Title: WHO / Endo
Tags: Endo::Thyroid::Neoplastic Endo::Pituitary::Neoplastic Endo::Adrenal::Neoplastic Endo::Pancreas::Neoplastic Endo::Parathyroid::Neoplastic Endo::Syndromes::Other Endo::Syndromes::MEN Endo::Neuroendocrine::Neoplastic Endo::Thyroid::Inflammatory Endo::Adrenal::Congenital_Structural Endo::Thyroid::Congenital_Structural Endo::Adrenal::Nonneoplastic Endo::Syndromes::Paraganglioma Endo::Syndromes::Parathyroid Endo::Syndromes::Thyroid Endo::Thyroid::Nonneoplastic Endo::Parathyroid::Nonneoplastic

Q: The epithelial variant of an Adrenal Cyst features a fibrous wall lined by mesothelial cells, which are characteristically positive for the immunohistochemical marker [...].
Epithelial (mesothelial) adrenal cyst. A cyst with a fibrous wall and mesothelial lining is shown here.
Epithelial (mesothelial) adrenal cyst. This cyst is lined by calretinin-positive mesothelial cells.
A: calretinin
Back Extra: Adrenal Cyst
- Clinical: Adrenal cysts often present as incidentalomas but can cause mass-related symptoms such as abdominal pain and vena cava compression.
- Micro: Epithelial cysts are lined by mesothelial cells, while vascular cysts are lined by endothelial cells. Pseudocysts contain fibrinous/haemorrhagic material.
- Ancillary: Immunohistochemistry for epithelial and endothelial markers can help distinguish between different types of adrenal cysts.
Reference Gallery:
Adrenal cyst. A 50 mm cyst in the left adrenal is visualized on CT.
Epithelial (mesothelial) adrenal cyst. A cyst with a fibrous wall and mesothelial lining is shown here.
Epithelial (mesothelial) adrenal cyst. This cyst is lined by calretinin-positive mesothelial cells.
Parasitic adrenal cyst. A cyst in the periadrenal fat with PAS-positive laminar membranes in the wall.
Adrenal pseudocyst. These are often demarcated by dense fibrous tissue, lack a cellular lining, and contain fibrinous/haemorrhagic material.
Vascular adrenal cyst. These cysts are lined by endothelial cells.
Vascular adrenal cyst. Vascular cysts are more commonly of lymphatic endothelium. This photomicrograph illustrates D2-40 immunoreactivity in the cyst lining of a vascular adrenal cyst.

Q: An Adrenal Cyst that lacks a true cellular lining and is demarcated by dense fibrous tissue containing fibrinous or hemorrhagic material is known as a [...].
Adrenal pseudocyst. These are often demarcated by dense fibrous tissue, lack a cellular lining, and contain fibrinous/haemorrhagic material.
A: pseudocyst
Back Extra: Adrenal Cyst
- Clinical: Adrenal cysts often present as incidentalomas but can cause mass-related symptoms such as abdominal pain and vena cava compression.
- Micro: Epithelial cysts are lined by mesothelial cells, while vascular cysts are lined by endothelial cells. Pseudocysts contain fibrinous/haemorrhagic material.
- Ancillary: Immunohistochemistry for epithelial and endothelial markers can help distinguish between different types of adrenal cysts.
Reference Gallery:
Adrenal cyst. A 50 mm cyst in the left adrenal is visualized on CT.
Epithelial (mesothelial) adrenal cyst. A cyst with a fibrous wall and mesothelial lining is shown here.
Epithelial (mesothelial) adrenal cyst. This cyst is lined by calretinin-positive mesothelial cells.
Parasitic adrenal cyst. A cyst in the periadrenal fat with PAS-positive laminar membranes in the wall.
Adrenal pseudocyst. These are often demarcated by dense fibrous tissue, lack a cellular lining, and contain fibrinous/haemorrhagic material.
Vascular adrenal cyst. These cysts are lined by endothelial cells.
Vascular adrenal cyst. Vascular cysts are more commonly of lymphatic endothelium. This photomicrograph illustrates D2-40 immunoreactivity in the cyst lining of a vascular adrenal cyst.

Q: The vascular variant of an Adrenal Cyst is commonly composed of lymphatic endothelium that demonstrates characteristic immunoreactivity for the marker [...].
Vascular adrenal cyst. These cysts are lined by endothelial cells.
Vascular adrenal cyst. Vascular cysts are more commonly of lymphatic endothelium. This photomicrograph illustrates D2-40 immunoreactivity in the cyst lining of a vascular adrenal cyst.
A: D2-40
Back Extra: Adrenal Cyst
- Clinical: Adrenal cysts often present as incidentalomas but can cause mass-related symptoms such as abdominal pain and vena cava compression.
- Micro: Epithelial cysts are lined by mesothelial cells, while vascular cysts are lined by endothelial cells. Pseudocysts contain fibrinous/haemorrhagic material.
- Ancillary: Immunohistochemistry for epithelial and endothelial markers can help distinguish between different types of adrenal cysts.
Reference Gallery:
Adrenal cyst. A 50 mm cyst in the left adrenal is visualized on CT.
Epithelial (mesothelial) adrenal cyst. A cyst with a fibrous wall and mesothelial lining is shown here.
Epithelial (mesothelial) adrenal cyst. This cyst is lined by calretinin-positive mesothelial cells.
Parasitic adrenal cyst. A cyst in the periadrenal fat with PAS-positive laminar membranes in the wall.
Adrenal pseudocyst. These are often demarcated by dense fibrous tissue, lack a cellular lining, and contain fibrinous/haemorrhagic material.
Vascular adrenal cyst. These cysts are lined by endothelial cells.
Vascular adrenal cyst. Vascular cysts are more commonly of lymphatic endothelium. This photomicrograph illustrates D2-40 immunoreactivity in the cyst lining of a vascular adrenal cyst.

Q: Morphologically, Adrenal Rests consist of aggregates of large polygonal cells with eosinophilic or clear cytoplasm that closely resemble normal orthotopic [...] cells.
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty tissue of the spermatic cord.
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty parasalpingeal tissue.
A: adrenocortical
Back Extra: Adrenal Rests
- Clinical: Adrenal rests are generally incidental findings in organs resected for other diseases. In the testis, they can be identified within specific screening for congenital adrenal hyperplasia, other endocrinological disorders, or subfertility.
- Micro: Adrenal rests appear as aggregates of large polygonal cells with eosinophilic or clear cytoplasm, a uniform round nucleus, and finely dispersed chromatin, resembling orthotopic adrenocortical cells.
- Ancillary: Immunohistochemical confirmation of adrenocortical cell differentiation is essential for diagnosis. SF1 positivity and adrenocortical steroidogenic enzyme positivity are desirable ancillary studies.
Reference Gallery:
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty tissue of the spermatic cord.
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty parasalpingeal tissue.
Adrenal rests. Ectopic adrenocortical cells in the fibrofatty tissue of the spermatic cord show SF1 immunoreactivity.

Q: Immunohistochemical confirmation is essential for diagnosing ectopic Adrenal Rests, which typically demonstrate nuclear positivity for [...] along with adrenocortical steroidogenic enzymes.
Adrenal rests. Ectopic adrenocortical cells in the fibrofatty tissue of the spermatic cord show SF1 immunoreactivity.
A: SF1
Back Extra: Adrenal Rests
- Clinical: Adrenal rests are generally incidental findings in organs resected for other diseases. In the testis, they can be identified within specific screening for congenital adrenal hyperplasia, other endocrinological disorders, or subfertility.
- Micro: Adrenal rests appear as aggregates of large polygonal cells with eosinophilic or clear cytoplasm, a uniform round nucleus, and finely dispersed chromatin, resembling orthotopic adrenocortical cells.
- Ancillary: Immunohistochemical confirmation of adrenocortical cell differentiation is essential for diagnosis. SF1 positivity and adrenocortical steroidogenic enzyme positivity are desirable ancillary studies.
Reference Gallery:
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty tissue of the spermatic cord.
Adrenal rests. A nodule of adrenocortical cells is embedded in the fibrofatty parasalpingeal tissue.
Adrenal rests. Ectopic adrenocortical cells in the fibrofatty tissue of the spermatic cord show SF1 immunoreactivity.

Q: The provided image reveals an adrenal mass composed of interanastomosing channels and microcysts lined by flattened to cuboidal cells within a delicate fibrous stroma. This morphology is diagnostic of an [...].
Adenomatoid tumour of the adrenal gland. An example showing channels and microcysts lined by flattened cells in a delicate fibrous stroma.
A: Adenomatoid tumor of the adrenal gland
Back Extra: Adenomatoid tumour of the adrenal gland
- Clinical: Most cases are diagnosed incidentally during imaging or surgical procedures, or found at autopsy. There is a marked male predominance (> 90% of cases are in men).
- Micro: Tumours show variably sized interanastomosing tubules, channels, and cystic spaces lined by flat to cuboidal cells with scant epithelioid cytoplasm or cytoplasmic vacuoles.
- Ancillary: The tumour stains for cytokeratins and mesothelial cell markers such as calretinin, D2-40, and WT1. They harbour somatic missense mutations in TRAF7.
Reference Gallery:
Adenomatoid tumour of the adrenal gland. An example showing channels and microcysts lined by flattened cells in a delicate fibrous stroma.

Q: Microscopically, a cortisol-secreting Adrenal Cortical Adenoma typically features a predominantly [...] appearance due to markedly vacuolated cytoplasm, often resembling the zona fasciculata.
Adrenal cortical adenoma. Cortisol-secreting adrenal cortical adenomas are often composed of zona fasciculata–like cells with markedly vacuolated cytoplasm, giving the lesion a clear appearance at low magnification. These lesions often have a nesting pattern of growth, or they may have trabeculae, cords of cells, or mixtures of cell types.
A: clear cell
Back Extra: Adrenal Cortical Adenoma
- Clinical: Adrenal cortisol-producing adenomas can lead to Cushing syndrome, characterized by central obesity, rounded facies, and skin striae.
- Micro: Cortisol-secreting adrenal cortical adenomas typically have a clear cell appearance and a nesting pattern of growth.
- Ancillary: Immunohistochemistry for CYP11B2 is useful in identifying functional sites in primary aldosteronism.
Reference Gallery:
Adrenal cortical adenoma. Adrenal cortical adenomas can show cystic, haemorrhagic, and degenerative features, which should not be misinterpreted as necrosis or as a vascular neoplasm.
Adrenal cortical adenoma. This virilizing adrenal cortical adenoma is composed of sheets of cells with compact eosinophilic cytoplasm. Virilizing adrenal tumours are more common in children, whereas feminizing tumours are more common in adults.
Adrenal cortical adenoma. Cortisol-secreting adrenal cortical adenomas are often composed of zona fasciculata–like cells with markedly vacuolated cytoplasm, giving the lesion a clear appearance at low magnification. These lesions often have a nesting pattern of growth, or they may have trabeculae, cords of cells, or mixtures of cell types.
Adrenal cortical adenoma. Adrenal cortical adenomas with primary hyperaldosteronism (Conn syndrome) are not associated with atrophy of the associated adrenal cortex, as is seen in cortisol-producing adrenal cortical adenomas.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas have a predominantly nesting or alveolar pattern of growth. Lipid-rich, pale-staining cells are often identified in the more central aspect of the tumour and may impart a gold appearance to the tumour grossly on cut section.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas often have lipid-rich clear cells centrally, with compact cells and zona glomerulosa–type cells at the peripheral aspect of the lesion.
Adrenal cortical adenoma. This aldosterone-secreting adrenal cortical adenoma is composed almost entirely of cells that resemble the zona glomerulosa. However, aldosterone-secreting adrenal cortical adenomas can have a heterogeneous appearance with many different cell types.
Adrenal cortical adenoma. A 23 mm aldosterone-producing adrenal cortical adenoma. The golden-yellow colour reflects the high lipid content.
Adrenal cortical adenoma. This photograph shows a 40 mm cortisol-producing adrenal cortical adenoma.
Non-functioning adrenal cortical adenoma. A non-functioning clear cell–rich adenoma is shown.
Adrenal cortical adenoma. An aldosterone-producing adenoma enriched in lipid-poor (compact) cells with variable spironolactone bodies (arrows).
Non-tumorous cortical atrophy in Cushing syndrome. The non-tumorous adrenal cortex shows atrophy in patients with cortisol-producing adrenal cortical neoplasms. The cortical atrophy is characterized by a thin adrenal cortex (often < 2 mm) and an absent or significantly reduced zona reticularis.

Q: In a cortisol-producing Adrenal Cortical Adenoma, the adjacent non-neoplastic adrenal cortex frequently demonstrates profound [...], a feature typically absent in aldosterone-producing tumors.
Adrenal cortical adenoma. Adrenal cortical adenomas with primary hyperaldosteronism (Conn syndrome) are not associated with atrophy of the associated adrenal cortex, as is seen in cortisol-producing adrenal cortical adenomas.
Non-tumorous cortical atrophy in Cushing syndrome. The non-tumorous adrenal cortex shows atrophy in patients with cortisol-producing adrenal cortical neoplasms. The cortical atrophy is characterized by a thin adrenal cortex (often < 2 mm) and an absent or significantly reduced zona reticularis.
A: atrophy
Back Extra: Adrenal Cortical Adenoma
- Clinical: Adrenal cortisol-producing adenomas can lead to Cushing syndrome, characterized by central obesity, rounded facies, and skin striae.
- Micro: Cortisol-secreting adrenal cortical adenomas typically have a clear cell appearance and a nesting pattern of growth.
- Ancillary: Immunohistochemistry for CYP11B2 is useful in identifying functional sites in primary aldosteronism.
Reference Gallery:
Adrenal cortical adenoma. Adrenal cortical adenomas can show cystic, haemorrhagic, and degenerative features, which should not be misinterpreted as necrosis or as a vascular neoplasm.
Adrenal cortical adenoma. This virilizing adrenal cortical adenoma is composed of sheets of cells with compact eosinophilic cytoplasm. Virilizing adrenal tumours are more common in children, whereas feminizing tumours are more common in adults.
Adrenal cortical adenoma. Cortisol-secreting adrenal cortical adenomas are often composed of zona fasciculata–like cells with markedly vacuolated cytoplasm, giving the lesion a clear appearance at low magnification. These lesions often have a nesting pattern of growth, or they may have trabeculae, cords of cells, or mixtures of cell types.
Adrenal cortical adenoma. Adrenal cortical adenomas with primary hyperaldosteronism (Conn syndrome) are not associated with atrophy of the associated adrenal cortex, as is seen in cortisol-producing adrenal cortical adenomas.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas have a predominantly nesting or alveolar pattern of growth. Lipid-rich, pale-staining cells are often identified in the more central aspect of the tumour and may impart a gold appearance to the tumour grossly on cut section.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas often have lipid-rich clear cells centrally, with compact cells and zona glomerulosa–type cells at the peripheral aspect of the lesion.
Adrenal cortical adenoma. This aldosterone-secreting adrenal cortical adenoma is composed almost entirely of cells that resemble the zona glomerulosa. However, aldosterone-secreting adrenal cortical adenomas can have a heterogeneous appearance with many different cell types.
Adrenal cortical adenoma. A 23 mm aldosterone-producing adrenal cortical adenoma. The golden-yellow colour reflects the high lipid content.
Adrenal cortical adenoma. This photograph shows a 40 mm cortisol-producing adrenal cortical adenoma.
Non-functioning adrenal cortical adenoma. A non-functioning clear cell–rich adenoma is shown.
Adrenal cortical adenoma. An aldosterone-producing adenoma enriched in lipid-poor (compact) cells with variable spironolactone bodies (arrows).
Non-tumorous cortical atrophy in Cushing syndrome. The non-tumorous adrenal cortex shows atrophy in patients with cortisol-producing adrenal cortical neoplasms. The cortical atrophy is characterized by a thin adrenal cortex (often < 2 mm) and an absent or significantly reduced zona reticularis.

Q: Aldosterone-producing variants of Adrenal Cortical Adenoma may contain lipid-poor compact cells that exhibit characteristic targetoid, eosinophilic cytoplasmic inclusions known as [...].
Adrenal cortical adenoma. An aldosterone-producing adenoma enriched in lipid-poor (compact) cells with variable spironolactone bodies (arrows).
A: spironolactone bodies
Back Extra: Adrenal Cortical Adenoma
- Clinical: Adrenal cortisol-producing adenomas can lead to Cushing syndrome, characterized by central obesity, rounded facies, and skin striae.
- Micro: Cortisol-secreting adrenal cortical adenomas typically have a clear cell appearance and a nesting pattern of growth.
- Ancillary: Immunohistochemistry for CYP11B2 is useful in identifying functional sites in primary aldosteronism.
Reference Gallery:
Adrenal cortical adenoma. Adrenal cortical adenomas can show cystic, haemorrhagic, and degenerative features, which should not be misinterpreted as necrosis or as a vascular neoplasm.
Adrenal cortical adenoma. This virilizing adrenal cortical adenoma is composed of sheets of cells with compact eosinophilic cytoplasm. Virilizing adrenal tumours are more common in children, whereas feminizing tumours are more common in adults.
Adrenal cortical adenoma. Cortisol-secreting adrenal cortical adenomas are often composed of zona fasciculata–like cells with markedly vacuolated cytoplasm, giving the lesion a clear appearance at low magnification. These lesions often have a nesting pattern of growth, or they may have trabeculae, cords of cells, or mixtures of cell types.
Adrenal cortical adenoma. Adrenal cortical adenomas with primary hyperaldosteronism (Conn syndrome) are not associated with atrophy of the associated adrenal cortex, as is seen in cortisol-producing adrenal cortical adenomas.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas have a predominantly nesting or alveolar pattern of growth. Lipid-rich, pale-staining cells are often identified in the more central aspect of the tumour and may impart a gold appearance to the tumour grossly on cut section.
Adrenal cortical adenoma. Aldosterone-secreting adrenal cortical adenomas often have lipid-rich clear cells centrally, with compact cells and zona glomerulosa–type cells at the peripheral aspect of the lesion.
Adrenal cortical adenoma. This aldosterone-secreting adrenal cortical adenoma is composed almost entirely of cells that resemble the zona glomerulosa. However, aldosterone-secreting adrenal cortical adenomas can have a heterogeneous appearance with many different cell types.
Adrenal cortical adenoma. A 23 mm aldosterone-producing adrenal cortical adenoma. The golden-yellow colour reflects the high lipid content.
Adrenal cortical adenoma. This photograph shows a 40 mm cortisol-producing adrenal cortical adenoma.
Non-functioning adrenal cortical adenoma. A non-functioning clear cell–rich adenoma is shown.
Adrenal cortical adenoma. An aldosterone-producing adenoma enriched in lipid-poor (compact) cells with variable spironolactone bodies (arrows).
Non-tumorous cortical atrophy in Cushing syndrome. The non-tumorous adrenal cortex shows atrophy in patients with cortisol-producing adrenal cortical neoplasms. The cortical atrophy is characterized by a thin adrenal cortex (often < 2 mm) and an absent or significantly reduced zona reticularis.

Q: Histologically, the granulosa cell subtype of an Adrenal sex cord stromal tumor typically shows tumor cells arranged in nests, cords, and tubules, often forming characteristic microfollicular structures known as [...].
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
A: Call-Exner bodies
Back Extra: Adrenal Sex Cord Stromal Tumour
- Clinical: Patients with Adrenal Granulosa Cell Tumour present with irregular uterine bleeding and/or an abdominal mass.
- Micro: Adrenal Granulosa Cell Tumour shows a microfollicular architecture with Call-Exner bodies and tumour cells arranged in nests, cords, and tubules.
- Ancillary: Adrenal Granulosa Cell Tumour is positive for inhibin and calretinin, and negative for chromogranin A.
Reference Gallery:
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
Adrenal granulosa cell tumour. Inhibin staining is positive.
Adrenal granulosa cell tumour. Chromogranin A is negative.

Q: To confirm the diagnosis of a granulosa cell subtype of an Adrenal sex cord stromal tumor, immunohistochemistry is typically negative for chromogranin A and positive for sex cord-stromal markers such as calretinin and [...].
Adrenal granulosa cell tumour. Inhibin staining is positive.
Adrenal granulosa cell tumour. Chromogranin A is negative.
A: inhibin
Back Extra: Adrenal Sex Cord Stromal Tumour
- Clinical: Patients with Adrenal Granulosa Cell Tumour present with irregular uterine bleeding and/or an abdominal mass.
- Micro: Adrenal Granulosa Cell Tumour shows a microfollicular architecture with Call-Exner bodies and tumour cells arranged in nests, cords, and tubules.
- Ancillary: Adrenal Granulosa Cell Tumour is positive for inhibin and calretinin, and negative for chromogranin A.
Reference Gallery:
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
Adrenal granulosa cell tumour. Tumour cells are arranged in nests, cords, and tubules.
Adrenal granulosa cell tumour. Inhibin staining is positive.
Adrenal granulosa cell tumour. Chromogranin A is negative.

Q: Microscopically, Adrenal Cortical Carcinoma typically demonstrates broad trabecular or solid growth patterns enriched with cytological atypia, necrosis, and [...], which are strongly indicative of abnormal chromosome content.
Adrenal cortical carcinoma. A conventional adrenal cortical carcinoma enriched in compact tumour cells with diffuse growth, variable cytological atypia, and an atypical mitotic figure.
Adrenal cortical carcinoma. In adrenal cortical carcinomas, atypical mitotic figures (arrow) are important findings suggestive of abnormal chromosome content.
A: atypical mitotic figures
Back Extra: Adrenal Cortical Carcinoma
- Clinical: Adrenal cortical carcinomas often present with symptoms of autonomous hormone secretion (e.g., Cushing syndrome, virilization) or an abdominal mass, with common signs including central obesity, muscle weakness, and fatigue.
- Micro: Adrenal cortical carcinomas typically show solid, broad trabecular, or large nested growth patterns with necrosis, haemorrhage, and atypical mitotic figures. Subtypes include oncocytic, myxoid, and sarcomatoid.
- Ancillary: SF1 is the most reliable biomarker for confirming the cortical origin, while IGF2 paranuclear immunoreactivity is useful in distinguishing adrenal cortical carcinoma from adenomas. p53 overexpression and nuclear β-catenin expression are indicative of biologically aggressive tumours.
Reference Gallery:
Adrenal cortical carcinoma. The cut surface of the tumour shows a yellowish-tan variegated appearance with necrosis and haemorrhage. The tumour shows no direct invasion into the kidney.
Adrenal cortical carcinoma. An example with diffuse solid and broad trabecular growth with tumour necrosis.
Adrenal cortical carcinoma. A conventional adrenal cortical carcinoma enriched in compact tumour cells with diffuse growth, variable cytological atypia, and an atypical mitotic figure.
Myxoid adrenal cortical carcinoma. Myxoid adrenal cortical carcinoma with abundant extracellular mucin deposition. The tumour cells show multiple mitotic figures.
Oncocytic adrenal cortical carcinoma. Oncocytic adrenal cortical neoplasms are often assessed using the Lin–Weiss–Bisceglia system. This is an oncocytic adrenal cortical carcinoma that shows increased mitotic activity and coagulative tumour necrosis.
Oncocytic adrenal cortical carcinoma. An oncocytic adrenal cortical carcinoma with focal comedonecrosis.
Sarcomatoid adrenal cortical carcinoma. These can be biphasic with typical differentiated areas (shown here), or they can have a monophasic appearance that can simulate a sarcoma.
Sarcomatoid adrenal cortical carcinoma. These can have a monophasic appearance (shown here) that can simulate a sarcoma, or they can be biphasic with typical differentiated areas.
Adrenal cortical carcinoma. Foci of venous angioinvasion (vascular invasion) in adrenal cortical carcinoma are characterized by intravascular tumour cells admixed with fibrin/thrombus.
Adrenal cortical carcinoma. In adrenal cortical carcinomas, atypical mitotic figures (arrow) are important findings suggestive of abnormal chromosome content.
Phosphohistone H3–assisted mitotic count. Phosphohistone H3 immunohistochemistry can facilitate mitotic count in adrenal cortical carcinomas with low-grade features. Mitotic figures are marked on this photomicrograph.
Adrenal cortical carcinoma. An example with intratumoural proliferative heterogeneity demonstrated using Ki-67 immunohistochemistry. Most adrenal cortical carcinomas show a Ki-67 labelling index > 5%.

Q: A highly specific ancillary finding used to evaluate the intratumoral proliferative heterogeneity and aggressiveness of Adrenal Cortical Carcinoma is a labeling index greater than 5% on [...] immunohistochemistry.
Adrenal cortical carcinoma. An example with intratumoural proliferative heterogeneity demonstrated using Ki-67 immunohistochemistry. Most adrenal cortical carcinomas show a Ki-67 labelling index > 5%.
A: Ki-67
Back Extra: Adrenal Cortical Carcinoma
- Clinical: Adrenal cortical carcinomas often present with symptoms of autonomous hormone secretion (e.g., Cushing syndrome, virilization) or an abdominal mass, with common signs including central obesity, muscle weakness, and fatigue.
- Micro: Adrenal cortical carcinomas typically show solid, broad trabecular, or large nested growth patterns with necrosis, haemorrhage, and atypical mitotic figures. Subtypes include oncocytic, myxoid, and sarcomatoid.
- Ancillary: SF1 is the most reliable biomarker for confirming the cortical origin, while IGF2 paranuclear immunoreactivity is useful in distinguishing adrenal cortical carcinoma from adenomas. p53 overexpression and nuclear β-catenin expression are indicative of biologically aggressive tumours.
Reference Gallery:
Adrenal cortical carcinoma. The cut surface of the tumour shows a yellowish-tan variegated appearance with necrosis and haemorrhage. The tumour shows no direct invasion into the kidney.
Adrenal cortical carcinoma. An example with diffuse solid and broad trabecular growth with tumour necrosis.
Adrenal cortical carcinoma. A conventional adrenal cortical carcinoma enriched in compact tumour cells with diffuse growth, variable cytological atypia, and an atypical mitotic figure.
Myxoid adrenal cortical carcinoma. Myxoid adrenal cortical carcinoma with abundant extracellular mucin deposition. The tumour cells show multiple mitotic figures.
Oncocytic adrenal cortical carcinoma. Oncocytic adrenal cortical neoplasms are often assessed using the Lin–Weiss–Bisceglia system. This is an oncocytic adrenal cortical carcinoma that shows increased mitotic activity and coagulative tumour necrosis.
Oncocytic adrenal cortical carcinoma. An oncocytic adrenal cortical carcinoma with focal comedonecrosis.
Sarcomatoid adrenal cortical carcinoma. These can be biphasic with typical differentiated areas (shown here), or they can have a monophasic appearance that can simulate a sarcoma.
Sarcomatoid adrenal cortical carcinoma. These can have a monophasic appearance (shown here) that can simulate a sarcoma, or they can be biphasic with typical differentiated areas.
Adrenal cortical carcinoma. Foci of venous angioinvasion (vascular invasion) in adrenal cortical carcinoma are characterized by intravascular tumour cells admixed with fibrin/thrombus.
Adrenal cortical carcinoma. In adrenal cortical carcinomas, atypical mitotic figures (arrow) are important findings suggestive of abnormal chromosome content.
Phosphohistone H3–assisted mitotic count. Phosphohistone H3 immunohistochemistry can facilitate mitotic count in adrenal cortical carcinomas with low-grade features. Mitotic figures are marked on this photomicrograph.
Adrenal cortical carcinoma. An example with intratumoural proliferative heterogeneity demonstrated using Ki-67 immunohistochemistry. Most adrenal cortical carcinomas show a Ki-67 labelling index > 5%.

Q: The oncocytic variant of Adrenal Cortical Carcinoma, characterized by cells with abundant eosinophilic cytoplasm, coagulative tumor necrosis, and increased mitotic activity, is typically assessed using the specialized [...] criteria.
Oncocytic adrenal cortical carcinoma. Oncocytic adrenal cortical neoplasms are often assessed using the Lin–Weiss–Bisceglia system. This is an oncocytic adrenal cortical carcinoma that shows increased mitotic activity and coagulative tumour necrosis.
Oncocytic adrenal cortical carcinoma. An oncocytic adrenal cortical carcinoma with focal comedonecrosis.
A: Lin-Weiss-Bisceglia
Back Extra: Adrenal Cortical Carcinoma
- Clinical: Adrenal cortical carcinomas often present with symptoms of autonomous hormone secretion (e.g., Cushing syndrome, virilization) or an abdominal mass, with common signs including central obesity, muscle weakness, and fatigue.
- Micro: Adrenal cortical carcinomas typically show solid, broad trabecular, or large nested growth patterns with necrosis, haemorrhage, and atypical mitotic figures. Subtypes include oncocytic, myxoid, and sarcomatoid.
- Ancillary: SF1 is the most reliable biomarker for confirming the cortical origin, while IGF2 paranuclear immunoreactivity is useful in distinguishing adrenal cortical carcinoma from adenomas. p53 overexpression and nuclear β-catenin expression are indicative of biologically aggressive tumours.
Reference Gallery:
Adrenal cortical carcinoma. The cut surface of the tumour shows a yellowish-tan variegated appearance with necrosis and haemorrhage. The tumour shows no direct invasion into the kidney.
Adrenal cortical carcinoma. An example with diffuse solid and broad trabecular growth with tumour necrosis.
Adrenal cortical carcinoma. A conventional adrenal cortical carcinoma enriched in compact tumour cells with diffuse growth, variable cytological atypia, and an atypical mitotic figure.
Myxoid adrenal cortical carcinoma. Myxoid adrenal cortical carcinoma with abundant extracellular mucin deposition. The tumour cells show multiple mitotic figures.
Oncocytic adrenal cortical carcinoma. Oncocytic adrenal cortical neoplasms are often assessed using the Lin–Weiss–Bisceglia system. This is an oncocytic adrenal cortical carcinoma that shows increased mitotic activity and coagulative tumour necrosis.
Oncocytic adrenal cortical carcinoma. An oncocytic adrenal cortical carcinoma with focal comedonecrosis.
Sarcomatoid adrenal cortical carcinoma. These can be biphasic with typical differentiated areas (shown here), or they can have a monophasic appearance that can simulate a sarcoma.
Sarcomatoid adrenal cortical carcinoma. These can have a monophasic appearance (shown here) that can simulate a sarcoma, or they can be biphasic with typical differentiated areas.
Adrenal cortical carcinoma. Foci of venous angioinvasion (vascular invasion) in adrenal cortical carcinoma are characterized by intravascular tumour cells admixed with fibrin/thrombus.
Adrenal cortical carcinoma. In adrenal cortical carcinomas, atypical mitotic figures (arrow) are important findings suggestive of abnormal chromosome content.
Phosphohistone H3–assisted mitotic count. Phosphohistone H3 immunohistochemistry can facilitate mitotic count in adrenal cortical carcinomas with low-grade features. Mitotic figures are marked on this photomicrograph.
Adrenal cortical carcinoma. An example with intratumoural proliferative heterogeneity demonstrated using Ki-67 immunohistochemistry. Most adrenal cortical carcinomas show a Ki-67 labelling index > 5%.

Q: In the spectrum of Adrenocortical Nodular Disease, the bilateral micronodular variant is most commonly [...], which is characterized by multiple small (< 10 mm) nodules enriched in compact (lipid-poor) cells.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Primary pigmented nodular adrenocortical disease. Gross examination of primary pigmented nodular adrenocortical disease identifies bilateral small pigmented cortical nodules (< 10 mm, often < 5 mm).
A: primary pigmented nodular adrenocortical disease (PPNAD)
Back Extra: Adrenocortical Nodular Disease
- Clinical: Bilateral micronodular adrenocortical disease (PPNAD) is often associated with Carney complex and presents with variable degrees of endogenous Cushing syndrome.
- Micro: Primary pigmented nodular adrenocortical disease (PPNAD) is characterized by multiple small pigmented nodules (< 10 mm) composed of compact (lipid-poor) adrenocortical cells.
- Ancillary: Germline testing for PRKAR1A, PRKACA, PDE11A, PDE8B, and ARMC5 variants is essential in diagnosing and managing patients with Adrenocortical Nodular Disease.
Reference Gallery:
Sporadic nodular adrenocortical disease. Sporadic nodular adrenocortical disease with a nodule measuring 7 mm. With the exception of its size (< 10 mm), sporadic nodular adrenocortical disease is indistinguishable from other non-functioning adenomas.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Bilateral macronodular adrenocortical disease. The disease is characterized by bilateral multiple clear cell–rich nodules, each measuring > 10 mm.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells.
Primary pigmented nodular adrenocortical disease. Gross examination of primary pigmented nodular adrenocortical disease identifies bilateral small pigmented cortical nodules (< 10 mm, often < 5 mm).
Bilateral macronodular adrenocortical disease. Irregular left adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Bilateral macronodular adrenocortical disease. Irregular right adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Sporadic nodular adrenocortical disease. Two foci of randomly distributed sporadic nodular adrenocortical disease that ranged in size from 1.5 to 3 mm are seen. The large focus is enriched in compact cells with variable pigment deposition, whereas the small focus is enriched in lipid-rich clear cells.

Q: Within the spectrum of Adrenocortical Nodular Disease, bilateral macronodular adrenocortical disease is characterized by multiple clear cell–rich nodules that individually measure [...] in size.
Bilateral macronodular adrenocortical disease. The disease is characterized by bilateral multiple clear cell–rich nodules, each measuring > 10 mm.
Bilateral macronodular adrenocortical disease. Irregular left adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
A: > 10 mm
Back Extra: Adrenocortical Nodular Disease
- Clinical: Bilateral micronodular adrenocortical disease (PPNAD) is often associated with Carney complex and presents with variable degrees of endogenous Cushing syndrome.
- Micro: Primary pigmented nodular adrenocortical disease (PPNAD) is characterized by multiple small pigmented nodules (< 10 mm) composed of compact (lipid-poor) adrenocortical cells.
- Ancillary: Germline testing for PRKAR1A, PRKACA, PDE11A, PDE8B, and ARMC5 variants is essential in diagnosing and managing patients with Adrenocortical Nodular Disease.
Reference Gallery:
Sporadic nodular adrenocortical disease. Sporadic nodular adrenocortical disease with a nodule measuring 7 mm. With the exception of its size (< 10 mm), sporadic nodular adrenocortical disease is indistinguishable from other non-functioning adenomas.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Bilateral macronodular adrenocortical disease. The disease is characterized by bilateral multiple clear cell–rich nodules, each measuring > 10 mm.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells.
Primary pigmented nodular adrenocortical disease. Gross examination of primary pigmented nodular adrenocortical disease identifies bilateral small pigmented cortical nodules (< 10 mm, often < 5 mm).
Bilateral macronodular adrenocortical disease. Irregular left adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Bilateral macronodular adrenocortical disease. Irregular right adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Sporadic nodular adrenocortical disease. Two foci of randomly distributed sporadic nodular adrenocortical disease that ranged in size from 1.5 to 3 mm are seen. The large focus is enriched in compact cells with variable pigment deposition, whereas the small focus is enriched in lipid-rich clear cells.

Q: A sporadic presentation of Adrenocortical Nodular Disease features small nodules (< 10 mm) that, aside from their size, are morphologically indistinguishable from [...].
Sporadic nodular adrenocortical disease. Sporadic nodular adrenocortical disease with a nodule measuring 7 mm. With the exception of its size (< 10 mm), sporadic nodular adrenocortical disease is indistinguishable from other non-functioning adenomas.
A: non-functioning adenomas
Back Extra: Adrenocortical Nodular Disease
- Clinical: Bilateral micronodular adrenocortical disease (PPNAD) is often associated with Carney complex and presents with variable degrees of endogenous Cushing syndrome.
- Micro: Primary pigmented nodular adrenocortical disease (PPNAD) is characterized by multiple small pigmented nodules (< 10 mm) composed of compact (lipid-poor) adrenocortical cells.
- Ancillary: Germline testing for PRKAR1A, PRKACA, PDE11A, PDE8B, and ARMC5 variants is essential in diagnosing and managing patients with Adrenocortical Nodular Disease.
Reference Gallery:
Sporadic nodular adrenocortical disease. Sporadic nodular adrenocortical disease with a nodule measuring 7 mm. With the exception of its size (< 10 mm), sporadic nodular adrenocortical disease is indistinguishable from other non-functioning adenomas.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Bilateral macronodular adrenocortical disease. The disease is characterized by bilateral multiple clear cell–rich nodules, each measuring > 10 mm.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells. Internodular cortical atrophy with reduced cortical thickness can be noted.
Primary pigmented nodular adrenocortical disease. This is the most common form of bilateral micronodular adrenocortical disease. It is characterized by multiple pigmented small nodules (< 10 mm) that often range in size from 1 to 4 mm. Cortical micronodules are enriched in compact (lipid-poor) adrenocortical cells.
Primary pigmented nodular adrenocortical disease. Gross examination of primary pigmented nodular adrenocortical disease identifies bilateral small pigmented cortical nodules (< 10 mm, often < 5 mm).
Bilateral macronodular adrenocortical disease. Irregular left adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Bilateral macronodular adrenocortical disease. Irregular right adrenal gland enlargement due to multiple adrenal cortical nodules, each > 10 mm.
Sporadic nodular adrenocortical disease. Two foci of randomly distributed sporadic nodular adrenocortical disease that ranged in size from 1.5 to 3 mm are seen. The large focus is enriched in compact cells with variable pigment deposition, whereas the small focus is enriched in lipid-rich clear cells.

Q: A unilateral suprarenal tumor characterized by pleomorphic epithelioid and fusiform cells with prominent nucleoli and distinct intracytoplasmic melanin pigment is characteristic of [...].
Primary adrenal melanoma. The focally pigmented tumour has a nodular architecture and is circumscribed. Adjacent adrenal cortical tissue is present (upper left).
Primary adrenal melanoma. The tumour is formed by pleomorphic polygonal and epithelioid cells. A lymphoid infiltrate is present at the periphery and focally within the tumour.
Primary adrenal melanoma. Many of the melanoma cells include intracytoplasmic melanin pigment. Occasional mitoses are present.
A: Primary Adrenal Melanoma
Back Extra: Primary Adrenal Melanoma
- Clinical: Primary adrenal melanoma usually presents as a unilateral suprarenal mass with constitutional symptoms, flank pain, or incidental findings on imaging.
- Micro: The tumour is characterized by pleomorphic epithelioid and fusiform cells with irregular nuclear membranes, vesicular chromatin, and prominent nucleoli. Intracytoplasmic melanin pigment is often present.
- Ancillary: Immunohistochemical stains for S100, SOX10, melan-A, and HMB45 are typically positive, while cytokeratins, synaptophysin, and chromogranin are consistently negative.
Reference Gallery:
Primary adrenal melanoma. The focally pigmented tumour has a nodular architecture and is circumscribed. Adjacent adrenal cortical tissue is present (upper left).
Primary adrenal melanoma. Melan-A immunostain showing strong positive staining of the melanoma cells. Weak positive staining is present in the adjacent adrenal cortex (upper left).
Primary adrenal melanoma. The tumour is formed by pleomorphic polygonal and epithelioid cells. A lymphoid infiltrate is present at the periphery and focally within the tumour.
Primary adrenal melanoma. Many of the melanoma cells include intracytoplasmic melanin pigment. Occasional mitoses are present.

Q: In Primary Adrenal Melanoma, the tumor cells show strong immunostaining for [...], which can be a diagnostic pitfall because the adjacent normal adrenal cortex also typically shows weak positivity for this marker.
Primary adrenal melanoma. Melan-A immunostain showing strong positive staining of the melanoma cells. Weak positive staining is present in the adjacent adrenal cortex (upper left).
A: Melan-A
Back Extra: Primary Adrenal Melanoma
- Clinical: Primary adrenal melanoma usually presents as a unilateral suprarenal mass with constitutional symptoms, flank pain, or incidental findings on imaging.
- Micro: The tumour is characterized by pleomorphic epithelioid and fusiform cells with irregular nuclear membranes, vesicular chromatin, and prominent nucleoli. Intracytoplasmic melanin pigment is often present.
- Ancillary: Immunohistochemical stains for S100, SOX10, melan-A, and HMB45 are typically positive, while cytokeratins, synaptophysin, and chromogranin are consistently negative.
Reference Gallery:
Primary adrenal melanoma. The focally pigmented tumour has a nodular architecture and is circumscribed. Adjacent adrenal cortical tissue is present (upper left).
Primary adrenal melanoma. Melan-A immunostain showing strong positive staining of the melanoma cells. Weak positive staining is present in the adjacent adrenal cortex (upper left).
Primary adrenal melanoma. The tumour is formed by pleomorphic polygonal and epithelioid cells. A lymphoid infiltrate is present at the periphery and focally within the tumour.
Primary adrenal melanoma. Many of the melanoma cells include intracytoplasmic melanin pigment. Occasional mitoses are present.

Q: Histologically, an Adrenal Myelolipoma is uniquely composed of a mixture of mature adipocytes and all three lineages of [...] cells.
Adrenal myelolipoma. Haematopoietic cells representing the three bone marrow lineages are evident adjacent to fat cells.
Adrenal myelolipoma. An example composed of mature adipocytes and haematopoietic cells including megakaryocytes that are admixed with adrenal cortical cells.
A: hematopoietic
Back Extra: Adrenal Myelolipoma
- Clinical: Adrenal myelolipomas are often asymptomatic and detected incidentally on imaging, but large tumors can cause compression, rupture, or hemorrhage.
- Micro: Histologically, adrenal myelolipomas are composed of mature adipocytes and all three hematopoietic cell lineages, with possible calcifications and osseous metaplasia.
- Ancillary: Ancillary studies are generally not clinically relevant for diagnosis.
Reference Gallery:
Adrenal myelolipoma. CT demonstrates a well-demarcated, fat-containing, 90 mm large lesion in the right adrenal.
Adrenal myelolipoma. Haematopoietic cells representing the three bone marrow lineages are evident adjacent to fat cells.
Adrenal myelolipoma. Macroscopic appearance of a 245 mm myelolipoma replacing almost the entire adrenal gland.
Adrenal myelolipoma. An example composed of mature adipocytes and haematopoietic cells including megakaryocytes that are admixed with adrenal cortical cells.

Q: Radiologically and macroscopically, an Adrenal Myelolipoma characteristically presents as a well-demarcated, [...]-containing lesion that is often asymptomatic but may cause hemorrhage if large.
Adrenal myelolipoma. CT demonstrates a well-demarcated, fat-containing, 90 mm large lesion in the right adrenal.
Adrenal myelolipoma. Macroscopic appearance of a 245 mm myelolipoma replacing almost the entire adrenal gland.
A: fat
Back Extra: Adrenal Myelolipoma
- Clinical: Adrenal myelolipomas are often asymptomatic and detected incidentally on imaging, but large tumors can cause compression, rupture, or hemorrhage.
- Micro: Histologically, adrenal myelolipomas are composed of mature adipocytes and all three hematopoietic cell lineages, with possible calcifications and osseous metaplasia.
- Ancillary: Ancillary studies are generally not clinically relevant for diagnosis.
Reference Gallery:
Adrenal myelolipoma. CT demonstrates a well-demarcated, fat-containing, 90 mm large lesion in the right adrenal.
Adrenal myelolipoma. Haematopoietic cells representing the three bone marrow lineages are evident adjacent to fat cells.
Adrenal myelolipoma. Macroscopic appearance of a 245 mm myelolipoma replacing almost the entire adrenal gland.
Adrenal myelolipoma. An example composed of mature adipocytes and haematopoietic cells including megakaryocytes that are admixed with adrenal cortical cells.

Q: Histologic evaluation of a Lipoma demonstrates a sheet-like proliferation of mature adipocytes characteristically lacking [...].
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.
A: atypical hyperchromatic stromal cells
Back Extra: Lipoma
- Clinical: Most lipomas of the pancreas and adrenal gland are usually asymptomatic and incidentally discovered; a small subset of patients may report abdominal pain. Rare cases of pancreatic lipoma result in pancreatitis.
- Micro: Histological review shows a sheet-like proliferation of mature adipocytes without atypical hyperchromatic stromal cells. Fat necrosis and dystrophic calcification may be present.
- Ancillary: FISH studies for MDM2 amplification may be helpful in excluding well-differentiated liposarcoma. Most lipomas harbour translocations involving 12q13-q15, resulting in the fusion of HMGA2 with a variety of gene partners, driving the pathogenesis of these tumours.
Reference Gallery:
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.

Q: To distinguish a Lipoma from a well-differentiated liposarcoma, FISH studies can be utilized to demonstrate the absence of [...] amplification.
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.
A: MDM2
Back Extra: Lipoma
- Clinical: Most lipomas of the pancreas and adrenal gland are usually asymptomatic and incidentally discovered; a small subset of patients may report abdominal pain. Rare cases of pancreatic lipoma result in pancreatitis.
- Micro: Histological review shows a sheet-like proliferation of mature adipocytes without atypical hyperchromatic stromal cells. Fat necrosis and dystrophic calcification may be present.
- Ancillary: FISH studies for MDM2 amplification may be helpful in excluding well-differentiated liposarcoma. Most lipomas harbour translocations involving 12q13-q15, resulting in the fusion of HMGA2 with a variety of gene partners, driving the pathogenesis of these tumours.
Reference Gallery:
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.

Q: The pathogenesis of most Lipomas is driven by translocations involving 12q13-q15, which most commonly result in the fusion of the [...] gene with various partners.
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.
A: HMGA2
Back Extra: Lipoma
- Clinical: Most lipomas of the pancreas and adrenal gland are usually asymptomatic and incidentally discovered; a small subset of patients may report abdominal pain. Rare cases of pancreatic lipoma result in pancreatitis.
- Micro: Histological review shows a sheet-like proliferation of mature adipocytes without atypical hyperchromatic stromal cells. Fat necrosis and dystrophic calcification may be present.
- Ancillary: FISH studies for MDM2 amplification may be helpful in excluding well-differentiated liposarcoma. Most lipomas harbour translocations involving 12q13-q15, resulting in the fusion of HMGA2 with a variety of gene partners, driving the pathogenesis of these tumours.
Reference Gallery:
Lipoma. Lipomas consist of mature adipocytes without fibrous septa or atypical hyperchromatic stromal cells.

Q: A defining architectural feature of Perivascular Epithelioid Cell Tumor (PEComa) is the arrangement of bland epithelioid cells with clear to granular eosinophilic cytoplasm immediately surrounding [...].
PEComa of the adrenal gland. The tumour cells are characteristically arranged around blood vessels, often approximating the endothelium.
PEComa of the adrenal gland. The cells may be spindled or epithelioid, are typically bland, and have variable amounts of clear or granular eosinophilic cytoplasm.
A: blood vessels
Back Extra: Perivascular Epithelioid Cell Tumour (PEComa)
- Clinical: PEComa of the adrenal gland is often incidentally detected radiologically, but can present as a mass or with endocrine dysfunction. It shows a female predilection with a peak in young to middle-aged adults.
- Micro: PEComa is characterized by a nested growth pattern with epithelioid cells arranged around blood vessels. The cells have abundant granular eosinophilic or clear cytoplasm and round nuclei with small nucleoli.
- Ancillary: PEComa cells typically express both melanocytic markers (e.g., HMB45, Melan-A) and muscle markers (e.g., SMA, desmin). TFE3 rearrangements and TSC2 mutations are also common.
Reference Gallery:
PEComa of adrenal gland. The neoplasm is well circumscribed, and adrenal cortex can be seen to the left.
PEComa of adrenal gland. A nested growth pattern is characteristic of PEComa. The stroma may be collagenous or hyalinized.
PEComa of the adrenal gland. The tumour cells are characteristically arranged around blood vessels, often approximating the endothelium.
PEComa of the adrenal gland. Strong diffuse desmin expression in neoplastic cells.
PEComa of the adrenal gland. Focal expression of HMB45 in neoplastic cells.
PEComa of the adrenal gland. The cells may be spindled or epithelioid, are typically bland, and have variable amounts of clear or granular eosinophilic cytoplasm.

Q: Immunohistochemically, a pathognomonic feature of Perivascular Epithelioid Cell Tumor (PEComa) is the unique co-expression of muscle markers (e.g., desmin) and [...] markers (e.g., HMB45).
PEComa of the adrenal gland. Strong diffuse desmin expression in neoplastic cells.
PEComa of the adrenal gland. Focal expression of HMB45 in neoplastic cells.
A: melanocytic
Back Extra: Perivascular Epithelioid Cell Tumour (PEComa)
- Clinical: PEComa of the adrenal gland is often incidentally detected radiologically, but can present as a mass or with endocrine dysfunction. It shows a female predilection with a peak in young to middle-aged adults.
- Micro: PEComa is characterized by a nested growth pattern with epithelioid cells arranged around blood vessels. The cells have abundant granular eosinophilic or clear cytoplasm and round nuclei with small nucleoli.
- Ancillary: PEComa cells typically express both melanocytic markers (e.g., HMB45, Melan-A) and muscle markers (e.g., SMA, desmin). TFE3 rearrangements and TSC2 mutations are also common.
Reference Gallery:
PEComa of adrenal gland. The neoplasm is well circumscribed, and adrenal cortex can be seen to the left.
PEComa of adrenal gland. A nested growth pattern is characteristic of PEComa. The stroma may be collagenous or hyalinized.
PEComa of the adrenal gland. The tumour cells are characteristically arranged around blood vessels, often approximating the endothelium.
PEComa of the adrenal gland. Strong diffuse desmin expression in neoplastic cells.
PEComa of the adrenal gland. Focal expression of HMB45 in neoplastic cells.
PEComa of the adrenal gland. The cells may be spindled or epithelioid, are typically bland, and have variable amounts of clear or granular eosinophilic cytoplasm.

Q: In Metastasis to the Adrenal Gland, metastatic clear cell renal carcinoma can morphologically mimic zona fasciculata-type cells, but is reliably distinguished by strong nuclear expression of [...].
Metastatic clear cell renal carcinoma in the adrenal gland. Given the clear cytoplasm, the malignant cells are morphologically similar to zona fasciculata–type cells. The presence of cystic change is a clue, but immunohistochemistry would be required for a definitive diagnosis.
Metastatic clear cell renal carcinoma in the adrenal gland. Diffuse strong nuclear expression of PAX8 in metastatic clear cell carcinoma in the adrenal gland allows ready distinction from zona glomerulosa–type adrenal cortical cells (PAX8 immunohistochemistry).
A: PAX8
Back Extra: Metastasis to the Adrenal Gland
- Clinical: Adrenal metastases are usually asymptomatic, but they may be associated with abdominal pain. Bilateral involvement is a key indicator of metastasis.
- Micro: Melanoma, lung, breast, kidney, and gastrointestinal tract carcinomas are common primary sites for metastasis to the adrenal gland. Immunohistochemistry is crucial for distinguishing metastatic lesions from primary adrenal cortical neoplasms.
- Ancillary: Molecular testing can help identify the primary site of origin and guide therapy in metastatic adrenal lesions.
Reference Gallery:
Metastatic clear cell renal carcinoma in the adrenal gland. Given the clear cytoplasm, the malignant cells are morphologically similar to zona fasciculata–type cells. The presence of cystic change is a clue, but immunohistochemistry would be required for a definitive diagnosis.
Metastatic clear cell renal carcinoma in the adrenal gland. Diffuse strong nuclear expression of PAX8 in metastatic clear cell carcinoma in the adrenal gland allows ready distinction from zona glomerulosa–type adrenal cortical cells (PAX8 immunohistochemistry).
Metastatic colorectal carcinoma to the adrenal gland. In this patient with known colorectal adenocarcinoma, the morphology of the metastatic deposit being composed of tall columnar cells with associated dirty necrosis allows definitive diagnosis without immunohistochemistry.
Metastatic lung carcinoma to the adrenal. This example is from a 37-year-old woman with a history of lung carcinoma. The adrenal, 9 g, revealed a 12 mm homogeneous grey-white, firm, infiltrative lesion focally replacing the cortex and the medulla.

Q: When evaluating Metastasis to the Adrenal Gland from a colorectal primary, the classic histologic deposit is composed of tall columnar cells associated with [...].
Metastatic colorectal carcinoma to the adrenal gland. In this patient with known colorectal adenocarcinoma, the morphology of the metastatic deposit being composed of tall columnar cells with associated dirty necrosis allows definitive diagnosis without immunohistochemistry.
A: dirty necrosis
Back Extra: Metastasis to the Adrenal Gland
- Clinical: Adrenal metastases are usually asymptomatic, but they may be associated with abdominal pain. Bilateral involvement is a key indicator of metastasis.
- Micro: Melanoma, lung, breast, kidney, and gastrointestinal tract carcinomas are common primary sites for metastasis to the adrenal gland. Immunohistochemistry is crucial for distinguishing metastatic lesions from primary adrenal cortical neoplasms.
- Ancillary: Molecular testing can help identify the primary site of origin and guide therapy in metastatic adrenal lesions.
Reference Gallery:
Metastatic clear cell renal carcinoma in the adrenal gland. Given the clear cytoplasm, the malignant cells are morphologically similar to zona fasciculata–type cells. The presence of cystic change is a clue, but immunohistochemistry would be required for a definitive diagnosis.
Metastatic clear cell renal carcinoma in the adrenal gland. Diffuse strong nuclear expression of PAX8 in metastatic clear cell carcinoma in the adrenal gland allows ready distinction from zona glomerulosa–type adrenal cortical cells (PAX8 immunohistochemistry).
Metastatic colorectal carcinoma to the adrenal gland. In this patient with known colorectal adenocarcinoma, the morphology of the metastatic deposit being composed of tall columnar cells with associated dirty necrosis allows definitive diagnosis without immunohistochemistry.
Metastatic lung carcinoma to the adrenal. This example is from a 37-year-old woman with a history of lung carcinoma. The adrenal, 9 g, revealed a 12 mm homogeneous grey-white, firm, infiltrative lesion focally replacing the cortex and the medulla.

