white matter, T1-isointense.
Gangliocytoma. Contrast enhancement is present after gadolinium administration.
Gangliocytoma. Clusters of large ganglion cells in a matrix indistinguishable from normal neuropil. Microcalcifications are present.
Gangliocytoma. Large ganglion cells with cytoplasmic ballooning; one is binucleated.
Gangliocytoma. Neoplastic ganglion cells are positive for chromogranin.
Gangliocytoma. Neurofilament, like synaptophysin, is typically immunopositive in ganglion cells as well as (diffusely) in background neuropil.

Q: A Gangliocytoma contains sparsely represented and strictly reactive glial elements; the presence of a neoplastic glial component alongside the dysplastic neuronal cells would instead define the tumor as a [...].
Gangliocytoma. Clusters of large ganglion cells in a matrix indistinguishable from normal neuropil. Microcalcifications are present.
A: ganglioglioma
Back Extra: Gangliocytoma
- Clinical: Gangliocytomas are benign (CNS WHO grade 1) neuroepithelial neoplasms predominantly affecting children; over 80% are associated with temporal lobe epilepsy.
- Microscopic: Characterized by irregular clusters of large, mature, but dysplastic ganglion cells showing features like binucleation and cytoplasmic ballooning in a neuropil-like matrix.
- Glial Component: Glial elements are sparsely represented and strictly reactive; the presence of a neoplastic glial component would shift the diagnosis to ganglioglioma.
- Ancillary: Neoplastic cells are typically immunopositive for synaptophysin, chromogranin, and neurofilament protein (NFP), while NeuN expression is frequently diminished or lost.
Reference Gallery:
Gangliocytoma. Right frontal lobe. Relatively circumscribed lesion involving cortex and superficial white matter, T2-hyperintense on MRI.
Gangliocytoma. Relatively circumscribed lesion involving cortex and superficial white matter, T1-isointense.
Gangliocytoma. Contrast enhancement is present after gadolinium administration.
Gangliocytoma. Clusters of large ganglion cells in a matrix indistinguishable from normal neuropil. Microcalcifications are present.
Gangliocytoma. Large ganglion cells with cytoplasmic ballooning; one is binucleated.
Gangliocytoma. Neoplastic ganglion cells are positive for chromogranin.
Gangliocytoma. Neurofilament, like synaptophysin, is typically immunopositive in ganglion cells as well as (diffusely) in background neuropil.

Q: Immunohistochemistry in Gangliocytoma demonstrates that the neoplastic cells are typically positive for synaptophysin, neurofilament protein (NFP), and [...].
Gangliocytoma. Large ganglion cells with cytoplasmic ballooning; one is binucleated.
Gangliocytoma. Neoplastic ganglion cells are positive for chromogranin.
Gangliocytoma. Neurofilament, like synaptophysin, is typically immunopositive in ganglion cells as well as (diffusely) in background neuropil.
A: chromogranin
Back Extra: Gangliocytoma
- Clinical: Gangliocytomas are benign (CNS WHO grade 1) neuroepithelial neoplasms predominantly affecting children; over 80% are associated with temporal lobe epilepsy.
- Microscopic: Characterized by irregular clusters of large, mature, but dysplastic ganglion cells showing features like binucleation and cytoplasmic ballooning in a neuropil-like matrix.
- Glial Component: Glial elements are sparsely represented and strictly reactive; the presence of a neoplastic glial component would shift the diagnosis to ganglioglioma.
- Ancillary: Neoplastic cells are typically immunopositive for synaptophysin, chromogranin, and neurofilament protein (NFP), while NeuN expression is frequently diminished or lost.
Reference Gallery:
Gangliocytoma. Right frontal lobe. Relatively circumscribed lesion involving cortex and superficial white matter, T2-hyperintense on MRI.
Gangliocytoma. Relatively circumscribed lesion involving cortex and superficial white matter, T1-isointense.
Gangliocytoma. Contrast enhancement is present after gadolinium administration.
Gangliocytoma. Clusters of large ganglion cells in a matrix indistinguishable from normal neuropil. Microcalcifications are present.
Gangliocytoma. Large ganglion cells with cytoplasmic ballooning; one is binucleated.
Gangliocytoma. Neoplastic ganglion cells are positive for chromogranin.
Gangliocytoma. Neurofilament, like synaptophysin, is typically immunopositive in ganglion cells as well as (diffusely) in background neuropil.

Q: Gangliogliomas are biphasic tumors composed of neoplastic glial elements and dysmorphic [...] cells that frequently exhibit abnormal clustering, cytomegaly, and binucleation.
Neoplastic ganglion cells showing abnormal clustering and cytomegaly.
Neoplastic ganglion cells demonstrating binucleated forms.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19189 View Original Diagnosis: Ganglioglioma. Gangliogliomas are glioneuronal neoplasms composed of an admixture of neoplastic ganglion and glial cells.
A: ganglion
Back Extra: Ganglioglioma
- Clinical: Most commonly occurs in the first and second decades of life (median age 12 years) with a slight male predominance. Clinically, it is the most common tumor associated with chronic temporal lobe epilepsy; patients often p…
- Micro: Gangliogliomas are biphasic tumors consisting of neoplastic neuronal and glial elements. Neuronal Component: Composed of dysmorphic ganglion cells showing abnormal clustering, lack of cytoarchitectural organization…
- Cyto: Not clinically relevant for standard diagnosis.
- Ancillary: Immunohistochemistry (IHC): - Neuronal markers: Neoplastic neurons express Synaptophysin, MAP2, and Neurofilament. Chromogranin A expression is often diffuse and strong (helping distinguish from normal neurons). …
Reference Gallery:
Coronal FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe.
Neoplastic ganglion cells showing abnormal clustering and cytomegaly.
Neoplastic ganglion cells demonstrating binucleated forms.
Diffuse strong expression of BRAF p.V600E-mutant protein.
CD34-positive ramified cells within the tumor.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19178 View Original Diagnosis: Ganglioglioma. Axial FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19179 View Original Diagnosis: Ganglioglioma. Axial T2-weighted MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19189 View Original Diagnosis: Ganglioglioma. Gangliogliomas are glioneuronal neoplasms composed of an admixture of neoplastic ganglion and glial cells.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19192 View Original Diagnosis: Ganglioglioma. The neoplastic glial cells in this ganglioglioma feature astrocytic morphology.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19194 View Original Diagnosis: Ganglioglioma. Gangliogliomas frequently demonstrate perivascular lymphoplasmacytic infiltrates.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19195 View Original Diagnosis: Ganglioglioma. Eosinophilic granular bodies are a common finding in gangliogliomas.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19198 View Original Diagnosis: Ganglioglioma. This ganglioglioma shows dystrophic calcification that is encrusting capillaries and neuronal cell bodies.

Q: A significant subset of Gangliogliomas harbor a p.V600E hotspot mutation in the [...] gene, which can be reliably detected via targeted immunohistochemistry (e.g., using the VE1 antibody).
Neoplastic ganglion cells showing abnormal clustering and cytomegaly.
Diffuse strong expression of BRAF p.V600E-mutant protein.
A: BRAF
Back Extra: Ganglioglioma
- Clinical: Most commonly occurs in the first and second decades of life (median age 12 years) with a slight male predominance. Clinically, it is the most common tumor associated with chronic temporal lobe epilepsy; patients often p…
- Micro: Gangliogliomas are biphasic tumors consisting of neoplastic neuronal and glial elements. Neuronal Component: Composed of dysmorphic ganglion cells showing abnormal clustering, lack of cytoarchitectural organization…
- Cyto: Not clinically relevant for standard diagnosis.
- Ancillary: Immunohistochemistry (IHC): - Neuronal markers: Neoplastic neurons express Synaptophysin, MAP2, and Neurofilament. Chromogranin A expression is often diffuse and strong (helping distinguish from normal neurons). …
Reference Gallery:
Coronal FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe.
Neoplastic ganglion cells showing abnormal clustering and cytomegaly.
Neoplastic ganglion cells demonstrating binucleated forms.
Diffuse strong expression of BRAF p.V600E-mutant protein.
CD34-positive ramified cells within the tumor.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19178 View Original Diagnosis: Ganglioglioma. Axial FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19179 View Original Diagnosis: Ganglioglioma. Axial T2-weighted MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19189 View Original Diagnosis: Ganglioglioma. Gangliogliomas are glioneuronal neoplasms composed of an admixture of neoplastic ganglion and glial cells.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19192 View Original Diagnosis: Ganglioglioma. The neoplastic glial cells in this ganglioglioma feature astrocytic morphology.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19194 View Original Diagnosis: Ganglioglioma. Gangliogliomas frequently demonstrate perivascular lymphoplasmacytic infiltrates.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19195 View Original Diagnosis: Ganglioglioma. Eosinophilic granular bodies are a common finding in gangliogliomas.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19198 View Original Diagnosis: Ganglioglioma. This ganglioglioma shows dystrophic calcification that is encrusting capillaries and neuronal cell bodies.

Q: In addition to an admixture of neuronal and glial elements, up to 80% of Gangliogliomas contain a network of ramified cells that strongly express the oncofetal surface marker [...] on immunohistochemistry.
CD34-positive ramified cells within the tumor.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19189 View Original Diagnosis: Ganglioglioma. Gangliogliomas are glioneuronal neoplasms composed of an admixture of neoplastic ganglion and glial cells.
A: CD34
Back Extra: Ganglioglioma
- Clinical: Most commonly occurs in the first and second decades of life (median age 12 years) with a slight male predominance. Clinically, it is the most common tumor associated with chronic temporal lobe epilepsy; patients often p…
- Micro: Gangliogliomas are biphasic tumors consisting of neoplastic neuronal and glial elements. Neuronal Component: Composed of dysmorphic ganglion cells showing abnormal clustering, lack of cytoarchitectural organization…
- Cyto: Not clinically relevant for standard diagnosis.
- Ancillary: Immunohistochemistry (IHC): - Neuronal markers: Neoplastic neurons express Synaptophysin, MAP2, and Neurofilament. Chromogranin A expression is often diffuse and strong (helping distinguish from normal neurons). …
Reference Gallery:
Coronal FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe.
Neoplastic ganglion cells showing abnormal clustering and cytomegaly.
Neoplastic ganglion cells demonstrating binucleated forms.
Diffuse strong expression of BRAF p.V600E-mutant protein.
CD34-positive ramified cells within the tumor.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19178 View Original Diagnosis: Ganglioglioma. Axial FLAIR MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19179 View Original Diagnosis: Ganglioglioma. Axial T2-weighted MRI showing a solid and cystic neoplasm in the temporal lobe of the brain.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19189 View Original Diagnosis: Ganglioglioma. Gangliogliomas are glioneuronal neoplasms composed of an admixture of neoplastic ganglion and glial cells.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19192 View Original Diagnosis: Ganglioglioma. The neoplastic glial cells in this ganglioglioma feature astrocytic morphology.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19194 View Original Diagnosis: Ganglioglioma. Gangliogliomas frequently demonstrate perivascular lymphoplasmacytic infiltrates.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19195 View Original Diagnosis: Ganglioglioma. Eosinophilic granular bodies are a common finding in gangliogliomas.
12 years) { 22120270 ; 29069555 }. In a single-centre study, ganglioglioma was more prevalent in male patients (59.8%) than in female patients (40.2%), and there was a similar ratio in the European Epilepsy Brain Bank cohort { 25603107 ; 29069555 }. Etiology   The vast majority of gangliogliomas are sporadic tumours. However, a small subset (< 2%) arise in the setting of neurofibromatosis type 1 due to germline mutations or deletions in the NF1 tumour suppressor gene { 18344915 ; 24192615 ; 29880043 }. No known risk factors or environmental exposures have been linked with ganglioglioma. Pathogenesis   Gangliogliomas result from genetic aberrations causing activation of the MAPK signalling pathway that drives cell proliferation. Most common are p.V600E hotspot mutations in the BRAF gene, which lead to the substitution of glutamic acid for valine at amino acid 600 within the P-loop of the serine/threonine kinase domain that causes constitutive activation. BRAF p.V600E mutation has been found in gangliogliomas at frequencies ranging from approximately 10% to 60% depending on the study and anatomical site, with the highest frequencies in cortical tumours and the lowest in spinal cord tumours { 20156809 ; 21274720 ; 23435618 ; 23442159 ; 23583981 ; 23609006 ; 23633565 ; 24238153 ; 24529209 ; 26810070 ; 26826417 ; 27984673 ; 28986151 ; 29058119 ; 29880043 ; 32289278 }. In gangliogliomas lacking p.V600E hotspot mutations, other oncogenic mutations in the BRAF gene are often present, including recurrent small in-frame insertions at codon p.R506 in approximately 10% of cases { 29880043 }. BRAF gene fusions are recurrently present in gangliogliomas lacking BRAF mutations, most commonly with KIAA1549 as the fusion partner in spinal cord tumours, and with other fusion partners in tumours within the cerebral hemispheres { 29880043 }. Gangliogliomas with wildtype BRAF alleles instead display a diverse array of other genetic alterations that similarly cause activation of the MAPK pathway, which include RAF1 gene fusions, activating KRAS mutations, and inactivating NF1 mutations or deletions { 29880043 }. The pathogenesis of ganglioglioma was addressed in a transgenic mouse model engineered to express Braf p.V600E mutations { 30224756 }. When the mutation was successfully integrated into neuronal cell progenies, 90% of the mice showed spontaneous tonic–clonic seizures, which could be prevented with the small-molecule RAF inhibitor vemurafenib. The tumorigenic properties were mostly due to Braf p.V600E integration into the glial cell lineage. These studies experimentally confirmed the long-term observation that tumorigenesis in ganglioglioma is related to the glial component, whereas the epileptogenic phenotype associates with the neuronal component { 12125736 }. Macroscopic appearance   Gangliogliomas are macroscopically well-delineated solid or cystic lesions, usually with little mass effect. Calcification may be observed. Haemorrhage and necrosis are rare. Histopathology   Gangliogliomas are biphasic tumours composed of a variable admixture of neuronal and glial elements, which may exhibit marked heterogeneity. The two components may be intermixed or geographically separate. The neuronal element is composed of dysmorphic ganglion cells that may demonstrate abnormal clustering, a lack of cytoarchitectural organization, cytomegaly, perimembranous aggregation of Nissl substance, or binucleated forms (seen in < 50% of cases). The glial component, which constitutes the proliferative cell population of the tumour, may resemble fibrillary astrocytoma, oligodendroglioma, or pilocytic astrocytoma { 24529209 ; 26826417 ; 29880043 }. Eosinophilic granular bodies are encountered more often than Rosenthal fibres { 7985497 ; 29880043 }. Although gangliogliomas are generally well demarcated on imaging, they often demonstrate an infiltrative growth pattern microscopically { 24529209 ; 24858213 ; 27857123 ; 30326153 ; 32151273 }. Extension into the subarachnoid space is common. Gangliogliomas may uncommonly develop a reticulin fibre network apart from the vasculature (which is a feature more typical of pleomorphic xanthoastrocytoma). Mitotic activity is typically low or absent. Additional histopathological features frequently include dystrophic calcification, either within the matrix or as neuronal/capillary incrustation; extensive lymphoid infiltrates along perivascular spaces; and a prominent capillary network { 12125736 }. Focal cortical dysplasia (FCD) arising in association with ganglioglioma is a frequently reported finding, but it remains controversial whether this actually represents infiltration of ganglioglioma or non-neoplastic dysplasia in most cases { 21219302 }. It should be diagnosed only in areas of cortical abnormalities without tumour cell infiltration and classified as FCD type 3b according to the classification proposed by the International League Against Epilepsy (ILAE) { 21219302 ; 22427329 }. Immunophenotype Neuronal markers such as MAP2, neurofilament, chromogranin A, and synaptophysin highlight the neuronal component in gangliogliomas { 15146346 }. However, to date, there is no specific marker to unequivocally differentiate neoplastic neurons from their normal counterparts. Chromogranin A expression is usually very weak or absent in normal neurons, whereas diffuse and strong expression suggests a neoplastic neuron. Additionally, neoplastic neurons typically have low or absent NeuN expression, in contrast to normal cortical neurons. Immunohistochemistry for GFAP and OLIG2 highlights the neoplastic glial cell component { 9041162 }. As many as 80% of gangliogliomas contain ramified cells either within the tumour or in the adjacent cortex that express the oncofetal epitope CD34, which is not normally expressed outside of vascular endothelial cells in the mature brain { 10334485 ; 12125736 }. Ki-67 labelling is typically low (< 5%) and usually limited to the glial component { 7541447 ; 9041162 }. The VE1 antibody that recognizes BRAF p.V600E-mutant protein can be used with appropriate controls to identify the subset of gangliogliomas that are positive for this genetic alteration { 23435618 }. However, the immunostaining intensity levels are typically lower than those observed in BRAF-mutant melanomas and other tumours, and in some gangliogliomas the positivity is most prominent in or exclusively limited to the ganglion cell component { 23435618 }. Grading Ganglioglioma is a CNS WHO grade 1 neoplasm. However, gangliogliomas with anaplasia in the glial component (termed “anaplastic ganglioglioma”), with features including conspicuous mitotic activity, high Ki-67 proliferation index, necrosis, and microvascular proliferation, have been reported both at initial presentation and at time of recurrence { 7541447 ; 8194028 ; 8246055 ; 15222000 ; 19043777 ; 25862009 ; 26826417 ; 27539475 ; 28453747 }. However, most of these prior studies lacked molecular analysis to exclude other high-grade glioma subtypes. Further studies are needed to confirm the existence of anaplastic ganglioglioma and establish its diagnostic criteria. Differential diagnosis The diagnosis of ganglioglioma requires the histological identification of a neuronal component, but the near-normal morphology of the neuronal component in some cases remains a challenging issue because there is no specific marker protein for differentiating the neoplastic ganglion cells from native neurons. The diagnosis of ganglioglioma should be considered in all cases of low-grade neuroepithelial tumours associated with focal seizures that are difficult to classify, especially when located in the temporal lobe. The differential diagnosis for ganglioglioma can include FCD, diffuse gliomas, and other glioneuronal tumours, specifically dysembryoplastic neuroepithelial tumour (DNT), polymorphous low-grade neuroepithelial tumour of the young (PLNTY), and multinodular and vacuolating neuronal tumour. The differentiation from FCD rests principally on the presence of a convincing neoplastic glial component in ganglioglioma; in challenging cases, the identification of BRAF p.V600E mutation or other MAPK pathway alterations provides support for a diagnosis of ganglioglioma, because FCD is genetically characterized by alterations in the PI3K/AKT/mTOR pathway and an absence of MAPK alterations { 21219302 ; 29359340 }. As discussed above, identifying the neoplastic neuronal component of ganglioglioma can be challenging, and diffuse gliomas with entrapped native neurons can enter the differential diagnosis in such cases. Reduced or absent NeuN expression in the neuronal cells, eosinophilic granular bodies, and CD34-positive ramified cells can all provide support for a diagnosis of ganglioglioma instead of diffuse glioma. Additionally, gangliogliomas harbour BRAF p.V600E mutation or other MAPK pathway alterations and lack the IDH mutation that characterizes IDH-mutant adult-type diffuse gliomas and the MYB or MYBL1 fusion that characterizes angiocentric glioma and paediatric-type diffuse low-grade gliomas { 21314850 ; 31563982 }. In low-grade glioneuronal tumours with an oligodendrocyte-like glial component, the differential diagnosis should include both DNT and PLNTY. Multinodular growth pattern, the presence of a specific glioneuronal element, absence of CD34 immunoreactivity, and pathogenic FGFR1 alteration all provide support for a diagnosis of DNT over ganglioglioma { 30326153 }. Abundant calcifications, diffuse strong CD34 staining of tumour cells, and FGFR2 or FGFR3 fusions all provide support for a diagnosis of PLNTY over ganglioglioma { 27812792 }. Multinodular growth pattern, stromal and neuronal vacuolation, OLIG2 positivity of neoplastic neuronal cells, and MAP2K1 mutation all provide support for a diagnosis of multinodular and vacuolating neuronal tumour over ganglioglioma { 23324039 ; 29428973 }. Lastly, ganglion cell differentiation has been reported in a wide spectrum of CNS tumour entities (e.g. central and extraventricular neurocytoma, diffuse leptomeningeal glioneuronal tumour, papillary glioneuronal tumour, pleomorphic xanthoastrocytoma, paraganglioma of the cauda equina, H3 G34–mutant diffuse hemispheric glioma, CNS neuroblastoma), which require differentiation from ganglioglioma. The presence of xanthomatous tumour cells, intercellular basement membrane deposition (as highlighted by reticulin staining), and focal CDKN2A homozygous/biallelic deletion all provide support for a diagnosis of pleomorphic xanthoastrocytoma over ganglioglioma. Cytology   Not clinically relevant Diagnostic molecular pathology   For patients with ganglioglioma with a typical clinical and histological presentation, molecular testing may not be critical. However, for cases with diagnostic uncertainty, the initial molecular workup should focus on BRAF p.V600E mutation testing either by sequencing or by immunohistochemistry using the mutant-specific antibody VE1 { 23435618 }. Many gangliogliomas have low tumour cell content, so the selection of areas for molecular testing should be made cautiously, and sensitive sequencing methods capable of detecting variants at low allele frequencies should be employed. In gangliogliomas negative for BRAF p.V600E mutation, other BRAF alterations including mutations and fusions are commonly found, as well as various other genetic alterations causing activation of the MAPK signalling pathway, such as RAF1 fusion, KRAS mutation, and NF1 mutation or deletion { 29880043 }. Most commonly, gangliogliomas harbour a solitary pathogenic alteration causing activation of the MAPK pathway. However, rare gangliogliomas have been reported with dual BRAF p.V600E mutation and CDKN2A homozygous deletion, which may potentially represent an adverse prognostic factor in ganglioglioma { 29880043 }. However, this genetic pattern is far more common in pleomorphic xanthoastrocytoma and should prompt consideration of this alternative diagnosis { 30051528 ; 32619305 }. A small number of ganglioglioma-like tumours centred in midline structures of the CNS have been reported with dual BRAF p.V600E and H3 p.K28M (K27M) mutations { 27984673 ; 28378357 ; 32289278 }; however, the exact nature of these tumours is unknown at present. A small subset of histologically defined gangliogliomas have been reported with FGFR1 or FGFR2 mutations or fusions { 29880043 }. However, FGFR1 alterations are more characteristic of other glioneuronal tumour entities (e.g. DNT, rosette-forming glioneuronal tumour, and extraventricular neurocytoma), and the finding of FGFR1 alteration in a low-grade neuroepithelial tumour should prompt consideration of these alternative entities. Additionally, FGFR2 fusions are characteristic of PLNTY, and the finding of FGFR2 fusion in a low-grade glioneuronal tumour should prompt consideration of this alternative diagnosis. IDH mutation (either IDH1 p.R132 or IDH2 p.R172), MYB or MYBL1 fusion, and PRKCA fusion are not compatible with the diagnosis of ganglioglioma. Lastly, genome-wide DNA methylation profiling has established a distinct epigenetic signature of ganglioglioma that may aid in the classification of diagnostically challenging tumours { 29058119 ; 29539639 }. However, the low tumour cell content in ganglioglioma often limits the applicability of DNA methylation profiling { 32242226 }. Essential and desirable diagnostic criteria   See #17883Box 2.18 . Staging   Not clinically relevant Prognosis and prediction   Prognostic factors are difficult to define because of the complexity of the clinical picture, anatomical location, and molecular interrelationships in retrospective cohorts over the past few decades, as well as the small numbers of patients. However, ganglioglioma is generally a low-grade indolent tumour with excellent prognosis in combined paediatric and adult cohorts (15-year overall survival rate: 83–94%) { 15222000 ; 22957524 ; 24305706 }. The best prognostic indicator, including for better seizure outcome, is complete surgical resection { 15222000 ; 22957524 ; 24305706 }. The incidence of tumour progression is quite variable depending on the series (range: 16–35%) { 24305706 ; 29882043 }, but no consistent correlations between histological features, imaging data, and clinical outcome have been found { 15222000 ; 23442159 ; 23609006 ; 29880043 }. In a recent large series, BRAF p.V600E mutation conferred poor outcome relative to other genetic alterations (such as BRAF fusion in paediatric low-grade glioma) when considered as a group { 32289278 }; however, the prognostic value of BRAF p.V600E mutation versus other alterations specifically in ganglioglioma was not clearly defined in that study. Prospective randomized studies testing small-molecule inhibitors of RAF and MEK will be important to validate the potential clinical benefit suggested by initial case reports { 23358987 ; 25524464 ; 26579623 ; 29380516 ; 30120137 ; 30984614 }. The rare gangliogliomas with dual BRAF p.V600E mutation and CDKN2A homozygous deletion may potentially have an increased risk of recurrence compared with the vast majority of gangliogliomas without this accompanying CDKN2A homozygous deletion { 28727518 ; 29880043 }. The ganglioglioma-like tumours centred in midline structures of the CNS with co-occurring BRAF p.V600E mutations and H3 p.K28M (K27M) mutation have been associated with poor outcomes { 27984673 ; 28378357 ; 32289278 }. View tables and boxes #19177 Ganglioglioma #19178 Ganglioglioma #19179 Ganglioglioma #19189 Ganglioglioma #19190 Ganglioglioma #19191 Ganglioglioma #19192 Ganglioglioma #19194 Ganglioglioma #19195 Ganglioglioma #19198 Ganglioglioma #19201 Ganglioglioma #19202 Ganglioglioma #19203 Ganglioglioma #19206 Ganglioglioma #19207 Ganglioglioma #19496 Ganglioglioma #19497 Ganglioglioma #28617 Ganglioglioma Whole Slide Image #19301 Ganglioglioma Whole Slide Image #19302 Ganglioglioma   Attachment #19198 View Original Diagnosis: Ganglioglioma. This ganglioglioma shows dystrophic calcification that is encrusting capillaries and neuronal cell bodies.

Q: Histologically, a Multinodular and vacuolating neuronal tumor is characterized by discrete or coalescent nodules at the gray-white junction containing mature-appearing neurons and prominent [...] changes in both the cells and the matrix.
Multinodular and vacuolating neuronal tumour. Discrete tumour nodules with vacuolar changes are apparent.
Multinodular and vacuolating neuronal tumour. Mature-appearing neurons of intermediate to large size populate this nodule with vacuolar matrix changes.
A: vacuolar
Back Extra: Multinodular and vacuolating neuronal tumour
- Clinical: Typically presents in adults (median 42 years) with seizures; imaging is highly characteristic, showing clustered T2/FLAIR-hyperintense nodules in the deep cortex and superficial white matter without mass effect or enhancement.
- Microscopic: Composed of discrete or coalescent nodules at the grey-white junction containing monomorphic neuronal elements with prominent vacuolar change in both the cells and the matrix.
- Ancillary: Neoplastic cells consistently express OLIG2, HuC/HuD, and doublecortin, but are typically negative or only weakly reactive for NeuN.
- Genetics: Characterized by MAPK pathway activation, most frequently involving mutations in MAP2K1, or less commonly BRAF or FGFR2 fusions.
- Prognosis: Excellent (CNS WHO grade 1); lesions are stable and do not show recurrence even after subtotal resection.
Reference Gallery:
Multinodular and vacuolating neuronal tumour. Confluent and nodular FLAIR hyperintensity, involvement of cortex and superficial white matter, and absence of mass effect are characteristic on MRI.
Multinodular and vacuolating neuronal tumour. Discrete tumour nodules with vacuolar changes are apparent.
Multinodular and vacuolating neuronal tumour. Mature-appearing neurons of intermediate to large size populate this nodule with vacuolar matrix changes.
Multinodular and vacuolating neuronal tumour. Neoplastic neurons exhibit nuclear and cytoplasmic HuC/HuD immunoreactivity.
Multinodular and vacuolating neuronal tumour. Neoplastic neuronal elements manifest nuclear OLIG2 immunoreactivity.
Multinodular and vacuolating neuronal tumour. MRI demonstrating FLAIR-hyperintense, clustered nodular lesions in the deep cortex and superficial subcortical white matter.

Q: On MRI, a Multinodular and vacuolating neuronal tumor classically presents as clustered [...] nodules in the deep cortex and superficial white matter without significant mass effect or enhancement.
Multinodular and vacuolating neuronal tumour. Confluent and nodular FLAIR hyperintensity, involvement of cortex and superficial white matter, and absence of mass effect are characteristic on MRI.
Multinodular and vacuolating neuronal tumour. MRI demonstrating FLAIR-hyperintense, clustered nodular lesions in the deep cortex and superficial subcortical white matter.
A: T2/FLAIR-hyperintense
Back Extra: Multinodular and vacuolating neuronal tumour
- Clinical: Typically presents in adults (median 42 years) with seizures; imaging is highly characteristic, showing clustered T2/FLAIR-hyperintense nodules in the deep cortex and superficial white matter without mass effect or enhancement.
- Microscopic: Composed of discrete or coalescent nodules at the grey-white junction containing monomorphic neuronal elements with prominent vacuolar change in both the cells and the matrix.
- Ancillary: Neoplastic cells consistently express OLIG2, HuC/HuD, and doublecortin, but are typically negative or only weakly reactive for NeuN.
- Genetics: Characterized by MAPK pathway activation, most frequently involving mutations in MAP2K1, or less commonly BRAF or FGFR2 fusions.
- Prognosis: Excellent (CNS WHO grade 1); lesions are stable and do not show recurrence even after subtotal resection.
Reference Gallery:
Multinodular and vacuolating neuronal tumour. Confluent and nodular FLAIR hyperintensity, involvement of cortex and superficial white matter, and absence of mass effect are characteristic on MRI.
Multinodular and vacuolating neuronal tumour. Discrete tumour nodules with vacuolar changes are apparent.
Multinodular and vacuolating neuronal tumour. Mature-appearing neurons of intermediate to large size populate this nodule with vacuolar matrix changes.
Multinodular and vacuolating neuronal tumour. Neoplastic neurons exhibit nuclear and cytoplasmic HuC/HuD immunoreactivity.
Multinodular and vacuolating neuronal tumour. Neoplastic neuronal elements manifest nuclear OLIG2 immunoreactivity.
Multinodular and vacuolating neuronal tumour. MRI demonstrating FLAIR-hyperintense, clustered nodular lesions in the deep cortex and superficial subcortical white matter.