Q: Grossly, Metastasis to the Adrenal Gland from a primary [...] often presents as a homogeneous gray-white, firm, infiltrative lesion that focally replaces the cortex and medulla.
Metastatic lung carcinoma to the adrenal. This example is from a 37-year-old woman with a history of lung carcinoma. The adrenal, 9 g, revealed a 12 mm homogeneous grey-white, firm, infiltrative lesion focally replacing the cortex and the medulla.
A: lung carcinoma
Back Extra: Metastasis to the Adrenal Gland
- Clinical: Adrenal metastases are usually asymptomatic, but they may be associated with abdominal pain. Bilateral involvement is a key indicator of metastasis.
- Micro: Melanoma, lung, breast, kidney, and gastrointestinal tract carcinomas are common primary sites for metastasis to the adrenal gland. Immunohistochemistry is crucial for distinguishing metastatic lesions from primary adrenal cortical neoplasms.
- Ancillary: Molecular testing can help identify the primary site of origin and guide therapy in metastatic adrenal lesions.
Reference Gallery:
Metastatic clear cell renal carcinoma in the adrenal gland. Given the clear cytoplasm, the malignant cells are morphologically similar to zona fasciculata–type cells. The presence of cystic change is a clue, but immunohistochemistry would be required for a definitive diagnosis.
Metastatic clear cell renal carcinoma in the adrenal gland. Diffuse strong nuclear expression of PAX8 in metastatic clear cell carcinoma in the adrenal gland allows ready distinction from zona glomerulosa–type adrenal cortical cells (PAX8 immunohistochemistry).
Metastatic colorectal carcinoma to the adrenal gland. In this patient with known colorectal adenocarcinoma, the morphology of the metastatic deposit being composed of tall columnar cells with associated dirty necrosis allows definitive diagnosis without immunohistochemistry.
Metastatic lung carcinoma to the adrenal. This example is from a 37-year-old woman with a history of lung carcinoma. The adrenal, 9 g, revealed a 12 mm homogeneous grey-white, firm, infiltrative lesion focally replacing the cortex and the medulla.

Q: [...] is a biphasic tumor characterized histologically by an admixture of typical chromaffin cells with basophilic granular cytoplasm and a ganglioneuroma component (mature ganglion cells in a fibrillary Schwannian stroma).
Composite phaeochromocytoma. Histology showing a phaeochromocytoma composed of chromaffin tumour cells with basophilic granular cytoplasm (left) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (right).
Bladder composite paraganglioma. A composite paraganglioma of the urinary bladder with chromaffin tumour cells that have basophilic granular cytoplasm (right) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (left).
A: Composite Phaeochromocytoma and Paraganglioma
Back Extra: Composite Phaeochromocytoma and Paraganglioma
- Clinical: Composite phaeochromocytomas and paragangliomas often present with signs and symptoms of catecholamine excess, such as paroxysmal hypertension, palpitations, headache, or sweating.
- Micro: Histologically, the phaeochromocytoma component is characterized by chromaffin tumour cells with basophilic granular cytoplasm, while the ganglioneuroma component shows mature ganglion cells in a fibrillary Schwannian stroma–rich background.
- Ancillary: Clinical or molecular screening for NF1, RET, VHL, or MAX mutations may be appropriate in selected cases of composite phaeochromocytoma and paraganglioma.
Reference Gallery:
Composite phaeochromocytoma. Adrenal gland with a mixture of a cystic brownish phaeochromocytoma region and a whitish ganglioneuroma region.
Composite phaeochromocytoma. Histology showing a phaeochromocytoma composed of chromaffin tumour cells with basophilic granular cytoplasm (left) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (right).
Bladder composite paraganglioma. A composite paraganglioma of the urinary bladder with chromaffin tumour cells that have basophilic granular cytoplasm (right) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (left).

Q: Grossly, the adrenal manifestation of Composite Phaeochromocytoma and Paraganglioma classically exhibits a brownish cystic region (representing the chromaffin cells) intermixed with a whitish region that corresponds to the [...] component.
Composite phaeochromocytoma. Adrenal gland with a mixture of a cystic brownish phaeochromocytoma region and a whitish ganglioneuroma region.
A: ganglioneuroma
Back Extra: Composite Phaeochromocytoma and Paraganglioma
- Clinical: Composite phaeochromocytomas and paragangliomas often present with signs and symptoms of catecholamine excess, such as paroxysmal hypertension, palpitations, headache, or sweating.
- Micro: Histologically, the phaeochromocytoma component is characterized by chromaffin tumour cells with basophilic granular cytoplasm, while the ganglioneuroma component shows mature ganglion cells in a fibrillary Schwannian stroma–rich background.
- Ancillary: Clinical or molecular screening for NF1, RET, VHL, or MAX mutations may be appropriate in selected cases of composite phaeochromocytoma and paraganglioma.
Reference Gallery:
Composite phaeochromocytoma. Adrenal gland with a mixture of a cystic brownish phaeochromocytoma region and a whitish ganglioneuroma region.
Composite phaeochromocytoma. Histology showing a phaeochromocytoma composed of chromaffin tumour cells with basophilic granular cytoplasm (left) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (right).
Bladder composite paraganglioma. A composite paraganglioma of the urinary bladder with chromaffin tumour cells that have basophilic granular cytoplasm (right) and ganglioneuroma with mature ganglion cells in a fibrillary Schwannian stroma–rich background (left).

Q: The microscopic hallmark of Ganglioneuroblastoma, intermixed consists of well-demarcated microscopic foci of neuroblastic cells embedded within [...], which are randomly distributed in a predominantly ganglioneuromatous background.
Ganglioneuroblastoma, intermixed. Hallmarks of intermixed ganglioneuroblastoma are well-demarcated microscopic foci containing neuroblastic cells embedded in neuropil. The foci are randomly distributed in ganglioneuromatous tissue composed of Schwannian cells and maturing/mature ganglionic cells. The ganglioneuromatous component exceeds 50% of the section.
Ganglioneuroblastoma, intermixed. The neuroblastic cells are at various stages of differentiation and are dominated by differentiating neuroblasts.
A: neuropil
Back Extra: Ganglioneuroblastoma, intermixed
- Clinical: Ganglioneuroblastoma, intermixed (GNBi) often presents as an asymptomatic mass, generally lacking the elevated urine catecholamines seen in neuroblastoma.
- Micro: Well-circumscribed lacunar areas of neuroblastic cells embedded in neuropil are randomly distributed in ganglioneuromatous tissue composed of Schwannian cells and maturing/mature ganglionic cells.
- Ancillary: Immunohistochemistry for synaptophysin and S100 aids in distinguishing neuropil and Schwann cells.
Reference Gallery:
Ganglioneuroblastoma, intermixed. Hallmarks of intermixed ganglioneuroblastoma are well-demarcated microscopic foci containing neuroblastic cells embedded in neuropil. The foci are randomly distributed in ganglioneuromatous tissue composed of Schwannian cells and maturing/mature ganglionic cells. The ganglioneuromatous component exceeds 50% of the section.
Ganglioneuroblastoma, intermixed. The neuroblastic cells are at various stages of differentiation and are dominated by differentiating neuroblasts.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for synaptophysin. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin but is negative for S100 (see Fig. 26681).
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for S100. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin (see Fig. 26680) but is negative for S100.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for synaptophysin. In addition to neuropil-containing tumour foci, intermixed ganglioneuroblastoma may show clusters of ganglionic cells that do not include appreciable amounts of synaptophysin-positive neuropil (shown here) but do show S100-positive Schwannian cells (see Fig. 26683), typically found in maturing and mature ganglioneuroma, thus demonstrating the ongoing differentiation from a stroma-rich to a stroma-dominant tumour. Immunostaining for synaptophysin might aid the identification of neuropil in the differential diagnosis between intermixed ganglioneuroblastoma and ganglioneuroma.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for S100. In addition to neuropil-containing tumour foci, intermixed ganglioneuroblastoma may show clusters of ganglionic cells that do not include appreciable amounts of synaptophysin-positive neuropil (see Fig. 26682), but do show S100-positive Schwannian cells (shown here), typically found in maturing and mature ganglioneuroma, thus demonstrating the ongoing differentiation from a stroma-rich to a stroma-dominant tumour. Immunostaining for synaptophysin might aid the identification of neuropil in the differential diagnosis between intermixed ganglioneuroblastoma and ganglioneuroma.

Q: To confirm the presence of neuropil within the tumor foci of Ganglioneuroblastoma, intermixed, immunohistochemical staining demonstrates strong positivity for [...] and negativity for S100.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for synaptophysin. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin but is negative for S100 (see Fig. 26681).
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for S100. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin (see Fig. 26680) but is negative for S100.
A: synaptophysin
Back Extra: Ganglioneuroblastoma, intermixed
- Clinical: Ganglioneuroblastoma, intermixed (GNBi) often presents as an asymptomatic mass, generally lacking the elevated urine catecholamines seen in neuroblastoma.
- Micro: Well-circumscribed lacunar areas of neuroblastic cells embedded in neuropil are randomly distributed in ganglioneuromatous tissue composed of Schwannian cells and maturing/mature ganglionic cells.
- Ancillary: Immunohistochemistry for synaptophysin and S100 aids in distinguishing neuropil and Schwann cells.
Reference Gallery:
Ganglioneuroblastoma, intermixed. Hallmarks of intermixed ganglioneuroblastoma are well-demarcated microscopic foci containing neuroblastic cells embedded in neuropil. The foci are randomly distributed in ganglioneuromatous tissue composed of Schwannian cells and maturing/mature ganglionic cells. The ganglioneuromatous component exceeds 50% of the section.
Ganglioneuroblastoma, intermixed. The neuroblastic cells are at various stages of differentiation and are dominated by differentiating neuroblasts.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for synaptophysin. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin but is negative for S100 (see Fig. 26681).
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for S100. The presence of neuropil in tumour foci is a prerequisite for the diagnosis of intermixed ganglioneuroblastoma. Neuropil strongly expresses synaptophysin (see Fig. 26680) but is negative for S100.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for synaptophysin. In addition to neuropil-containing tumour foci, intermixed ganglioneuroblastoma may show clusters of ganglionic cells that do not include appreciable amounts of synaptophysin-positive neuropil (shown here) but do show S100-positive Schwannian cells (see Fig. 26683), typically found in maturing and mature ganglioneuroma, thus demonstrating the ongoing differentiation from a stroma-rich to a stroma-dominant tumour. Immunostaining for synaptophysin might aid the identification of neuropil in the differential diagnosis between intermixed ganglioneuroblastoma and ganglioneuroma.
Ganglioneuroblastoma, intermixed. Immunohistochemical staining for S100. In addition to neuropil-containing tumour foci, intermixed ganglioneuroblastoma may show clusters of ganglionic cells that do not include appreciable amounts of synaptophysin-positive neuropil (see Fig. 26682), but do show S100-positive Schwannian cells (shown here), typically found in maturing and mature ganglioneuroma, thus demonstrating the ongoing differentiation from a stroma-rich to a stroma-dominant tumour. Immunostaining for synaptophysin might aid the identification of neuropil in the differential diagnosis between intermixed ganglioneuroblastoma and ganglioneuroma.

Q: A composite adrenal tumor demonstrating both a Schwannian stroma-rich component (ganglioneuroma or intermixed ganglioneuroblastoma) and a discrete, often hemorrhagic Schwannian stroma-poor neuroblastoma nodule is diagnostic of [...].
Ganglioneuroblastoma, nodular. Composite Schwannian stroma–rich/dominant tumour with a discrete haemorrhagic neuroblastoma (Schwannian stroma–poor) nodule.
A: Ganglioneuroblastoma, Nodular
Back Extra: Ganglioneuroblastoma, Nodular
- Clinical: Adrenal {{Ganglioneuroblastoma, Nodular}} is detected as a suprarenal mass, often in children aged > 18 months.
- Micro: Diagnosis of {{Ganglioneuroblastoma, Nodular}} requires identifying both ganglioneuroblastoma (GNBi) or ganglioneuroma and neuroblastoma in a single tumour.
- Ancillary: Genomic/molecular investigations focus on the neuroblastoma component, with MYCN amplification being rare (2%).
Reference Gallery:
Ganglioneuroblastoma, nodular. Composite Schwannian stroma–rich/dominant tumour with a discrete haemorrhagic neuroblastoma (Schwannian stroma–poor) nodule.
Ganglioneuroblastoma nodular. Neuroblastoma (Schwannian stroma–poor, poorly differentiated) nodule with a pushing margin at the junction with ganglioneuroblastoma, intermixed (Schwannian stroma–rich).

Q: Histologically, Ganglioneuroblastoma, Nodular is characterized by a biphasic appearance, where a stroma-rich background often shares a pushing margin with a discrete nodule of poorly differentiated, Schwannian stroma-poor [...].
Ganglioneuroblastoma nodular. Neuroblastoma (Schwannian stroma–poor, poorly differentiated) nodule with a pushing margin at the junction with ganglioneuroblastoma, intermixed (Schwannian stroma–rich).
A: neuroblastoma
Back Extra: Ganglioneuroblastoma, Nodular
- Clinical: Adrenal {{Ganglioneuroblastoma, Nodular}} is detected as a suprarenal mass, often in children aged > 18 months.
- Micro: Diagnosis of {{Ganglioneuroblastoma, Nodular}} requires identifying both ganglioneuroblastoma (GNBi) or ganglioneuroma and neuroblastoma in a single tumour.
- Ancillary: Genomic/molecular investigations focus on the neuroblastoma component, with MYCN amplification being rare (2%).
Reference Gallery:
Ganglioneuroblastoma, nodular. Composite Schwannian stroma–rich/dominant tumour with a discrete haemorrhagic neuroblastoma (Schwannian stroma–poor) nodule.
Ganglioneuroblastoma nodular. Neuroblastoma (Schwannian stroma–poor, poorly differentiated) nodule with a pushing margin at the junction with ganglioneuroblastoma, intermixed (Schwannian stroma–rich).

Q: Ganglioneuroma is typically characterized microscopically by an abundant background of [...] arranged in sheets and fascicles, intermixed with mature and maturing ganglion cells.
Ganglioneuroma. Schwannian stroma–dominant.
Ganglioneuroma. Maturing subtype, composed of mature Schwannian stroma and ganglion cells, some of which are not completely mature.
A: Schwann cells
Back Extra: Ganglioneuroma
- Clinical: Most ganglioneuromas are incidental findings during imaging for unrelated events and are usually non-functioning.
- Micro: Contains abundant Schwann cells in sheets and fascicles, with variable numbers of mature and maturing ganglion cells.
- Ancillary: Ancillary studies are not clinically relevant for diagnosis.
Reference Gallery:
Ganglioneuroma. Schwannian stroma–dominant.
Ganglioneuroma. Maturing subtype, composed of mature Schwannian stroma and ganglion cells, some of which are not completely mature.

Q: Histologically, a Ganglioneuroma is composed of abundant mature Schwannian stroma interspersed with variable numbers of large, mature or maturing [...].
Ganglioneuroma. Schwannian stroma–dominant.
Ganglioneuroma. Maturing subtype, composed of mature Schwannian stroma and ganglion cells, some of which are not completely mature.
A: ganglion cells
Back Extra: Ganglioneuroma
- Clinical: Most ganglioneuromas are incidental findings during imaging for unrelated events and are usually non-functioning.
- Micro: Contains abundant Schwann cells in sheets and fascicles, with variable numbers of mature and maturing ganglion cells.
- Ancillary: Ancillary studies are not clinically relevant for diagnosis.
Reference Gallery:
Ganglioneuroma. Schwannian stroma–dominant.
Ganglioneuroma. Maturing subtype, composed of mature Schwannian stroma and ganglion cells, some of which are not completely mature.

Q: The most common site of origin for Neuroblastoma is the [...], which typically presents grossly as a large, hemorrhagic mass with focal necrosis and calcification.
Adrenal neuroblastoma. Gross appearance of adrenal neuroblastoma. The tumour has a haemorrhagic appearance with focal necrosis and calcification.
A: adrenal medulla
Back Extra: Neuroblastoma
- Clinical: Neuroblastoma is most commonly found in the adrenal gland, particularly the adrenal medulla, and can present with metastases causing lymphadenopathy, hepatomegaly, bone pain, and raccoon eyes.
- Micro: The poorly differentiated subtype of neuroblastoma often shows Homer Wright rosettes, which are characteristic structures formed by cells surrounding a central fibrillary space.
- Ancillary: MYCN amplification and MYC protein overexpression are significant prognostic markers for neuroblastoma, with MYCN amplification being associated with advanced-stage disease and aggressive clinical behavior.
Reference Gallery:
Adrenal neuroblastoma. Gross appearance of adrenal neuroblastoma. The tumour has a haemorrhagic appearance with focal necrosis and calcification.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, undifferentiated subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, poorly differentiated subtype (inset: Homer Wright rosette).
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, differentiating subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Large cell neuroblastoma with uniquely enlarged and euchromatin-rich nuclei and nucleolar hypertrophy.
Molecular and immunohistochemical features of neuroblastoma. MYCN amplification in neuroblastoma as determined by FISH. Multiple MYCN signals (green), along with two control signals (red), in neuroblastoma interphase nuclei, counterstained with DAPI (blue).
Molecular and immunohistochemical features of neuroblastoma. MYCN protein positivity in neuroblastoma MYC-driven neuroblastoma. MYC protein immunostaining without haematoxylin counterstaining.
Molecular and immunohistochemical features of neuroblastoma. MYC protein–positive neuroblastoma. MYC-driven neuroblastoma. MYC (c-myc) immunostaining with haematoxylin counterstaining.
Molecular features of neuroblastoma. TERT rearrangement in neuroblastoma. Break-apart FISH of TERT in metaphase, with split TERT (green) and control (red) signals in two derivative chromosomes, indicating rearrangement of the TERT locus (arrowheads), in addition to the colocalization of the signals in two normal copies of chromosome 5 (asterisks).
Molecular features of neuroblastoma. Alternative-lengthening-of-telomeres phenotype in neuroblastoma cells, as indicated by alternative lengthening of telomeres–associated promyelocytic leukaemia (PML) nuclear bodies (APBs) in interphase nuclei. Telomeric FISH (green) and PML immunofluorescence (red) were combined, and APB was identified by the colocalization of bright telomere and PML signals.

Q: The poorly differentiated subtype of Neuroblastoma is classically characterized by the presence of [...], which consist of tumor cells surrounding a central fibrillary space.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, poorly differentiated subtype (inset: Homer Wright rosette).
A: Homer Wright rosettes
Back Extra: Neuroblastoma
- Clinical: Neuroblastoma is most commonly found in the adrenal gland, particularly the adrenal medulla, and can present with metastases causing lymphadenopathy, hepatomegaly, bone pain, and raccoon eyes.
- Micro: The poorly differentiated subtype of neuroblastoma often shows Homer Wright rosettes, which are characteristic structures formed by cells surrounding a central fibrillary space.
- Ancillary: MYCN amplification and MYC protein overexpression are significant prognostic markers for neuroblastoma, with MYCN amplification being associated with advanced-stage disease and aggressive clinical behavior.
Reference Gallery:
Adrenal neuroblastoma. Gross appearance of adrenal neuroblastoma. The tumour has a haemorrhagic appearance with focal necrosis and calcification.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, undifferentiated subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, poorly differentiated subtype (inset: Homer Wright rosette).
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, differentiating subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Large cell neuroblastoma with uniquely enlarged and euchromatin-rich nuclei and nucleolar hypertrophy.
Molecular and immunohistochemical features of neuroblastoma. MYCN amplification in neuroblastoma as determined by FISH. Multiple MYCN signals (green), along with two control signals (red), in neuroblastoma interphase nuclei, counterstained with DAPI (blue).
Molecular and immunohistochemical features of neuroblastoma. MYCN protein positivity in neuroblastoma MYC-driven neuroblastoma. MYC protein immunostaining without haematoxylin counterstaining.
Molecular and immunohistochemical features of neuroblastoma. MYC protein–positive neuroblastoma. MYC-driven neuroblastoma. MYC (c-myc) immunostaining with haematoxylin counterstaining.
Molecular features of neuroblastoma. TERT rearrangement in neuroblastoma. Break-apart FISH of TERT in metaphase, with split TERT (green) and control (red) signals in two derivative chromosomes, indicating rearrangement of the TERT locus (arrowheads), in addition to the colocalization of the signals in two normal copies of chromosome 5 (asterisks).
Molecular features of neuroblastoma. Alternative-lengthening-of-telomeres phenotype in neuroblastoma cells, as indicated by alternative lengthening of telomeres–associated promyelocytic leukaemia (PML) nuclear bodies (APBs) in interphase nuclei. Telomeric FISH (green) and PML immunofluorescence (red) were combined, and APB was identified by the colocalization of bright telomere and PML signals.

Q: A significant poor prognostic marker in Neuroblastoma is [...] amplification, which is strongly associated with advanced-stage disease and aggressive clinical behavior.
Molecular and immunohistochemical features of neuroblastoma. MYCN amplification in neuroblastoma as determined by FISH. Multiple MYCN signals (green), along with two control signals (red), in neuroblastoma interphase nuclei, counterstained with DAPI (blue).
A: MYCN
Back Extra: Neuroblastoma
- Clinical: Neuroblastoma is most commonly found in the adrenal gland, particularly the adrenal medulla, and can present with metastases causing lymphadenopathy, hepatomegaly, bone pain, and raccoon eyes.
- Micro: The poorly differentiated subtype of neuroblastoma often shows Homer Wright rosettes, which are characteristic structures formed by cells surrounding a central fibrillary space.
- Ancillary: MYCN amplification and MYC protein overexpression are significant prognostic markers for neuroblastoma, with MYCN amplification being associated with advanced-stage disease and aggressive clinical behavior.
Reference Gallery:
Adrenal neuroblastoma. Gross appearance of adrenal neuroblastoma. The tumour has a haemorrhagic appearance with focal necrosis and calcification.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, undifferentiated subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, poorly differentiated subtype (inset: Homer Wright rosette).
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Neuroblastoma, differentiating subtype.
Neuroblastoma. Histopathology of tumours in the neuroblastoma (Schwannian stroma–poor) category. Large cell neuroblastoma with uniquely enlarged and euchromatin-rich nuclei and nucleolar hypertrophy.
Molecular and immunohistochemical features of neuroblastoma. MYCN amplification in neuroblastoma as determined by FISH. Multiple MYCN signals (green), along with two control signals (red), in neuroblastoma interphase nuclei, counterstained with DAPI (blue).
Molecular and immunohistochemical features of neuroblastoma. MYCN protein positivity in neuroblastoma MYC-driven neuroblastoma. MYC protein immunostaining without haematoxylin counterstaining.
Molecular and immunohistochemical features of neuroblastoma. MYC protein–positive neuroblastoma. MYC-driven neuroblastoma. MYC (c-myc) immunostaining with haematoxylin counterstaining.
Molecular features of neuroblastoma. TERT rearrangement in neuroblastoma. Break-apart FISH of TERT in metaphase, with split TERT (green) and control (red) signals in two derivative chromosomes, indicating rearrangement of the TERT locus (arrowheads), in addition to the colocalization of the signals in two normal copies of chromosome 5 (asterisks).
Molecular features of neuroblastoma. Alternative-lengthening-of-telomeres phenotype in neuroblastoma cells, as indicated by alternative lengthening of telomeres–associated promyelocytic leukaemia (PML) nuclear bodies (APBs) in interphase nuclei. Telomeric FISH (green) and PML immunofluorescence (red) were combined, and APB was identified by the colocalization of bright telomere and PML signals.

Q: The classic histologic hallmark of a Parasympathetic Paraganglioma is a nested, highly vascularized architecture composed of chief cells and sustentacular cells known as the [...] pattern.
SDHB-related carotid body paraganglioma. Areas with a nested Zellballen pattern are present focally at the periphery of the tumour, but the tumour mostly consists of small cells with solid and infiltrative growth.
A: Zellballen
Back Extra: Parasympathetic Paraganglioma
- Clinical: Parasympathetic paragangliomas are typically associated with the vagus and glossopharyngeal nerves, often presenting as asymptomatic mass lesions or with symptoms like pulsatile tinnitus and hearing abnormalities.
- Micro: Tumours exhibit a variable Zellballen architecture with chief cells and peripherally located sustentacular cells, and a highly vascular stroma.
- Ancillary: Chief cells express neuroendocrine markers such as INSM1, synaptophysin, and chromogranin A, and sustentacular cells express S100 and SOX10.
Reference Gallery:
Carotid body paraganglioma. This paraganglioma encircles the carotid bulb and partially surrounds the internal carotid artery.
SDHB-related carotid body paraganglioma. This fibrotic SDHB-mutated paraganglioma encases the carotid artery and extends to the resection margins.
SDHB-related carotid body paraganglioma. Areas with a nested Zellballen pattern are present focally at the periphery of the tumour, but the tumour mostly consists of small cells with solid and infiltrative growth.
SDHB-related carotid body paraganglioma. S100 immunohistochemistry shows extremely rare sustentacular cells in these areas.
SSTR2A expression in a carotid body paraganglioma. Diffuse strong expression of SSTR2A correlates with bright images in PET-CT using 68Ga-DOTATOC or other radiolabelled somatostatin analogues.
SDHB-related carotid body paraganglioma. This tumour was removed in an en bloc resection followed by a synthetic carotid artery graft. The patient, who was 22 years old when the tumour was discovered, was found to have a germline SDHB mutation.

Q: In a Parasympathetic Paraganglioma, the peripherally located sustentacular cells characteristically express the immunohistochemical marker [...], though these cells may be extremely rare in SDHB-mutated variants.
SDHB-related carotid body paraganglioma. S100 immunohistochemistry shows extremely rare sustentacular cells in these areas.
A: S100
Back Extra: Parasympathetic Paraganglioma
- Clinical: Parasympathetic paragangliomas are typically associated with the vagus and glossopharyngeal nerves, often presenting as asymptomatic mass lesions or with symptoms like pulsatile tinnitus and hearing abnormalities.
- Micro: Tumours exhibit a variable Zellballen architecture with chief cells and peripherally located sustentacular cells, and a highly vascular stroma.
- Ancillary: Chief cells express neuroendocrine markers such as INSM1, synaptophysin, and chromogranin A, and sustentacular cells express S100 and SOX10.
Reference Gallery:
Carotid body paraganglioma. This paraganglioma encircles the carotid bulb and partially surrounds the internal carotid artery.
SDHB-related carotid body paraganglioma. This fibrotic SDHB-mutated paraganglioma encases the carotid artery and extends to the resection margins.
SDHB-related carotid body paraganglioma. Areas with a nested Zellballen pattern are present focally at the periphery of the tumour, but the tumour mostly consists of small cells with solid and infiltrative growth.
SDHB-related carotid body paraganglioma. S100 immunohistochemistry shows extremely rare sustentacular cells in these areas.
SSTR2A expression in a carotid body paraganglioma. Diffuse strong expression of SSTR2A correlates with bright images in PET-CT using 68Ga-DOTATOC or other radiolabelled somatostatin analogues.
SDHB-related carotid body paraganglioma. This tumour was removed in an en bloc resection followed by a synthetic carotid artery graft. The patient, who was 22 years old when the tumour was discovered, was found to have a germline SDHB mutation.

Q: A classic example of a Parasympathetic Paraganglioma is a tumor of the [...], which typically presents as a mass lesion that grossly encircles the carotid bulb and internal carotid artery.
Carotid body paraganglioma. This paraganglioma encircles the carotid bulb and partially surrounds the internal carotid artery.
SDHB-related carotid body paraganglioma. This fibrotic SDHB-mutated paraganglioma encases the carotid artery and extends to the resection margins.
A: carotid body
Back Extra: Parasympathetic Paraganglioma
- Clinical: Parasympathetic paragangliomas are typically associated with the vagus and glossopharyngeal nerves, often presenting as asymptomatic mass lesions or with symptoms like pulsatile tinnitus and hearing abnormalities.
- Micro: Tumours exhibit a variable Zellballen architecture with chief cells and peripherally located sustentacular cells, and a highly vascular stroma.
- Ancillary: Chief cells express neuroendocrine markers such as INSM1, synaptophysin, and chromogranin A, and sustentacular cells express S100 and SOX10.
Reference Gallery:
Carotid body paraganglioma. This paraganglioma encircles the carotid bulb and partially surrounds the internal carotid artery.
SDHB-related carotid body paraganglioma. This fibrotic SDHB-mutated paraganglioma encases the carotid artery and extends to the resection margins.
SDHB-related carotid body paraganglioma. Areas with a nested Zellballen pattern are present focally at the periphery of the tumour, but the tumour mostly consists of small cells with solid and infiltrative growth.
SDHB-related carotid body paraganglioma. S100 immunohistochemistry shows extremely rare sustentacular cells in these areas.
SSTR2A expression in a carotid body paraganglioma. Diffuse strong expression of SSTR2A correlates with bright images in PET-CT using 68Ga-DOTATOC or other radiolabelled somatostatin analogues.
SDHB-related carotid body paraganglioma. This tumour was removed in an en bloc resection followed by a synthetic carotid artery graft. The patient, who was 22 years old when the tumour was discovered, was found to have a germline SDHB mutation.

Q: Microscopically, Phaeochromocytoma classically exhibits a [...] pattern, which is defined as characteristic nests of tumor cells surrounded by a rich peripheral capillary network.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. A range of cytological and architectural variations are identified in von Hippel–Lindau syndrome–related phaeochromocytomas. Like in conventional phaeochromocytomas, a nested Zellballen pattern can be identified. These phaeochromocytomas display variable degrees of clear cell change.
A: Zellballen
Back Extra: Phaeochromocytoma
- Clinical: Most phaeochromocytomas synthesize catecholamines, leading to hypertension, headache, palpitations, and diaphoresis. However, a widening clinical spectrum is now recognized, with many patients having few or no symptoms.
- Micro: Phaeochromocytomas exhibit a Zellballen pattern, consisting of nests of tumour cells separated by peripheral capillaries. Other patterns include trabecular, diffuse, and pseudorosette arrangements.
- Ancillary: Immunohistochemistry is crucial for confirming the diagnosis, with tumours being positive for tyrosine hydroxylase, DBH, and neuroendocrine markers (chromogranin A, synaptophysin, INSM1), and negative for cytokeratins.
Reference Gallery:
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (shown here) and/or pseudorosettes (see Fig. <<32489>>) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (see Fig. <<32488>>) and/or pseudorosettes (shown here) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. These phaeochromocytomas display variable degree of clear cell change. Increased stromal vascularity and degenerative changes can feature in von Hippel–Lindau syndrome–related tumours.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. A range of cytological and architectural variations are identified in von Hippel–Lindau syndrome–related phaeochromocytomas. Like in conventional phaeochromocytomas, a nested Zellballen pattern can be identified. These phaeochromocytomas display variable degrees of clear cell change.
Biomarkers of phaeochromocytomas. Several immunohistochemical biomarkers can be used to confirm the diagnosis of phaeochromocytoma. The tumour cells are strongly and diffusely positive for chromogranin A (shown here) and negative for cytokeratins.
Biomarkers of phaeochromocytomas. The tumour cells are negative for cytokeratins (AE1/AE3).
Biomarkers of phaeochromocytomas. Positivity for GATA3 is variably reported.
Biomarkers of phaeochromocytomas. Immunohistochemistry for tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis) is very useful for confirming the diagnosis of phaeochromocytoma.
Biomarkers of phaeochromocytomas. DBH, which converts dopamine into norepinephrine (noradrenaline), has been found useful in supporting the diagnosis.
Biomarkers of phaeochromocytomas. Like in other epithelial neuroendocrine neoplasms (NENs), Ki-67 (MIB1) labelling is assessed by counting ≥ 1000 tumour cells from hotspots, either by automated image analysis or in a printed image. Markers not shown here are synaptophysin and INSM1. Although synaptophysin is positive in phaeochromocytomas, it is also expressed in adrenal cortical tumours and should not be used to distinguish the two tumour types. Because expression of GATA3 and INSM1 is not specific to paraganglial NENs, it should be assessed along with other biomarkers and correlated to the clinical context.
Clear cell change in a phaeochromocytoma. Clear cell change in a phaeochromocytoma should not be mistaken for an adrenal cortical neoplasm. The spectrum of clear cell change varies in phaeochromocytomas. This photomicrograph shows an example of diffuse zona fasciculata–like clear cell change in a von Hippel–Lindau syndrome–related phaeochromocytoma.
Clear cell change in a phaeochromocytoma. This tumour was negative for SF1 (not shown) and diffusely positive for tyrosine hydroxylase (shown here), GATA3 (not shown), and chromogranin A (not shown).

Q: To confirm a diagnosis of Phaeochromocytoma, immunohistochemistry can demonstrate the presence of catecholamine-synthesizing enzymes, such as dopamine beta-hydroxylase (DBH) and [...].
Biomarkers of phaeochromocytomas. Immunohistochemistry for tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis) is very useful for confirming the diagnosis of phaeochromocytoma.
Biomarkers of phaeochromocytomas. DBH, which converts dopamine into norepinephrine (noradrenaline), has been found useful in supporting the diagnosis.
A: tyrosine hydroxylase
Back Extra: Phaeochromocytoma
- Clinical: Most phaeochromocytomas synthesize catecholamines, leading to hypertension, headache, palpitations, and diaphoresis. However, a widening clinical spectrum is now recognized, with many patients having few or no symptoms.
- Micro: Phaeochromocytomas exhibit a Zellballen pattern, consisting of nests of tumour cells separated by peripheral capillaries. Other patterns include trabecular, diffuse, and pseudorosette arrangements.
- Ancillary: Immunohistochemistry is crucial for confirming the diagnosis, with tumours being positive for tyrosine hydroxylase, DBH, and neuroendocrine markers (chromogranin A, synaptophysin, INSM1), and negative for cytokeratins.
Reference Gallery:
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (shown here) and/or pseudorosettes (see Fig. <<32489>>) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (see Fig. <<32488>>) and/or pseudorosettes (shown here) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. These phaeochromocytomas display variable degree of clear cell change. Increased stromal vascularity and degenerative changes can feature in von Hippel–Lindau syndrome–related tumours.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. A range of cytological and architectural variations are identified in von Hippel–Lindau syndrome–related phaeochromocytomas. Like in conventional phaeochromocytomas, a nested Zellballen pattern can be identified. These phaeochromocytomas display variable degrees of clear cell change.
Biomarkers of phaeochromocytomas. Several immunohistochemical biomarkers can be used to confirm the diagnosis of phaeochromocytoma. The tumour cells are strongly and diffusely positive for chromogranin A (shown here) and negative for cytokeratins.
Biomarkers of phaeochromocytomas. The tumour cells are negative for cytokeratins (AE1/AE3).
Biomarkers of phaeochromocytomas. Positivity for GATA3 is variably reported.
Biomarkers of phaeochromocytomas. Immunohistochemistry for tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis) is very useful for confirming the diagnosis of phaeochromocytoma.
Biomarkers of phaeochromocytomas. DBH, which converts dopamine into norepinephrine (noradrenaline), has been found useful in supporting the diagnosis.
Biomarkers of phaeochromocytomas. Like in other epithelial neuroendocrine neoplasms (NENs), Ki-67 (MIB1) labelling is assessed by counting ≥ 1000 tumour cells from hotspots, either by automated image analysis or in a printed image. Markers not shown here are synaptophysin and INSM1. Although synaptophysin is positive in phaeochromocytomas, it is also expressed in adrenal cortical tumours and should not be used to distinguish the two tumour types. Because expression of GATA3 and INSM1 is not specific to paraganglial NENs, it should be assessed along with other biomarkers and correlated to the clinical context.
Clear cell change in a phaeochromocytoma. Clear cell change in a phaeochromocytoma should not be mistaken for an adrenal cortical neoplasm. The spectrum of clear cell change varies in phaeochromocytomas. This photomicrograph shows an example of diffuse zona fasciculata–like clear cell change in a von Hippel–Lindau syndrome–related phaeochromocytoma.
Clear cell change in a phaeochromocytoma. This tumour was negative for SF1 (not shown) and diffusely positive for tyrosine hydroxylase (shown here), GATA3 (not shown), and chromogranin A (not shown).

Q: Phaeochromocytoma is typically positive for neuroendocrine markers such as chromogranin A, but is characteristically negative for [...], which helps differentiate it from epithelial neuroendocrine tumors.
Biomarkers of phaeochromocytomas. Several immunohistochemical biomarkers can be used to confirm the diagnosis of phaeochromocytoma. The tumour cells are strongly and diffusely positive for chromogranin A (shown here) and negative for cytokeratins.
Biomarkers of phaeochromocytomas. The tumour cells are negative for cytokeratins (AE1/AE3).
A: cytokeratins
Back Extra: Phaeochromocytoma
- Clinical: Most phaeochromocytomas synthesize catecholamines, leading to hypertension, headache, palpitations, and diaphoresis. However, a widening clinical spectrum is now recognized, with many patients having few or no symptoms.
- Micro: Phaeochromocytomas exhibit a Zellballen pattern, consisting of nests of tumour cells separated by peripheral capillaries. Other patterns include trabecular, diffuse, and pseudorosette arrangements.
- Ancillary: Immunohistochemistry is crucial for confirming the diagnosis, with tumours being positive for tyrosine hydroxylase, DBH, and neuroendocrine markers (chromogranin A, synaptophysin, INSM1), and negative for cytokeratins.
Reference Gallery:
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (shown here) and/or pseudorosettes (see Fig. <<32489>>) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. Trabecular or diffuse growth with large confluent nests (see Fig. <<32488>>) and/or pseudorosettes (shown here) can also occur. The illustrated case also shows comedonecrosis. These phaeochromocytomas display variable degrees of clear cell change.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. These phaeochromocytomas display variable degree of clear cell change. Increased stromal vascularity and degenerative changes can feature in von Hippel–Lindau syndrome–related tumours.
Spectrum of morphological changes in a von Hippel–Lindau syndrome–related paediatric phaeochromocytoma. A range of cytological and architectural variations are identified in von Hippel–Lindau syndrome–related phaeochromocytomas. Like in conventional phaeochromocytomas, a nested Zellballen pattern can be identified. These phaeochromocytomas display variable degrees of clear cell change.
Biomarkers of phaeochromocytomas. Several immunohistochemical biomarkers can be used to confirm the diagnosis of phaeochromocytoma. The tumour cells are strongly and diffusely positive for chromogranin A (shown here) and negative for cytokeratins.
Biomarkers of phaeochromocytomas. The tumour cells are negative for cytokeratins (AE1/AE3).
Biomarkers of phaeochromocytomas. Positivity for GATA3 is variably reported.
Biomarkers of phaeochromocytomas. Immunohistochemistry for tyrosine hydroxylase (the rate-limiting enzyme in catecholamine synthesis) is very useful for confirming the diagnosis of phaeochromocytoma.
Biomarkers of phaeochromocytomas. DBH, which converts dopamine into norepinephrine (noradrenaline), has been found useful in supporting the diagnosis.
Biomarkers of phaeochromocytomas. Like in other epithelial neuroendocrine neoplasms (NENs), Ki-67 (MIB1) labelling is assessed by counting ≥ 1000 tumour cells from hotspots, either by automated image analysis or in a printed image. Markers not shown here are synaptophysin and INSM1. Although synaptophysin is positive in phaeochromocytomas, it is also expressed in adrenal cortical tumours and should not be used to distinguish the two tumour types. Because expression of GATA3 and INSM1 is not specific to paraganglial NENs, it should be assessed along with other biomarkers and correlated to the clinical context.
Clear cell change in a phaeochromocytoma. Clear cell change in a phaeochromocytoma should not be mistaken for an adrenal cortical neoplasm. The spectrum of clear cell change varies in phaeochromocytomas. This photomicrograph shows an example of diffuse zona fasciculata–like clear cell change in a von Hippel–Lindau syndrome–related phaeochromocytoma.
Clear cell change in a phaeochromocytoma. This tumour was negative for SF1 (not shown) and diffusely positive for tyrosine hydroxylase (shown here), GATA3 (not shown), and chromogranin A (not shown).

Q: Histologically, a Sympathetic Paraganglioma exhibits a nested architecture that closely resembles a [...], but it typically arises in extra-adrenal locations (e.g., abdomen, retroperitoneum, or thorax).
Sympathetic paraganglioma
A: pheochromocytoma
Back Extra: Sympathetic Paraganglioma
- Clinical: Sympathetic paragangliomas typically present in the fifth or sixth decade of life and are often located in the abdomen, retroperitoneum, pelvis, and thorax.
- Micro: Histologically, sympathetic paragangliomas can resemble phaeochromocytomas and may have cells with clear cytoplasm, causing them to be mistaken for urinary bladder, prostate, or kidney carcinomas.
- Ancillary: Essential ancillary studies include biochemical testing for metanephrines and structural imaging, while genetic testing for SDHB mutations is highly recommended.
Reference Gallery:
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Sympathetic paraganglioma

Q: Due to the high association with hereditary syndromes, genetic testing is strongly recommended for a Sympathetic Paraganglioma, particularly to evaluate for mutations in the [...] gene, which can also be screened via immunohistochemistry.
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
A: SDHB
Back Extra: Sympathetic Paraganglioma
- Clinical: Sympathetic paragangliomas typically present in the fifth or sixth decade of life and are often located in the abdomen, retroperitoneum, pelvis, and thorax.
- Micro: Histologically, sympathetic paragangliomas can resemble phaeochromocytomas and may have cells with clear cytoplasm, causing them to be mistaken for urinary bladder, prostate, or kidney carcinomas.
- Ancillary: Essential ancillary studies include biochemical testing for metanephrines and structural imaging, while genetic testing for SDHB mutations is highly recommended.
Reference Gallery:
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Sympathetic paraganglioma

Q: Because a Sympathetic Paraganglioma is frequently a functionally active neuroendocrine tumor, essential ancillary workup involves anatomical/functional imaging and biochemical testing for elevated plasma or urine [...].
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
A: metanephrines
Back Extra: Sympathetic Paraganglioma
- Clinical: Sympathetic paragangliomas typically present in the fifth or sixth decade of life and are often located in the abdomen, retroperitoneum, pelvis, and thorax.
- Micro: Histologically, sympathetic paragangliomas can resemble phaeochromocytomas and may have cells with clear cytoplasm, causing them to be mistaken for urinary bladder, prostate, or kidney carcinomas.
- Ancillary: Essential ancillary studies include biochemical testing for metanephrines and structural imaging, while genetic testing for SDHB mutations is highly recommended.
Reference Gallery:
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Anatomical and functional imaging in a patient with an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Biomarker expression in an abdominal paraganglioma
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Multicentric paragangliomas
Sympathetic paraganglioma

Q: The most common cause of Congenital Adrenal Hyperplasia, which often presents with elevated 17-hydroxyprogesterone and virilization, is a deficiency of the enzyme [...].
Schematic overview of adrenal cortical hormone biosynthesis and aberrant enzyme expression in various congenital adrenal hyperplasia (CAH) subtypes. By far the most common cause of CAH is 21-hydroxylase deficiency.
A: 21-hydroxylase
Back Extra: Congenital Adrenal Hyperplasia
- Clinical: Infants with classic CAH are identified by neonatal screening (elevated 17-hydroxyprogesterone) and may have ambiguous genitalia, virilization, and electrolyte imbalances such as hyponatremia and hyperkalemia.
- Micro: The adrenal glands show marked bilateral cortical compact cell hyperplasia with a lipid depletion pattern, giving the adrenal glands a dark color due to the predominance of zona reticularis-like cells.
- Ancillary: Genetic testing is essential for identifying the specific mutation causing CAH, and the diagnosis is confirmed by physical and laboratory findings, including hypocortisolism and hypoaldosteronism.
Reference Gallery:
Schematic overview of adrenal cortical hormone biosynthesis and aberrant enzyme expression in various congenital adrenal hyperplasia (CAH) subtypes. By far the most common cause of CAH is 21-hydroxylase deficiency.
Congenital adrenal hyperplasia. Expansion of the zona fasciculata in congenital adrenal hyperplasia. Enlarged hyperplastic accessory cortical nodules are also present.
Congenital adrenal hyperplasia. Trophic stimulation by ACTH results in hyperplasia of the zona fasciculata.
Congenital adrenal hyperplasia. Congenital adrenal hyperplasia has cells with marked eosinophilic cytoplasm due to ACTH stimulation, rather than the lipid-rich, pale-staining cells of normal zona fasciculata.
Congenital adrenal hyperplasia. In congenital adrenal hyperplasia, adrenal myelolipomas are identified more frequently in individuals with undiagnosed or poorly managed congenital adrenal hyperplasia.
Congenital adrenal hyperplasia. This myelolipoma was identified in an individual with congenital adrenal hyperplasia. The lesion is composed of mature adipose tissue admixed with haematopoietic elements.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are usually identified in the mediastinum (hilum) of the testis and are often bilateral. They must be differentiated from Leydig cell tumours, which they closely resemble.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are composed of nests and sheets of cells with granular pink cytoplasm. The tumour cells resemble Leydig cells. The presence of bilateral disease and the knowledge that the lesion is occurring in the setting of congenital adrenal hyperplasia are helpful in differentiating testicular adrenal rest tumour from Leydig cell tumour.

Q: Histologically, the adrenal cortex in Congenital Adrenal Hyperplasia exhibits bilateral compact cell hyperplasia with a lipid depletion pattern, characterized by cells with prominent [...] cytoplasm due to chronic ACTH stimulation.
Congenital adrenal hyperplasia. Trophic stimulation by ACTH results in hyperplasia of the zona fasciculata.
Congenital adrenal hyperplasia. Congenital adrenal hyperplasia has cells with marked eosinophilic cytoplasm due to ACTH stimulation, rather than the lipid-rich, pale-staining cells of normal zona fasciculata.
A: eosinophilic
Back Extra: Congenital Adrenal Hyperplasia
- Clinical: Infants with classic CAH are identified by neonatal screening (elevated 17-hydroxyprogesterone) and may have ambiguous genitalia, virilization, and electrolyte imbalances such as hyponatremia and hyperkalemia.
- Micro: The adrenal glands show marked bilateral cortical compact cell hyperplasia with a lipid depletion pattern, giving the adrenal glands a dark color due to the predominance of zona reticularis-like cells.
- Ancillary: Genetic testing is essential for identifying the specific mutation causing CAH, and the diagnosis is confirmed by physical and laboratory findings, including hypocortisolism and hypoaldosteronism.
Reference Gallery:
Schematic overview of adrenal cortical hormone biosynthesis and aberrant enzyme expression in various congenital adrenal hyperplasia (CAH) subtypes. By far the most common cause of CAH is 21-hydroxylase deficiency.
Congenital adrenal hyperplasia. Expansion of the zona fasciculata in congenital adrenal hyperplasia. Enlarged hyperplastic accessory cortical nodules are also present.
Congenital adrenal hyperplasia. Trophic stimulation by ACTH results in hyperplasia of the zona fasciculata.
Congenital adrenal hyperplasia. Congenital adrenal hyperplasia has cells with marked eosinophilic cytoplasm due to ACTH stimulation, rather than the lipid-rich, pale-staining cells of normal zona fasciculata.
Congenital adrenal hyperplasia. In congenital adrenal hyperplasia, adrenal myelolipomas are identified more frequently in individuals with undiagnosed or poorly managed congenital adrenal hyperplasia.
Congenital adrenal hyperplasia. This myelolipoma was identified in an individual with congenital adrenal hyperplasia. The lesion is composed of mature adipose tissue admixed with haematopoietic elements.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are usually identified in the mediastinum (hilum) of the testis and are often bilateral. They must be differentiated from Leydig cell tumours, which they closely resemble.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are composed of nests and sheets of cells with granular pink cytoplasm. The tumour cells resemble Leydig cells. The presence of bilateral disease and the knowledge that the lesion is occurring in the setting of congenital adrenal hyperplasia are helpful in differentiating testicular adrenal rest tumour from Leydig cell tumour.

Q: Male patients with Congenital Adrenal Hyperplasia may develop bilateral masses in the mediastinum (hilum) of the testis known as [...], which are composed of granular pink cells that closely resemble Leydig cells.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are usually identified in the mediastinum (hilum) of the testis and are often bilateral. They must be differentiated from Leydig cell tumours, which they closely resemble.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are composed of nests and sheets of cells with granular pink cytoplasm. The tumour cells resemble Leydig cells. The presence of bilateral disease and the knowledge that the lesion is occurring in the setting of congenital adrenal hyperplasia are helpful in differentiating testicular adrenal rest tumour from Leydig cell tumour.
A: testicular adrenal rest tumors
Back Extra: Congenital Adrenal Hyperplasia
- Clinical: Infants with classic CAH are identified by neonatal screening (elevated 17-hydroxyprogesterone) and may have ambiguous genitalia, virilization, and electrolyte imbalances such as hyponatremia and hyperkalemia.
- Micro: The adrenal glands show marked bilateral cortical compact cell hyperplasia with a lipid depletion pattern, giving the adrenal glands a dark color due to the predominance of zona reticularis-like cells.
- Ancillary: Genetic testing is essential for identifying the specific mutation causing CAH, and the diagnosis is confirmed by physical and laboratory findings, including hypocortisolism and hypoaldosteronism.
Reference Gallery:
Schematic overview of adrenal cortical hormone biosynthesis and aberrant enzyme expression in various congenital adrenal hyperplasia (CAH) subtypes. By far the most common cause of CAH is 21-hydroxylase deficiency.
Congenital adrenal hyperplasia. Expansion of the zona fasciculata in congenital adrenal hyperplasia. Enlarged hyperplastic accessory cortical nodules are also present.
Congenital adrenal hyperplasia. Trophic stimulation by ACTH results in hyperplasia of the zona fasciculata.
Congenital adrenal hyperplasia. Congenital adrenal hyperplasia has cells with marked eosinophilic cytoplasm due to ACTH stimulation, rather than the lipid-rich, pale-staining cells of normal zona fasciculata.
Congenital adrenal hyperplasia. In congenital adrenal hyperplasia, adrenal myelolipomas are identified more frequently in individuals with undiagnosed or poorly managed congenital adrenal hyperplasia.
Congenital adrenal hyperplasia. This myelolipoma was identified in an individual with congenital adrenal hyperplasia. The lesion is composed of mature adipose tissue admixed with haematopoietic elements.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are usually identified in the mediastinum (hilum) of the testis and are often bilateral. They must be differentiated from Leydig cell tumours, which they closely resemble.
Testicular adrenal rest tumour in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumours are composed of nests and sheets of cells with granular pink cytoplasm. The tumour cells resemble Leydig cells. The presence of bilateral disease and the knowledge that the lesion is occurring in the setting of congenital adrenal hyperplasia are helpful in differentiating testicular adrenal rest tumour from Leydig cell tumour.

Q: Microscopically, Large Cell Neuroendocrine Carcinoma (LCNEC) exhibits organoid or diffuse growth with large atypical cells containing moderately abundant eosinophilic cytoplasm and prominent [...], along with frequent areas of necrosis.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Sheets and irregular cords of large atypical cells with zonal necrosis.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells have moderately abundant eosinophilic and granular cytoplasm, large nuclei with evident nuclear membranes, and eosinophilic macronucleoli.
A: nucleoli
Back Extra: Large Cell Neuroendocrine Carcinoma (LCNEC)
- Clinical: Large cell neuroendocrine carcinoma (LCNEC) often presents with mass compressive symptoms, lumen occlusion, ulceration, and bleeding, and is frequently diagnosed at an advanced stage.
- Micro: LCNEC shows organoid or diffuse growth with large atypical cells, prominent nucleoli, and frequent necrosis. The Ki-67 proliferation index is usually very high (> 55%).
- Ancillary: General neuroendocrine markers such as synaptophysin, chromogranin A, and INSM1 are essential for confirming the diagnosis of LCNEC. p53 overexpression is also commonly observed.
Reference Gallery:
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Sheets and irregular cords of large atypical cells with zonal necrosis.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells have moderately abundant eosinophilic and granular cytoplasm, large nuclei with evident nuclear membranes, and eosinophilic macronucleoli.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Low-molecular-weight cytokeratins are strongly positive (CAM5.2).
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells display diffuse immunoreactivity for synaptophysin.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Chromogranin A is expressed in scattered cells, with a punctate pattern.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. The Ki-67 proliferation index is very high.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. p53 is overexpressed in all neoplastic cells.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. INSM1 is strongly and diffusely positive.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Gastric LCNEC.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Chromogranin A is strongly and diffusely expressed.
Large cell neuroendocrine carcinoma (LCNEC). Many large and loosely cohesive tumor cells contain abundant cytoplasm and vesicular nuclei.
Large cell neuroendocrine carcinoma (LCNEC). Most tumor cells are immunohistochemically positive for synaptophysin in the cytoplasm.

Q: Because Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade neuroendocrine tumor, it typically demonstrates a very high [...] proliferation index (usually > 55%).
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. The Ki-67 proliferation index is very high.
A: Ki-67
Back Extra: Large Cell Neuroendocrine Carcinoma (LCNEC)
- Clinical: Large cell neuroendocrine carcinoma (LCNEC) often presents with mass compressive symptoms, lumen occlusion, ulceration, and bleeding, and is frequently diagnosed at an advanced stage.
- Micro: LCNEC shows organoid or diffuse growth with large atypical cells, prominent nucleoli, and frequent necrosis. The Ki-67 proliferation index is usually very high (> 55%).
- Ancillary: General neuroendocrine markers such as synaptophysin, chromogranin A, and INSM1 are essential for confirming the diagnosis of LCNEC. p53 overexpression is also commonly observed.
Reference Gallery:
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Sheets and irregular cords of large atypical cells with zonal necrosis.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells have moderately abundant eosinophilic and granular cytoplasm, large nuclei with evident nuclear membranes, and eosinophilic macronucleoli.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Low-molecular-weight cytokeratins are strongly positive (CAM5.2).
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells display diffuse immunoreactivity for synaptophysin.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Chromogranin A is expressed in scattered cells, with a punctate pattern.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. The Ki-67 proliferation index is very high.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. p53 is overexpressed in all neoplastic cells.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. INSM1 is strongly and diffusely positive.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Gastric LCNEC.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Chromogranin A is strongly and diffusely expressed.
Large cell neuroendocrine carcinoma (LCNEC). Many large and loosely cohesive tumor cells contain abundant cytoplasm and vesicular nuclei.
Large cell neuroendocrine carcinoma (LCNEC). Most tumor cells are immunohistochemically positive for synaptophysin in the cytoplasm.

Q: The diagnosis of Large Cell Neuroendocrine Carcinoma (LCNEC) is supported by diffuse immunoreactivity for neuroendocrine markers such as synaptophysin, chromogranin A, and the highly sensitive nuclear marker [...].
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells display diffuse immunoreactivity for synaptophysin.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Chromogranin A is expressed in scattered cells, with a punctate pattern.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. INSM1 is strongly and diffusely positive.
A: INSM1
Back Extra: Large Cell Neuroendocrine Carcinoma (LCNEC)
- Clinical: Large cell neuroendocrine carcinoma (LCNEC) often presents with mass compressive symptoms, lumen occlusion, ulceration, and bleeding, and is frequently diagnosed at an advanced stage.
- Micro: LCNEC shows organoid or diffuse growth with large atypical cells, prominent nucleoli, and frequent necrosis. The Ki-67 proliferation index is usually very high (> 55%).
- Ancillary: General neuroendocrine markers such as synaptophysin, chromogranin A, and INSM1 are essential for confirming the diagnosis of LCNEC. p53 overexpression is also commonly observed.
Reference Gallery:
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Sheets and irregular cords of large atypical cells with zonal necrosis.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells have moderately abundant eosinophilic and granular cytoplasm, large nuclei with evident nuclear membranes, and eosinophilic macronucleoli.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Low-molecular-weight cytokeratins are strongly positive (CAM5.2).
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Neoplastic cells display diffuse immunoreactivity for synaptophysin.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. Chromogranin A is expressed in scattered cells, with a punctate pattern.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. The Ki-67 proliferation index is very high.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. p53 is overexpressed in all neoplastic cells.
Large cell neuroendocrine carcinoma (LCNEC) of the nasal cavity. INSM1 is strongly and diffusely positive.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Gastric LCNEC.
Large cell neuroendocrine carcinoma (LCNEC) of the stomach. Chromogranin A is strongly and diffusely expressed.
Large cell neuroendocrine carcinoma (LCNEC). Many large and loosely cohesive tumor cells contain abundant cytoplasm and vesicular nuclei.
Large cell neuroendocrine carcinoma (LCNEC). Most tumor cells are immunohistochemically positive for synaptophysin in the cytoplasm.

Q: In Benign Vascular Tumours, immunohistochemistry of the neoplastic endothelial cells reveals strong and diffuse positivity for vascular markers such as CD34, FLI1, ERG, and [...].
Thyroid haemangioma. There is strong and diffuse CD31 immunoreactivity in endothelial cells.
A: CD31
Back Extra: Benign Vascular Tumours
- Clinical: Benign vascular tumours can present in various locations, such as the adrenal gland, thyroid, and pituitary, with symptoms including abdominal pain, hypertension, and headache.
- Micro: Haemangiomas of endocrine organs are characterized by multiple vascular channels, with cavernous haemangiomas showing large-diameter, thin-walled channels and venous haemangiomas having thick-walled veins.
- Ancillary: Immunohistochemistry shows endothelial cells in haemangiomas and vascular malformations to be positive for CD34, CD31, FLI1, and ERG, and negative for D2-40, keratin, and KSHV/HHV8.
Reference Gallery:
Thyroid haemangioma. In some cases, cavernous vascular spaces predominate.
Thyroid haemangioma. At higher magnification, the endothelial cells lack cytological atypia.
Thyroid haemangioma. There is strong and diffuse CD31 immunoreactivity in endothelial cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.

Q: Histologically, Benign Vascular Tumours of endocrine organs frequently present as [...], which are characterized by large-diameter, thin-walled vascular channels lacking cytological atypia.
Thyroid haemangioma. In some cases, cavernous vascular spaces predominate.
Thyroid haemangioma. At higher magnification, the endothelial cells lack cytological atypia.
A: cavernous hemangiomas
Back Extra: Benign Vascular Tumours
- Clinical: Benign vascular tumours can present in various locations, such as the adrenal gland, thyroid, and pituitary, with symptoms including abdominal pain, hypertension, and headache.
- Micro: Haemangiomas of endocrine organs are characterized by multiple vascular channels, with cavernous haemangiomas showing large-diameter, thin-walled channels and venous haemangiomas having thick-walled veins.
- Ancillary: Immunohistochemistry shows endothelial cells in haemangiomas and vascular malformations to be positive for CD34, CD31, FLI1, and ERG, and negative for D2-40, keratin, and KSHV/HHV8.
Reference Gallery:
Thyroid haemangioma. In some cases, cavernous vascular spaces predominate.
Thyroid haemangioma. At higher magnification, the endothelial cells lack cytological atypia.
Thyroid haemangioma. There is strong and diffuse CD31 immunoreactivity in endothelial cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.

Q: When Benign Vascular Tumours (such as hemangiomas) arise in the adrenal gland, microscopic examination shows well-developed vascular channels uniquely intermixed with native [...].
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.
A: adrenal cortical cells
Back Extra: Benign Vascular Tumours
- Clinical: Benign vascular tumours can present in various locations, such as the adrenal gland, thyroid, and pituitary, with symptoms including abdominal pain, hypertension, and headache.
- Micro: Haemangiomas of endocrine organs are characterized by multiple vascular channels, with cavernous haemangiomas showing large-diameter, thin-walled channels and venous haemangiomas having thick-walled veins.
- Ancillary: Immunohistochemistry shows endothelial cells in haemangiomas and vascular malformations to be positive for CD34, CD31, FLI1, and ERG, and negative for D2-40, keratin, and KSHV/HHV8.
Reference Gallery:
Thyroid haemangioma. In some cases, cavernous vascular spaces predominate.
Thyroid haemangioma. At higher magnification, the endothelial cells lack cytological atypia.
Thyroid haemangioma. There is strong and diffuse CD31 immunoreactivity in endothelial cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.
Haemangioma of the adrenal cortex. Well-developed vascular channels are intermixed with adrenal cortical cells.

Q: A well-circumscribed mass in the lower spinal canal presents clinically with sciatica. Histologic examination reveals nests of uniform, round chief cells separated by a capillary network, with diffuse immunoreactivity for chromogranin A and synaptophysin. This describes a [...].
Cauda equina neuroendocrine tumour (NET). Nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour (NET). Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour (NET). Hyperintense T2-weighted image showing the well-demarcated tumour in the cauda equina region.
A: Cauda Equina Neuroendocrine Tumor (NET)
Back Extra: Cauda Equina Neuroendocrine Tumour (NET)
- Clinical: Common presenting symptoms include low back pain and sciatica. Fully developed cauda equina syndrome is uncommon.
- Micro: Well-differentiated neuroendocrine cells arranged in nests or lobules, surrounded by a capillary network and a reticulin fibre network.
- Ancillary: Neuroendocrine cells are immunoreactive for chromogranin A and synaptophysin, and show variable S100 immunoreactivity.
Reference Gallery:
Cauda equina neuroendocrine tumour (NET). Nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour (NET). The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Cytokeratin is expressed in most tumours (MNF116).
Cauda equina neuroendocrine tumour (NET). Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour (NET). S100 immunohistochemistry labels the sustentacellular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour (NET). Hyperintense T2-weighted image showing the well-demarcated tumour in the cauda equina region.
Cauda equina neuroendocrine tumour (NET). A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: In Cauda Equina Neuroendocrine Tumor (NET), the characteristic architecture consists of lobules of well-differentiated neuroendocrine cells that are encompassed by a rim of S100-positive [...] cells.
Cauda equina neuroendocrine tumour (NET). S100 immunohistochemistry labels the sustentacellular cells, encompassing the lobules.
A: sustentacular
Back Extra: Cauda Equina Neuroendocrine Tumour (NET)
- Clinical: Common presenting symptoms include low back pain and sciatica. Fully developed cauda equina syndrome is uncommon.
- Micro: Well-differentiated neuroendocrine cells arranged in nests or lobules, surrounded by a capillary network and a reticulin fibre network.
- Ancillary: Neuroendocrine cells are immunoreactive for chromogranin A and synaptophysin, and show variable S100 immunoreactivity.
Reference Gallery:
Cauda equina neuroendocrine tumour (NET). Nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour (NET). The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Cytokeratin is expressed in most tumours (MNF116).
Cauda equina neuroendocrine tumour (NET). Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour (NET). S100 immunohistochemistry labels the sustentacellular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour (NET). Hyperintense T2-weighted image showing the well-demarcated tumour in the cauda equina region.
Cauda equina neuroendocrine tumour (NET). A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: The lobular nests of tumor cells in Cauda Equina Neuroendocrine Tumor (NET) are characteristically surrounded by a delicate, supporting network of [...] fibers.
Cauda equina neuroendocrine tumour (NET). The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
A: reticulin
Back Extra: Cauda Equina Neuroendocrine Tumour (NET)
- Clinical: Common presenting symptoms include low back pain and sciatica. Fully developed cauda equina syndrome is uncommon.
- Micro: Well-differentiated neuroendocrine cells arranged in nests or lobules, surrounded by a capillary network and a reticulin fibre network.
- Ancillary: Neuroendocrine cells are immunoreactive for chromogranin A and synaptophysin, and show variable S100 immunoreactivity.
Reference Gallery:
Cauda equina neuroendocrine tumour (NET). Nests of uniform round or polygonal chief cells surrounded by a capillary and fibre network.
Cauda equina neuroendocrine tumour (NET). The nests of tumour cells are surrounded by a delicate supporting reticulin fibre network (reticulin silver stain).
Cauda equina neuroendocrine tumour. Cytokeratin is expressed in most tumours (MNF116).
Cauda equina neuroendocrine tumour (NET). Chromogranin A immunostaining labels the neuroendocrine (chief) cells.
Cauda equina neuroendocrine tumour (NET). S100 immunohistochemistry labels the sustentacellular cells, encompassing the lobules.
Cauda equina neuroendocrine tumour (NET). Hyperintense T2-weighted image showing the well-demarcated tumour in the cauda equina region.
Cauda equina neuroendocrine tumour (NET). A well-circumscribed, encapsulated tumour with prominent vasculature on the surface.

Q: A characteristic stromal finding in many cases of Insulinoma is the deposition of [...], which appears as amorphous extracellular pink material on H&E and stains positive with Congo red.
Pancreatic insulinoma, indolent small. Typical morphology with trabecular architecture and amyloid deposits.
Pancreatic insulinoma, indolent small. Amyloid deposits are stained red with Congo red.
A: amyloid
Back Extra: Insulinoma
- Clinical: Insulinomas cause hyperinsulinaemic hypoglycaemia, leading to adrenergic and neuroglycopenic symptoms.
- Micro: Insulinomas typically show well-differentiated neuroendocrine cells forming trabecular, solid, or tubuloacinar structures with possible amyloid deposits.
- Ancillary: Immunohistochemistry reveals strong positivity for insulin, proinsulin, and IAPP, with varying patterns of glucagon and other hormones.
Reference Gallery:
Pancreatic insulinoma. Top row: PET-CT 68Ga-DOTATOC axial images showing low uptake on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–15; d). Bottom row: PET-CT 68Ga-DOTATOC axial images showing high uptake (maximum standardized uptake value: 114) on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–20; d).
Pancreatic insulinoma, indolent small. Gross appearance of a well-circumscribed tumour showing a reddish-tan cut surface.
Pancreatic insulinoma, aggressive. Distal pancreatectomy and splenectomy revealing a 90 mm tumour. Histological features of this insulinoma are shown in <<25265>>, <<25266>>, and <<25267>>.
Pancreatic insulinoma, indolent small. Trabecular architecture.
Pancreatic insulinoma, indolent small. Solid architecture.
Pancreatic insulinoma, indolent small. Tubuloacinar architecture with hyalinized stroma.
Pancreatic insulinoma, indolent small. In this case, entrapped non-neoplastic ducts are observed.
Pancreatic insulinoma, indolent small. Typical morphology with trabecular architecture and amyloid deposits.
Pancreatic insulinoma, indolent small. Amyloid deposits are stained red with Congo red.
Pancreatic insulinoma. Insulin expression is intense and observed in most cells.
Pancreatic insulinoma. Sometimes, insulin expression is not observed in all neoplastic cells.
Pancreatic insulinoma. Proinsulin generally shows a paranuclear immunoreactivity.

Q: Immunohistochemistry for Insulinoma typically shows diffuse cytoplasmic positivity for insulin, while staining for [...] classically demonstrates a localized paranuclear pattern.
Pancreatic insulinoma. Insulin expression is intense and observed in most cells.
Pancreatic insulinoma. Proinsulin generally shows a paranuclear immunoreactivity.
A: proinsulin
Back Extra: Insulinoma
- Clinical: Insulinomas cause hyperinsulinaemic hypoglycaemia, leading to adrenergic and neuroglycopenic symptoms.
- Micro: Insulinomas typically show well-differentiated neuroendocrine cells forming trabecular, solid, or tubuloacinar structures with possible amyloid deposits.
- Ancillary: Immunohistochemistry reveals strong positivity for insulin, proinsulin, and IAPP, with varying patterns of glucagon and other hormones.
Reference Gallery:
Pancreatic insulinoma. Top row: PET-CT 68Ga-DOTATOC axial images showing low uptake on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–15; d). Bottom row: PET-CT 68Ga-DOTATOC axial images showing high uptake (maximum standardized uptake value: 114) on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–20; d).
Pancreatic insulinoma, indolent small. Gross appearance of a well-circumscribed tumour showing a reddish-tan cut surface.
Pancreatic insulinoma, aggressive. Distal pancreatectomy and splenectomy revealing a 90 mm tumour. Histological features of this insulinoma are shown in <<25265>>, <<25266>>, and <<25267>>.
Pancreatic insulinoma, indolent small. Trabecular architecture.
Pancreatic insulinoma, indolent small. Solid architecture.
Pancreatic insulinoma, indolent small. Tubuloacinar architecture with hyalinized stroma.
Pancreatic insulinoma, indolent small. In this case, entrapped non-neoplastic ducts are observed.
Pancreatic insulinoma, indolent small. Typical morphology with trabecular architecture and amyloid deposits.
Pancreatic insulinoma, indolent small. Amyloid deposits are stained red with Congo red.
Pancreatic insulinoma. Insulin expression is intense and observed in most cells.
Pancreatic insulinoma. Sometimes, insulin expression is not observed in all neoplastic cells.
Pancreatic insulinoma. Proinsulin generally shows a paranuclear immunoreactivity.

Q: Histologically, a well-differentiated Insulinoma frequently organizes into solid, tubuloacinar, or [...] architectural patterns.
Pancreatic insulinoma, indolent small. Trabecular architecture.
Pancreatic insulinoma, indolent small. Solid architecture.
Pancreatic insulinoma, indolent small. Tubuloacinar architecture with hyalinized stroma.
A: trabecular
Back Extra: Insulinoma
- Clinical: Insulinomas cause hyperinsulinaemic hypoglycaemia, leading to adrenergic and neuroglycopenic symptoms.
- Micro: Insulinomas typically show well-differentiated neuroendocrine cells forming trabecular, solid, or tubuloacinar structures with possible amyloid deposits.
- Ancillary: Immunohistochemistry reveals strong positivity for insulin, proinsulin, and IAPP, with varying patterns of glucagon and other hormones.
Reference Gallery:
Pancreatic insulinoma. Top row: PET-CT 68Ga-DOTATOC axial images showing low uptake on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–15; d). Bottom row: PET-CT 68Ga-DOTATOC axial images showing high uptake (maximum standardized uptake value: 114) on PET (a), low-dose CT (b), fused PET-CT (c), and maximum intensity projection image (standardized uptake value scale: 0–20; d).
Pancreatic insulinoma, indolent small. Gross appearance of a well-circumscribed tumour showing a reddish-tan cut surface.
Pancreatic insulinoma, aggressive. Distal pancreatectomy and splenectomy revealing a 90 mm tumour. Histological features of this insulinoma are shown in <<25265>>, <<25266>>, and <<25267>>.
Pancreatic insulinoma, indolent small. Trabecular architecture.
Pancreatic insulinoma, indolent small. Solid architecture.
Pancreatic insulinoma, indolent small. Tubuloacinar architecture with hyalinized stroma.
Pancreatic insulinoma, indolent small. In this case, entrapped non-neoplastic ducts are observed.
Pancreatic insulinoma, indolent small. Typical morphology with trabecular architecture and amyloid deposits.
Pancreatic insulinoma, indolent small. Amyloid deposits are stained red with Congo red.
Pancreatic insulinoma. Insulin expression is intense and observed in most cells.
Pancreatic insulinoma. Sometimes, insulin expression is not observed in all neoplastic cells.
Pancreatic insulinoma. Proinsulin generally shows a paranuclear immunoreactivity.

Q: Innumerable multicentric islet B-cell proliferations (ranging from dysplastic cords to microtumors) that stain exclusively for insulin are the characteristic microscopic finding in [...].
MAFA-related familial insulinomatosis. The pancreas in MAFA-related insulinomatosis contains innumerable multicentric islet B-cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. Multicentric islet B-cell proliferations range from dysplastic B-cell cords to microtumours and well-differentiated tumours, all staining intensely and exclusively for insulin.
A: MAFA-related familial insulinomatosis
Back Extra: MAFA-related familial insulinomatosis
- Clinical: MAFA-related familial insulinomatosis typically presents with hyperinsulinaemic hypoglycaemia, more common in females, or diabetes, more common in males. Diagnostic clues include a normal BMI and negative islet autoantibodies.
- Micro: The pancreas contains innumerable multicentric islet B-cell proliferations, ranging from dysplastic B-cell cords to microtumours and well-differentiated tumours, all staining intensely and exclusively for insulin.
- Ancillary: Immunohistochemistry (IHC) shows strong and exclusive insulin positivity, with no expression of glucagon, PP, or somatostatin. Genetic testing reveals a missense MAFA c.191C>T p.S64F sequence variant.
Reference Gallery:
MAFA-related familial insulinomatosis. The pancreas in MAFA-related insulinomatosis contains innumerable multicentric islet B-cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microtumours (< 5 mm) and well-differentiated islet B-cell neuroendocrine tumours (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric islet B-cell proliferations range from dysplastic B-cell cords to microtumours and well-differentiated tumours, all staining intensely and exclusively for insulin.

Q: In MAFA-related familial insulinomatosis, the multiple neuroendocrine trabecular microtumors and well-differentiated tumors show strong and exclusive immunohistochemical positivity for [...], with no expression of glucagon, PP, or somatostatin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microtumours (< 5 mm) and well-differentiated islet B-cell neuroendocrine tumours (> 5 mm) that are composed exclusively of insulin-positive cells.
A: insulin
Back Extra: MAFA-related familial insulinomatosis
- Clinical: MAFA-related familial insulinomatosis typically presents with hyperinsulinaemic hypoglycaemia, more common in females, or diabetes, more common in males. Diagnostic clues include a normal BMI and negative islet autoantibodies.
- Micro: The pancreas contains innumerable multicentric islet B-cell proliferations, ranging from dysplastic B-cell cords to microtumours and well-differentiated tumours, all staining intensely and exclusively for insulin.
- Ancillary: Immunohistochemistry (IHC) shows strong and exclusive insulin positivity, with no expression of glucagon, PP, or somatostatin. Genetic testing reveals a missense MAFA c.191C>T p.S64F sequence variant.
Reference Gallery:
MAFA-related familial insulinomatosis. The pancreas in MAFA-related insulinomatosis contains innumerable multicentric islet B-cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microtumours (< 5 mm) and well-differentiated islet B-cell neuroendocrine tumours (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric islet B-cell proliferations range from dysplastic B-cell cords to microtumours and well-differentiated tumours, all staining intensely and exclusively for insulin.

Q: The characteristic microscopic appearance of Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET) is a triphasic pattern comprising epithelioid neuroendocrine cells, spindle cells with Schwann cell differentiation, and [...] cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Characteristic triphasic appearance including epithelioid neuroendocrine cells, ganglion cells, and spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). FNAB demonstrating epithelioid neuroendocrine cells and a large binucleated ganglion cell. The specimen was diagnosed as CoGNET after excision (Pap).
A: ganglion
Q: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Patients with [...] usually present with gastrointestinal bleeding due to mucosal ulceration or nonspecific epigastric pain.
- Micro: [...] display three morphologically distinct cell components: epithelial cells, spindle cells with Schwann cell differentiation, and ganglion cells.
- Ancillary: Almost all epithelial cells in [...] express cytokeratins, chromogranin A, synaptophysin, NSE, and PR.
Reference Gallery:
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET typically presents as a polypoid submucosal mass in the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Characteristic triphasic appearance including epithelioid neuroendocrine cells, ganglion cells, and spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Epithelioid cells with neuroendocrine features.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Synaptophysin is positive in the epithelioid cells and the ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 is positive in the spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CK8/18 may show limited positivity in the epithelioid cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Endoscopic image of a CoGNET presenting as a 20 mm submucosal mass with mucosal ulceration in the second part of the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). FNAB demonstrating epithelioid neuroendocrine cells and a large binucleated ganglion cell. The specimen was diagnosed as CoGNET after excision (Pap).
A: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET); CoGNETs; CoGNET

Q: Patients with Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET) often present with gastrointestinal bleeding from mucosal ulceration overlying a polypoid submucosal mass typically located in the [...].
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET typically presents as a polypoid submucosal mass in the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Endoscopic image of a CoGNET presenting as a 20 mm submucosal mass with mucosal ulceration in the second part of the duodenum.
A: duodenum
Q: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Patients with [...] usually present with gastrointestinal bleeding due to mucosal ulceration or nonspecific epigastric pain.
- Micro: [...] display three morphologically distinct cell components: epithelial cells, spindle cells with Schwann cell differentiation, and ganglion cells.
- Ancillary: Almost all epithelial cells in [...] express cytokeratins, chromogranin A, synaptophysin, NSE, and PR.
Reference Gallery:
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET typically presents as a polypoid submucosal mass in the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Characteristic triphasic appearance including epithelioid neuroendocrine cells, ganglion cells, and spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Epithelioid cells with neuroendocrine features.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Synaptophysin is positive in the epithelioid cells and the ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 is positive in the spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CK8/18 may show limited positivity in the epithelioid cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Endoscopic image of a CoGNET presenting as a 20 mm submucosal mass with mucosal ulceration in the second part of the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). FNAB demonstrating epithelioid neuroendocrine cells and a large binucleated ganglion cell. The specimen was diagnosed as CoGNET after excision (Pap).
A: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET); CoGNETs; CoGNET

Q: In Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET), the spindle cell component exhibits Schwann cell differentiation and is characteristically positive for the immunohistochemical stain [...].
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 is positive in the spindle cells with Schwann cell differentiation.
A: S100
Q: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Patients with [...] usually present with gastrointestinal bleeding due to mucosal ulceration or nonspecific epigastric pain.
- Micro: [...] display three morphologically distinct cell components: epithelial cells, spindle cells with Schwann cell differentiation, and ganglion cells.
- Ancillary: Almost all epithelial cells in [...] express cytokeratins, chromogranin A, synaptophysin, NSE, and PR.
Reference Gallery:
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET typically presents as a polypoid submucosal mass in the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Characteristic triphasic appearance including epithelioid neuroendocrine cells, ganglion cells, and spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Epithelioid cells with neuroendocrine features.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Synaptophysin is positive in the epithelioid cells and the ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 is positive in the spindle cells with Schwann cell differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CK8/18 may show limited positivity in the epithelioid cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Endoscopic image of a CoGNET presenting as a 20 mm submucosal mass with mucosal ulceration in the second part of the duodenum.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). FNAB demonstrating epithelioid neuroendocrine cells and a large binucleated ganglion cell. The specimen was diagnosed as CoGNET after excision (Pap).
A: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET); CoGNETs; CoGNET

Q: Zollinger-Ellison syndrome, characterized by severe peptic ulcer disease and diarrhea, is clinically driven by a Gastrinoma, which characteristically shows strong immunohistochemical positivity for [...].
Gastrinoma. The tumour cells are immunopositive for gastrin.
A: gastrin
Back Extra: Gastrinoma
- Clinical: The typical clinical features of Zollinger–Ellison syndrome include advanced peptic ulcer disease, gastro-oesophageal reflux disease, diarrhoea, nausea, vomiting, and abdominal pain.
- Micro: Gastrinomas often display trabecular and/or glandular structures with a delicate stroma, and the proportion of gastrin-producing cells is not crucial for the clinical syndrome.
- Ancillary: The tumour cells are positive for neuroendocrine markers (chromogranin A, synaptophysin) and SSTR2A, making them eligible for somatostatin analogues and SSTR-targeted radiotherapy.
Reference Gallery:
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern.
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern with low nuclear atypia.
Gastrinoma. The tumour cells are immunopositive for gastrin.

Q: Histologically, a [...] is a well-differentiated neuroendocrine tumor that often displays a trabecular, tubuloacinar, or pseudoglandular growth pattern with low nuclear atypia and a delicate stroma.
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern.
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern with low nuclear atypia.
A: Gastrinoma
Back Extra: Gastrinoma
- Clinical: The typical clinical features of Zollinger–Ellison syndrome include advanced peptic ulcer disease, gastro-oesophageal reflux disease, diarrhoea, nausea, vomiting, and abdominal pain.
- Micro: Gastrinomas often display trabecular and/or glandular structures with a delicate stroma, and the proportion of gastrin-producing cells is not crucial for the clinical syndrome.
- Ancillary: The tumour cells are positive for neuroendocrine markers (chromogranin A, synaptophysin) and SSTR2A, making them eligible for somatostatin analogues and SSTR-targeted radiotherapy.
Reference Gallery:
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern.
Gastrinoma. An example with a typical tubuloacinar and pseudoglandular growth pattern with low nuclear atypia.
Gastrinoma. The tumour cells are immunopositive for gastrin.

Q: Microscopically, the presence of multiple enlarged endocrine islets and microtumors that exhibit almost exclusive glucagon expression by immunohistochemistry is characteristic of [...].
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
A: Glucagon Cell Hyperplasia and Neoplasia
Back Extra: Glucagon Cell Hyperplasia and Neoplasia
- Clinical: Patients with Glucagon Cell Hyperplasia and Neoplasia present with nonspecific symptoms such as abdominal pain, altered bowel habits, and fatigue. Serum glucagon levels are very high, but the typical glucagonoma syndrome is rare due to receptor signaling defects.
- Micro: The pancreas shows multiple enlarged endocrine islets and microtumours that are almost exclusively glucagon-positive. Large tumours may undergo cystic transformation and focal calcification.
- Ancillary: Sequencing all exons of the GCGR gene, including splice sites, is essential for diagnosing Glucagon Cell Hyperplasia and Neoplasia.
Reference Gallery:
Glucagon cell hyperplasia and neoplasia. The pancreas is diffusely enlarged. Its cut surface has a firm texture due to multiple coalescing glucagon-producing neoplasms.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Enlarged and numerous endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively and may have minimal and focal insulin expression by immunohistochemistry.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.

Q: Patients with Glucagon Cell Hyperplasia and Neoplasia often present with very high serum glucagon levels but rarely develop typical glucagonoma syndrome due to receptor signaling defects associated with mutations in the [...] gene.
Glucagon cell hyperplasia and neoplasia. The pancreas is diffusely enlarged. Its cut surface has a firm texture due to multiple coalescing glucagon-producing neoplasms.
Glucagon cell hyperplasia and neoplasia. Enlarged and numerous endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively and may have minimal and focal insulin expression by immunohistochemistry.
A: GCGR
Back Extra: Glucagon Cell Hyperplasia and Neoplasia
- Clinical: Patients with Glucagon Cell Hyperplasia and Neoplasia present with nonspecific symptoms such as abdominal pain, altered bowel habits, and fatigue. Serum glucagon levels are very high, but the typical glucagonoma syndrome is rare due to receptor signaling defects.
- Micro: The pancreas shows multiple enlarged endocrine islets and microtumours that are almost exclusively glucagon-positive. Large tumours may undergo cystic transformation and focal calcification.
- Ancillary: Sequencing all exons of the GCGR gene, including splice sites, is essential for diagnosing Glucagon Cell Hyperplasia and Neoplasia.
Reference Gallery:
Glucagon cell hyperplasia and neoplasia. The pancreas is diffusely enlarged. Its cut surface has a firm texture due to multiple coalescing glucagon-producing neoplasms.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively.
Glucagon cell hyperplasia and neoplasia. Enlarged and numerous endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. Hypertrophic islets and tumours exhibit glucagon expression almost exclusively and may have minimal and focal insulin expression by immunohistochemistry.
Glucagon cell hyperplasia and neoplasia. Multiple enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas. By immunohistochemistry, hypertrophic islets and tumours exhibit glucagon expression almost exclusively.

Q: Patients with glucagonoma classically present with a paraneoplastic skin rash known as [...], alongside weight loss and new-onset diabetes.
Glucagonoma. Necrolytic migratory erythema in a patient with pancreatic glucagonoma.
A: necrolytic migratory erythema
Back Extra: Glucagonoma
- Clinical: Glucagonoma syndrome includes necrolytic migratory erythema, painful glossitis, cheilitis, onychodystrophy, significant weight loss, deep vein thrombosis, and new-onset or worsening diabetes mellitus.
- Micro: Glucagonomas are composed of well-differentiated cells forming densely packed trabecular structures with scant fibrous stroma.
- Ancillary: Tumour cells are positive for glucagon, keratin, and general neuroendocrine markers. FOXA2 and DAXX mutations are also noted.
Reference Gallery:
Glucagonoma. Necrolytic migratory erythema in a patient with pancreatic glucagonoma.
Glucagonoma. 68Ga-DOTATATE PET-CT and 3-phase CT images (arterial phase) of a 54-year-old woman with an 84 mm glucagonoma of the pancreatic tail, with multilobar metastases in the liver, periaortic and pericaval lymph node metastases, a left adrenal metastasis (31 mm), and a 49 mm supraclavicular lymph node metastasis at the left side.
Glucagonoma. Macroscopic appearance of a pancreatic glucagonoma measuring 80 mm located in the distal pancreas and involving peripancreatic lymph nodes.
Glucagonoma. The tumour is composed of well-differentiated cells and shows a trabecular architecture.
Glucagonoma. A venous thrombus is present.
Glucagonoma. Tumour cells are positive for glucagon.

Q: Histologically, a glucagonoma consists of well-differentiated neuroendocrine cells forming trabecular structures; the diagnosis is confirmed when tumor cells are strongly positive for [...] on immunohistochemistry.
Glucagonoma. The tumour is composed of well-differentiated cells and shows a trabecular architecture.
Glucagonoma. Tumour cells are positive for glucagon.
A: glucagon
Back Extra: Glucagonoma
- Clinical: Glucagonoma syndrome includes necrolytic migratory erythema, painful glossitis, cheilitis, onychodystrophy, significant weight loss, deep vein thrombosis, and new-onset or worsening diabetes mellitus.
- Micro: Glucagonomas are composed of well-differentiated cells forming densely packed trabecular structures with scant fibrous stroma.
- Ancillary: Tumour cells are positive for glucagon, keratin, and general neuroendocrine markers. FOXA2 and DAXX mutations are also noted.
Reference Gallery:
Glucagonoma. Necrolytic migratory erythema in a patient with pancreatic glucagonoma.
Glucagonoma. 68Ga-DOTATATE PET-CT and 3-phase CT images (arterial phase) of a 54-year-old woman with an 84 mm glucagonoma of the pancreatic tail, with multilobar metastases in the liver, periaortic and pericaval lymph node metastases, a left adrenal metastasis (31 mm), and a 49 mm supraclavicular lymph node metastasis at the left side.
Glucagonoma. Macroscopic appearance of a pancreatic glucagonoma measuring 80 mm located in the distal pancreas and involving peripancreatic lymph nodes.
Glucagonoma. The tumour is composed of well-differentiated cells and shows a trabecular architecture.
Glucagonoma. A venous thrombus is present.
Glucagonoma. Tumour cells are positive for glucagon.

Q: A classic complication of glucagonoma is a hypercoagulable state, which is often clinically and microscopically evident as deep [...].
Glucagonoma. A venous thrombus is present.
A: venous thrombosis
Back Extra: Glucagonoma
- Clinical: Glucagonoma syndrome includes necrolytic migratory erythema, painful glossitis, cheilitis, onychodystrophy, significant weight loss, deep vein thrombosis, and new-onset or worsening diabetes mellitus.
- Micro: Glucagonomas are composed of well-differentiated cells forming densely packed trabecular structures with scant fibrous stroma.
- Ancillary: Tumour cells are positive for glucagon, keratin, and general neuroendocrine markers. FOXA2 and DAXX mutations are also noted.
Reference Gallery:
Glucagonoma. Necrolytic migratory erythema in a patient with pancreatic glucagonoma.
Glucagonoma. 68Ga-DOTATATE PET-CT and 3-phase CT images (arterial phase) of a 54-year-old woman with an 84 mm glucagonoma of the pancreatic tail, with multilobar metastases in the liver, periaortic and pericaval lymph node metastases, a left adrenal metastasis (31 mm), and a 49 mm supraclavicular lymph node metastasis at the left side.
Glucagonoma. Macroscopic appearance of a pancreatic glucagonoma measuring 80 mm located in the distal pancreas and involving peripancreatic lymph nodes.
Glucagonoma. The tumour is composed of well-differentiated cells and shows a trabecular architecture.
Glucagonoma. A venous thrombus is present.
Glucagonoma. Tumour cells are positive for glucagon.

Q: Morphologically, Mixed Acinar-Neuroendocrine Carcinoma characteristically displays two distinct tumor populations: solid acinar structures and [...] components.
Mixed acinar–neuroendocrine carcinoma. The tumour is showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
A: trabecular neuroendocrine
Back Extra: Mixed Acinar-Neuroendocrine Carcinoma
- Clinical: Patients usually present with nonspecific symptoms like abdominal pain and weight loss, but mixed acinar–neuroendocrine carcinomas can also cause jaundice or lipase hypersecretion syndrome.
- Micro: These carcinomas typically present as large, poorly defined, multilobulated tumours with a fleshy cut surface, and haemorrhage and necrosis are common. Morphologically, they show both solid acinar and trabecular neuroendocrine components.
- Ancillary: Immunohistochemical expression of both acinar (trypsin, chymotrypsin, BCL10) and neuroendocrine (chromogranin A, synaptophysin, INSM1) markers is crucial for diagnosis, and Ki-67 staining helps assess cell proliferation.
Reference Gallery:
Mixed acinar–neuroendocrine carcinoma. The tumour is showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is strongly positive for chromogranin A.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is negative for trypsin, which is positive in the acinar component.

Q: To confirm a diagnosis of Mixed Acinar-Neuroendocrine Carcinoma, the neuroendocrine component typically demonstrates strong immunohistochemical positivity for markers such as synaptophysin, INSM1, and [...].
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is strongly positive for chromogranin A.
A: chromogranin A
Back Extra: Mixed Acinar-Neuroendocrine Carcinoma
- Clinical: Patients usually present with nonspecific symptoms like abdominal pain and weight loss, but mixed acinar–neuroendocrine carcinomas can also cause jaundice or lipase hypersecretion syndrome.
- Micro: These carcinomas typically present as large, poorly defined, multilobulated tumours with a fleshy cut surface, and haemorrhage and necrosis are common. Morphologically, they show both solid acinar and trabecular neuroendocrine components.
- Ancillary: Immunohistochemical expression of both acinar (trypsin, chymotrypsin, BCL10) and neuroendocrine (chromogranin A, synaptophysin, INSM1) markers is crucial for diagnosis, and Ki-67 staining helps assess cell proliferation.
Reference Gallery:
Mixed acinar–neuroendocrine carcinoma. The tumour is showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is strongly positive for chromogranin A.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is negative for trypsin, which is positive in the acinar component.

Q: In Mixed Acinar-Neuroendocrine Carcinoma, the acinar component is distinguished from the neuroendocrine component by its immunohistochemical positivity for markers such as BCL10, chymotrypsin, and [...].
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is negative for trypsin, which is positive in the acinar component.
A: trypsin
Back Extra: Mixed Acinar-Neuroendocrine Carcinoma
- Clinical: Patients usually present with nonspecific symptoms like abdominal pain and weight loss, but mixed acinar–neuroendocrine carcinomas can also cause jaundice or lipase hypersecretion syndrome.
- Micro: These carcinomas typically present as large, poorly defined, multilobulated tumours with a fleshy cut surface, and haemorrhage and necrosis are common. Morphologically, they show both solid acinar and trabecular neuroendocrine components.
- Ancillary: Immunohistochemical expression of both acinar (trypsin, chymotrypsin, BCL10) and neuroendocrine (chromogranin A, synaptophysin, INSM1) markers is crucial for diagnosis, and Ki-67 staining helps assess cell proliferation.
Reference Gallery:
Mixed acinar–neuroendocrine carcinoma. The tumour is showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is strongly positive for chromogranin A.
Mixed acinar–neuroendocrine carcinoma. The neuroendocrine component is negative for trypsin, which is positive in the acinar component.

Q: To be classified as Mixed ductal adenocarcinoma–neuroendocrine neoplasms, each of the two distinct tumor components (ductal and neuroendocrine) must constitute at least [...] of the tumor volume.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The tumour is composed of ductal adenocarcinoma (bottom of image) associated with a well-differentiated NET showing a trabecular pattern of growth.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). This tumour is composed of ductal adenocarcinoma (left) and large cell neuroendocrine carcinoma (LCNEC; right). The two components are morphologically recognizable.
A: 30%
Back Extra: Mixed ductal adenocarcinoma–neuroendocrine neoplasms
- Clinical: Mixed ductal adenocarcinoma–neuroendocrine neoplasms are rare, comprising about 0.5–2% of all ductal adenocarcinomas, and are most commonly diagnosed in patients around 68 years of age.
- Micro: The tumour is composed of a ductal adenocarcinoma component and a neuroendocrine component, which can either be a well-differentiated neuroendocrine tumour (NET) or a poorly differentiated neuroendocrine carcinoma (NEC). Each component constitutes ≥ 30% of the tumour volume.
- Ancillary: Immunohistochemistry (IHC) is crucial for diagnosis, with the ductal adenocarcinoma component positive for CEA, EMA (MUC1), and/or MUC2, and the neuroendocrine component positive for synaptophysin, chromogranin A, and INSM1.
Reference Gallery:
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The tumour is composed of ductal adenocarcinoma (bottom of image) associated with a well-differentiated NET showing a trabecular pattern of growth.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The adenocarcinoma component is positive for CK7, which is negative in the trabecular NET component.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The NET component is positive for chromogranin A. A glandular structure is chromogranin A–negative.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The Ki-67 proliferation index of the trabecular NET component is low.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). This tumour is composed of ductal adenocarcinoma (left) and large cell neuroendocrine carcinoma (LCNEC; right). The two components are morphologically recognizable.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). The Ki-67 proliferation index of the NEC component is > 20%.

Q: In Mixed ductal adenocarcinoma–neuroendocrine neoplasms, immunohistochemistry is crucial for diagnosis; the neuroendocrine component characteristically expresses synaptophysin, INSM1, and [...].
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The NET component is positive for chromogranin A. A glandular structure is chromogranin A–negative.
A: chromogranin A
Back Extra: Mixed ductal adenocarcinoma–neuroendocrine neoplasms
- Clinical: Mixed ductal adenocarcinoma–neuroendocrine neoplasms are rare, comprising about 0.5–2% of all ductal adenocarcinomas, and are most commonly diagnosed in patients around 68 years of age.
- Micro: The tumour is composed of a ductal adenocarcinoma component and a neuroendocrine component, which can either be a well-differentiated neuroendocrine tumour (NET) or a poorly differentiated neuroendocrine carcinoma (NEC). Each component constitutes ≥ 30% of the tumour volume.
- Ancillary: Immunohistochemistry (IHC) is crucial for diagnosis, with the ductal adenocarcinoma component positive for CEA, EMA (MUC1), and/or MUC2, and the neuroendocrine component positive for synaptophysin, chromogranin A, and INSM1.
Reference Gallery:
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The tumour is composed of ductal adenocarcinoma (bottom of image) associated with a well-differentiated NET showing a trabecular pattern of growth.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The adenocarcinoma component is positive for CK7, which is negative in the trabecular NET component.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The NET component is positive for chromogranin A. A glandular structure is chromogranin A–negative.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The Ki-67 proliferation index of the trabecular NET component is low.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). This tumour is composed of ductal adenocarcinoma (left) and large cell neuroendocrine carcinoma (LCNEC; right). The two components are morphologically recognizable.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). The Ki-67 proliferation index of the NEC component is > 20%.

Q: The neuroendocrine component of Mixed ductal adenocarcinoma–neuroendocrine neoplasms can be a well-differentiated neuroendocrine tumor (NET) or a poorly differentiated [...] (NEC), which typically exhibits a Ki-67 proliferation index > 20%.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). This tumour is composed of ductal adenocarcinoma (left) and large cell neuroendocrine carcinoma (LCNEC; right). The two components are morphologically recognizable.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). The Ki-67 proliferation index of the NEC component is > 20%.
A: neuroendocrine carcinoma
Back Extra: Mixed ductal adenocarcinoma–neuroendocrine neoplasms
- Clinical: Mixed ductal adenocarcinoma–neuroendocrine neoplasms are rare, comprising about 0.5–2% of all ductal adenocarcinomas, and are most commonly diagnosed in patients around 68 years of age.
- Micro: The tumour is composed of a ductal adenocarcinoma component and a neuroendocrine component, which can either be a well-differentiated neuroendocrine tumour (NET) or a poorly differentiated neuroendocrine carcinoma (NEC). Each component constitutes ≥ 30% of the tumour volume.
- Ancillary: Immunohistochemistry (IHC) is crucial for diagnosis, with the ductal adenocarcinoma component positive for CEA, EMA (MUC1), and/or MUC2, and the neuroendocrine component positive for synaptophysin, chromogranin A, and INSM1.
Reference Gallery:
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The tumour is composed of ductal adenocarcinoma (bottom of image) associated with a well-differentiated NET showing a trabecular pattern of growth.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The adenocarcinoma component is positive for CK7, which is negative in the trabecular NET component.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The NET component is positive for chromogranin A. A glandular structure is chromogranin A–negative.
Mixed ductal adenocarcinoma–neuroendocrine tumour (NET). The Ki-67 proliferation index of the trabecular NET component is low.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). This tumour is composed of ductal adenocarcinoma (left) and large cell neuroendocrine carcinoma (LCNEC; right). The two components are morphologically recognizable.
Mixed ductal adenocarcinoma–neuroendocrine carcinoma (NEC). The Ki-67 proliferation index of the NEC component is > 20%.

Q: A [...] is defined by the morphologically recognizable presence of both a neuroendocrine component (e.g., small or large cell neuroendocrine carcinoma) and a non-neuroendocrine component (e.g., adenocarcinoma or squamous cell carcinoma) within the same tumor.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and adenocarcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and squamous cell carcinoma (right).
A: Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN)
Back Extra: Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN)
- Clinical: Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) account for 2–30% of all NENs, with a variable site-specific incidence. They are more common in men and typically diagnosed in the sixth or seventh decade of life.
- Micro: The diagnosis of MiNEN subtypes requires that both neuroendocrine and non-neuroendocrine components are morphologically recognizable. The neuroendocrine component is usually represented by a NEC (small cell or large cell), while the non-neuroendocrine component can be adenocarcinoma or squamous cell carcinoma.
- Ancillary: Immunohistochemistry is crucial for confirming the neuroendocrine nature of the neuroendocrine component, with synaptophysin, chromogranin A, and INSM1 being the most sensitive markers. The Ki-67 proliferation index is necessary to grade the NET component.
Reference Gallery:
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and adenocarcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The adenocarcinoma component is positive for napsin A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and squamous cell carcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The squamous cell carcinoma component is positive for p40.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. This MiNEN is composed of well-differentiated neuroendocrine tumour (NET; right) and moderately differentiated adenocarcinoma (left).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The neuroendocrine tumour (NET) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The Ki-67 proliferation index of the neuroendocrine tumour (NET) component is < 3%.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The endometrioid carcinoma component is positive for ER.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The large cell neuroendocrine carcinoma (LCNEC) component is positive for SSTR2A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the urinary bladder. This MiNEN is composed of urothelial carcinoma (bottom), adenocarcinoma (centre right), and small cell neuroendocrine carcinoma (SCNEC; top).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.

Q: In a Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN), the neuroendocrine component is confirmed using immunohistochemical stains for sensitive markers such as chromogranin A, INSM1, and [...].
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The neuroendocrine tumour (NET) component is positive for synaptophysin.
A: synaptophysin
Back Extra: Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN)
- Clinical: Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) account for 2–30% of all NENs, with a variable site-specific incidence. They are more common in men and typically diagnosed in the sixth or seventh decade of life.
- Micro: The diagnosis of MiNEN subtypes requires that both neuroendocrine and non-neuroendocrine components are morphologically recognizable. The neuroendocrine component is usually represented by a NEC (small cell or large cell), while the non-neuroendocrine component can be adenocarcinoma or squamous cell carcinoma.
- Ancillary: Immunohistochemistry is crucial for confirming the neuroendocrine nature of the neuroendocrine component, with synaptophysin, chromogranin A, and INSM1 being the most sensitive markers. The Ki-67 proliferation index is necessary to grade the NET component.
Reference Gallery:
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and adenocarcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The adenocarcinoma component is positive for napsin A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and squamous cell carcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The squamous cell carcinoma component is positive for p40.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. This MiNEN is composed of well-differentiated neuroendocrine tumour (NET; right) and moderately differentiated adenocarcinoma (left).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The neuroendocrine tumour (NET) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The Ki-67 proliferation index of the neuroendocrine tumour (NET) component is < 3%.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The endometrioid carcinoma component is positive for ER.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The large cell neuroendocrine carcinoma (LCNEC) component is positive for SSTR2A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the urinary bladder. This MiNEN is composed of urothelial carcinoma (bottom), adenocarcinoma (centre right), and small cell neuroendocrine carcinoma (SCNEC; top).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.

Q: When evaluating a Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN) with a well-differentiated neuroendocrine tumor component, grading must be determined by assessing the [...].
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The Ki-67 proliferation index of the neuroendocrine tumour (NET) component is < 3%.
A: Ki-67 proliferation index
Back Extra: Mixed Neuroendocrine-Non-Neuroendocrine Neoplasm (MiNEN)
- Clinical: Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) account for 2–30% of all NENs, with a variable site-specific incidence. They are more common in men and typically diagnosed in the sixth or seventh decade of life.
- Micro: The diagnosis of MiNEN subtypes requires that both neuroendocrine and non-neuroendocrine components are morphologically recognizable. The neuroendocrine component is usually represented by a NEC (small cell or large cell), while the non-neuroendocrine component can be adenocarcinoma or squamous cell carcinoma.
- Ancillary: Immunohistochemistry is crucial for confirming the neuroendocrine nature of the neuroendocrine component, with synaptophysin, chromogranin A, and INSM1 being the most sensitive markers. The Ki-67 proliferation index is necessary to grade the NET component.
Reference Gallery:
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and adenocarcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The adenocarcinoma component is positive for napsin A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). This MiNEN is composed of large cell neuroendocrine carcinoma (LCNEC; left) and squamous cell carcinoma (right).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The squamous cell carcinoma component is positive for p40.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. This MiNEN is composed of well-differentiated neuroendocrine tumour (NET; right) and moderately differentiated adenocarcinoma (left).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The neuroendocrine tumour (NET) component is positive for synaptophysin.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the colon. The Ki-67 proliferation index of the neuroendocrine tumour (NET) component is < 3%.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The endometrioid carcinoma component is positive for ER.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the ovary. The large cell neuroendocrine carcinoma (LCNEC) component is positive for SSTR2A.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the urinary bladder. This MiNEN is composed of urothelial carcinoma (bottom), adenocarcinoma (centre right), and small cell neuroendocrine carcinoma (SCNEC; top).
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the lung (combined neoplasm). The large cell neuroendocrine carcinoma (LCNEC) component is positive for synaptophysin.

Q: Microscopically, a Non-functioning Pancreatic Neuroendocrine Tumor (NF-PanNET) is characterized by an [...] growth pattern, commonly demonstrating solid, nested, or trabecular architectures.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-nested pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular NOS pattern.
A: organoid
Back Extra: Non-functioning Pancreatic Neuroendocrine Tumour (NF-PanNET)
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) can present at any age between 10 and 80 years, often incidentally detected or due to local/metastatic spread.
- Micro: NF-PanNETs exhibit organoid growth patterns, commonly solid and trabecular. They can also show oncocytic, pleomorphic, and clear cell cytological features.
- Ancillary: Immunohistochemistry is crucial for diagnosis, with positive staining for cytokeratin, synaptophysin, chromogranin A, and INSM1. Ki-67 index helps in grading and predicting prognosis.
Reference Gallery:
Non-functioning pancreatic neuroendocrine tumour (PanNET). Small (14 mm), solid, well-demarcated tumour in the pancreatic body.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Lobulated (35 mm) solid tumour in the pancreatic head.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed microcystic tumour.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed tumour with conspicuous stromal sclerosis.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-nested pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-paraganglioma-like pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular NOS pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-reticulated pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-glandular pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Oncocytic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Pleomorphic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Clear cell cytological features.

Q: In addition to its classic morphology, a Non-functioning Pancreatic Neuroendocrine Tumor (NF-PanNET) can exhibit prominent cytological variations, including pleomorphic, clear cell, and [...] features characterized by abundant granular, eosinophilic cytoplasm.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Oncocytic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Pleomorphic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Clear cell cytological features.
A: oncocytic
Back Extra: Non-functioning Pancreatic Neuroendocrine Tumour (NF-PanNET)
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) can present at any age between 10 and 80 years, often incidentally detected or due to local/metastatic spread.
- Micro: NF-PanNETs exhibit organoid growth patterns, commonly solid and trabecular. They can also show oncocytic, pleomorphic, and clear cell cytological features.
- Ancillary: Immunohistochemistry is crucial for diagnosis, with positive staining for cytokeratin, synaptophysin, chromogranin A, and INSM1. Ki-67 index helps in grading and predicting prognosis.
Reference Gallery:
Non-functioning pancreatic neuroendocrine tumour (PanNET). Small (14 mm), solid, well-demarcated tumour in the pancreatic body.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Lobulated (35 mm) solid tumour in the pancreatic head.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed microcystic tumour.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed tumour with conspicuous stromal sclerosis.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-nested pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-paraganglioma-like pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular NOS pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-reticulated pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-glandular pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Oncocytic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Pleomorphic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Clear cell cytological features.

Q: Macroscopically, a Non-functioning Pancreatic Neuroendocrine Tumor (NF-PanNET) typically presents as a solid and [...] mass, though variants can display microcystic changes or marked stromal sclerosis.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Small (14 mm), solid, well-demarcated tumour in the pancreatic body.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed microcystic tumour.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed tumour with conspicuous stromal sclerosis.
A: well-circumscribed
Back Extra: Non-functioning Pancreatic Neuroendocrine Tumour (NF-PanNET)
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) can present at any age between 10 and 80 years, often incidentally detected or due to local/metastatic spread.
- Micro: NF-PanNETs exhibit organoid growth patterns, commonly solid and trabecular. They can also show oncocytic, pleomorphic, and clear cell cytological features.
- Ancillary: Immunohistochemistry is crucial for diagnosis, with positive staining for cytokeratin, synaptophysin, chromogranin A, and INSM1. Ki-67 index helps in grading and predicting prognosis.
Reference Gallery:
Non-functioning pancreatic neuroendocrine tumour (PanNET). Small (14 mm), solid, well-demarcated tumour in the pancreatic body.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Lobulated (35 mm) solid tumour in the pancreatic head.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed microcystic tumour.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Well-circumscribed tumour with conspicuous stromal sclerosis.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-nested pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Solid-paraganglioma-like pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular NOS pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-reticulated pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Trabecular-glandular pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Oncocytic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Pleomorphic cytological features.
Non-functioning pancreatic neuroendocrine tumour (PanNET). Clear cell cytological features.

Q: Microscopically, Other Pancreatic Neuroendocrine Tumours with Ectopic Hormone Production are well-differentiated tumors that characteristically display bland cytology and a [...] growth pattern.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. An ACTH-producing PanNET with a trabecular growth pattern.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. Sections reveal trabecular architecture and bland cytology.
A: trabecular
Back Extra: Other Pancreatic Neuroendocrine Tumours with Ectopic Hormone Production
- Clinical: Rare PanNETs with ectopic hormone secretion can cause Cushing syndrome, Zollinger–Ellison syndrome, and inappropriate insulin secretion.
- Micro: PanNETs with ectopic hormone production are well-differentiated with a trabecular architecture and bland cytology.
- Ancillary: Immunohistochemistry shows positivity for neuroendocrine markers (chromogranin A, synaptophysin) and the specific ectopic hormone (e.g., ACTH, GHRH).
Reference Gallery:
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. An ACTH-producing PanNET with a trabecular growth pattern.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for ACTH immunohistochemical stain.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. GHRH-producing PanNET. The tumour is well circumscribed.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. Sections reveal trabecular architecture and bland cytology.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for GHRH immunohistochemical stain.

Q: In Other Pancreatic Neuroendocrine Tumours with Ectopic Hormone Production, immunohistochemistry confirms the diagnosis by demonstrating positivity for general neuroendocrine markers and the specific secreted hormone, such as GHRH or [...] (which can cause ectopic Cushing syndrome).
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for ACTH immunohistochemical stain.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for GHRH immunohistochemical stain.
A: ACTH
Back Extra: Other Pancreatic Neuroendocrine Tumours with Ectopic Hormone Production
- Clinical: Rare PanNETs with ectopic hormone secretion can cause Cushing syndrome, Zollinger–Ellison syndrome, and inappropriate insulin secretion.
- Micro: PanNETs with ectopic hormone production are well-differentiated with a trabecular architecture and bland cytology.
- Ancillary: Immunohistochemistry shows positivity for neuroendocrine markers (chromogranin A, synaptophysin) and the specific ectopic hormone (e.g., ACTH, GHRH).
Reference Gallery:
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. An ACTH-producing PanNET with a trabecular growth pattern.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for ACTH immunohistochemical stain.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. GHRH-producing PanNET. The tumour is well circumscribed.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. Sections reveal trabecular architecture and bland cytology.
Other pancreatic neuroendocrine tumours (PanNETs) with ectopic hormone production. The tumour cells are positive for GHRH immunohistochemical stain.

Q: Immunohistochemistry in Pancreatic Neuroendocrine Carcinoma frequently demonstrates abnormal p53 expression and a complete loss of [...] protein expression.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Loss of RB1 protein expression.
A: RB1
Back Extra: Pancreatic Neuroendocrine Carcinoma
- Clinical: Pancreatic Neuroendocrine Carcinoma (PanNEC) often presents with back pain, jaundice, and nonspecific abdominal symptoms. Serum calcitonin levels may be elevated in some patients.
- Micro: PanNECs show high-grade cytology with minimal cytoplasm, large nuclei, and a high N:C ratio. Mitotic activity is brisk, and necrosis is common.
- Ancillary: Immunohistochemistry shows abnormal p53 expression and complete loss of RB1 in 95% and 74% of cases, respectively. Synaptophysin and chromogranin A are key markers for confirming neuroendocrine differentiation.
Reference Gallery:
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), small cell type. The cells have high-grade cytology, with minimal cytoplasm and a high N:C ratio. Mitotic activity is brisk, and necrosis is readily evident.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Ki-67 immunostaining shows diffuse nuclear labelling, with a Ki-67 proliferation index > 90%.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Loss of RB1 protein expression.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. Diffuse growth of relatively monotonous cells with a nested/organoid pattern indicating neuroendocrine differentiation, which was confirmed by synaptophysin staining. Cytological atypia and prominent mitotic activity indicate the high-grade nature of this carcinoma.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. The cells have moderate cytoplasm and large nuclei with prominent nucleoli.