Q: By immunohistochemistry, the neoplastic cells of a Multinodular and vacuolating neuronal tumor paradoxically express the glial marker OLIG2 alongside the neuronal marker [...], while being characteristically negative or weakly reactive for NeuN.
Multinodular and vacuolating neuronal tumour. Neoplastic neurons exhibit nuclear and cytoplasmic HuC/HuD immunoreactivity.
Multinodular and vacuolating neuronal tumour. Neoplastic neuronal elements manifest nuclear OLIG2 immunoreactivity.
A: HuC/HuD
Back Extra: Multinodular and vacuolating neuronal tumour
- Clinical: Typically presents in adults (median 42 years) with seizures; imaging is highly characteristic, showing clustered T2/FLAIR-hyperintense nodules in the deep cortex and superficial white matter without mass effect or enhancement.
- Microscopic: Composed of discrete or coalescent nodules at the grey-white junction containing monomorphic neuronal elements with prominent vacuolar change in both the cells and the matrix.
- Ancillary: Neoplastic cells consistently express OLIG2, HuC/HuD, and doublecortin, but are typically negative or only weakly reactive for NeuN.
- Genetics: Characterized by MAPK pathway activation, most frequently involving mutations in MAP2K1, or less commonly BRAF or FGFR2 fusions.
- Prognosis: Excellent (CNS WHO grade 1); lesions are stable and do not show recurrence even after subtotal resection.
Reference Gallery:
Multinodular and vacuolating neuronal tumour. Confluent and nodular FLAIR hyperintensity, involvement of cortex and superficial white matter, and absence of mass effect are characteristic on MRI.
Multinodular and vacuolating neuronal tumour. Discrete tumour nodules with vacuolar changes are apparent.
Multinodular and vacuolating neuronal tumour. Mature-appearing neurons of intermediate to large size populate this nodule with vacuolar matrix changes.
Multinodular and vacuolating neuronal tumour. Neoplastic neurons exhibit nuclear and cytoplasmic HuC/HuD immunoreactivity.
Multinodular and vacuolating neuronal tumour. Neoplastic neuronal elements manifest nuclear OLIG2 immunoreactivity.
Multinodular and vacuolating neuronal tumour. MRI demonstrating FLAIR-hyperintense, clustered nodular lesions in the deep cortex and superficial subcortical white matter.

Q: Myxoid glioneuronal tumor typically arises in the midline (e.g., septal nuclei) and is molecularly defined by a characteristic recurrent dinucleotide mutation at codon p.K385 in the [...] gene.
Myxoid glioneuronal tumour. Diagram of the PDGFRA protein annotated with the location of the characteristic p.K385L or p.K385I dinucleotide mutation found in 8 cases of myxoid glioneuronal tumour.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
A: PDGFRA
Q: Myxoid glioneuronal tumour
- Clinical: Low-grade (CNS WHO grade 1) glioneuronal tumour typically arising in the septal nuclei, septum pellucidum, or corpus callosum in children and young adults.
- Microscopic: Characterized by oligodendrocyte-like cells embedded in a prominent myxoid stroma with delicate capillaries; may contain [...] or neurocytic rosettes.
- Molecular: Defined by a recurrent dinucleotide mutation at codon [...] in the [...] gene.
- Differential: Distinguished from cortical dysembryoplastic neuroepithelial tumour (DNET) by its midline location, lack of multinodularity, and presence of PDGFRA mutation.
Reference Gallery:
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on sagittal T2-FLAIR MRI. There is also disseminated disease throughout the ventricular system, with hyperintense nodules along the ependymal surface of the lateral, third, and fourth ventricles.
Myxoid glioneuronal tumour. Diagram of the PDGFRA protein annotated with the location of the characteristic p.K385L or p.K385I dinucleotide mutation found in 8 cases of myxoid glioneuronal tumour.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on axial T2-FLAIR MRI.
A: "floating neurons"; p.K385; PDGFRA

Q: Histologically, Myxoid glioneuronal tumor is characterized by oligodendrocyte-like cells embedded in a prominent myxoid stroma with delicate capillaries, and it frequently contains distinctive [...] or neurocytic rosettes.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
A: floating neurons
Q: Myxoid glioneuronal tumour
- Clinical: Low-grade (CNS WHO grade 1) glioneuronal tumour typically arising in the septal nuclei, septum pellucidum, or corpus callosum in children and young adults.
- Microscopic: Characterized by oligodendrocyte-like cells embedded in a prominent myxoid stroma with delicate capillaries; may contain [...] or neurocytic rosettes.
- Molecular: Defined by a recurrent dinucleotide mutation at codon [...] in the [...] gene.
- Differential: Distinguished from cortical dysembryoplastic neuroepithelial tumour (DNET) by its midline location, lack of multinodularity, and presence of PDGFRA mutation.
Reference Gallery:
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on sagittal T2-FLAIR MRI. There is also disseminated disease throughout the ventricular system, with hyperintense nodules along the ependymal surface of the lateral, third, and fourth ventricles.
Myxoid glioneuronal tumour. Diagram of the PDGFRA protein annotated with the location of the characteristic p.K385L or p.K385I dinucleotide mutation found in 8 cases of myxoid glioneuronal tumour.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on axial T2-FLAIR MRI.
A: "floating neurons"; p.K385; PDGFRA

Q: On neuroimaging, Myxoid glioneuronal tumor classically presents as a T2-FLAIR hyperintense mass centered in the midline, specifically within the [...] or septum pellucidum.
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on sagittal T2-FLAIR MRI. There is also disseminated disease throughout the ventricular system, with hyperintense nodules along the ependymal surface of the lateral, third, and fourth ventricles.
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on axial T2-FLAIR MRI.
A: septal nuclei
Q: Myxoid glioneuronal tumour
- Clinical: Low-grade (CNS WHO grade 1) glioneuronal tumour typically arising in the septal nuclei, septum pellucidum, or corpus callosum in children and young adults.
- Microscopic: Characterized by oligodendrocyte-like cells embedded in a prominent myxoid stroma with delicate capillaries; may contain [...] or neurocytic rosettes.
- Molecular: Defined by a recurrent dinucleotide mutation at codon [...] in the [...] gene.
- Differential: Distinguished from cortical dysembryoplastic neuroepithelial tumour (DNET) by its midline location, lack of multinodularity, and presence of PDGFRA mutation.
Reference Gallery:
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on sagittal T2-FLAIR MRI. There is also disseminated disease throughout the ventricular system, with hyperintense nodules along the ependymal surface of the lateral, third, and fourth ventricles.
Myxoid glioneuronal tumour. Diagram of the PDGFRA protein annotated with the location of the characteristic p.K385L or p.K385I dinucleotide mutation found in 8 cases of myxoid glioneuronal tumour.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. These tumours are histologically characterized by a proliferation of oligodendrocyte-like cells in a myxoid stroma with a delicate capillary network, occasionally containing floating neurons, neurocytic rosettes, and/or perivascular neuropil.
Myxoid glioneuronal tumour. This tumour with characteristic PDGFRA p.K385 mutation is centred in the septal nuclei at the base of the septum pellucidum and is hyperintense on axial T2-FLAIR MRI.
A: "floating neurons"; p.K385; PDGFRA

Q: In Papillary glioneuronal tumor, the microscopic hallmark is a biphasic pattern featuring an interpapillary neuronal component and cuboidal glial cells that form [...] over hyalinized blood vessels.
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. Hyalinized vessels can be prominent.
Papillary glioneuronal tumour. Interpapillary component comprises neurocytes and ganglioid cells.
A: pseudopapillae
Q: Papillary glioneuronal tumour
- Clinical: Rare CNS WHO grade 1 tumour primarily affecting young adults (median age 16); typically presents as a well-demarcated, solid and cystic mass in the temporal lobe near the lateral ventricles.
- Microscopic: Characterized by a hallmark biphasic pattern: 1) cuboidal glial cells forming pseudopapillae over hyalinized blood vessels, and 2) an interpapillary neuronal component of neurocytes and neurons within a neuropil background.
- Ancillary: The glial component is GFAP/S100 positive, while the neuronal component expresses synaptophysin and NeuN; the Ki-67 proliferation index is generally low (< 2%).
- Genetics: The diagnostic hallmark is the [...] gene fusion, most commonly the [...]::PRKCA fusion resulting from t(9;17)(q31;q24).
Reference Gallery:
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. GFAP-positive cells in pseudopapillary structures.
Papillary glioneuronal tumour. Interpapillary cells show synaptophysin immunoreactivity.
Papillary glioneuronal tumour. Hyalinized vessels can be prominent.
Papillary glioneuronal tumour. Interpapillary component comprises neurocytes and ganglioid cells.
Papillary glioneuronal tumour. Interphase FISH using a fusion probe for SLC44A1 (green) and PRKCA (orange), showing SLC44A1::PRKCA fusion signals (arrows).
Papillary glioneuronal tumour. T2-weighted image shows a cystic mass pushing the anterior horn of the lateral ventricle.
Papillary glioneuronal tumour. Contrast-enhanced T1-weighted image reveals peripheral enhancement in the cyst.
A: PRKCA; SLC44A1

Q: In Papillary glioneuronal tumor, the biphasic cell population can be demonstrated with immunohistochemistry; the pseudopapillary glial cells are GFAP positive, while the interpapillary neuronal cells prominently express [...].
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. GFAP-positive cells in pseudopapillary structures.
Papillary glioneuronal tumour. Interpapillary cells show synaptophysin immunoreactivity.
A: synaptophysin
Q: Papillary glioneuronal tumour
- Clinical: Rare CNS WHO grade 1 tumour primarily affecting young adults (median age 16); typically presents as a well-demarcated, solid and cystic mass in the temporal lobe near the lateral ventricles.
- Microscopic: Characterized by a hallmark biphasic pattern: 1) cuboidal glial cells forming pseudopapillae over hyalinized blood vessels, and 2) an interpapillary neuronal component of neurocytes and neurons within a neuropil background.
- Ancillary: The glial component is GFAP/S100 positive, while the neuronal component expresses synaptophysin and NeuN; the Ki-67 proliferation index is generally low (< 2%).
- Genetics: The diagnostic hallmark is the [...] gene fusion, most commonly the [...]::PRKCA fusion resulting from t(9;17)(q31;q24).
Reference Gallery:
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. GFAP-positive cells in pseudopapillary structures.
Papillary glioneuronal tumour. Interpapillary cells show synaptophysin immunoreactivity.
Papillary glioneuronal tumour. Hyalinized vessels can be prominent.
Papillary glioneuronal tumour. Interpapillary component comprises neurocytes and ganglioid cells.
Papillary glioneuronal tumour. Interphase FISH using a fusion probe for SLC44A1 (green) and PRKCA (orange), showing SLC44A1::PRKCA fusion signals (arrows).
Papillary glioneuronal tumour. T2-weighted image shows a cystic mass pushing the anterior horn of the lateral ventricle.
Papillary glioneuronal tumour. Contrast-enhanced T1-weighted image reveals peripheral enhancement in the cyst.
A: PRKCA; SLC44A1

Q: The defining genetic hallmark of Papillary glioneuronal tumor is a chromosomal translocation resulting in a fusion involving the [...] gene (most commonly SLC44A1::PRKCA).
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. Interphase FISH using a fusion probe for SLC44A1 (green) and PRKCA (orange), showing SLC44A1::PRKCA fusion signals (arrows).
A: PRKCA
Q: Papillary glioneuronal tumour
- Clinical: Rare CNS WHO grade 1 tumour primarily affecting young adults (median age 16); typically presents as a well-demarcated, solid and cystic mass in the temporal lobe near the lateral ventricles.
- Microscopic: Characterized by a hallmark biphasic pattern: 1) cuboidal glial cells forming pseudopapillae over hyalinized blood vessels, and 2) an interpapillary neuronal component of neurocytes and neurons within a neuropil background.
- Ancillary: The glial component is GFAP/S100 positive, while the neuronal component expresses synaptophysin and NeuN; the Ki-67 proliferation index is generally low (< 2%).
- Genetics: The diagnostic hallmark is the [...] gene fusion, most commonly the [...]::PRKCA fusion resulting from t(9;17)(q31;q24).
Reference Gallery:
Papillary glioneuronal tumour. Biphasic appearance with pseudopapillary glial structures and interpapillary neuronal component.
Papillary glioneuronal tumour. GFAP-positive cells in pseudopapillary structures.
Papillary glioneuronal tumour. Interpapillary cells show synaptophysin immunoreactivity.
Papillary glioneuronal tumour. Hyalinized vessels can be prominent.
Papillary glioneuronal tumour. Interpapillary component comprises neurocytes and ganglioid cells.
Papillary glioneuronal tumour. Interphase FISH using a fusion probe for SLC44A1 (green) and PRKCA (orange), showing SLC44A1::PRKCA fusion signals (arrows).
Papillary glioneuronal tumour. T2-weighted image shows a cystic mass pushing the anterior horn of the lateral ventricle.
Papillary glioneuronal tumour. Contrast-enhanced T1-weighted image reveals peripheral enhancement in the cyst.
A: PRKCA; SLC44A1

Q: Histologically, a Rosette-forming glioneuronal tumor demonstrates a biphasic architecture consisting of a piloid glial component and uniform neurocytes forming characteristic [...] (ring-shaped arrays of nuclei around eosinophilic neuropil cores).
Rosette-forming glioneuronal tumour. Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
Rosette-forming glioneuronal tumour. Neurocytic rosettes: ring-like array of neurocytic tumour cell nuclei around eosinophilic neuropil cores.
Rosette-forming glioneuronal tumour. Glial tumour component with piloid histomorphology.
A: neurocytic rosettes
Back Extra: Rosette-forming glioneuronal tumour
- Clinical: RGNTs primarily affect young adults and children and typically arise in midline structures, most commonly the fourth ventricle or aqueduct, frequently involving the brainstem or cerebellum. Patients often present with sy…
- Micro: RGNT is characterized by a biphasic neurocytic and glial architecture: * Neurocytic component: Uniform neurocytes forming neurocytic rosettes (ring-shaped arrays of nuclei around eosinophilic neuropil cores) and/or …
- Cyto: In smear preparations, RGNT demonstrates biphasic features: Neurocytic cells: Round nuclei with granular chromatin and scant cytoplasm, often with delicate processes in the background. Glial cells: Piloid as…
- Ancillary: Immunohistochemistry (IHC): Synaptophysin: Strong reactivity in the centers of neurocytic rosettes and the neuropil of pseudorosettes. MAP2: Expressed in the cytoplasm and processes of neurocytes. *O…
Reference Gallery:
Rosette-forming glioneuronal tumour. Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
Rosette-forming glioneuronal tumour. Neurocytic rosettes: ring-like array of neurocytic tumour cell nuclei around eosinophilic neuropil cores.
Rosette-forming glioneuronal tumour. Glial tumour component with piloid histomorphology.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity of the neuropil cores of neurocytic rosettes.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity in the pericapillary area of perivascular pseudorosettes.
Rosette-forming glioneuronal tumour. Nuclear expression of OLIG2 in the tumour cell nuclei.
Rosette-forming glioneuronal tumour. Axial T1-weighted MRI without contrast showing a cerebellar midline mass with solid and cystic components.
Rosette-forming glioneuronal tumour. Axial T2-weighted MRI with cerebrospinal fluid suppression demonstrating the heterogeneous signal of the partially solid, partially cystic midline mass. Note that the content of the cystic components is not isointense to cerebrospinal fluid.
Rosette-forming glioneuronal tumour. Sagittal T2-weighted MRI showing compression of the fourth ventricle due to the cerebellar midline mass. As an effect of the obstructive hydrocephalus, the floor of the third ventricle is herniated into the suprasellar cistern.

Q: In a Rosette-forming glioneuronal tumor, immunohistochemistry for [...] typically demonstrates strong, characteristic reactivity specifically within the eosinophilic neuropil cores of the rosettes.
Rosette-forming glioneuronal tumour. Neurocytic rosettes: ring-like array of neurocytic tumour cell nuclei around eosinophilic neuropil cores.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity of the neuropil cores of neurocytic rosettes.
A: synaptophysin
Back Extra: Rosette-forming glioneuronal tumour
- Clinical: RGNTs primarily affect young adults and children and typically arise in midline structures, most commonly the fourth ventricle or aqueduct, frequently involving the brainstem or cerebellum. Patients often present with sy…
- Micro: RGNT is characterized by a biphasic neurocytic and glial architecture: * Neurocytic component: Uniform neurocytes forming neurocytic rosettes (ring-shaped arrays of nuclei around eosinophilic neuropil cores) and/or …
- Cyto: In smear preparations, RGNT demonstrates biphasic features: Neurocytic cells: Round nuclei with granular chromatin and scant cytoplasm, often with delicate processes in the background. Glial cells: Piloid as…
- Ancillary: Immunohistochemistry (IHC): Synaptophysin: Strong reactivity in the centers of neurocytic rosettes and the neuropil of pseudorosettes. MAP2: Expressed in the cytoplasm and processes of neurocytes. *O…
Reference Gallery:
Rosette-forming glioneuronal tumour. Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
Rosette-forming glioneuronal tumour. Neurocytic rosettes: ring-like array of neurocytic tumour cell nuclei around eosinophilic neuropil cores.
Rosette-forming glioneuronal tumour. Glial tumour component with piloid histomorphology.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity of the neuropil cores of neurocytic rosettes.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity in the pericapillary area of perivascular pseudorosettes.
Rosette-forming glioneuronal tumour. Nuclear expression of OLIG2 in the tumour cell nuclei.
Rosette-forming glioneuronal tumour. Axial T1-weighted MRI without contrast showing a cerebellar midline mass with solid and cystic components.
Rosette-forming glioneuronal tumour. Axial T2-weighted MRI with cerebrospinal fluid suppression demonstrating the heterogeneous signal of the partially solid, partially cystic midline mass. Note that the content of the cystic components is not isointense to cerebrospinal fluid.
Rosette-forming glioneuronal tumour. Sagittal T2-weighted MRI showing compression of the fourth ventricle due to the cerebellar midline mass. As an effect of the obstructive hydrocephalus, the floor of the third ventricle is herniated into the suprasellar cistern.

Q: Rosette-forming glioneuronal tumors typically arise in midline structures of young adults, most commonly presenting as a solid and cystic mass compressing or involving the [...] (or aqueduct), which can be visualized on sagittal T2-weighted MRI.
Rosette-forming glioneuronal tumour. Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
Rosette-forming glioneuronal tumour. Sagittal T2-weighted MRI showing compression of the fourth ventricle due to the cerebellar midline mass. As an effect of the obstructive hydrocephalus, the floor of the third ventricle is herniated into the suprasellar cistern.
A: fourth ventricle
Back Extra: Rosette-forming glioneuronal tumour
- Clinical: RGNTs primarily affect young adults and children and typically arise in midline structures, most commonly the fourth ventricle or aqueduct, frequently involving the brainstem or cerebellum. Patients often present with sy…
- Micro: RGNT is characterized by a biphasic neurocytic and glial architecture: * Neurocytic component: Uniform neurocytes forming neurocytic rosettes (ring-shaped arrays of nuclei around eosinophilic neuropil cores) and/or …
- Cyto: In smear preparations, RGNT demonstrates biphasic features: Neurocytic cells: Round nuclei with granular chromatin and scant cytoplasm, often with delicate processes in the background. Glial cells: Piloid as…
- Ancillary: Immunohistochemistry (IHC): Synaptophysin: Strong reactivity in the centers of neurocytic rosettes and the neuropil of pseudorosettes. MAP2: Expressed in the cytoplasm and processes of neurocytes. *O…
Reference Gallery:
Rosette-forming glioneuronal tumour. Rosette-forming glioneuronal tumour consists of two components: neurocytic (left) and astrocytic (right).
Rosette-forming glioneuronal tumour. Neurocytic rosettes: ring-like array of neurocytic tumour cell nuclei around eosinophilic neuropil cores.
Rosette-forming glioneuronal tumour. Glial tumour component with piloid histomorphology.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity of the neuropil cores of neurocytic rosettes.
Rosette-forming glioneuronal tumour. Synaptophysin immunoreactivity in the pericapillary area of perivascular pseudorosettes.
Rosette-forming glioneuronal tumour. Nuclear expression of OLIG2 in the tumour cell nuclei.
Rosette-forming glioneuronal tumour. Axial T1-weighted MRI without contrast showing a cerebellar midline mass with solid and cystic components.
Rosette-forming glioneuronal tumour. Axial T2-weighted MRI with cerebrospinal fluid suppression demonstrating the heterogeneous signal of the partially solid, partially cystic midline mass. Note that the content of the cystic components is not isointense to cerebrospinal fluid.
Rosette-forming glioneuronal tumour. Sagittal T2-weighted MRI showing compression of the fourth ventricle due to the cerebellar midline mass. As an effect of the obstructive hydrocephalus, the floor of the third ventricle is herniated into the suprasellar cistern.

Q: Primary diffuse leptomeningeal melanocytic lesions, including Meningeal Melanocytosis and Melanomatosis, are primarily associated with somatic mutations in the [...] gene (most commonly at codon 61).
Meningeal melanocytosis: Benign-appearing melanocytic cells proliferating between the nerve roots of the spinal cord.
Meningeal melanomatosis: Malignant melanocytic cells infiltrating the brain parenchyma (NRAS p.Q61R mutated).
A: NRAS
Q: Meningeal Melanocytosis and Melanomatosis
- Clinical: Often occurs in the setting of neurocutaneous melanosis (associated with giant congenital nevi); symptoms arise from hydrocephalus or CNS invasion.
- Imaging: Characteristically appears as diffuse leptomeningeal thickening that is T1-hyperintense and T2-hypointense due to the paramagnetic properties of melanin.
- Microscopic: Melanocytosis features cytologically bland cells confined to the meninges, while melanomatosis shows CNS parenchymal invasion, atypia, and mitotic activity.
- Ancillary: Primarily associated with somatic mutations in [...] (most commonly codon 61); DNA methylation profiling is useful to distinguish from metastatic cutaneous melanoma.
Reference Gallery:
Meningeal melanocytosis: Autopsy findings in a child showing the meninges of the lower spinal cord diffusely packed with tumor tissue (NRAS p.Q61K mutated).
Meningeal melanocytosis: Benign-appearing melanocytic cells proliferating between the nerve roots of the spinal cord.
Meningeal melanomatosis: T1-weighted axial MRI showing a hyperintense, contrast-enhancing lesion outlining the gyri and sulci.
Meningeal melanomatosis: Macroscopic brownish/black discoloration of the thickened leptomeninges and underlying cortex.
Meningeal melanomatosis: Malignant melanocytic cells infiltrating the brain parenchyma (NRAS p.Q61R mutated).
Meningeal melanomatosis: High-power view of heavily pigmented malignant melanoma cells.
Melanoma arising from meningeal melanocytosis: Tumor cells infiltrating the brain parenchyma along small vessels.
Meningeal melanomatosis: Macroscopic view of rapid disease progression in a child with neurocutaneous melanosis.
A: NRAS

Q: When evaluating Meningeal Melanocytosis and Melanomatosis, the distinguishing microscopic feature of melanomatosis is the presence of atypia, mitotic activity, and frank [...] into the CNS.
Meningeal melanomatosis: Malignant melanocytic cells infiltrating the brain parenchyma (NRAS p.Q61R mutated).
Melanoma arising from meningeal melanocytosis: Tumor cells infiltrating the brain parenchyma along small vessels.
A: parenchymal invasion
Q: Meningeal Melanocytosis and Melanomatosis
- Clinical: Often occurs in the setting of neurocutaneous melanosis (associated with giant congenital nevi); symptoms arise from hydrocephalus or CNS invasion.
- Imaging: Characteristically appears as diffuse leptomeningeal thickening that is T1-hyperintense and T2-hypointense due to the paramagnetic properties of melanin.
- Microscopic: Melanocytosis features cytologically bland cells confined to the meninges, while melanomatosis shows CNS parenchymal invasion, atypia, and mitotic activity.
- Ancillary: Primarily associated with somatic mutations in [...] (most commonly codon 61); DNA methylation profiling is useful to distinguish from metastatic cutaneous melanoma.
Reference Gallery:
Meningeal melanocytosis: Autopsy findings in a child showing the meninges of the lower spinal cord diffusely packed with tumor tissue (NRAS p.Q61K mutated).
Meningeal melanocytosis: Benign-appearing melanocytic cells proliferating between the nerve roots of the spinal cord.
Meningeal melanomatosis: T1-weighted axial MRI showing a hyperintense, contrast-enhancing lesion outlining the gyri and sulci.
Meningeal melanomatosis: Macroscopic brownish/black discoloration of the thickened leptomeninges and underlying cortex.
Meningeal melanomatosis: Malignant melanocytic cells infiltrating the brain parenchyma (NRAS p.Q61R mutated).
Meningeal melanomatosis: High-power view of heavily pigmented malignant melanoma cells.
Melanoma arising from meningeal melanocytosis: Tumor cells infiltrating the brain parenchyma along small vessels.
Meningeal melanomatosis: Macroscopic view of rapid disease progression in a child with neurocutaneous melanosis.
A: NRAS

Q: Because of the paramagnetic properties of melanin, the diffuse leptomeningeal thickening in Meningeal Melanocytosis and Melanomatosis characteristically appears hyperintense on [...]-weighted MRI scans.
Meningeal melanomatosis: T1-weighted axial MRI showing a hyperintense, contrast-enhancing lesion outlining the gyri and sulci.
A: T1
Q: Meningeal Melanocytosis and Melanomatosis
- Clinical: Often occurs in the setting of neurocutaneous melanosis (associated with giant congenital nevi); symptoms arise from hydrocephalus or CNS invasion.
- Imaging: Characteristically appears as diffuse leptomeningeal thickening that is T1-hyperintense and T2-hypointense due to the paramagnetic properties of melanin.
- Microscopic: Melanocytosis features cytologically bland cells confined to the meninges, while melanomatosis shows CNS parenchymal invasion, atypia, and mitotic activity.
- Ancillary: Primarily associated with somatic mutations in [...] (most commonly codon 61); DNA methylation profiling is useful to distinguish from metastatic cutaneous melanoma.
Reference Gallery:
Meningeal melanocytosis: Autopsy findings in a child showing the meninges of the lower spinal cord diffusely packed with tumor tissue (NRAS p.Q61K mutated).
Meningeal melanocytosis: Benign-appearing melanocytic cells proliferating between the nerve roots of the spinal cord.
Meningeal melanomatosis: T1-weighted axial MRI showing a hyperintense, contrast-enhancing lesion outlining the gyri and sulci.
Meningeal melanomatosis: Macroscopic brownish/black discoloration of the thickened leptomeninges and underlying cortex.
Meningeal melanomatosis: Malignant melanocytic cells infiltrating the brain parenchyma (NRAS p.Q61R mutated).
Meningeal melanomatosis: High-power view of heavily pigmented malignant melanoma cells.
Melanoma arising from meningeal melanocytosis: Tumor cells infiltrating the brain parenchyma along small vessels.
Meningeal melanomatosis: Macroscopic view of rapid disease progression in a child with neurocutaneous melanosis.
A: NRAS

Q: Due to their high melanin content, Circumscribed Meningeal Melanocytic Neoplasms characteristically demonstrate [...] on magnetic resonance imaging.
Meningeal melanocytoma. On T2-weighted MRI, the lesion is hypointense.
Meningeal melanocytoma. T1-weighted pre-contrast MRI reveals a slightly hyperintense lesion at the T8–T9 level of the spinal cord.
A: T1-hyperintensity and T2-hypointensity
Back Extra: Circumscribed Meningeal Melanocytic Neoplasms
- Clinical: These neoplasms represent extra-axial masses typically located in the spinal cord, posterior fossa, or trigeminal cave; imaging characteristically shows T1-hyperintensity and T2-hypointensity due to melanin content.
- Microscopic: Features exist on a spectrum: Meningeal Melanocytoma (CNS WHO grade 1) shows bland cells with rare mitoses (<0.5/mm²), while Meningeal Melanoma (CNS WHO grade 3) shows pleomorphism, necrosis, and frequent mitoses (>1.5/mm²).
- Ancillary: Tumors are positive for S100, HMB45, and Melan-A; loss of nuclear BAP1 expression is a marker of high-risk disease/progression.
- Molecular: Primary drivers are usually mutually exclusive activating mutations in GNAQ, GNA11, PLCB4, or CYSLTR2; the absence of BRAF or TERT promoter mutations helps exclude metastasis from cutaneous sites.
Reference Gallery:
Meningeal melanocytoma. A melanocytoma, harbouring a GNAQ p.Q209L mutation, is composed of densely packed, slightly spindled or oval tumour cells containing variable melanin pigment.
Meningeal melanoma. The tumour is composed of pleomorphic cells arranged in loose nests.
Meningeal melanoma. The tumour shows loss of BAP1 expression immunohistochemically, corresponding at the molecular level to a BAP1 p.Q267 frameshift mutation.
Meningeal melanocytoma. On T2-weighted MRI, the lesion is hypointense.
Meningeal melanocytoma. T1-weighted pre-contrast MRI reveals a slightly hyperintense lesion at the T8–T9 level of the spinal cord.
Meningeal melanocytoma. The lesion shows strong contrast enhancement (T1-weighted MRI).
Meningeal melanocytoma, intermediate grade. This tumour, affecting the tentorium, is composed of rounded cells without marked nuclear polymorphism but with increased mitotic activity. The tumour carries GNA11 and EIF1AX mutations.
Meningeal melanocytoma, intermediate grade. This GNAQ-mutant tumour diffusely infiltrates CNS tissue of the filum terminale.
Meningeal melanoma. This GNA11-mutant meningeal melanoma shows a prominent epithelioid cytology and variable melanin content.
Meningeal melanocytoma. The tumour does not show marked nuclear polymorphism.
Meningeal melanocytoma. Detection of a GNAQ p.Q209L mutation by Sanger sequencing.
Meningeal melanoma. Copy-number variation plot shows multiple chromosomal changes.

Q: In Circumscribed Meningeal Melanocytic Neoplasms, immunohistochemical loss of nuclear [...] expression serves as a marker of high-risk disease and progression to melanoma.
Meningeal melanoma. The tumour is composed of pleomorphic cells arranged in loose nests.
Meningeal melanoma. The tumour shows loss of BAP1 expression immunohistochemically, corresponding at the molecular level to a BAP1 p.Q267 frameshift mutation.
A: BAP1
Back Extra: Circumscribed Meningeal Melanocytic Neoplasms
- Clinical: These neoplasms represent extra-axial masses typically located in the spinal cord, posterior fossa, or trigeminal cave; imaging characteristically shows T1-hyperintensity and T2-hypointensity due to melanin content.
- Microscopic: Features exist on a spectrum: Meningeal Melanocytoma (CNS WHO grade 1) shows bland cells with rare mitoses (<0.5/mm²), while Meningeal Melanoma (CNS WHO grade 3) shows pleomorphism, necrosis, and frequent mitoses (>1.5/mm²).
- Ancillary: Tumors are positive for S100, HMB45, and Melan-A; loss of nuclear BAP1 expression is a marker of high-risk disease/progression.
- Molecular: Primary drivers are usually mutually exclusive activating mutations in GNAQ, GNA11, PLCB4, or CYSLTR2; the absence of BRAF or TERT promoter mutations helps exclude metastasis from cutaneous sites.
Reference Gallery:
Meningeal melanocytoma. A melanocytoma, harbouring a GNAQ p.Q209L mutation, is composed of densely packed, slightly spindled or oval tumour cells containing variable melanin pigment.
Meningeal melanoma. The tumour is composed of pleomorphic cells arranged in loose nests.
Meningeal melanoma. The tumour shows loss of BAP1 expression immunohistochemically, corresponding at the molecular level to a BAP1 p.Q267 frameshift mutation.
Meningeal melanocytoma. On T2-weighted MRI, the lesion is hypointense.
Meningeal melanocytoma. T1-weighted pre-contrast MRI reveals a slightly hyperintense lesion at the T8–T9 level of the spinal cord.
Meningeal melanocytoma. The lesion shows strong contrast enhancement (T1-weighted MRI).
Meningeal melanocytoma, intermediate grade. This tumour, affecting the tentorium, is composed of rounded cells without marked nuclear polymorphism but with increased mitotic activity. The tumour carries GNA11 and EIF1AX mutations.
Meningeal melanocytoma, intermediate grade. This GNAQ-mutant tumour diffusely infiltrates CNS tissue of the filum terminale.
Meningeal melanoma. This GNA11-mutant meningeal melanoma shows a prominent epithelioid cytology and variable melanin content.
Meningeal melanocytoma. The tumour does not show marked nuclear polymorphism.
Meningeal melanocytoma. Detection of a GNAQ p.Q209L mutation by Sanger sequencing.
Meningeal melanoma. Copy-number variation plot shows multiple chromosomal changes.