Q: The large cell type of [...] is characterized by a nested/organoid growth pattern, moderate cytoplasm, large nuclei with prominent nucleoli, and marked cytologic atypia.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. Diffuse growth of relatively monotonous cells with a nested/organoid pattern indicating neuroendocrine differentiation, which was confirmed by synaptophysin staining. Cytological atypia and prominent mitotic activity indicate the high-grade nature of this carcinoma.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. The cells have moderate cytoplasm and large nuclei with prominent nucleoli.
A: Pancreatic Neuroendocrine Carcinoma
Back Extra: Pancreatic Neuroendocrine Carcinoma
- Clinical: Pancreatic Neuroendocrine Carcinoma (PanNEC) often presents with back pain, jaundice, and nonspecific abdominal symptoms. Serum calcitonin levels may be elevated in some patients.
- Micro: PanNECs show high-grade cytology with minimal cytoplasm, large nuclei, and a high N:C ratio. Mitotic activity is brisk, and necrosis is common.
- Ancillary: Immunohistochemistry shows abnormal p53 expression and complete loss of RB1 in 95% and 74% of cases, respectively. Synaptophysin and chromogranin A are key markers for confirming neuroendocrine differentiation.
Reference Gallery:
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), small cell type. The cells have high-grade cytology, with minimal cytoplasm and a high N:C ratio. Mitotic activity is brisk, and necrosis is readily evident.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Ki-67 immunostaining shows diffuse nuclear labelling, with a Ki-67 proliferation index > 90%.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Loss of RB1 protein expression.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. Diffuse growth of relatively monotonous cells with a nested/organoid pattern indicating neuroendocrine differentiation, which was confirmed by synaptophysin staining. Cytological atypia and prominent mitotic activity indicate the high-grade nature of this carcinoma.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. The cells have moderate cytoplasm and large nuclei with prominent nucleoli.

Q: To confirm the high-grade, rapid proliferation characteristic of Pancreatic Neuroendocrine Carcinoma, immunostaining for [...] is often performed, frequently demonstrating a proliferation index > 90%.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Ki-67 immunostaining shows diffuse nuclear labelling, with a Ki-67 proliferation index > 90%.
A: Ki-67
Back Extra: Pancreatic Neuroendocrine Carcinoma
- Clinical: Pancreatic Neuroendocrine Carcinoma (PanNEC) often presents with back pain, jaundice, and nonspecific abdominal symptoms. Serum calcitonin levels may be elevated in some patients.
- Micro: PanNECs show high-grade cytology with minimal cytoplasm, large nuclei, and a high N:C ratio. Mitotic activity is brisk, and necrosis is common.
- Ancillary: Immunohistochemistry shows abnormal p53 expression and complete loss of RB1 in 95% and 74% of cases, respectively. Synaptophysin and chromogranin A are key markers for confirming neuroendocrine differentiation.
Reference Gallery:
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), small cell type. The cells have high-grade cytology, with minimal cytoplasm and a high N:C ratio. Mitotic activity is brisk, and necrosis is readily evident.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Ki-67 immunostaining shows diffuse nuclear labelling, with a Ki-67 proliferation index > 90%.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm). Loss of RB1 protein expression.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. Diffuse growth of relatively monotonous cells with a nested/organoid pattern indicating neuroendocrine differentiation, which was confirmed by synaptophysin staining. Cytological atypia and prominent mitotic activity indicate the high-grade nature of this carcinoma.
Pancreatic neuroendocrine carcinoma (poorly differentiated neuroendocrine neoplasm), large cell type. The cells have moderate cytoplasm and large nuclei with prominent nucleoli.

Q: Functioning cases of Serotonin-producing pancreatic neuroendocrine tumor (PanNET) can present with [...], which is characterized by abdominal pain, diarrhea, and flushing.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of the tumour. This tumour is not close to the main duct.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of a 7 mm tumour of the head of the pancreas, located close to the main pancreatic duct, causing obstruction.
A: carcinoid syndrome
Back Extra: Serotonin-producing pancreatic neuroendocrine tumour (PanNET)
- Clinical: Patients with serotonin-producing pancreatic neuroendocrine tumours (PanNETs) can be asymptomatic or present with nonspecific symptoms. Functioning tumours can cause carcinoid syndrome, characterized by abdominal pain, diarrhoea, and flushing.
- Micro: Serotonin-producing PanNETs typically show a trabecular, solid-nested, or acinar growth pattern, with occasional marked stromal fibrosis.
- Ancillary: The tumour cells express serotonin, SSTR2A, and neuroendocrine markers (synaptophysin, chromogranin A, and INSM1), but are negative for pancreatic hormones and gastrointestinal markers.
Reference Gallery:
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). 68Ga PET-CT total body: high tracer uptake by a non-functioning neuroendocrine tumour (NET) of the pancreatic body.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of the tumour. This tumour is not close to the main duct.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of a 7 mm tumour of the head of the pancreas, located close to the main pancreatic duct, causing obstruction.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Microscopic appearance of the tumour at low magnification.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Low-power magnification of a case showing trabecular architecture and marked stromal fibrosis.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show mild atypia.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells express serotonin.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show membrane immunoreactivity for SSTR2A.

Q: Microscopically, Serotonin-producing pancreatic neuroendocrine tumor (PanNET) typically exhibits a trabecular, solid-nested, or acinar growth pattern, occasionally accompanied by marked [...].
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Microscopic appearance of the tumour at low magnification.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Low-power magnification of a case showing trabecular architecture and marked stromal fibrosis.
A: stromal fibrosis
Back Extra: Serotonin-producing pancreatic neuroendocrine tumour (PanNET)
- Clinical: Patients with serotonin-producing pancreatic neuroendocrine tumours (PanNETs) can be asymptomatic or present with nonspecific symptoms. Functioning tumours can cause carcinoid syndrome, characterized by abdominal pain, diarrhoea, and flushing.
- Micro: Serotonin-producing PanNETs typically show a trabecular, solid-nested, or acinar growth pattern, with occasional marked stromal fibrosis.
- Ancillary: The tumour cells express serotonin, SSTR2A, and neuroendocrine markers (synaptophysin, chromogranin A, and INSM1), but are negative for pancreatic hormones and gastrointestinal markers.
Reference Gallery:
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). 68Ga PET-CT total body: high tracer uptake by a non-functioning neuroendocrine tumour (NET) of the pancreatic body.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of the tumour. This tumour is not close to the main duct.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of a 7 mm tumour of the head of the pancreas, located close to the main pancreatic duct, causing obstruction.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Microscopic appearance of the tumour at low magnification.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Low-power magnification of a case showing trabecular architecture and marked stromal fibrosis.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show mild atypia.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells express serotonin.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show membrane immunoreactivity for SSTR2A.

Q: By immunohistochemistry, Serotonin-producing pancreatic neuroendocrine tumor (PanNET) is characteristically positive for neuroendocrine markers, SSTR2A, and [...].
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells express serotonin.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show membrane immunoreactivity for SSTR2A.
A: serotonin
Back Extra: Serotonin-producing pancreatic neuroendocrine tumour (PanNET)
- Clinical: Patients with serotonin-producing pancreatic neuroendocrine tumours (PanNETs) can be asymptomatic or present with nonspecific symptoms. Functioning tumours can cause carcinoid syndrome, characterized by abdominal pain, diarrhoea, and flushing.
- Micro: Serotonin-producing PanNETs typically show a trabecular, solid-nested, or acinar growth pattern, with occasional marked stromal fibrosis.
- Ancillary: The tumour cells express serotonin, SSTR2A, and neuroendocrine markers (synaptophysin, chromogranin A, and INSM1), but are negative for pancreatic hormones and gastrointestinal markers.
Reference Gallery:
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). 68Ga PET-CT total body: high tracer uptake by a non-functioning neuroendocrine tumour (NET) of the pancreatic body.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of the tumour. This tumour is not close to the main duct.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Macroscopic appearance of a 7 mm tumour of the head of the pancreas, located close to the main pancreatic duct, causing obstruction.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Microscopic appearance of the tumour at low magnification.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). Low-power magnification of a case showing trabecular architecture and marked stromal fibrosis.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show mild atypia.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells express serotonin.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET). The tumour cells show membrane immunoreactivity for SSTR2A.

Q: On cytology and histology, Small Cell Neuroendocrine Carcinoma is characterized by small cells with scant cytoplasm, nuclear molding, and finely granular or [...] chromatin with inconspicuous nucleoli.
Small cell carcinoma of the lung. FNAC. A dirty background containing clusters of cells with scant cytoplasm and overlapping nuclei with moulding and dispersed chromatin. Nucleoli are inconspicuous.
Gastric small cell carcinoma. Tumour cells are densely packed in a discohesive pattern with a poor stroma component. Nuclear chromatin is finely dispersed or has a salt-and-pepper appearance. Small nucleoli are present in only very few cells.
A: salt-and-pepper
Back Extra: Small Cell Neuroendocrine Carcinoma
- Clinical: Small Cell Neuroendocrine Carcinoma (SCNEC) is a rapidly growing neoplasm with signs and symptoms related to the obstruction/infiltration of surrounding structures, or (often) to the presence of distant metastases.
- Micro: The microscopic appearance is characterized by small cells with scant cytoplasm, finely granular chromatin, and a high mitotic rate, often with extensive necrosis.
- Ancillary: Immunohistochemistry shows neuroendocrine markers such as chromogranin A, synaptophysin, and INSM1, and a high Ki-67 index (> 75%).
Reference Gallery:
Small cell carcinoma of the lung. FNAC. A dirty background containing clusters of cells with scant cytoplasm and overlapping nuclei with moulding and dispersed chromatin. Nucleoli are inconspicuous.
Small cell carcinoma of the lung. Core biopsy. Sheets of small cells showing discohesive pattern in a fibrotic stromal background. Nuclei are irregular, with finely granular chromatin and no evident nucleoli.
Small cell carcinoma of the lung. Ki-67 (MIB1) immunohistochemistry on a core biopsy. Necrosis may be absent and mitotic figures may be difficult to evaluate in biopsy samples. Ki-67 (MIB1) staining may be very helpful to sustain a diagnosis of small cell carcinoma in this setting, such as in the present case with a high (albeit heterogeneous) proliferation rate (exceeding 70%).
Gastric small cell carcinoma. Tumour cells are densely packed in a discohesive pattern with a poor stroma component. Nuclear chromatin is finely dispersed or has a salt-and-pepper appearance. Small nucleoli are present in only very few cells.
Gastric small cell carcinoma. Neoplastic cells show diffuse and intense cytoplasmic positivity for synaptophysin.
Gastric small cell carcinoma. Neoplastic cells show diffuse nuclear positivity for INSM1, although with heterogeneous intensity.
Bladder small cell carcinoma. A malignant neoplasm infiltrating the bladder wall made of spindling small cells in a solid growth pattern intersected by rare fibrotic bands.
Bladder small cell carcinoma. Neoplastic cells show a heterogeneous pattern of cytoplasmic positivity for synaptophysin.
Bladder small cell carcinoma. The Ki-67 index in neoplastic cells is homogeneously high (> 70% in this example).

Q: Immunohistochemistry for Small Cell Neuroendocrine Carcinoma typically demonstrates positivity for cytoplasmic neuroendocrine markers like synaptophysin, as well as the diffusely positive nuclear marker [...].
Gastric small cell carcinoma. Neoplastic cells show diffuse and intense cytoplasmic positivity for synaptophysin.
Gastric small cell carcinoma. Neoplastic cells show diffuse nuclear positivity for INSM1, although with heterogeneous intensity.
A: INSM1
Back Extra: Small Cell Neuroendocrine Carcinoma
- Clinical: Small Cell Neuroendocrine Carcinoma (SCNEC) is a rapidly growing neoplasm with signs and symptoms related to the obstruction/infiltration of surrounding structures, or (often) to the presence of distant metastases.
- Micro: The microscopic appearance is characterized by small cells with scant cytoplasm, finely granular chromatin, and a high mitotic rate, often with extensive necrosis.
- Ancillary: Immunohistochemistry shows neuroendocrine markers such as chromogranin A, synaptophysin, and INSM1, and a high Ki-67 index (> 75%).
Reference Gallery:
Small cell carcinoma of the lung. FNAC. A dirty background containing clusters of cells with scant cytoplasm and overlapping nuclei with moulding and dispersed chromatin. Nucleoli are inconspicuous.
Small cell carcinoma of the lung. Core biopsy. Sheets of small cells showing discohesive pattern in a fibrotic stromal background. Nuclei are irregular, with finely granular chromatin and no evident nucleoli.
Small cell carcinoma of the lung. Ki-67 (MIB1) immunohistochemistry on a core biopsy. Necrosis may be absent and mitotic figures may be difficult to evaluate in biopsy samples. Ki-67 (MIB1) staining may be very helpful to sustain a diagnosis of small cell carcinoma in this setting, such as in the present case with a high (albeit heterogeneous) proliferation rate (exceeding 70%).
Gastric small cell carcinoma. Tumour cells are densely packed in a discohesive pattern with a poor stroma component. Nuclear chromatin is finely dispersed or has a salt-and-pepper appearance. Small nucleoli are present in only very few cells.
Gastric small cell carcinoma. Neoplastic cells show diffuse and intense cytoplasmic positivity for synaptophysin.
Gastric small cell carcinoma. Neoplastic cells show diffuse nuclear positivity for INSM1, although with heterogeneous intensity.
Bladder small cell carcinoma. A malignant neoplasm infiltrating the bladder wall made of spindling small cells in a solid growth pattern intersected by rare fibrotic bands.
Bladder small cell carcinoma. Neoplastic cells show a heterogeneous pattern of cytoplasmic positivity for synaptophysin.
Bladder small cell carcinoma. The Ki-67 index in neoplastic cells is homogeneously high (> 70% in this example).

Q: Small Cell Neuroendocrine Carcinoma is a highly aggressive tumor characterized by frequent necrosis, high mitotic activity, and a uniquely high [...] proliferation index (typically exceeding 70-75%).
Small cell carcinoma of the lung. Ki-67 (MIB1) immunohistochemistry on a core biopsy. Necrosis may be absent and mitotic figures may be difficult to evaluate in biopsy samples. Ki-67 (MIB1) staining may be very helpful to sustain a diagnosis of small cell carcinoma in this setting, such as in the present case with a high (albeit heterogeneous) proliferation rate (exceeding 70%).
Bladder small cell carcinoma. The Ki-67 index in neoplastic cells is homogeneously high (> 70% in this example).
A: Ki-67
Back Extra: Small Cell Neuroendocrine Carcinoma
- Clinical: Small Cell Neuroendocrine Carcinoma (SCNEC) is a rapidly growing neoplasm with signs and symptoms related to the obstruction/infiltration of surrounding structures, or (often) to the presence of distant metastases.
- Micro: The microscopic appearance is characterized by small cells with scant cytoplasm, finely granular chromatin, and a high mitotic rate, often with extensive necrosis.
- Ancillary: Immunohistochemistry shows neuroendocrine markers such as chromogranin A, synaptophysin, and INSM1, and a high Ki-67 index (> 75%).
Reference Gallery:
Small cell carcinoma of the lung. FNAC. A dirty background containing clusters of cells with scant cytoplasm and overlapping nuclei with moulding and dispersed chromatin. Nucleoli are inconspicuous.
Small cell carcinoma of the lung. Core biopsy. Sheets of small cells showing discohesive pattern in a fibrotic stromal background. Nuclei are irregular, with finely granular chromatin and no evident nucleoli.
Small cell carcinoma of the lung. Ki-67 (MIB1) immunohistochemistry on a core biopsy. Necrosis may be absent and mitotic figures may be difficult to evaluate in biopsy samples. Ki-67 (MIB1) staining may be very helpful to sustain a diagnosis of small cell carcinoma in this setting, such as in the present case with a high (albeit heterogeneous) proliferation rate (exceeding 70%).
Gastric small cell carcinoma. Tumour cells are densely packed in a discohesive pattern with a poor stroma component. Nuclear chromatin is finely dispersed or has a salt-and-pepper appearance. Small nucleoli are present in only very few cells.
Gastric small cell carcinoma. Neoplastic cells show diffuse and intense cytoplasmic positivity for synaptophysin.
Gastric small cell carcinoma. Neoplastic cells show diffuse nuclear positivity for INSM1, although with heterogeneous intensity.
Bladder small cell carcinoma. A malignant neoplasm infiltrating the bladder wall made of spindling small cells in a solid growth pattern intersected by rare fibrotic bands.
Bladder small cell carcinoma. Neoplastic cells show a heterogeneous pattern of cytoplasmic positivity for synaptophysin.
Bladder small cell carcinoma. The Ki-67 index in neoplastic cells is homogeneously high (> 70% in this example).

Q: The classic clinical triad of Somatostatinoma syndrome includes diabetes mellitus, diarrhea/steatorrhea, and [...].
Somatostatinoma. CT of a large tumour in the pancreatic head.
Somatostatinoma. Gross appearance of a large tumour with yellow to tan parenchyma and a multinodular growth pattern.
A: cholelithiasis
Back Extra: Somatostatinoma
- Clinical: The classic triad of somatostatinoma syndrome includes diabetes mellitus, cholelithiasis, and diarrhoea/steatorrhoea.
- Micro: Most somatostatinomas have a trabecular, solid, and/or acinar architecture with frequent vascular and perineural invasion.
- Ancillary: Immunohistochemistry shows diffuse positivity for somatostatin and less consistent positivity for other neuroendocrine markers like calcitonin.
Reference Gallery:
Somatostatinoma. CT of a large tumour in the pancreatic head.
Somatostatinoma. Gross appearance of a large tumour with yellow to tan parenchyma and a multinodular growth pattern.
Somatostatinoma. Most pancreatic tumours have the typical appearance of other pancreatic neuroendocrine tumours (PanNETs), with trabecular, solid, and/or acinar architecture.
Somatostatinoma. Perineural invasion is frequent.
Somatostatinoma. A subset of pancreatic tumours show histological features similar to those of their ampullary/duodenal analogues, with tubular and glandular architecture and intraglandular psammomatous calcification.
Somatostatinoma. Vascular invasion is frequent.
Somatostatinoma. Tumour showing diffuse immunopositivity for somatostatin.
Somatostatinoma. Tumour showing scattered immunopositivity for calcitonin.

Q: A subset of Somatostatinoma tumors display tubular and glandular architecture with characteristic intraglandular [...].
Somatostatinoma. A subset of pancreatic tumours show histological features similar to those of their ampullary/duodenal analogues, with tubular and glandular architecture and intraglandular psammomatous calcification.
A: psammomatous calcifications
Back Extra: Somatostatinoma
- Clinical: The classic triad of somatostatinoma syndrome includes diabetes mellitus, cholelithiasis, and diarrhoea/steatorrhoea.
- Micro: Most somatostatinomas have a trabecular, solid, and/or acinar architecture with frequent vascular and perineural invasion.
- Ancillary: Immunohistochemistry shows diffuse positivity for somatostatin and less consistent positivity for other neuroendocrine markers like calcitonin.
Reference Gallery:
Somatostatinoma. CT of a large tumour in the pancreatic head.
Somatostatinoma. Gross appearance of a large tumour with yellow to tan parenchyma and a multinodular growth pattern.
Somatostatinoma. Most pancreatic tumours have the typical appearance of other pancreatic neuroendocrine tumours (PanNETs), with trabecular, solid, and/or acinar architecture.
Somatostatinoma. Perineural invasion is frequent.
Somatostatinoma. A subset of pancreatic tumours show histological features similar to those of their ampullary/duodenal analogues, with tubular and glandular architecture and intraglandular psammomatous calcification.
Somatostatinoma. Vascular invasion is frequent.
Somatostatinoma. Tumour showing diffuse immunopositivity for somatostatin.
Somatostatinoma. Tumour showing scattered immunopositivity for calcitonin.

Q: Immunohistochemistry for Somatostatinoma typically demonstrates diffuse positivity for [...] and less consistent, scattered positivity for markers like calcitonin.
Somatostatinoma. Tumour showing diffuse immunopositivity for somatostatin.
Somatostatinoma. Tumour showing scattered immunopositivity for calcitonin.
A: somatostatin
Back Extra: Somatostatinoma
- Clinical: The classic triad of somatostatinoma syndrome includes diabetes mellitus, cholelithiasis, and diarrhoea/steatorrhoea.
- Micro: Most somatostatinomas have a trabecular, solid, and/or acinar architecture with frequent vascular and perineural invasion.
- Ancillary: Immunohistochemistry shows diffuse positivity for somatostatin and less consistent positivity for other neuroendocrine markers like calcitonin.
Reference Gallery:
Somatostatinoma. CT of a large tumour in the pancreatic head.
Somatostatinoma. Gross appearance of a large tumour with yellow to tan parenchyma and a multinodular growth pattern.
Somatostatinoma. Most pancreatic tumours have the typical appearance of other pancreatic neuroendocrine tumours (PanNETs), with trabecular, solid, and/or acinar architecture.
Somatostatinoma. Perineural invasion is frequent.
Somatostatinoma. A subset of pancreatic tumours show histological features similar to those of their ampullary/duodenal analogues, with tubular and glandular architecture and intraglandular psammomatous calcification.
Somatostatinoma. Vascular invasion is frequent.
Somatostatinoma. Tumour showing diffuse immunopositivity for somatostatin.
Somatostatinoma. Tumour showing scattered immunopositivity for calcitonin.

Q: Clinically, VIPoma presents with [...] syndrome, which is characterized by massive watery diarrhea, hypokalemia, and achlorhydria.
VIPoma. Functional imaging studies of a 54-year-old man with WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria) due to pancreatic VIPoma. 68Ga-DOTATATE PET-CT showing a 45 mm SSTR2-positive neuroendocrine tumour (NET) in the pancreatic body–tail area.
A: WDHA
Back Extra: VIPoma
- Clinical: VIPoma causes the WDHA syndrome, characterized by watery diarrhoea, hypokalaemia, and achlorhydria.
- Micro: VIPomas often show solid, trabecular, or tubuloacinar patterns with variable oncocytic or clear cell change.
- Ancillary: VIPomas are positive for neuroendocrine markers (chromogranin A, synaptophysin, INSM1) and SSTR2A.
Reference Gallery:
VIPoma. Functional imaging studies of a 54-year-old man with WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria) due to pancreatic VIPoma. 68Ga-DOTATATE PET-CT showing a 45 mm SSTR2-positive neuroendocrine tumour (NET) in the pancreatic body–tail area.
VIPoma. Functional imaging showing liver metastases of a pancreatic VIPoma. 68Ga-DOTATATE PET-MRI performed 1 year after surgery, showing multiple SSTR2-positive liver metastases.
VIPoma. Well-differentiated VIPoma. This photomicrograph shows a tumour with predominant trabecular growth.
VIPoma. The tumour cells are diffusely and strongly positive for CK8/18.
VIPoma. The extent of VIP immunoreactivity in pancreatic VIPoma is often variable.
VIPoma. This photomicrograph shows a tumour that shows coexpression of PP.
VIPoma. Diffuse membranous SSTR2A expression.

Q: By immunohistochemistry, VIPoma characteristically exhibits diffuse membranous expression of [...], which is targeted in DOTATATE functional imaging.
VIPoma. Functional imaging studies of a 54-year-old man with WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria) due to pancreatic VIPoma. 68Ga-DOTATATE PET-CT showing a 45 mm SSTR2-positive neuroendocrine tumour (NET) in the pancreatic body–tail area.
VIPoma. Diffuse membranous SSTR2A expression.
A: SSTR2A
Back Extra: VIPoma
- Clinical: VIPoma causes the WDHA syndrome, characterized by watery diarrhoea, hypokalaemia, and achlorhydria.
- Micro: VIPomas often show solid, trabecular, or tubuloacinar patterns with variable oncocytic or clear cell change.
- Ancillary: VIPomas are positive for neuroendocrine markers (chromogranin A, synaptophysin, INSM1) and SSTR2A.
Reference Gallery:
VIPoma. Functional imaging studies of a 54-year-old man with WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria) due to pancreatic VIPoma. 68Ga-DOTATATE PET-CT showing a 45 mm SSTR2-positive neuroendocrine tumour (NET) in the pancreatic body–tail area.
VIPoma. Functional imaging showing liver metastases of a pancreatic VIPoma. 68Ga-DOTATATE PET-MRI performed 1 year after surgery, showing multiple SSTR2-positive liver metastases.
VIPoma. Well-differentiated VIPoma. This photomicrograph shows a tumour with predominant trabecular growth.
VIPoma. The tumour cells are diffusely and strongly positive for CK8/18.
VIPoma. The extent of VIP immunoreactivity in pancreatic VIPoma is often variable.
VIPoma. This photomicrograph shows a tumour that shows coexpression of PP.
VIPoma. Diffuse membranous SSTR2A expression.

Q: Histologically, a well-differentiated VIPoma typically demonstrates a solid, tubuloacinar, or [...] growth pattern.
VIPoma. Well-differentiated VIPoma. This photomicrograph shows a tumour with predominant trabecular growth.
A: trabecular
Back Extra: VIPoma
- Clinical: VIPoma causes the WDHA syndrome, characterized by watery diarrhoea, hypokalaemia, and achlorhydria.
- Micro: VIPomas often show solid, trabecular, or tubuloacinar patterns with variable oncocytic or clear cell change.
- Ancillary: VIPomas are positive for neuroendocrine markers (chromogranin A, synaptophysin, INSM1) and SSTR2A.
Reference Gallery:
VIPoma. Functional imaging studies of a 54-year-old man with WDHA syndrome (watery diarrhoea, hypokalaemia, and achlorhydria) due to pancreatic VIPoma. 68Ga-DOTATATE PET-CT showing a 45 mm SSTR2-positive neuroendocrine tumour (NET) in the pancreatic body–tail area.
VIPoma. Functional imaging showing liver metastases of a pancreatic VIPoma. 68Ga-DOTATATE PET-MRI performed 1 year after surgery, showing multiple SSTR2-positive liver metastases.
VIPoma. Well-differentiated VIPoma. This photomicrograph shows a tumour with predominant trabecular growth.
VIPoma. The tumour cells are diffusely and strongly positive for CK8/18.
VIPoma. The extent of VIP immunoreactivity in pancreatic VIPoma is often variable.
VIPoma. This photomicrograph shows a tumour that shows coexpression of PP.
VIPoma. Diffuse membranous SSTR2A expression.

Q: Grossly and microscopically, a Parathyroid Adenoma is typically well-circumscribed and often features an adjacent, compressed rim of [...].
Parathyroid adenoma. Cut section. Note the normal parathyroid (superior) with associated adipose tissue.
Oncocytic parathyroid adenoma. The tumour is composed entirely of oncocytes. Note the rim of non-neoplastic parathyroid.
A: non-neoplastic parathyroid tissue
Back Extra: Parathyroid Adenoma
- Clinical: Parathyroid adenomas account for > 85% of primary hyperparathyroidism, often presenting with asymptomatic hypercalcemia or mild symptoms like weakness and fatigue.
- Micro: Parathyroid adenomas are well-circumscribed, usually composed of chief cells, and may show cystic changes, fibrosis, and oncocytic or clear cell features.
- Ancillary: Immunohistochemistry shows positivity for PTH and GATA3, and the absence of thyroglobulin and TTF1.
Reference Gallery:
Parathyroid adenoma. Macroscopy of parathyroid adenoma.
Parathyroid adenoma. Cystic parathyroid adenoma. More than 50% of the volume of the adenoma is cystic.
Parathyroid adenoma. Cut section. Note the normal parathyroid (superior) with associated adipose tissue.
Oncocytic parathyroid adenoma. The tumour is composed entirely of oncocytes. Note the rim of non-neoplastic parathyroid.
Parathyroid adenoma. Degenerative changes including fibrosis and haemosiderin deposition. Note the pseudovascular spaces, devoid of endothelial cell lining, not to be confused with vascular invasion.
Ectopic parathyroid adenoma. CT of ectopic parathyroid adenoma (arrow).
Parathyroid adenoma. FNA specimen showing a monotonous population of lesional cells with round nuclei and delicate cytoplasm (air-dried smear preparation, Diff-Quik stain).
Parathyroid adenoma. Water-clear cell parathyroid adenoma. This parathyroid adenoma is composed of large cells with abundant clear cytoplasm that displaces the nuclei to the cell periphery.

Q: Degenerative changes in a Parathyroid Adenoma frequently include cyst formation, fibrosis, hemosiderin deposition, and the presence of [...], which lack an endothelial lining and should not be confused with true vascular invasion.
Parathyroid adenoma. Cystic parathyroid adenoma. More than 50% of the volume of the adenoma is cystic.
Parathyroid adenoma. Degenerative changes including fibrosis and haemosiderin deposition. Note the pseudovascular spaces, devoid of endothelial cell lining, not to be confused with vascular invasion.
A: pseudovascular spaces
Back Extra: Parathyroid Adenoma
- Clinical: Parathyroid adenomas account for > 85% of primary hyperparathyroidism, often presenting with asymptomatic hypercalcemia or mild symptoms like weakness and fatigue.
- Micro: Parathyroid adenomas are well-circumscribed, usually composed of chief cells, and may show cystic changes, fibrosis, and oncocytic or clear cell features.
- Ancillary: Immunohistochemistry shows positivity for PTH and GATA3, and the absence of thyroglobulin and TTF1.
Reference Gallery:
Parathyroid adenoma. Macroscopy of parathyroid adenoma.
Parathyroid adenoma. Cystic parathyroid adenoma. More than 50% of the volume of the adenoma is cystic.
Parathyroid adenoma. Cut section. Note the normal parathyroid (superior) with associated adipose tissue.
Oncocytic parathyroid adenoma. The tumour is composed entirely of oncocytes. Note the rim of non-neoplastic parathyroid.
Parathyroid adenoma. Degenerative changes including fibrosis and haemosiderin deposition. Note the pseudovascular spaces, devoid of endothelial cell lining, not to be confused with vascular invasion.
Ectopic parathyroid adenoma. CT of ectopic parathyroid adenoma (arrow).
Parathyroid adenoma. FNA specimen showing a monotonous population of lesional cells with round nuclei and delicate cytoplasm (air-dried smear preparation, Diff-Quik stain).
Parathyroid adenoma. Water-clear cell parathyroid adenoma. This parathyroid adenoma is composed of large cells with abundant clear cytoplasm that displaces the nuclei to the cell periphery.

Q: The [...] variant of a Parathyroid Adenoma is microscopically characterized by large cells with abundant, optically empty cytoplasm that typically displaces the nuclei to the cell periphery.
Parathyroid adenoma. Water-clear cell parathyroid adenoma. This parathyroid adenoma is composed of large cells with abundant clear cytoplasm that displaces the nuclei to the cell periphery.
A: water-clear cell
Back Extra: Parathyroid Adenoma
- Clinical: Parathyroid adenomas account for > 85% of primary hyperparathyroidism, often presenting with asymptomatic hypercalcemia or mild symptoms like weakness and fatigue.
- Micro: Parathyroid adenomas are well-circumscribed, usually composed of chief cells, and may show cystic changes, fibrosis, and oncocytic or clear cell features.
- Ancillary: Immunohistochemistry shows positivity for PTH and GATA3, and the absence of thyroglobulin and TTF1.
Reference Gallery:
Parathyroid adenoma. Macroscopy of parathyroid adenoma.
Parathyroid adenoma. Cystic parathyroid adenoma. More than 50% of the volume of the adenoma is cystic.
Parathyroid adenoma. Cut section. Note the normal parathyroid (superior) with associated adipose tissue.
Oncocytic parathyroid adenoma. The tumour is composed entirely of oncocytes. Note the rim of non-neoplastic parathyroid.
Parathyroid adenoma. Degenerative changes including fibrosis and haemosiderin deposition. Note the pseudovascular spaces, devoid of endothelial cell lining, not to be confused with vascular invasion.
Ectopic parathyroid adenoma. CT of ectopic parathyroid adenoma (arrow).
Parathyroid adenoma. FNA specimen showing a monotonous population of lesional cells with round nuclei and delicate cytoplasm (air-dried smear preparation, Diff-Quik stain).
Parathyroid adenoma. Water-clear cell parathyroid adenoma. This parathyroid adenoma is composed of large cells with abundant clear cytoplasm that displaces the nuclei to the cell periphery.

Q: The essential diagnostic feature of a Parathyroid Lipoadenoma is a functioning tumor that demonstrates a significant increase in both parenchymal cells and [...] (> 50% of the glandular volume).
Parathyroid lipoadenoma. Parathyroid lipoadenoma composed of increased amounts of both acinar and adipose tissue. The glandular component grows in branching cords.
Parathyroid lipoadenoma. Gross appearance of a parathyroid lipoadenoma.
A: adipose tissue
Q: Parathyroid Lipoadenoma
- Clinical: Most [...] are functioning, and patients usually exhibit mild biochemical evidence of hyperparathyroidism with classic symptomatology.
- Micro: The diagnosis should be restricted to [...] with a significant increase in both adipose and parenchymal tissue. A useful general rule is that > 50% of the volume of the gland should be adipose tissue.
- Ancillary: Essential criteria for diagnosis include a definite increase in both parenchymal and adipose tissue in a parathyroid tumour; > 50% of the glandular volume is adipose tissue.
Reference Gallery:
Parathyroid lipoadenoma. Parathyroid lipoadenoma composed of increased amounts of both acinar and adipose tissue. The glandular component grows in branching cords.
Parathyroid lipoadenoma. High-magnification view revealing a mixture of both chief cells and oncocytic cells.
Parathyroid lipoadenoma. Strong and diffuse PTH immunoreactivity in the acinar component.
Parathyroid lipoadenoma. Gross appearance of a parathyroid lipoadenoma.
A: parathyroid lipoadenomas; parathyroid lipoadenomas

Q: At high magnification, the parenchymal component of a Parathyroid Lipoadenoma typically grows in branching cords and reveals a mixture of chief cells and [...].
Parathyroid lipoadenoma. High-magnification view revealing a mixture of both chief cells and oncocytic cells.
A: oncocytic cells
Q: Parathyroid Lipoadenoma
- Clinical: Most [...] are functioning, and patients usually exhibit mild biochemical evidence of hyperparathyroidism with classic symptomatology.
- Micro: The diagnosis should be restricted to [...] with a significant increase in both adipose and parenchymal tissue. A useful general rule is that > 50% of the volume of the gland should be adipose tissue.
- Ancillary: Essential criteria for diagnosis include a definite increase in both parenchymal and adipose tissue in a parathyroid tumour; > 50% of the glandular volume is adipose tissue.
Reference Gallery:
Parathyroid lipoadenoma. Parathyroid lipoadenoma composed of increased amounts of both acinar and adipose tissue. The glandular component grows in branching cords.
Parathyroid lipoadenoma. High-magnification view revealing a mixture of both chief cells and oncocytic cells.
Parathyroid lipoadenoma. Strong and diffuse PTH immunoreactivity in the acinar component.
Parathyroid lipoadenoma. Gross appearance of a parathyroid lipoadenoma.
A: parathyroid lipoadenomas; parathyroid lipoadenomas

Q: In Parathyroid Carcinoma, a triad of high-risk histopathological features includes prominent macronucleoli, increased mitotic activity (> 5 mitoses/10 mm²), and foci of [...].
Parathyroid carcinoma. The triad of high-risk histopathological features comprises foci of coagulative tumour necrosis in association with prominent macronucleoli and increased mitotic activity (> 5 mitoses/10 mm²). Inset: High magnification showing mitosis.
A: coagulative necrosis
Back Extra: Parathyroid Carcinoma
- Clinical: Most patients with parathyroid carcinomas present with symptomatic primary hyperparathyroidism and significantly elevated levels of PTH and calcium.
- Micro: High mitotic counts (> 5 mitoses/10 mm²) and coagulative necrosis are worrisome for malignancy in parathyroid carcinomas.
- Ancillary: Loss of nuclear parafibromin expression and increased Ki-67 labelling index (often > 5%) are key immunohistochemical findings in parathyroid carcinomas.
Reference Gallery:
Parathyroid carcinoma. Schematic overview of CDC73 gene aberrancies and associated genomic hallmarks in parathyroid carcinoma. Positioned at chromosome 1q25-q31, the CDC73 gene locus recurrently exhibits loss of heterozygosity in parathyroid carcinoma, in addition to gene mutations occurring most frequently in exons 1, 2, and 7. At the pangenomic level, CDC73-mutated parathyroid carcinomas display a higher mutation burden, more copy-number alterations, and poorer patient outcomes than CDC73-wildtype cases.
Parathyroid carcinoma. Parafibromin (PFIB) exhibits numerous tumour-suppressor functions in the cell. As a member of the RNA polymerase II–associated factor (PAF) complex, parafibromin is required for mRNA elongation and quality control processes, and it also controls the expression of the proto-oncogenes CCND1 (encoding cyclin D1) and MYC via epigenetic mechanisms. Upon loss of parafibromin, these processes are dysregulated, which in turn has been associated with cell-cycle activation and increased proliferative ability.
Parathyroid carcinoma. Gross image of a tumour infiltrating the oesophagus.
Parathyroid carcinoma. Locally invasive tumour with strap muscle invasion.
Parathyroid carcinoma. Tumour infiltrating the vagus nerve.
Parathyroid carcinoma. PTH expression in a parathyroid carcinoma that shows invasion into the vagus nerve.
Parathyroid carcinoma. A focus of angioinvasion characterized by intravascular tumour cells admixed with fibrin/thrombus. Vascular invasion (angioinvasion) is typically assessed at the tumour periphery or at the tumour capsule, but not within the tumour substance.
Parathyroid carcinoma. Local gross nodular invasion into the adjacent soft tissue. The tumour also showed angioinvasion (not shown here).
Parathyroid carcinoma. Broad sheets of tumour nests separated by thin fibrotic bands. The tumour also showed angioinvasion in a separate section.
Parathyroid carcinoma. Fibrous bands in parathyroid carcinoma. However, this finding alone does not warrant the diagnosis of malignancy.
Parathyroid carcinoma. The triad of high-risk histopathological features comprises foci of coagulative tumour necrosis in association with prominent macronucleoli and increased mitotic activity (> 5 mitoses/10 mm²). Inset: High magnification showing mitosis.
Parathyroid carcinoma. Parafibromin immunohistochemistry. Loss of nuclear parafibromin expression has been regarded as a reliable biomarker of malignancy in the appropriate morphological setting. This photomicrograph shows loss of nuclear parafibromin expression in a morphologically diagnosed parathyroid carcinoma. Note that the intratumoural endothelial cells, which serve as an internal control, show retained nuclear parafibromin reactivity.

Q: A key immunohistochemical finding that supports the diagnosis of Parathyroid Carcinoma in the appropriate morphological setting is the loss of nuclear expression of [...].
Parathyroid carcinoma. Parafibromin immunohistochemistry. Loss of nuclear parafibromin expression has been regarded as a reliable biomarker of malignancy in the appropriate morphological setting. This photomicrograph shows loss of nuclear parafibromin expression in a morphologically diagnosed parathyroid carcinoma. Note that the intratumoural endothelial cells, which serve as an internal control, show retained nuclear parafibromin reactivity.
A: parafibromin
Back Extra: Parathyroid Carcinoma
- Clinical: Most patients with parathyroid carcinomas present with symptomatic primary hyperparathyroidism and significantly elevated levels of PTH and calcium.
- Micro: High mitotic counts (> 5 mitoses/10 mm²) and coagulative necrosis are worrisome for malignancy in parathyroid carcinomas.
- Ancillary: Loss of nuclear parafibromin expression and increased Ki-67 labelling index (often > 5%) are key immunohistochemical findings in parathyroid carcinomas.
Reference Gallery:
Parathyroid carcinoma. Schematic overview of CDC73 gene aberrancies and associated genomic hallmarks in parathyroid carcinoma. Positioned at chromosome 1q25-q31, the CDC73 gene locus recurrently exhibits loss of heterozygosity in parathyroid carcinoma, in addition to gene mutations occurring most frequently in exons 1, 2, and 7. At the pangenomic level, CDC73-mutated parathyroid carcinomas display a higher mutation burden, more copy-number alterations, and poorer patient outcomes than CDC73-wildtype cases.
Parathyroid carcinoma. Parafibromin (PFIB) exhibits numerous tumour-suppressor functions in the cell. As a member of the RNA polymerase II–associated factor (PAF) complex, parafibromin is required for mRNA elongation and quality control processes, and it also controls the expression of the proto-oncogenes CCND1 (encoding cyclin D1) and MYC via epigenetic mechanisms. Upon loss of parafibromin, these processes are dysregulated, which in turn has been associated with cell-cycle activation and increased proliferative ability.
Parathyroid carcinoma. Gross image of a tumour infiltrating the oesophagus.
Parathyroid carcinoma. Locally invasive tumour with strap muscle invasion.
Parathyroid carcinoma. Tumour infiltrating the vagus nerve.
Parathyroid carcinoma. PTH expression in a parathyroid carcinoma that shows invasion into the vagus nerve.
Parathyroid carcinoma. A focus of angioinvasion characterized by intravascular tumour cells admixed with fibrin/thrombus. Vascular invasion (angioinvasion) is typically assessed at the tumour periphery or at the tumour capsule, but not within the tumour substance.
Parathyroid carcinoma. Local gross nodular invasion into the adjacent soft tissue. The tumour also showed angioinvasion (not shown here).
Parathyroid carcinoma. Broad sheets of tumour nests separated by thin fibrotic bands. The tumour also showed angioinvasion in a separate section.
Parathyroid carcinoma. Fibrous bands in parathyroid carcinoma. However, this finding alone does not warrant the diagnosis of malignancy.
Parathyroid carcinoma. The triad of high-risk histopathological features comprises foci of coagulative tumour necrosis in association with prominent macronucleoli and increased mitotic activity (> 5 mitoses/10 mm²). Inset: High magnification showing mitosis.
Parathyroid carcinoma. Parafibromin immunohistochemistry. Loss of nuclear parafibromin expression has been regarded as a reliable biomarker of malignancy in the appropriate morphological setting. This photomicrograph shows loss of nuclear parafibromin expression in a morphologically diagnosed parathyroid carcinoma. Note that the intratumoural endothelial cells, which serve as an internal control, show retained nuclear parafibromin reactivity.

Q: Definitive morphological diagnosis of Parathyroid Carcinoma requires evidence of local invasion into adjacent structures, perineural invasion, or [...] (which is assessed at the tumor periphery or capsule).
Parathyroid carcinoma. Tumour infiltrating the vagus nerve.
Parathyroid carcinoma. A focus of angioinvasion characterized by intravascular tumour cells admixed with fibrin/thrombus. Vascular invasion (angioinvasion) is typically assessed at the tumour periphery or at the tumour capsule, but not within the tumour substance.
A: angioinvasion
Back Extra: Parathyroid Carcinoma
- Clinical: Most patients with parathyroid carcinomas present with symptomatic primary hyperparathyroidism and significantly elevated levels of PTH and calcium.
- Micro: High mitotic counts (> 5 mitoses/10 mm²) and coagulative necrosis are worrisome for malignancy in parathyroid carcinomas.
- Ancillary: Loss of nuclear parafibromin expression and increased Ki-67 labelling index (often > 5%) are key immunohistochemical findings in parathyroid carcinomas.
Reference Gallery:
Parathyroid carcinoma. Schematic overview of CDC73 gene aberrancies and associated genomic hallmarks in parathyroid carcinoma. Positioned at chromosome 1q25-q31, the CDC73 gene locus recurrently exhibits loss of heterozygosity in parathyroid carcinoma, in addition to gene mutations occurring most frequently in exons 1, 2, and 7. At the pangenomic level, CDC73-mutated parathyroid carcinomas display a higher mutation burden, more copy-number alterations, and poorer patient outcomes than CDC73-wildtype cases.
Parathyroid carcinoma. Parafibromin (PFIB) exhibits numerous tumour-suppressor functions in the cell. As a member of the RNA polymerase II–associated factor (PAF) complex, parafibromin is required for mRNA elongation and quality control processes, and it also controls the expression of the proto-oncogenes CCND1 (encoding cyclin D1) and MYC via epigenetic mechanisms. Upon loss of parafibromin, these processes are dysregulated, which in turn has been associated with cell-cycle activation and increased proliferative ability.
Parathyroid carcinoma. Gross image of a tumour infiltrating the oesophagus.
Parathyroid carcinoma. Locally invasive tumour with strap muscle invasion.
Parathyroid carcinoma. Tumour infiltrating the vagus nerve.
Parathyroid carcinoma. PTH expression in a parathyroid carcinoma that shows invasion into the vagus nerve.
Parathyroid carcinoma. A focus of angioinvasion characterized by intravascular tumour cells admixed with fibrin/thrombus. Vascular invasion (angioinvasion) is typically assessed at the tumour periphery or at the tumour capsule, but not within the tumour substance.
Parathyroid carcinoma. Local gross nodular invasion into the adjacent soft tissue. The tumour also showed angioinvasion (not shown here).
Parathyroid carcinoma. Broad sheets of tumour nests separated by thin fibrotic bands. The tumour also showed angioinvasion in a separate section.
Parathyroid carcinoma. Fibrous bands in parathyroid carcinoma. However, this finding alone does not warrant the diagnosis of malignancy.
Parathyroid carcinoma. The triad of high-risk histopathological features comprises foci of coagulative tumour necrosis in association with prominent macronucleoli and increased mitotic activity (> 5 mitoses/10 mm²). Inset: High magnification showing mitosis.
Parathyroid carcinoma. Parafibromin immunohistochemistry. Loss of nuclear parafibromin expression has been regarded as a reliable biomarker of malignancy in the appropriate morphological setting. This photomicrograph shows loss of nuclear parafibromin expression in a morphologically diagnosed parathyroid carcinoma. Note that the intratumoural endothelial cells, which serve as an internal control, show retained nuclear parafibromin reactivity.

Q: Histologically, an Atypical Parathyroid Tumor may exhibit worrisome features like mitotic activity, solid growth, and thick fibrous bands, but by definition it lacks definitive capsular or vascular [...].
Atypical parathyroid tumour. An example with fibrosis adjacent to the thyroid gland, but not invading it.
Atypical parathyroid tumour. These tumours may show fibrosis including thick fibrous bands, but they do not show definitive invasion.
Atypical parathyroid tumour. This tumour shows irregular growth with prominent areas of fibrosis but does not show definitive capsular or vascular invasion or invasion into adjacent structures.
A: invasion
Back Extra: Atypical Parathyroid Tumour
- Clinical: Atypical parathyroid tumours (APTs) usually present with hypercalcemia, but symptoms are generally less severe than in parathyroid carcinoma. Patients may be asymptomatic or have fatigue, weakness, and polyuria.
- Micro: APTs are characterized by architectural and cytological atypia, such as mitotic activity, cytological atypia, and fibrosis, but lack definitive capsular or vascular invasion.
- Ancillary: Parafibromin immunostaining is crucial in differentiating APTs from parathyroid carcinomas. Retained nuclear parafibromin staining is typical in APTs.
Reference Gallery:
Atypical parathyroid tumour. An example with fibrosis adjacent to the thyroid gland, but not invading it.
Atypical parathyroid tumour. This example shows solid growth and fibrosis.
Atypical parathyroid tumour. These tumours may show fibrosis including thick fibrous bands, but they do not show definitive invasion.
Atypical parathyroid tumour. This tumour shows irregular growth with prominent areas of fibrosis but does not show definitive capsular or vascular invasion or invasion into adjacent structures.
Atypical parathyroid tumour. Parafibromin shows retained nuclear immunostaining in this atypical parathyroid tumour.
Atypical parathyroid tumour. Ki-67 immunostain shows only scattered positive cells in this atypical parathyroid tumour with a low proliferation index.
Atypical parathyroid tumour. Mitotic activity can be seen in any parathyroid lesion, whether benign or malignant. Although prominent mitotic activity is a worrisome feature, the presence of mitotic activity is insufficient for a diagnosis of parathyroid carcinoma.
Parathyroid neoplasms. Diagnostic algorithm.

Q: In an Atypical Parathyroid Tumor, immunohistochemical staining for parafibromin characteristically shows [...] nuclear expression, which helps differentiate it from parathyroid carcinoma.
Atypical parathyroid tumour. Parafibromin shows retained nuclear immunostaining in this atypical parathyroid tumour.
A: retained
Back Extra: Atypical Parathyroid Tumour
- Clinical: Atypical parathyroid tumours (APTs) usually present with hypercalcemia, but symptoms are generally less severe than in parathyroid carcinoma. Patients may be asymptomatic or have fatigue, weakness, and polyuria.
- Micro: APTs are characterized by architectural and cytological atypia, such as mitotic activity, cytological atypia, and fibrosis, but lack definitive capsular or vascular invasion.
- Ancillary: Parafibromin immunostaining is crucial in differentiating APTs from parathyroid carcinomas. Retained nuclear parafibromin staining is typical in APTs.
Reference Gallery:
Atypical parathyroid tumour. An example with fibrosis adjacent to the thyroid gland, but not invading it.
Atypical parathyroid tumour. This example shows solid growth and fibrosis.
Atypical parathyroid tumour. These tumours may show fibrosis including thick fibrous bands, but they do not show definitive invasion.
Atypical parathyroid tumour. This tumour shows irregular growth with prominent areas of fibrosis but does not show definitive capsular or vascular invasion or invasion into adjacent structures.
Atypical parathyroid tumour. Parafibromin shows retained nuclear immunostaining in this atypical parathyroid tumour.
Atypical parathyroid tumour. Ki-67 immunostain shows only scattered positive cells in this atypical parathyroid tumour with a low proliferation index.
Atypical parathyroid tumour. Mitotic activity can be seen in any parathyroid lesion, whether benign or malignant. Although prominent mitotic activity is a worrisome feature, the presence of mitotic activity is insufficient for a diagnosis of parathyroid carcinoma.
Parathyroid neoplasms. Diagnostic algorithm.

Q: Although prominent mitotic activity can occasionally be seen in an Atypical Parathyroid Tumor, the Ki-67 proliferation index is typically [...], demonstrating only scattered positive cells.
Atypical parathyroid tumour. Ki-67 immunostain shows only scattered positive cells in this atypical parathyroid tumour with a low proliferation index.
Atypical parathyroid tumour. Mitotic activity can be seen in any parathyroid lesion, whether benign or malignant. Although prominent mitotic activity is a worrisome feature, the presence of mitotic activity is insufficient for a diagnosis of parathyroid carcinoma.
A: low
Back Extra: Atypical Parathyroid Tumour
- Clinical: Atypical parathyroid tumours (APTs) usually present with hypercalcemia, but symptoms are generally less severe than in parathyroid carcinoma. Patients may be asymptomatic or have fatigue, weakness, and polyuria.
- Micro: APTs are characterized by architectural and cytological atypia, such as mitotic activity, cytological atypia, and fibrosis, but lack definitive capsular or vascular invasion.
- Ancillary: Parafibromin immunostaining is crucial in differentiating APTs from parathyroid carcinomas. Retained nuclear parafibromin staining is typical in APTs.
Reference Gallery:
Atypical parathyroid tumour. An example with fibrosis adjacent to the thyroid gland, but not invading it.
Atypical parathyroid tumour. This example shows solid growth and fibrosis.
Atypical parathyroid tumour. These tumours may show fibrosis including thick fibrous bands, but they do not show definitive invasion.
Atypical parathyroid tumour. This tumour shows irregular growth with prominent areas of fibrosis but does not show definitive capsular or vascular invasion or invasion into adjacent structures.
Atypical parathyroid tumour. Parafibromin shows retained nuclear immunostaining in this atypical parathyroid tumour.
Atypical parathyroid tumour. Ki-67 immunostain shows only scattered positive cells in this atypical parathyroid tumour with a low proliferation index.
Atypical parathyroid tumour. Mitotic activity can be seen in any parathyroid lesion, whether benign or malignant. Although prominent mitotic activity is a worrisome feature, the presence of mitotic activity is insufficient for a diagnosis of parathyroid carcinoma.
Parathyroid neoplasms. Diagnostic algorithm.

Q: Histologically, Thyroid Tumors of Uncertain Malignant Potential that display questionable vascular invasion alongside papillary thyroid carcinoma–type nuclear alterations (e.g., chromatin clearing, nuclear grooves) are classified as [...].
Questionable vascular invasion in well-differentiated tumour of uncertain malignant potential. Intraluminal tumour cell nest showing neither endothelial lining nor definite evidence of associated thrombus loosely attached to the wall of a vessel within the tumour capsule. Neoplastic cells show some of the nuclear alteration of papillary carcinoma: chromatin clearing and occasional nuclear grooves.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Irregular outgrowth of neoplastic cells within vascular spaces of the tumour capsule. The tumour cells show papillary thyroid carcinoma–type nuclear alterations with chromatin clearing.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Tumour cells with papillary thyroid carcinoma–type nuclear alterations closely intermixed with vascular spaces of the tumour capsule.
A: well-differentiated tumors of uncertain malignant potential (WDT-UMP)
Back Extra: Thyroid Tumours of Uncertain Malignant Potential
- Clinical: Patients with Thyroid Tumours of Uncertain Malignant Potential (UMP) usually present with single, oval, solid, slightly hypoechoic or isoechoic nodules with a hypoechoic halo by ultrasound.
- Micro: Histologically, UMP tumours can be classified into follicular tumours of uncertain malignant potential (FT-UMP) and well-differentiated tumours of uncertain malignant potential (WDT-UMP), with nuclear features ranging from benign to papillary thyroid carcinoma–type nuclear alterations.
- Ancillary: HRAS, KRAS, or NRAS mutations are identified in up to 40% of Thyroid Tumours of Uncertain Malignant Potential, with NRAS p.Q61R being the most common.
Reference Gallery:
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Irregular outgrowths of tumour cells undermining the endothelium of small blood vessel cells within a thick fibrous capsule: the close intertwining of vascular spaces and tumour cells raises concern for early vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
Questionable vascular invasion in well-differentiated tumour of uncertain malignant potential. Intraluminal tumour cell nest showing neither endothelial lining nor definite evidence of associated thrombus loosely attached to the wall of a vessel within the tumour capsule. Neoplastic cells show some of the nuclear alteration of papillary carcinoma: chromatin clearing and occasional nuclear grooves.
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Sharply outlined collections of tumour cells covered by endothelium protrude and float into vascular spaces at the parenchymal interface of a well-circumscribed nodule that has a thin, poorly defined capsule. It is difficult to be sure whether intravascular tumour nests belong to the inside of the nodule and are therefore not to be regarded as evidence of vascular invasion, or whether the tumour nests are within the capsule and are therefore diagnostic of vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Irregular outgrowth of neoplastic cells within vascular spaces of the tumour capsule. The tumour cells show papillary thyroid carcinoma–type nuclear alterations with chromatin clearing.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Tumour cells with papillary thyroid carcinoma–type nuclear alterations closely intermixed with vascular spaces of the tumour capsule.

Q: In Thyroid Tumors of Uncertain Malignant Potential, encapsulated lesions that exhibit questionable vascular invasion but lack the diagnostic nuclear alterations of papillary carcinoma are classified as [...].
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Irregular outgrowths of tumour cells undermining the endothelium of small blood vessel cells within a thick fibrous capsule: the close intertwining of vascular spaces and tumour cells raises concern for early vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Sharply outlined collections of tumour cells covered by endothelium protrude and float into vascular spaces at the parenchymal interface of a well-circumscribed nodule that has a thin, poorly defined capsule. It is difficult to be sure whether intravascular tumour nests belong to the inside of the nodule and are therefore not to be regarded as evidence of vascular invasion, or whether the tumour nests are within the capsule and are therefore diagnostic of vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
A: follicular tumors of uncertain malignant potential (FT-UMP)
Back Extra: Thyroid Tumours of Uncertain Malignant Potential
- Clinical: Patients with Thyroid Tumours of Uncertain Malignant Potential (UMP) usually present with single, oval, solid, slightly hypoechoic or isoechoic nodules with a hypoechoic halo by ultrasound.
- Micro: Histologically, UMP tumours can be classified into follicular tumours of uncertain malignant potential (FT-UMP) and well-differentiated tumours of uncertain malignant potential (WDT-UMP), with nuclear features ranging from benign to papillary thyroid carcinoma–type nuclear alterations.
- Ancillary: HRAS, KRAS, or NRAS mutations are identified in up to 40% of Thyroid Tumours of Uncertain Malignant Potential, with NRAS p.Q61R being the most common.
Reference Gallery:
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Irregular outgrowths of tumour cells undermining the endothelium of small blood vessel cells within a thick fibrous capsule: the close intertwining of vascular spaces and tumour cells raises concern for early vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
Questionable vascular invasion in well-differentiated tumour of uncertain malignant potential. Intraluminal tumour cell nest showing neither endothelial lining nor definite evidence of associated thrombus loosely attached to the wall of a vessel within the tumour capsule. Neoplastic cells show some of the nuclear alteration of papillary carcinoma: chromatin clearing and occasional nuclear grooves.
Questionable vascular invasion in a follicular tumour of uncertain malignant potential. Sharply outlined collections of tumour cells covered by endothelium protrude and float into vascular spaces at the parenchymal interface of a well-circumscribed nodule that has a thin, poorly defined capsule. It is difficult to be sure whether intravascular tumour nests belong to the inside of the nodule and are therefore not to be regarded as evidence of vascular invasion, or whether the tumour nests are within the capsule and are therefore diagnostic of vascular invasion. The tumour cells lack the nuclear alterations of papillary carcinoma.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Irregular outgrowth of neoplastic cells within vascular spaces of the tumour capsule. The tumour cells show papillary thyroid carcinoma–type nuclear alterations with chromatin clearing.
Questionable vascular invasion in a well-differentiated tumour of uncertain malignant potential. Tumour cells with papillary thyroid carcinoma–type nuclear alterations closely intermixed with vascular spaces of the tumour capsule.

Q: Histologically, the presence of multiple nodules, increased cellularity, and a distinct decrease in stromal and intracellular fat across the gland parenchyma is characteristic of [...].
Parathyroid hyperplasia. Hyperplasia in tertiary hyperparathyroidism. Low-power view of the right superior gland (patient after renal transplantation) showing multiple nodules and parathyroid parenchyma with remaining fat cells.
Parathyroid hyperplasia. Secondary parathyroid gland hyperplasia. The patient had a long history of dialysis due to renal failure. Note the numerous nodules and increased cellularity of chief, oncocytic, and clear parathyroid parenchymal cells, with a decrease in stromal adipose tissue.
A: Parathyroid Hyperplasia
Back Extra: Parathyroid Hyperplasia
- Clinical: Primary hyperplasia is extremely rare and often associated with hereditary syndromes, while secondary hyperplasia is usually due to chronic renal disease.
- Micro: Histologically, hyperplasia is characterized by multiple nodules and increased cellularity, with a decrease in stromal and intracellular fat.
- Ancillary: Screening for germline abnormalities is recommended in primary hyperplasia or multiglandular disease.
Reference Gallery:
Parathyroid hyperplasia. Hyperplasia in tertiary hyperparathyroidism. Low-power view of the right superior gland (patient after renal transplantation) showing multiple nodules and parathyroid parenchyma with remaining fat cells.
Parathyroid hyperplasia. Hyperplasia in tertiary hyperparathyroidism. Medium magnification of left superior gland.
Parathyroid hyperplasia in secondary hyperparathyroidism. Secondary parathyroid hyperplasia with abundant fibrosis and irregular growth (low magnification). Additional gland with hyperplasia was also submitted.
Parathyroid hyperplasia. Secondary parathyroid gland hyperplasia. The patient had a long history of dialysis due to renal failure. Note the numerous nodules and increased cellularity of chief, oncocytic, and clear parathyroid parenchymal cells, with a decrease in stromal adipose tissue.

Q: While primary cases are rare and often hereditary, secondary Parathyroid Hyperplasia is most commonly caused by [...], frequently seen in patients with a long history of dialysis.
Parathyroid hyperplasia in secondary hyperparathyroidism. Secondary parathyroid hyperplasia with abundant fibrosis and irregular growth (low magnification). Additional gland with hyperplasia was also submitted.
Parathyroid hyperplasia. Secondary parathyroid gland hyperplasia. The patient had a long history of dialysis due to renal failure. Note the numerous nodules and increased cellularity of chief, oncocytic, and clear parathyroid parenchymal cells, with a decrease in stromal adipose tissue.
A: chronic renal disease
Back Extra: Parathyroid Hyperplasia
- Clinical: Primary hyperplasia is extremely rare and often associated with hereditary syndromes, while secondary hyperplasia is usually due to chronic renal disease.
- Micro: Histologically, hyperplasia is characterized by multiple nodules and increased cellularity, with a decrease in stromal and intracellular fat.
- Ancillary: Screening for germline abnormalities is recommended in primary hyperplasia or multiglandular disease.
Reference Gallery:
Parathyroid hyperplasia. Hyperplasia in tertiary hyperparathyroidism. Low-power view of the right superior gland (patient after renal transplantation) showing multiple nodules and parathyroid parenchyma with remaining fat cells.
Parathyroid hyperplasia. Hyperplasia in tertiary hyperparathyroidism. Medium magnification of left superior gland.
Parathyroid hyperplasia in secondary hyperparathyroidism. Secondary parathyroid hyperplasia with abundant fibrosis and irregular growth (low magnification). Additional gland with hyperplasia was also submitted.
Parathyroid hyperplasia. Secondary parathyroid gland hyperplasia. The patient had a long history of dialysis due to renal failure. Note the numerous nodules and increased cellularity of chief, oncocytic, and clear parathyroid parenchymal cells, with a decrease in stromal adipose tissue.

Q: Histologically, Pituitary Blastoma is characterized by a distinctive triphasic appearance comprising large neuroendocrine cells, undifferentiated blastemal cells, and cuboidal primitive [...] epithelium.
Pituitary blastoma. The cellular components of pituitary blastomas include large adenohypophysial neuroendocrine cells arranged in lobules or diffuse sheets, cuboidal primitive Rathke pouch epithelium with rosette or gland/follicle formation, and scattered undifferentiated blastemal cells.
Pituitary blastoma. The adenohypophysial neuroendocrine tumour cells are arranged in diffuse sheets or lobules and are variably positive for ACTH. Unlike the cells arranged in sheets, rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium and blastemal undifferentiated cells tend to be negative for ACTH.
A: Rathke pouch
Back Extra: Pituitary Blastoma
- Clinical: Pituitary blastoma often presents with Cushing disease, due to overexpression of hormones, and ophthalmoplegia from tumour growth into the optic chiasm.
- Micro: Histologically, pituitary blastoma is characterized by the presence of large neuroendocrine cells, cuboidal Rathke pouch epithelium, and undifferentiated blastemal cells.
- Ancillary: DICER1 mutations are a key molecular marker for pituitary blastoma, with biallelic mutations leading to impaired microRNA processing and dysregulation of genetic pathways.
Reference Gallery:
Pituitary blastoma. The cellular components of pituitary blastomas include large adenohypophysial neuroendocrine cells arranged in lobules or diffuse sheets, cuboidal primitive Rathke pouch epithelium with rosette or gland/follicle formation, and scattered undifferentiated blastemal cells.
Pituitary blastoma. The adenohypophysial neuroendocrine tumour cells are arranged in diffuse sheets or lobules and are variably positive for ACTH. Unlike the cells arranged in sheets, rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium and blastemal undifferentiated cells tend to be negative for ACTH.
Pituitary blastoma. CAM5.2 (low-molecular-weight cytokeratin) immunohistochemistry stains almost all cellular components in pituitary blastomas.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells, whereas other cellular elements show reduced staining intensity for CD56.
Pituitary blastoma. EMA shows variable staining in cellular components, with stronger staining in areas with rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium.
Pituitary blastoma. S100 stains scattered folliculostellate cells in a pituitary blastoma.
Pituitary blastoma. Proliferative heterogeneity of the various cellular components. The follicle-forming cuboidal or columnar primitive Rathke pouch epithelium shows a higher Ki-67 proliferation index than other cellular elements.
Pituitary blastoma. ACTH-positive neuroendocrine cells show reduced nuclear p27 expression, as seen in most functioning corticotroph tumours.
Pituitary blastoma pathogenesis. From DICER1 mutation to tumorigenesis. Each tumour starts with presumptively biallelic mutations in DICER1 (RNase IIIb hotspot mutation coupled with a loss-of-function variant [LOF] or loss of heterozygosity [LOH]). Because the RNase IIIa domain of DICER1 remains functional, the processing of microRNA precursors (pre-miRNAs) will generate a skewed distribution of 5p/3p mature microRNA; as shown in the graphic, this improper dicing of precursors results in aberrant 5p products and a skewed distribution of microRNAs favouring 3p over 5p microRNAs. This in turn leads to the dysregulation of hundreds of 5p and 3p microRNAs, with the concomitant dysregulation of many target mRNAs. In the case of pituitary blastoma (PitB), this includes the upregulation of PRAME (fold-change: > 500). Gene-set analyses showed that the retinoic acid receptor (RAR) pathway and the WNT, NOTCH, and PI3K pathways are activated in pituitary blastoma tumours, as compared with normal postnatal pituitary (NPP) samples. The analysis revealed that, like normal fetal pituitary (NFP), PitB samples have a high level of undifferentiated cells as compared with NPP samples. PitB tumours have the lowest level of differentiated cells, as compared with NPP and NFP samples. Pink represents upregulated processes and blue represents a downregulated process.

Q: The key molecular driver in the pathogenesis of Pituitary Blastoma is a biallelic mutation in the [...] gene, which leads to impaired microRNA processing and dysregulation of downstream pathways.
Pituitary blastoma pathogenesis. From DICER1 mutation to tumorigenesis. Each tumour starts with presumptively biallelic mutations in DICER1 (RNase IIIb hotspot mutation coupled with a loss-of-function variant [LOF] or loss of heterozygosity [LOH]). Because the RNase IIIa domain of DICER1 remains functional, the processing of microRNA precursors (pre-miRNAs) will generate a skewed distribution of 5p/3p mature microRNA; as shown in the graphic, this improper dicing of precursors results in aberrant 5p products and a skewed distribution of microRNAs favouring 3p over 5p microRNAs. This in turn leads to the dysregulation of hundreds of 5p and 3p microRNAs, with the concomitant dysregulation of many target mRNAs. In the case of pituitary blastoma (PitB), this includes the upregulation of PRAME (fold-change: > 500). Gene-set analyses showed that the retinoic acid receptor (RAR) pathway and the WNT, NOTCH, and PI3K pathways are activated in pituitary blastoma tumours, as compared with normal postnatal pituitary (NPP) samples. The analysis revealed that, like normal fetal pituitary (NFP), PitB samples have a high level of undifferentiated cells as compared with NPP samples. PitB tumours have the lowest level of differentiated cells, as compared with NPP and NFP samples. Pink represents upregulated processes and blue represents a downregulated process.
A: DICER1
Back Extra: Pituitary Blastoma
- Clinical: Pituitary blastoma often presents with Cushing disease, due to overexpression of hormones, and ophthalmoplegia from tumour growth into the optic chiasm.
- Micro: Histologically, pituitary blastoma is characterized by the presence of large neuroendocrine cells, cuboidal Rathke pouch epithelium, and undifferentiated blastemal cells.
- Ancillary: DICER1 mutations are a key molecular marker for pituitary blastoma, with biallelic mutations leading to impaired microRNA processing and dysregulation of genetic pathways.
Reference Gallery:
Pituitary blastoma. The cellular components of pituitary blastomas include large adenohypophysial neuroendocrine cells arranged in lobules or diffuse sheets, cuboidal primitive Rathke pouch epithelium with rosette or gland/follicle formation, and scattered undifferentiated blastemal cells.
Pituitary blastoma. The adenohypophysial neuroendocrine tumour cells are arranged in diffuse sheets or lobules and are variably positive for ACTH. Unlike the cells arranged in sheets, rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium and blastemal undifferentiated cells tend to be negative for ACTH.
Pituitary blastoma. CAM5.2 (low-molecular-weight cytokeratin) immunohistochemistry stains almost all cellular components in pituitary blastomas.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells, whereas other cellular elements show reduced staining intensity for CD56.
Pituitary blastoma. EMA shows variable staining in cellular components, with stronger staining in areas with rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium.
Pituitary blastoma. S100 stains scattered folliculostellate cells in a pituitary blastoma.
Pituitary blastoma. Proliferative heterogeneity of the various cellular components. The follicle-forming cuboidal or columnar primitive Rathke pouch epithelium shows a higher Ki-67 proliferation index than other cellular elements.
Pituitary blastoma. ACTH-positive neuroendocrine cells show reduced nuclear p27 expression, as seen in most functioning corticotroph tumours.
Pituitary blastoma pathogenesis. From DICER1 mutation to tumorigenesis. Each tumour starts with presumptively biallelic mutations in DICER1 (RNase IIIb hotspot mutation coupled with a loss-of-function variant [LOF] or loss of heterozygosity [LOH]). Because the RNase IIIa domain of DICER1 remains functional, the processing of microRNA precursors (pre-miRNAs) will generate a skewed distribution of 5p/3p mature microRNA; as shown in the graphic, this improper dicing of precursors results in aberrant 5p products and a skewed distribution of microRNAs favouring 3p over 5p microRNAs. This in turn leads to the dysregulation of hundreds of 5p and 3p microRNAs, with the concomitant dysregulation of many target mRNAs. In the case of pituitary blastoma (PitB), this includes the upregulation of PRAME (fold-change: > 500). Gene-set analyses showed that the retinoic acid receptor (RAR) pathway and the WNT, NOTCH, and PI3K pathways are activated in pituitary blastoma tumours, as compared with normal postnatal pituitary (NPP) samples. The analysis revealed that, like normal fetal pituitary (NFP), PitB samples have a high level of undifferentiated cells as compared with NPP samples. PitB tumours have the lowest level of differentiated cells, as compared with NPP and NFP samples. Pink represents upregulated processes and blue represents a downregulated process.

Q: In Pituitary Blastoma, the neuroendocrine tumor cells frequently express [...], which correlates with the common clinical presentation of Cushing disease.
Pituitary blastoma. The adenohypophysial neuroendocrine tumour cells are arranged in diffuse sheets or lobules and are variably positive for ACTH. Unlike the cells arranged in sheets, rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium and blastemal undifferentiated cells tend to be negative for ACTH.
Pituitary blastoma. ACTH-positive neuroendocrine cells show reduced nuclear p27 expression, as seen in most functioning corticotroph tumours.
A: ACTH
Back Extra: Pituitary Blastoma
- Clinical: Pituitary blastoma often presents with Cushing disease, due to overexpression of hormones, and ophthalmoplegia from tumour growth into the optic chiasm.
- Micro: Histologically, pituitary blastoma is characterized by the presence of large neuroendocrine cells, cuboidal Rathke pouch epithelium, and undifferentiated blastemal cells.
- Ancillary: DICER1 mutations are a key molecular marker for pituitary blastoma, with biallelic mutations leading to impaired microRNA processing and dysregulation of genetic pathways.
Reference Gallery:
Pituitary blastoma. The cellular components of pituitary blastomas include large adenohypophysial neuroendocrine cells arranged in lobules or diffuse sheets, cuboidal primitive Rathke pouch epithelium with rosette or gland/follicle formation, and scattered undifferentiated blastemal cells.
Pituitary blastoma. The adenohypophysial neuroendocrine tumour cells are arranged in diffuse sheets or lobules and are variably positive for ACTH. Unlike the cells arranged in sheets, rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium and blastemal undifferentiated cells tend to be negative for ACTH.
Pituitary blastoma. CAM5.2 (low-molecular-weight cytokeratin) immunohistochemistry stains almost all cellular components in pituitary blastomas.
Pituitary blastoma. Strong membranous CD56 expression distinguishes areas of neuroendocrine cells, whereas other cellular elements show reduced staining intensity for CD56.
Pituitary blastoma. EMA shows variable staining in cellular components, with stronger staining in areas with rosette- or follicle-forming cuboidal or columnar primitive Rathke pouch epithelium.
Pituitary blastoma. S100 stains scattered folliculostellate cells in a pituitary blastoma.
Pituitary blastoma. Proliferative heterogeneity of the various cellular components. The follicle-forming cuboidal or columnar primitive Rathke pouch epithelium shows a higher Ki-67 proliferation index than other cellular elements.
Pituitary blastoma. ACTH-positive neuroendocrine cells show reduced nuclear p27 expression, as seen in most functioning corticotroph tumours.
Pituitary blastoma pathogenesis. From DICER1 mutation to tumorigenesis. Each tumour starts with presumptively biallelic mutations in DICER1 (RNase IIIb hotspot mutation coupled with a loss-of-function variant [LOF] or loss of heterozygosity [LOH]). Because the RNase IIIa domain of DICER1 remains functional, the processing of microRNA precursors (pre-miRNAs) will generate a skewed distribution of 5p/3p mature microRNA; as shown in the graphic, this improper dicing of precursors results in aberrant 5p products and a skewed distribution of microRNAs favouring 3p over 5p microRNAs. This in turn leads to the dysregulation of hundreds of 5p and 3p microRNAs, with the concomitant dysregulation of many target mRNAs. In the case of pituitary blastoma (PitB), this includes the upregulation of PRAME (fold-change: > 500). Gene-set analyses showed that the retinoic acid receptor (RAR) pathway and the WNT, NOTCH, and PI3K pathways are activated in pituitary blastoma tumours, as compared with normal postnatal pituitary (NPP) samples. The analysis revealed that, like normal fetal pituitary (NFP), PitB samples have a high level of undifferentiated cells as compared with NPP samples. PitB tumours have the lowest level of differentiated cells, as compared with NPP and NFP samples. Pink represents upregulated processes and blue represents a downregulated process.

Q: Histologically, an adamantinomatous craniopharyngioma is characterized by peripheral palisading, a loose stellate reticulum, and characteristic nodules of anucleate squamous remnants known as [...].
Adamantinomatous craniopharyngioma. Basal palisading of tumour cells along the tumour–brain interface, epithelial whorls, stellate reticulum, and wet keratin.
A: wet keratin
Back Extra: Adamantinomatous Craniopharyngioma
- Clinical: Common symptoms include visual impairment (62–84%) and endocrine deficits (52–87%), affecting growth hormone, LH/FSH, TSH, ACTH, and vasopressin.
- Micro: Characterized by peripheral palisading, epithelial whorls, stellate reticulum, and nodules of anucleate remnants of wet keratin.
- Ancillary: activating mutations in exon 3 of CTNNB1, leading to overexpression of β-catenin targets.
Reference Gallery:
Adamantinomatous craniopharyngioma. Basal palisading of tumour cells along the tumour–brain interface, epithelial whorls, stellate reticulum, and wet keratin.
Adamantinomatous craniopharyngioma. Tumour extending into adjacent brain tissue, which has reactive changes including piloid gliosis and Rosenthal fibres. Epithelial whorling is commonly present in protrusions.
Adamantinomatous craniopharyngioma. High-power view of the interface of adamantinomatous craniopharyngioma and brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Adamantinomatous craniopharyngioma. Even though mutations in exon 3 of the CTNNB1 gene, which encodes β-catenin, are clonal and present across the neoplastic epithelium, β-catenin protein only accumulates in the nucleus in subset of cells, such as those that are scattered individually and present in small clusters.
Adamantinomatous craniopharyngioma. Recurrence 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and foci of necrosis.
Adamantinomatous craniopharyngioma. High-power view of malignant craniopharyngioma emerging 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and necrosis.
Adamantinomatous craniopharyngioma. Characteristic very high tumour cell proliferation in malignant craniopharyngioma, as indicated by the Ki-67 index.
Adamantinomatous craniopharyngioma. A solid and cystic mass with calcification (arrow), first diagnosed 4 years earlier.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.

Q: The genetic hallmark of adamantinomatous craniopharyngioma is an activating mutation in exon 3 of the CTNNB1 gene, which results in the abnormal nuclear accumulation of [...] in scattered cell clusters.
Adamantinomatous craniopharyngioma. Even though mutations in exon 3 of the CTNNB1 gene, which encodes β-catenin, are clonal and present across the neoplastic epithelium, β-catenin protein only accumulates in the nucleus in subset of cells, such as those that are scattered individually and present in small clusters.
A: β-catenin
Back Extra: Adamantinomatous Craniopharyngioma
- Clinical: Common symptoms include visual impairment (62–84%) and endocrine deficits (52–87%), affecting growth hormone, LH/FSH, TSH, ACTH, and vasopressin.
- Micro: Characterized by peripheral palisading, epithelial whorls, stellate reticulum, and nodules of anucleate remnants of wet keratin.
- Ancillary: activating mutations in exon 3 of CTNNB1, leading to overexpression of β-catenin targets.
Reference Gallery:
Adamantinomatous craniopharyngioma. Basal palisading of tumour cells along the tumour–brain interface, epithelial whorls, stellate reticulum, and wet keratin.
Adamantinomatous craniopharyngioma. Tumour extending into adjacent brain tissue, which has reactive changes including piloid gliosis and Rosenthal fibres. Epithelial whorling is commonly present in protrusions.
Adamantinomatous craniopharyngioma. High-power view of the interface of adamantinomatous craniopharyngioma and brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Adamantinomatous craniopharyngioma. Even though mutations in exon 3 of the CTNNB1 gene, which encodes β-catenin, are clonal and present across the neoplastic epithelium, β-catenin protein only accumulates in the nucleus in subset of cells, such as those that are scattered individually and present in small clusters.
Adamantinomatous craniopharyngioma. Recurrence 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and foci of necrosis.
Adamantinomatous craniopharyngioma. High-power view of malignant craniopharyngioma emerging 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and necrosis.
Adamantinomatous craniopharyngioma. Characteristic very high tumour cell proliferation in malignant craniopharyngioma, as indicated by the Ki-67 index.
Adamantinomatous craniopharyngioma. A solid and cystic mass with calcification (arrow), first diagnosed 4 years earlier.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.

Q: On neuroimaging, a childhood adamantinomatous craniopharyngioma typically presents as a suprasellar mixed solid and cystic mass that frequently demonstrates prominent [...].
Adamantinomatous craniopharyngioma. A solid and cystic mass with calcification (arrow), first diagnosed 4 years earlier.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.
A: calcifications
Back Extra: Adamantinomatous Craniopharyngioma
- Clinical: Common symptoms include visual impairment (62–84%) and endocrine deficits (52–87%), affecting growth hormone, LH/FSH, TSH, ACTH, and vasopressin.
- Micro: Characterized by peripheral palisading, epithelial whorls, stellate reticulum, and nodules of anucleate remnants of wet keratin.
- Ancillary: activating mutations in exon 3 of CTNNB1, leading to overexpression of β-catenin targets.
Reference Gallery:
Adamantinomatous craniopharyngioma. Basal palisading of tumour cells along the tumour–brain interface, epithelial whorls, stellate reticulum, and wet keratin.
Adamantinomatous craniopharyngioma. Tumour extending into adjacent brain tissue, which has reactive changes including piloid gliosis and Rosenthal fibres. Epithelial whorling is commonly present in protrusions.
Adamantinomatous craniopharyngioma. High-power view of the interface of adamantinomatous craniopharyngioma and brain tissue; Rosenthal fibres are present in the reactive piloid gliosis.
Adamantinomatous craniopharyngioma. Even though mutations in exon 3 of the CTNNB1 gene, which encodes β-catenin, are clonal and present across the neoplastic epithelium, β-catenin protein only accumulates in the nucleus in subset of cells, such as those that are scattered individually and present in small clusters.
Adamantinomatous craniopharyngioma. Recurrence 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and foci of necrosis.
Adamantinomatous craniopharyngioma. High-power view of malignant craniopharyngioma emerging 19 years after resection and radiation treatment of an adamantinomatous craniopharyngioma that was previously CNS WHO grade 1. Sheets of poorly differentiated cells showing severe cytological atypia, large vesicular nuclei, prominent nucleoli, mitotic activity, and necrosis.
Adamantinomatous craniopharyngioma. Characteristic very high tumour cell proliferation in malignant craniopharyngioma, as indicated by the Ki-67 index.
Adamantinomatous craniopharyngioma. A solid and cystic mass with calcification (arrow), first diagnosed 4 years earlier.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.
Adamantinomatous craniopharyngioma. A 6-year-old girl presented with severe headache and vomiting. MRI disclosed a large cystic and solid mixed suprasellar tumour with unilateral hydrocephalus. She also showed panhypopituitarism.

Q: In patients with a Sellar Meningioma, the most common presenting symptoms are headaches and [...], which often correlate with a well-demarcated suprasellar tumor seen on MRI.
Sellar meningioma. A 76-year-old man with visual disturbance. Gadolinium-enhanced T1-weighted MRI shows a well-demarcated suprasellar tumour.
A: visual deficits
Back Extra: Sellar Meningioma
- Clinical: Visual deficits and headache are the most common signs and symptoms at presentation. Endocrine abnormality is uncommon.
- Micro: Meningiomas have several histopathological appearances, including the meningothelial subtype which shows a frequent whorling pattern of uniform spindle cells.
- Ancillary: Meningiomas are typically immunoreactive for vimentin and EMA. Meningothelial meningiomas often carry AKT1 p.E17K mutations.
Reference Gallery:
Sellar meningioma. A 76-year-old man with visual disturbance. Gadolinium-enhanced T1-weighted MRI shows a well-demarcated suprasellar tumour.
Sellar meningioma, meningothelial. Frequent whorling pattern of uniform spindle cells.

Q: Histologically, the meningothelial subtype of a Sellar Meningioma frequently exhibits a characteristic [...] composed of uniform spindle cells.
Sellar meningioma, meningothelial. Frequent whorling pattern of uniform spindle cells.
A: whorling pattern
Back Extra: Sellar Meningioma
- Clinical: Visual deficits and headache are the most common signs and symptoms at presentation. Endocrine abnormality is uncommon.
- Micro: Meningiomas have several histopathological appearances, including the meningothelial subtype which shows a frequent whorling pattern of uniform spindle cells.
- Ancillary: Meningiomas are typically immunoreactive for vimentin and EMA. Meningothelial meningiomas often carry AKT1 p.E17K mutations.
Reference Gallery:
Sellar meningioma. A 76-year-old man with visual disturbance. Gadolinium-enhanced T1-weighted MRI shows a well-demarcated suprasellar tumour.
Sellar meningioma, meningothelial. Frequent whorling pattern of uniform spindle cells.

Q: Microscopically, Papillary Craniopharyngioma is characterized by non-keratinizing squamous epithelium with a papillary architecture and characteristic tumor-infiltrating [...].
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with tumour-infiltrating neutrophils, which are common in these tumours. Occasional collagenous whorls and mitoses are found.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils. Occasional mitoses can be found.
A: neutrophils
Back Extra: Papillary Craniopharyngioma
- Clinical: Papillary craniopharyngiomas commonly present with headache (70%) and visual deficits (63%), often resulting from compression of the optic chiasm.
- Micro: Non-keratinizing mature squamous epithelium with a papillary architecture, occasional mitoses, and tumour-infiltrating neutrophils are characteristic.
- Ancillary: BRAF p.V600E mutations are nearly universal in papillary craniopharyngiomas, aiding in diagnosis.
Reference Gallery:
Papillary craniopharyngioma. Low-power view highlights the papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with tumour-infiltrating neutrophils, which are common in these tumours. Occasional collagenous whorls and mitoses are found.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils. Occasional mitoses can be found.
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. Essentially all papillary craniopharyngiomas show cytoplasmic (and occasionally nuclear) immunoreactivity for BRAF p.V600E.
Papillary craniopharyngioma. Whereas adamantinomatous craniopharyngiomas have a subset of cells with nuclear localization of β-catenin, in papillary craniopharyngioma β-catenin localizes to the cytoplasmic membrane.
Papillary craniopharyngioma. A fixed coronal section 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. A solid suprasellar tumour was noted on MRI in this 43-year-old man who presented with visual disturbance and partial hypopituitarism.

Q: The defining genetic alteration in Papillary Craniopharyngioma, which can be identified via immunohistochemistry, is the [...] mutation.
Papillary craniopharyngioma. Essentially all papillary craniopharyngiomas show cytoplasmic (and occasionally nuclear) immunoreactivity for BRAF p.V600E.
A: BRAF p.V600E
Back Extra: Papillary Craniopharyngioma
- Clinical: Papillary craniopharyngiomas commonly present with headache (70%) and visual deficits (63%), often resulting from compression of the optic chiasm.
- Micro: Non-keratinizing mature squamous epithelium with a papillary architecture, occasional mitoses, and tumour-infiltrating neutrophils are characteristic.
- Ancillary: BRAF p.V600E mutations are nearly universal in papillary craniopharyngiomas, aiding in diagnosis.
Reference Gallery:
Papillary craniopharyngioma. Low-power view highlights the papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with tumour-infiltrating neutrophils, which are common in these tumours. Occasional collagenous whorls and mitoses are found.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils. Occasional mitoses can be found.
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. Essentially all papillary craniopharyngiomas show cytoplasmic (and occasionally nuclear) immunoreactivity for BRAF p.V600E.
Papillary craniopharyngioma. Whereas adamantinomatous craniopharyngiomas have a subset of cells with nuclear localization of β-catenin, in papillary craniopharyngioma β-catenin localizes to the cytoplasmic membrane.
Papillary craniopharyngioma. A fixed coronal section 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. A solid suprasellar tumour was noted on MRI in this 43-year-old man who presented with visual disturbance and partial hypopituitarism.

Q: Clinically, patients with a suprasellar Papillary Craniopharyngioma frequently present with visual deficits due to mass effect and compression of the [...].
Papillary craniopharyngioma. A fixed coronal section 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. A solid suprasellar tumour was noted on MRI in this 43-year-old man who presented with visual disturbance and partial hypopituitarism.
A: optic chiasm
Back Extra: Papillary Craniopharyngioma
- Clinical: Papillary craniopharyngiomas commonly present with headache (70%) and visual deficits (63%), often resulting from compression of the optic chiasm.
- Micro: Non-keratinizing mature squamous epithelium with a papillary architecture, occasional mitoses, and tumour-infiltrating neutrophils are characteristic.
- Ancillary: BRAF p.V600E mutations are nearly universal in papillary craniopharyngiomas, aiding in diagnosis.
Reference Gallery:
Papillary craniopharyngioma. Low-power view highlights the papillary architecture.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with tumour-infiltrating neutrophils, which are common in these tumours. Occasional collagenous whorls and mitoses are found.
Papillary craniopharyngioma. Well-differentiated non-keratinizing squamous epithelium with intercellular bridges and abundant tumour-infiltrating neutrophils. Occasional mitoses can be found.
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. Essentially all papillary craniopharyngiomas show cytoplasmic (and occasionally nuclear) immunoreactivity for BRAF p.V600E.
Papillary craniopharyngioma. Whereas adamantinomatous craniopharyngiomas have a subset of cells with nuclear localization of β-catenin, in papillary craniopharyngioma β-catenin localizes to the cytoplasmic membrane.
Papillary craniopharyngioma. A fixed coronal section 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. A solid suprasellar tumour was noted on MRI in this 43-year-old man who presented with visual disturbance and partial hypopituitarism.

Q: In Chordoma, the characteristic large tumor cells with a bubbly or vacuolated cytoplasm found within a myxoid matrix are known as [...] cells.
Chordoma. Conventional chordoma. Chords of tumour cells in a myxoid stroma. Note that occasional cells display a bubbly cytoplasm (physaliphorous cells).
Chordoma. Chordoma of the clivus. Neoplastic cells, including clusters of physaliphorous cells, in a fibrillary matrix in this squash preparation.
A: physaliphorous
Back Extra: Chordoma
- Clinical: Chordomas are bone-destructive midline lesions often presenting with cranial nerve deficits, visual disturbances, and endocrine abnormalities such as hyperprolactinaemia and hypopituitarism.
- Micro: Conventional chordomas show a lobular architecture with cords or ribbons of large cells with clear to eosinophilic cytoplasm, within a myxoid matrix. Physaliphorous cells, with vacuolated or bubbly cytoplasm, are characteristic.
- Ancillary: Brachyury expression is the diagnostic hallmark of chordomas. Homozygous SMARCB1 deletions are seen in poorly differentiated chordomas.
Reference Gallery:
Chordoma. Midsagittal postcontrast MRI showing a clival chordoma that invaded upward into the sella and suprasellar space.
Chordoma. Conventional chordoma. Chords of tumour cells in a myxoid stroma. Note that occasional cells display a bubbly cytoplasm (physaliphorous cells).
Chordoma. Conventional chordoma. Chordomas typically show nuclear immunoreactivity for brachyury.
Chordoma. Chordoma of the clivus. Neoplastic cells, including clusters of physaliphorous cells, in a fibrillary matrix in this squash preparation.

Q: The diagnostic immunohistochemical hallmark for Chordoma is strong nuclear expression of [...].
Chordoma. Conventional chordoma. Chordomas typically show nuclear immunoreactivity for brachyury.
A: brachyury
Back Extra: Chordoma
- Clinical: Chordomas are bone-destructive midline lesions often presenting with cranial nerve deficits, visual disturbances, and endocrine abnormalities such as hyperprolactinaemia and hypopituitarism.
- Micro: Conventional chordomas show a lobular architecture with cords or ribbons of large cells with clear to eosinophilic cytoplasm, within a myxoid matrix. Physaliphorous cells, with vacuolated or bubbly cytoplasm, are characteristic.
- Ancillary: Brachyury expression is the diagnostic hallmark of chordomas. Homozygous SMARCB1 deletions are seen in poorly differentiated chordomas.
Reference Gallery:
Chordoma. Midsagittal postcontrast MRI showing a clival chordoma that invaded upward into the sella and suprasellar space.
Chordoma. Conventional chordoma. Chords of tumour cells in a myxoid stroma. Note that occasional cells display a bubbly cytoplasm (physaliphorous cells).
Chordoma. Conventional chordoma. Chordomas typically show nuclear immunoreactivity for brachyury.
Chordoma. Chordoma of the clivus. Neoplastic cells, including clusters of physaliphorous cells, in a fibrillary matrix in this squash preparation.

Q: Clinically and radiographically, a Chordoma typically presents as a bone-destructive [...] lesion, often involving the clivus and resulting in cranial nerve deficits.
Chordoma. Midsagittal postcontrast MRI showing a clival chordoma that invaded upward into the sella and suprasellar space.
A: midline
Back Extra: Chordoma
- Clinical: Chordomas are bone-destructive midline lesions often presenting with cranial nerve deficits, visual disturbances, and endocrine abnormalities such as hyperprolactinaemia and hypopituitarism.
- Micro: Conventional chordomas show a lobular architecture with cords or ribbons of large cells with clear to eosinophilic cytoplasm, within a myxoid matrix. Physaliphorous cells, with vacuolated or bubbly cytoplasm, are characteristic.
- Ancillary: Brachyury expression is the diagnostic hallmark of chordomas. Homozygous SMARCB1 deletions are seen in poorly differentiated chordomas.
Reference Gallery:
Chordoma. Midsagittal postcontrast MRI showing a clival chordoma that invaded upward into the sella and suprasellar space.
Chordoma. Conventional chordoma. Chords of tumour cells in a myxoid stroma. Note that occasional cells display a bubbly cytoplasm (physaliphorous cells).
Chordoma. Conventional chordoma. Chordomas typically show nuclear immunoreactivity for brachyury.
Chordoma. Chordoma of the clivus. Neoplastic cells, including clusters of physaliphorous cells, in a fibrillary matrix in this squash preparation.

Q: The tumor cells in Pituicytoma characteristically show diffuse nuclear immunoreactivity for [...], which confidently distinguishes it from sellar schwannomas, meningiomas, and pituitary adenomas.
Pituicytoma. Diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1) is typical of pituicytoma and confidently distinguishes it from schwannoma, meningioma, or pituitary adenoma, all of which are immunonegative.
A: TTF1
Back Extra: Pituicytoma
- Clinical: Pituicytomas are often clinically indistinguishable from non-functioning pituitary neuroendocrine tumours (PitNETs)/adenomas, presenting with symptoms such as headaches, visual field defects, and hypopituitarism.
- Micro: Pituicytomas are composed of elongate bipolar spindle cells arranged in solid sheets and short fascicles, lacking eosinophilic granular bodies, Rosenthal fibres, and hyalinized blood vessels.
- Ancillary: Pituicytomas invariably express TTF1 and are negative for cytokeratins, pituitary hormones, and chromogranin A, but may express S100, vimentin, and other markers like EMA and CD56.
Reference Gallery:
Pituicytoma. This 55-year-old man presented with symptoms of a non-functioning sellar tumour, and his preoperative neuroimaging studies were thought to indicate non-functioning PitNET/adenoma on the basis of the presence of a homogeneous, well-demarcated sellar/suprasellar mass, as seen here; biopsy, however, proved this to be a pituicytoma.
Pituicytoma. The tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1) is typical of pituicytoma and confidently distinguishes it from schwannoma, meningioma, or pituitary adenoma, all of which are immunonegative.
Granular cell tumour of the sellar region / granular cell pituicytoma. These tumours are characterized by eosinophilic polygonal cells with abundant granular eosinophilic cytoplasm.
Granular cell tumour of the sellar region / granular cell pituicytoma. The cells show marked PAS positivity.
Spindle cell oncocytoma / oncocytic pituicytoma. Coronal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Tumour cells generally show more oval nuclei than those seen in schwannoma, which usually contains tapering nuclei with pointed ends. Note the absence of nuclear pseudoinclusions, which are seen in some meningioma cells. Note also the uniformity of nuclear features and absence of mitotic activity.
Spindle cell oncocytoma / oncocytic pituicytoma. Intersecting fascicles of tumour cells show the plump eosinophilic cytoplasm typical of this tumour; increased cytoplasmic volume is due to increased mitochondrial content.
Spindle cell oncocytoma / oncocytic pituicytoma. These tumours show diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1), but so do pituicytomas, granular cell tumours of the posterior pituitary, and even normal posterior pituitary gland, so this immunostain does not distinguish between these lesions.
Granular cell tumour of the sellar region / granular cell pituicytoma. Sagittal postcontrast image demonstrating homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Spindle cell oncocytoma / oncocytic pituicytoma. Sagittal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Spindle cell oncocytomas show immunoreactivity for galectin-3, as seen here, as well as vimentin, S100, and antimitochondrial antibody.

Q: On neuroimaging, Pituicytoma typically presents as a well-demarcated sellar or suprasellar mass that is clinically and radiologically indistinguishable from a non-functioning [...] (PitNET).
Pituicytoma. This 55-year-old man presented with symptoms of a non-functioning sellar tumour, and his preoperative neuroimaging studies were thought to indicate non-functioning PitNET/adenoma on the basis of the presence of a homogeneous, well-demarcated sellar/suprasellar mass, as seen here; biopsy, however, proved this to be a pituicytoma.
A: pituitary adenoma
Back Extra: Pituicytoma
- Clinical: Pituicytomas are often clinically indistinguishable from non-functioning pituitary neuroendocrine tumours (PitNETs)/adenomas, presenting with symptoms such as headaches, visual field defects, and hypopituitarism.
- Micro: Pituicytomas are composed of elongate bipolar spindle cells arranged in solid sheets and short fascicles, lacking eosinophilic granular bodies, Rosenthal fibres, and hyalinized blood vessels.
- Ancillary: Pituicytomas invariably express TTF1 and are negative for cytokeratins, pituitary hormones, and chromogranin A, but may express S100, vimentin, and other markers like EMA and CD56.
Reference Gallery:
Pituicytoma. This 55-year-old man presented with symptoms of a non-functioning sellar tumour, and his preoperative neuroimaging studies were thought to indicate non-functioning PitNET/adenoma on the basis of the presence of a homogeneous, well-demarcated sellar/suprasellar mass, as seen here; biopsy, however, proved this to be a pituicytoma.
Pituicytoma. The tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1) is typical of pituicytoma and confidently distinguishes it from schwannoma, meningioma, or pituitary adenoma, all of which are immunonegative.
Granular cell tumour of the sellar region / granular cell pituicytoma. These tumours are characterized by eosinophilic polygonal cells with abundant granular eosinophilic cytoplasm.
Granular cell tumour of the sellar region / granular cell pituicytoma. The cells show marked PAS positivity.
Spindle cell oncocytoma / oncocytic pituicytoma. Coronal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Tumour cells generally show more oval nuclei than those seen in schwannoma, which usually contains tapering nuclei with pointed ends. Note the absence of nuclear pseudoinclusions, which are seen in some meningioma cells. Note also the uniformity of nuclear features and absence of mitotic activity.
Spindle cell oncocytoma / oncocytic pituicytoma. Intersecting fascicles of tumour cells show the plump eosinophilic cytoplasm typical of this tumour; increased cytoplasmic volume is due to increased mitochondrial content.
Spindle cell oncocytoma / oncocytic pituicytoma. These tumours show diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1), but so do pituicytomas, granular cell tumours of the posterior pituitary, and even normal posterior pituitary gland, so this immunostain does not distinguish between these lesions.
Granular cell tumour of the sellar region / granular cell pituicytoma. Sagittal postcontrast image demonstrating homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Spindle cell oncocytoma / oncocytic pituicytoma. Sagittal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Spindle cell oncocytomas show immunoreactivity for galectin-3, as seen here, as well as vimentin, S100, and antimitochondrial antibody.

Q: Microscopically, Pituicytoma is characterized by solid sheets and short fascicles of bland, elongate, [...] cells with oval nuclei and eosinophilic cytoplasm, lacking Rosenthal fibers.
Pituicytoma. The tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
A: bipolar spindle
Back Extra: Pituicytoma
- Clinical: Pituicytomas are often clinically indistinguishable from non-functioning pituitary neuroendocrine tumours (PitNETs)/adenomas, presenting with symptoms such as headaches, visual field defects, and hypopituitarism.
- Micro: Pituicytomas are composed of elongate bipolar spindle cells arranged in solid sheets and short fascicles, lacking eosinophilic granular bodies, Rosenthal fibres, and hyalinized blood vessels.
- Ancillary: Pituicytomas invariably express TTF1 and are negative for cytokeratins, pituitary hormones, and chromogranin A, but may express S100, vimentin, and other markers like EMA and CD56.
Reference Gallery:
Pituicytoma. This 55-year-old man presented with symptoms of a non-functioning sellar tumour, and his preoperative neuroimaging studies were thought to indicate non-functioning PitNET/adenoma on the basis of the presence of a homogeneous, well-demarcated sellar/suprasellar mass, as seen here; biopsy, however, proved this to be a pituicytoma.
Pituicytoma. The tumour cells are cytologically bland, with oval nuclei, minimal hyperchromatism, and eosinophilic cytoplasm.
Pituicytoma. Diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1) is typical of pituicytoma and confidently distinguishes it from schwannoma, meningioma, or pituitary adenoma, all of which are immunonegative.
Granular cell tumour of the sellar region / granular cell pituicytoma. These tumours are characterized by eosinophilic polygonal cells with abundant granular eosinophilic cytoplasm.
Granular cell tumour of the sellar region / granular cell pituicytoma. The cells show marked PAS positivity.
Spindle cell oncocytoma / oncocytic pituicytoma. Coronal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Tumour cells generally show more oval nuclei than those seen in schwannoma, which usually contains tapering nuclei with pointed ends. Note the absence of nuclear pseudoinclusions, which are seen in some meningioma cells. Note also the uniformity of nuclear features and absence of mitotic activity.
Spindle cell oncocytoma / oncocytic pituicytoma. Intersecting fascicles of tumour cells show the plump eosinophilic cytoplasm typical of this tumour; increased cytoplasmic volume is due to increased mitochondrial content.
Spindle cell oncocytoma / oncocytic pituicytoma. These tumours show diffuse nuclear immunoreactivity for thyroid transcription factor 1 (TTF1), but so do pituicytomas, granular cell tumours of the posterior pituitary, and even normal posterior pituitary gland, so this immunostain does not distinguish between these lesions.
Granular cell tumour of the sellar region / granular cell pituicytoma. Sagittal postcontrast image demonstrating homogeneous mild enhancement within the mass and a relatively normal calibre of the more caudal stalk.
Spindle cell oncocytoma / oncocytic pituicytoma. Sagittal postcontrast T1-weighted image demonstrating a large, expansile, heterogeneously enhancing sellar mass with parasellar extension and invasion of the clivus.
Spindle cell oncocytoma / oncocytic pituicytoma. Spindle cell oncocytomas show immunoreactivity for galectin-3, as seen here, as well as vimentin, S100, and antimitochondrial antibody.

Q: Patients with a known primary malignancy (e.g., breast or pancreatic carcinoma) who present with a large intrasuprasellar mass (such as a dumbbell enhancing lesion on MRI) invading adjacent structures like the optic chiasm should be suspected of having [...].
MRI of breast carcinoma metastatic to the pituitary. Postcontrast axial T1-weighted sequence shows a dumbbell intrasuprasellar enhancing lesion.
Pancreatic adenocarcinoma metastatic to the pituitary, hypothalamus, and optic apparatus. Coronal brain section demonstrating a large tumour (adjacent to asterisk) replacing the pituitary gland and optic chiasm and invading the hypothalamus and third ventricle.
A: Metastasis to the Pituitary Gland
Back Extra: Metastasis to the Pituitary Gland
- Clinical: Common presenting signs and symptoms of metastasis to the pituitary gland include headache, visual field defects, cranial nerve palsy, and ophthalmoplegia.
- Micro: Histological features of metastatic tumours in the pituitary are similar to those of the tumour of origin, and may appear as a discrete mass, small aggregates, or single cells.
- Ancillary: Molecular testing can help identify the primary site of origin and guide therapy, while IHC shows an absence of pituitary hormones and transcription factors in tumour cells.
Reference Gallery:
MRI of breast carcinoma metastatic to the pituitary. Postcontrast axial T1-weighted sequence shows a dumbbell intrasuprasellar enhancing lesion.
Colon adenocarcinoma metastatic to gonadotroph pituitary neuroendocrine tumour (PitNET)/adenoma. Neoplastic glands composed of severely atypical columnar cells are admixed with acini of uniform tumour cells of the PitNET/adenoma (asterisk).
Pancreatic adenocarcinoma metastatic to the pituitary, hypothalamus, and optic apparatus. Coronal brain section demonstrating a large tumour (adjacent to asterisk) replacing the pituitary gland and optic chiasm and invading the hypothalamus and third ventricle.

Q: Microscopically, [...] demonstrates tumor cells resembling the primary site of origin (e.g., atypical adenocarcinoma glands) that are immunohistochemically negative for normal pituitary hormones and transcription factors.
Colon adenocarcinoma metastatic to gonadotroph pituitary neuroendocrine tumour (PitNET)/adenoma. Neoplastic glands composed of severely atypical columnar cells are admixed with acini of uniform tumour cells of the PitNET/adenoma (asterisk).
A: Metastasis to the Pituitary Gland
Back Extra: Metastasis to the Pituitary Gland
- Clinical: Common presenting signs and symptoms of metastasis to the pituitary gland include headache, visual field defects, cranial nerve palsy, and ophthalmoplegia.
- Micro: Histological features of metastatic tumours in the pituitary are similar to those of the tumour of origin, and may appear as a discrete mass, small aggregates, or single cells.
- Ancillary: Molecular testing can help identify the primary site of origin and guide therapy, while IHC shows an absence of pituitary hormones and transcription factors in tumour cells.
Reference Gallery:
MRI of breast carcinoma metastatic to the pituitary. Postcontrast axial T1-weighted sequence shows a dumbbell intrasuprasellar enhancing lesion.
Colon adenocarcinoma metastatic to gonadotroph pituitary neuroendocrine tumour (PitNET)/adenoma. Neoplastic glands composed of severely atypical columnar cells are admixed with acini of uniform tumour cells of the PitNET/adenoma (asterisk).
Pancreatic adenocarcinoma metastatic to the pituitary, hypothalamus, and optic apparatus. Coronal brain section demonstrating a large tumour (adjacent to asterisk) replacing the pituitary gland and optic chiasm and invading the hypothalamus and third ventricle.

Q: In Corticotroph PitNET/adenoma, a specific morphological variant exhibits prominent accumulation of perinuclear hyaline material with ring-like cytokeratin expression, known as a [...].
Corticotroph PitNET. Crooke cell tumour in a patient with a clinically non-functioning PitNET. Crooke hyaline change is present in a majority of the tumour cells.
Corticotroph PitNET. Strong perinuclear and ring-like expression of the low-molecular-weight cytokeratin CAM5.2 corresponding to hyaline material accumulation in tumour cells of Crooke cell PitNET.
A: Crooke cell tumor
Back Extra: Corticotroph PitNET/adenoma
- Clinical: Corticotroph PitNETs cause Cushing syndrome, characterized by insulin resistance, depression, obesity, and hypertension. In children, weight gain with growth failure is characteristic.
- Micro: Corticotroph tumours are composed of neuroendocrine cells with variable amounts of basophilic secretory granules and may show perivascular pseudorosettes. Crooke cell tumours exhibit neuroendocrine cells with Crooke hyaline change and ring-like cytokeratin expression.
- Ancillary: Immunohistochemistry shows positivity for ACTH, TPIT, and NeuroD1, and negativity for PIT1, SF1, and hormones of PIT1 and SF1 lineages. Loss of p27 is frequent in functioning corticotroph tumours.
Reference Gallery:
Corticotroph PitNET. Crooke cell tumour in a patient with a clinically non-functioning PitNET. Crooke hyaline change is present in a majority of the tumour cells.
Corticotroph PitNET. Perinuclear hyaline material in the tumour cells of Crooke cell PitNET is PAS-negative.
Corticotroph PitNET. Strong perinuclear and ring-like expression of the low-molecular-weight cytokeratin CAM5.2 corresponding to hyaline material accumulation in tumour cells of Crooke cell PitNET.
Corticotroph PitNET. There is a lack of ACTH expression in the perinuclear and ring-like hyaline aggregates in tumour cells with Crooke hyaline change. ACTH immunolabelling is diffusely present in the cytoplasm of tumour cells without Crooke hyaline change or dislocated to the cell periphery in the tumour cells demonstrating Crooke hyaline change.
Corticotroph PitNET. Strong nuclear expression of TPIT in tumour cells of the Crooke cell PitNET.
Corticotroph PitNET. Generally low Ki-67 index, with only the focal presence of cells positive for Ki-67 within this Crooke cell tumour.
Corticotroph PitNET. Lack of SSTR2A immunolabelling in the tumour cells of this case of Crooke cell PitNET.
Corticotroph PitNET. The majority of tumour cells in this case of Crooke cell PitNET show a strong membranous and a variable cytoplasmic expression of SSTR3.
Corticotroph PitNET. Lack of SSTR5 expression in the tumour cells in this case of Crooke cell tumour.
Corticotroph PitNET, metastatic, ATRX-mutated. The tumour in a patient with Cushing disease is composed of basophilic tumour cells.
Corticotroph PitNET, metastatic, ATRX-mutated. Strong expression of ACTH in a metastatic corticotroph tumour causing Cushing disease.
Corticotroph PitNET, metastatic, ATRX-mutated. Lack of ATRX immunolabelling in the tumour cells of an ATRX-mutated metastatic corticotroph PitNET. Normal ATRX expression in endothelial cells serves as a positive control.