Q: The primary molecular drivers of Circumscribed Meningeal Melanocytic Neoplasms are typically mutually exclusive activating mutations in [...]; testing helps distinguish primary CNS tumors from cutaneous metastases, which frequently harbor BRAF or TERT mutations.
Meningeal melanocytoma. A melanocytoma, harbouring a GNAQ p.Q209L mutation, is composed of densely packed, slightly spindled or oval tumour cells containing variable melanin pigment.
Meningeal melanocytoma. Detection of a GNAQ p.Q209L mutation by Sanger sequencing.
A: GNAQ or GNA11
Back Extra: Circumscribed Meningeal Melanocytic Neoplasms
- Clinical: These neoplasms represent extra-axial masses typically located in the spinal cord, posterior fossa, or trigeminal cave; imaging characteristically shows T1-hyperintensity and T2-hypointensity due to melanin content.
- Microscopic: Features exist on a spectrum: Meningeal Melanocytoma (CNS WHO grade 1) shows bland cells with rare mitoses (<0.5/mm²), while Meningeal Melanoma (CNS WHO grade 3) shows pleomorphism, necrosis, and frequent mitoses (>1.5/mm²).
- Ancillary: Tumors are positive for S100, HMB45, and Melan-A; loss of nuclear BAP1 expression is a marker of high-risk disease/progression.
- Molecular: Primary drivers are usually mutually exclusive activating mutations in GNAQ, GNA11, PLCB4, or CYSLTR2; the absence of BRAF or TERT promoter mutations helps exclude metastasis from cutaneous sites.
Reference Gallery:
Meningeal melanocytoma. A melanocytoma, harbouring a GNAQ p.Q209L mutation, is composed of densely packed, slightly spindled or oval tumour cells containing variable melanin pigment.
Meningeal melanoma. The tumour is composed of pleomorphic cells arranged in loose nests.
Meningeal melanoma. The tumour shows loss of BAP1 expression immunohistochemically, corresponding at the molecular level to a BAP1 p.Q267 frameshift mutation.
Meningeal melanocytoma. On T2-weighted MRI, the lesion is hypointense.
Meningeal melanocytoma. T1-weighted pre-contrast MRI reveals a slightly hyperintense lesion at the T8–T9 level of the spinal cord.
Meningeal melanocytoma. The lesion shows strong contrast enhancement (T1-weighted MRI).
Meningeal melanocytoma, intermediate grade. This tumour, affecting the tentorium, is composed of rounded cells without marked nuclear polymorphism but with increased mitotic activity. The tumour carries GNA11 and EIF1AX mutations.
Meningeal melanocytoma, intermediate grade. This GNAQ-mutant tumour diffusely infiltrates CNS tissue of the filum terminale.
Meningeal melanoma. This GNA11-mutant meningeal melanoma shows a prominent epithelioid cytology and variable melanin content.
Meningeal melanocytoma. The tumour does not show marked nuclear polymorphism.
Meningeal melanocytoma. Detection of a GNAQ p.Q209L mutation by Sanger sequencing.
Meningeal melanoma. Copy-number variation plot shows multiple chromosomal changes.

Q: While soft tissue variants often harbor CIC::DUX4 fusions, primary central nervous system CIC-rearranged sarcoma most frequently involves fusions with the [...] gene, which can be demonstrated via nuclear immunohistochemistry.
CIC-rearranged sarcoma. There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
CIC-rearranged sarcoma. CIC::NUTM1 fusion–positive tumours in the CNS can be identified by nuclear immunoreactivity for NUT protein.
A: NUTM1
Back Extra: CIC-rearranged sarcoma
- Clinical & Grading: A highly aggressive CNS WHO grade 4 sarcoma predominantly affecting adolescents and young adults; prognosis is significantly worse than Ewing sarcoma.
- Morphology: Typically presents as a well-circumscribed mass showing sheets of undifferentiated small round cells with prominent nucleoli, though epithelioid, spindle cell, and myxoid variants occur.
- Immunohistochemistry: Characterized by frequent positivity for WT1 and ETV4, and patchy/weak CD99; importantly, they are typically NKX2-2 negative.
- Molecular Profile: Defined by CIC fusions; while CIC::DUX4 is common in soft tissues, CIC::NUTM1 is the most frequent partner in CNS-primary cases.
Reference Gallery:
CIC-rearranged sarcoma. A primary tumour in the cerebrum showing a well-circumscribed nodule in the brain parenchyma.
CIC-rearranged sarcoma. There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
CIC-rearranged sarcoma. Some tumours are composed of epithelioid cells, mimicking metastatic carcinoma.
CIC-rearranged sarcoma. CIC::NUTM1 fusion–positive tumours in the CNS can be identified by nuclear immunoreactivity for NUT protein.
CIC-rearranged sarcoma. T2-weighted coronal MRI shows a large cystic tumour with several mural nodules in the right frontal lobe.

Q: Morphologically, CIC-rearranged sarcoma typically consists of diffuse, undifferentiated small round cells with prominent nucleoli, though it may predominantly feature [...] cells that mimic a metastatic carcinoma.
CIC-rearranged sarcoma. There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
CIC-rearranged sarcoma. Some tumours are composed of epithelioid cells, mimicking metastatic carcinoma.
A: epithelioid
Back Extra: CIC-rearranged sarcoma
- Clinical & Grading: A highly aggressive CNS WHO grade 4 sarcoma predominantly affecting adolescents and young adults; prognosis is significantly worse than Ewing sarcoma.
- Morphology: Typically presents as a well-circumscribed mass showing sheets of undifferentiated small round cells with prominent nucleoli, though epithelioid, spindle cell, and myxoid variants occur.
- Immunohistochemistry: Characterized by frequent positivity for WT1 and ETV4, and patchy/weak CD99; importantly, they are typically NKX2-2 negative.
- Molecular Profile: Defined by CIC fusions; while CIC::DUX4 is common in soft tissues, CIC::NUTM1 is the most frequent partner in CNS-primary cases.
Reference Gallery:
CIC-rearranged sarcoma. A primary tumour in the cerebrum showing a well-circumscribed nodule in the brain parenchyma.
CIC-rearranged sarcoma. There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
CIC-rearranged sarcoma. Some tumours are composed of epithelioid cells, mimicking metastatic carcinoma.
CIC-rearranged sarcoma. CIC::NUTM1 fusion–positive tumours in the CNS can be identified by nuclear immunoreactivity for NUT protein.
CIC-rearranged sarcoma. T2-weighted coronal MRI shows a large cystic tumour with several mural nodules in the right frontal lobe.

Q: Radiologically, a primary central nervous system CIC-rearranged sarcoma can present on a T2-weighted MRI as a large [...] tumor with mural nodules.
CIC-rearranged sarcoma. T2-weighted coronal MRI shows a large cystic tumour with several mural nodules in the right frontal lobe.
A: cystic
Back Extra: CIC-rearranged sarcoma
- Clinical & Grading: A highly aggressive CNS WHO grade 4 sarcoma predominantly affecting adolescents and young adults; prognosis is significantly worse than Ewing sarcoma.
- Morphology: Typically presents as a well-circumscribed mass showing sheets of undifferentiated small round cells with prominent nucleoli, though epithelioid, spindle cell, and myxoid variants occur.
- Immunohistochemistry: Characterized by frequent positivity for WT1 and ETV4, and patchy/weak CD99; importantly, they are typically NKX2-2 negative.
- Molecular Profile: Defined by CIC fusions; while CIC::DUX4 is common in soft tissues, CIC::NUTM1 is the most frequent partner in CNS-primary cases.
Reference Gallery:
CIC-rearranged sarcoma. A primary tumour in the cerebrum showing a well-circumscribed nodule in the brain parenchyma.
CIC-rearranged sarcoma. There is a diffuse proliferation of small round cells with minimally pleomorphic nuclei and variably prominent nucleoli.
CIC-rearranged sarcoma. Some tumours are composed of epithelioid cells, mimicking metastatic carcinoma.
CIC-rearranged sarcoma. CIC::NUTM1 fusion–positive tumours in the CNS can be identified by nuclear immunoreactivity for NUT protein.
CIC-rearranged sarcoma. T2-weighted coronal MRI shows a large cystic tumour with several mural nodules in the right frontal lobe.

Q: At the molecular level, Ewing sarcoma is defined by a pathognomonic FET::ETS gene fusion, most commonly t(11;22)(q24;q12) resulting in [FLI1].
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma of the dura. Locus-specific identifier (LSI) EWSR1 gene (22q12) dual-colour break-apart FISH shows separated SpectrumOrange and SpectrumGreen signals.
Ewing sarcoma. EWSR1::FLI1 fusion in the Integrative Genomics Viewer (IGV).
A: EWSR1
Back Extra: Ewing sarcoma
- Clinical: Aggressive CNS WHO grade 4 extraosseous small round cell sarcoma typically presenting with mass effect (pain, neuropathies); requires multimodal therapy (chemotherapy, surgery, radiation).
- Microscopic: Composed of sheets of monomorphic small round cells with delicate chromatin and high N:C ratios; neuronal differentiation (e.g., Homer Wright rosettes) may be present.
- Ancillary (IHC): Characteristically shows diffuse membranous CD99 expression, along with NKX2-2 and PAX7 positivity.
- Molecular: Defined by a pathognomonic FET::ETS gene fusion, most commonly t(11;22)(q24;q12) resulting in EWSR1::FLI1 (approx. 85% of cases).
Reference Gallery:
Ewing sarcoma. Postcontrast MRI showing a dural-based mass attached to the falx cerebri.
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma. The focal Homer Wright (neuroblastic) rosettes in this tumour are a sign of neuronal differentiation.
Ewing sarcoma. Diffuse membranous immunostaining with CD99.
Ewing sarcoma of the dura. Locus-specific identifier (LSI) EWSR1 gene (22q12) dual-colour break-apart FISH shows separated SpectrumOrange and SpectrumGreen signals.
Ewing sarcoma. EWSR1::FLI1 fusion in the Integrative Genomics Viewer (IGV).
Ewing sarcoma. Most Ewing sarcomas express NKX2-2.
Ewing sarcoma. Most Ewing sarcomas express PAX7.
Ewing sarcoma. Scattered synaptophysin-positive cells provide evidence of limited neuronal differentiation.
Ewing sarcoma. Extensive NeuN positivity in regions of ganglion cell differentiation.
Ewing sarcoma. Cauda equina lesion. Native nerves are entrapped in this small round cell neoplasm.
Ewing sarcoma. A rare form of neuronal differentiation in Ewing sarcoma is ganglion cell maturation.

Q: Immunohistochemistry in Ewing sarcoma characteristically demonstrates diffuse membranous expression of [...], often accompanied by NKX2-2 and PAX7 positivity.
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma. Diffuse membranous immunostaining with CD99.
Ewing sarcoma. Most Ewing sarcomas express NKX2-2.
A: CD99
Back Extra: Ewing sarcoma
- Clinical: Aggressive CNS WHO grade 4 extraosseous small round cell sarcoma typically presenting with mass effect (pain, neuropathies); requires multimodal therapy (chemotherapy, surgery, radiation).
- Microscopic: Composed of sheets of monomorphic small round cells with delicate chromatin and high N:C ratios; neuronal differentiation (e.g., Homer Wright rosettes) may be present.
- Ancillary (IHC): Characteristically shows diffuse membranous CD99 expression, along with NKX2-2 and PAX7 positivity.
- Molecular: Defined by a pathognomonic FET::ETS gene fusion, most commonly t(11;22)(q24;q12) resulting in EWSR1::FLI1 (approx. 85% of cases).
Reference Gallery:
Ewing sarcoma. Postcontrast MRI showing a dural-based mass attached to the falx cerebri.
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma. The focal Homer Wright (neuroblastic) rosettes in this tumour are a sign of neuronal differentiation.
Ewing sarcoma. Diffuse membranous immunostaining with CD99.
Ewing sarcoma of the dura. Locus-specific identifier (LSI) EWSR1 gene (22q12) dual-colour break-apart FISH shows separated SpectrumOrange and SpectrumGreen signals.
Ewing sarcoma. EWSR1::FLI1 fusion in the Integrative Genomics Viewer (IGV).
Ewing sarcoma. Most Ewing sarcomas express NKX2-2.
Ewing sarcoma. Most Ewing sarcomas express PAX7.
Ewing sarcoma. Scattered synaptophysin-positive cells provide evidence of limited neuronal differentiation.
Ewing sarcoma. Extensive NeuN positivity in regions of ganglion cell differentiation.
Ewing sarcoma. Cauda equina lesion. Native nerves are entrapped in this small round cell neoplasm.
Ewing sarcoma. A rare form of neuronal differentiation in Ewing sarcoma is ganglion cell maturation.

Q: Microscopically, Ewing sarcoma consists of monomorphic small round cells that can show neuronal differentiation, classically forming [...].
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma. The focal Homer Wright (neuroblastic) rosettes in this tumour are a sign of neuronal differentiation.
A: Homer Wright rosettes
Back Extra: Ewing sarcoma
- Clinical: Aggressive CNS WHO grade 4 extraosseous small round cell sarcoma typically presenting with mass effect (pain, neuropathies); requires multimodal therapy (chemotherapy, surgery, radiation).
- Microscopic: Composed of sheets of monomorphic small round cells with delicate chromatin and high N:C ratios; neuronal differentiation (e.g., Homer Wright rosettes) may be present.
- Ancillary (IHC): Characteristically shows diffuse membranous CD99 expression, along with NKX2-2 and PAX7 positivity.
- Molecular: Defined by a pathognomonic FET::ETS gene fusion, most commonly t(11;22)(q24;q12) resulting in EWSR1::FLI1 (approx. 85% of cases).
Reference Gallery:
Ewing sarcoma. Postcontrast MRI showing a dural-based mass attached to the falx cerebri.
Ewing sarcoma. Sheets and nests of primitive-appearing small round cells with delicate chromatin, high N:C ratios, and high mitotic count.
Ewing sarcoma. The focal Homer Wright (neuroblastic) rosettes in this tumour are a sign of neuronal differentiation.
Ewing sarcoma. Diffuse membranous immunostaining with CD99.
Ewing sarcoma of the dura. Locus-specific identifier (LSI) EWSR1 gene (22q12) dual-colour break-apart FISH shows separated SpectrumOrange and SpectrumGreen signals.
Ewing sarcoma. EWSR1::FLI1 fusion in the Integrative Genomics Viewer (IGV).
Ewing sarcoma. Most Ewing sarcomas express NKX2-2.
Ewing sarcoma. Most Ewing sarcomas express PAX7.
Ewing sarcoma. Scattered synaptophysin-positive cells provide evidence of limited neuronal differentiation.
Ewing sarcoma. Extensive NeuN positivity in regions of ganglion cell differentiation.
Ewing sarcoma. Cauda equina lesion. Native nerves are entrapped in this small round cell neoplasm.
Ewing sarcoma. A rare form of neuronal differentiation in Ewing sarcoma is ganglion cell maturation.

Q: Microscopic examination of a Haemangioblastoma reveals neoplastic lipid-filled stromal cells interspersed with a dense capillary network, often featuring characteristic branching [...].
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
Thin-walled, highly branching "staghorn" vessels within the tumour.
A: "staghorn" vessels
Back Extra: Haemangioblastoma
- Clinical: Highly vascular CNS WHO grade 1 tumour occurring sporadically or as a component of von Hippel–Lindau (VHL) syndrome; often presents as a contrast-enhancing mural nodule in a cerebellar cyst.
- Microscopic: Composed of neoplastic vacuolated (lipid-filled) stromal cells and a dense reactive capillary network, often featuring branching "staghorn" vessels and occasional nuclear pleomorphism.
- Ancillary: Neoplastic stromal cells are typically positive for alpha-inhibin, D2-40, and NSE, while being negative for epithelial markers (EMA, CD10) and endothelial markers (CD31, CD34).
- Molecular: Driven by inactivation of the VHL gene (3p25.3), leading to HIF1α accumulation and subsequent upregulation of VEGF and erythropoietin.
- Differential: The primary differential is metastatic renal clear cell carcinoma (RCC), which is EMA/CD10 positive and alpha-inhibin negative.
Reference Gallery:
Haemangioblastoma in the posterior fossa demonstrating typical solid-cystic features on MRI.
Gross specimen showing a multicystic tumour well-demarcated from the surrounding cerebellum.
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
Thin-walled, highly branching "staghorn" vessels within the tumour.
Stromal cell nuclei showing occasional enlargement, atypia, and hyperchromasia.
Reticulin stain highlighting small capillary vessels and larger vessels with a staghorn appearance.
Inhibin immunohistochemistry is focally positive in the neoplastic stromal cells.
Endothelial markers (CD31/CD34/ERG) highlight the abundant vascular network but are negative in stromal cells.
Typical intradural, extramedullary localization for a spinal haemangioblastoma.
Haemangioblastoma (Whole Slide Image)

Q: Immunohistochemistry for a Haemangioblastoma reveals that the neoplastic stromal cells are typically positive for [...], helping distinguish this tumor from metastatic clear cell renal cell carcinoma.
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
Inhibin immunohistochemistry is focally positive in the neoplastic stromal cells.
A: alpha-inhibin
Back Extra: Haemangioblastoma
- Clinical: Highly vascular CNS WHO grade 1 tumour occurring sporadically or as a component of von Hippel–Lindau (VHL) syndrome; often presents as a contrast-enhancing mural nodule in a cerebellar cyst.
- Microscopic: Composed of neoplastic vacuolated (lipid-filled) stromal cells and a dense reactive capillary network, often featuring branching "staghorn" vessels and occasional nuclear pleomorphism.
- Ancillary: Neoplastic stromal cells are typically positive for alpha-inhibin, D2-40, and NSE, while being negative for epithelial markers (EMA, CD10) and endothelial markers (CD31, CD34).
- Molecular: Driven by inactivation of the VHL gene (3p25.3), leading to HIF1α accumulation and subsequent upregulation of VEGF and erythropoietin.
- Differential: The primary differential is metastatic renal clear cell carcinoma (RCC), which is EMA/CD10 positive and alpha-inhibin negative.
Reference Gallery:
Haemangioblastoma in the posterior fossa demonstrating typical solid-cystic features on MRI.
Gross specimen showing a multicystic tumour well-demarcated from the surrounding cerebellum.
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
Thin-walled, highly branching "staghorn" vessels within the tumour.
Stromal cell nuclei showing occasional enlargement, atypia, and hyperchromasia.
Reticulin stain highlighting small capillary vessels and larger vessels with a staghorn appearance.
Inhibin immunohistochemistry is focally positive in the neoplastic stromal cells.
Endothelial markers (CD31/CD34/ERG) highlight the abundant vascular network but are negative in stromal cells.
Typical intradural, extramedullary localization for a spinal haemangioblastoma.
Haemangioblastoma (Whole Slide Image)

Q: Haemangioblastoma is a highly vascular CNS WHO grade 1 tumor that frequently arises in the cerebellum as a cyst with a mural nodule, and is classically associated with [...] syndrome.
Haemangioblastoma in the posterior fossa demonstrating typical solid-cystic features on MRI.
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
A: von Hippel-Lindau
Back Extra: Haemangioblastoma
- Clinical: Highly vascular CNS WHO grade 1 tumour occurring sporadically or as a component of von Hippel–Lindau (VHL) syndrome; often presents as a contrast-enhancing mural nodule in a cerebellar cyst.
- Microscopic: Composed of neoplastic vacuolated (lipid-filled) stromal cells and a dense reactive capillary network, often featuring branching "staghorn" vessels and occasional nuclear pleomorphism.
- Ancillary: Neoplastic stromal cells are typically positive for alpha-inhibin, D2-40, and NSE, while being negative for epithelial markers (EMA, CD10) and endothelial markers (CD31, CD34).
- Molecular: Driven by inactivation of the VHL gene (3p25.3), leading to HIF1α accumulation and subsequent upregulation of VEGF and erythropoietin.
- Differential: The primary differential is metastatic renal clear cell carcinoma (RCC), which is EMA/CD10 positive and alpha-inhibin negative.
Reference Gallery:
Haemangioblastoma in the posterior fossa demonstrating typical solid-cystic features on MRI.
Gross specimen showing a multicystic tumour well-demarcated from the surrounding cerebellum.
High-power view showing neoplastic stromal cells with clear to vacuolated cytoplasm admixed with abundant capillary vessels.
Thin-walled, highly branching "staghorn" vessels within the tumour.
Stromal cell nuclei showing occasional enlargement, atypia, and hyperchromasia.
Reticulin stain highlighting small capillary vessels and larger vessels with a staghorn appearance.
Inhibin immunohistochemistry is focally positive in the neoplastic stromal cells.
Endothelial markers (CD31/CD34/ERG) highlight the abundant vascular network but are negative in stromal cells.
Typical intradural, extramedullary localization for a spinal haemangioblastoma.
Haemangioblastoma (Whole Slide Image)

Q: Morphologically, Intracranial mesenchymal tumour, FET::CREB fusion-positive often demonstrates peripheral lymphoplasmacytic cuffing, an Alcian blue-positive myxoid stroma, and prominent small vessels in an [...] pattern.
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Prominent small vessels in an angiomatoid pattern in a tumor harboring an EWSR1::CREB fusion.
Alcian blue highlights the myxoid background often observed in these intracranial tumors.
A: angiomatoid
Back Extra: Intracranial mesenchymal tumour, FET::CREB fusion-positive
- Clinical: Typically presents in children and young adults as a supratentorial, extra-axial mass frequently attached to the dura, mimicking a meningioma.
- Microscopic: Demonstrates a wide morphological spectrum including cord-like, reticular, or sheet-like growth, often with a myxoid stroma, 'angiomatoid' vasculature, and peripheral lymphoplasmacytic cuffing.
- Ancillary: Characterized by fusions between FET family genes (most commonly EWSR1) and CREB family genes (CREB1, ATF1, or CREM).
- Immunohistochemistry: Tumors are typically positive for CD99, EMA, and desmin, while characteristically maintaining nuclear expression of SMARCB1 and SMARCA4.
- Differential Diagnosis: Distinguishing from ATRT is critical and relies on the preservation of SMARCB1/A4; SSTR2A negativity helps differentiate it from meningioma.
Reference Gallery:
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Immunostaining for CD99 is strong and diffuse in this example with an EWSR1::ATF1 fusion.
Desmin immunoreactivity is frequently positive, as seen in this EWSR1::ATF1 fusion–positive case.
Prominent small vessels in an angiomatoid pattern in a tumor harboring an EWSR1::CREB fusion.
Retention of nuclear SMARCA4 (BRG1) expression, which helps exclude atypical teratoid/rhabdoid tumour (ATRT).
Smear preparation showing rounded cytoplasmic profiles and prominent nucleoli, mimicking ATRT cytology.
Histological variant showing numerous clear cells in an EWSR1::ATF1 fusion–positive tumor.
Sheet-like architectural pattern in an intracranial mesenchymal tumour, FET::CREB fusion–positive.
Alcian blue highlights the myxoid background often observed in these intracranial tumors.
Focal AE1/AE3 immunoreactivity in an intracranial mesenchymal tumour.
Patchy EMA immunoreactivity, which is often identified in this tumor type.
Strong desmin immunoreactivity highlighting cellular morphology and slight variation in cell types.

Q: To distinguish Intracranial mesenchymal tumour, FET::CREB fusion-positive from atypical teratoid/rhabdoid tumors (ATRT), it is critical to demonstrate the immunohistochemical retention of [...].
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Retention of nuclear SMARCA4 (BRG1) expression, which helps exclude atypical teratoid/rhabdoid tumour (ATRT).
Smear preparation showing rounded cytoplasmic profiles and prominent nucleoli, mimicking ATRT cytology.
A: SMARCB1 and SMARCA4
Back Extra: Intracranial mesenchymal tumour, FET::CREB fusion-positive
- Clinical: Typically presents in children and young adults as a supratentorial, extra-axial mass frequently attached to the dura, mimicking a meningioma.
- Microscopic: Demonstrates a wide morphological spectrum including cord-like, reticular, or sheet-like growth, often with a myxoid stroma, 'angiomatoid' vasculature, and peripheral lymphoplasmacytic cuffing.
- Ancillary: Characterized by fusions between FET family genes (most commonly EWSR1) and CREB family genes (CREB1, ATF1, or CREM).
- Immunohistochemistry: Tumors are typically positive for CD99, EMA, and desmin, while characteristically maintaining nuclear expression of SMARCB1 and SMARCA4.
- Differential Diagnosis: Distinguishing from ATRT is critical and relies on the preservation of SMARCB1/A4; SSTR2A negativity helps differentiate it from meningioma.
Reference Gallery:
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Immunostaining for CD99 is strong and diffuse in this example with an EWSR1::ATF1 fusion.
Desmin immunoreactivity is frequently positive, as seen in this EWSR1::ATF1 fusion–positive case.
Prominent small vessels in an angiomatoid pattern in a tumor harboring an EWSR1::CREB fusion.
Retention of nuclear SMARCA4 (BRG1) expression, which helps exclude atypical teratoid/rhabdoid tumour (ATRT).
Smear preparation showing rounded cytoplasmic profiles and prominent nucleoli, mimicking ATRT cytology.
Histological variant showing numerous clear cells in an EWSR1::ATF1 fusion–positive tumor.
Sheet-like architectural pattern in an intracranial mesenchymal tumour, FET::CREB fusion–positive.
Alcian blue highlights the myxoid background often observed in these intracranial tumors.
Focal AE1/AE3 immunoreactivity in an intracranial mesenchymal tumour.
Patchy EMA immunoreactivity, which is often identified in this tumor type.
Strong desmin immunoreactivity highlighting cellular morphology and slight variation in cell types.

Q: Immunohistochemically, Intracranial mesenchymal tumour, FET::CREB fusion-positive is typically positive for EMA, desmin, and [...].
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Immunostaining for CD99 is strong and diffuse in this example with an EWSR1::ATF1 fusion.
Desmin immunoreactivity is frequently positive, as seen in this EWSR1::ATF1 fusion–positive case.
A: CD99
Back Extra: Intracranial mesenchymal tumour, FET::CREB fusion-positive
- Clinical: Typically presents in children and young adults as a supratentorial, extra-axial mass frequently attached to the dura, mimicking a meningioma.
- Microscopic: Demonstrates a wide morphological spectrum including cord-like, reticular, or sheet-like growth, often with a myxoid stroma, 'angiomatoid' vasculature, and peripheral lymphoplasmacytic cuffing.
- Ancillary: Characterized by fusions between FET family genes (most commonly EWSR1) and CREB family genes (CREB1, ATF1, or CREM).
- Immunohistochemistry: Tumors are typically positive for CD99, EMA, and desmin, while characteristically maintaining nuclear expression of SMARCB1 and SMARCA4.
- Differential Diagnosis: Distinguishing from ATRT is critical and relies on the preservation of SMARCB1/A4; SSTR2A negativity helps differentiate it from meningioma.
Reference Gallery:
Intracranial mesenchymal tumour, FET::CREB fusion–positive showing cords of small, cytologically uniform cells.
Immunostaining for CD99 is strong and diffuse in this example with an EWSR1::ATF1 fusion.
Desmin immunoreactivity is frequently positive, as seen in this EWSR1::ATF1 fusion–positive case.
Prominent small vessels in an angiomatoid pattern in a tumor harboring an EWSR1::CREB fusion.
Retention of nuclear SMARCA4 (BRG1) expression, which helps exclude atypical teratoid/rhabdoid tumour (ATRT).
Smear preparation showing rounded cytoplasmic profiles and prominent nucleoli, mimicking ATRT cytology.
Histological variant showing numerous clear cells in an EWSR1::ATF1 fusion–positive tumor.
Sheet-like architectural pattern in an intracranial mesenchymal tumour, FET::CREB fusion–positive.
Alcian blue highlights the myxoid background often observed in these intracranial tumors.
Focal AE1/AE3 immunoreactivity in an intracranial mesenchymal tumour.
Patchy EMA immunoreactivity, which is often identified in this tumor type.
Strong desmin immunoreactivity highlighting cellular morphology and slight variation in cell types.

Q: A highly cellular tumor characterized by a biphasic pattern of undifferentiated small round cells, hemangiopericytoma-like staghorn vessels, and distinct islands of well-differentiated hyaline cartilage is classic for [...].
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma is a highly cellular biphasic tumour composed of areas of undifferentiated round cells with high N:C ratios, as well as numerous staghorn vessels, and islands of hyaline cartilage.
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma typically shows a biphasic pattern of small malignant cells with scant cytoplasm and islands of hyaline cartilage, both seen here.
A: Mesenchymal chondrosarcoma
Back Extra: Mesenchymal chondrosarcoma
- Clinical: The tumour is most frequent in the second and third decades of life. Intracranial locations are more common than intraspinal, and approximately 60% of cases exhibit a dural attachment. Symptoms typically relate to mass e…
- Micro: The tumour exhibits a classic biphasic pattern consisting of primitive small round cells intermingled with islands of well-differentiated hyaline cartilage. CNS-specific examples often show more spindling and less necros…
- Cyto: Cytology preparations show oval to spindled cells with high N:C ratios and hyperchromatic nuclei. The cytoplasm may be vacuolated. Cells may be associated with myxoid stromal material and/or necrotic debris. Intraoperati…
- Ancillary: Immunohistochemistry (IHC): * Positive markers: The primitive small round cells express CD99, EMA, desmin, myogenin, MYOD1, NKX3-1, and SOX9. S100 and SOX10 can be positive in both the small cell and cartilaginou…
Reference Gallery:
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma is a highly cellular biphasic tumour composed of areas of undifferentiated round cells with high N:C ratios, as well as numerous staghorn vessels, and islands of hyaline cartilage.
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma typically shows a biphasic pattern of small malignant cells with scant cytoplasm and islands of hyaline cartilage, both seen here.
Mesenchymal chondrosarcoma. The small, poorly differentiated cells express diffuse cytoplasmic CD99.
Mesenchymal chondrosarcoma. Axial CT shows a partially calcified right paraspinal soft tissue mass that extends into the adjacent neural foramen.
Mesenchymal chondrosarcoma. T2-weighted axial MRI shows the mass is hyperintense compared with adjacent paraspinal musculature and contains an irregular, very hyperintense necrotic centre.
Mesenchymal chondrosarcoma. T1-weighted axial postcontrast MRI shows an intensely enhancing ring of tumour surrounding a central non-enhancing necrotic core.