Q: Immunohistochemistry of Corticotroph PitNET/adenoma is typically positive for ACTH, NeuroD1, and the lineage-defining transcription factor [...].
Corticotroph PitNET. Strong nuclear expression of TPIT in tumour cells of the Crooke cell PitNET.
A: TPIT
Back Extra: Corticotroph PitNET/adenoma
- Clinical: Corticotroph PitNETs cause Cushing syndrome, characterized by insulin resistance, depression, obesity, and hypertension. In children, weight gain with growth failure is characteristic.
- Micro: Corticotroph tumours are composed of neuroendocrine cells with variable amounts of basophilic secretory granules and may show perivascular pseudorosettes. Crooke cell tumours exhibit neuroendocrine cells with Crooke hyaline change and ring-like cytokeratin expression.
- Ancillary: Immunohistochemistry shows positivity for ACTH, TPIT, and NeuroD1, and negativity for PIT1, SF1, and hormones of PIT1 and SF1 lineages. Loss of p27 is frequent in functioning corticotroph tumours.
Reference Gallery:
Corticotroph PitNET. Crooke cell tumour in a patient with a clinically non-functioning PitNET. Crooke hyaline change is present in a majority of the tumour cells.
Corticotroph PitNET. Perinuclear hyaline material in the tumour cells of Crooke cell PitNET is PAS-negative.
Corticotroph PitNET. Strong perinuclear and ring-like expression of the low-molecular-weight cytokeratin CAM5.2 corresponding to hyaline material accumulation in tumour cells of Crooke cell PitNET.
Corticotroph PitNET. There is a lack of ACTH expression in the perinuclear and ring-like hyaline aggregates in tumour cells with Crooke hyaline change. ACTH immunolabelling is diffusely present in the cytoplasm of tumour cells without Crooke hyaline change or dislocated to the cell periphery in the tumour cells demonstrating Crooke hyaline change.
Corticotroph PitNET. Strong nuclear expression of TPIT in tumour cells of the Crooke cell PitNET.
Corticotroph PitNET. Generally low Ki-67 index, with only the focal presence of cells positive for Ki-67 within this Crooke cell tumour.
Corticotroph PitNET. Lack of SSTR2A immunolabelling in the tumour cells of this case of Crooke cell PitNET.
Corticotroph PitNET. The majority of tumour cells in this case of Crooke cell PitNET show a strong membranous and a variable cytoplasmic expression of SSTR3.
Corticotroph PitNET. Lack of SSTR5 expression in the tumour cells in this case of Crooke cell tumour.
Corticotroph PitNET, metastatic, ATRX-mutated. The tumour in a patient with Cushing disease is composed of basophilic tumour cells.
Corticotroph PitNET, metastatic, ATRX-mutated. Strong expression of ACTH in a metastatic corticotroph tumour causing Cushing disease.
Corticotroph PitNET, metastatic, ATRX-mutated. Lack of ATRX immunolabelling in the tumour cells of an ATRX-mutated metastatic corticotroph PitNET. Normal ATRX expression in endothelial cells serves as a positive control.

Q: In the Crooke cell variant of Corticotroph PitNET/adenoma, the accumulated perinuclear hyaline material is PAS-negative and characteristically displaces ACTH immunolabeling to the [...].
Corticotroph PitNET. Perinuclear hyaline material in the tumour cells of Crooke cell PitNET is PAS-negative.
Corticotroph PitNET. There is a lack of ACTH expression in the perinuclear and ring-like hyaline aggregates in tumour cells with Crooke hyaline change. ACTH immunolabelling is diffusely present in the cytoplasm of tumour cells without Crooke hyaline change or dislocated to the cell periphery in the tumour cells demonstrating Crooke hyaline change.
A: cell periphery
Back Extra: Corticotroph PitNET/adenoma
- Clinical: Corticotroph PitNETs cause Cushing syndrome, characterized by insulin resistance, depression, obesity, and hypertension. In children, weight gain with growth failure is characteristic.
- Micro: Corticotroph tumours are composed of neuroendocrine cells with variable amounts of basophilic secretory granules and may show perivascular pseudorosettes. Crooke cell tumours exhibit neuroendocrine cells with Crooke hyaline change and ring-like cytokeratin expression.
- Ancillary: Immunohistochemistry shows positivity for ACTH, TPIT, and NeuroD1, and negativity for PIT1, SF1, and hormones of PIT1 and SF1 lineages. Loss of p27 is frequent in functioning corticotroph tumours.
Reference Gallery:
Corticotroph PitNET. Crooke cell tumour in a patient with a clinically non-functioning PitNET. Crooke hyaline change is present in a majority of the tumour cells.
Corticotroph PitNET. Perinuclear hyaline material in the tumour cells of Crooke cell PitNET is PAS-negative.
Corticotroph PitNET. Strong perinuclear and ring-like expression of the low-molecular-weight cytokeratin CAM5.2 corresponding to hyaline material accumulation in tumour cells of Crooke cell PitNET.
Corticotroph PitNET. There is a lack of ACTH expression in the perinuclear and ring-like hyaline aggregates in tumour cells with Crooke hyaline change. ACTH immunolabelling is diffusely present in the cytoplasm of tumour cells without Crooke hyaline change or dislocated to the cell periphery in the tumour cells demonstrating Crooke hyaline change.
Corticotroph PitNET. Strong nuclear expression of TPIT in tumour cells of the Crooke cell PitNET.
Corticotroph PitNET. Generally low Ki-67 index, with only the focal presence of cells positive for Ki-67 within this Crooke cell tumour.
Corticotroph PitNET. Lack of SSTR2A immunolabelling in the tumour cells of this case of Crooke cell PitNET.
Corticotroph PitNET. The majority of tumour cells in this case of Crooke cell PitNET show a strong membranous and a variable cytoplasmic expression of SSTR3.
Corticotroph PitNET. Lack of SSTR5 expression in the tumour cells in this case of Crooke cell tumour.
Corticotroph PitNET, metastatic, ATRX-mutated. The tumour in a patient with Cushing disease is composed of basophilic tumour cells.
Corticotroph PitNET, metastatic, ATRX-mutated. Strong expression of ACTH in a metastatic corticotroph tumour causing Cushing disease.
Corticotroph PitNET, metastatic, ATRX-mutated. Lack of ATRX immunolabelling in the tumour cells of an ATRX-mutated metastatic corticotroph PitNET. Normal ATRX expression in endothelial cells serves as a positive control.

Q: Because it is most often clinically non-functioning, a [...] typically presents as a large intra- and suprasellar mass (macroadenoma) with symptoms related to mass effect, such as visual disturbances and hypopituitarism.
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. These tumours are often found as larger tumour masses. Typically, they are intrasellar with suprasellar extension.
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. Some are invasive giant tumours.
A: Gonadotroph PitNET/adenoma
Q: Gonadotroph PitNET/adenoma
- Clinical: Most [...] are clinically non-functioning and present with symptoms related to mass effects such as visual disturbances, headaches, and hypopituitarism.
- Micro: Histologically, [...] are characterized by chromophobic cells arranged in nests, sinusoidal, and trabecular patterns, with possible oncocytic changes.
- Ancillary: Immunohistochemistry of [...] shows variable immunopositivity for FSH-β, LH-β, and SF1, with strong and diffuse nuclear SF1 expression.
Reference Gallery:
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. These tumours are often found as larger tumour masses. Typically, they are intrasellar with suprasellar extension.
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. Some are invasive giant tumours.
Functioning gonadotroph PitNET/adenoma. Transvaginal ovarian ultrasonography in a 34-year-old woman with a clinically functioning gonadotroph PitNET/adenoma showing multiple cysts.
Gonadotroph PitNET/adenoma histopathology. These tumours are composed of chromophobic cells arranged in nests and in diffuse, sinusoidal, and trabecular (shown here) arrangements.
Gonadotroph PitNET/adenoma histopathology. Prominent perivascular arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Prominent papillary arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Oncocytic changes characterized by abundant eosinophilic cytoplasm due to mitochondria accumulation may be present.
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins FSH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins LH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of SF1 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of GATA3 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma SF1 expression pattern. Variable-intensity SF1 nuclear expression is seen in gonadotroph PitNETs/adenomas. Well-differentiated papillary tumour.
A: gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas

Q: Histologically, a [...] is composed of chromophobic to oncocytic cells that often form diffuse, sinusoidal, perivascular, papillary, or trabecular arrangements.
Gonadotroph PitNET/adenoma histopathology. These tumours are composed of chromophobic cells arranged in nests and in diffuse, sinusoidal, and trabecular (shown here) arrangements.
Gonadotroph PitNET/adenoma histopathology. Prominent perivascular arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Oncocytic changes characterized by abundant eosinophilic cytoplasm due to mitochondria accumulation may be present.
A: Gonadotroph PitNET/adenoma
Q: Gonadotroph PitNET/adenoma
- Clinical: Most [...] are clinically non-functioning and present with symptoms related to mass effects such as visual disturbances, headaches, and hypopituitarism.
- Micro: Histologically, [...] are characterized by chromophobic cells arranged in nests, sinusoidal, and trabecular patterns, with possible oncocytic changes.
- Ancillary: Immunohistochemistry of [...] shows variable immunopositivity for FSH-β, LH-β, and SF1, with strong and diffuse nuclear SF1 expression.
Reference Gallery:
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. These tumours are often found as larger tumour masses. Typically, they are intrasellar with suprasellar extension.
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. Some are invasive giant tumours.
Functioning gonadotroph PitNET/adenoma. Transvaginal ovarian ultrasonography in a 34-year-old woman with a clinically functioning gonadotroph PitNET/adenoma showing multiple cysts.
Gonadotroph PitNET/adenoma histopathology. These tumours are composed of chromophobic cells arranged in nests and in diffuse, sinusoidal, and trabecular (shown here) arrangements.
Gonadotroph PitNET/adenoma histopathology. Prominent perivascular arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Prominent papillary arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Oncocytic changes characterized by abundant eosinophilic cytoplasm due to mitochondria accumulation may be present.
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins FSH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins LH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of SF1 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of GATA3 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma SF1 expression pattern. Variable-intensity SF1 nuclear expression is seen in gonadotroph PitNETs/adenomas. Well-differentiated papillary tumour.
A: gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas

Q: By immunohistochemistry, a Gonadotroph PitNET/adenoma is characterized by variable positivity for FSH-β and LH-β, as well as diffuse nuclear expression of the lineage-defining transcription factors GATA3 and [...].
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins FSH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins LH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of SF1 is present in the majority of the tumours.
A: SF1
Q: Gonadotroph PitNET/adenoma
- Clinical: Most [...] are clinically non-functioning and present with symptoms related to mass effects such as visual disturbances, headaches, and hypopituitarism.
- Micro: Histologically, [...] are characterized by chromophobic cells arranged in nests, sinusoidal, and trabecular patterns, with possible oncocytic changes.
- Ancillary: Immunohistochemistry of [...] shows variable immunopositivity for FSH-β, LH-β, and SF1, with strong and diffuse nuclear SF1 expression.
Reference Gallery:
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. These tumours are often found as larger tumour masses. Typically, they are intrasellar with suprasellar extension.
Gonadotroph PitNET/adenoma. T1-weighted coronal MRI. Some are invasive giant tumours.
Functioning gonadotroph PitNET/adenoma. Transvaginal ovarian ultrasonography in a 34-year-old woman with a clinically functioning gonadotroph PitNET/adenoma showing multiple cysts.
Gonadotroph PitNET/adenoma histopathology. These tumours are composed of chromophobic cells arranged in nests and in diffuse, sinusoidal, and trabecular (shown here) arrangements.
Gonadotroph PitNET/adenoma histopathology. Prominent perivascular arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Prominent papillary arrangements of elongate cells are seen.
Gonadotroph PitNET/adenoma histopathology. Oncocytic changes characterized by abundant eosinophilic cytoplasm due to mitochondria accumulation may be present.
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins FSH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. The tumours may show variable immunopositivity for the gonadotropins LH-β (shown here) and α-subunit (not shown).
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of SF1 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma immunohistochemistry. Nuclear expression of GATA3 is present in the majority of the tumours.
Gonadotroph PitNET/adenoma SF1 expression pattern. Variable-intensity SF1 nuclear expression is seen in gonadotroph PitNETs/adenomas. Well-differentiated papillary tumour.
A: gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas; gonadotroph PitNET/adenomas

Q: In Lactotroph PitNET/adenoma, the sparsely granulated variant typically exhibits chromophobic cells with a characteristic [...] pattern on prolactin immunostaining.
Lactotroph PitNET/adenoma, sparsely granulated. A PitNET with mostly chromophobic tumour cells, in this case arranged in sheets.
Lactotroph PitNET/adenoma, sparsely granulated. Prolactin immunostain showing mostly paranuclear Golgi-pattern (spherical) staining.
A: paranuclear Golgi
Back Extra: Lactotroph PitNET/adenoma
- Clinical: Lactotroph PitNET/adenomas often present with hyperprolactinemia, leading to reproductive and sexual dysfunction such as galactorrhea, amenorrhea, and erectile dysfunction.
- Micro: Histologically, lactotroph PitNET/adenomas can be sparsely granulated (SGLT) or densely granulated (DGLT), with SGLT showing chromophobic cells and DGLT showing acidophilic cells.
- Ancillary: Immunohistochemically, lactotroph PitNET/adenomas are positive for prolactin, PIT1, and often ERα, and can show SF3B1 p.R625H mutations.
Reference Gallery:
Lactotroph PitNET/adenoma, sparsely granulated. A PitNET with mostly chromophobic tumour cells, in this case arranged in sheets.
Lactotroph PitNET/adenoma, sparsely granulated. Prolactin immunostain showing mostly paranuclear Golgi-pattern (spherical) staining.
Lactotroph PitNET/adenoma, sparsely granulated. Diffuse nuclear immunoreactivity for PIT1.
Lactotroph PitNET/adenoma, densely granulated. Acidophilic cells reflecting a densely granulated cytoplasm.
Lactotroph PitNET/adenoma, densely granulated. Extensive granular cytoplasmic immunoreactivity pattern for prolactin.
Lactotroph PitNET/adenoma, sparsely granulated. Scattered psammoma bodies and perivascular/interstitial fibrosis.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. This sparsely granulated lactotroph tumour that was resected after therapy with a dopamine agonist shows extensive perivascular and interstitial fibrosis, along with small cell change due to loss of tumour cytoplasm.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are diffusely positive for PIT1.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are variably immunoreactive for prolactin, with minimal staining in some of the tumour cells due to limited hormone production.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. A Congo red stain highlights the spherical amyloid collections.

Q: Immunohistochemically, a Lactotroph PitNET/adenoma demonstrates positivity for prolactin, ERα, and the lineage-specific pituitary transcription factor [...].
Lactotroph PitNET/adenoma, sparsely granulated. Diffuse nuclear immunoreactivity for PIT1.
A: PIT1
Back Extra: Lactotroph PitNET/adenoma
- Clinical: Lactotroph PitNET/adenomas often present with hyperprolactinemia, leading to reproductive and sexual dysfunction such as galactorrhea, amenorrhea, and erectile dysfunction.
- Micro: Histologically, lactotroph PitNET/adenomas can be sparsely granulated (SGLT) or densely granulated (DGLT), with SGLT showing chromophobic cells and DGLT showing acidophilic cells.
- Ancillary: Immunohistochemically, lactotroph PitNET/adenomas are positive for prolactin, PIT1, and often ERα, and can show SF3B1 p.R625H mutations.
Reference Gallery:
Lactotroph PitNET/adenoma, sparsely granulated. A PitNET with mostly chromophobic tumour cells, in this case arranged in sheets.
Lactotroph PitNET/adenoma, sparsely granulated. Prolactin immunostain showing mostly paranuclear Golgi-pattern (spherical) staining.
Lactotroph PitNET/adenoma, sparsely granulated. Diffuse nuclear immunoreactivity for PIT1.
Lactotroph PitNET/adenoma, densely granulated. Acidophilic cells reflecting a densely granulated cytoplasm.
Lactotroph PitNET/adenoma, densely granulated. Extensive granular cytoplasmic immunoreactivity pattern for prolactin.
Lactotroph PitNET/adenoma, sparsely granulated. Scattered psammoma bodies and perivascular/interstitial fibrosis.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. This sparsely granulated lactotroph tumour that was resected after therapy with a dopamine agonist shows extensive perivascular and interstitial fibrosis, along with small cell change due to loss of tumour cytoplasm.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are diffusely positive for PIT1.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are variably immunoreactive for prolactin, with minimal staining in some of the tumour cells due to limited hormone production.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. A Congo red stain highlights the spherical amyloid collections.

Q: Resection of a Lactotroph PitNET/adenoma following dopamine agonist medical therapy characteristically reveals small cell change (due to loss of tumor cytoplasm) and extensive perivascular and interstitial [...].
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. This sparsely granulated lactotroph tumour that was resected after therapy with a dopamine agonist shows extensive perivascular and interstitial fibrosis, along with small cell change due to loss of tumour cytoplasm.
A: fibrosis
Back Extra: Lactotroph PitNET/adenoma
- Clinical: Lactotroph PitNET/adenomas often present with hyperprolactinemia, leading to reproductive and sexual dysfunction such as galactorrhea, amenorrhea, and erectile dysfunction.
- Micro: Histologically, lactotroph PitNET/adenomas can be sparsely granulated (SGLT) or densely granulated (DGLT), with SGLT showing chromophobic cells and DGLT showing acidophilic cells.
- Ancillary: Immunohistochemically, lactotroph PitNET/adenomas are positive for prolactin, PIT1, and often ERα, and can show SF3B1 p.R625H mutations.
Reference Gallery:
Lactotroph PitNET/adenoma, sparsely granulated. A PitNET with mostly chromophobic tumour cells, in this case arranged in sheets.
Lactotroph PitNET/adenoma, sparsely granulated. Prolactin immunostain showing mostly paranuclear Golgi-pattern (spherical) staining.
Lactotroph PitNET/adenoma, sparsely granulated. Diffuse nuclear immunoreactivity for PIT1.
Lactotroph PitNET/adenoma, densely granulated. Acidophilic cells reflecting a densely granulated cytoplasm.
Lactotroph PitNET/adenoma, densely granulated. Extensive granular cytoplasmic immunoreactivity pattern for prolactin.
Lactotroph PitNET/adenoma, sparsely granulated. Scattered psammoma bodies and perivascular/interstitial fibrosis.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. This sparsely granulated lactotroph tumour that was resected after therapy with a dopamine agonist shows extensive perivascular and interstitial fibrosis, along with small cell change due to loss of tumour cytoplasm.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are diffusely positive for PIT1.
Lactotroph PitNET/adenoma, sparsely granulated after medical therapy. The lactotroph tumour cells are variably immunoreactive for prolactin, with minimal staining in some of the tumour cells due to limited hormone production.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. Spherical amyloid collections are seen in rare lactotroph tumours.
Lactotroph PitNET/adenoma, sparsely granulated. A Congo red stain highlights the spherical amyloid collections.

Q: In [...], patients present with two or more discrete pituitary tumors of different cell derivations (e.g., an SF1-positive gonadotroph tumor and a PIT1-positive somatotroph tumor) that can be difficult to distinguish on routine H&E.
Multiple synchronous PitNETs/adenomas of distinct lineages. On H&E-stained slides, it may be difficult to appreciate the presence of two distinct tumours.
Multiple synchronous PitNETs/adenomas of distinct lineages. SF1 immunohistochemistry stains the gonadotroph tumour.
Multiple synchronous PitNETs/adenomas of distinct lineages. The sparsely granulated somatotroph tumour component is positive for PIT1.
A: Multiple Synchronous PitNETs/Adenomas of Distinct Lineages
Back Extra: Multiple Synchronous PitNETs/Adenomas of Distinct Lineages
- Clinical: Multiple Synchronous PitNETs/Adenomas of Distinct Lineages can present with acromegaly, Cushing disease, hyperthyroidism, and galactorrhoea-amenorrhoea.
- Micro: These tumours often show variable Ki-67 labelling indexes, ranging from 1% to 5%.
- Ancillary: Germline screening for genetic susceptibility is recommended, especially in patients under 30 years old or with a family history.
Reference Gallery:
Multiple synchronous PitNETs/adenomas of distinct lineages. On H&E-stained slides, it may be difficult to appreciate the presence of two distinct tumours.
Multiple synchronous PitNETs/adenomas of distinct lineages. SF1 immunohistochemistry stains the gonadotroph tumour.
Multiple synchronous PitNETs/adenomas of distinct lineages. The sparsely granulated somatotroph tumour component is positive for PIT1.
Multiple synchronous PitNETs/adenomas of distinct lineages. CAM5.2 shows fibrous bodies in the sparsely granulated somatotroph tumour component.

Q: When evaluating Multiple Synchronous PitNETs/Adenomas of Distinct Lineages, specific tumor components can be characterized by additional stains; for example, CAM5.2 immunohistochemistry highlights pathognomonic [...] in sparsely granulated somatotroph tumors.
Multiple synchronous PitNETs/adenomas of distinct lineages. CAM5.2 shows fibrous bodies in the sparsely granulated somatotroph tumour component.
A: fibrous bodies
Back Extra: Multiple Synchronous PitNETs/Adenomas of Distinct Lineages
- Clinical: Multiple Synchronous PitNETs/Adenomas of Distinct Lineages can present with acromegaly, Cushing disease, hyperthyroidism, and galactorrhoea-amenorrhoea.
- Micro: These tumours often show variable Ki-67 labelling indexes, ranging from 1% to 5%.
- Ancillary: Germline screening for genetic susceptibility is recommended, especially in patients under 30 years old or with a family history.
Reference Gallery:
Multiple synchronous PitNETs/adenomas of distinct lineages. On H&E-stained slides, it may be difficult to appreciate the presence of two distinct tumours.
Multiple synchronous PitNETs/adenomas of distinct lineages. SF1 immunohistochemistry stains the gonadotroph tumour.
Multiple synchronous PitNETs/adenomas of distinct lineages. The sparsely granulated somatotroph tumour component is positive for PIT1.
Multiple synchronous PitNETs/adenomas of distinct lineages. CAM5.2 shows fibrous bodies in the sparsely granulated somatotroph tumour component.

Q: On histology, Acidophil Stem Cell PitNET/Adenoma classically shows sheets of pleomorphic, chromophobic to slightly acidophilic cells featuring clear, rimmed vacuoles that correspond to [...].
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. An antimitochondrial antigen immunostain highlights the oncocytic changes (increased mitochondria), and the rimmed vacuoles are suggestive of giant mitochondria.
A: giant mitochondria
Back Extra: Acidophil Stem Cell PitNET/Adenoma
- Clinical: Acidophil Stem Cell PitNET/Adenoma often presents with hyperprolactinaemia and signs of mass effect, such as headaches and visual deficits.
- Micro: Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles and oncocytic changes are characteristic.
- Ancillary: Diffuse PIT1 positivity and variable prolactin staining, with minimal to absent growth hormone expression, are seen on immunohistochemistry.
Reference Gallery:
Acidophil stem cell tumour. Postcontrast sagittal MRI showing a predominant pattern of invasion inferiorly.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Prolactin positivity is seen in many, but not all, tumour cells.
Acidophil stem cell tumour. Focal weak positivity for growth hormone, with intense staining of entrapped non-neoplastic cells.
Acidophil stem cell tumour. A CAM5.2 cytokeratin immunostain highlights scattered fibrous bodies.
Acidophil stem cell tumour. Diffuse PIT1 immunoreactivity.
Acidophil stem cell tumour. An antimitochondrial antigen immunostain highlights the oncocytic changes (increased mitochondria), and the rimmed vacuoles are suggestive of giant mitochondria.

Q: By immunohistochemistry, Acidophil Stem Cell PitNET/Adenoma is characterized by diffuse nuclear expression of the transcription factor [...], along with variable prolactin staining and scattered fibrous bodies highlighted by cytokeratin stains (e.g., CAM5.2).
Acidophil stem cell tumour. A CAM5.2 cytokeratin immunostain highlights scattered fibrous bodies.
Acidophil stem cell tumour. Diffuse PIT1 immunoreactivity.
A: PIT1
Back Extra: Acidophil Stem Cell PitNET/Adenoma
- Clinical: Acidophil Stem Cell PitNET/Adenoma often presents with hyperprolactinaemia and signs of mass effect, such as headaches and visual deficits.
- Micro: Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles and oncocytic changes are characteristic.
- Ancillary: Diffuse PIT1 positivity and variable prolactin staining, with minimal to absent growth hormone expression, are seen on immunohistochemistry.
Reference Gallery:
Acidophil stem cell tumour. Postcontrast sagittal MRI showing a predominant pattern of invasion inferiorly.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Prolactin positivity is seen in many, but not all, tumour cells.
Acidophil stem cell tumour. Focal weak positivity for growth hormone, with intense staining of entrapped non-neoplastic cells.
Acidophil stem cell tumour. A CAM5.2 cytokeratin immunostain highlights scattered fibrous bodies.
Acidophil stem cell tumour. Diffuse PIT1 immunoreactivity.
Acidophil stem cell tumour. An antimitochondrial antigen immunostain highlights the oncocytic changes (increased mitochondria), and the rimmed vacuoles are suggestive of giant mitochondria.

Q: Clinically, patients with an Acidophil Stem Cell PitNET/Adenoma most commonly present with signs of mass effect and [...], which corresponds to variable immunohistochemical positivity for prolactin and minimal to absent growth hormone expression.
Acidophil stem cell tumour. Prolactin positivity is seen in many, but not all, tumour cells.
Acidophil stem cell tumour. Focal weak positivity for growth hormone, with intense staining of entrapped non-neoplastic cells.
A: hyperprolactinemia
Back Extra: Acidophil Stem Cell PitNET/Adenoma
- Clinical: Acidophil Stem Cell PitNET/Adenoma often presents with hyperprolactinaemia and signs of mass effect, such as headaches and visual deficits.
- Micro: Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles and oncocytic changes are characteristic.
- Ancillary: Diffuse PIT1 positivity and variable prolactin staining, with minimal to absent growth hormone expression, are seen on immunohistochemistry.
Reference Gallery:
Acidophil stem cell tumour. Postcontrast sagittal MRI showing a predominant pattern of invasion inferiorly.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Sheets of pleomorphic, chromophobic to slightly acidophilic cells with clear vacuoles.
Acidophil stem cell tumour. Prolactin positivity is seen in many, but not all, tumour cells.
Acidophil stem cell tumour. Focal weak positivity for growth hormone, with intense staining of entrapped non-neoplastic cells.
Acidophil stem cell tumour. A CAM5.2 cytokeratin immunostain highlights scattered fibrous bodies.
Acidophil stem cell tumour. Diffuse PIT1 immunoreactivity.
Acidophil stem cell tumour. An antimitochondrial antigen immunostain highlights the oncocytic changes (increased mitochondria), and the rimmed vacuoles are suggestive of giant mitochondria.

Q: Microscopically, Immature PIT1-lineage PitNET/adenoma is characterized by diffuse to nodular proliferations of polygonal to spindle-shaped cells displaying marked nuclear atypia, macronucleoli, and characteristic [...].
Immature PIT1-lineage PitNET/adenoma. Large pleomorphic cells forming sheets and nests.
Immature PIT1-lineage PitNET/adenoma. Note the nuclear pseudoinclusions and large nucleoli.
A: intranuclear cytoplasmic pseudoinclusions
Back Extra: Immature PIT1-lineage PitNET/adenoma
- Clinical: The majority of immature PIT1-lineage PitNET/adenomas are clinically non-functioning, but up to 30% can show hormone excess, including hyperthyroidism, acromegaly, galactorrhoea, amenorrhoea, and hyperprolactinaemia.
- Micro: Immature PIT1-lineage PitNET/adenomas are characterized by diffuse to nodular proliferations of polygonal to spindle-shaped cells with marked nuclear atypia, intranuclear cytoplasmic pseudoinclusions, and macronucleoli.
- Ancillary: These tumours are diffusely PIT1-immunoreactive, with variable but usually limited expression of TSH, growth hormone, and/or prolactin, and often show diffuse α-subunit, ER, and GATA3 expression.
Reference Gallery:
Immature PIT1-lineage PitNET/adenoma. Large pleomorphic cells forming sheets and nests.
Immature PIT1-lineage PitNET/adenoma. Note the nuclear pseudoinclusions and large nucleoli.
Immature PIT1-lineage PitNET/adenoma. Diffuse PIT1 immunoreactivity.
Immature PIT1-lineage PitNET/adenoma. Patchy TSH positivity.
Immature PIT1-lineage PitNET/adenoma. Limited prolactin positivity.

Q: Immunohistochemically, Immature PIT1-lineage PitNET/adenoma demonstrates diffuse, strong nuclear expression of [...], while expression of downstream hormones like TSH, growth hormone, and prolactin is typically variable and limited.
Immature PIT1-lineage PitNET/adenoma. Diffuse PIT1 immunoreactivity.
Immature PIT1-lineage PitNET/adenoma. Patchy TSH positivity.
Immature PIT1-lineage PitNET/adenoma. Limited prolactin positivity.
A: PIT1
Back Extra: Immature PIT1-lineage PitNET/adenoma
- Clinical: The majority of immature PIT1-lineage PitNET/adenomas are clinically non-functioning, but up to 30% can show hormone excess, including hyperthyroidism, acromegaly, galactorrhoea, amenorrhoea, and hyperprolactinaemia.
- Micro: Immature PIT1-lineage PitNET/adenomas are characterized by diffuse to nodular proliferations of polygonal to spindle-shaped cells with marked nuclear atypia, intranuclear cytoplasmic pseudoinclusions, and macronucleoli.
- Ancillary: These tumours are diffusely PIT1-immunoreactive, with variable but usually limited expression of TSH, growth hormone, and/or prolactin, and often show diffuse α-subunit, ER, and GATA3 expression.
Reference Gallery:
Immature PIT1-lineage PitNET/adenoma. Large pleomorphic cells forming sheets and nests.
Immature PIT1-lineage PitNET/adenoma. Note the nuclear pseudoinclusions and large nucleoli.
Immature PIT1-lineage PitNET/adenoma. Diffuse PIT1 immunoreactivity.
Immature PIT1-lineage PitNET/adenoma. Patchy TSH positivity.
Immature PIT1-lineage PitNET/adenoma. Limited prolactin positivity.

Q: A patient presents with acromegaly, hyperthyroidism, and/or hyperprolactinemia. Resection of the pituitary tumor reveals a solid or sinusoidal growth pattern predominantly composed of acidophilic cells with interspersed chromophobes. This clinico-pathologic profile is characteristic of [...].
Mature plurihormonal PIT1-lineage PitNET/adenoma. Sagittal postcontrast T1-weighted MRI reveals a modest-sized intrasellar tumour, without evidence of invasion into adjacent structures.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Mostly acidophilic cells are seen, with scattered chromophobe cells. Clinically, this patient presented with acromegaly.
A: Mature Plurihormonal PIT1-lineage PitNET/Adenoma
Back Extra: Mature Plurihormonal PIT1-lineage PitNET/Adenoma
- Clinical: Patients with mature plurihormonal PIT1-lineage PitNET/adenoma typically present with acromegaly, hyperthyroidism, and/or hyperprolactinaemia.
- Micro: The tumour shows a solid or sinusoidal growth pattern, predominantly composed of acidophilic cells with interspersed chromophobes.
- Ancillary: Immunohistochemistry reveals diffuse nuclear positivity for PIT1, extensive cytoplasmic positivity for GH, and variable positivity for prolactin and TSH.
Reference Gallery:
Mature plurihormonal PIT1-lineage PitNET/adenoma. Sagittal postcontrast T1-weighted MRI reveals a modest-sized intrasellar tumour, without evidence of invasion into adjacent structures.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Mostly acidophilic cells are seen, with scattered chromophobe cells. Clinically, this patient presented with acromegaly.
Mature plurihormonal PIT1-lineage PitNET/adenoma. A growth hormone immunostain shows expression in most, but not all, tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. A prolactin stain highlights a subset of tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Scattered tumour cells are immunoreactive for TSH.
Mature plurihormonal PIT1-lineage PitNET/adenoma. An immunostain for PIT1 displays diffuse nuclear positivity in tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. There is strong and diffuse SSTR2A immunoreactivity in tumour cells.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET composed mostly of acidophilic tumour cells, in a patient with acromegaly.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with extensive expression of growth hormone.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with extensive expression of prolactin.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with expression of TSH in scattered tumour cells.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with nuclear expression of PIT1 in tumour cells.

Q: The defining immunohistochemical profile of Mature Plurihormonal PIT1-lineage PitNET/Adenoma involves diffuse nuclear positivity for the transcription factor [...], combined with extensive cytoplasmic positivity for growth hormone (GH) and variable expression of prolactin and TSH.
Mature plurihormonal PIT1-lineage PitNET/adenoma. An immunostain for PIT1 displays diffuse nuclear positivity in tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. A growth hormone immunostain shows expression in most, but not all, tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Scattered tumour cells are immunoreactive for TSH.
A: PIT1
Back Extra: Mature Plurihormonal PIT1-lineage PitNET/Adenoma
- Clinical: Patients with mature plurihormonal PIT1-lineage PitNET/adenoma typically present with acromegaly, hyperthyroidism, and/or hyperprolactinaemia.
- Micro: The tumour shows a solid or sinusoidal growth pattern, predominantly composed of acidophilic cells with interspersed chromophobes.
- Ancillary: Immunohistochemistry reveals diffuse nuclear positivity for PIT1, extensive cytoplasmic positivity for GH, and variable positivity for prolactin and TSH.
Reference Gallery:
Mature plurihormonal PIT1-lineage PitNET/adenoma. Sagittal postcontrast T1-weighted MRI reveals a modest-sized intrasellar tumour, without evidence of invasion into adjacent structures.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Mostly acidophilic cells are seen, with scattered chromophobe cells. Clinically, this patient presented with acromegaly.
Mature plurihormonal PIT1-lineage PitNET/adenoma. A growth hormone immunostain shows expression in most, but not all, tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. A prolactin stain highlights a subset of tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. Scattered tumour cells are immunoreactive for TSH.
Mature plurihormonal PIT1-lineage PitNET/adenoma. An immunostain for PIT1 displays diffuse nuclear positivity in tumour cells.
Mature plurihormonal PIT1-lineage PitNET/adenoma. There is strong and diffuse SSTR2A immunoreactivity in tumour cells.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET composed mostly of acidophilic tumour cells, in a patient with acromegaly.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with extensive expression of growth hormone.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with extensive expression of prolactin.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with expression of TSH in scattered tumour cells.
Mature plurihormonal PIT1-lineage PitNET. A mature plurihormonal PIT1-lineage PitNET with nuclear expression of PIT1 in tumour cells.

Q: Histologically, a [...] is a biphasic tumor composed of two distinct cell populations: large, eosinophilic, densely granulated somatotrophs intermixed with smaller, chromophobic, sparsely granulated lactotrophs.
Mixed somatotroph–lactotroph PitNET/adenoma. Such tumours consist of two cell populations of large, eosinophilic somatotroph cells intermixed with smaller, chromophobic lactotroph cells that may be distinguished by H&E.
A: Mixed somatotroph–lactotroph PitNET/adenoma
Back Extra: Mixed somatotroph–lactotroph PitNET/adenoma
- Clinical: Most mixed somatotroph–lactotroph PitNET/adenomas are clinically functioning tumours causing gigantism and/or acromegaly and hyperprolactinaemia.
- Micro: These tumours are composed of two distinct cell populations: large, eosinophilic, densely granulated somatotrophs and chromophobic, sparsely granulated lactotrophs.
- Ancillary: Somatotroph cells are immunoreactive for GH, while lactotroph cells are immunoreactive for prolactin and ER.
Reference Gallery:
Mixed somatotroph–lactotroph PitNET/adenoma. Such tumours consist of two cell populations of large, eosinophilic somatotroph cells intermixed with smaller, chromophobic lactotroph cells that may be distinguished by H&E.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for growth hormone.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for prolactin.
Mixed somatotroph–lactotroph PitNET/adenoma. ER immunoreactivity is observed in lactotroph cells, whereas the somatotroph cells with larger nuclei are negative (arrows).
Mixed somatotroph–lactotroph PitNET/adenoma, X-linked acrogigantism–associated. A mixed somatotroph–lactotroph adenoma in a young female patient with gigantism and a somatic GPR101 duplication. Pathology showed a bicellular tumour with distinct somatotroph and lactotroph cells.

Q: In Mixed somatotroph–lactotroph PitNET/adenoma, immunohistochemistry highlights two distinct populations: the somatotrophs are immunoreactive for GH, while the lactotrophs are uniquely immunoreactive for prolactin and [...].
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for growth hormone.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for prolactin.
Mixed somatotroph–lactotroph PitNET/adenoma. ER immunoreactivity is observed in lactotroph cells, whereas the somatotroph cells with larger nuclei are negative (arrows).
A: ER
Back Extra: Mixed somatotroph–lactotroph PitNET/adenoma
- Clinical: Most mixed somatotroph–lactotroph PitNET/adenomas are clinically functioning tumours causing gigantism and/or acromegaly and hyperprolactinaemia.
- Micro: These tumours are composed of two distinct cell populations: large, eosinophilic, densely granulated somatotrophs and chromophobic, sparsely granulated lactotrophs.
- Ancillary: Somatotroph cells are immunoreactive for GH, while lactotroph cells are immunoreactive for prolactin and ER.
Reference Gallery:
Mixed somatotroph–lactotroph PitNET/adenoma. Such tumours consist of two cell populations of large, eosinophilic somatotroph cells intermixed with smaller, chromophobic lactotroph cells that may be distinguished by H&E.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for growth hormone.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for prolactin.
Mixed somatotroph–lactotroph PitNET/adenoma. ER immunoreactivity is observed in lactotroph cells, whereas the somatotroph cells with larger nuclei are negative (arrows).
Mixed somatotroph–lactotroph PitNET/adenoma, X-linked acrogigantism–associated. A mixed somatotroph–lactotroph adenoma in a young female patient with gigantism and a somatic GPR101 duplication. Pathology showed a bicellular tumour with distinct somatotroph and lactotroph cells.

Q: A Mixed somatotroph–lactotroph PitNET/adenoma presenting with early-onset gigantism (X-linked acrogigantism) in a young female patient may be associated with somatic duplications in the [...] gene.
Mixed somatotroph–lactotroph PitNET/adenoma, X-linked acrogigantism–associated. A mixed somatotroph–lactotroph adenoma in a young female patient with gigantism and a somatic GPR101 duplication. Pathology showed a bicellular tumour with distinct somatotroph and lactotroph cells.
A: GPR101
Back Extra: Mixed somatotroph–lactotroph PitNET/adenoma
- Clinical: Most mixed somatotroph–lactotroph PitNET/adenomas are clinically functioning tumours causing gigantism and/or acromegaly and hyperprolactinaemia.
- Micro: These tumours are composed of two distinct cell populations: large, eosinophilic, densely granulated somatotrophs and chromophobic, sparsely granulated lactotrophs.
- Ancillary: Somatotroph cells are immunoreactive for GH, while lactotroph cells are immunoreactive for prolactin and ER.
Reference Gallery:
Mixed somatotroph–lactotroph PitNET/adenoma. Such tumours consist of two cell populations of large, eosinophilic somatotroph cells intermixed with smaller, chromophobic lactotroph cells that may be distinguished by H&E.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for growth hormone.
Mixed somatotroph–lactotroph PitNET/adenoma. Distinct cell populations are immunoreactive for prolactin.
Mixed somatotroph–lactotroph PitNET/adenoma. ER immunoreactivity is observed in lactotroph cells, whereas the somatotroph cells with larger nuclei are negative (arrows).
Mixed somatotroph–lactotroph PitNET/adenoma, X-linked acrogigantism–associated. A mixed somatotroph–lactotroph adenoma in a young female patient with gigantism and a somatic GPR101 duplication. Pathology showed a bicellular tumour with distinct somatotroph and lactotroph cells.

Q: The defining immunohistochemical feature of a plurihormonal PitNET/adenoma is the coexpression of hormones and transcription factors (such as PIT1 and SF1) belonging to at least [...] different pituitary cell lineages.
Plurihormonal PitNET/adenoma. There is coexpression of PIT1 (shown here) and SF1 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. There is coexpression of SF1 (shown here) and PIT1 in tumour cells of a plurihormonal PitNET/adenoma.
A: two
Back Extra: Plurihormonal PitNET/adenoma
- Clinical: Plurihormonal PitNET/adenomas may cause clinical symptoms due to hypersecretion of any or all hormones expressed in the tumour cells, or they may be clinically non-functioning.
- Micro: The microscopic appearance of plurihormonal PitNET/adenoma is similar to that of its individual cell lineages, with coexpression of transcription factors PIT1 and SF1, and associated hormones such as growth hormone, prolactin, TSH, and LH.
- Ancillary: Immunohistochemistry shows essential coexpression of adenohypophysial hormones and transcription factors belonging to at least two different pituitary cell lineages.
Reference Gallery:
Plurihormonal PitNET/adenoma. A case of plurihormonal PitNET composed mainly of acidophilic tumour cells, in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Extensive expression of growth hormone in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Positivity for prolactin in a subset of tumour cells in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Positivity for TSH in a subset of tumour cells in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Focal LH expression in a plurihormonal PitNET/adenoma in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Expression of the α-subunit of glycoprotein hormones in a plurihormonal PitNET/adenoma in a patient with acromegaly.
Plurihormonal PitNET/adenoma. There is coexpression of PIT1 (shown here) and SF1 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. There is coexpression of SF1 (shown here) and PIT1 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Low cell proliferation, with only a few cells positive for Ki-67, in a case of plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong membranous expression of SSTR2A in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong, mainly cytoplasmic expression of SSTR3 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong membranous expression of SSTR5 in tumour cells of a plurihormonal PitNET/adenoma.

Q: A pituitary tumor demonstrating unusual coexpression of transcription factors and hormones from multiple distinct lineages (e.g., PIT1 with growth hormone, alongside SF1 with luteinizing hormone) is diagnostic of a [...].
Plurihormonal PitNET/adenoma. Extensive expression of growth hormone in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Focal LH expression in a plurihormonal PitNET/adenoma in a patient with acromegaly.
A: plurihormonal PitNET/adenoma
Back Extra: Plurihormonal PitNET/adenoma
- Clinical: Plurihormonal PitNET/adenomas may cause clinical symptoms due to hypersecretion of any or all hormones expressed in the tumour cells, or they may be clinically non-functioning.
- Micro: The microscopic appearance of plurihormonal PitNET/adenoma is similar to that of its individual cell lineages, with coexpression of transcription factors PIT1 and SF1, and associated hormones such as growth hormone, prolactin, TSH, and LH.
- Ancillary: Immunohistochemistry shows essential coexpression of adenohypophysial hormones and transcription factors belonging to at least two different pituitary cell lineages.
Reference Gallery:
Plurihormonal PitNET/adenoma. A case of plurihormonal PitNET composed mainly of acidophilic tumour cells, in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Extensive expression of growth hormone in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Positivity for prolactin in a subset of tumour cells in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Positivity for TSH in a subset of tumour cells in a plurihormonal PitNET in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Focal LH expression in a plurihormonal PitNET/adenoma in a patient with acromegaly.
Plurihormonal PitNET/adenoma. Expression of the α-subunit of glycoprotein hormones in a plurihormonal PitNET/adenoma in a patient with acromegaly.
Plurihormonal PitNET/adenoma. There is coexpression of PIT1 (shown here) and SF1 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. There is coexpression of SF1 (shown here) and PIT1 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Low cell proliferation, with only a few cells positive for Ki-67, in a case of plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong membranous expression of SSTR2A in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong, mainly cytoplasmic expression of SSTR3 in tumour cells of a plurihormonal PitNET/adenoma.
Plurihormonal PitNET/adenoma. Strong membranous expression of SSTR5 in tumour cells of a plurihormonal PitNET/adenoma.

Q: Histologically, a Sellar Neurocytoma consists of lobules of uniform tumor cells with small round nuclei and clear cytoplasm embedded in a rich, [...] matrix.
Neurocytoma. The tumour is composed of lobules of uniform neoplastic cells in a rich fibrillar neuropil.
Neurocytoma. The tumour cells have small round nuclei, often with finely speckled chromatin and clear cytoplasm that merges with the fibrillary matrix.
A: fibrillar neuropil
Back Extra: Sellar Neurocytoma
- Clinical: Patients often present with visual disturbances and hypothalamic–pituitary dysfunction, including galactorrhoea, menstrual irregularities, and infertility due to prolactin excess.
- Micro: Histologically, tumour cells have small round nuclei with finely speckled chromatin and clear cytoplasm embedded in a fibrillar neuropil matrix.
- Ancillary: Immunohistochemistry shows diffuse positivity for synaptophysin, neurofilament, and chromogranin A, with focal NeuN and TTF1 expression.
Reference Gallery:
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T1-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T2-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. The tumour is composed of lobules of uniform neoplastic cells in a rich fibrillar neuropil.
Neurocytoma. The tumour cells have small round nuclei, often with finely speckled chromatin and clear cytoplasm that merges with the fibrillary matrix.
Neurocytoma. The tumour cells are strongly positive for neurofilament.
Neurocytoma. Chromogranin A is diffusely positive and highlights axonal terminals that resemble the Herring bodies of the normal posterior pituitary.
Neurocytoma. Tumour cell nuclei stain for NeuN, confirming neuronal differentiation.
Neurocytoma. Thyroid transcription factor 1 (TTF1) reactivity is variable and is a feature of tumours of the basal hypothalamus.
Neurocytoma. Vasopressin reactivity is very strong, especially in axon terminals resembling Herring bodies.

Q: In Sellar Neurocytoma, immunohistochemistry for chromogranin A and vasopressin frequently highlights swollen axonal terminals that morphologically resemble [...] of the normal posterior pituitary.
Neurocytoma. Chromogranin A is diffusely positive and highlights axonal terminals that resemble the Herring bodies of the normal posterior pituitary.
Neurocytoma. Vasopressin reactivity is very strong, especially in axon terminals resembling Herring bodies.
A: Herring bodies
Back Extra: Sellar Neurocytoma
- Clinical: Patients often present with visual disturbances and hypothalamic–pituitary dysfunction, including galactorrhoea, menstrual irregularities, and infertility due to prolactin excess.
- Micro: Histologically, tumour cells have small round nuclei with finely speckled chromatin and clear cytoplasm embedded in a fibrillar neuropil matrix.
- Ancillary: Immunohistochemistry shows diffuse positivity for synaptophysin, neurofilament, and chromogranin A, with focal NeuN and TTF1 expression.
Reference Gallery:
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T1-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T2-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. The tumour is composed of lobules of uniform neoplastic cells in a rich fibrillar neuropil.
Neurocytoma. The tumour cells have small round nuclei, often with finely speckled chromatin and clear cytoplasm that merges with the fibrillary matrix.
Neurocytoma. The tumour cells are strongly positive for neurofilament.
Neurocytoma. Chromogranin A is diffusely positive and highlights axonal terminals that resemble the Herring bodies of the normal posterior pituitary.
Neurocytoma. Tumour cell nuclei stain for NeuN, confirming neuronal differentiation.
Neurocytoma. Thyroid transcription factor 1 (TTF1) reactivity is variable and is a feature of tumours of the basal hypothalamus.
Neurocytoma. Vasopressin reactivity is very strong, especially in axon terminals resembling Herring bodies.

Q: The tumor cells of a Sellar Neurocytoma show characteristic nuclear reactivity for neuronal markers like NeuN, alongside variable expression of [...], which indicates an origin from the basal hypothalamus.
Neurocytoma. Tumour cell nuclei stain for NeuN, confirming neuronal differentiation.
Neurocytoma. Thyroid transcription factor 1 (TTF1) reactivity is variable and is a feature of tumours of the basal hypothalamus.
A: thyroid transcription factor 1 (TTF1)
Back Extra: Sellar Neurocytoma
- Clinical: Patients often present with visual disturbances and hypothalamic–pituitary dysfunction, including galactorrhoea, menstrual irregularities, and infertility due to prolactin excess.
- Micro: Histologically, tumour cells have small round nuclei with finely speckled chromatin and clear cytoplasm embedded in a fibrillar neuropil matrix.
- Ancillary: Immunohistochemistry shows diffuse positivity for synaptophysin, neurofilament, and chromogranin A, with focal NeuN and TTF1 expression.
Reference Gallery:
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T1-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. MRI of a neurocytoma in the sellar region. The large mass is heterogeneous on T2-weighted MRI. The predominant component is in the suprasellar space, with extension into the right cavernous sinus and circumferential involvement of the carotid. Note that the sella itself is only minimally enlarged.
Neurocytoma. The tumour is composed of lobules of uniform neoplastic cells in a rich fibrillar neuropil.
Neurocytoma. The tumour cells have small round nuclei, often with finely speckled chromatin and clear cytoplasm that merges with the fibrillary matrix.
Neurocytoma. The tumour cells are strongly positive for neurofilament.
Neurocytoma. Chromogranin A is diffusely positive and highlights axonal terminals that resemble the Herring bodies of the normal posterior pituitary.
Neurocytoma. Tumour cell nuclei stain for NeuN, confirming neuronal differentiation.
Neurocytoma. Thyroid transcription factor 1 (TTF1) reactivity is variable and is a feature of tumours of the basal hypothalamus.
Neurocytoma. Vasopressin reactivity is very strong, especially in axon terminals resembling Herring bodies.

Q: The defining histologic feature of Gangliocytoma and mixed gangliocytoma-PitNET/adenoma is the presence of large, mature [...] within a fibrillary matrix resembling neuropil, often admixed with uniform epithelial cells.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Ganglion cells resembling those of the hypothalamic magnocellular nuclei are dispersed within a rich neuropil and admixed with small round epithelial cells of a somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma. Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells.
A: ganglion cells
Back Extra: Gangliocytoma and mixed gangliocytoma-PitNET/adenoma
- Clinical: Headache and visual impairment are common at onset. Acromegaly and hyperprolactinaemia are the most frequent hormonal dysfunctions.
- Micro: Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells. The proportion of ganglion cells and the fibrillary matrix varies among cases.
- Ancillary: The molecular profile has not been investigated, but immunohistochemistry shows expression of synaptophysin, NeuN, NSE, NFPs, and MAP2 in ganglion cells.
Reference Gallery:
Mixed gangliocytoma–adenoma/PitNET. This postcontrast sagittal T1-weighted image shows a sellar tumour extending downward into the sphenoidal sinus.
Mixed gangliocytoma–adenoma/PitNET. The lesion has a cystic component, evidenced in this coronal T2-weighted sequence.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. CAM5.2 immunohistochemistry decorates fibrous bodies in the somatotroph component, confirming that this is a sparsely granulated somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Growth hormone immunohistochemistry shows variable positivity in the somatotrophs.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. PIT1 immunohistochemistry yields strong nuclear staining in the somatotroph component.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Ganglion cells resembling those of the hypothalamic magnocellular nuclei are dispersed within a rich neuropil and admixed with small round epithelial cells of a somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma. Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells.
Gangliocytoma. The tumour was associated with acromegaly, without a PitNET.

Q: When Gangliocytoma and mixed gangliocytoma-PitNET/adenoma features a sparsely granulated somatotroph tumor component, the epithelial cells typically contain fibrous bodies that are highlighted by [...] immunohistochemistry.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. CAM5.2 immunohistochemistry decorates fibrous bodies in the somatotroph component, confirming that this is a sparsely granulated somatotroph tumour.
A: CAM5.2
Back Extra: Gangliocytoma and mixed gangliocytoma-PitNET/adenoma
- Clinical: Headache and visual impairment are common at onset. Acromegaly and hyperprolactinaemia are the most frequent hormonal dysfunctions.
- Micro: Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells. The proportion of ganglion cells and the fibrillary matrix varies among cases.
- Ancillary: The molecular profile has not been investigated, but immunohistochemistry shows expression of synaptophysin, NeuN, NSE, NFPs, and MAP2 in ganglion cells.
Reference Gallery:
Mixed gangliocytoma–adenoma/PitNET. This postcontrast sagittal T1-weighted image shows a sellar tumour extending downward into the sphenoidal sinus.
Mixed gangliocytoma–adenoma/PitNET. The lesion has a cystic component, evidenced in this coronal T2-weighted sequence.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. CAM5.2 immunohistochemistry decorates fibrous bodies in the somatotroph component, confirming that this is a sparsely granulated somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Growth hormone immunohistochemistry shows variable positivity in the somatotrophs.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. PIT1 immunohistochemistry yields strong nuclear staining in the somatotroph component.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Ganglion cells resembling those of the hypothalamic magnocellular nuclei are dispersed within a rich neuropil and admixed with small round epithelial cells of a somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma. Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells.
Gangliocytoma. The tumour was associated with acromegaly, without a PitNET.

Q: In cases of Gangliocytoma and mixed gangliocytoma-PitNET/adenoma that are associated with a somatotroph tumor, the epithelial component will demonstrate strong nuclear staining for the lineage-specific transcription factor [...].
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. PIT1 immunohistochemistry yields strong nuclear staining in the somatotroph component.
A: PIT1
Back Extra: Gangliocytoma and mixed gangliocytoma-PitNET/adenoma
- Clinical: Headache and visual impairment are common at onset. Acromegaly and hyperprolactinaemia are the most frequent hormonal dysfunctions.
- Micro: Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells. The proportion of ganglion cells and the fibrillary matrix varies among cases.
- Ancillary: The molecular profile has not been investigated, but immunohistochemistry shows expression of synaptophysin, NeuN, NSE, NFPs, and MAP2 in ganglion cells.
Reference Gallery:
Mixed gangliocytoma–adenoma/PitNET. This postcontrast sagittal T1-weighted image shows a sellar tumour extending downward into the sphenoidal sinus.
Mixed gangliocytoma–adenoma/PitNET. The lesion has a cystic component, evidenced in this coronal T2-weighted sequence.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. CAM5.2 immunohistochemistry decorates fibrous bodies in the somatotroph component, confirming that this is a sparsely granulated somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Growth hormone immunohistochemistry shows variable positivity in the somatotrophs.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. PIT1 immunohistochemistry yields strong nuclear staining in the somatotroph component.
Mixed gangliocytoma–PitNET/adenoma: gangliocytoma with sparsely granulated somatotroph tumour. Ganglion cells resembling those of the hypothalamic magnocellular nuclei are dispersed within a rich neuropil and admixed with small round epithelial cells of a somatotroph tumour.
Mixed gangliocytoma–PitNET/adenoma. Ganglion cells in a fibrillary matrix resembling neuropil are admixed with groups of uniform epithelial cells.
Gangliocytoma. The tumour was associated with acromegaly, without a PitNET.

Q: Microscopically, a Mammosomatotroph PitNET/adenoma consists of a monomorphic cell population with densely eosinophilic cytoplasm containing secretory granules that co-express both growth hormone (GH) and [...].
Mammosomatotroph tumour. The tumour consists of a monomorphic (single cell type) cell population with densely eosinophilic (acidophilic) cytoplasm.
Mammosomatotroph tumour. These tumours consist of a monomorphic cell population with both growth hormone–containing and prolactin-containing secretory granules. The extent of prolactin immunoreactivity (shown here) is usually smaller than that of growth hormone.
A: prolactin
Back Extra: Mammosomatotroph PitNET/adenoma
- Clinical: Mammosomatotroph PitNET/adenomas often present with elevated growth hormone (GH) and IGF1 levels, but lower serum prolactin levels compared to mixed lactotroph and somatotroph tumours.
- Micro: These tumours consist of a monomorphic cell population with densely eosinophilic cytoplasm containing secretory granules with both GH and prolactin.
- Ancillary: Mammosomatotroph PitNET/adenomas are positive for PIT1, ER, GH, prolactin, and α-subunit, and show near-diffuse CAM5.2 immunoreactivity.
Reference Gallery:
Mammosomatotroph tumour. Preoperative T1-weighted sagittal MRI from a 32-year-old male patient with a microtumour that had a final pathological diagnosis of mammosomatotroph tumour.
Mammosomatotroph tumour. Preoperative T1-weighted coronal MRI from a 32-year-old male patient with a microtumour that had a final pathological diagnosis of mammosomatotroph tumour.
Mammosomatotroph tumour (intraoperative gross findings). A macrotumour extending mainly into the sphenoidal sinus with dural invasion and destruction of the sellar floor, as depicted by the intraoperative photograph.
Mammosomatotroph tumour. The tumour consists of a monomorphic (single cell type) cell population with densely eosinophilic (acidophilic) cytoplasm.
Mammosomatotroph tumour. These tumours are diffusely positive for the transcription factor PIT1.
Mammosomatotroph tumour. Unlike somatotroph tumours, mammosomatotroph tumours often show near-diffuse ER expression.
Mammosomatotroph tumour. These tumours are composed of a single monomorphic cell population that often shows diffuse growth hormone immunoreactivity.
Mammosomatotroph tumour. These tumours consist of a monomorphic cell population with both growth hormone–containing and prolactin-containing secretory granules. The extent of prolactin immunoreactivity (shown here) is usually smaller than that of growth hormone.
Mammosomatotroph tumour. Unlike lactotroph tumours, mammosomatotroph tumours often show α-subunit immunoreactivity.
Mammosomatotroph tumour. Similarly to densely granulated somatotroph tumours, mammosomatotroph tumours show perinuclear CAM5.2 immunoreactivity.

Q: By immunohistochemistry, a Mammosomatotroph PitNET/adenoma is driven by the PIT1 transcription factor and characteristically exhibits near-diffuse expression of [...], which helps distinguish it from pure somatotroph tumors.
Mammosomatotroph tumour. These tumours are diffusely positive for the transcription factor PIT1.
Mammosomatotroph tumour. Unlike somatotroph tumours, mammosomatotroph tumours often show near-diffuse ER expression.
A: estrogen receptor (ER)
Back Extra: Mammosomatotroph PitNET/adenoma
- Clinical: Mammosomatotroph PitNET/adenomas often present with elevated growth hormone (GH) and IGF1 levels, but lower serum prolactin levels compared to mixed lactotroph and somatotroph tumours.
- Micro: These tumours consist of a monomorphic cell population with densely eosinophilic cytoplasm containing secretory granules with both GH and prolactin.
- Ancillary: Mammosomatotroph PitNET/adenomas are positive for PIT1, ER, GH, prolactin, and α-subunit, and show near-diffuse CAM5.2 immunoreactivity.
Reference Gallery:
Mammosomatotroph tumour. Preoperative T1-weighted sagittal MRI from a 32-year-old male patient with a microtumour that had a final pathological diagnosis of mammosomatotroph tumour.
Mammosomatotroph tumour. Preoperative T1-weighted coronal MRI from a 32-year-old male patient with a microtumour that had a final pathological diagnosis of mammosomatotroph tumour.
Mammosomatotroph tumour (intraoperative gross findings). A macrotumour extending mainly into the sphenoidal sinus with dural invasion and destruction of the sellar floor, as depicted by the intraoperative photograph.
Mammosomatotroph tumour. The tumour consists of a monomorphic (single cell type) cell population with densely eosinophilic (acidophilic) cytoplasm.
Mammosomatotroph tumour. These tumours are diffusely positive for the transcription factor PIT1.
Mammosomatotroph tumour. Unlike somatotroph tumours, mammosomatotroph tumours often show near-diffuse ER expression.
Mammosomatotroph tumour. These tumours are composed of a single monomorphic cell population that often shows diffuse growth hormone immunoreactivity.
Mammosomatotroph tumour. These tumours consist of a monomorphic cell population with both growth hormone–containing and prolactin-containing secretory granules. The extent of prolactin immunoreactivity (shown here) is usually smaller than that of growth hormone.
Mammosomatotroph tumour. Unlike lactotroph tumours, mammosomatotroph tumours often show α-subunit immunoreactivity.
Mammosomatotroph tumour. Similarly to densely granulated somatotroph tumours, mammosomatotroph tumours show perinuclear CAM5.2 immunoreactivity.

Q: In Somatotroph PitNET/adenoma, the densely granulated subtype is morphologically characterized by abundant eosinophilic cytoplasm and demonstrates diffuse immunohistochemical positivity for [...].
Somatotroph PitNET/adenoma. This densely granulated somatotroph tumour is composed of cells that have abundant eosinophilic (acidophilic) cytoplasm.
Somatotroph PitNET/adenoma. Densely granulated somatotroph tumour showing diffuse positivity for growth hormone, a finding consistent with the dense content of growth hormone–containing secretory granules in these tumours.
A: growth hormone
Back Extra: Somatotroph PitNET/adenoma
- Clinical: Somatotroph PitNET/adenomas often cause acromegaly and gigantism, with a median delay of 8 years from first symptoms to diagnosis.
- Micro: Densely granulated somatotroph tumours show abundant eosinophilic cytoplasm and diffuse positivity for growth hormone, while sparsely granulated tumours have chromophobic to pale eosinophilic cytoplasm and abundant fibrous bodies.
- Ancillary: Densely granulated somatotroph tumours typically show high expression of SSTR2 and SSTR5, indicating a good response to somatostatin analogues.
Reference Gallery:
Molecular pathogenesis of somatotroph tumours. Sporadic or germline activating mutations in GNAS result in the constitutive activation of Gsα, which upregulates adenylyl cyclase, resulting in increased cAMP, causing the phosphorylation of CREB and the synthesis of growth hormone and α-subunit. In patients with Carney complex, mutations inactivating PRKAR1A have the same effect by enhancing CREB activation. Tumours with these alterations have a densely granulated phenotype and respond well to somatostatin analogue therapy that reduces cAMP. In contrast, changes shown on the right, including AIP mutation or silencing, GHR inactivation, or other mechanisms of reducing STAT signalling, result in sparsely granulated somatotroph tumours that have fibrous bodies.
Somatotroph PitNET/adenoma. Scattered fibrous bodies in the background of predominant perinuclear CAM5.2 expression in a densely granulated somatotroph tumour. The term “intermediate-type somatotroph tumour” has been proposed for a subset of densely granulated somatotroph tumours that display occasional fibrous bodies. These tumours are considered within the morphological spectrum of densely granulated somatotroph tumours.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Densely granulated somatotroph tumour.
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Densely granulated somatotroph tumours often show T2 hypointensity.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case).
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case) that often show T2 hyperintensity.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR2. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR5. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows reduced reactivity for SSTR2. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows strong reactivity for SSTR5. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This densely granulated somatotroph tumour is composed of cells that have abundant eosinophilic (acidophilic) cytoplasm.
Somatotroph PitNET/adenoma. Densely granulated somatotroph tumour showing diffuse positivity for growth hormone, a finding consistent with the dense content of growth hormone–containing secretory granules in these tumours.

Q: Densely granulated Somatotroph PitNET/adenomas characteristically show high expression of SSTR2 and SSTR5, which predicts a favorable therapeutic response to [...].
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR2. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR5. This patient had a good response to first-line somatostatin analogues.
A: somatostatin analogs
Back Extra: Somatotroph PitNET/adenoma
- Clinical: Somatotroph PitNET/adenomas often cause acromegaly and gigantism, with a median delay of 8 years from first symptoms to diagnosis.
- Micro: Densely granulated somatotroph tumours show abundant eosinophilic cytoplasm and diffuse positivity for growth hormone, while sparsely granulated tumours have chromophobic to pale eosinophilic cytoplasm and abundant fibrous bodies.
- Ancillary: Densely granulated somatotroph tumours typically show high expression of SSTR2 and SSTR5, indicating a good response to somatostatin analogues.
Reference Gallery:
Molecular pathogenesis of somatotroph tumours. Sporadic or germline activating mutations in GNAS result in the constitutive activation of Gsα, which upregulates adenylyl cyclase, resulting in increased cAMP, causing the phosphorylation of CREB and the synthesis of growth hormone and α-subunit. In patients with Carney complex, mutations inactivating PRKAR1A have the same effect by enhancing CREB activation. Tumours with these alterations have a densely granulated phenotype and respond well to somatostatin analogue therapy that reduces cAMP. In contrast, changes shown on the right, including AIP mutation or silencing, GHR inactivation, or other mechanisms of reducing STAT signalling, result in sparsely granulated somatotroph tumours that have fibrous bodies.
Somatotroph PitNET/adenoma. Scattered fibrous bodies in the background of predominant perinuclear CAM5.2 expression in a densely granulated somatotroph tumour. The term “intermediate-type somatotroph tumour” has been proposed for a subset of densely granulated somatotroph tumours that display occasional fibrous bodies. These tumours are considered within the morphological spectrum of densely granulated somatotroph tumours.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Densely granulated somatotroph tumour.
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Densely granulated somatotroph tumours often show T2 hypointensity.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case).
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case) that often show T2 hyperintensity.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR2. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR5. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows reduced reactivity for SSTR2. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows strong reactivity for SSTR5. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This densely granulated somatotroph tumour is composed of cells that have abundant eosinophilic (acidophilic) cytoplasm.
Somatotroph PitNET/adenoma. Densely granulated somatotroph tumour showing diffuse positivity for growth hormone, a finding consistent with the dense content of growth hormone–containing secretory granules in these tumours.

Q: On plain T2-weighted MRI, the densely granulated subtype of Somatotroph PitNET/adenoma typically demonstrates relative [...], contrasting with sparsely granulated tumors which are often hyperintense and invasive.
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Densely granulated somatotroph tumours often show T2 hypointensity.
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case) that often show T2 hyperintensity.
A: hypointensity
Back Extra: Somatotroph PitNET/adenoma
- Clinical: Somatotroph PitNET/adenomas often cause acromegaly and gigantism, with a median delay of 8 years from first symptoms to diagnosis.
- Micro: Densely granulated somatotroph tumours show abundant eosinophilic cytoplasm and diffuse positivity for growth hormone, while sparsely granulated tumours have chromophobic to pale eosinophilic cytoplasm and abundant fibrous bodies.
- Ancillary: Densely granulated somatotroph tumours typically show high expression of SSTR2 and SSTR5, indicating a good response to somatostatin analogues.
Reference Gallery:
Molecular pathogenesis of somatotroph tumours. Sporadic or germline activating mutations in GNAS result in the constitutive activation of Gsα, which upregulates adenylyl cyclase, resulting in increased cAMP, causing the phosphorylation of CREB and the synthesis of growth hormone and α-subunit. In patients with Carney complex, mutations inactivating PRKAR1A have the same effect by enhancing CREB activation. Tumours with these alterations have a densely granulated phenotype and respond well to somatostatin analogue therapy that reduces cAMP. In contrast, changes shown on the right, including AIP mutation or silencing, GHR inactivation, or other mechanisms of reducing STAT signalling, result in sparsely granulated somatotroph tumours that have fibrous bodies.
Somatotroph PitNET/adenoma. Scattered fibrous bodies in the background of predominant perinuclear CAM5.2 expression in a densely granulated somatotroph tumour. The term “intermediate-type somatotroph tumour” has been proposed for a subset of densely granulated somatotroph tumours that display occasional fibrous bodies. These tumours are considered within the morphological spectrum of densely granulated somatotroph tumours.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Densely granulated somatotroph tumour.
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Densely granulated somatotroph tumours often show T2 hypointensity.
Somatotroph PitNET/adenoma. Enhanced T1-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case).
Somatotroph PitNET/adenoma. Plain T2-weighted MRI. Sparsely granulated somatotroph tumours tend to be invasive macrotumours (Knosp 4 in this case) that often show T2 hyperintensity.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR2. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. A densely granulated somatotroph tumour showing diffuse strong reactivity for SSTR5. This patient had a good response to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows reduced reactivity for SSTR2. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This sparsely granulated somatotroph tumour shows strong reactivity for SSTR5. This patient did not respond to first-line somatostatin analogues.
Somatotroph PitNET/adenoma. This densely granulated somatotroph tumour is composed of cells that have abundant eosinophilic (acidophilic) cytoplasm.
Somatotroph PitNET/adenoma. Densely granulated somatotroph tumour showing diffuse positivity for growth hormone, a finding consistent with the dense content of growth hormone–containing secretory granules in these tumours.

Q: Histologically, a Thyrotroph PitNET/adenoma typically exhibits diffuse and sinusoidal growth patterns composed of spindled to [...] cells with chromophobic cytoplasm.
Thyrotroph PitNET/adenoma. Sheets of polygonal tumour cells.
A: polygonal
Back Extra: Thyrotroph PitNET/adenoma
- Clinical: Thyrotroph PitNET/adenoma may present with hyperthyroidism, hypothyroidism, or rarely euthyroidism, and often shows signs of mass effect such as headaches and visual deficits.
- Micro: These tumours typically grow in diffuse and sinusoidal patterns, with spindled to polygonal cells and chromophobic cytoplasm.
- Ancillary: Thyrotroph PitNET/adenomas show diffuse PIT1 positivity and extensive TSH immunoreactivity, with variable α-subunit staining.
Reference Gallery:
Thyrotroph PitNET/adenoma. Diffuse nuclear PIT1 immunostaining.
Thyrotroph PitNET/adenoma. Sheets of polygonal tumour cells.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for α-subunit.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for TSH.

Q: Thyrotroph PitNET/adenoma is defined by its specific pituitary lineage, demonstrating diffuse nuclear immunohistochemical positivity for the transcription factor [...].
Thyrotroph PitNET/adenoma. Diffuse nuclear PIT1 immunostaining.
A: PIT1
Back Extra: Thyrotroph PitNET/adenoma
- Clinical: Thyrotroph PitNET/adenoma may present with hyperthyroidism, hypothyroidism, or rarely euthyroidism, and often shows signs of mass effect such as headaches and visual deficits.
- Micro: These tumours typically grow in diffuse and sinusoidal patterns, with spindled to polygonal cells and chromophobic cytoplasm.
- Ancillary: Thyrotroph PitNET/adenomas show diffuse PIT1 positivity and extensive TSH immunoreactivity, with variable α-subunit staining.
Reference Gallery:
Thyrotroph PitNET/adenoma. Diffuse nuclear PIT1 immunostaining.
Thyrotroph PitNET/adenoma. Sheets of polygonal tumour cells.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for α-subunit.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for TSH.

Q: By immunohistochemistry, a Thyrotroph PitNET/adenoma characteristically shows extensive reactivity for [...], often accompanied by variable staining for the α-subunit.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for α-subunit.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for TSH.
A: TSH
Back Extra: Thyrotroph PitNET/adenoma
- Clinical: Thyrotroph PitNET/adenoma may present with hyperthyroidism, hypothyroidism, or rarely euthyroidism, and often shows signs of mass effect such as headaches and visual deficits.
- Micro: These tumours typically grow in diffuse and sinusoidal patterns, with spindled to polygonal cells and chromophobic cytoplasm.
- Ancillary: Thyrotroph PitNET/adenomas show diffuse PIT1 positivity and extensive TSH immunoreactivity, with variable α-subunit staining.
Reference Gallery:
Thyrotroph PitNET/adenoma. Diffuse nuclear PIT1 immunostaining.
Thyrotroph PitNET/adenoma. Sheets of polygonal tumour cells.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for α-subunit.
Thyrotroph PitNET/adenoma. Extensive immunoreactivity for TSH.

Q: In a Metastatic Pituitary Neuroendocrine Tumour (PitNET) of the corticotroph subtype spreading to bone, the tumor cells typically stain positive for ACTH and low-molecular-weight keratins (e.g., CAM5.2) and may exhibit hyaline changes characteristic of [...] cells.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The invading tumour cells are positive for ACTH.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The metastatic tumour stains intensely for keratins using the CAM5.2 antibody.
Metastatic PitNET. The metastatic tumour cells are mainly large and pleomorphic. Nuclei are atypical. Some cells (arrow) demonstrate the appearance of Crooke cells.
A: Crooke
Back Extra: Metastatic Pituitary Neuroendocrine Tumour (PitNET)
- Clinical: Metastatic PitNETs often present with symptoms of the primary PitNET, such as Cushing disease or Nelson syndrome, and later with metastatic spread to lymph nodes, CNS, and other distant sites.
- Micro: Histologically, metastatic PitNETs show hypercellularity, nuclear pleomorphism, mitoses, necrosis, and invasion. Pseudorosettes around vascular channels may be observed, and the Ki-67 labelling index is often high.
- Ancillary: Immunohistochemistry shows diffuse synaptophysin positivity and high Ki-67 labelling index. The tumour cells are negative for pituitary hormones and cytokeratins, with positive staining for keratins using CAM5.2 in metastatic corticotroph PitNETs.
Reference Gallery:
Metastatic PitNET. PET identified extensive 68Ga-DOTATATE reactivity involving the sella, extending into the suprasellar space and inferiorly to the posterior fossa and upper cervical spine (short arrow). Multiple intrathecal deposits in the mid-cervical and upper thoracic spine are also noted, with abnormal radiotracer uptake in the hilar, mediastinal, periportal, and retroperitoneal nodes (long arrows).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour cells are relatively homogeneous and there is a pseudorosette around a vascular channel. Note the mitosis (arrow).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour invades into surrounding brain parenchyma.
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. A smear preparation shows cellular homogeneity but identifies a mitosis (arrow).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour shows diffuse synaptophysin positivity.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour cells are negative for all pituitary hormones and cytokeratins (shown here).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. GFAP highlights reactive astrocytes in the region of brain invasion. The Ki-67 labelling index of this tumour was very high.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The Ki-67 labelling index of this tumour is very high.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The presence of tumour invading bone confirms the diagnosis.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The invading tumour cells are positive for ACTH.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The metastatic tumour stains intensely for keratins using the CAM5.2 antibody.
Metastatic PitNET. The metastatic tumour cells are mainly large and pleomorphic. Nuclei are atypical. Some cells (arrow) demonstrate the appearance of Crooke cells.

Q: Immunohistochemical evaluation of a Metastatic Pituitary Neuroendocrine Tumour (PitNET) typically demonstrates diffuse positivity for synaptophysin accompanied by an exceptionally high [...] labeling index.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour shows diffuse synaptophysin positivity.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The Ki-67 labelling index of this tumour is very high.
A: Ki-67
Back Extra: Metastatic Pituitary Neuroendocrine Tumour (PitNET)
- Clinical: Metastatic PitNETs often present with symptoms of the primary PitNET, such as Cushing disease or Nelson syndrome, and later with metastatic spread to lymph nodes, CNS, and other distant sites.
- Micro: Histologically, metastatic PitNETs show hypercellularity, nuclear pleomorphism, mitoses, necrosis, and invasion. Pseudorosettes around vascular channels may be observed, and the Ki-67 labelling index is often high.
- Ancillary: Immunohistochemistry shows diffuse synaptophysin positivity and high Ki-67 labelling index. The tumour cells are negative for pituitary hormones and cytokeratins, with positive staining for keratins using CAM5.2 in metastatic corticotroph PitNETs.
Reference Gallery:
Metastatic PitNET. PET identified extensive 68Ga-DOTATATE reactivity involving the sella, extending into the suprasellar space and inferiorly to the posterior fossa and upper cervical spine (short arrow). Multiple intrathecal deposits in the mid-cervical and upper thoracic spine are also noted, with abnormal radiotracer uptake in the hilar, mediastinal, periportal, and retroperitoneal nodes (long arrows).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour cells are relatively homogeneous and there is a pseudorosette around a vascular channel. Note the mitosis (arrow).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour invades into surrounding brain parenchyma.
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. A smear preparation shows cellular homogeneity but identifies a mitosis (arrow).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour shows diffuse synaptophysin positivity.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour cells are negative for all pituitary hormones and cytokeratins (shown here).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. GFAP highlights reactive astrocytes in the region of brain invasion. The Ki-67 labelling index of this tumour was very high.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The Ki-67 labelling index of this tumour is very high.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The presence of tumour invading bone confirms the diagnosis.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The invading tumour cells are positive for ACTH.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The metastatic tumour stains intensely for keratins using the CAM5.2 antibody.
Metastatic PitNET. The metastatic tumour cells are mainly large and pleomorphic. Nuclei are atypical. Some cells (arrow) demonstrate the appearance of Crooke cells.

Q: Histologic examination of a Metastatic Pituitary Neuroendocrine Tumour (PitNET) invading the brain parenchyma frequently reveals increased mitoses and the formation of [...] around vascular channels.
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour cells are relatively homogeneous and there is a pseudorosette around a vascular channel. Note the mitosis (arrow).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour invades into surrounding brain parenchyma.
A: pseudorosettes
Back Extra: Metastatic Pituitary Neuroendocrine Tumour (PitNET)
- Clinical: Metastatic PitNETs often present with symptoms of the primary PitNET, such as Cushing disease or Nelson syndrome, and later with metastatic spread to lymph nodes, CNS, and other distant sites.
- Micro: Histologically, metastatic PitNETs show hypercellularity, nuclear pleomorphism, mitoses, necrosis, and invasion. Pseudorosettes around vascular channels may be observed, and the Ki-67 labelling index is often high.
- Ancillary: Immunohistochemistry shows diffuse synaptophysin positivity and high Ki-67 labelling index. The tumour cells are negative for pituitary hormones and cytokeratins, with positive staining for keratins using CAM5.2 in metastatic corticotroph PitNETs.
Reference Gallery:
Metastatic PitNET. PET identified extensive 68Ga-DOTATATE reactivity involving the sella, extending into the suprasellar space and inferiorly to the posterior fossa and upper cervical spine (short arrow). Multiple intrathecal deposits in the mid-cervical and upper thoracic spine are also noted, with abnormal radiotracer uptake in the hilar, mediastinal, periportal, and retroperitoneal nodes (long arrows).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour cells are relatively homogeneous and there is a pseudorosette around a vascular channel. Note the mitosis (arrow).
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. The tumour invades into surrounding brain parenchyma.
Metastatic PitNET. A PitNET with both extensive cerebrospinal fluid dissemination and focal brain invasion. A smear preparation shows cellular homogeneity but identifies a mitosis (arrow).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour shows diffuse synaptophysin positivity.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The tumour cells are negative for all pituitary hormones and cytokeratins (shown here).
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. GFAP highlights reactive astrocytes in the region of brain invasion. The Ki-67 labelling index of this tumour was very high.
Metastatic PitNET. Immunohistochemical features of the metastatic PitNET. The Ki-67 labelling index of this tumour is very high.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The presence of tumour invading bone confirms the diagnosis.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The invading tumour cells are positive for ACTH.
Metastatic PitNET. Metastatic corticotroph PitNET to bone. The metastatic tumour stains intensely for keratins using the CAM5.2 antibody.
Metastatic PitNET. The metastatic tumour cells are mainly large and pleomorphic. Nuclei are atypical. Some cells (arrow) demonstrate the appearance of Crooke cells.

Q: On histopathology, Merkel Cell Carcinoma classically presents as a densely cellular dermal tumor composed of cells with scant cytoplasm, round to oval nuclei, and finely [...] chromatin.
Figure 1: Histopathological appearance of Merkel cell carcinoma. (A) Densely cellular dermal malignancy with infiltrative borders. (B) High magnification showing tumour cells with round to oval nuclei and finely granular chromatin.
A: granular
Back Extra: Merkel Cell Carcinoma
- Clinical: Merkel cell carcinoma (MCC) presents as a rapidly growing, often violaceous papule or nodule, with a broad differential diagnosis that includes basal cell and squamous cell carcinomas, lymphoma, atypical fibroxanthoma, and melanoma.
- Micro: Histopathology of MCC shows a densely cellular dermal malignancy with infiltrative borders, tumour cells with scant cytoplasm, round to oval nuclei, and finely granular chromatin.
- Ancillary: Immunohistochemical studies are crucial for diagnosing MCC, with CK20 being the most specific marker, highlighting most MCCs (~88%) with characteristic perinuclear dots.
Reference Gallery:
Figure 1: Histopathological appearance of Merkel cell carcinoma. (A) Densely cellular dermal malignancy with infiltrative borders. (B) High magnification showing tumour cells with round to oval nuclei and finely granular chromatin.

Q: The cardinal manifestations of Multiple Endocrine Neoplasia Type 1 include primary hyperparathyroidism, pituitary adenomas, and duodenopancreatic [...].
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple NETs (asterisks) in the pancreatic tail of a patient with multiple endocrine neoplasia type 1.
A: neuroendocrine tumors
Back Extra: Multiple Endocrine Neoplasia Type 1
- Clinical: Primary hyperparathyroidism, pituitary adenomas, and duodenopancreatic neuroendocrine tumours (NETs) are the cardinal manifestations of Multiple Endocrine Neoplasia Type 1 (MEN1).
- Micro: Histology of MEN1-related parathyroid disease shows multiple adenomas or microadenomas, while pancreatic NETs are characterized by multifocal plurihormonal microtumours with frequent glucagon expression.
- Ancillary: Loss of nuclear menin expression is a key immunohistochemical finding in MEN1-related tumours, aiding in their diagnosis.
Reference Gallery:
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma, presenting with a macrotumour. Coronal MRI reveals a large sellar mass with extensive suprasellar growth measuring approximately 40 mm. The lesion extends laterally into the left cavernous sinus surrounding most of the left internal carotid artery. The lesion extends through the floor of the sella into the sphenoidal sinus. The optic chiasm is draped over the superior aspect of the mass.
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma presenting with microtumour. Coronal MRI shows an irregular 4–5 mm area of abnormal signal intensity without any mass effect.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple NETs (asterisks) in the pancreatic tail of a patient with multiple endocrine neoplasia type 1.
68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. At the histological level, this thymic NET is indistinguishable from its sporadic counterpart.
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. There is global loss of nuclear menin expression in the tumour, supporting multiple endocrine neoplasia type 1–related pathogenesis. Note that the non-tumorous elements at the top of the image show a normal staining pattern for menin.
Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1–related parathyroid disease is characterized by multiglandular multiple adenomas. This photomicrograph shows one of the affected glands with multiple microscopic nodules/adenomas.
Multiple endocrine neoplasia type 1. Global loss of nuclear menin expression (green bars) is illustrated in multiple pancreatic neuroendocrine microtumours, consistent with multiple endocrine neoplasia type 1 syndrome.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
68Ga DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. The tumour expresses chromogranin A.

Q: A key immunohistochemical finding that supports the pathogenesis of Multiple Endocrine Neoplasia Type 1 is the global loss of nuclear [...] expression in the tumor cells.
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. There is global loss of nuclear menin expression in the tumour, supporting multiple endocrine neoplasia type 1–related pathogenesis. Note that the non-tumorous elements at the top of the image show a normal staining pattern for menin.
Multiple endocrine neoplasia type 1. Global loss of nuclear menin expression (green bars) is illustrated in multiple pancreatic neuroendocrine microtumours, consistent with multiple endocrine neoplasia type 1 syndrome.
A: menin
Back Extra: Multiple Endocrine Neoplasia Type 1
- Clinical: Primary hyperparathyroidism, pituitary adenomas, and duodenopancreatic neuroendocrine tumours (NETs) are the cardinal manifestations of Multiple Endocrine Neoplasia Type 1 (MEN1).
- Micro: Histology of MEN1-related parathyroid disease shows multiple adenomas or microadenomas, while pancreatic NETs are characterized by multifocal plurihormonal microtumours with frequent glucagon expression.
- Ancillary: Loss of nuclear menin expression is a key immunohistochemical finding in MEN1-related tumours, aiding in their diagnosis.
Reference Gallery:
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma, presenting with a macrotumour. Coronal MRI reveals a large sellar mass with extensive suprasellar growth measuring approximately 40 mm. The lesion extends laterally into the left cavernous sinus surrounding most of the left internal carotid artery. The lesion extends through the floor of the sella into the sphenoidal sinus. The optic chiasm is draped over the superior aspect of the mass.
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma presenting with microtumour. Coronal MRI shows an irregular 4–5 mm area of abnormal signal intensity without any mass effect.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple NETs (asterisks) in the pancreatic tail of a patient with multiple endocrine neoplasia type 1.
68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. At the histological level, this thymic NET is indistinguishable from its sporadic counterpart.
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. There is global loss of nuclear menin expression in the tumour, supporting multiple endocrine neoplasia type 1–related pathogenesis. Note that the non-tumorous elements at the top of the image show a normal staining pattern for menin.
Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1–related parathyroid disease is characterized by multiglandular multiple adenomas. This photomicrograph shows one of the affected glands with multiple microscopic nodules/adenomas.
Multiple endocrine neoplasia type 1. Global loss of nuclear menin expression (green bars) is illustrated in multiple pancreatic neuroendocrine microtumours, consistent with multiple endocrine neoplasia type 1 syndrome.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
68Ga DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. The tumour expresses chromogranin A.

Q: Parathyroid disease associated with Multiple Endocrine Neoplasia Type 1 is typically multiglandular and characterized histologically by [...] or microadenomas.
Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1–related parathyroid disease is characterized by multiglandular multiple adenomas. This photomicrograph shows one of the affected glands with multiple microscopic nodules/adenomas.
A: multiple adenomas
Back Extra: Multiple Endocrine Neoplasia Type 1
- Clinical: Primary hyperparathyroidism, pituitary adenomas, and duodenopancreatic neuroendocrine tumours (NETs) are the cardinal manifestations of Multiple Endocrine Neoplasia Type 1 (MEN1).
- Micro: Histology of MEN1-related parathyroid disease shows multiple adenomas or microadenomas, while pancreatic NETs are characterized by multifocal plurihormonal microtumours with frequent glucagon expression.
- Ancillary: Loss of nuclear menin expression is a key immunohistochemical finding in MEN1-related tumours, aiding in their diagnosis.
Reference Gallery:
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma, presenting with a macrotumour. Coronal MRI reveals a large sellar mass with extensive suprasellar growth measuring approximately 40 mm. The lesion extends laterally into the left cavernous sinus surrounding most of the left internal carotid artery. The lesion extends through the floor of the sella into the sphenoidal sinus. The optic chiasm is draped over the superior aspect of the mass.
MRI from a patient with multiple endocrine neoplasia type 1–related pituitary neuroendocrine tumour (PitNET) / pituitary adenoma presenting with microtumour. Coronal MRI shows an irregular 4–5 mm area of abnormal signal intensity without any mass effect.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple NETs (asterisks) in the pancreatic tail of a patient with multiple endocrine neoplasia type 1.
68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. At the histological level, this thymic NET is indistinguishable from its sporadic counterpart.
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. There is global loss of nuclear menin expression in the tumour, supporting multiple endocrine neoplasia type 1–related pathogenesis. Note that the non-tumorous elements at the top of the image show a normal staining pattern for menin.
Multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1–related parathyroid disease is characterized by multiglandular multiple adenomas. This photomicrograph shows one of the affected glands with multiple microscopic nodules/adenomas.
Multiple endocrine neoplasia type 1. Global loss of nuclear menin expression (green bars) is illustrated in multiple pancreatic neuroendocrine microtumours, consistent with multiple endocrine neoplasia type 1 syndrome.
Multiple endocrine neoplasia type 1–associated multiple neuroendocrine tumours (NETs). Macroscopic appearance of multiple duodenal NETs (asterisks).
68Ga DOTA PET-CT in a patient with multiple endocrine neoplasia type 1. This image shows the diagnostic utility of 68Ga-DOTA PET-CT in a patient with multiple endocrine neoplasia type 1 with multiple small (< 10 mm) pancreatic neuroendocrine tumours (PanNETs) and metastatic spread to the liver. The functional imaging studies using 68Ga-DOTA PET-CT showed two hotspots corresponding to small PanNETs in the pancreatic head, another hotspot in the ventral pars ascendens of the duodenum (lymph node metastasis), and one larger and one small hotspot in the liver (metastases segment 6 and segments 3/4).
Multiple endocrine neoplasia type 1–related thymic neuroendocrine tumour (TNET). A well-differentiated TNET in a patient with multiple endocrine neoplasia type 1. The tumour expresses chromogranin A.

Q: In Multiple Endocrine Neoplasia Type 2, the precursor lesion to medullary thyroid carcinoma is C-cell hyperplasia, which can be highlighted using an immunohistochemical stain for [...].
C-cell hyperplasia in multiple endocrine neoplasia type 2. Clusters of clear cells are seen at low magnification, disrupting the normal thyroid architecture.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Calcitonin staining identifies a markedly increased number of C cells arranged singly, in small groups, surrounding follicles, and forming solid nests.
A: calcitonin
Back Extra: Multiple Endocrine Neoplasia Type 2
- Clinical: Patients with Multiple Endocrine Neoplasia Type 2 (MEN2) often present with medullary thyroid carcinoma (MTC), which can cause neck masses, hoarseness, and dysphagia.
- Micro: Histologically, MEN2-associated MTC shows solid, follicular, papillary, and spindled patterns, with amyloid deposition and C-cell hyperplasia.
- Ancillary: MTC in MEN2 is positive for calcitonin and chromogranin A on immunohistochemistry, and the diagnosis is confirmed by identifying a germline RET mutation.
Reference Gallery:
Medullary thyroid carcinoma in multiple endocrine neoplasia type 2B. MRI shows bilateral medullary thyroid carcinomas (arrows) arising in the lateral thyroid lobes.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Clusters of clear cells are seen at low magnification, disrupting the normal thyroid architecture.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Calcitonin staining identifies a markedly increased number of C cells arranged singly, in small groups, surrounding follicles, and forming solid nests.
The adrenal in multiple endocrine neoplasia type 2. This case contains multiple lesions and intervening medullary hyperplasia.
Mucosal neuroma in multiple endocrine neoplasia type 2. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.
Mucosal neuroma in multiple endocrine neoplasia type 2B. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.

Q: Patients with Multiple Endocrine Neoplasia Type 2 harbor a germline RET mutation and frequently present with bilateral [...], which can be visualized as lateral thyroid lobe masses on MRI.
Medullary thyroid carcinoma in multiple endocrine neoplasia type 2B. MRI shows bilateral medullary thyroid carcinomas (arrows) arising in the lateral thyroid lobes.
A: medullary thyroid carcinomas
Back Extra: Multiple Endocrine Neoplasia Type 2
- Clinical: Patients with Multiple Endocrine Neoplasia Type 2 (MEN2) often present with medullary thyroid carcinoma (MTC), which can cause neck masses, hoarseness, and dysphagia.
- Micro: Histologically, MEN2-associated MTC shows solid, follicular, papillary, and spindled patterns, with amyloid deposition and C-cell hyperplasia.
- Ancillary: MTC in MEN2 is positive for calcitonin and chromogranin A on immunohistochemistry, and the diagnosis is confirmed by identifying a germline RET mutation.
Reference Gallery:
Medullary thyroid carcinoma in multiple endocrine neoplasia type 2B. MRI shows bilateral medullary thyroid carcinomas (arrows) arising in the lateral thyroid lobes.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Clusters of clear cells are seen at low magnification, disrupting the normal thyroid architecture.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Calcitonin staining identifies a markedly increased number of C cells arranged singly, in small groups, surrounding follicles, and forming solid nests.
The adrenal in multiple endocrine neoplasia type 2. This case contains multiple lesions and intervening medullary hyperplasia.
Mucosal neuroma in multiple endocrine neoplasia type 2. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.
Mucosal neuroma in multiple endocrine neoplasia type 2B. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.

Q: A characteristic gastrointestinal finding in the 2B variant of Multiple Endocrine Neoplasia Type 2 is the presence of [...], featuring an expansion of the gut mucosa with scattered trapped ganglion cells.
Mucosal neuroma in multiple endocrine neoplasia type 2. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.
Mucosal neuroma in multiple endocrine neoplasia type 2B. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.
A: mucosal neuromas
Back Extra: Multiple Endocrine Neoplasia Type 2
- Clinical: Patients with Multiple Endocrine Neoplasia Type 2 (MEN2) often present with medullary thyroid carcinoma (MTC), which can cause neck masses, hoarseness, and dysphagia.
- Micro: Histologically, MEN2-associated MTC shows solid, follicular, papillary, and spindled patterns, with amyloid deposition and C-cell hyperplasia.
- Ancillary: MTC in MEN2 is positive for calcitonin and chromogranin A on immunohistochemistry, and the diagnosis is confirmed by identifying a germline RET mutation.
Reference Gallery:
Medullary thyroid carcinoma in multiple endocrine neoplasia type 2B. MRI shows bilateral medullary thyroid carcinomas (arrows) arising in the lateral thyroid lobes.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Clusters of clear cells are seen at low magnification, disrupting the normal thyroid architecture.
C-cell hyperplasia in multiple endocrine neoplasia type 2. Calcitonin staining identifies a markedly increased number of C cells arranged singly, in small groups, surrounding follicles, and forming solid nests.
The adrenal in multiple endocrine neoplasia type 2. This case contains multiple lesions and intervening medullary hyperplasia.
Mucosal neuroma in multiple endocrine neoplasia type 2. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.
Mucosal neuroma in multiple endocrine neoplasia type 2B. A tumour from a patient with multiple endocrine neoplasia type 2B. The gut mucosa is expanded by a proliferation with scattered trapped ganglion cells.

Q: Parathyroid adenomas associated with Multiple Endocrine Neoplasia Type 4 characteristically demonstrate a loss of nuclear immunohistochemical reactivity for [...], reflecting an underlying CDKN1B gene mutation.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The non-tumorous parenchyma shows strong nuclear reactivity but the neoplasm lacks nuclear staining in the adenomatous cells.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The neoplastic parathyroid cells lack nuclear p27 reactivity. The stromal cells provide an internal positive control.
A: p27
Back Extra: Multiple Endocrine Neoplasia Type 4
- Clinical: Primary hyperparathyroidism, pituitary tumours, and pancreatic neuroendocrine tumours are common in Multiple Endocrine Neoplasia Type 4.
- Micro: Parathyroid adenomas in MEN4 may show a delineated nodule with surrounding non-neoplastic parenchyma and loss of nuclear p27 reactivity.
- Ancillary: Diagnostic criteria include a documented germline pathogenic sequence variant of the CDKN1B gene, and genetic testing is essential for confirmation.
Reference Gallery:
Parathyroid adenoma in multiple endocrine neoplasia type 4. The parathyroid contains a delineated nodule with surrounding non-neoplastic parenchyma.
Parathyroid adenoma in multiple endocrine neoplasia type 4. The neoplastic parathyroid cells are crowded and the lesion is devoid of stromal fat. Pleomorphism is minimal.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The non-tumorous parenchyma shows strong nuclear reactivity but the neoplasm lacks nuclear staining in the adenomatous cells.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The neoplastic parathyroid cells lack nuclear p27 reactivity. The stromal cells provide an internal positive control.

Q: In Multiple Endocrine Neoplasia Type 4, parathyroid adenomas typically form a delineated nodule of crowded neoplastic cells that, unlike the surrounding normal parathyroid tissue, are characteristically devoid of [...].
Parathyroid adenoma in multiple endocrine neoplasia type 4. The parathyroid contains a delineated nodule with surrounding non-neoplastic parenchyma.
Parathyroid adenoma in multiple endocrine neoplasia type 4. The neoplastic parathyroid cells are crowded and the lesion is devoid of stromal fat. Pleomorphism is minimal.
A: stromal fat
Back Extra: Multiple Endocrine Neoplasia Type 4
- Clinical: Primary hyperparathyroidism, pituitary tumours, and pancreatic neuroendocrine tumours are common in Multiple Endocrine Neoplasia Type 4.
- Micro: Parathyroid adenomas in MEN4 may show a delineated nodule with surrounding non-neoplastic parenchyma and loss of nuclear p27 reactivity.
- Ancillary: Diagnostic criteria include a documented germline pathogenic sequence variant of the CDKN1B gene, and genetic testing is essential for confirmation.
Reference Gallery:
Parathyroid adenoma in multiple endocrine neoplasia type 4. The parathyroid contains a delineated nodule with surrounding non-neoplastic parenchyma.
Parathyroid adenoma in multiple endocrine neoplasia type 4. The neoplastic parathyroid cells are crowded and the lesion is devoid of stromal fat. Pleomorphism is minimal.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The non-tumorous parenchyma shows strong nuclear reactivity but the neoplasm lacks nuclear staining in the adenomatous cells.
Parathyroid adenoma in multiple endocrine neoplasia type 4. Loss of nuclear p27. The neoplastic parathyroid cells lack nuclear p27 reactivity. The stromal cells provide an internal positive control.

Q: In Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours), the underlying germline mutation often results in a loss of expression of the mutated protein in neoplastic cells, which can sometimes be visualized using [...] immunohistochemistry.
Neuroblastoma. MAX immunohistochemistry for the tumour in Fig. 28217. The non-neoplastic inflammatory cells and endothelial cells demonstrate preserved positive staining for MAX, whereas there is loss of staining in the neoplastic cells of the neuroblastoma. Although some authors have found that MAX immunohistochemistry could have a role in triaging patients for genetic testing for MAX germline mutation, others have found that it lacks sensitivity and specificity, and it is not recommended in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28219. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is decreased expression in the neoplastic cells of the phaeochromocytoma component as well as in the Schwannian spindle cells and ganglion cells of the ganglioneuroma component. This tumour is morphologically indistinguishable from a sporadic neoplasm.
A: MAX
Back Extra: Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours)
- Clinical: Individuals with Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours) often present with bilateral phaeochromocytomas and metachronous paragangliomas, symptoms of catecholamine excess, and pituitary neuroendocrine tumours causing acromegaly or hyperprolactinaemia.
- Micro: MAX-associated tumours are histologically indistinguishable from their sporadic counterparts, but they tend to be multifocal or bilateral, and may include neuroblastic tumours like ganglioneuroma and neuroblastoma.
- Ancillary: Germline pathogenic variants in the MAX gene are most frequent in exons 3 and 4, and genetic testing is recommended for all individuals with phaeochromocytoma/paraganglioma and asymptomatic family members of carriers.
Reference Gallery:
Neuroblastoma. A neuroblastoma from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Neuroblastoma. MAX immunohistochemistry for the tumour in Fig. 28217. The non-neoplastic inflammatory cells and endothelial cells demonstrate preserved positive staining for MAX, whereas there is loss of staining in the neoplastic cells of the neuroblastoma. Although some authors have found that MAX immunohistochemistry could have a role in triaging patients for genetic testing for MAX germline mutation, others have found that it lacks sensitivity and specificity, and it is not recommended in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28219. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is decreased expression in the neoplastic cells of the phaeochromocytoma component as well as in the Schwannian spindle cells and ganglion cells of the ganglioneuroma component. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28221. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is variable loss of staining in the ganglion cells and Schwannian stromal cells of the ganglioneuroma. The variable loss of expression in this case illustrates the difficulty in interpreting MAX immunohistochemistry in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with acromegaly and a known pathogenic germline MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. GHRH immunohistochemistry of the tumour in Fig. 28576 from a patient with secondary acromegaly due to GHRH-producing MAX-related paraganglioma and/or phaeochromocytoma. The tumour cells are positive for GHRH, whereas the stromal cells are negative.

Q: Individuals with Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours) classically present with bilateral pheochromocytomas and neuroblastic tumors, which may take the form of neuroblastomas, composite tumors, or isolated [...].
Neuroblastoma. A neuroblastoma from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
A: ganglioneuromas
Back Extra: Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours)
- Clinical: Individuals with Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours) often present with bilateral phaeochromocytomas and metachronous paragangliomas, symptoms of catecholamine excess, and pituitary neuroendocrine tumours causing acromegaly or hyperprolactinaemia.
- Micro: MAX-associated tumours are histologically indistinguishable from their sporadic counterparts, but they tend to be multifocal or bilateral, and may include neuroblastic tumours like ganglioneuroma and neuroblastoma.
- Ancillary: Germline pathogenic variants in the MAX gene are most frequent in exons 3 and 4, and genetic testing is recommended for all individuals with phaeochromocytoma/paraganglioma and asymptomatic family members of carriers.
Reference Gallery:
Neuroblastoma. A neuroblastoma from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Neuroblastoma. MAX immunohistochemistry for the tumour in Fig. 28217. The non-neoplastic inflammatory cells and endothelial cells demonstrate preserved positive staining for MAX, whereas there is loss of staining in the neoplastic cells of the neuroblastoma. Although some authors have found that MAX immunohistochemistry could have a role in triaging patients for genetic testing for MAX germline mutation, others have found that it lacks sensitivity and specificity, and it is not recommended in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28219. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is decreased expression in the neoplastic cells of the phaeochromocytoma component as well as in the Schwannian spindle cells and ganglion cells of the ganglioneuroma component. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28221. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is variable loss of staining in the ganglion cells and Schwannian stromal cells of the ganglioneuroma. The variable loss of expression in this case illustrates the difficulty in interpreting MAX immunohistochemistry in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with acromegaly and a known pathogenic germline MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. GHRH immunohistochemistry of the tumour in Fig. 28576 from a patient with secondary acromegaly due to GHRH-producing MAX-related paraganglioma and/or phaeochromocytoma. The tumour cells are positive for GHRH, whereas the stromal cells are negative.

Q: Secondary acromegaly in Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours) can occur when a related composite pheochromocytoma or paraganglioma ectopically secretes [...].
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with acromegaly and a known pathogenic germline MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. GHRH immunohistochemistry of the tumour in Fig. 28576 from a patient with secondary acromegaly due to GHRH-producing MAX-related paraganglioma and/or phaeochromocytoma. The tumour cells are positive for GHRH, whereas the stromal cells are negative.
A: growth hormone-releasing hormone (GHRH)
Back Extra: Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours)
- Clinical: Individuals with Multiple Endocrine Neoplasia Type 5 (MAX-related Tumours) often present with bilateral phaeochromocytomas and metachronous paragangliomas, symptoms of catecholamine excess, and pituitary neuroendocrine tumours causing acromegaly or hyperprolactinaemia.
- Micro: MAX-associated tumours are histologically indistinguishable from their sporadic counterparts, but they tend to be multifocal or bilateral, and may include neuroblastic tumours like ganglioneuroma and neuroblastoma.
- Ancillary: Germline pathogenic variants in the MAX gene are most frequent in exons 3 and 4, and genetic testing is recommended for all individuals with phaeochromocytoma/paraganglioma and asymptomatic family members of carriers.
Reference Gallery:
Neuroblastoma. A neuroblastoma from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Neuroblastoma. MAX immunohistochemistry for the tumour in Fig. 28217. The non-neoplastic inflammatory cells and endothelial cells demonstrate preserved positive staining for MAX, whereas there is loss of staining in the neoplastic cells of the neuroblastoma. Although some authors have found that MAX immunohistochemistry could have a role in triaging patients for genetic testing for MAX germline mutation, others have found that it lacks sensitivity and specificity, and it is not recommended in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28219. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is decreased expression in the neoplastic cells of the phaeochromocytoma component as well as in the Schwannian spindle cells and ganglion cells of the ganglioneuroma component. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. An example from a patient with a known germline pathogenic MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Ganglioneuroma. MAX immunohistochemistry in a section of the tumour in Fig. 28221. The non-neoplastic inflammatory cells demonstrate preserved positive staining for MAX, whereas there is variable loss of staining in the ganglion cells and Schwannian stromal cells of the ganglioneuroma. The variable loss of expression in this case illustrates the difficulty in interpreting MAX immunohistochemistry in routine clinical practice.
Composite phaeochromocytoma-ganglioneuroma. An example from a patient with acromegaly and a known pathogenic germline MAX variant. This tumour is morphologically indistinguishable from a sporadic neoplasm.
Composite phaeochromocytoma-ganglioneuroma. GHRH immunohistochemistry of the tumour in Fig. 28576 from a patient with secondary acromegaly due to GHRH-producing MAX-related paraganglioma and/or phaeochromocytoma. The tumour cells are positive for GHRH, whereas the stromal cells are negative.

Q: Pituitary neuroendocrine tumors (PitNETs) associated with Carney Complex are frequently mixed somatotroph and lactotroph tumors that demonstrate diffuse immunoreactivity for the transcription factor [...].
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. The tumour consists of a mixture of acidophilic (densely granulated somatotroph tumour) and chromophobic (sparsely granulated lactotroph) cells.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. There is diffuse PIT1 reactivity.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. ERα is positive in the lactotroph tumour component, whereas the somatotroph tumour cells are negative for ERα.
A: PIT1
Back Extra: Carney Complex
- Clinical: Carney Complex (CNC) is characterized by skin pigmentation, cardiac myxomas, and endocrine manifestations such as PPNAD and pituitary adenomas.
- Micro: PPNAD in CNC shows bilateral cortical micronodules enriched in compact adrenocortical cells, often < 5 mm in size.
- Ancillary: Pathogenic germline mutations in PRKAR1A are the most common cause of Carney Complex.
Reference Gallery:
Follicular thyroid adenoma with papillary architecture in a patient with Carney complex. This tumour has intrafollicular centripetal papillary projections. Consistent with the morphological findings, the patient had a suppressed TSH level.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. The tumour consists of a mixture of acidophilic (densely granulated somatotroph tumour) and chromophobic (sparsely granulated lactotroph) cells.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. There is diffuse PIT1 reactivity.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. ERα is positive in the lactotroph tumour component, whereas the somatotroph tumour cells are negative for ERα.
Growth hormone–producing adenoma in a patient with Carney complex. MRI after gadolinium enhancement of the pituitary gland of a patient with Carney complex who had few obvious clinical signs of acromegaly. A developing microadenoma can be seen on the left side as a hypodense region with the gland. This is a common scenario among patients with the complex: biochemically, they meet all criteria of acromegaly, with elevated growth hormone levels and high IGF1. Yet in most patients, adenomas develop slowly within the background of hyperplasia. In this patient, who was followed for > 20 years, an obvious adenoma developed > 10 years after the first biochemical evidence of acromegaly.

Q: In Carney Complex, patients may develop benign thyroid neoplasms, classically presenting as [...] with distinct intrafollicular centripetal papillary projections.
Follicular thyroid adenoma with papillary architecture in a patient with Carney complex. This tumour has intrafollicular centripetal papillary projections. Consistent with the morphological findings, the patient had a suppressed TSH level.
A: follicular thyroid adenomas
Back Extra: Carney Complex
- Clinical: Carney Complex (CNC) is characterized by skin pigmentation, cardiac myxomas, and endocrine manifestations such as PPNAD and pituitary adenomas.
- Micro: PPNAD in CNC shows bilateral cortical micronodules enriched in compact adrenocortical cells, often < 5 mm in size.
- Ancillary: Pathogenic germline mutations in PRKAR1A are the most common cause of Carney Complex.
Reference Gallery:
Follicular thyroid adenoma with papillary architecture in a patient with Carney complex. This tumour has intrafollicular centripetal papillary projections. Consistent with the morphological findings, the patient had a suppressed TSH level.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. The tumour consists of a mixture of acidophilic (densely granulated somatotroph tumour) and chromophobic (sparsely granulated lactotroph) cells.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. There is diffuse PIT1 reactivity.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. ERα is positive in the lactotroph tumour component, whereas the somatotroph tumour cells are negative for ERα.
Growth hormone–producing adenoma in a patient with Carney complex. MRI after gadolinium enhancement of the pituitary gland of a patient with Carney complex who had few obvious clinical signs of acromegaly. A developing microadenoma can be seen on the left side as a hypodense region with the gland. This is a common scenario among patients with the complex: biochemically, they meet all criteria of acromegaly, with elevated growth hormone levels and high IGF1. Yet in most patients, adenomas develop slowly within the background of hyperplasia. In this patient, who was followed for > 20 years, an obvious adenoma developed > 10 years after the first biochemical evidence of acromegaly.

Q: On contrast-enhanced MRI, patients with Carney Complex and biochemical evidence of acromegaly characteristically develop slowly progressive growth hormone-producing [...] arising within a background of pituitary hyperplasia.
Growth hormone–producing adenoma in a patient with Carney complex. MRI after gadolinium enhancement of the pituitary gland of a patient with Carney complex who had few obvious clinical signs of acromegaly. A developing microadenoma can be seen on the left side as a hypodense region with the gland. This is a common scenario among patients with the complex: biochemically, they meet all criteria of acromegaly, with elevated growth hormone levels and high IGF1. Yet in most patients, adenomas develop slowly within the background of hyperplasia. In this patient, who was followed for > 20 years, an obvious adenoma developed > 10 years after the first biochemical evidence of acromegaly.
A: microadenomas
Back Extra: Carney Complex
- Clinical: Carney Complex (CNC) is characterized by skin pigmentation, cardiac myxomas, and endocrine manifestations such as PPNAD and pituitary adenomas.
- Micro: PPNAD in CNC shows bilateral cortical micronodules enriched in compact adrenocortical cells, often < 5 mm in size.
- Ancillary: Pathogenic germline mutations in PRKAR1A are the most common cause of Carney Complex.
Reference Gallery:
Follicular thyroid adenoma with papillary architecture in a patient with Carney complex. This tumour has intrafollicular centripetal papillary projections. Consistent with the morphological findings, the patient had a suppressed TSH level.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. The tumour consists of a mixture of acidophilic (densely granulated somatotroph tumour) and chromophobic (sparsely granulated lactotroph) cells.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. There is diffuse PIT1 reactivity.
Carney complex–related pituitary neuroendocrine tumour (PitNET)/adenoma consisting of a mixed somatotroph and lactotroph tumour. ERα is positive in the lactotroph tumour component, whereas the somatotroph tumour cells are negative for ERα.
Growth hormone–producing adenoma in a patient with Carney complex. MRI after gadolinium enhancement of the pituitary gland of a patient with Carney complex who had few obvious clinical signs of acromegaly. A developing microadenoma can be seen on the left side as a hypodense region with the gland. This is a common scenario among patients with the complex: biochemically, they meet all criteria of acromegaly, with elevated growth hormone levels and high IGF1. Yet in most patients, adenomas develop slowly within the background of hyperplasia. In this patient, who was followed for > 20 years, an obvious adenoma developed > 10 years after the first biochemical evidence of acromegaly.