Q: In Mesenchymal chondrosarcoma, the undifferentiated primitive small round cell component characteristically shows diffuse, strong positivity for the immunohistochemical marker [...].
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma typically shows a biphasic pattern of small malignant cells with scant cytoplasm and islands of hyaline cartilage, both seen here.
Mesenchymal chondrosarcoma. The small, poorly differentiated cells express diffuse cytoplasmic CD99.
A: CD99
Back Extra: Mesenchymal chondrosarcoma
- Clinical: The tumour is most frequent in the second and third decades of life. Intracranial locations are more common than intraspinal, and approximately 60% of cases exhibit a dural attachment. Symptoms typically relate to mass e…
- Micro: The tumour exhibits a classic biphasic pattern consisting of primitive small round cells intermingled with islands of well-differentiated hyaline cartilage. CNS-specific examples often show more spindling and less necros…
- Cyto: Cytology preparations show oval to spindled cells with high N:C ratios and hyperchromatic nuclei. The cytoplasm may be vacuolated. Cells may be associated with myxoid stromal material and/or necrotic debris. Intraoperati…
- Ancillary: Immunohistochemistry (IHC): * Positive markers: The primitive small round cells express CD99, EMA, desmin, myogenin, MYOD1, NKX3-1, and SOX9. S100 and SOX10 can be positive in both the small cell and cartilaginou…
Reference Gallery:
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma is a highly cellular biphasic tumour composed of areas of undifferentiated round cells with high N:C ratios, as well as numerous staghorn vessels, and islands of hyaline cartilage.
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma typically shows a biphasic pattern of small malignant cells with scant cytoplasm and islands of hyaline cartilage, both seen here.
Mesenchymal chondrosarcoma. The small, poorly differentiated cells express diffuse cytoplasmic CD99.
Mesenchymal chondrosarcoma. Axial CT shows a partially calcified right paraspinal soft tissue mass that extends into the adjacent neural foramen.
Mesenchymal chondrosarcoma. T2-weighted axial MRI shows the mass is hyperintense compared with adjacent paraspinal musculature and contains an irregular, very hyperintense necrotic centre.
Mesenchymal chondrosarcoma. T1-weighted axial postcontrast MRI shows an intensely enhancing ring of tumour surrounding a central non-enhancing necrotic core.

Q: On computed tomography (CT) imaging, Mesenchymal chondrosarcoma typically presents as a soft tissue mass containing focal [...] corresponding to the cartilaginous matrix.
Mesenchymal chondrosarcoma. Axial CT shows a partially calcified right paraspinal soft tissue mass that extends into the adjacent neural foramen.
A: calcifications
Back Extra: Mesenchymal chondrosarcoma
- Clinical: The tumour is most frequent in the second and third decades of life. Intracranial locations are more common than intraspinal, and approximately 60% of cases exhibit a dural attachment. Symptoms typically relate to mass e…
- Micro: The tumour exhibits a classic biphasic pattern consisting of primitive small round cells intermingled with islands of well-differentiated hyaline cartilage. CNS-specific examples often show more spindling and less necros…
- Cyto: Cytology preparations show oval to spindled cells with high N:C ratios and hyperchromatic nuclei. The cytoplasm may be vacuolated. Cells may be associated with myxoid stromal material and/or necrotic debris. Intraoperati…
- Ancillary: Immunohistochemistry (IHC): * Positive markers: The primitive small round cells express CD99, EMA, desmin, myogenin, MYOD1, NKX3-1, and SOX9. S100 and SOX10 can be positive in both the small cell and cartilaginou…
Reference Gallery:
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma is a highly cellular biphasic tumour composed of areas of undifferentiated round cells with high N:C ratios, as well as numerous staghorn vessels, and islands of hyaline cartilage.
Mesenchymal chondrosarcoma. Mesenchymal chondrosarcoma typically shows a biphasic pattern of small malignant cells with scant cytoplasm and islands of hyaline cartilage, both seen here.
Mesenchymal chondrosarcoma. The small, poorly differentiated cells express diffuse cytoplasmic CD99.
Mesenchymal chondrosarcoma. Axial CT shows a partially calcified right paraspinal soft tissue mass that extends into the adjacent neural foramen.
Mesenchymal chondrosarcoma. T2-weighted axial MRI shows the mass is hyperintense compared with adjacent paraspinal musculature and contains an irregular, very hyperintense necrotic centre.
Mesenchymal chondrosarcoma. T1-weighted axial postcontrast MRI shows an intensely enhancing ring of tumour surrounding a central non-enhancing necrotic core.

Q: A classic histologic hallmark of Primary intracranial sarcoma, DICER1-mutant is the presence of PAS-positive [...] amidst high-grade pleomorphic spindle cells.
Characteristic prominent eosinophilic cytoplasmic globules within the tumor cells.
High-grade morphology featuring pleomorphic spindle cells in disorganized sheets with brisk mitotic activity.
A: eosinophilic cytoplasmic globules
Back Extra: Primary intracranial sarcoma, DICER1-mutant
- Clinical: Primarily a pediatric tumor (median age 6 years) presenting as a large, heterogeneously enhancing, supratentorial mass often involving the dura and leptomeninges.
- Micro: Composed of pleomorphic spindle cells with high mitotic activity and a classic hallmark: PAS-positive "eosinophilic cytoplasmic globules".
- Ancillary: Defined by pathogenic DICER1 mutations (typically an RNase IIIb domain hotspot mutation and a truncating mutation); often shows myogenic differentiation (Desmin+, SMA+).
- Differential: Distinguished from rhabdomyosarcoma by limited/absent myogenin expression and from pleuropulmonary blastoma (PPB) metastasis by clinical history and imaging.
Reference Gallery:
Coronal T1-weighted postcontrast MRI showing a heterogeneously enhancing mass with dural involvement and marked mass effect.
Characteristic prominent eosinophilic cytoplasmic globules within the tumor cells.
High-grade morphology featuring pleomorphic spindle cells in disorganized sheets with brisk mitotic activity.
Immunophenotypic evidence of myogenic differentiation demonstrated by desmin expression.
Absence of nuclear staining for myogenin helps distinguish this entity from rhabdomyosarcoma.
A subset of cases display foci of chondroid differentiation.
Reticulin staining highlights dense intercellular basement membrane deposition.
Immunohistochemical loss of ATRX protein expression, a common secondary genetic alteration.
Aberrant p53 protein accumulation corresponding to TP53 mutation.
Although often solid and compact, these tumors can show invasion into the underlying brain parenchyma.

Q: Primary intracranial sarcoma, DICER1-mutant frequently demonstrates myogenic differentiation marked by desmin positivity, but is distinguished from rhabdomyosarcoma by the typical absence of nuclear staining for [...].
High-grade morphology featuring pleomorphic spindle cells in disorganized sheets with brisk mitotic activity.
Immunophenotypic evidence of myogenic differentiation demonstrated by desmin expression.
Absence of nuclear staining for myogenin helps distinguish this entity from rhabdomyosarcoma.
A: myogenin
Back Extra: Primary intracranial sarcoma, DICER1-mutant
- Clinical: Primarily a pediatric tumor (median age 6 years) presenting as a large, heterogeneously enhancing, supratentorial mass often involving the dura and leptomeninges.
- Micro: Composed of pleomorphic spindle cells with high mitotic activity and a classic hallmark: PAS-positive "eosinophilic cytoplasmic globules".
- Ancillary: Defined by pathogenic DICER1 mutations (typically an RNase IIIb domain hotspot mutation and a truncating mutation); often shows myogenic differentiation (Desmin+, SMA+).
- Differential: Distinguished from rhabdomyosarcoma by limited/absent myogenin expression and from pleuropulmonary blastoma (PPB) metastasis by clinical history and imaging.
Reference Gallery:
Coronal T1-weighted postcontrast MRI showing a heterogeneously enhancing mass with dural involvement and marked mass effect.
Characteristic prominent eosinophilic cytoplasmic globules within the tumor cells.
High-grade morphology featuring pleomorphic spindle cells in disorganized sheets with brisk mitotic activity.
Immunophenotypic evidence of myogenic differentiation demonstrated by desmin expression.
Absence of nuclear staining for myogenin helps distinguish this entity from rhabdomyosarcoma.
A subset of cases display foci of chondroid differentiation.
Reticulin staining highlights dense intercellular basement membrane deposition.
Immunohistochemical loss of ATRX protein expression, a common secondary genetic alteration.
Aberrant p53 protein accumulation corresponding to TP53 mutation.
Although often solid and compact, these tumors can show invasion into the underlying brain parenchyma.

Q: Microscopically, Rhabdomyosarcoma features varying proportions of undifferentiated small round cells and characteristic eosinophilic [...] with cross-striations.
Alveolar rhabdomyosarcoma. A highly cellular tumour composed of primitive round cells with scant cytoplasm and hyperchromatic nuclei. Fibrovascular septa are seen in this example of the solid type of tumour.
Rhabdomyosarcoma. Tumours occasionally contain elongate strap cells with eosinophilic cytoplasm, as seen here. Note, however, that the majority of tumour cells are poorly differentiated and contain scant cytoplasm.
A: strap cells
Rhabdomyosarcoma
- Clinical: Rare primary malignant CNS neoplasms; 66% involve the skull base or infratentorial regions, often causing cranial nerve palsies.
- Microscopic: Features varying proportions of undifferentiated small cells and characteristic eosinophilic "strap cells" with cross-striations; the alveolar subtype frequently exhibits "wreath-like" multinucleated giant cells.
- Ancillary: Diagnostic IHC requires cytoplasmic Desmin and the skeletal muscle-specific nuclear markers Myogenin (MYF4) or MYOD1.
- Genetics: Alveolar subtypes are defined by PAX3 or PAX7::FOXO1 fusions, while adult-onset spindle cell variants frequently harbor MYOD1 mutations.
Reference Gallery:
Alveolar rhabdomyosarcoma. A highly cellular tumour composed of primitive round cells with scant cytoplasm and hyperchromatic nuclei. Fibrovascular septa are seen in this example of the solid type of tumour.
Rhabdomyosarcoma. This example of a sclerosing rhabdomyosarcoma shows abundant collagenized stroma creating cords of tumour cells.
Alveolar rhabdomyosarcoma. The alveolar type often contains scattered multinucleated, wreath-like, giant tumour cells, as seen here.
Rhabdomyosarcoma. Tumours occasionally contain elongate strap cells with eosinophilic cytoplasm, as seen here. Note, however, that the majority of tumour cells are poorly differentiated and contain scant cytoplasm.
Primary CNS alveolar rhabdomyosarcoma. Myogenin (MYF4) stains the majority of tumour nuclei in this PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma.
Primary CNS alveolar rhabdomyosarcoma. After chemotherapy, this tumour showed cytodifferentiation. Differentiated tumour cells have abundant eosinophilic cytoplasm and eccentrically located nuclei with stippled chromatin and small nucleoli.

Q: The alveolar subtype of Rhabdomyosarcoma frequently exhibits characteristic multinucleated giant cells that are morphologically described as [...].
Alveolar rhabdomyosarcoma. The alveolar type often contains scattered multinucleated, wreath-like, giant tumour cells, as seen here.
A: wreath-like
Rhabdomyosarcoma
- Clinical: Rare primary malignant CNS neoplasms; 66% involve the skull base or infratentorial regions, often causing cranial nerve palsies.
- Microscopic: Features varying proportions of undifferentiated small cells and characteristic eosinophilic "strap cells" with cross-striations; the alveolar subtype frequently exhibits "wreath-like" multinucleated giant cells.
- Ancillary: Diagnostic IHC requires cytoplasmic Desmin and the skeletal muscle-specific nuclear markers Myogenin (MYF4) or MYOD1.
- Genetics: Alveolar subtypes are defined by PAX3 or PAX7::FOXO1 fusions, while adult-onset spindle cell variants frequently harbor MYOD1 mutations.
Reference Gallery:
Alveolar rhabdomyosarcoma. A highly cellular tumour composed of primitive round cells with scant cytoplasm and hyperchromatic nuclei. Fibrovascular septa are seen in this example of the solid type of tumour.
Rhabdomyosarcoma. This example of a sclerosing rhabdomyosarcoma shows abundant collagenized stroma creating cords of tumour cells.
Alveolar rhabdomyosarcoma. The alveolar type often contains scattered multinucleated, wreath-like, giant tumour cells, as seen here.
Rhabdomyosarcoma. Tumours occasionally contain elongate strap cells with eosinophilic cytoplasm, as seen here. Note, however, that the majority of tumour cells are poorly differentiated and contain scant cytoplasm.
Primary CNS alveolar rhabdomyosarcoma. Myogenin (MYF4) stains the majority of tumour nuclei in this PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma.
Primary CNS alveolar rhabdomyosarcoma. After chemotherapy, this tumour showed cytodifferentiation. Differentiated tumour cells have abundant eosinophilic cytoplasm and eccentrically located nuclei with stippled chromatin and small nucleoli.

Q: Diagnostic immunohistochemistry for Rhabdomyosarcoma typically requires positivity for cytoplasmic desmin and the skeletal muscle-specific nuclear marker [...] (MYF4) or MYOD1.
Primary CNS alveolar rhabdomyosarcoma. Myogenin (MYF4) stains the majority of tumour nuclei in this PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma.
A: myogenin
Rhabdomyosarcoma
- Clinical: Rare primary malignant CNS neoplasms; 66% involve the skull base or infratentorial regions, often causing cranial nerve palsies.
- Microscopic: Features varying proportions of undifferentiated small cells and characteristic eosinophilic "strap cells" with cross-striations; the alveolar subtype frequently exhibits "wreath-like" multinucleated giant cells.
- Ancillary: Diagnostic IHC requires cytoplasmic Desmin and the skeletal muscle-specific nuclear markers Myogenin (MYF4) or MYOD1.
- Genetics: Alveolar subtypes are defined by PAX3 or PAX7::FOXO1 fusions, while adult-onset spindle cell variants frequently harbor MYOD1 mutations.
Reference Gallery:
Alveolar rhabdomyosarcoma. A highly cellular tumour composed of primitive round cells with scant cytoplasm and hyperchromatic nuclei. Fibrovascular septa are seen in this example of the solid type of tumour.
Rhabdomyosarcoma. This example of a sclerosing rhabdomyosarcoma shows abundant collagenized stroma creating cords of tumour cells.
Alveolar rhabdomyosarcoma. The alveolar type often contains scattered multinucleated, wreath-like, giant tumour cells, as seen here.
Rhabdomyosarcoma. Tumours occasionally contain elongate strap cells with eosinophilic cytoplasm, as seen here. Note, however, that the majority of tumour cells are poorly differentiated and contain scant cytoplasm.
Primary CNS alveolar rhabdomyosarcoma. Myogenin (MYF4) stains the majority of tumour nuclei in this PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma.
Primary CNS alveolar rhabdomyosarcoma. After chemotherapy, this tumour showed cytodifferentiation. Differentiated tumour cells have abundant eosinophilic cytoplasm and eccentrically located nuclei with stippled chromatin and small nucleoli.

Q: Microscopically, a Solitary fibrous tumor typically displays a "patternless" architecture of monomorphic spindle cells and characteristic thin-walled, branching [...] vessels.
Solitary fibrous tumour. The typical patternless architecture is shown.
Solitary fibrous tumour. A highly cellular tumour with thin-walled, branching (staghorn) vessels.
A: staghorn
Q: Solitary fibrous tumour
- Clinical: Dural-based fibroblastic neoplasm (SFT/HPC) that often mimics meningioma radiologically with a 'dural tail' and intense enhancement.
- Microscopic: Characterized by a patternless architecture of monomorphic spindle cells, variable collagen (keloidal-type), and thin-walled, branching "[...]" vessels.
- Grading: CNS WHO grade (1–3) is assigned based on mitotic activity (cutoff: 2.5 mitoses/mm²) and the presence or absence of necrosis.
- Ancillary: Diagnostic hallmark is diffuse and intense nuclear expression of [...], resulting from the pathognomonic [STAT6] fusion.
Reference Gallery:
Solitary fibrous tumour. This large and multiloculated falcine tumour in a 74-year-old man shows diffuse postgadolinium enhancement.
Solitary fibrous tumour. This dural-based posterior fossa tumour in a 73-year-old man is strongly and diffusely enhancing, and it has a small dural tail.
Solitary fibrous tumour (SFT). A dural tail (16 mm in length) is visible in this tumour of the upper thoracic spine in a 45-year-old man.
Solitary fibrous tumour. The typical patternless architecture is shown.
Solitary fibrous tumour. This tumour is composed of cells with bland spindle-shaped nuclei and scant eosinophilic cytoplasm immersed in a collagenous background.
Solitary fibrous tumour. A highly cellular tumour with thin-walled, branching (staghorn) vessels.
Solitary fibrous tumour. Numerous mitoses (arrows) are present in this tumour.
Solitary fibrous tumour. Strong and diffuse positivity for CD34 in a CNS WHO grade 1 tumour.
Solitary fibrous tumour. All tumours show nuclear localization of STAT6 by immunohistochemistry.
Solitary fibrous tumour. There is often stromal and perivascular hyaline collagen deposition.
Solitary fibrous tumour. This tumour shows keloidal or amianthoid collagen.
Solitary fibrous tumour. There may be closely apposed cells with round to ovoid nuclei arranged in a haphazard pattern, with limited intervening stroma.
A: staghorn; STAT6; NAB2

Q: The diagnostic immunohistochemical hallmark of a Solitary fibrous tumor is diffuse and intense nuclear expression of [...].
Solitary fibrous tumour. This tumour is composed of cells with bland spindle-shaped nuclei and scant eosinophilic cytoplasm immersed in a collagenous background.
Solitary fibrous tumour. All tumours show nuclear localization of STAT6 by immunohistochemistry.
A: STAT6
Q: Solitary fibrous tumour
- Clinical: Dural-based fibroblastic neoplasm (SFT/HPC) that often mimics meningioma radiologically with a 'dural tail' and intense enhancement.
- Microscopic: Characterized by a patternless architecture of monomorphic spindle cells, variable collagen (keloidal-type), and thin-walled, branching "[...]" vessels.
- Grading: CNS WHO grade (1–3) is assigned based on mitotic activity (cutoff: 2.5 mitoses/mm²) and the presence or absence of necrosis.
- Ancillary: Diagnostic hallmark is diffuse and intense nuclear expression of [...], resulting from the pathognomonic [STAT6] fusion.
Reference Gallery:
Solitary fibrous tumour. This large and multiloculated falcine tumour in a 74-year-old man shows diffuse postgadolinium enhancement.
Solitary fibrous tumour. This dural-based posterior fossa tumour in a 73-year-old man is strongly and diffusely enhancing, and it has a small dural tail.
Solitary fibrous tumour (SFT). A dural tail (16 mm in length) is visible in this tumour of the upper thoracic spine in a 45-year-old man.
Solitary fibrous tumour. The typical patternless architecture is shown.
Solitary fibrous tumour. This tumour is composed of cells with bland spindle-shaped nuclei and scant eosinophilic cytoplasm immersed in a collagenous background.
Solitary fibrous tumour. A highly cellular tumour with thin-walled, branching (staghorn) vessels.
Solitary fibrous tumour. Numerous mitoses (arrows) are present in this tumour.
Solitary fibrous tumour. Strong and diffuse positivity for CD34 in a CNS WHO grade 1 tumour.
Solitary fibrous tumour. All tumours show nuclear localization of STAT6 by immunohistochemistry.
Solitary fibrous tumour. There is often stromal and perivascular hyaline collagen deposition.
Solitary fibrous tumour. This tumour shows keloidal or amianthoid collagen.
Solitary fibrous tumour. There may be closely apposed cells with round to ovoid nuclei arranged in a haphazard pattern, with limited intervening stroma.
A: staghorn; STAT6; NAB2

Q: A Solitary fibrous tumor is characterized by a pathognomonic molecular driver, specifically the [STAT6] gene fusion.
Solitary fibrous tumour. The typical patternless architecture is shown.
Solitary fibrous tumour. All tumours show nuclear localization of STAT6 by immunohistochemistry.
A: NAB2
Q: Solitary fibrous tumour
- Clinical: Dural-based fibroblastic neoplasm (SFT/HPC) that often mimics meningioma radiologically with a 'dural tail' and intense enhancement.
- Microscopic: Characterized by a patternless architecture of monomorphic spindle cells, variable collagen (keloidal-type), and thin-walled, branching "[...]" vessels.
- Grading: CNS WHO grade (1–3) is assigned based on mitotic activity (cutoff: 2.5 mitoses/mm²) and the presence or absence of necrosis.
- Ancillary: Diagnostic hallmark is diffuse and intense nuclear expression of [...], resulting from the pathognomonic [STAT6] fusion.
Reference Gallery:
Solitary fibrous tumour. This large and multiloculated falcine tumour in a 74-year-old man shows diffuse postgadolinium enhancement.
Solitary fibrous tumour. This dural-based posterior fossa tumour in a 73-year-old man is strongly and diffusely enhancing, and it has a small dural tail.
Solitary fibrous tumour (SFT). A dural tail (16 mm in length) is visible in this tumour of the upper thoracic spine in a 45-year-old man.
Solitary fibrous tumour. The typical patternless architecture is shown.
Solitary fibrous tumour. This tumour is composed of cells with bland spindle-shaped nuclei and scant eosinophilic cytoplasm immersed in a collagenous background.
Solitary fibrous tumour. A highly cellular tumour with thin-walled, branching (staghorn) vessels.
Solitary fibrous tumour. Numerous mitoses (arrows) are present in this tumour.
Solitary fibrous tumour. Strong and diffuse positivity for CD34 in a CNS WHO grade 1 tumour.
Solitary fibrous tumour. All tumours show nuclear localization of STAT6 by immunohistochemistry.
Solitary fibrous tumour. There is often stromal and perivascular hyaline collagen deposition.
Solitary fibrous tumour. This tumour shows keloidal or amianthoid collagen.
Solitary fibrous tumour. There may be closely apposed cells with round to ovoid nuclei arranged in a haphazard pattern, with limited intervening stroma.
A: staghorn; STAT6; NAB2

Q: In the skull base, Chondrosarcoma is often in the differential diagnosis with chordoma; however, it can be distinguished by its lack of cytokeratin and brachyury expression, while exhibiting strong, diffuse immunoreactivity for [...].
Chondrosarcoma. Chondrosarcomas of the skull base show moderate hypercellularity, individual tumour chondrocytes with mild nuclear hyperchromasia, and absence of mitotic activity.
Chondrosarcoma. This skull base chondrosarcoma shows the typical strong diffuse immunoreactivity for S100 in tumoural cells, both in cytoplasm and in nuclei. Strong immunostaining for S100 can also be found in chordomas of the skull base; chordoma often is the main tumour type in the differential diagnosis, so S100 immunostaining does not help distinguish these two tumour types.
A: S100
Back Extra: Chondrosarcoma
- Clinical: Rare intracranial tumor (~1% of chondrosarcomas) typically arising in the skull base (synchondroses) of adults (mean age 39); presents with pain and site-dependent cranial nerve palsies.
- Micro: Characterized by an infiltrative, lobular growth of malignant cartilage; skull base tumors are most frequently low-grade (CNS WHO Grade 1) with uniform nuclei and no mitoses.
- Ancillary: Strong diffuse positivity for S100 and D2-40; critically, these tumors are negative for Brachyury and Cytokeratin, which distinguishes them from chordoma.
- Genetics: Approximately 60% of central conventional chondrosarcomas harbor mutations in IDH1 or IDH2, particularly in skull base locations.
Reference Gallery:
Chondrosarcoma. Chondrosarcomas of the skull base show moderate hypercellularity, individual tumour chondrocytes with mild nuclear hyperchromasia, and absence of mitotic activity.
Chondrosarcoma. This skull base chondrosarcoma shows the typical strong diffuse immunoreactivity for S100 in tumoural cells, both in cytoplasm and in nuclei. Strong immunostaining for S100 can also be found in chordomas of the skull base; chordoma often is the main tumour type in the differential diagnosis, so S100 immunostaining does not help distinguish these two tumour types.
Chondrosarcoma. T2-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves the left side (right side of image).
Chondrosarcoma. T1-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves left-sided basilar skull regions (right side of image).
Chondrosarcoma. T1-weighted postcontrast coronal MRI of a 56-year-old man with a skull base low-grade tumour shows the characteristic heterogeneous signal seen within the tumour.
Chondrosarcoma. CT of a 56-year-old man who presented with ataxia and weakness demonstrates a heavily calcified skull base mass near the prepontine and basal cisterns, behind the sella. Preoperative considerations included craniopharyngioma and chondrosarcoma. Biopsy proved that the lesion was a low-grade chondrosarcoma.

Q: Approximately 60% of central conventional Chondrosarcomas (particularly in skull base locations) harbor characteristic mutations in the [...] genes.
Chondrosarcoma. Chondrosarcomas of the skull base show moderate hypercellularity, individual tumour chondrocytes with mild nuclear hyperchromasia, and absence of mitotic activity.
A: IDH1 or IDH2
Back Extra: Chondrosarcoma
- Clinical: Rare intracranial tumor (~1% of chondrosarcomas) typically arising in the skull base (synchondroses) of adults (mean age 39); presents with pain and site-dependent cranial nerve palsies.
- Micro: Characterized by an infiltrative, lobular growth of malignant cartilage; skull base tumors are most frequently low-grade (CNS WHO Grade 1) with uniform nuclei and no mitoses.
- Ancillary: Strong diffuse positivity for S100 and D2-40; critically, these tumors are negative for Brachyury and Cytokeratin, which distinguishes them from chordoma.
- Genetics: Approximately 60% of central conventional chondrosarcomas harbor mutations in IDH1 or IDH2, particularly in skull base locations.
Reference Gallery:
Chondrosarcoma. Chondrosarcomas of the skull base show moderate hypercellularity, individual tumour chondrocytes with mild nuclear hyperchromasia, and absence of mitotic activity.
Chondrosarcoma. This skull base chondrosarcoma shows the typical strong diffuse immunoreactivity for S100 in tumoural cells, both in cytoplasm and in nuclei. Strong immunostaining for S100 can also be found in chordomas of the skull base; chordoma often is the main tumour type in the differential diagnosis, so S100 immunostaining does not help distinguish these two tumour types.
Chondrosarcoma. T2-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves the left side (right side of image).
Chondrosarcoma. T1-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves left-sided basilar skull regions (right side of image).
Chondrosarcoma. T1-weighted postcontrast coronal MRI of a 56-year-old man with a skull base low-grade tumour shows the characteristic heterogeneous signal seen within the tumour.
Chondrosarcoma. CT of a 56-year-old man who presented with ataxia and weakness demonstrates a heavily calcified skull base mass near the prepontine and basal cisterns, behind the sella. Preoperative considerations included craniopharyngioma and chondrosarcoma. Biopsy proved that the lesion was a low-grade chondrosarcoma.

Q: On computed tomography (CT), a skull base Chondrosarcoma frequently presents as a heavily [...] mass arising near the synchondroses.
Chondrosarcoma. CT of a 56-year-old man who presented with ataxia and weakness demonstrates a heavily calcified skull base mass near the prepontine and basal cisterns, behind the sella. Preoperative considerations included craniopharyngioma and chondrosarcoma. Biopsy proved that the lesion was a low-grade chondrosarcoma.
A: calcified
Back Extra: Chondrosarcoma
- Clinical: Rare intracranial tumor (~1% of chondrosarcomas) typically arising in the skull base (synchondroses) of adults (mean age 39); presents with pain and site-dependent cranial nerve palsies.
- Micro: Characterized by an infiltrative, lobular growth of malignant cartilage; skull base tumors are most frequently low-grade (CNS WHO Grade 1) with uniform nuclei and no mitoses.
- Ancillary: Strong diffuse positivity for S100 and D2-40; critically, these tumors are negative for Brachyury and Cytokeratin, which distinguishes them from chordoma.
- Genetics: Approximately 60% of central conventional chondrosarcomas harbor mutations in IDH1 or IDH2, particularly in skull base locations.
Reference Gallery:
Chondrosarcoma. Chondrosarcomas of the skull base show moderate hypercellularity, individual tumour chondrocytes with mild nuclear hyperchromasia, and absence of mitotic activity.
Chondrosarcoma. This skull base chondrosarcoma shows the typical strong diffuse immunoreactivity for S100 in tumoural cells, both in cytoplasm and in nuclei. Strong immunostaining for S100 can also be found in chordomas of the skull base; chordoma often is the main tumour type in the differential diagnosis, so S100 immunostaining does not help distinguish these two tumour types.
Chondrosarcoma. T2-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves the left side (right side of image).
Chondrosarcoma. T1-weighted coronal MRI of a 33-year-old man who presented with dysphagia shows a skull base lesion that extensively involves left-sided basilar skull regions (right side of image).
Chondrosarcoma. T1-weighted postcontrast coronal MRI of a 56-year-old man with a skull base low-grade tumour shows the characteristic heterogeneous signal seen within the tumour.
Chondrosarcoma. CT of a 56-year-old man who presented with ataxia and weakness demonstrates a heavily calcified skull base mass near the prepontine and basal cisterns, behind the sella. Preoperative considerations included craniopharyngioma and chondrosarcoma. Biopsy proved that the lesion was a low-grade chondrosarcoma.

Q: In Metastases to the brain and spinal cord parenchyma, post-contrast T1 MRI typically demonstrates well-circumscribed, [...] lesions accompanied by extensive, surrounding vasogenic edema on FLAIR sequences.
Single brain metastasis from colorectal cancer. Ring-enhancing lesion in the cerebellum on T1-weighted, postcontrast axial MRI.
Single brain metastasis from colorectal cancer. FLAIR MRI showing a great extent of vasogenic oedema.
A: ring-enhancing
Back Extra: Metastases to the brain and spinal cord parenchyma
- Clinical: Presents with symptoms of increased intracranial pressure (headache, nausea, seizures); MRI typically shows circumscribed, ring-enhancing lesions with significant surrounding vasogenic oedema.
- Microscopic: Tumours are generally well-demarcated and mirror the histology of the primary site, though they often exhibit perivascular growth in adjacent CNS tissue, termed "vascular cooption".
- Ancillary: Immunohistochemistry is essential for identifying the primary site of origin (e.g., TTF1, GATA3, SOX10); molecular profiling is critical for identifying therapeutic targets like EGFR mutations, ALK fusions, and BRAF mutations.
- Prognosis: Outcomes are influenced by patient age, Karnofsky performance status, number of metastases, and specific molecular drivers such as ERBB2 (HER2) status in breast cancer.
Reference Gallery:
Single brain metastasis from colorectal cancer. Ring-enhancing lesion in the cerebellum on T1-weighted, postcontrast axial MRI.
Single brain metastasis from colorectal cancer. FLAIR MRI showing a great extent of vasogenic oedema.
Relative frequencies of primary tumours and of brain metastases derived from them. Tumours with a high propensity to metastasize to the brain are lung cancer, breast cancer, renal cell carcinoma, and melanoma.

Q: On MRI, Metastases to the meninges characteristically presents with contrast enhancement and focal or diffuse [...].
Leptomeningeal metastases from breast carcinoma. Diffuse enhancement of cortical sulci on T1-weighted, postcontrast axial MRI.
Leptomeningeal metastases from breast carcinoma. Linear enhancement of the spinal leptomeninges on T1-weighted, postcontrast sagittal MRI.
A: leptomeningeal thickening
Back Extra: Metastases to the meninges
- Clinical: Presents with multifocal neurological symptoms (headache, ataxia, cranial nerve palsy); MRI characteristically shows focal or diffuse leptomeningeal thickening and contrast enhancement.
- Cytology: CSF reveals malignant cells in ~50% of initial samples, increasing to >80% with repeated high-volume (≥ 10 mL) sampling; look for large nuclei, prominent nucleoli, and mitoses.
- Microscopic: Tumour cells are dispersed within the subarachnoid space and Virchow–Robin spaces, sometimes invading adjacent CNS parenchyma or nerve roots.
- Ancillary: Liquid biopsy of CSF for cell-free tumor DNA (cfDNA) can improve diagnostic precision; IHC (e.g., S100 for melanoma) helps identify the primary source.
- Biochemistry: Typical non-diagnostic CSF features include increased opening pressure, elevated protein (> 50 mg/dL), and decreased glucose (< 60 mg/dL).
Reference Gallery:
Leptomeningeal metastases from breast carcinoma. Diffuse enhancement of cortical sulci on T1-weighted, postcontrast axial MRI.
Leptomeningeal metastases from breast carcinoma. Linear enhancement of the spinal leptomeninges on T1-weighted, postcontrast sagittal MRI.
Cerebrospinal fluid (CSF) metastasis of B-cell lymphoma. Tumour cells are primarily recognized by their large nuclei (4–5 times larger than normal lymphocytes), which are often irregular and hyperchromatic. (Pappenheim stain)
Diffuse meningeal metastasis. Cerebrospinal fluid showing numerous metastatic breast adenocarcinoma cells with clustering and large size in relation to small lymphocytes.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: lobular breast carcinoma, showing single-file–like group and mitosis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis, S100 immunochemistry.

Q: In Metastases to the meninges, the diagnostic yield for detecting malignant tumor cells on cerebrospinal fluid (CSF) cytology increases to >80% with repeated [...] sampling (≥ 10 mL).
Diffuse meningeal metastasis. Cerebrospinal fluid showing numerous metastatic breast adenocarcinoma cells with clustering and large size in relation to small lymphocytes.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: lobular breast carcinoma, showing single-file–like group and mitosis.
A: high-volume
Back Extra: Metastases to the meninges
- Clinical: Presents with multifocal neurological symptoms (headache, ataxia, cranial nerve palsy); MRI characteristically shows focal or diffuse leptomeningeal thickening and contrast enhancement.
- Cytology: CSF reveals malignant cells in ~50% of initial samples, increasing to >80% with repeated high-volume (≥ 10 mL) sampling; look for large nuclei, prominent nucleoli, and mitoses.
- Microscopic: Tumour cells are dispersed within the subarachnoid space and Virchow–Robin spaces, sometimes invading adjacent CNS parenchyma or nerve roots.
- Ancillary: Liquid biopsy of CSF for cell-free tumor DNA (cfDNA) can improve diagnostic precision; IHC (e.g., S100 for melanoma) helps identify the primary source.
- Biochemistry: Typical non-diagnostic CSF features include increased opening pressure, elevated protein (> 50 mg/dL), and decreased glucose (< 60 mg/dL).
Reference Gallery:
Leptomeningeal metastases from breast carcinoma. Diffuse enhancement of cortical sulci on T1-weighted, postcontrast axial MRI.
Leptomeningeal metastases from breast carcinoma. Linear enhancement of the spinal leptomeninges on T1-weighted, postcontrast sagittal MRI.
Cerebrospinal fluid (CSF) metastasis of B-cell lymphoma. Tumour cells are primarily recognized by their large nuclei (4–5 times larger than normal lymphocytes), which are often irregular and hyperchromatic. (Pappenheim stain)
Diffuse meningeal metastasis. Cerebrospinal fluid showing numerous metastatic breast adenocarcinoma cells with clustering and large size in relation to small lymphocytes.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: lobular breast carcinoma, showing single-file–like group and mitosis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis, S100 immunochemistry.

Q: When determining the primary source of Metastases to the meninges, cerebrospinal fluid cytology can be evaluated with ancillary testing, such as utilizing the [...] immunohistochemical stain to identify metastatic melanoma.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis, S100 immunochemistry.
A: S100
Back Extra: Metastases to the meninges
- Clinical: Presents with multifocal neurological symptoms (headache, ataxia, cranial nerve palsy); MRI characteristically shows focal or diffuse leptomeningeal thickening and contrast enhancement.
- Cytology: CSF reveals malignant cells in ~50% of initial samples, increasing to >80% with repeated high-volume (≥ 10 mL) sampling; look for large nuclei, prominent nucleoli, and mitoses.
- Microscopic: Tumour cells are dispersed within the subarachnoid space and Virchow–Robin spaces, sometimes invading adjacent CNS parenchyma or nerve roots.
- Ancillary: Liquid biopsy of CSF for cell-free tumor DNA (cfDNA) can improve diagnostic precision; IHC (e.g., S100 for melanoma) helps identify the primary source.
- Biochemistry: Typical non-diagnostic CSF features include increased opening pressure, elevated protein (> 50 mg/dL), and decreased glucose (< 60 mg/dL).
Reference Gallery:
Leptomeningeal metastases from breast carcinoma. Diffuse enhancement of cortical sulci on T1-weighted, postcontrast axial MRI.
Leptomeningeal metastases from breast carcinoma. Linear enhancement of the spinal leptomeninges on T1-weighted, postcontrast sagittal MRI.
Cerebrospinal fluid (CSF) metastasis of B-cell lymphoma. Tumour cells are primarily recognized by their large nuclei (4–5 times larger than normal lymphocytes), which are often irregular and hyperchromatic. (Pappenheim stain)
Diffuse meningeal metastasis. Cerebrospinal fluid showing numerous metastatic breast adenocarcinoma cells with clustering and large size in relation to small lymphocytes.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: lobular breast carcinoma, showing single-file–like group and mitosis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis.
Metastases to the meninges. Cytological preparation showing metastatic cells within the cerebrospinal fluid: melanoma metastasis, S100 immunochemistry.

Q: Histologically, a Cauda equina neuroendocrine tumor classically features a [...] architecture, characterized by nests of chief cells surrounded by sustentacular cells and a delicate capillary network.
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
A: Zellballen
Back Extra: Cauda equina neuroendocrine tumour
- Clinical: Typically presents with low back pain and sciatica; MRI may reveal a 'cap sign' (subcapsular haemosiderin) or 'salt-and-pepper' appearance due to high vascularity.
- Microscopic: Characterized by a 'Zellballen' architecture (nests of round/polygonal chief cells) surrounded by spindle-shaped sustentacular cells and a delicate capillary network.
- Ancillary: Chief cells are positive for synaptophysin, chromogranin A, and HOXB13; sustentacular cells are positive for S100 and SOX10.
- Prognosis: Slow-growing, CNS WHO grade 1 neoplasm that is generally curable by gross total excision; recurrence is rare (approx. 4%).
Reference Gallery:
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour. The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Synaptophysin immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour. Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Neuroendocrine tumour / paraganglioma. S100 immunostaining labels the sustentacular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour. Hypointense tumour on T2-weighted image with prominent flow voids from enlarged draining veins superiorly.
Cauda equina neuroendocrine tumour. T1-weighted image with marked contrast enhancement.
Cauda equina neuroendocrine tumour. A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: Immunohistochemistry of a Cauda equina neuroendocrine tumor reveals that the uniform, round chief cells are strongly positive for neuroendocrine markers such as chromogranin A and [...].
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour. Synaptophysin immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour. Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
A: synaptophysin
Back Extra: Cauda equina neuroendocrine tumour
- Clinical: Typically presents with low back pain and sciatica; MRI may reveal a 'cap sign' (subcapsular haemosiderin) or 'salt-and-pepper' appearance due to high vascularity.
- Microscopic: Characterized by a 'Zellballen' architecture (nests of round/polygonal chief cells) surrounded by spindle-shaped sustentacular cells and a delicate capillary network.
- Ancillary: Chief cells are positive for synaptophysin, chromogranin A, and HOXB13; sustentacular cells are positive for S100 and SOX10.
- Prognosis: Slow-growing, CNS WHO grade 1 neoplasm that is generally curable by gross total excision; recurrence is rare (approx. 4%).
Reference Gallery:
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour. The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Synaptophysin immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour. Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Neuroendocrine tumour / paraganglioma. S100 immunostaining labels the sustentacular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour. Hypointense tumour on T2-weighted image with prominent flow voids from enlarged draining veins superiorly.
Cauda equina neuroendocrine tumour. T1-weighted image with marked contrast enhancement.
Cauda equina neuroendocrine tumour. A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: In a Cauda equina neuroendocrine tumor, the spindle-shaped sustentacular cells that surround the tumor nests are characteristically positive for [...] and SOX10.
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Neuroendocrine tumour / paraganglioma. S100 immunostaining labels the sustentacular cells, encompassing the lobules.
A: S100
Back Extra: Cauda equina neuroendocrine tumour
- Clinical: Typically presents with low back pain and sciatica; MRI may reveal a 'cap sign' (subcapsular haemosiderin) or 'salt-and-pepper' appearance due to high vascularity.
- Microscopic: Characterized by a 'Zellballen' architecture (nests of round/polygonal chief cells) surrounded by spindle-shaped sustentacular cells and a delicate capillary network.
- Ancillary: Chief cells are positive for synaptophysin, chromogranin A, and HOXB13; sustentacular cells are positive for S100 and SOX10.
- Prognosis: Slow-growing, CNS WHO grade 1 neoplasm that is generally curable by gross total excision; recurrence is rare (approx. 4%).
Reference Gallery:
Cauda equina neuroendocrine tumour. H&E staining shows nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour. The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Synaptophysin immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour. Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Neuroendocrine tumour / paraganglioma. S100 immunostaining labels the sustentacular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour. Hypointense tumour on T2-weighted image with prominent flow voids from enlarged draining veins superiorly.
Cauda equina neuroendocrine tumour. T1-weighted image with marked contrast enhancement.
Cauda equina neuroendocrine tumour. A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: Immunohistochemically, Malignant melanotic nerve sheath tumor is frequently associated with Carney complex and uniquely demonstrates a characteristic loss of [...] expression.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
Malignant melanotic nerve sheath tumour. Tumour cell–specific loss of PRKAR1A expression (immunohistochemistry for PRKAR1A with red chromogen).
A: PRKAR1A
Back Extra: Malignant melanotic nerve sheath tumour
- Definition: An aggressive peripheral nerve sheath tumour with both Schwannian and melanocytic differentiation, frequently associated with Carney complex.
- Clinical: Most commonly arises in the spinal nerve roots or autonomic nerves of adults; patients with Carney complex present at a younger average age.
- Microscopic: Characterized by sheets or fascicles of epithelioid to spindled cells with heavy melanin pigment and psammoma bodies (seen in ~50% of cases).
- Immunohistochemistry: Tumour cells are positive for S100, SOX10, and melanocytic markers (HMB45, Melan-A), but typically show loss of PRKAR1A expression.
- Molecular: Lacks mutations in BRAF, NRAS, GNAQ, or GNA11, which helps differentiate it from melanoma and CNS melanocytoma.
Reference Gallery:
Malignant melanotic nerve sheath tumour. Tumour arising in a spinal nerve root. The tumour is heavily pigmented and partially encapsulated.
Malignant melanotic nerve sheath tumour. Cellular detail is often obscured by heavy pigment deposition.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
Malignant melanotic nerve sheath tumour. Tumour cell–specific loss of PRKAR1A expression (immunohistochemistry for PRKAR1A with red chromogen).

Q: Microscopically, Malignant melanotic nerve sheath tumor is characterized by epithelioid to spindled cells with heavy melanin pigment and the presence of [...] in approximately 50% of cases.
Malignant melanotic nerve sheath tumour. Cellular detail is often obscured by heavy pigment deposition.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
A: psammoma bodies
Back Extra: Malignant melanotic nerve sheath tumour
- Definition: An aggressive peripheral nerve sheath tumour with both Schwannian and melanocytic differentiation, frequently associated with Carney complex.
- Clinical: Most commonly arises in the spinal nerve roots or autonomic nerves of adults; patients with Carney complex present at a younger average age.
- Microscopic: Characterized by sheets or fascicles of epithelioid to spindled cells with heavy melanin pigment and psammoma bodies (seen in ~50% of cases).
- Immunohistochemistry: Tumour cells are positive for S100, SOX10, and melanocytic markers (HMB45, Melan-A), but typically show loss of PRKAR1A expression.
- Molecular: Lacks mutations in BRAF, NRAS, GNAQ, or GNA11, which helps differentiate it from melanoma and CNS melanocytoma.
Reference Gallery:
Malignant melanotic nerve sheath tumour. Tumour arising in a spinal nerve root. The tumour is heavily pigmented and partially encapsulated.
Malignant melanotic nerve sheath tumour. Cellular detail is often obscured by heavy pigment deposition.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
Malignant melanotic nerve sheath tumour. Tumour cell–specific loss of PRKAR1A expression (immunohistochemistry for PRKAR1A with red chromogen).

Q: An aggressive, heavily pigmented peripheral nerve sheath tumor that is frequently associated with Carney complex and characteristically lacks BRAF mutations is best diagnosed as a [...].
Malignant melanotic nerve sheath tumour. Cellular detail is often obscured by heavy pigment deposition.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
A: Malignant melanotic nerve sheath tumor
Back Extra: Malignant melanotic nerve sheath tumour
- Definition: An aggressive peripheral nerve sheath tumour with both Schwannian and melanocytic differentiation, frequently associated with Carney complex.
- Clinical: Most commonly arises in the spinal nerve roots or autonomic nerves of adults; patients with Carney complex present at a younger average age.
- Microscopic: Characterized by sheets or fascicles of epithelioid to spindled cells with heavy melanin pigment and psammoma bodies (seen in ~50% of cases).
- Immunohistochemistry: Tumour cells are positive for S100, SOX10, and melanocytic markers (HMB45, Melan-A), but typically show loss of PRKAR1A expression.
- Molecular: Lacks mutations in BRAF, NRAS, GNAQ, or GNA11, which helps differentiate it from melanoma and CNS melanocytoma.
Reference Gallery:
Malignant melanotic nerve sheath tumour. Tumour arising in a spinal nerve root. The tumour is heavily pigmented and partially encapsulated.
Malignant melanotic nerve sheath tumour. Cellular detail is often obscured by heavy pigment deposition.
Malignant melanotic nerve sheath tumour. Sheets of vaguely syncytial epithelioid cells.
Malignant melanotic nerve sheath tumour. Tumour cell–specific loss of PRKAR1A expression (immunohistochemistry for PRKAR1A with red chromogen).

Q: Histologically, a conventional malignant peripheral nerve sheath tumor often exhibits alternating hypercellular and hypocellular areas composed of spindle cells, creating a characteristic [...] appearance.
Malignant peripheral nerve sheath tumour. Areas of alternating cellularity (marbling).
Malignant peripheral nerve sheath tumour. Tumour cells have spindle-shaped nuclei, often with tapered ends, that frequently appear wavy or buckled. The cytoplasm is palely eosinophilic and fibrillary.
A: marbled
Back Extra: Malignant peripheral nerve sheath tumour
- Clinical: MPNST occurs most commonly in patients aged 20–50 years, with NF1-associated cases appearing about a decade younger than sporadic cases. Patients present with enlarging masses causing pain or neuropathic symptoms. About …
- Micro: Conventional high-grade MPNST is a hypercellular spindle cell tumour arranged in interlacing fascicles. Tumour cells feature wavy or buckled nuclei and pale, indistinct cytoplasm. A characteristic 'marbled' appearance is…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): * Lineage Markers: Conventional MPNST is usually negative or only patchily positive for Schwann cell markers (S100, SOX10, GFAP). Positivity is often restricted to a subpopulation or e…
Reference Gallery:
Malignant peripheral nerve sheath tumour. Accentuated perivascular cellularity.
Perineurial malignant peripheral nerve sheath tumour. Cellular whorls showing concentric arrangement of tumour cells.
Perineurial malignant peripheral nerve sheath tumour. Storiform and whorling pattern.
Perineurial malignant peripheral nerve sheath tumour. Immunoreactivity for EMA.
Malignant peripheral nerve sheath tumour. Nodular herniation of tumour cells into the vessel lumen.
Epithelioid malignant peripheral nerve sheath tumour. Lobulated growth of epithelioid cells.
Epithelioid malignant peripheral nerve sheath tumour. Epithelioid cells have atypical nuclei with prominent nucleoli and eosinophilic cytoplasm.
Epithelioid malignant peripheral nerve sheath tumour. Loss of SMARCB1 staining is a feature of epithelioid malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Areas of alternating cellularity (marbling).
Malignant peripheral nerve sheath tumour. Tumour cells have spindle-shaped nuclei, often with tapered ends, that frequently appear wavy or buckled. The cytoplasm is palely eosinophilic and fibrillary.
Malignant peripheral nerve sheath tumour. H3 p.K28me3 (K27me3) stain showing complete loss of expression in tumour cells but retained expression in non-neoplastic elements.
Malignant peripheral nerve sheath tumour. Patchy S100 expression.

Q: A highly specific immunohistochemical finding in the conventional form of malignant peripheral nerve sheath tumor is the complete loss of [...] expression (also known as H3 p.K28me3), while non-neoplastic elements retain expression.
Malignant peripheral nerve sheath tumour. H3 p.K28me3 (K27me3) stain showing complete loss of expression in tumour cells but retained expression in non-neoplastic elements.
A: H3K27me3
Back Extra: Malignant peripheral nerve sheath tumour
- Clinical: MPNST occurs most commonly in patients aged 20–50 years, with NF1-associated cases appearing about a decade younger than sporadic cases. Patients present with enlarging masses causing pain or neuropathic symptoms. About …
- Micro: Conventional high-grade MPNST is a hypercellular spindle cell tumour arranged in interlacing fascicles. Tumour cells feature wavy or buckled nuclei and pale, indistinct cytoplasm. A characteristic 'marbled' appearance is…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): * Lineage Markers: Conventional MPNST is usually negative or only patchily positive for Schwann cell markers (S100, SOX10, GFAP). Positivity is often restricted to a subpopulation or e…
Reference Gallery:
Malignant peripheral nerve sheath tumour. Accentuated perivascular cellularity.
Perineurial malignant peripheral nerve sheath tumour. Cellular whorls showing concentric arrangement of tumour cells.
Perineurial malignant peripheral nerve sheath tumour. Storiform and whorling pattern.
Perineurial malignant peripheral nerve sheath tumour. Immunoreactivity for EMA.
Malignant peripheral nerve sheath tumour. Nodular herniation of tumour cells into the vessel lumen.
Epithelioid malignant peripheral nerve sheath tumour. Lobulated growth of epithelioid cells.
Epithelioid malignant peripheral nerve sheath tumour. Epithelioid cells have atypical nuclei with prominent nucleoli and eosinophilic cytoplasm.
Epithelioid malignant peripheral nerve sheath tumour. Loss of SMARCB1 staining is a feature of epithelioid malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Areas of alternating cellularity (marbling).
Malignant peripheral nerve sheath tumour. Tumour cells have spindle-shaped nuclei, often with tapered ends, that frequently appear wavy or buckled. The cytoplasm is palely eosinophilic and fibrillary.
Malignant peripheral nerve sheath tumour. H3 p.K28me3 (K27me3) stain showing complete loss of expression in tumour cells but retained expression in non-neoplastic elements.
Malignant peripheral nerve sheath tumour. Patchy S100 expression.

Q: Unlike benign schwannomas, a conventional malignant peripheral nerve sheath tumor typically shows negative or only patchy immunostaining for the Schwann cell marker [...].
Malignant peripheral nerve sheath tumour. Patchy S100 expression.
A: S100
Back Extra: Malignant peripheral nerve sheath tumour
- Clinical: MPNST occurs most commonly in patients aged 20–50 years, with NF1-associated cases appearing about a decade younger than sporadic cases. Patients present with enlarging masses causing pain or neuropathic symptoms. About …
- Micro: Conventional high-grade MPNST is a hypercellular spindle cell tumour arranged in interlacing fascicles. Tumour cells feature wavy or buckled nuclei and pale, indistinct cytoplasm. A characteristic 'marbled' appearance is…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): * Lineage Markers: Conventional MPNST is usually negative or only patchily positive for Schwann cell markers (S100, SOX10, GFAP). Positivity is often restricted to a subpopulation or e…
Reference Gallery:
Malignant peripheral nerve sheath tumour. Accentuated perivascular cellularity.
Perineurial malignant peripheral nerve sheath tumour. Cellular whorls showing concentric arrangement of tumour cells.
Perineurial malignant peripheral nerve sheath tumour. Storiform and whorling pattern.
Perineurial malignant peripheral nerve sheath tumour. Immunoreactivity for EMA.
Malignant peripheral nerve sheath tumour. Nodular herniation of tumour cells into the vessel lumen.
Epithelioid malignant peripheral nerve sheath tumour. Lobulated growth of epithelioid cells.
Epithelioid malignant peripheral nerve sheath tumour. Epithelioid cells have atypical nuclei with prominent nucleoli and eosinophilic cytoplasm.
Epithelioid malignant peripheral nerve sheath tumour. Loss of SMARCB1 staining is a feature of epithelioid malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Areas of alternating cellularity (marbling).
Malignant peripheral nerve sheath tumour. Tumour cells have spindle-shaped nuclei, often with tapered ends, that frequently appear wavy or buckled. The cytoplasm is palely eosinophilic and fibrillary.
Malignant peripheral nerve sheath tumour. H3 p.K28me3 (K27me3) stain showing complete loss of expression in tumour cells but retained expression in non-neoplastic elements.
Malignant peripheral nerve sheath tumour. Patchy S100 expression.

Q: Microscopic examination of a Neurofibroma typically reveals bland, wavy spindle cells embedded in a stroma with thick collagen bundles colloquially described as resembling [...].
Neurofibroma. Note the wavy nuclei and cytoplasmic processes within a mucin-rich matrix and variable collagen.
Neurofibroma. Increased cellularity (cellular neurofibroma) may be present usually as a focal finding in large, longstanding neurofibromas, but it lacks prognostic significance in the absence of other atypical features.
A: "shredded carrots"
Q: Neurofibroma
- Clinical: Benign peripheral nerve sheath tumors (CNS WHO grade 1) that are often sporadic, though plexiform and massive variants are pathognomonic for Neurofibromatosis type 1 (NF1).
- Microscopic: Characterized by bland, wavy spindle cells (Schwann cells) mixed with fibroblasts and mast cells in a stroma containing collagen bundles resembling [...].
- Subtypes: Plexiform neurofibromas involve multiple nerve fascicles (creating a "bag-of-worms" appearance) and, along with ANNUBP, serve as precursors to Malignant Peripheral Nerve Sheath Tumor (MPNST).
- Ancillary: Shows patchy, less intense S100/SOX10 staining compared to schwannomas and typically retains entrapped axons (highlighted by Neurofilament/NFP).
- Genetics: Driven by biallelic inactivation of [...]; progression to ANNUBP is marked by deletions of [...].
Reference Gallery:
Neurofibroma. Note the wavy nuclei and cytoplasmic processes within a mucin-rich matrix and variable collagen.
Neurofibroma. Neurofibromas associated with the nerve root frequently extend to sensory ganglia, a finding that should not be mistaken for ganglioneuroma.
Neurofibroma. Increased cellularity (cellular neurofibroma) may be present usually as a focal finding in large, longstanding neurofibromas, but it lacks prognostic significance in the absence of other atypical features.
Neurofibroma. Concentric arrangements (whorls) of Schwann cells around axons, resembling onion bulbs.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as S100 usually labels most, but not all, cells in neurofibromas.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as SOX10 usually results in nuclear labelling in most, but not all, cells of neurofibromas.
Plexiform neurofibroma. Gross appearance, demonstrating a tortuous architecture and a yellow, slightly heterogeneous cut surface.
Plexiform neurofibroma. By definition, involvement of multiple fascicles must be present, which imparts a multinodular appearance on low magnification.
Plexiform neurofibroma. Higher-power view of the adjacent enlarged nerve fibres.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Tumours designated as ANNUBP in patients with neurofibromatosis type 1 may have several worrisome features, including cytological atypia.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). ANNUBP with increased cellularity and mitotic activity, but otherwise falling short of a malignant diagnosis.
Neurofibroma. Total spine MRI in a patient with neurofibromatosis type 1 with extensive bilateral paraspinal disease burden. Neurofibromas involve nearly every nerve root; also note the thoracic spine curvature defect (scoliosis).
A: "shredded carrots"; NF1; CDKN2A/B

Q: Unlike schwannomas which stain diffusely, a [...] demonstrates a characteristically patchy staining pattern for Schwann cell markers like S100 and SOX10 due to an admixed population of fibroblasts and other cells.
Neurofibroma. Note the wavy nuclei and cytoplasmic processes within a mucin-rich matrix and variable collagen.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as S100 usually labels most, but not all, cells in neurofibromas.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as SOX10 usually results in nuclear labelling in most, but not all, cells of neurofibromas.
A: Neurofibroma
Q: Neurofibroma
- Clinical: Benign peripheral nerve sheath tumors (CNS WHO grade 1) that are often sporadic, though plexiform and massive variants are pathognomonic for Neurofibromatosis type 1 (NF1).
- Microscopic: Characterized by bland, wavy spindle cells (Schwann cells) mixed with fibroblasts and mast cells in a stroma containing collagen bundles resembling [...].
- Subtypes: Plexiform neurofibromas involve multiple nerve fascicles (creating a "bag-of-worms" appearance) and, along with ANNUBP, serve as precursors to Malignant Peripheral Nerve Sheath Tumor (MPNST).
- Ancillary: Shows patchy, less intense S100/SOX10 staining compared to schwannomas and typically retains entrapped axons (highlighted by Neurofilament/NFP).
- Genetics: Driven by biallelic inactivation of [...]; progression to ANNUBP is marked by deletions of [...].
Reference Gallery:
Neurofibroma. Note the wavy nuclei and cytoplasmic processes within a mucin-rich matrix and variable collagen.
Neurofibroma. Neurofibromas associated with the nerve root frequently extend to sensory ganglia, a finding that should not be mistaken for ganglioneuroma.
Neurofibroma. Increased cellularity (cellular neurofibroma) may be present usually as a focal finding in large, longstanding neurofibromas, but it lacks prognostic significance in the absence of other atypical features.
Neurofibroma. Concentric arrangements (whorls) of Schwann cells around axons, resembling onion bulbs.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as S100 usually labels most, but not all, cells in neurofibromas.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as SOX10 usually results in nuclear labelling in most, but not all, cells of neurofibromas.
Plexiform neurofibroma. Gross appearance, demonstrating a tortuous architecture and a yellow, slightly heterogeneous cut surface.
Plexiform neurofibroma. By definition, involvement of multiple fascicles must be present, which imparts a multinodular appearance on low magnification.
Plexiform neurofibroma. Higher-power view of the adjacent enlarged nerve fibres.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Tumours designated as ANNUBP in patients with neurofibromatosis type 1 may have several worrisome features, including cytological atypia.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). ANNUBP with increased cellularity and mitotic activity, but otherwise falling short of a malignant diagnosis.
Neurofibroma. Total spine MRI in a patient with neurofibromatosis type 1 with extensive bilateral paraspinal disease burden. Neurofibromas involve nearly every nerve root; also note the thoracic spine curvature defect (scoliosis).
A: "shredded carrots"; NF1; CDKN2A/B

Q: The plexiform variant of Neurofibroma, characterized by the microscopic expansion of multiple nerve fascicles into a "bag-of-worms" appearance, is pathognomonic for the genetic disorder [...].
Plexiform neurofibroma. By definition, involvement of multiple fascicles must be present, which imparts a multinodular appearance on low magnification.
Plexiform neurofibroma. Higher-power view of the adjacent enlarged nerve fibres.
A: Neurofibromatosis type 1
Q: Neurofibroma
- Clinical: Benign peripheral nerve sheath tumors (CNS WHO grade 1) that are often sporadic, though plexiform and massive variants are pathognomonic for Neurofibromatosis type 1 (NF1).
- Microscopic: Characterized by bland, wavy spindle cells (Schwann cells) mixed with fibroblasts and mast cells in a stroma containing collagen bundles resembling [...].
- Subtypes: Plexiform neurofibromas involve multiple nerve fascicles (creating a "bag-of-worms" appearance) and, along with ANNUBP, serve as precursors to Malignant Peripheral Nerve Sheath Tumor (MPNST).
- Ancillary: Shows patchy, less intense S100/SOX10 staining compared to schwannomas and typically retains entrapped axons (highlighted by Neurofilament/NFP).
- Genetics: Driven by biallelic inactivation of [...]; progression to ANNUBP is marked by deletions of [...].
Reference Gallery:
Neurofibroma. Note the wavy nuclei and cytoplasmic processes within a mucin-rich matrix and variable collagen.
Neurofibroma. Neurofibromas associated with the nerve root frequently extend to sensory ganglia, a finding that should not be mistaken for ganglioneuroma.
Neurofibroma. Increased cellularity (cellular neurofibroma) may be present usually as a focal finding in large, longstanding neurofibromas, but it lacks prognostic significance in the absence of other atypical features.
Neurofibroma. Concentric arrangements (whorls) of Schwann cells around axons, resembling onion bulbs.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as S100 usually labels most, but not all, cells in neurofibromas.
Neurofibroma. Immunohistochemistry for Schwann cell markers such as SOX10 usually results in nuclear labelling in most, but not all, cells of neurofibromas.
Plexiform neurofibroma. Gross appearance, demonstrating a tortuous architecture and a yellow, slightly heterogeneous cut surface.
Plexiform neurofibroma. By definition, involvement of multiple fascicles must be present, which imparts a multinodular appearance on low magnification.
Plexiform neurofibroma. Higher-power view of the adjacent enlarged nerve fibres.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Tumours designated as ANNUBP in patients with neurofibromatosis type 1 may have several worrisome features, including cytological atypia.
Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). ANNUBP with increased cellularity and mitotic activity, but otherwise falling short of a malignant diagnosis.
Neurofibroma. Total spine MRI in a patient with neurofibromatosis type 1 with extensive bilateral paraspinal disease burden. Neurofibromas involve nearly every nerve root; also note the thoracic spine curvature defect (scoliosis).
A: "shredded carrots"; NF1; CDKN2A/B

Q: The intraneural subtype of perineurioma is microscopically characterized by concentric layers of neoplastic spindle cells surrounding axons, forming distinctive structures known as [...].
Intraneural perineurioma. Pseudo–onion bulbs and variable collagenization on cross-section.
Intraneural perineurioma. High magnification view of pseudo–onion bulb formation.
Intraneural perineurioma. On a toluidine blue–stained plastic section, myelinated axons are surrounded by concentric rings of perineurial cell processes (pseudo–onion bulbs).
A: pseudo-onion bulbs
Back Extra: Perineurioma
- Clinical: Benign (CNS WHO grade 1) tumor of neoplastic perineurial cells; the intraneural subtype primarily affects young adults' extremities, presenting with muscle weakness.
- Microscopic: Characterized by concentric layers of spindle cells around axons forming "pseudo–onion bulbs" (intraneural) or spindle cells with wavy nuclei in a storiform/whorled pattern (soft tissue).
- Immunohistochemistry: Tumor cells are positive for EMA, claudin-1, and GLUT1, but characteristically negative for S100 and SOX10.
- Genetics: The majority of intraneural perineuriomas harbor missense mutations in TRAF7, while the soft tissue subtype frequently shows deletions of 22q.
Reference Gallery:
Intraneural perineurioma. Pseudo–onion bulbs and variable collagenization on cross-section.
Intraneural perineurioma. High magnification view of pseudo–onion bulb formation.
Intraneural perineurioma. On a toluidine blue–stained plastic section, myelinated axons are surrounded by concentric rings of perineurial cell processes (pseudo–onion bulbs).
Intraneural perineurioma. EMA staining highlights concentric layers of perineurial cells in pseudo–onion bulbs.
Intraneural perineurioma. S100 staining shows entrapped centrally located Schwann cells in pseudo–onion bulbs.
Intraneural perineurioma. NFP staining highlights entrapped centrally located axons in pseudo–onion bulbs.

Q: An intraneural [...] is a benign peripheral nerve sheath tumor characterized by EMA-positive pseudo-onion bulbs that contain centrally entrapped normal elements, such as S100-positive Schwann cells and NFP-positive axons.
Intraneural perineurioma. High magnification view of pseudo–onion bulb formation.
Intraneural perineurioma. EMA staining highlights concentric layers of perineurial cells in pseudo–onion bulbs.
Intraneural perineurioma. S100 staining shows entrapped centrally located Schwann cells in pseudo–onion bulbs.
A: perineurioma
Back Extra: Perineurioma
- Clinical: Benign (CNS WHO grade 1) tumor of neoplastic perineurial cells; the intraneural subtype primarily affects young adults' extremities, presenting with muscle weakness.
- Microscopic: Characterized by concentric layers of spindle cells around axons forming "pseudo–onion bulbs" (intraneural) or spindle cells with wavy nuclei in a storiform/whorled pattern (soft tissue).
- Immunohistochemistry: Tumor cells are positive for EMA, claudin-1, and GLUT1, but characteristically negative for S100 and SOX10.
- Genetics: The majority of intraneural perineuriomas harbor missense mutations in TRAF7, while the soft tissue subtype frequently shows deletions of 22q.
Reference Gallery:
Intraneural perineurioma. Pseudo–onion bulbs and variable collagenization on cross-section.
Intraneural perineurioma. High magnification view of pseudo–onion bulb formation.
Intraneural perineurioma. On a toluidine blue–stained plastic section, myelinated axons are surrounded by concentric rings of perineurial cell processes (pseudo–onion bulbs).
Intraneural perineurioma. EMA staining highlights concentric layers of perineurial cells in pseudo–onion bulbs.
Intraneural perineurioma. S100 staining shows entrapped centrally located Schwann cells in pseudo–onion bulbs.
Intraneural perineurioma. NFP staining highlights entrapped centrally located axons in pseudo–onion bulbs.

Q: The classic microscopic appearance of a schwannoma features loose, hypocellular Antoni B areas alternating with compact Antoni A tissue, which often contains nuclear palisades known as [...].
Conventional schwannoma. Compact Antoni A tissue (left) adjacent to loose Antoni B tissue (right).
Conventional schwannoma. Nuclear palisades, known as Verocay bodies, are a typical feature of schwannoma in Antoni A areas.
A: Verocay bodies
Back Extra: Schwannoma
- Clinical: Benign, slow-growing masses often involving peripheral nerves or the vestibular nerve; bilateral vestibular involvement is diagnostic of neurofibromatosis type 2 (NF2).
- Microscopic: Biphasic architecture comprising compact, hypercellular Antoni A areas (often with Verocay bodies) and loose, hypocellular Antoni B areas with hyalinized vessels.
- Ancillary: Shows strong and diffuse nuclear/cytoplasmic staining for S100 and SOX10; mosaic SMARCB1 (INI1) loss is common in syndromic cases.
- Genetics: Primarily driven by inactivation of the NF2 gene (22q12.2), leading to loss of the protein merlin.
Reference Gallery:
Schwannoma. Cut surface showing a globoid encapsulated tan-grey tumour with areas of xanthic change (yellow) and attached nerve.
Conventional schwannoma. Compact Antoni A tissue (left) adjacent to loose Antoni B tissue (right).
Conventional schwannoma. Nuclear palisades, known as Verocay bodies, are a typical feature of schwannoma in Antoni A areas.
Ancient schwannoma. Scattered bizarre, atypical nuclei are often considered to represent a degenerative change that does not impact prognosis.
Cellular schwannoma. Marked hypercellularity and compact arrangement, which may prompt the consideration of sarcoma in the differential diagnosis.
Cellular schwannoma. Diffuse S100 positivity helps distinguish the cellular schwannoma subtype from malignant peripheral nerve sheath tumour.
Syndrome-associated schwannoma. Mosaic pattern of SMARCB1 (INI1) immunostaining, suggestive of a schwannoma arising in neurofibromatosis type 2 or schwannomatosis.
Epithelioid schwannoma. Multilobular growth pattern at low magnification.
Epithelioid schwannoma. Loss of SMARCB1 expression, which occurs in 40% of cases.
Schwannoma. T1-weighted MRI showing the characteristic dumbbell shape of a spinal root schwannoma.

Q: To help distinguish cellular schwannoma from a malignant peripheral nerve sheath tumor, immunohistochemistry characteristically shows strong and diffuse positivity for SOX10 and [...].
Cellular schwannoma. Marked hypercellularity and compact arrangement, which may prompt the consideration of sarcoma in the differential diagnosis.
Cellular schwannoma. Diffuse S100 positivity helps distinguish the cellular schwannoma subtype from malignant peripheral nerve sheath tumour.
A: S100
Back Extra: Schwannoma
- Clinical: Benign, slow-growing masses often involving peripheral nerves or the vestibular nerve; bilateral vestibular involvement is diagnostic of neurofibromatosis type 2 (NF2).
- Microscopic: Biphasic architecture comprising compact, hypercellular Antoni A areas (often with Verocay bodies) and loose, hypocellular Antoni B areas with hyalinized vessels.
- Ancillary: Shows strong and diffuse nuclear/cytoplasmic staining for S100 and SOX10; mosaic SMARCB1 (INI1) loss is common in syndromic cases.
- Genetics: Primarily driven by inactivation of the NF2 gene (22q12.2), leading to loss of the protein merlin.
Reference Gallery:
Schwannoma. Cut surface showing a globoid encapsulated tan-grey tumour with areas of xanthic change (yellow) and attached nerve.
Conventional schwannoma. Compact Antoni A tissue (left) adjacent to loose Antoni B tissue (right).
Conventional schwannoma. Nuclear palisades, known as Verocay bodies, are a typical feature of schwannoma in Antoni A areas.
Ancient schwannoma. Scattered bizarre, atypical nuclei are often considered to represent a degenerative change that does not impact prognosis.
Cellular schwannoma. Marked hypercellularity and compact arrangement, which may prompt the consideration of sarcoma in the differential diagnosis.
Cellular schwannoma. Diffuse S100 positivity helps distinguish the cellular schwannoma subtype from malignant peripheral nerve sheath tumour.
Syndrome-associated schwannoma. Mosaic pattern of SMARCB1 (INI1) immunostaining, suggestive of a schwannoma arising in neurofibromatosis type 2 or schwannomatosis.
Epithelioid schwannoma. Multilobular growth pattern at low magnification.
Epithelioid schwannoma. Loss of SMARCB1 expression, which occurs in 40% of cases.
Schwannoma. T1-weighted MRI showing the characteristic dumbbell shape of a spinal root schwannoma.

Q: In cases of syndrome-associated schwannoma (e.g., neurofibromatosis type 2), immunostaining characteristically demonstrates a mosaic pattern of [...] (INI1) expression.
Syndrome-associated schwannoma. Mosaic pattern of SMARCB1 (INI1) immunostaining, suggestive of a schwannoma arising in neurofibromatosis type 2 or schwannomatosis.
A: SMARCB1
Back Extra: Schwannoma
- Clinical: Benign, slow-growing masses often involving peripheral nerves or the vestibular nerve; bilateral vestibular involvement is diagnostic of neurofibromatosis type 2 (NF2).
- Microscopic: Biphasic architecture comprising compact, hypercellular Antoni A areas (often with Verocay bodies) and loose, hypocellular Antoni B areas with hyalinized vessels.
- Ancillary: Shows strong and diffuse nuclear/cytoplasmic staining for S100 and SOX10; mosaic SMARCB1 (INI1) loss is common in syndromic cases.
- Genetics: Primarily driven by inactivation of the NF2 gene (22q12.2), leading to loss of the protein merlin.
Reference Gallery:
Schwannoma. Cut surface showing a globoid encapsulated tan-grey tumour with areas of xanthic change (yellow) and attached nerve.
Conventional schwannoma. Compact Antoni A tissue (left) adjacent to loose Antoni B tissue (right).
Conventional schwannoma. Nuclear palisades, known as Verocay bodies, are a typical feature of schwannoma in Antoni A areas.
Ancient schwannoma. Scattered bizarre, atypical nuclei are often considered to represent a degenerative change that does not impact prognosis.
Cellular schwannoma. Marked hypercellularity and compact arrangement, which may prompt the consideration of sarcoma in the differential diagnosis.
Cellular schwannoma. Diffuse S100 positivity helps distinguish the cellular schwannoma subtype from malignant peripheral nerve sheath tumour.
Syndrome-associated schwannoma. Mosaic pattern of SMARCB1 (INI1) immunostaining, suggestive of a schwannoma arising in neurofibromatosis type 2 or schwannomatosis.
Epithelioid schwannoma. Multilobular growth pattern at low magnification.
Epithelioid schwannoma. Loss of SMARCB1 expression, which occurs in 40% of cases.
Schwannoma. T1-weighted MRI showing the characteristic dumbbell shape of a spinal root schwannoma.

Q: When screening for SDH-complex mutations in Familial paraganglioma syndromes, immunohistochemistry will characteristically demonstrate the loss of [...] within the tumor cells, with retained granular staining in the stromal endothelial cells.
SDH-deficient paraganglioma showing complete loss of SDHB immunostaining in tumor cells with granular cytoplasmic staining retained in endothelial (stromal) cells.
SDH-related paraganglioma with abundant granular eosinophilic cytoplasm.
A: SDHB
Q: Familial paraganglioma syndromes
- Clinical: Approximately 30–40% of paragangliomas are hereditary, characterized by germline mutations (e.g., SDHB, SDHD, VHL, FH) and often present as multifocal or asynchronous tumors.
- Micro: Classic architecture consists of well-formed, nested patterns known as "[...]"; SDH-related cases often show eosinophilic vacuolated cytoplasm, while VHL-related cases often show clear cytoplasm and stromal edema.
- Ancillary: Screening for familial disease involves IHC for loss of [...] (indicates SDH-complex mutations) or loss of FH; VHL-related tumors are typically positive for CAIX and inhibin.
- Markers: Tumors are positive for neuroendocrine markers (INSM1, synaptophysin, chromogranin) and tyrosine hydroxylase; S100 highlights peripheral sustentacular cells.
Reference Gallery:
Paragangliomas in familial paraganglioma syndrome. Multiple para-aortic and pelvic paragangliomas are identified with 68Ga-DOTATATE PET-CT in a patient with a pathogenic germline SDHB mutation.
Biochemical and genetic clusters of familial paraganglioma syndromes.
SDH-deficient paraganglioma showing complete loss of SDHB immunostaining in tumor cells with granular cytoplasmic staining retained in endothelial (stromal) cells.
SDH-related paraganglioma with abundant granular eosinophilic cytoplasm.
Von Hippel–Lindau syndrome (VHL)-related paraganglioma frequently demonstrating cells with abundant clear cytoplasm (top) and stromal oedema (bottom).
Fumarate hydratase–deficient phaeochromocytoma showing loss of FH reactivity in the cytoplasm.
SDH-related paraganglioma expressing cytoplasmic tyrosine hydroxylase.
Inhibin expression in a paraganglioma associated with a pseudohypoxia pathway alteration.
High power view of VHL-related tumor showing abundant clear cytoplasm.
High power view of VHL-related tumor highlighting prominent stromal oedema.
H&E of a fumarate hydratase–deficient phaeochromocytoma; these often lack specific diagnostic morphological features.
Intact staining for 2-succinocysteine in a fumarate hydratase–deficient phaeochromocytoma.
A: Zellballen; SDHB

Q: In VHL-associated Familial paraganglioma syndromes, tumors classically exhibit prominent stromal edema and abundant clear cytoplasm, and they will typically stain positive for [...] by immunohistochemistry.
Inhibin expression in a paraganglioma associated with a pseudohypoxia pathway alteration.
High power view of VHL-related tumor showing abundant clear cytoplasm.
High power view of VHL-related tumor highlighting prominent stromal oedema.
A: inhibin
Q: Familial paraganglioma syndromes
- Clinical: Approximately 30–40% of paragangliomas are hereditary, characterized by germline mutations (e.g., SDHB, SDHD, VHL, FH) and often present as multifocal or asynchronous tumors.
- Micro: Classic architecture consists of well-formed, nested patterns known as "[...]"; SDH-related cases often show eosinophilic vacuolated cytoplasm, while VHL-related cases often show clear cytoplasm and stromal edema.
- Ancillary: Screening for familial disease involves IHC for loss of [...] (indicates SDH-complex mutations) or loss of FH; VHL-related tumors are typically positive for CAIX and inhibin.
- Markers: Tumors are positive for neuroendocrine markers (INSM1, synaptophysin, chromogranin) and tyrosine hydroxylase; S100 highlights peripheral sustentacular cells.
Reference Gallery:
Paragangliomas in familial paraganglioma syndrome. Multiple para-aortic and pelvic paragangliomas are identified with 68Ga-DOTATATE PET-CT in a patient with a pathogenic germline SDHB mutation.
Biochemical and genetic clusters of familial paraganglioma syndromes.
SDH-deficient paraganglioma showing complete loss of SDHB immunostaining in tumor cells with granular cytoplasmic staining retained in endothelial (stromal) cells.
SDH-related paraganglioma with abundant granular eosinophilic cytoplasm.
Von Hippel–Lindau syndrome (VHL)-related paraganglioma frequently demonstrating cells with abundant clear cytoplasm (top) and stromal oedema (bottom).
Fumarate hydratase–deficient phaeochromocytoma showing loss of FH reactivity in the cytoplasm.
SDH-related paraganglioma expressing cytoplasmic tyrosine hydroxylase.
Inhibin expression in a paraganglioma associated with a pseudohypoxia pathway alteration.
High power view of VHL-related tumor showing abundant clear cytoplasm.
High power view of VHL-related tumor highlighting prominent stromal oedema.
H&E of a fumarate hydratase–deficient phaeochromocytoma; these often lack specific diagnostic morphological features.
Intact staining for 2-succinocysteine in a fumarate hydratase–deficient phaeochromocytoma.
A: Zellballen; SDHB

Q: Regardless of the specific germline mutation in Familial paraganglioma syndromes, the classic microscopic architecture consists of well-formed, nested patterns of neuroendocrine cells known as "[...]".
SDH-related paraganglioma with abundant granular eosinophilic cytoplasm.
Von Hippel–Lindau syndrome (VHL)-related paraganglioma frequently demonstrating cells with abundant clear cytoplasm (top) and stromal oedema (bottom).
A: Zellballen
Q: Familial paraganglioma syndromes
- Clinical: Approximately 30–40% of paragangliomas are hereditary, characterized by germline mutations (e.g., SDHB, SDHD, VHL, FH) and often present as multifocal or asynchronous tumors.
- Micro: Classic architecture consists of well-formed, nested patterns known as "[...]"; SDH-related cases often show eosinophilic vacuolated cytoplasm, while VHL-related cases often show clear cytoplasm and stromal edema.
- Ancillary: Screening for familial disease involves IHC for loss of [...] (indicates SDH-complex mutations) or loss of FH; VHL-related tumors are typically positive for CAIX and inhibin.
- Markers: Tumors are positive for neuroendocrine markers (INSM1, synaptophysin, chromogranin) and tyrosine hydroxylase; S100 highlights peripheral sustentacular cells.
Reference Gallery:
Paragangliomas in familial paraganglioma syndrome. Multiple para-aortic and pelvic paragangliomas are identified with 68Ga-DOTATATE PET-CT in a patient with a pathogenic germline SDHB mutation.
Biochemical and genetic clusters of familial paraganglioma syndromes.
SDH-deficient paraganglioma showing complete loss of SDHB immunostaining in tumor cells with granular cytoplasmic staining retained in endothelial (stromal) cells.
SDH-related paraganglioma with abundant granular eosinophilic cytoplasm.
Von Hippel–Lindau syndrome (VHL)-related paraganglioma frequently demonstrating cells with abundant clear cytoplasm (top) and stromal oedema (bottom).
Fumarate hydratase–deficient phaeochromocytoma showing loss of FH reactivity in the cytoplasm.
SDH-related paraganglioma expressing cytoplasmic tyrosine hydroxylase.
Inhibin expression in a paraganglioma associated with a pseudohypoxia pathway alteration.
High power view of VHL-related tumor showing abundant clear cytoplasm.
High power view of VHL-related tumor highlighting prominent stromal oedema.
H&E of a fumarate hydratase–deficient phaeochromocytoma; these often lack specific diagnostic morphological features.
Intact staining for 2-succinocysteine in a fumarate hydratase–deficient phaeochromocytoma.
A: Zellballen; SDHB

Q: In a conventional Chordoma, the hallmark microscopic finding is the presence of bubbly, vacuolated cells known as [...] cells.
Conventional chordoma. This shows a lobular architecture and abundant myxoid matrix.
Conventional chordoma. Nests and cords of cells, sometimes with vacuolated bubbly cytoplasm (physaliphorous cells).
A: physaliphorous
Back Extra: Chordoma
- Clinical: Malignant midline bone neoplasms (notochordal origin) presenting as destructive, lobular lesions; hyperintense on T2 MRI.
- Microscopic: Conventional types feature a lobular architecture with cords of cells in a myxoid matrix, including hallmark bubbly "physaliphorous cells".
- Ancillary: Nuclear expression of Brachyury is highly specific; poorly differentiated chordomas are defined by the loss of SMARCB1 (INI1).
- Genetics: Often associated with duplications or mutations of the TBXT (brachyury) gene.
- Prognosis: Poorly differentiated and dedifferentiated subtypes carry a significantly worse prognosis than conventional or chondroid types.
Reference Gallery:
Conventional chordoma. This shows a lobular architecture and abundant myxoid matrix.
Conventional chordoma. Nests and cords of cells, sometimes with vacuolated bubbly cytoplasm (physaliphorous cells).
Conventional chordoma. Diffuse nuclear expression of brachyury.
Poorly differentiated chordoma. Spindle or epithelioid cells with little myxoid matrix.
Poorly differentiated chordoma. The chordoma cells express nuclear brachyury.
Poorly differentiated chordoma. Loss of SMARCB1 (INI1) expression is essential for this diagnosis.
Poorly differentiated chordoma. T2-weighted axial MRI showing a large enhancing tumour arising in the skull base.

Q: The highly specific immunohistochemical marker characterized by diffuse nuclear expression in a Chordoma is [...].
Conventional chordoma. Nests and cords of cells, sometimes with vacuolated bubbly cytoplasm (physaliphorous cells).
Conventional chordoma. Diffuse nuclear expression of brachyury.
A: brachyury
Back Extra: Chordoma
- Clinical: Malignant midline bone neoplasms (notochordal origin) presenting as destructive, lobular lesions; hyperintense on T2 MRI.
- Microscopic: Conventional types feature a lobular architecture with cords of cells in a myxoid matrix, including hallmark bubbly "physaliphorous cells".
- Ancillary: Nuclear expression of Brachyury is highly specific; poorly differentiated chordomas are defined by the loss of SMARCB1 (INI1).
- Genetics: Often associated with duplications or mutations of the TBXT (brachyury) gene.
- Prognosis: Poorly differentiated and dedifferentiated subtypes carry a significantly worse prognosis than conventional or chondroid types.
Reference Gallery:
Conventional chordoma. This shows a lobular architecture and abundant myxoid matrix.
Conventional chordoma. Nests and cords of cells, sometimes with vacuolated bubbly cytoplasm (physaliphorous cells).
Conventional chordoma. Diffuse nuclear expression of brachyury.
Poorly differentiated chordoma. Spindle or epithelioid cells with little myxoid matrix.
Poorly differentiated chordoma. The chordoma cells express nuclear brachyury.
Poorly differentiated chordoma. Loss of SMARCB1 (INI1) expression is essential for this diagnosis.
Poorly differentiated chordoma. T2-weighted axial MRI showing a large enhancing tumour arising in the skull base.

Q: A poorly differentiated Chordoma is diagnostically defined by the loss of expression of the immunohistochemical marker [...].
Poorly differentiated chordoma. Spindle or epithelioid cells with little myxoid matrix.
Poorly differentiated chordoma. Loss of SMARCB1 (INI1) expression is essential for this diagnosis.
A: SMARCB1 (INI1)
Back Extra: Chordoma
- Clinical: Malignant midline bone neoplasms (notochordal origin) presenting as destructive, lobular lesions; hyperintense on T2 MRI.
- Microscopic: Conventional types feature a lobular architecture with cords of cells in a myxoid matrix, including hallmark bubbly "physaliphorous cells".
- Ancillary: Nuclear expression of Brachyury is highly specific; poorly differentiated chordomas are defined by the loss of SMARCB1 (INI1).
- Genetics: Often associated with duplications or mutations of the TBXT (brachyury) gene.
- Prognosis: Poorly differentiated and dedifferentiated subtypes carry a significantly worse prognosis than conventional or chondroid types.
Reference Gallery:
Conventional chordoma. This shows a lobular architecture and abundant myxoid matrix.
Conventional chordoma. Nests and cords of cells, sometimes with vacuolated bubbly cytoplasm (physaliphorous cells).
Conventional chordoma. Diffuse nuclear expression of brachyury.
Poorly differentiated chordoma. Spindle or epithelioid cells with little myxoid matrix.
Poorly differentiated chordoma. The chordoma cells express nuclear brachyury.
Poorly differentiated chordoma. Loss of SMARCB1 (INI1) expression is essential for this diagnosis.
Poorly differentiated chordoma. T2-weighted axial MRI showing a large enhancing tumour arising in the skull base.

Q: The immunohistochemical hallmark of Diffuse midline glioma, H3 K27–altered is the global loss of nuclear expression for [...] (also known as H3 p.K28me3), which can be seen with retained expression in background endothelial cells.
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
Immunohistochemical staining for H3 p.K28me3 (K27me3) shows loss of expression in tumour cells, with retention in endothelial cells.
A: H3 K27me3
Back Extra: Diffuse midline glioma, H3 K27–altered
- Definition: An infiltrative midline glioma (pons, thalamus, or spinal cord) characterized by the loss of H3 p.K28me3 (K27me3) and an H3 K27 mutation, EZHIP overexpression, or EGFR mutation.
- Clinical: Presents in children as Diffuse Intrinsic Pontine Glioma (DIPG) with cranial nerve palsies and ataxia; adults more commonly present with unilateral thalamic or spinal cord lesions.
- Microscopic: Diffusely infiltrative growth; cytology is variable (astrocytic, oligodendroglial, or pleomorphic). It is classified as CNS WHO grade 4 even in the absence of brisk mitoses, necrosis, or microvascular proliferation.
- Ancillary (IHC): Hallmark is global loss of H3 K27me3 nuclear expression. Diagnosis is often supported by nuclear positivity for H3 K27M-mutant protein or EZHIP overexpression.
- Molecular: Mutations typically involve H3.3 (H3F3A) or H3.1 (HIST1H3B/C); EGFR exon 20 insertions are characteristic of the bithalamic subtype.
Reference Gallery:
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
Immunohistochemical staining for H3 p.K28me3 (K27me3) shows loss of expression in tumour cells, with retention in endothelial cells.
Intense nuclear staining for H3 p.K28 (K27)-mutant protein.
Neurofilament stain highlighting the diffusely infiltrative growth pattern typical of this entity.
Axial FLAIR MRI of a bithalamic EGFR-mutant glioma, a subtype of H3 K27-altered diffuse midline glioma.
Loss of H3 p.K28me3 (K27me3) in an EGFR-mutant bithalamic glioma that is H3-wildtype.
Intense nuclear staining for EZHIP in an H3-wildtype diffuse midline glioma (a molecular mimic).
Axial MRI showing a T2-bright lesion expanding the pons and encasing the basilar artery (DIPG pattern).
Axial MRI of a unithalamic T2-bright lesion with associated obstructive hydrocephalus.
Sagittal postgadolinium T1 sequence showing an intramedullary spinal cord tumour with heterogeneous enhancement.
Negativity for EZHIP immunostaining in an H3 K27-mutant case.
Histology of a bithalamic EGFR-mutant glioma demonstrating a diffuse astrocytic morphology.

Q: Regardless of the absence of traditional high-grade microscopic features such as brisk mitoses, necrosis, or microvascular proliferation, Diffuse midline glioma, H3 K27–altered is by definition always classified as [...].
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
A: CNS WHO grade 4
Back Extra: Diffuse midline glioma, H3 K27–altered
- Definition: An infiltrative midline glioma (pons, thalamus, or spinal cord) characterized by the loss of H3 p.K28me3 (K27me3) and an H3 K27 mutation, EZHIP overexpression, or EGFR mutation.
- Clinical: Presents in children as Diffuse Intrinsic Pontine Glioma (DIPG) with cranial nerve palsies and ataxia; adults more commonly present with unilateral thalamic or spinal cord lesions.
- Microscopic: Diffusely infiltrative growth; cytology is variable (astrocytic, oligodendroglial, or pleomorphic). It is classified as CNS WHO grade 4 even in the absence of brisk mitoses, necrosis, or microvascular proliferation.
- Ancillary (IHC): Hallmark is global loss of H3 K27me3 nuclear expression. Diagnosis is often supported by nuclear positivity for H3 K27M-mutant protein or EZHIP overexpression.
- Molecular: Mutations typically involve H3.3 (H3F3A) or H3.1 (HIST1H3B/C); EGFR exon 20 insertions are characteristic of the bithalamic subtype.
Reference Gallery:
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
Immunohistochemical staining for H3 p.K28me3 (K27me3) shows loss of expression in tumour cells, with retention in endothelial cells.
Intense nuclear staining for H3 p.K28 (K27)-mutant protein.
Neurofilament stain highlighting the diffusely infiltrative growth pattern typical of this entity.
Axial FLAIR MRI of a bithalamic EGFR-mutant glioma, a subtype of H3 K27-altered diffuse midline glioma.
Loss of H3 p.K28me3 (K27me3) in an EGFR-mutant bithalamic glioma that is H3-wildtype.
Intense nuclear staining for EZHIP in an H3-wildtype diffuse midline glioma (a molecular mimic).
Axial MRI showing a T2-bright lesion expanding the pons and encasing the basilar artery (DIPG pattern).
Axial MRI of a unithalamic T2-bright lesion with associated obstructive hydrocephalus.
Sagittal postgadolinium T1 sequence showing an intramedullary spinal cord tumour with heterogeneous enhancement.
Negativity for EZHIP immunostaining in an H3 K27-mutant case.
Histology of a bithalamic EGFR-mutant glioma demonstrating a diffuse astrocytic morphology.

Q: In children, Diffuse midline glioma, H3 K27–altered frequently involves the pons, presenting with cranial nerve palsies and ataxia, a classic clinico-radiologic presentation historically referred to as [...].
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
Axial MRI showing a T2-bright lesion expanding the pons and encasing the basilar artery (DIPG pattern).
A: Diffuse Intrinsic Pontine Glioma (DIPG)
Back Extra: Diffuse midline glioma, H3 K27–altered
- Definition: An infiltrative midline glioma (pons, thalamus, or spinal cord) characterized by the loss of H3 p.K28me3 (K27me3) and an H3 K27 mutation, EZHIP overexpression, or EGFR mutation.
- Clinical: Presents in children as Diffuse Intrinsic Pontine Glioma (DIPG) with cranial nerve palsies and ataxia; adults more commonly present with unilateral thalamic or spinal cord lesions.
- Microscopic: Diffusely infiltrative growth; cytology is variable (astrocytic, oligodendroglial, or pleomorphic). It is classified as CNS WHO grade 4 even in the absence of brisk mitoses, necrosis, or microvascular proliferation.
- Ancillary (IHC): Hallmark is global loss of H3 K27me3 nuclear expression. Diagnosis is often supported by nuclear positivity for H3 K27M-mutant protein or EZHIP overexpression.
- Molecular: Mutations typically involve H3.3 (H3F3A) or H3.1 (HIST1H3B/C); EGFR exon 20 insertions are characteristic of the bithalamic subtype.
Reference Gallery:
Diffuse midline glioma, H3 K27–altered: Pontine glioma showing infiltrative neoplastic cells in an oedematous background with residual neurons.
Immunohistochemical staining for H3 p.K28me3 (K27me3) shows loss of expression in tumour cells, with retention in endothelial cells.
Intense nuclear staining for H3 p.K28 (K27)-mutant protein.
Neurofilament stain highlighting the diffusely infiltrative growth pattern typical of this entity.
Axial FLAIR MRI of a bithalamic EGFR-mutant glioma, a subtype of H3 K27-altered diffuse midline glioma.
Loss of H3 p.K28me3 (K27me3) in an EGFR-mutant bithalamic glioma that is H3-wildtype.
Intense nuclear staining for EZHIP in an H3-wildtype diffuse midline glioma (a molecular mimic).
Axial MRI showing a T2-bright lesion expanding the pons and encasing the basilar artery (DIPG pattern).
Axial MRI of a unithalamic T2-bright lesion with associated obstructive hydrocephalus.
Sagittal postgadolinium T1 sequence showing an intramedullary spinal cord tumour with heterogeneous enhancement.
Negativity for EZHIP immunostaining in an H3 K27-mutant case.
Histology of a bithalamic EGFR-mutant glioma demonstrating a diffuse astrocytic morphology.

Q: A neoplasm characterized by cords of small to medium-sized epithelioid and spindled cells embedded in a loose, pale basophilic myxoid and heavily collagenized matrix is diagnostic of [...].
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Tumour cells embedded in loose, pale basophilic myxoid matrix with dispersed heavily collagenized material.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Small to medium-sized oval to spindled and epithelioid cells.
A: desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant
Back Extra: Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant
- Clinical: The clinical features are similar to those of pineal parenchymal tumours. All reported cases to date were localized in the pineal region. The median patient age is 40 years (range: 15–61 years), with a balanced sex distr…
- Micro: The tumour is characterized by an admixture of variably dense cords of small to medium-sized oval to spindled and epithelioid cells. These cells are embedded in a heavily collagenized matrix and a loose pale basophilic m…
- Cyto: Insufficient data available.
- Ancillary: 1) Immunohistochemistry (IHC): - SMARCB1 (INI1): Mandatory loss of nuclear expression in tumour cells (non-neoplastic cells serve as internal positive controls). - CD34: Often expressed. - EMA: Often expr…
Reference Gallery:
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Tumour cells embedded in loose, pale basophilic myxoid matrix with dispersed heavily collagenized material.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Small to medium-sized oval to spindled and epithelioid cells.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Note loss of nuclear SMARCB1 staining in the tumour cells but not the non-neoplastic cells.

Q: In desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant, immunohistochemistry characteristically demonstrates a mandatory loss of nuclear expression for [...] in the neoplastic cells.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Small to medium-sized oval to spindled and epithelioid cells.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Note loss of nuclear SMARCB1 staining in the tumour cells but not the non-neoplastic cells.
A: SMARCB1 (INI1)
Back Extra: Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant
- Clinical: The clinical features are similar to those of pineal parenchymal tumours. All reported cases to date were localized in the pineal region. The median patient age is 40 years (range: 15–61 years), with a balanced sex distr…
- Micro: The tumour is characterized by an admixture of variably dense cords of small to medium-sized oval to spindled and epithelioid cells. These cells are embedded in a heavily collagenized matrix and a loose pale basophilic m…
- Cyto: Insufficient data available.
- Ancillary: 1) Immunohistochemistry (IHC): - SMARCB1 (INI1): Mandatory loss of nuclear expression in tumour cells (non-neoplastic cells serve as internal positive controls). - CD34: Often expressed. - EMA: Often expr…
Reference Gallery:
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Tumour cells embedded in loose, pale basophilic myxoid matrix with dispersed heavily collagenized material.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Small to medium-sized oval to spindled and epithelioid cells.
Desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant. Note loss of nuclear SMARCB1 staining in the tumour cells but not the non-neoplastic cells.

Q: Histologically, Papillary tumor of the pineal region is characterized by papillae covered by large columnar cells; the neoplastic cells often detach from the vascular core to create characteristic [...].
Papillary tumour of the pineal region. Papillae are covered by large, columnar, epithelial-like cells.
Papillary tumour of the pineal region. Neoplastic cells, detached from the papillary vascularized core, create an apparent clear perivascular space. Note the extensive necrosis in this case.
A: clear perivascular spaces
Back Extra: Papillary tumour of the pineal region
- Clinical: A CNS WHO grade 2 or 3 neuroepithelial tumor presenting in both children and adults (median age 35) as a heterogeneous mass in the pineal region, often causing hydrocephalus.
- Microscopic: Characterized by papillary structures and solid areas; large columnar, epithelial-like cells cover hyalinized vessels. Features may include 'clear perivascular spaces' and ependymal-like rosettes.
- Ancillary: Typically positive for CK18, SPDEF (diagnostic marker), and vimentin; notably negative for Kir7.1 and E-cadherin (helps differentiate from choroid plexus tumors).
- Genetics & Prognosis: Frequently demonstrates losses of chromosome 10 and PTEN alterations; clinical course is often marked by high local recurrence rates (up to 72%).
Reference Gallery:
Papillary tumour of the pineal region. Papillae are covered by large, columnar, epithelial-like cells.
Papillary tumour of the pineal region. Immunoexpression for CK18 typically predominates in perivascular areas.
Papillary tumour of the pineal region. Neoplastic cells, detached from the papillary vascularized core, create an apparent clear perivascular space. Note the extensive necrosis in this case.
Papillary tumour of the pineal region. Sagittal, contrast-enhanced, T1-weighted MRI showing a heterogeneously enhancing tumour of the pineal region.

Q: In terms of immunohistochemistry, Papillary tumor of the pineal region characteristically shows strong expression of [...], which typically predominates in the perivascular areas.
Papillary tumour of the pineal region. Papillae are covered by large, columnar, epithelial-like cells.
Papillary tumour of the pineal region. Immunoexpression for CK18 typically predominates in perivascular areas.
A: CK18
Back Extra: Papillary tumour of the pineal region
- Clinical: A CNS WHO grade 2 or 3 neuroepithelial tumor presenting in both children and adults (median age 35) as a heterogeneous mass in the pineal region, often causing hydrocephalus.
- Microscopic: Characterized by papillary structures and solid areas; large columnar, epithelial-like cells cover hyalinized vessels. Features may include 'clear perivascular spaces' and ependymal-like rosettes.
- Ancillary: Typically positive for CK18, SPDEF (diagnostic marker), and vimentin; notably negative for Kir7.1 and E-cadherin (helps differentiate from choroid plexus tumors).
- Genetics & Prognosis: Frequently demonstrates losses of chromosome 10 and PTEN alterations; clinical course is often marked by high local recurrence rates (up to 72%).
Reference Gallery:
Papillary tumour of the pineal region. Papillae are covered by large, columnar, epithelial-like cells.
Papillary tumour of the pineal region. Immunoexpression for CK18 typically predominates in perivascular areas.
Papillary tumour of the pineal region. Neoplastic cells, detached from the papillary vascularized core, create an apparent clear perivascular space. Note the extensive necrosis in this case.
Papillary tumour of the pineal region. Sagittal, contrast-enhanced, T1-weighted MRI showing a heterogeneously enhancing tumour of the pineal region.

Q: A highly characteristic molecular finding in many cases of Pineal parenchymal tumor of intermediate differentiation is the presence of recurrent small in-frame insertions in the [...] gene.
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Diffuse sheets of monomorphic round cells.
A: KBTBD4
Q: Pineal parenchymal tumour of intermediate differentiation
- Clinical: Intermediate malignancy tumor (CNS WHO grade 2 or 3) occurring at a median age of 33 years; has potential for local recurrence and craniospinal dissemination.
- Microscopic: Characterized by diffuse or lobulated sheets of monomorphic round cells with "salt-and-pepper" chromatin and more discernible cytoplasm than pineoblastoma.
- Ancillary (IHC): Demonstrates diffuse synaptophysin positivity and diffuse nuclear expression of [...], which confirms pineal/retinal lineage.
- Molecular: Highly characteristic recurrent small in-frame insertions in the [...] gene are found in many cases.
- Differential: Distinguished from central neurocytoma by location and [...] negativity (PPTID is typically negative).
Reference Gallery:
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
Pineal parenchymal tumour of intermediate differentiation. A few neoplastic cells show cytoplasmic immunoexpression of NFP.
Pineal parenchymal tumour of intermediate differentiation. In this example, the Ki-67 proliferation index is about 15%.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Diffuse sheets of monomorphic round cells.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Strong and diffuse synaptophysin immunopositivity.
Pineal parenchymal tumour of intermediate differentiation. Diffuse nuclear immunoexpression of CRX, consistent with pineal differentiation.
Pineal parenchymal tumour of intermediate differentiation. A tumour located in the pineal region shows mild and heterogeneous contrast enhancement with invasion of the tectal plate and compression of the aqueduct of Sylvius (T1 gadolinium).
A: CRX; KBTBD4; NeuN

Q: To confirm pineal or retinal lineage, Pineal parenchymal tumor of intermediate differentiation classically demonstrates diffuse nuclear immunohistochemical expression of [...].
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
Pineal parenchymal tumour of intermediate differentiation. Diffuse nuclear immunoexpression of CRX, consistent with pineal differentiation.
A: CRX
Q: Pineal parenchymal tumour of intermediate differentiation
- Clinical: Intermediate malignancy tumor (CNS WHO grade 2 or 3) occurring at a median age of 33 years; has potential for local recurrence and craniospinal dissemination.
- Microscopic: Characterized by diffuse or lobulated sheets of monomorphic round cells with "salt-and-pepper" chromatin and more discernible cytoplasm than pineoblastoma.
- Ancillary (IHC): Demonstrates diffuse synaptophysin positivity and diffuse nuclear expression of [...], which confirms pineal/retinal lineage.
- Molecular: Highly characteristic recurrent small in-frame insertions in the [...] gene are found in many cases.
- Differential: Distinguished from central neurocytoma by location and [...] negativity (PPTID is typically negative).
Reference Gallery:
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
Pineal parenchymal tumour of intermediate differentiation. A few neoplastic cells show cytoplasmic immunoexpression of NFP.
Pineal parenchymal tumour of intermediate differentiation. In this example, the Ki-67 proliferation index is about 15%.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Diffuse sheets of monomorphic round cells.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Strong and diffuse synaptophysin immunopositivity.
Pineal parenchymal tumour of intermediate differentiation. Diffuse nuclear immunoexpression of CRX, consistent with pineal differentiation.
Pineal parenchymal tumour of intermediate differentiation. A tumour located in the pineal region shows mild and heterogeneous contrast enhancement with invasion of the tectal plate and compression of the aqueduct of Sylvius (T1 gadolinium).
A: CRX; KBTBD4; NeuN

Q: Pineal parenchymal tumor of intermediate differentiation consists of monomorphic round cells that demonstrate strong and diffuse immunohistochemical positivity for the synaptic vesicle marker [...].
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Strong and diffuse synaptophysin immunopositivity.
A: synaptophysin
Q: Pineal parenchymal tumour of intermediate differentiation
- Clinical: Intermediate malignancy tumor (CNS WHO grade 2 or 3) occurring at a median age of 33 years; has potential for local recurrence and craniospinal dissemination.
- Microscopic: Characterized by diffuse or lobulated sheets of monomorphic round cells with "salt-and-pepper" chromatin and more discernible cytoplasm than pineoblastoma.
- Ancillary (IHC): Demonstrates diffuse synaptophysin positivity and diffuse nuclear expression of [...], which confirms pineal/retinal lineage.
- Molecular: Highly characteristic recurrent small in-frame insertions in the [...] gene are found in many cases.
- Differential: Distinguished from central neurocytoma by location and [...] negativity (PPTID is typically negative).
Reference Gallery:
Pineal parenchymal tumour of intermediate differentiation. Tumour cells are round and relatively monomorphic, with a conspicuous cytoplasm. Nuclei are round to oval with a finely dispersed chromatin and a small nucleolus.
Pineal parenchymal tumour of intermediate differentiation. A few neoplastic cells show cytoplasmic immunoexpression of NFP.
Pineal parenchymal tumour of intermediate differentiation. In this example, the Ki-67 proliferation index is about 15%.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Diffuse sheets of monomorphic round cells.
KBTBD4-mutant pineal parenchymal tumour of intermediate differentiation. Strong and diffuse synaptophysin immunopositivity.
Pineal parenchymal tumour of intermediate differentiation. Diffuse nuclear immunoexpression of CRX, consistent with pineal differentiation.
Pineal parenchymal tumour of intermediate differentiation. A tumour located in the pineal region shows mild and heterogeneous contrast enhancement with invasion of the tectal plate and compression of the aqueduct of Sylvius (T1 gadolinium).
A: CRX; KBTBD4; NeuN

Q: Pineoblastoma is a highly cellular embryonal tumor characterized microscopically by patternless sheets of densely packed [...] with irregular, hyperchromatic nuclei, a high N:C ratio, and frequent mitoses.
Pineoblastoma. This is a highly cellular tumour composed of small cells with a high N:C ratio; atypical, angular, hyperchromatic nuclei; and frequent mitoses and apoptotic bodies.
Pineoblastoma. These tumours frequently show areas of necrosis.
A: small round blue cells
Back Extra: Pineoblastoma
- Clinical: Pineoblastomas mostly occur in children (median age 6 years) but can arise at any age. Clinical presentation is typical of pineal region masses, including obstructive hydrocephalus. It is associated with genetic suscepti…
- Micro: The tumor is composed of highly cellular, patternless sheets of densely packed small round blue cells. Cytology shows irregular nuclear shapes, a high N:C ratio, hyperchromatic nuclei, and scant cytoplasm with indistinct…
- Cyto: CSF Cytology: Utilized for staging. Dissemination is characterized by clusters of poorly differentiated cells with round, hyperchromatic nuclei and scant cytoplasm.
- Ancillary: Immunohistochemistry (IHC): - Positive: Synaptophysin (often diffuse or paranuclear dot-like), NSE, and diffuse nuclear expression of CRX (>50% of cells). - Retained: SMARCB1 (INI1) and SMARCA4 (BRG1) (distinguishes…
Reference Gallery:
Pineoblastoma. This is a highly cellular tumour composed of small cells with a high N:C ratio; atypical, angular, hyperchromatic nuclei; and frequent mitoses and apoptotic bodies.
Pineoblastoma. These tumours frequently show areas of necrosis.
Pineoblastoma. There is diffuse expression of synaptophysin with paranuclear dot–like reactivity.
Pineal anlage tumour. Striated muscle cells.
Pineal anlage tumour. Tubular structures composed of epithelioid cells containing melanin pigment.
Pineoblastoma. A tumour located in the pineal region appears mildly hypointense on T2-weighted MRI.
Pineoblastoma. This patient has obstructive triventricular hydrocephalus (T2-weighted MRI).

Q: In Pineoblastoma, immunohistochemistry typically shows diffuse positivity for [...], often exhibiting characteristic paranuclear dot-like reactivity.
Pineoblastoma. There is diffuse expression of synaptophysin with paranuclear dot–like reactivity.
A: synaptophysin
Back Extra: Pineoblastoma
- Clinical: Pineoblastomas mostly occur in children (median age 6 years) but can arise at any age. Clinical presentation is typical of pineal region masses, including obstructive hydrocephalus. It is associated with genetic suscepti…
- Micro: The tumor is composed of highly cellular, patternless sheets of densely packed small round blue cells. Cytology shows irregular nuclear shapes, a high N:C ratio, hyperchromatic nuclei, and scant cytoplasm with indistinct…
- Cyto: CSF Cytology: Utilized for staging. Dissemination is characterized by clusters of poorly differentiated cells with round, hyperchromatic nuclei and scant cytoplasm.
- Ancillary: Immunohistochemistry (IHC): - Positive: Synaptophysin (often diffuse or paranuclear dot-like), NSE, and diffuse nuclear expression of CRX (>50% of cells). - Retained: SMARCB1 (INI1) and SMARCA4 (BRG1) (distinguishes…
Reference Gallery:
Pineoblastoma. This is a highly cellular tumour composed of small cells with a high N:C ratio; atypical, angular, hyperchromatic nuclei; and frequent mitoses and apoptotic bodies.
Pineoblastoma. These tumours frequently show areas of necrosis.
Pineoblastoma. There is diffuse expression of synaptophysin with paranuclear dot–like reactivity.
Pineal anlage tumour. Striated muscle cells.
Pineal anlage tumour. Tubular structures composed of epithelioid cells containing melanin pigment.
Pineoblastoma. A tumour located in the pineal region appears mildly hypointense on T2-weighted MRI.
Pineoblastoma. This patient has obstructive triventricular hydrocephalus (T2-weighted MRI).

Q: On T2-weighted MRI, Pineoblastoma typically presents as a mildly hypointense pineal region mass that frequently causes [...].
Pineoblastoma. A tumour located in the pineal region appears mildly hypointense on T2-weighted MRI.
Pineoblastoma. This patient has obstructive triventricular hydrocephalus (T2-weighted MRI).
A: obstructive hydrocephalus
Back Extra: Pineoblastoma
- Clinical: Pineoblastomas mostly occur in children (median age 6 years) but can arise at any age. Clinical presentation is typical of pineal region masses, including obstructive hydrocephalus. It is associated with genetic suscepti…
- Micro: The tumor is composed of highly cellular, patternless sheets of densely packed small round blue cells. Cytology shows irregular nuclear shapes, a high N:C ratio, hyperchromatic nuclei, and scant cytoplasm with indistinct…
- Cyto: CSF Cytology: Utilized for staging. Dissemination is characterized by clusters of poorly differentiated cells with round, hyperchromatic nuclei and scant cytoplasm.
- Ancillary: Immunohistochemistry (IHC): - Positive: Synaptophysin (often diffuse or paranuclear dot-like), NSE, and diffuse nuclear expression of CRX (>50% of cells). - Retained: SMARCB1 (INI1) and SMARCA4 (BRG1) (distinguishes…
Reference Gallery:
Pineoblastoma. This is a highly cellular tumour composed of small cells with a high N:C ratio; atypical, angular, hyperchromatic nuclei; and frequent mitoses and apoptotic bodies.
Pineoblastoma. These tumours frequently show areas of necrosis.
Pineoblastoma. There is diffuse expression of synaptophysin with paranuclear dot–like reactivity.
Pineal anlage tumour. Striated muscle cells.
Pineal anlage tumour. Tubular structures composed of epithelioid cells containing melanin pigment.
Pineoblastoma. A tumour located in the pineal region appears mildly hypointense on T2-weighted MRI.
Pineoblastoma. This patient has obstructive triventricular hydrocephalus (T2-weighted MRI).

Q: The histologic hallmark of a Pineocytoma is the presence of large, irregular, eosinophilic zones with anucleate centers containing neuropil-like processes, known as [...].
Pineocytoma. Large fibrillary pineocytomatous rosettes are a characteristic feature.
Pineocytoma. Pineocytomatous rosettes are large irregular eosinophilic fibrillary areas surrounded by pinealocyte-like neoplastic cells.
A: pineocytomatous rosettes
Back Extra: Pineocytoma
- Clinical: Typically presents in adults with signs of increased intracranial pressure (aqueductal obstruction) and neuro-ophthalmological dysfunction (Parinaud syndrome).
- Microscopic: CNS WHO grade 1 tumor characterized by small, uniform cells forming large, irregular, eosinophilic "pineocytomatous rosettes" with anucleate centers containing neuropil-like processes.
- Pleomorphic Variant: May contain large ganglion cells or multinucleated giant cells; despite pleomorphism, these remain grade 1 and lack the glial component of ganglioglioma.
- Ancillary: Shows strong immunoreactivity for synaptophysin, NFP, and the pineal marker CRX; lacks the KBTBD4 alterations seen in higher-grade pineal parenchymal tumors.
Reference Gallery:
Pineocytoma. Large fibrillary pineocytomatous rosettes are a characteristic feature.
Pineocytoma. Immunoreactivity for synaptophysin is diffuse and highlights the pineocytomatous rosettes.
Pineocytoma. NFP immunoexpression is especially strong in the pineocytomatous rosettes.
Pleomorphic pineocytoma. Multinucleated pleomorphic cell.
Pleomorphic pineocytoma. Pleomorphic cells often show immunoreactivity for NFP.
Pineocytoma. Pineocytomatous rosettes are large irregular eosinophilic fibrillary areas surrounded by pinealocyte-like neoplastic cells.
Pineocytoma. Sagittal, gadolinium-enhanced, T1-weighted MRI showing a well-delineated tumour with strong contrast enhancement.

Q: In a Pineocytoma, the characteristic rosettes exhibit strong, diffuse immunoreactivity for neural markers such as NFP and [...].
Pineocytoma. Large fibrillary pineocytomatous rosettes are a characteristic feature.
Pineocytoma. Immunoreactivity for synaptophysin is diffuse and highlights the pineocytomatous rosettes.
Pineocytoma. NFP immunoexpression is especially strong in the pineocytomatous rosettes.
A: synaptophysin
Back Extra: Pineocytoma
- Clinical: Typically presents in adults with signs of increased intracranial pressure (aqueductal obstruction) and neuro-ophthalmological dysfunction (Parinaud syndrome).
- Microscopic: CNS WHO grade 1 tumor characterized by small, uniform cells forming large, irregular, eosinophilic "pineocytomatous rosettes" with anucleate centers containing neuropil-like processes.
- Pleomorphic Variant: May contain large ganglion cells or multinucleated giant cells; despite pleomorphism, these remain grade 1 and lack the glial component of ganglioglioma.
- Ancillary: Shows strong immunoreactivity for synaptophysin, NFP, and the pineal marker CRX; lacks the KBTBD4 alterations seen in higher-grade pineal parenchymal tumors.
Reference Gallery:
Pineocytoma. Large fibrillary pineocytomatous rosettes are a characteristic feature.
Pineocytoma. Immunoreactivity for synaptophysin is diffuse and highlights the pineocytomatous rosettes.
Pineocytoma. NFP immunoexpression is especially strong in the pineocytomatous rosettes.
Pleomorphic pineocytoma. Multinucleated pleomorphic cell.
Pleomorphic pineocytoma. Pleomorphic cells often show immunoreactivity for NFP.
Pineocytoma. Pineocytomatous rosettes are large irregular eosinophilic fibrillary areas surrounded by pinealocyte-like neoplastic cells.
Pineocytoma. Sagittal, gadolinium-enhanced, T1-weighted MRI showing a well-delineated tumour with strong contrast enhancement.

Q: Despite the presence of large ganglion cells or multinucleated giant cells, the pleomorphic variant of Pineocytoma lacks a glial component and remains a CNS WHO grade [...] tumor.
Pleomorphic pineocytoma. Multinucleated pleomorphic cell.
Pleomorphic pineocytoma. Pleomorphic cells often show immunoreactivity for NFP.
A: 1
Back Extra: Pineocytoma
- Clinical: Typically presents in adults with signs of increased intracranial pressure (aqueductal obstruction) and neuro-ophthalmological dysfunction (Parinaud syndrome).
- Microscopic: CNS WHO grade 1 tumor characterized by small, uniform cells forming large, irregular, eosinophilic "pineocytomatous rosettes" with anucleate centers containing neuropil-like processes.
- Pleomorphic Variant: May contain large ganglion cells or multinucleated giant cells; despite pleomorphism, these remain grade 1 and lack the glial component of ganglioglioma.
- Ancillary: Shows strong immunoreactivity for synaptophysin, NFP, and the pineal marker CRX; lacks the KBTBD4 alterations seen in higher-grade pineal parenchymal tumors.
Reference Gallery:
Pineocytoma. Large fibrillary pineocytomatous rosettes are a characteristic feature.
Pineocytoma. Immunoreactivity for synaptophysin is diffuse and highlights the pineocytomatous rosettes.
Pineocytoma. NFP immunoexpression is especially strong in the pineocytomatous rosettes.
Pleomorphic pineocytoma. Multinucleated pleomorphic cell.
Pleomorphic pineocytoma. Pleomorphic cells often show immunoreactivity for NFP.
Pineocytoma. Pineocytomatous rosettes are large irregular eosinophilic fibrillary areas surrounded by pinealocyte-like neoplastic cells.
Pineocytoma. Sagittal, gadolinium-enhanced, T1-weighted MRI showing a well-delineated tumour with strong contrast enhancement.

Q: The pathognomonic microscopic finding in Adamantinomatous craniopharyngioma consists of clusters of anucleate ghost cells known as [...].
Adamantinomatous craniopharyngioma showing basal palisading of tumour cells, epithelial whorls, stellate reticulum, and wet keratin.
Characteristic wet keratin (anucleate ghost cells) and peripheral tumour palisading.
A: "wet keratin"
Back Extra: Adamantinomatous craniopharyngioma
- Clinical: Bimodal age distribution (5–15 and 45–60 years); presents with visual impairment, endocrine deficits, and the '90% rule' on imaging (cystic, calcified, and contrast-enhancing).
- Microscopic: Characterized by well-differentiated squamous epithelium with peripheral palisading, "stellate reticulum", and pathognomonic "wet keratin" (anucleate ghost cells).
- Brain Interface: Finger-like protrusions into the brain often induce a dense piloid gliosis rich in "Rosenthal fibres", which can mimic a pilocytic astrocytoma on small biopsies.
- Ancillary: Activating mutations in exon 3 of the CTNNB1 gene (beta-catenin) are the hallmark driver, resulting in focal nuclear accumulation of beta-catenin by IHC.
Reference Gallery:
Adamantinomatous craniopharyngioma showing basal palisading of tumour cells, epithelial whorls, stellate reticulum, and wet keratin.
High-power view of the interface with brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Beta-catenin IHC: Although CTNNB1 mutations are clonal, nuclear accumulation is restricted to small clusters of cells.
Characteristic wet keratin (anucleate ghost cells) and peripheral tumour palisading.
T1-weighted postcontrast MRI showing a sellar mass with suprasellar extension.
Solid and cystic mass with calcification, following the '90% rule'.

Q: The hallmark driver of Adamantinomatous craniopharyngioma is an activating mutation in the CTNNB1 gene, leading to focal nuclear accumulation of [...] on immunohistochemistry.
Adamantinomatous craniopharyngioma showing basal palisading of tumour cells, epithelial whorls, stellate reticulum, and wet keratin.
Beta-catenin IHC: Although CTNNB1 mutations are clonal, nuclear accumulation is restricted to small clusters of cells.
A: beta-catenin
Back Extra: Adamantinomatous craniopharyngioma
- Clinical: Bimodal age distribution (5–15 and 45–60 years); presents with visual impairment, endocrine deficits, and the '90% rule' on imaging (cystic, calcified, and contrast-enhancing).
- Microscopic: Characterized by well-differentiated squamous epithelium with peripheral palisading, "stellate reticulum", and pathognomonic "wet keratin" (anucleate ghost cells).
- Brain Interface: Finger-like protrusions into the brain often induce a dense piloid gliosis rich in "Rosenthal fibres", which can mimic a pilocytic astrocytoma on small biopsies.
- Ancillary: Activating mutations in exon 3 of the CTNNB1 gene (beta-catenin) are the hallmark driver, resulting in focal nuclear accumulation of beta-catenin by IHC.
Reference Gallery:
Adamantinomatous craniopharyngioma showing basal palisading of tumour cells, epithelial whorls, stellate reticulum, and wet keratin.
High-power view of the interface with brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Beta-catenin IHC: Although CTNNB1 mutations are clonal, nuclear accumulation is restricted to small clusters of cells.
Characteristic wet keratin (anucleate ghost cells) and peripheral tumour palisading.
T1-weighted postcontrast MRI showing a sellar mass with suprasellar extension.
Solid and cystic mass with calcification, following the '90% rule'.

Q: Finger-like protrusions of Adamantinomatous craniopharyngioma into the adjacent brain tissue often induce a dense reactive piloid gliosis rich in [...], potentially mimicking a pilocytic astrocytoma on small biopsies.
High-power view of the interface with brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
A: Rosenthal fibers
Back Extra: Adamantinomatous craniopharyngioma
- Clinical: Bimodal age distribution (5–15 and 45–60 years); presents with visual impairment, endocrine deficits, and the '90% rule' on imaging (cystic, calcified, and contrast-enhancing).
- Microscopic: Characterized by well-differentiated squamous epithelium with peripheral palisading, "stellate reticulum", and pathognomonic "wet keratin" (anucleate ghost cells).
- Brain Interface: Finger-like protrusions into the brain often induce a dense piloid gliosis rich in "Rosenthal fibres", which can mimic a pilocytic astrocytoma on small biopsies.
- Ancillary: Activating mutations in exon 3 of the CTNNB1 gene (beta-catenin) are the hallmark driver, resulting in focal nuclear accumulation of beta-catenin by IHC.
Reference Gallery:
Adamantinomatous craniopharyngioma showing basal palisading of tumour cells, epithelial whorls, stellate reticulum, and wet keratin.
High-power view of the interface with brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Beta-catenin IHC: Although CTNNB1 mutations are clonal, nuclear accumulation is restricted to small clusters of cells.
Characteristic wet keratin (anucleate ghost cells) and peripheral tumour palisading.
T1-weighted postcontrast MRI showing a sellar mass with suprasellar extension.
Solid and cystic mass with calcification, following the '90% rule'.

Q: In Papillary craniopharyngioma, the histologic hallmark is a papillary architecture lined by well-differentiated, [...] squamous epithelium covering fibrovascular cores.
Papillary craniopharyngioma. Low-power view of an H&E-stained section highlights papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium covering fibrovascular cores that contain a low density of fibroblasts and immune cells including lymphocytes, macrophages, and neutrophils.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils, which are common in these tumours.
A: non-keratinizing
Back Extra: Papillary craniopharyngioma
- Clinical: Epidemiology: Principally an adult disease (peak 30–59 years); rare in children. No sex predilection. Symptoms: Common manifestations include headache (70%), visual deficits (63%) due to optic chiasm compression…
- Micro: Architecture: Non-keratinizing mature squamous epithelium covering fibrovascular cores or lining a cyst wall, often with a papillary pattern. Cellular Features: * Squamous Epithelium: Well-differentiated, …
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): BRAF V600E: Mutation-specific antibodies show cytoplasmic immunoreactivity across the tumour epithelium (distinguishes it from adamantinomatous craniopharyngioma). Cytokerati…
Reference Gallery:
Papillary craniopharyngioma. Low-power view of an H&E-stained section highlights papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium covering fibrovascular cores that contain a low density of fibroblasts and immune cells including lymphocytes, macrophages, and neutrophils.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils, which are common in these tumours.
Papillary craniopharyngioma. Fixed coronal section of papillary craniopharyngioma showing a solid and cystic mass involving the infundibulotuberal region and third ventricle in an adult patient without prior surgical intervention. The tumour mass has a cauliflower-like configuration. Calcifications are absent.
Papillary craniopharyngioma. Immunohistochemistry for CK5/6 (an antibody against the intermediate-weight keratins CK5 [58 kDa] and CK6 [56 kDa]) is positive throughout all layers. Staining for CK19 is also positive. Another marker commonly used to assess squamous cell carcinomas of all types, p63, is also immunoreactive in almost all papillary and adamantinomatous craniopharyngiomas.
Papillary craniopharyngioma. T1-weighted postcontrast MRI showing a cystic and solid mass with peripheral and central enhancement, which proved on biopsy to be a papillary craniopharyngioma. Although the cyst and papillary mural nodule pattern is archetypal for this tumour on imaging, other examples of papillary craniopharyngioma can be predominantly solid or cystic.
Papillary craniopharyngioma. T1-weighted postcontrast coronal MRI of a 28 mm complex cystic mass with nodular enhancement in the infundibulotuberal region and cystic components extending up into the third ventricle. The mass involved the pituitary stalk, was predominantly posterior to the optic chiasm, and abutted and displaced the hypothalamus superiorly. The 31-year-old woman presented with visual loss, headache, and mild endocrine disturbance.
Papillary craniopharyngioma. All papillary craniopharyngiomas show cytoplasmic immunoreactivity for BRAF p.V600E.

Q: Unlike the adamantinomatous subtype, Papillary craniopharyngioma is characterized by a high frequency of [...] mutations, which show strong, diffuse cytoplasmic staining on mutation-specific immunohistochemistry.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium covering fibrovascular cores that contain a low density of fibroblasts and immune cells including lymphocytes, macrophages, and neutrophils.
Papillary craniopharyngioma. All papillary craniopharyngiomas show cytoplasmic immunoreactivity for BRAF p.V600E.
A: BRAF V600E
Back Extra: Papillary craniopharyngioma
- Clinical: Epidemiology: Principally an adult disease (peak 30–59 years); rare in children. No sex predilection. Symptoms: Common manifestations include headache (70%), visual deficits (63%) due to optic chiasm compression…
- Micro: Architecture: Non-keratinizing mature squamous epithelium covering fibrovascular cores or lining a cyst wall, often with a papillary pattern. Cellular Features: * Squamous Epithelium: Well-differentiated, …
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): BRAF V600E: Mutation-specific antibodies show cytoplasmic immunoreactivity across the tumour epithelium (distinguishes it from adamantinomatous craniopharyngioma). Cytokerati…
Reference Gallery:
Papillary craniopharyngioma. Low-power view of an H&E-stained section highlights papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium covering fibrovascular cores that contain a low density of fibroblasts and immune cells including lymphocytes, macrophages, and neutrophils.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils, which are common in these tumours.
Papillary craniopharyngioma. Fixed coronal section of papillary craniopharyngioma showing a solid and cystic mass involving the infundibulotuberal region and third ventricle in an adult patient without prior surgical intervention. The tumour mass has a cauliflower-like configuration. Calcifications are absent.
Papillary craniopharyngioma. Immunohistochemistry for CK5/6 (an antibody against the intermediate-weight keratins CK5 [58 kDa] and CK6 [56 kDa]) is positive throughout all layers. Staining for CK19 is also positive. Another marker commonly used to assess squamous cell carcinomas of all types, p63, is also immunoreactive in almost all papillary and adamantinomatous craniopharyngiomas.
Papillary craniopharyngioma. T1-weighted postcontrast MRI showing a cystic and solid mass with peripheral and central enhancement, which proved on biopsy to be a papillary craniopharyngioma. Although the cyst and papillary mural nodule pattern is archetypal for this tumour on imaging, other examples of papillary craniopharyngioma can be predominantly solid or cystic.
Papillary craniopharyngioma. T1-weighted postcontrast coronal MRI of a 28 mm complex cystic mass with nodular enhancement in the infundibulotuberal region and cystic components extending up into the third ventricle. The mass involved the pituitary stalk, was predominantly posterior to the optic chiasm, and abutted and displaced the hypothalamus superiorly. The 31-year-old woman presented with visual loss, headache, and mild endocrine disturbance.
Papillary craniopharyngioma. All papillary craniopharyngiomas show cytoplasmic immunoreactivity for BRAF p.V600E.

Q: A unifying immunohistochemical feature of Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma is the ubiquitous nuclear expression of [...].
Pituicytoma. Fascicles of fibrillary spindle cells.
Pituicytoma. Diffuse nuclear TTF1 immunoreactivity.
Spindle cell oncocytoma. Diffuse nuclear TTF1 expression.
A: TTF1
Back Extra: Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma
- Clinical: These rare tumours typically occur in adults (5th-6th decades). Symptoms include headaches, visual field defects, and hypopituitarism (diabetes insipidus is uncommon). Spindle cell oncocytomas are often hypervascular and…
- Micro: The three subtypes share a morphological spectrum: - Pituicytoma: Composed of elongate, bipolar spindle cells in solid sheets or short fascicles (storiform). Lacks Rosenthal fibers, eosinophilic granular bodies, and …
- Cyto: Pituicytoma: Fibrillary to fine, wispy cytoplasm with occasional spindle cell morphology; shares features with glia or meningioma. Granular Cell Tumour: Uniform polygonal cells with round/ovoid nuclei and abundan…
- Ancillary: Immunohistochemistry (IHC): - Unified Marker: All subtypes show ubiquitous nuclear expression of TTF1. - Subtype Markers: - Pituicytoma: Vimentin+, S100+, variable GFAP, EMA, and CD56. Negative for …
Reference Gallery:
Pituicytoma. MRI of a well-demarcated sellar/suprasellar mass.
Pituicytoma. Fascicles of fibrillary spindle cells.
Pituicytoma. Diffuse nuclear TTF1 immunoreactivity.
Granular cell tumour. Eosinophilic polygonal cells with abundant granular cytoplasm.
Granular cell tumour. Marked PAS positivity.
Spindle cell oncocytoma. Intersecting fascicles of plump eosinophilic cells.
Spindle cell oncocytoma. Diffuse nuclear TTF1 expression.
Pituicytoma. Tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Pituicytomas show variable immunoreactivity for GFAP (shown), and they are also immunoreactive for vimentin.
Granular cell tumour. Postcontrast coronal MRI shows homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Granular cell tumour of the sellar region. The cells show strong EMA expression.
Granular cell tumour of the sellar region. The cells show nuclear expression of thyroid transcription factor 1 (TTF1).

Q: Within the morphologic spectrum of Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma, the granular cell subtype is characterized by uniform polygonal cells with abundant granular cytoplasm that demonstrates marked positivity for the [...] stain.
Granular cell tumour. Eosinophilic polygonal cells with abundant granular cytoplasm.
Granular cell tumour. Marked PAS positivity.
A: PAS
Back Extra: Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma
- Clinical: These rare tumours typically occur in adults (5th-6th decades). Symptoms include headaches, visual field defects, and hypopituitarism (diabetes insipidus is uncommon). Spindle cell oncocytomas are often hypervascular and…
- Micro: The three subtypes share a morphological spectrum: - Pituicytoma: Composed of elongate, bipolar spindle cells in solid sheets or short fascicles (storiform). Lacks Rosenthal fibers, eosinophilic granular bodies, and …
- Cyto: Pituicytoma: Fibrillary to fine, wispy cytoplasm with occasional spindle cell morphology; shares features with glia or meningioma. Granular Cell Tumour: Uniform polygonal cells with round/ovoid nuclei and abundan…
- Ancillary: Immunohistochemistry (IHC): - Unified Marker: All subtypes show ubiquitous nuclear expression of TTF1. - Subtype Markers: - Pituicytoma: Vimentin+, S100+, variable GFAP, EMA, and CD56. Negative for …
Reference Gallery:
Pituicytoma. MRI of a well-demarcated sellar/suprasellar mass.
Pituicytoma. Fascicles of fibrillary spindle cells.
Pituicytoma. Diffuse nuclear TTF1 immunoreactivity.
Granular cell tumour. Eosinophilic polygonal cells with abundant granular cytoplasm.
Granular cell tumour. Marked PAS positivity.
Spindle cell oncocytoma. Intersecting fascicles of plump eosinophilic cells.
Spindle cell oncocytoma. Diffuse nuclear TTF1 expression.
Pituicytoma. Tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Pituicytomas show variable immunoreactivity for GFAP (shown), and they are also immunoreactive for vimentin.
Granular cell tumour. Postcontrast coronal MRI shows homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Granular cell tumour of the sellar region. The cells show strong EMA expression.
Granular cell tumour of the sellar region. The cells show nuclear expression of thyroid transcription factor 1 (TTF1).

Q: In the diagnostic spectrum of Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma, the pituicytoma subtype typically presents as a well-demarcated mass on MRI and is histologically characterized by solid sheets or fascicles of fibrillary [...].
Pituicytoma. MRI of a well-demarcated sellar/suprasellar mass.
Pituicytoma. Fascicles of fibrillary spindle cells.
Pituicytoma. Tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
A: bipolar spindle cells
Back Extra: Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma
- Clinical: These rare tumours typically occur in adults (5th-6th decades). Symptoms include headaches, visual field defects, and hypopituitarism (diabetes insipidus is uncommon). Spindle cell oncocytomas are often hypervascular and…
- Micro: The three subtypes share a morphological spectrum: - Pituicytoma: Composed of elongate, bipolar spindle cells in solid sheets or short fascicles (storiform). Lacks Rosenthal fibers, eosinophilic granular bodies, and …
- Cyto: Pituicytoma: Fibrillary to fine, wispy cytoplasm with occasional spindle cell morphology; shares features with glia or meningioma. Granular Cell Tumour: Uniform polygonal cells with round/ovoid nuclei and abundan…
- Ancillary: Immunohistochemistry (IHC): - Unified Marker: All subtypes show ubiquitous nuclear expression of TTF1. - Subtype Markers: - Pituicytoma: Vimentin+, S100+, variable GFAP, EMA, and CD56. Negative for …
Reference Gallery:
Pituicytoma. MRI of a well-demarcated sellar/suprasellar mass.
Pituicytoma. Fascicles of fibrillary spindle cells.
Pituicytoma. Diffuse nuclear TTF1 immunoreactivity.
Granular cell tumour. Eosinophilic polygonal cells with abundant granular cytoplasm.
Granular cell tumour. Marked PAS positivity.
Spindle cell oncocytoma. Intersecting fascicles of plump eosinophilic cells.
Spindle cell oncocytoma. Diffuse nuclear TTF1 expression.
Pituicytoma. Tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Pituicytomas show variable immunoreactivity for GFAP (shown), and they are also immunoreactive for vimentin.
Granular cell tumour. Postcontrast coronal MRI shows homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Granular cell tumour of the sellar region. The cells show strong EMA expression.
Granular cell tumour of the sellar region. The cells show nuclear expression of thyroid transcription factor 1 (TTF1).

Q: Occurring almost exclusively in infants frequently presenting with Cushing syndrome, [...] is an embryonal sellar tumor characterized by a triphasic microscopic pattern consisting of neuroendocrine cells, primitive Rathke pouch epithelium, and small blastemal cells.
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
A: Pituitary blastoma
Back Extra: Pituitary blastoma
- Clinical: Exceptionally rare embryonal sellar tumor occurring almost exclusively in infants (median age 9 months); frequently presents with Cushing syndrome due to ACTH overexpression.
- Genetics: Strongly linked to DICER1 syndrome, typically harboring a germline loss-of-function variant and a somatic RNase IIIb hotspot mutation.
- Microscopic: Characterized by a triphasic pattern: (1) large neuroendocrine cells in sheets/lobules, (2) cuboidal/columnar primitive Rathke pouch epithelium (forming rosettes/glands), and (3) small undifferentiated blastemal cells.
- Ancillary: Neuroendocrine components are variably positive for ACTH and CD56; the entire tumor is typically CAM5.2 positive; Ki-67 is highest in the Rathke pouch component (up to 60%).
- Prognosis: Guarded, with approximately 38% mortality resulting from both disease progression and treatment-related complications.
Reference Gallery:
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
Pituitary blastoma. Anterior pituitary neuroendocrine tumour cells are variably positive for ACTH, whereas primitive Rathke pouch epithelium and blastemal cells are negative.
Pituitary blastoma. CAM5.2 stains almost all cellular components of the tumor.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells.
Pituitary blastoma. S100 stains scattered folliculostellate cells.
Pituitary blastoma. Proliferative heterogeneity is seen, with primitive Rathke pouch epithelium showing a higher Ki-67 proliferation index than other elements.

Q: Pituitary blastoma is strongly linked to [...] syndrome, typically harboring a germline loss-of-function variant and a somatic RNase IIIb hotspot mutation.
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
A: DICER1
Back Extra: Pituitary blastoma
- Clinical: Exceptionally rare embryonal sellar tumor occurring almost exclusively in infants (median age 9 months); frequently presents with Cushing syndrome due to ACTH overexpression.
- Genetics: Strongly linked to DICER1 syndrome, typically harboring a germline loss-of-function variant and a somatic RNase IIIb hotspot mutation.
- Microscopic: Characterized by a triphasic pattern: (1) large neuroendocrine cells in sheets/lobules, (2) cuboidal/columnar primitive Rathke pouch epithelium (forming rosettes/glands), and (3) small undifferentiated blastemal cells.
- Ancillary: Neuroendocrine components are variably positive for ACTH and CD56; the entire tumor is typically CAM5.2 positive; Ki-67 is highest in the Rathke pouch component (up to 60%).
- Prognosis: Guarded, with approximately 38% mortality resulting from both disease progression and treatment-related complications.
Reference Gallery:
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
Pituitary blastoma. Anterior pituitary neuroendocrine tumour cells are variably positive for ACTH, whereas primitive Rathke pouch epithelium and blastemal cells are negative.
Pituitary blastoma. CAM5.2 stains almost all cellular components of the tumor.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells.
Pituitary blastoma. S100 stains scattered folliculostellate cells.
Pituitary blastoma. Proliferative heterogeneity is seen, with primitive Rathke pouch epithelium showing a higher Ki-67 proliferation index than other elements.

Q: In Pituitary blastoma, the neuroendocrine cell component is characteristically positive for [...] by immunohistochemistry, which explains the frequent clinical presentation of Cushing syndrome in affected infants.
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
Pituitary blastoma. Anterior pituitary neuroendocrine tumour cells are variably positive for ACTH, whereas primitive Rathke pouch epithelium and blastemal cells are negative.
A: ACTH
Back Extra: Pituitary blastoma
- Clinical: Exceptionally rare embryonal sellar tumor occurring almost exclusively in infants (median age 9 months); frequently presents with Cushing syndrome due to ACTH overexpression.
- Genetics: Strongly linked to DICER1 syndrome, typically harboring a germline loss-of-function variant and a somatic RNase IIIb hotspot mutation.
- Microscopic: Characterized by a triphasic pattern: (1) large neuroendocrine cells in sheets/lobules, (2) cuboidal/columnar primitive Rathke pouch epithelium (forming rosettes/glands), and (3) small undifferentiated blastemal cells.
- Ancillary: Neuroendocrine components are variably positive for ACTH and CD56; the entire tumor is typically CAM5.2 positive; Ki-67 is highest in the Rathke pouch component (up to 60%).
- Prognosis: Guarded, with approximately 38% mortality resulting from both disease progression and treatment-related complications.
Reference Gallery:
Pituitary blastoma. The cellular components include large anterior pituitary neuroendocrine cells arranged in lobules, cuboidal primitive Rathke pouch epithelium with rosette or gland formation, and scattered small undifferentiated blastemal cells.
Pituitary blastoma. Anterior pituitary neuroendocrine tumour cells are variably positive for ACTH, whereas primitive Rathke pouch epithelium and blastemal cells are negative.
Pituitary blastoma. CAM5.2 stains almost all cellular components of the tumor.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells.
Pituitary blastoma. S100 stains scattered folliculostellate cells.
Pituitary blastoma. Proliferative heterogeneity is seen, with primitive Rathke pouch epithelium showing a higher Ki-67 proliferation index than other elements.

Q: In sparsely granulated somatotroph variants of Pituitary adenoma / pituitary neuroendocrine tumour (PitNET), cytokeratin (CAM5.2) immunostaining classically highlights paranuclear [...].
Somatotroph adenomas/tumours. Cytokeratin (CAM5.2) staining highlights a large proportion (> 70%) of fibrous bodies in this sparsely granulated somatotroph tumour.
Somatotroph adenomas/tumours. A sparsely granulated somatotroph tumour with slightly eosinophilic cytoplasm and showing paranuclear fibrous bodies.
A: fibrous bodies
Back Extra: Pituitary adenoma / pituitary neuroendocrine tumour (PitNET)
- Clinical: Clinical features range from small incidentalomas to hormone excess syndromes (acromegaly/gigantism, Cushing disease, hyperthyroidism, hyperprolactinaemia). Large tumours cause mass effects like headache, visual field di…
- Micro: Tumours are generally monomorphic with diffuse, papillary, or trabecular patterns. Tinctorial characteristics (acidophilic, basophilic, chromophobic) reflect cytoplasmic granulation density. Lineage-Based Classificat…
- Cyto: Cytological preparations are hypercellular compared to normal gland. Cells appear monomorphic, predominantly as individuals or small clusters due to scant stroma. Nuclei may be pleomorphic or atypical; cytoplasm sits in …
- Ancillary: Immunohistochemistry (IHC): Lineage Transcription Factors: TPIT (corticotroph), PIT1 (somatotroph, lactotroph, thyrotroph), SF1 (gonadotroph), GATA3 (gonadotroph, thyrotroph, PIT1-immature). Hormones: ACT…
Reference Gallery:
Transcriptome of pituitary neuroendocrine tumours (PitNETs). A Unsupervised classification of PitNETs identifies six main groups. B Heat map of NMF ranks. C Proportion of canonical signatures. D IHC for TPIT, SF1, and GATA3 in subtypes.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing eosinophilic, granular cytoplasm and a central nucleus with a prominent nucleolus.
Somatotroph adenomas/tumours. Cytokeratin (CAM5.2) staining highlights a large proportion (> 70%) of fibrous bodies in this sparsely granulated somatotroph tumour.
Immature PIT1-lineage tumour. This tumour expressed nuclear PIT1 with variable growth hormone (GH) and TSH but no prolactin (PRL); there is diffuse α-subunit (αSU) positivity.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Invasive adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates a very large heterogeneously enhancing tumour centred in the sellar region with suprasellar and parasellar extension and invasion of the sphenoid sinus and clivus.
Densely and sparsely granulated corticotroph adenomas/tumours. Irrespective of their subtypes, these tumours are positive for TPIT.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing intense and diffuse growth hormone expression.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour stained for cytokeratin (CAM5.2) shows perinuclear deposition with very few fibrous bodies.
Somatotroph adenomas/tumours. A sparsely granulated somatotroph tumour with slightly eosinophilic cytoplasm and showing paranuclear fibrous bodies.
Somatotroph adenomas/tumours. Growth hormone expression is focal in the cytoplasm of this sparsely granulated somatotroph tumour.
Multiple synchronous pituitary adenomas / pituitary neuroendocrine tumours (PitNETs). These pituitary adenomas / PitNETs occur in about 1% of patients. In this example, a densely granulated somatotroph tumour stains for PIT1 and growth hormone (GH) and shows diffuse cytoplasmic CAM5.2 reactivity. It traps a small gonadotroph tumour that stains for SF1 and is negative for the other biomarkers examined. Tumours like this one and the common occurrence of trapped non-tumorous tissue may explain why SF1 expression is detected in some tumours causing acromegaly.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Corticotroph adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates the classic appearance of a homogeneously hypoenhancing pituitary lesion compatible with corticotroph microadenoma.

Q: In a Pituitary adenoma / pituitary neuroendocrine tumour (PitNET), immunohistochemical expression of the lineage transcription factor [...] is diagnostic of a corticotroph tumor.
Densely and sparsely granulated corticotroph adenomas/tumours. Irrespective of their subtypes, these tumours are positive for TPIT.
A: TPIT
Back Extra: Pituitary adenoma / pituitary neuroendocrine tumour (PitNET)
- Clinical: Clinical features range from small incidentalomas to hormone excess syndromes (acromegaly/gigantism, Cushing disease, hyperthyroidism, hyperprolactinaemia). Large tumours cause mass effects like headache, visual field di…
- Micro: Tumours are generally monomorphic with diffuse, papillary, or trabecular patterns. Tinctorial characteristics (acidophilic, basophilic, chromophobic) reflect cytoplasmic granulation density. Lineage-Based Classificat…
- Cyto: Cytological preparations are hypercellular compared to normal gland. Cells appear monomorphic, predominantly as individuals or small clusters due to scant stroma. Nuclei may be pleomorphic or atypical; cytoplasm sits in …
- Ancillary: Immunohistochemistry (IHC): Lineage Transcription Factors: TPIT (corticotroph), PIT1 (somatotroph, lactotroph, thyrotroph), SF1 (gonadotroph), GATA3 (gonadotroph, thyrotroph, PIT1-immature). Hormones: ACT…
Reference Gallery:
Transcriptome of pituitary neuroendocrine tumours (PitNETs). A Unsupervised classification of PitNETs identifies six main groups. B Heat map of NMF ranks. C Proportion of canonical signatures. D IHC for TPIT, SF1, and GATA3 in subtypes.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing eosinophilic, granular cytoplasm and a central nucleus with a prominent nucleolus.
Somatotroph adenomas/tumours. Cytokeratin (CAM5.2) staining highlights a large proportion (> 70%) of fibrous bodies in this sparsely granulated somatotroph tumour.
Immature PIT1-lineage tumour. This tumour expressed nuclear PIT1 with variable growth hormone (GH) and TSH but no prolactin (PRL); there is diffuse α-subunit (αSU) positivity.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Invasive adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates a very large heterogeneously enhancing tumour centred in the sellar region with suprasellar and parasellar extension and invasion of the sphenoid sinus and clivus.
Densely and sparsely granulated corticotroph adenomas/tumours. Irrespective of their subtypes, these tumours are positive for TPIT.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing intense and diffuse growth hormone expression.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour stained for cytokeratin (CAM5.2) shows perinuclear deposition with very few fibrous bodies.
Somatotroph adenomas/tumours. A sparsely granulated somatotroph tumour with slightly eosinophilic cytoplasm and showing paranuclear fibrous bodies.
Somatotroph adenomas/tumours. Growth hormone expression is focal in the cytoplasm of this sparsely granulated somatotroph tumour.
Multiple synchronous pituitary adenomas / pituitary neuroendocrine tumours (PitNETs). These pituitary adenomas / PitNETs occur in about 1% of patients. In this example, a densely granulated somatotroph tumour stains for PIT1 and growth hormone (GH) and shows diffuse cytoplasmic CAM5.2 reactivity. It traps a small gonadotroph tumour that stains for SF1 and is negative for the other biomarkers examined. Tumours like this one and the common occurrence of trapped non-tumorous tissue may explain why SF1 expression is detected in some tumours causing acromegaly.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Corticotroph adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates the classic appearance of a homogeneously hypoenhancing pituitary lesion compatible with corticotroph microadenoma.

Q: Histologic preparations of a Pituitary adenoma / pituitary neuroendocrine tumour (PitNET) are classically hypercellular and composed of a [...] population of cells, which contrasts with the heterogeneous acini seen in the normal anterior gland.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing eosinophilic, granular cytoplasm and a central nucleus with a prominent nucleolus.
A: monomorphic
Back Extra: Pituitary adenoma / pituitary neuroendocrine tumour (PitNET)
- Clinical: Clinical features range from small incidentalomas to hormone excess syndromes (acromegaly/gigantism, Cushing disease, hyperthyroidism, hyperprolactinaemia). Large tumours cause mass effects like headache, visual field di…
- Micro: Tumours are generally monomorphic with diffuse, papillary, or trabecular patterns. Tinctorial characteristics (acidophilic, basophilic, chromophobic) reflect cytoplasmic granulation density. Lineage-Based Classificat…
- Cyto: Cytological preparations are hypercellular compared to normal gland. Cells appear monomorphic, predominantly as individuals or small clusters due to scant stroma. Nuclei may be pleomorphic or atypical; cytoplasm sits in …
- Ancillary: Immunohistochemistry (IHC): Lineage Transcription Factors: TPIT (corticotroph), PIT1 (somatotroph, lactotroph, thyrotroph), SF1 (gonadotroph), GATA3 (gonadotroph, thyrotroph, PIT1-immature). Hormones: ACT…
Reference Gallery:
Transcriptome of pituitary neuroendocrine tumours (PitNETs). A Unsupervised classification of PitNETs identifies six main groups. B Heat map of NMF ranks. C Proportion of canonical signatures. D IHC for TPIT, SF1, and GATA3 in subtypes.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing eosinophilic, granular cytoplasm and a central nucleus with a prominent nucleolus.
Somatotroph adenomas/tumours. Cytokeratin (CAM5.2) staining highlights a large proportion (> 70%) of fibrous bodies in this sparsely granulated somatotroph tumour.
Immature PIT1-lineage tumour. This tumour expressed nuclear PIT1 with variable growth hormone (GH) and TSH but no prolactin (PRL); there is diffuse α-subunit (αSU) positivity.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Invasive adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates a very large heterogeneously enhancing tumour centred in the sellar region with suprasellar and parasellar extension and invasion of the sphenoid sinus and clivus.
Densely and sparsely granulated corticotroph adenomas/tumours. Irrespective of their subtypes, these tumours are positive for TPIT.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour showing intense and diffuse growth hormone expression.
Somatotroph adenomas/tumours. A densely granulated somatotroph tumour stained for cytokeratin (CAM5.2) shows perinuclear deposition with very few fibrous bodies.
Somatotroph adenomas/tumours. A sparsely granulated somatotroph tumour with slightly eosinophilic cytoplasm and showing paranuclear fibrous bodies.
Somatotroph adenomas/tumours. Growth hormone expression is focal in the cytoplasm of this sparsely granulated somatotroph tumour.
Multiple synchronous pituitary adenomas / pituitary neuroendocrine tumours (PitNETs). These pituitary adenomas / PitNETs occur in about 1% of patients. In this example, a densely granulated somatotroph tumour stains for PIT1 and growth hormone (GH) and shows diffuse cytoplasmic CAM5.2 reactivity. It traps a small gonadotroph tumour that stains for SF1 and is negative for the other biomarkers examined. Tumours like this one and the common occurrence of trapped non-tumorous tissue may explain why SF1 expression is detected in some tumours causing acromegaly.
Pituitary adenoma / pituitary neuroendocrine tumour (PitNET). Corticotroph adenoma/tumour. T1-weighted postcontrast coronal MRI demonstrates the classic appearance of a homogeneously hypoenhancing pituitary lesion compatible with corticotroph microadenoma.

Q: In Hybrid nerve sheath tumors (specifically the hybrid neurofibroma/schwannoma subtype), the loose neurofibromatous component characteristically shows a lattice-like fibroblastic network that is highlighted by [...] immunohistochemistry.
Hybrid neurofibroma/schwannoma. Solid schwannomatous nodule surrounded by loose, hypocellular neurofibromatous tumour.
Hybrid neurofibroma/schwannoma. CD34 stain reveals a lattice-like fibroblastic network in the neurofibromatous component, which is absent in the solid Schwann cell nodule.
A: CD34
Back Extra: Hybrid nerve sheath tumours
- Clinical: These tumours typically present as painless masses in the dermis or subcutaneous tissue, although involvement of large peripheral or spinal nerves may lead to pain or neurological deficits. They show a wide anatomical di…
- Micro: The histopathology varies by hybrid subtype: - Hybrid schwannoma/perineurioma: Shows a storiform or fascicular growth. It consists of Schwann cells (plump nuclei, eosinophilic cytoplasm) admixed with perineurial cel…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): - Schwann cell component: Positive for S100 and SOX10. - Perineurial component: Positive for EMA, claudin-1, and GLUT1. - Fibroblastic component (Neurofibroma): CD34-positive l…
Reference Gallery:
Hybrid neurofibroma/schwannoma. Solid schwannomatous nodule surrounded by loose, hypocellular neurofibromatous tumour.
Hybrid neurofibroma/schwannoma. CD34 stain reveals a lattice-like fibroblastic network in the neurofibromatous component, which is absent in the solid Schwann cell nodule.
Hybrid schwannoma/perineurioma. The tumour shows a storiform architecture, similar to that of soft tissue perineurioma.
Hybrid schwannoma/perineurioma. Double immunolabelling for S100 (red) and EMA (brown) highlights alternating Schwann cells and perineurial cells, respectively.
Hybrid schwannoma/perineurioma. Many of the tumour cells have plump, tapering nuclei and eosinophilic cytoplasm, typical of Schwann cells. The perineurial cell component is often inconspicuous.

Q: The hybrid schwannoma/perineurioma subtype of Hybrid nerve sheath tumors typically has a storiform architecture and consists of an admixture of S100-positive Schwann cells and [...]-positive perineurial cells.
Hybrid schwannoma/perineurioma. The tumour shows a storiform architecture, similar to that of soft tissue perineurioma.
Hybrid schwannoma/perineurioma. Double immunolabelling for S100 (red) and EMA (brown) highlights alternating Schwann cells and perineurial cells, respectively.
Hybrid schwannoma/perineurioma. Many of the tumour cells have plump, tapering nuclei and eosinophilic cytoplasm, typical of Schwann cells. The perineurial cell component is often inconspicuous.
A: EMA
Back Extra: Hybrid nerve sheath tumours
- Clinical: These tumours typically present as painless masses in the dermis or subcutaneous tissue, although involvement of large peripheral or spinal nerves may lead to pain or neurological deficits. They show a wide anatomical di…
- Micro: The histopathology varies by hybrid subtype: - Hybrid schwannoma/perineurioma: Shows a storiform or fascicular growth. It consists of Schwann cells (plump nuclei, eosinophilic cytoplasm) admixed with perineurial cel…
- Cyto: Not clinically relevant.
- Ancillary: Immunohistochemistry (IHC): - Schwann cell component: Positive for S100 and SOX10. - Perineurial component: Positive for EMA, claudin-1, and GLUT1. - Fibroblastic component (Neurofibroma): CD34-positive l…
Reference Gallery:
Hybrid neurofibroma/schwannoma. Solid schwannomatous nodule surrounded by loose, hypocellular neurofibromatous tumour.
Hybrid neurofibroma/schwannoma. CD34 stain reveals a lattice-like fibroblastic network in the neurofibromatous component, which is absent in the solid Schwann cell nodule.
Hybrid schwannoma/perineurioma. The tumour shows a storiform architecture, similar to that of soft tissue perineurioma.
Hybrid schwannoma/perineurioma. Double immunolabelling for S100 (red) and EMA (brown) highlights alternating Schwann cells and perineurial cells, respectively.
Hybrid schwannoma/perineurioma. Many of the tumour cells have plump, tapering nuclei and eosinophilic cytoplasm, typical of Schwann cells. The perineurial cell component is often inconspicuous.