Q: Patients with Erdheim–Chester Disease frequently present with endocrine abnormalities (e.g., anterior pituitary dysfunction, diabetes insipidus) due to characteristic histiocytic infiltration of the [...] region.
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells (left) and anterior pituitary gland with atrophy and fibrosis (right).
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells and reactive lymphocytic cells (PAS).
A: sellar
Back Extra: Erdheim–Chester Disease
- Clinical: Erdheim–Chester Disease often presents with endocrine involvement, including anterior pituitary dysfunction, diabetes insipidus, and adrenal insufficiency.
- Micro: The affected tissue is infiltrated by foamy to epithelioid histiocytes, Touton-type multinucleated giant cells, and variable fibrosis.
- Ancillary: Testing for BRAF mutations and other pathway-related alterations (e.g., PIK3CA, MAP2K1, KRAS/NRAS) is crucial for diagnosis.
Reference Gallery:
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells (left) and anterior pituitary gland with atrophy and fibrosis (right).
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells and reactive lymphocytic cells (PAS).

Q: Histologically, Erdheim–Chester Disease is characterized by an infiltrate of foamy to epithelioid histiocytes, variable fibrosis, and classic multinucleated giant cells known as [...] giant cells.
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells (left) and anterior pituitary gland with atrophy and fibrosis (right).
A: Touton
Back Extra: Erdheim–Chester Disease
- Clinical: Erdheim–Chester Disease often presents with endocrine involvement, including anterior pituitary dysfunction, diabetes insipidus, and adrenal insufficiency.
- Micro: The affected tissue is infiltrated by foamy to epithelioid histiocytes, Touton-type multinucleated giant cells, and variable fibrosis.
- Ancillary: Testing for BRAF mutations and other pathway-related alterations (e.g., PIK3CA, MAP2K1, KRAS/NRAS) is crucial for diagnosis.
Reference Gallery:
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells (left) and anterior pituitary gland with atrophy and fibrosis (right).
Erdheim–Chester disease. An example from the sellar region showing histiocytic tumour cells and reactive lymphocytic cells (PAS).

Q: The classic clinical triad of McCune-Albright Syndrome consists of polyostotic fibrous dysplasia, endocrine disorders (e.g., precocious puberty), and irregular [...] skin macules that characteristically respect the body's midline.
Pituitary and cranial pathology in McCune–Albright syndrome. Coronal MRI shows extensive residual soft tissue tumour despite frontal craniotomy in a patient with McCune–Albright syndrome. Note the fibrous dysplasia throughout the cranium and skull base.
McCune–Albright syndrome. Photograph showing characteristic skin hyperpigmentation, including irregular borders and location respecting the midline of the body.
A: café-au-lait
Back Extra: McCune-Albright Syndrome
- Clinical: McCune-Albright Syndrome (MAS) is characterized by the triad of polyostotic fibrous dysplasia, café-au-lait skin macules, and endocrine disorders, including precocious puberty, hyperthyroidism, and growth hormone excess.
- Micro: In MAS, thyroid nodules exhibit a papillary architecture with centripetally organized papillae and uniform, bland epithelial cells with basally located nuclei.
- Ancillary: Somatic activating mutations in the GNAS gene, particularly at residues R201 and Q227, confirm the diagnosis of MAS.
Reference Gallery:
Pituitary and cranial pathology in McCune–Albright syndrome. Coronal MRI shows extensive residual soft tissue tumour despite frontal craniotomy in a patient with McCune–Albright syndrome. Note the fibrous dysplasia throughout the cranium and skull base.
Pituitary and cranial pathology in McCune–Albright syndrome. Sagittal MRI shows extensive residual soft tissue tumour despite frontal craniotomy in a patient with McCune–Albright syndrome. Note the fibrous dysplasia throughout the cranium and skull base.
Thyroid nodule in McCune–Albright syndrome. The thyroid nodules exhibit a papillary architecture, with the formation of true papillae that have fibrovascular cores, but the papillae are organized in a centripetal fashion within the follicles and are lined by uniform epithelial cells with bland, basally located nuclei.
Thyroid nodule in McCune–Albright syndrome. Despite the formation of true papillae, the follicular epithelial cells forming the thyroid nodules have uniform, bland cytology with round basal nuclei that have dark chromatin.
McCune–Albright syndrome. Photograph showing characteristic skin hyperpigmentation, including irregular borders and location respecting the midline of the body.
McCune–Albright syndrome. Testicular ultrasonography in a patient with macro-orchidism demonstrates diffuse microlithiasis.

Q: Thyroid nodules in McCune-Albright Syndrome often form true papillae with fibrovascular cores; however, they uniquely display a [...] organization within the follicles and are lined by uniform epithelial cells with bland, basally located nuclei.
Thyroid nodule in McCune–Albright syndrome. The thyroid nodules exhibit a papillary architecture, with the formation of true papillae that have fibrovascular cores, but the papillae are organized in a centripetal fashion within the follicles and are lined by uniform epithelial cells with bland, basally located nuclei.
Thyroid nodule in McCune–Albright syndrome. Despite the formation of true papillae, the follicular epithelial cells forming the thyroid nodules have uniform, bland cytology with round basal nuclei that have dark chromatin.
A: centripetal
Back Extra: McCune-Albright Syndrome
- Clinical: McCune-Albright Syndrome (MAS) is characterized by the triad of polyostotic fibrous dysplasia, café-au-lait skin macules, and endocrine disorders, including precocious puberty, hyperthyroidism, and growth hormone excess.
- Micro: In MAS, thyroid nodules exhibit a papillary architecture with centripetally organized papillae and uniform, bland epithelial cells with basally located nuclei.
- Ancillary: Somatic activating mutations in the GNAS gene, particularly at residues R201 and Q227, confirm the diagnosis of MAS.
Reference Gallery:
Pituitary and cranial pathology in McCune–Albright syndrome. Coronal MRI shows extensive residual soft tissue tumour despite frontal craniotomy in a patient with McCune–Albright syndrome. Note the fibrous dysplasia throughout the cranium and skull base.
Pituitary and cranial pathology in McCune–Albright syndrome. Sagittal MRI shows extensive residual soft tissue tumour despite frontal craniotomy in a patient with McCune–Albright syndrome. Note the fibrous dysplasia throughout the cranium and skull base.
Thyroid nodule in McCune–Albright syndrome. The thyroid nodules exhibit a papillary architecture, with the formation of true papillae that have fibrovascular cores, but the papillae are organized in a centripetal fashion within the follicles and are lined by uniform epithelial cells with bland, basally located nuclei.
Thyroid nodule in McCune–Albright syndrome. Despite the formation of true papillae, the follicular epithelial cells forming the thyroid nodules have uniform, bland cytology with round basal nuclei that have dark chromatin.
McCune–Albright syndrome. Photograph showing characteristic skin hyperpigmentation, including irregular borders and location respecting the midline of the body.
McCune–Albright syndrome. Testicular ultrasonography in a patient with macro-orchidism demonstrates diffuse microlithiasis.

Q: In Neurofibromatosis Type 1, patients can develop composite [...] (often bilateral with ganglioneuroma components) that are positive for GATA3 and tyrosine hydroxylase.
Bilateral composite phaeochromocytoma of a patient with neurofibromatosis type 1. Bilateral phaeochromocytoma, whitish area corresponding to ganglioneuroma components.
A: pheochromocytomas
Back Extra: Neurofibromatosis Type 1
- Clinical: Neurofibromatosis Type 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple neurofibromas, and Lisch nodules.
- Micro: NF1-related phaeochromocytomas are positive for GATA3 and tyrosine hydroxylase, and negative for keratins and pseudohypoxia biomarkers.
- Ancillary: NF1 defects are found in >90% of individuals with a clinical diagnosis of NF1. Genetic testing should include various methods to test for splicing defects, deletions, large chromosomal and smaller gene rearrangements, and other mutations.
Reference Gallery:
Bilateral composite phaeochromocytoma of a patient with neurofibromatosis type 1. Bilateral phaeochromocytoma, whitish area corresponding to ganglioneuroma components.
Somatostatinoma of the ampulla of Vater in a patient with neurofibromatosis type 1. Ampullary somatostatinoma of a patient with neurofibromatosis type 1.
Somatostatinoma. Ampullary somatostatinoma in a patient with neurofibromatosis type 1. Note the pseudoglandular growth.

Q: Patients with Neurofibromatosis Type 1 have an increased risk for developing neuroendocrine tumors of the ampulla of Vater, most characteristically [...], which often display pseudoglandular growth on histology.
Somatostatinoma of the ampulla of Vater in a patient with neurofibromatosis type 1. Ampullary somatostatinoma of a patient with neurofibromatosis type 1.
Somatostatinoma. Ampullary somatostatinoma in a patient with neurofibromatosis type 1. Note the pseudoglandular growth.
A: somatostatinomas
Back Extra: Neurofibromatosis Type 1
- Clinical: Neurofibromatosis Type 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple neurofibromas, and Lisch nodules.
- Micro: NF1-related phaeochromocytomas are positive for GATA3 and tyrosine hydroxylase, and negative for keratins and pseudohypoxia biomarkers.
- Ancillary: NF1 defects are found in >90% of individuals with a clinical diagnosis of NF1. Genetic testing should include various methods to test for splicing defects, deletions, large chromosomal and smaller gene rearrangements, and other mutations.
Reference Gallery:
Bilateral composite phaeochromocytoma of a patient with neurofibromatosis type 1. Bilateral phaeochromocytoma, whitish area corresponding to ganglioneuroma components.
Somatostatinoma of the ampulla of Vater in a patient with neurofibromatosis type 1. Ampullary somatostatinoma of a patient with neurofibromatosis type 1.
Somatostatinoma. Ampullary somatostatinoma in a patient with neurofibromatosis type 1. Note the pseudoglandular growth.

Q: A hallmark central nervous system tumor in Von Hippel-Lindau Syndrome is the [...], which microscopically shows a proliferation of neoplastic stromal cells.
Imaging of von Hippel–Lindau syndrome. Imaging of a patient with von Hippel–Lindau syndrome identifies multiple lesions. Left panel: The bilateral enhancing adrenal lesions (upper arrows) are suspicious for phaeochromocytoma, the left renal lesion (lower arrow) is most likely renal cell carcinoma, and there are multiple pancreatic cysts (not shown). Right panel: The central spinal canal enhancing mass lesions (arrows) are most likely haemangioblastomas.
Haemangioblastoma in von Hippel–Lindau syndrome. The tumour is composed of a proliferation of neoplastic so-called stromal cells thought to be haemangioblast progenitor cells.
A: hemangioblastoma
Back Extra: Von Hippel-Lindau Syndrome
- Clinical: Patients with von Hippel-Lindau syndrome commonly present with retinal angiomas, haemangioblastomas, and phaeochromocytomas, leading to symptoms such as cerebellar ataxia and hypertension.
- Micro: Clear cell renal cell carcinomas in von Hippel-Lindau syndrome are characterized by an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
- Ancillary: Immunohistochemistry (IHC) for CAIX is crucial in distinguishing VHL-related tumours from other neoplasms, as CAIX typically shows membranous staining in VHL cases.
Reference Gallery:
Imaging of von Hippel–Lindau syndrome. Imaging of a patient with von Hippel–Lindau syndrome identifies multiple lesions. Left panel: The bilateral enhancing adrenal lesions (upper arrows) are suspicious for phaeochromocytoma, the left renal lesion (lower arrow) is most likely renal cell carcinoma, and there are multiple pancreatic cysts (not shown). Right panel: The central spinal canal enhancing mass lesions (arrows) are most likely haemangioblastomas.
Haemangioblastoma in von Hippel–Lindau syndrome. The tumour is composed of a proliferation of neoplastic so-called stromal cells thought to be haemangioblast progenitor cells.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The tumour cells have abundant clear, lipid-rich cytoplasm but are confirmed to be paraganglioma on the basis of their positivity for INSM1, chromogranin, GATA3, and tyrosine hydroxylase (not shown).
Clear cell renal cell carcinoma in von Hippel–Lindau syndrome. The tumours have an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
Endolymphatic sac tumour in von Hippel–Lindau syndrome. Endolymphatic sac tumours exhibit a papillary architecture with a markedly vascular stroma.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The adrenal gland of a patient with von Hippel–Lindau syndrome contains multiple nodules of phaeochromocytoma.

Q: The characteristic renal neoplasms that occur in Von Hippel-Lindau Syndrome are [...] renal cell carcinomas, which exhibit an alveolar arrangement of neoplastic cells with a delicate vascular network.
Clear cell renal cell carcinoma in von Hippel–Lindau syndrome. The tumours have an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
A: clear cell
Back Extra: Von Hippel-Lindau Syndrome
- Clinical: Patients with von Hippel-Lindau syndrome commonly present with retinal angiomas, haemangioblastomas, and phaeochromocytomas, leading to symptoms such as cerebellar ataxia and hypertension.
- Micro: Clear cell renal cell carcinomas in von Hippel-Lindau syndrome are characterized by an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
- Ancillary: Immunohistochemistry (IHC) for CAIX is crucial in distinguishing VHL-related tumours from other neoplasms, as CAIX typically shows membranous staining in VHL cases.
Reference Gallery:
Imaging of von Hippel–Lindau syndrome. Imaging of a patient with von Hippel–Lindau syndrome identifies multiple lesions. Left panel: The bilateral enhancing adrenal lesions (upper arrows) are suspicious for phaeochromocytoma, the left renal lesion (lower arrow) is most likely renal cell carcinoma, and there are multiple pancreatic cysts (not shown). Right panel: The central spinal canal enhancing mass lesions (arrows) are most likely haemangioblastomas.
Haemangioblastoma in von Hippel–Lindau syndrome. The tumour is composed of a proliferation of neoplastic so-called stromal cells thought to be haemangioblast progenitor cells.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The tumour cells have abundant clear, lipid-rich cytoplasm but are confirmed to be paraganglioma on the basis of their positivity for INSM1, chromogranin, GATA3, and tyrosine hydroxylase (not shown).
Clear cell renal cell carcinoma in von Hippel–Lindau syndrome. The tumours have an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
Endolymphatic sac tumour in von Hippel–Lindau syndrome. Endolymphatic sac tumours exhibit a papillary architecture with a markedly vascular stroma.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The adrenal gland of a patient with von Hippel–Lindau syndrome contains multiple nodules of phaeochromocytoma.

Q: Patients with Von Hippel-Lindau Syndrome frequently develop multifocal adrenal [...], which can microscopically mimic renal tumors due to their abundant clear, lipid-rich cytoplasm.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The tumour cells have abundant clear, lipid-rich cytoplasm but are confirmed to be paraganglioma on the basis of their positivity for INSM1, chromogranin, GATA3, and tyrosine hydroxylase (not shown).
Von Hippel–Lindau syndrome–related phaeochromocytoma. The adrenal gland of a patient with von Hippel–Lindau syndrome contains multiple nodules of phaeochromocytoma.
A: pheochromocytomas
Back Extra: Von Hippel-Lindau Syndrome
- Clinical: Patients with von Hippel-Lindau syndrome commonly present with retinal angiomas, haemangioblastomas, and phaeochromocytomas, leading to symptoms such as cerebellar ataxia and hypertension.
- Micro: Clear cell renal cell carcinomas in von Hippel-Lindau syndrome are characterized by an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
- Ancillary: Immunohistochemistry (IHC) for CAIX is crucial in distinguishing VHL-related tumours from other neoplasms, as CAIX typically shows membranous staining in VHL cases.
Reference Gallery:
Imaging of von Hippel–Lindau syndrome. Imaging of a patient with von Hippel–Lindau syndrome identifies multiple lesions. Left panel: The bilateral enhancing adrenal lesions (upper arrows) are suspicious for phaeochromocytoma, the left renal lesion (lower arrow) is most likely renal cell carcinoma, and there are multiple pancreatic cysts (not shown). Right panel: The central spinal canal enhancing mass lesions (arrows) are most likely haemangioblastomas.
Haemangioblastoma in von Hippel–Lindau syndrome. The tumour is composed of a proliferation of neoplastic so-called stromal cells thought to be haemangioblast progenitor cells.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The tumour cells have abundant clear, lipid-rich cytoplasm but are confirmed to be paraganglioma on the basis of their positivity for INSM1, chromogranin, GATA3, and tyrosine hydroxylase (not shown).
Clear cell renal cell carcinoma in von Hippel–Lindau syndrome. The tumours have an alveolar arrangement of nests of epithelial clear cells with a delicate vascular network.
Endolymphatic sac tumour in von Hippel–Lindau syndrome. Endolymphatic sac tumours exhibit a papillary architecture with a markedly vascular stroma.
Von Hippel–Lindau syndrome–related phaeochromocytoma. The adrenal gland of a patient with von Hippel–Lindau syndrome contains multiple nodules of phaeochromocytoma.

Q: The hallmark ancillary finding across all SDH-deficient tumor syndromes is the loss of [...] expression on immunohistochemistry, which sharply contrasts with the retained granular cytoplasmic staining in non-neoplastic internal control cells.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Immunohistochemistry for SDHB in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. There is no expression of SDHB in any of the neoplastic cells. The granular cytoplasmic expression in the non-neoplastic cells, which acts as an internal positive control, is emphasized.
Succinate dehydrogenase–deficient paraganglioma. Loss of expression of SDHB in succinate dehydrogenase–deficient paraganglioma. The presence of distinct granular staining in the non-neoplastic cells, which contrasts with the pale diffuse cytoplasmic blush in the neoplastic cells, is emphasized.
A: SDHB
Back Extra: SDH-deficient tumour syndromes
- Clinical: SDH-deficient tumour syndromes often present with multifocal neoplasms, including paragangliomas, phaeochromocytomas, gastrointestinal stromal tumours (GISTs), renal carcinomas, pituitary neuroendocrine tumours (PitNETs/adenomas), and pulmonary chondromas.
- Micro: SDH-deficient paragangliomas and phaeochromocytomas may exhibit well-formed, almost circular nests of epithelioid cells, sometimes with clear or vacuolated cytoplasm.
- Ancillary: Loss of SDHB expression on immunohistochemistry is a hallmark of SDH-deficient tumours and is crucial for diagnosis.
Reference Gallery:
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, the pulmonary chondromas associated with Carney triad do not show entrapped respiratory epithelium between the lobules of cartilage and do not contain other mesenchymal elements such as fat, smooth muscle, or myxoid spindle cells.
Succinate dehydrogenase–deficient paraganglioma. Immunohistochemistry for SDHB is not always easy to interpret. In this paraganglioma associated with germline mutation, there is a diffuse cytoplasmic blush in all the neoplastic cells. Because this staining contrasts with the intense granular expression in non-neoplastic internal controls, the tumour is still considered to be succinate dehydrogenase–deficient.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Immunohistochemistry for SDHB in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. There is no expression of SDHB in any of the neoplastic cells. The granular cytoplasmic expression in the non-neoplastic cells, which acts as an internal positive control, is emphasized.
Succinate dehydrogenase–deficient pituitary neuroendocrine tumour (PitNET)/adenoma. This succinate dehydrogenase–deficient PitNET is indistinguishable morphologically from a sporadic tumour.
Succinate dehydrogenase (SDH) complex. The SDH complex comprises two anchoring subunits, SDHC and SDHD; the catalytic components SDHA and SDHB; and SDHAF2, responsible for the flavination of the SDHA component of the complex. If any component of the SDH complex is lost, the complex becomes dysfunctional and SDHB immunohistochemistry becomes negative. PPGL, paraganglioma and/or phaeochromocytoma.
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, pulmonary chondromas associated with Carney triad show a smooth contour, lacking invaginations of entrapped respiratory epithelium between cartilage.
Succinate dehydrogenase–deficient paraganglioma. Morphological clues to succinate dehydrogenase–deficient paragangliomas are inconsistent but include well-developed, almost circular nests of epithelioid cells, sometimes with pale or vacuolated cytoplasm {31789631}.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Succinate dehydrogenase–deficient gastrointestinal stromal tumour commonly demonstrates a multilobulated or plexiform growth pattern.
Succinate dehydrogenase–deficient paraganglioma. Loss of expression of SDHB in succinate dehydrogenase–deficient paraganglioma. The presence of distinct granular staining in the non-neoplastic cells, which contrasts with the pale diffuse cytoplasmic blush in the neoplastic cells, is emphasized.
Phaeochromocytoma. This phaeochromocytoma not associated with SDH mutation demonstrates diffuse strong SDHB expression. The cytoplasmic and distinctly granular (mitochondrial) pattern of expression is noted.

Q: Renal cell carcinomas associated with SDH-deficient tumor syndromes typically feature bland cells with eosinophilic cytoplasm containing distinctive flocculent or pale [...].
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
A: intracytoplasmic inclusions
Back Extra: SDH-deficient tumour syndromes
- Clinical: SDH-deficient tumour syndromes often present with multifocal neoplasms, including paragangliomas, phaeochromocytomas, gastrointestinal stromal tumours (GISTs), renal carcinomas, pituitary neuroendocrine tumours (PitNETs/adenomas), and pulmonary chondromas.
- Micro: SDH-deficient paragangliomas and phaeochromocytomas may exhibit well-formed, almost circular nests of epithelioid cells, sometimes with clear or vacuolated cytoplasm.
- Ancillary: Loss of SDHB expression on immunohistochemistry is a hallmark of SDH-deficient tumours and is crucial for diagnosis.
Reference Gallery:
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, the pulmonary chondromas associated with Carney triad do not show entrapped respiratory epithelium between the lobules of cartilage and do not contain other mesenchymal elements such as fat, smooth muscle, or myxoid spindle cells.
Succinate dehydrogenase–deficient paraganglioma. Immunohistochemistry for SDHB is not always easy to interpret. In this paraganglioma associated with germline mutation, there is a diffuse cytoplasmic blush in all the neoplastic cells. Because this staining contrasts with the intense granular expression in non-neoplastic internal controls, the tumour is still considered to be succinate dehydrogenase–deficient.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Immunohistochemistry for SDHB in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. There is no expression of SDHB in any of the neoplastic cells. The granular cytoplasmic expression in the non-neoplastic cells, which acts as an internal positive control, is emphasized.
Succinate dehydrogenase–deficient pituitary neuroendocrine tumour (PitNET)/adenoma. This succinate dehydrogenase–deficient PitNET is indistinguishable morphologically from a sporadic tumour.
Succinate dehydrogenase (SDH) complex. The SDH complex comprises two anchoring subunits, SDHC and SDHD; the catalytic components SDHA and SDHB; and SDHAF2, responsible for the flavination of the SDHA component of the complex. If any component of the SDH complex is lost, the complex becomes dysfunctional and SDHB immunohistochemistry becomes negative. PPGL, paraganglioma and/or phaeochromocytoma.
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, pulmonary chondromas associated with Carney triad show a smooth contour, lacking invaginations of entrapped respiratory epithelium between cartilage.
Succinate dehydrogenase–deficient paraganglioma. Morphological clues to succinate dehydrogenase–deficient paragangliomas are inconsistent but include well-developed, almost circular nests of epithelioid cells, sometimes with pale or vacuolated cytoplasm {31789631}.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Succinate dehydrogenase–deficient gastrointestinal stromal tumour commonly demonstrates a multilobulated or plexiform growth pattern.
Succinate dehydrogenase–deficient paraganglioma. Loss of expression of SDHB in succinate dehydrogenase–deficient paraganglioma. The presence of distinct granular staining in the non-neoplastic cells, which contrasts with the pale diffuse cytoplasmic blush in the neoplastic cells, is emphasized.
Phaeochromocytoma. This phaeochromocytoma not associated with SDH mutation demonstrates diffuse strong SDHB expression. The cytoplasmic and distinctly granular (mitochondrial) pattern of expression is noted.

Q: Gastrointestinal stromal tumors (GISTs) that occur as part of SDH-deficient tumor syndromes characteristically demonstrate a [...] growth pattern on histologic evaluation.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Succinate dehydrogenase–deficient gastrointestinal stromal tumour commonly demonstrates a multilobulated or plexiform growth pattern.
A: multilobulated or plexiform
Back Extra: SDH-deficient tumour syndromes
- Clinical: SDH-deficient tumour syndromes often present with multifocal neoplasms, including paragangliomas, phaeochromocytomas, gastrointestinal stromal tumours (GISTs), renal carcinomas, pituitary neuroendocrine tumours (PitNETs/adenomas), and pulmonary chondromas.
- Micro: SDH-deficient paragangliomas and phaeochromocytomas may exhibit well-formed, almost circular nests of epithelioid cells, sometimes with clear or vacuolated cytoplasm.
- Ancillary: Loss of SDHB expression on immunohistochemistry is a hallmark of SDH-deficient tumours and is crucial for diagnosis.
Reference Gallery:
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, the pulmonary chondromas associated with Carney triad do not show entrapped respiratory epithelium between the lobules of cartilage and do not contain other mesenchymal elements such as fat, smooth muscle, or myxoid spindle cells.
Succinate dehydrogenase–deficient paraganglioma. Immunohistochemistry for SDHB is not always easy to interpret. In this paraganglioma associated with germline mutation, there is a diffuse cytoplasmic blush in all the neoplastic cells. Because this staining contrasts with the intense granular expression in non-neoplastic internal controls, the tumour is still considered to be succinate dehydrogenase–deficient.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Immunohistochemistry for SDHB in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. There is no expression of SDHB in any of the neoplastic cells. The granular cytoplasmic expression in the non-neoplastic cells, which acts as an internal positive control, is emphasized.
Succinate dehydrogenase–deficient pituitary neuroendocrine tumour (PitNET)/adenoma. This succinate dehydrogenase–deficient PitNET is indistinguishable morphologically from a sporadic tumour.
Succinate dehydrogenase (SDH) complex. The SDH complex comprises two anchoring subunits, SDHC and SDHD; the catalytic components SDHA and SDHB; and SDHAF2, responsible for the flavination of the SDHA component of the complex. If any component of the SDH complex is lost, the complex becomes dysfunctional and SDHB immunohistochemistry becomes negative. PPGL, paraganglioma and/or phaeochromocytoma.
Succinate dehydrogenase–deficient renal cell carcinoma. Succinate dehydrogenase–deficient renal cell carcinoma composed of bland cells with eosinophilic (but not oncocytic) cytoplasm. Intracytoplasmic inclusions containing eosinophilic, flocculent, or pale material are a common and distinctive feature.
Pulmonary chondroma arising in Carney triad. In contrast to pulmonary hamartoma, pulmonary chondromas associated with Carney triad show a smooth contour, lacking invaginations of entrapped respiratory epithelium between cartilage.
Succinate dehydrogenase–deficient paraganglioma. Morphological clues to succinate dehydrogenase–deficient paragangliomas are inconsistent but include well-developed, almost circular nests of epithelioid cells, sometimes with pale or vacuolated cytoplasm {31789631}.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Succinate dehydrogenase–deficient gastrointestinal stromal tumour commonly demonstrates a multilobulated or plexiform growth pattern.
Succinate dehydrogenase–deficient paraganglioma. Loss of expression of SDHB in succinate dehydrogenase–deficient paraganglioma. The presence of distinct granular staining in the non-neoplastic cells, which contrasts with the pale diffuse cytoplasmic blush in the neoplastic cells, is emphasized.
Phaeochromocytoma. This phaeochromocytoma not associated with SDH mutation demonstrates diffuse strong SDHB expression. The cytoplasmic and distinctly granular (mitochondrial) pattern of expression is noted.

Q: A key diagnostic feature of parathyroid tumors in Hyperparathyroidism-Jaw Tumor Syndrome is the loss of nuclear immunohistochemical expression of [...], which is associated with CDC73 gene mutations.
Parafibromin-deficient parathyroid tumour. Immunohistochemistry for parafibromin can be difficult to interpret. It is emphasized that significance is placed on nuclear expression only, and nonspecific cytoplasmic expression should be disregarded. In this case, all the neoplastic cells show loss of expression of parafibromin and there is preserved expression in non-neoplastic cells. Therefore, the tumour is considered parafibromin-deficient.
A: parafibromin
Back Extra: Hyperparathyroidism-Jaw Tumour Syndrome
- Clinical: Hyperparathyroidism–jaw tumour syndrome (HPT-JT) often presents with primary hyperparathyroidism and parathyroid tumours, with jaw lesions being relatively uncommon but characteristic.
- Micro: Parathyroid tumours in HPT-JT exhibit a sheet-like growth pattern, eosinophilic cytoplasm, perinuclear cytoplasmic clearing, nuclear enlargement, multinucleation, and prominent vasculature.
- Ancillary: Loss of nuclear expression of parafibromin is a key diagnostic feature in HPT-JT, and genetic testing for CDC73 mutations is indicated.
Reference Gallery:
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells associated with bony trabeculae.
Parafibromin-deficient parathyroid tumour. The morphological features of parafibromin-deficient parathyroid tumours are inconsistent but include a thickened and somewhat hyalinized fibrous capsule, a sheet-like growth pattern, eosinophilic cells, and prominent vasculature. A little microcystic change is noted.
Parafibromin-deficient parathyroid tumour. In contrast to most usual parathyroid adenomas, which demonstrate a somewhat nested architecture, parafibromin-deficient parathyroid tumours commonly show a sheet-like architecture with prominent vasculature.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement, perinuclear cytoplasmic clearing, and eosinophilic cells.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement often with preserved N:C ratios, multinucleation, perinuclear cytoplasmic clearing, and eosinophilic cells, sometimes with a glassy quality.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. There is a densely hypercellular stroma surrounding entrapped glands.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. Parafibromin immunohistochemistry has not been well validated as a diagnostic marker of adenosarcoma in the setting of hyperparathyroidism–jaw tumour syndrome. However, in this case, the stromal component of the adenosarcoma demonstrates loss of nuclear expression that contrasts with the preserved expression in the glandular component and the adjacent non-neoplastic stroma.
Parafibromin-deficient parathyroid tumour. Immunohistochemistry for parafibromin can be difficult to interpret. It is emphasized that significance is placed on nuclear expression only, and nonspecific cytoplasmic expression should be disregarded. In this case, all the neoplastic cells show loss of expression of parafibromin and there is preserved expression in non-neoplastic cells. Therefore, the tumour is considered parafibromin-deficient.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells surrounding bony trabeculae.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. A hypovascular stroma surrounds bony trabeculae.
Parafibromin-deficient parathyroid tumour. Sheet-like growth pattern of cells with eosinophilic cytoplasm and microcystic change.
Parathyroid carcinoma associated with hyperparathyroidism–jaw tumour syndrome. The diagnosis of carcinoma arising in the setting of hyperparathyroidism–jaw tumour syndrome relies on the same histological criteria as sporadic carcinomas: the demonstration of unequivocally invasive growth or vascular space invasion. In this instance, in addition to invasive growth, the neoplastic cells show typical cytological features of a parafibromin-deficient tumour.

Q: Unlike typical sporadic parathyroid adenomas that show nested architecture, parathyroid tumors in Hyperparathyroidism-Jaw Tumor Syndrome typically exhibit a [...] growth pattern with eosinophilic cytoplasm, perinuclear clearing, and prominent vasculature.
Parafibromin-deficient parathyroid tumour. In contrast to most usual parathyroid adenomas, which demonstrate a somewhat nested architecture, parafibromin-deficient parathyroid tumours commonly show a sheet-like architecture with prominent vasculature.
Parafibromin-deficient parathyroid tumour. Sheet-like growth pattern of cells with eosinophilic cytoplasm and microcystic change.
A: sheet-like
Back Extra: Hyperparathyroidism-Jaw Tumour Syndrome
- Clinical: Hyperparathyroidism–jaw tumour syndrome (HPT-JT) often presents with primary hyperparathyroidism and parathyroid tumours, with jaw lesions being relatively uncommon but characteristic.
- Micro: Parathyroid tumours in HPT-JT exhibit a sheet-like growth pattern, eosinophilic cytoplasm, perinuclear cytoplasmic clearing, nuclear enlargement, multinucleation, and prominent vasculature.
- Ancillary: Loss of nuclear expression of parafibromin is a key diagnostic feature in HPT-JT, and genetic testing for CDC73 mutations is indicated.
Reference Gallery:
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells associated with bony trabeculae.
Parafibromin-deficient parathyroid tumour. The morphological features of parafibromin-deficient parathyroid tumours are inconsistent but include a thickened and somewhat hyalinized fibrous capsule, a sheet-like growth pattern, eosinophilic cells, and prominent vasculature. A little microcystic change is noted.
Parafibromin-deficient parathyroid tumour. In contrast to most usual parathyroid adenomas, which demonstrate a somewhat nested architecture, parafibromin-deficient parathyroid tumours commonly show a sheet-like architecture with prominent vasculature.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement, perinuclear cytoplasmic clearing, and eosinophilic cells.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement often with preserved N:C ratios, multinucleation, perinuclear cytoplasmic clearing, and eosinophilic cells, sometimes with a glassy quality.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. There is a densely hypercellular stroma surrounding entrapped glands.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. Parafibromin immunohistochemistry has not been well validated as a diagnostic marker of adenosarcoma in the setting of hyperparathyroidism–jaw tumour syndrome. However, in this case, the stromal component of the adenosarcoma demonstrates loss of nuclear expression that contrasts with the preserved expression in the glandular component and the adjacent non-neoplastic stroma.
Parafibromin-deficient parathyroid tumour. Immunohistochemistry for parafibromin can be difficult to interpret. It is emphasized that significance is placed on nuclear expression only, and nonspecific cytoplasmic expression should be disregarded. In this case, all the neoplastic cells show loss of expression of parafibromin and there is preserved expression in non-neoplastic cells. Therefore, the tumour is considered parafibromin-deficient.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells surrounding bony trabeculae.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. A hypovascular stroma surrounds bony trabeculae.
Parafibromin-deficient parathyroid tumour. Sheet-like growth pattern of cells with eosinophilic cytoplasm and microcystic change.
Parathyroid carcinoma associated with hyperparathyroidism–jaw tumour syndrome. The diagnosis of carcinoma arising in the setting of hyperparathyroidism–jaw tumour syndrome relies on the same histological criteria as sporadic carcinomas: the demonstration of unequivocally invasive growth or vascular space invasion. In this instance, in addition to invasive growth, the neoplastic cells show typical cytological features of a parafibromin-deficient tumour.

Q: The characteristic (though uncommon) gnathic lesions seen in Hyperparathyroidism-Jaw Tumor Syndrome are histologically classified as [...], featuring a relatively avascular spindled stroma surrounding bony trabeculae.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells associated with bony trabeculae.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells surrounding bony trabeculae.
A: ossifying fibromas
Back Extra: Hyperparathyroidism-Jaw Tumour Syndrome
- Clinical: Hyperparathyroidism–jaw tumour syndrome (HPT-JT) often presents with primary hyperparathyroidism and parathyroid tumours, with jaw lesions being relatively uncommon but characteristic.
- Micro: Parathyroid tumours in HPT-JT exhibit a sheet-like growth pattern, eosinophilic cytoplasm, perinuclear cytoplasmic clearing, nuclear enlargement, multinucleation, and prominent vasculature.
- Ancillary: Loss of nuclear expression of parafibromin is a key diagnostic feature in HPT-JT, and genetic testing for CDC73 mutations is indicated.
Reference Gallery:
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells associated with bony trabeculae.
Parafibromin-deficient parathyroid tumour. The morphological features of parafibromin-deficient parathyroid tumours are inconsistent but include a thickened and somewhat hyalinized fibrous capsule, a sheet-like growth pattern, eosinophilic cells, and prominent vasculature. A little microcystic change is noted.
Parafibromin-deficient parathyroid tumour. In contrast to most usual parathyroid adenomas, which demonstrate a somewhat nested architecture, parafibromin-deficient parathyroid tumours commonly show a sheet-like architecture with prominent vasculature.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement, perinuclear cytoplasmic clearing, and eosinophilic cells.
Parafibromin-deficient parathyroid tumour. Cytological features include nuclear enlargement often with preserved N:C ratios, multinucleation, perinuclear cytoplasmic clearing, and eosinophilic cells, sometimes with a glassy quality.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. There is a densely hypercellular stroma surrounding entrapped glands.
Adenosarcoma of the uterus arising in hyperparathyroidism–jaw tumour syndrome. Parafibromin immunohistochemistry has not been well validated as a diagnostic marker of adenosarcoma in the setting of hyperparathyroidism–jaw tumour syndrome. However, in this case, the stromal component of the adenosarcoma demonstrates loss of nuclear expression that contrasts with the preserved expression in the glandular component and the adjacent non-neoplastic stroma.
Parafibromin-deficient parathyroid tumour. Immunohistochemistry for parafibromin can be difficult to interpret. It is emphasized that significance is placed on nuclear expression only, and nonspecific cytoplasmic expression should be disregarded. In this case, all the neoplastic cells show loss of expression of parafibromin and there is preserved expression in non-neoplastic cells. Therefore, the tumour is considered parafibromin-deficient.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. There is a relatively avascular hypercellular stroma composed of bland spindled cells surrounding bony trabeculae.
Ossifying fibroma arising in hyperparathyroidism–jaw tumour syndrome. A hypovascular stroma surrounds bony trabeculae.
Parafibromin-deficient parathyroid tumour. Sheet-like growth pattern of cells with eosinophilic cytoplasm and microcystic change.
Parathyroid carcinoma associated with hyperparathyroidism–jaw tumour syndrome. The diagnosis of carcinoma arising in the setting of hyperparathyroidism–jaw tumour syndrome relies on the same histological criteria as sporadic carcinomas: the demonstration of unequivocally invasive growth or vascular space invasion. In this instance, in addition to invasive growth, the neoplastic cells show typical cytological features of a parafibromin-deficient tumour.

Q: A classic pulmonary tumor associated with DICER1 Syndrome is the [...], which typically features Type I cysts lined by benign epithelium overlying primitive mesenchymal tumor cells.
DICER1-related pleuropulmonary blastoma. Type I cysts are lined by epithelial cells, beneath which lie primitive mesenchymal tumour cells.
DICER1-related pleuropulmonary blastoma. Type I cysts in pleuropulmonary blastoma are lined by keratin-positive epithelial cells.
A: pleuropulmonary blastoma
Back Extra: DICER1 Syndrome
- Clinical: Characteristic tumours include multinodular goitre, differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma, ovarian Sertoli–Leydig cell tumour (SLCT), and pituitary blastoma.
- Micro: Thyroid follicular nodules in DICER1 syndrome often show multiple benign nodules or follicular adenomas, and papillary growth patterns may be observed.
- Ancillary: Germline DICER1 alterations are loss-of-function mutations, and somatic mutations often occur at hotspots within the RNase IIIb domain, leading to impaired processing of 5p microRNAs.
Reference Gallery:
Differentiated thyroid carcinoma arising in DICER1 syndrome. The diagnosis of thyroid carcinoma in DICER1 syndrome should be restricted to lesions showing invasive growth. Here, a follicular carcinoma shows mushrooming growth into the adjacent thyroid.
Differentiated thyroid carcinoma arising in DICER1 syndrome. The differentiated thyroid carcinomas arising in DICER1 syndrome usually demonstrate a follicular or solid architecture. The nuclei may show subtle nuclear atypia.
Sertoli–Leydig cell tumour. An example with intermediate differentiation. These tumours often grow in cellular lobules, as seen in this picture. The lobules are usually predominantly composed of dark-staining Sertoli cells with fewer Leydig cells. The latter are often conspicuous at the periphery of the lobules, as seen to some degree in this picture at the 3 o’clock position.
Sertoli–Leydig cell tumour. DICER1-related Sertoli–Leydig cell tumours are always moderately poorly differentiated, solid and cystic, and pale tan.
DICER1-related pleuropulmonary blastoma. Type I cysts are lined by epithelial cells, beneath which lie primitive mesenchymal tumour cells.
DICER1-related pleuropulmonary blastoma. Type I cysts in pleuropulmonary blastoma are lined by keratin-positive epithelial cells.
Thyroblastoma. This is an underrecognized DICER1-associated tumour with primitive thyroid follicles surrounded by primitive spindle cell stroma, mimicking thyroid in development.

Q: An ovarian sex cord-stromal tumor characteristically associated with DICER1 Syndrome is the [...], which often exhibits an intermediate to poor degree of differentiation with cellular lobules of dark-staining cells.
Sertoli–Leydig cell tumour. An example with intermediate differentiation. These tumours often grow in cellular lobules, as seen in this picture. The lobules are usually predominantly composed of dark-staining Sertoli cells with fewer Leydig cells. The latter are often conspicuous at the periphery of the lobules, as seen to some degree in this picture at the 3 o’clock position.
Sertoli–Leydig cell tumour. DICER1-related Sertoli–Leydig cell tumours are always moderately poorly differentiated, solid and cystic, and pale tan.
A: Sertoli-Leydig cell tumor
Back Extra: DICER1 Syndrome
- Clinical: Characteristic tumours include multinodular goitre, differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma, ovarian Sertoli–Leydig cell tumour (SLCT), and pituitary blastoma.
- Micro: Thyroid follicular nodules in DICER1 syndrome often show multiple benign nodules or follicular adenomas, and papillary growth patterns may be observed.
- Ancillary: Germline DICER1 alterations are loss-of-function mutations, and somatic mutations often occur at hotspots within the RNase IIIb domain, leading to impaired processing of 5p microRNAs.
Reference Gallery:
Differentiated thyroid carcinoma arising in DICER1 syndrome. The diagnosis of thyroid carcinoma in DICER1 syndrome should be restricted to lesions showing invasive growth. Here, a follicular carcinoma shows mushrooming growth into the adjacent thyroid.
Differentiated thyroid carcinoma arising in DICER1 syndrome. The differentiated thyroid carcinomas arising in DICER1 syndrome usually demonstrate a follicular or solid architecture. The nuclei may show subtle nuclear atypia.
Sertoli–Leydig cell tumour. An example with intermediate differentiation. These tumours often grow in cellular lobules, as seen in this picture. The lobules are usually predominantly composed of dark-staining Sertoli cells with fewer Leydig cells. The latter are often conspicuous at the periphery of the lobules, as seen to some degree in this picture at the 3 o’clock position.
Sertoli–Leydig cell tumour. DICER1-related Sertoli–Leydig cell tumours are always moderately poorly differentiated, solid and cystic, and pale tan.
DICER1-related pleuropulmonary blastoma. Type I cysts are lined by epithelial cells, beneath which lie primitive mesenchymal tumour cells.
DICER1-related pleuropulmonary blastoma. Type I cysts in pleuropulmonary blastoma are lined by keratin-positive epithelial cells.
Thyroblastoma. This is an underrecognized DICER1-associated tumour with primitive thyroid follicles surrounded by primitive spindle cell stroma, mimicking thyroid in development.

Q: In DICER1 Syndrome, patients may develop a primitive thyroid neoplasm composed of primitive follicles surrounded by spindle cell stroma, an underrecognized entity known as [...].
Thyroblastoma. This is an underrecognized DICER1-associated tumour with primitive thyroid follicles surrounded by primitive spindle cell stroma, mimicking thyroid in development.
A: thyroblastoma
Back Extra: DICER1 Syndrome
- Clinical: Characteristic tumours include multinodular goitre, differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma, ovarian Sertoli–Leydig cell tumour (SLCT), and pituitary blastoma.
- Micro: Thyroid follicular nodules in DICER1 syndrome often show multiple benign nodules or follicular adenomas, and papillary growth patterns may be observed.
- Ancillary: Germline DICER1 alterations are loss-of-function mutations, and somatic mutations often occur at hotspots within the RNase IIIb domain, leading to impaired processing of 5p microRNAs.
Reference Gallery:
Differentiated thyroid carcinoma arising in DICER1 syndrome. The diagnosis of thyroid carcinoma in DICER1 syndrome should be restricted to lesions showing invasive growth. Here, a follicular carcinoma shows mushrooming growth into the adjacent thyroid.
Differentiated thyroid carcinoma arising in DICER1 syndrome. The differentiated thyroid carcinomas arising in DICER1 syndrome usually demonstrate a follicular or solid architecture. The nuclei may show subtle nuclear atypia.
Sertoli–Leydig cell tumour. An example with intermediate differentiation. These tumours often grow in cellular lobules, as seen in this picture. The lobules are usually predominantly composed of dark-staining Sertoli cells with fewer Leydig cells. The latter are often conspicuous at the periphery of the lobules, as seen to some degree in this picture at the 3 o’clock position.
Sertoli–Leydig cell tumour. DICER1-related Sertoli–Leydig cell tumours are always moderately poorly differentiated, solid and cystic, and pale tan.
DICER1-related pleuropulmonary blastoma. Type I cysts are lined by epithelial cells, beneath which lie primitive mesenchymal tumour cells.
DICER1-related pleuropulmonary blastoma. Type I cysts in pleuropulmonary blastoma are lined by keratin-positive epithelial cells.
Thyroblastoma. This is an underrecognized DICER1-associated tumour with primitive thyroid follicles surrounded by primitive spindle cell stroma, mimicking thyroid in development.

Q: Clinically, a Thyroglossal Duct Cyst typically presents as a painless, midline neck mass that characteristically moves [...] with swallowing.
Thyroglossal duct cyst. A midline subcutaneous mass is identified at the level of the hyoid bone in this young man.
Thyroglossal duct cyst. Sagittal CT of a cystic mass just below the tongue and above the hyoid bone.
A: upward
Back Extra: Thyroglossal Duct Cyst
- Clinical: Thyroglossal duct cysts typically present as a mobile, midline, infrahyoid, painless neck mass that moves upward with swallowing.
- Micro: The cyst is lined by respiratory or squamous epithelium, often with thyroid follicles in the cyst wall.
- Ancillary: Cytology of thyroglossal duct cysts is often nondiagnostic, but malignancy can be suspected if nuclear features of papillary thyroid carcinoma are present.
Reference Gallery:
Thyroglossal duct cyst. A midline subcutaneous mass is identified at the level of the hyoid bone in this young man.
Neck thyroglossal duct cyst. Immediately adjacent to the hyoid bone, within the soft tissue are follicles of thyroid epithelium adjacent to a respiratory epithelium–lined cyst.
Neck thyroglossal duct cyst. Thyroid follicles are usually identified in the soft tissues immediately adjacent to the cyst. This cyst shows a respiratory epithelium.
Neck thyroglossal duct cyst. Cysts commonly rupture or become inflamed, here seen with a metaplastic squamous lining. Note the thyroid follicles in the cyst wall.
Papillary carcinoma arising in a neck thyroglossal duct cyst. This sagittal CT shows a cystic lesion immediately adjacent to the hyoid bone. Nodular soft tissue excrescences within the cyst suggested carcinoma, which was confirmed histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. An ultrasound image of a midline neck cyst with an irregular contour and a nodular, soft tissue excrescence projecting into the lumen. This finding is worrisome for carcinoma, which was identified histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The characteristic histological features of conventional papillary thyroid carcinoma are noted, including psammoma bodies. Note the uninvolved thyroid gland follicles within the skeletal muscle.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The histological features of papillary thyroid carcinoma are easily identified at high magnification. Note the adjacent uninvolved thyroid follicles (left).
Thyroglossal duct cyst. Sagittal CT of a cystic mass just below the tongue and above the hyoid bone.

Q: Microscopically, a Thyroglossal Duct Cyst is lined by respiratory or squamous epithelium and characteristically contains [...] within the adjacent cyst wall.
Neck thyroglossal duct cyst. Immediately adjacent to the hyoid bone, within the soft tissue are follicles of thyroid epithelium adjacent to a respiratory epithelium–lined cyst.
Neck thyroglossal duct cyst. Thyroid follicles are usually identified in the soft tissues immediately adjacent to the cyst. This cyst shows a respiratory epithelium.
A: thyroid follicles
Back Extra: Thyroglossal Duct Cyst
- Clinical: Thyroglossal duct cysts typically present as a mobile, midline, infrahyoid, painless neck mass that moves upward with swallowing.
- Micro: The cyst is lined by respiratory or squamous epithelium, often with thyroid follicles in the cyst wall.
- Ancillary: Cytology of thyroglossal duct cysts is often nondiagnostic, but malignancy can be suspected if nuclear features of papillary thyroid carcinoma are present.
Reference Gallery:
Thyroglossal duct cyst. A midline subcutaneous mass is identified at the level of the hyoid bone in this young man.
Neck thyroglossal duct cyst. Immediately adjacent to the hyoid bone, within the soft tissue are follicles of thyroid epithelium adjacent to a respiratory epithelium–lined cyst.
Neck thyroglossal duct cyst. Thyroid follicles are usually identified in the soft tissues immediately adjacent to the cyst. This cyst shows a respiratory epithelium.
Neck thyroglossal duct cyst. Cysts commonly rupture or become inflamed, here seen with a metaplastic squamous lining. Note the thyroid follicles in the cyst wall.
Papillary carcinoma arising in a neck thyroglossal duct cyst. This sagittal CT shows a cystic lesion immediately adjacent to the hyoid bone. Nodular soft tissue excrescences within the cyst suggested carcinoma, which was confirmed histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. An ultrasound image of a midline neck cyst with an irregular contour and a nodular, soft tissue excrescence projecting into the lumen. This finding is worrisome for carcinoma, which was identified histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The characteristic histological features of conventional papillary thyroid carcinoma are noted, including psammoma bodies. Note the uninvolved thyroid gland follicles within the skeletal muscle.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The histological features of papillary thyroid carcinoma are easily identified at high magnification. Note the adjacent uninvolved thyroid follicles (left).
Thyroglossal duct cyst. Sagittal CT of a cystic mass just below the tongue and above the hyoid bone.

Q: Although typically benign, a Thyroglossal Duct Cyst may rarely undergo malignant transformation, most commonly developing into a [...] (often seen as nodular excrescences on imaging).
Papillary carcinoma arising in a neck thyroglossal duct cyst. This sagittal CT shows a cystic lesion immediately adjacent to the hyoid bone. Nodular soft tissue excrescences within the cyst suggested carcinoma, which was confirmed histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The characteristic histological features of conventional papillary thyroid carcinoma are noted, including psammoma bodies. Note the uninvolved thyroid gland follicles within the skeletal muscle.
A: papillary thyroid carcinoma
Back Extra: Thyroglossal Duct Cyst
- Clinical: Thyroglossal duct cysts typically present as a mobile, midline, infrahyoid, painless neck mass that moves upward with swallowing.
- Micro: The cyst is lined by respiratory or squamous epithelium, often with thyroid follicles in the cyst wall.
- Ancillary: Cytology of thyroglossal duct cysts is often nondiagnostic, but malignancy can be suspected if nuclear features of papillary thyroid carcinoma are present.
Reference Gallery:
Thyroglossal duct cyst. A midline subcutaneous mass is identified at the level of the hyoid bone in this young man.
Neck thyroglossal duct cyst. Immediately adjacent to the hyoid bone, within the soft tissue are follicles of thyroid epithelium adjacent to a respiratory epithelium–lined cyst.
Neck thyroglossal duct cyst. Thyroid follicles are usually identified in the soft tissues immediately adjacent to the cyst. This cyst shows a respiratory epithelium.
Neck thyroglossal duct cyst. Cysts commonly rupture or become inflamed, here seen with a metaplastic squamous lining. Note the thyroid follicles in the cyst wall.
Papillary carcinoma arising in a neck thyroglossal duct cyst. This sagittal CT shows a cystic lesion immediately adjacent to the hyoid bone. Nodular soft tissue excrescences within the cyst suggested carcinoma, which was confirmed histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. An ultrasound image of a midline neck cyst with an irregular contour and a nodular, soft tissue excrescence projecting into the lumen. This finding is worrisome for carcinoma, which was identified histologically.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The characteristic histological features of conventional papillary thyroid carcinoma are noted, including psammoma bodies. Note the uninvolved thyroid gland follicles within the skeletal muscle.
Papillary carcinoma arising in a neck thyroglossal duct cyst. The histological features of papillary thyroid carcinoma are easily identified at high magnification. Note the adjacent uninvolved thyroid follicles (left).
Thyroglossal duct cyst. Sagittal CT of a cystic mass just below the tongue and above the hyoid bone.

Q: As part of the spectrum of Congenital Thyroid Abnormalities, [...] tissue typically presents histologically as normal follicular architecture intermixed with native surrounding structures (e.g., skeletal muscle, adipose tissue, or thymus).
Ectopic thyroid. Lingual thyroid demonstrates an intact squamous epithelium with subepithelial minor mucoserous glands in addition to the follicles of unremarkable thyroid gland parenchyma.
Ectopic thyroid. Ectopic thyroid tissue in the thymus.
A: ectopic thyroid
Back Extra: Congenital Thyroid Abnormalities
- Clinical: Most cases of ectopic thyroid are asymptomatic, but cases associated with compressive symptoms (dysphagia, dyspnoea, airway obstruction) can occur, especially during puberty and pregnancy.
- Micro: Ectopic thyroid tissue shows normal follicular architecture intermixed with surrounding structures (skeletal muscle, adipose) native to the location. Thyroid nodules in dyshormonogenetic goitre (DG) are hypercellular and can show papillary, trabecular/solid, microfollicular, and microcystic architecture.
- Ancillary: Molecular testing on specimens from ectopic locations can help differentiate between reactive and neoplastic thyroid conditions.
Reference Gallery:
Ectopic thyroid. Lingual thyroid demonstrates an intact squamous epithelium with subepithelial minor mucoserous glands in addition to the follicles of unremarkable thyroid gland parenchyma.
Ectopic thyroid. Islands and follicles of normal-appearing thyroid gland tissue are noted in the adipose tissue and within the parathyroid gland parenchyma.
Ectopic thyroid. Normal-appearing thyroid and parathyroid tissue are noted in the adipose tissue of the mediastinum, along with thymic tissue.
Ectopic thyroid tissue in the larynx. Laryngectomy specimen showing ectopic thyroid tissue in soft tissue and muscle, infiltrated by squamous cell carcinoma (arrow).
Ectopic thyroid. Ectopic thyroid tissue in the thymus.
Dyshormonogenetic goitre. The thyroid is composed of nodules (usually hypercellular) separated by internodular fibrous tissue.
Dyshormonogenetic goitre. Random nuclear atypia, concentrated in the internodular regions, is one characteristic feature of this disease.
Dyshormonogenetic goitre. The nuclear atypia consists of irregularly shaped enlarged and hyperchromatic nuclei.

Q: In Congenital Thyroid Abnormalities, patients with [...] characteristically exhibit hypercellular thyroid nodules separated by internodular fibrous tissue with random, bizarre nuclear atypia.
Dyshormonogenetic goitre. The thyroid is composed of nodules (usually hypercellular) separated by internodular fibrous tissue.
Dyshormonogenetic goitre. The nuclear atypia consists of irregularly shaped enlarged and hyperchromatic nuclei.
A: dyshormonogenetic goiter
Back Extra: Congenital Thyroid Abnormalities
- Clinical: Most cases of ectopic thyroid are asymptomatic, but cases associated with compressive symptoms (dysphagia, dyspnoea, airway obstruction) can occur, especially during puberty and pregnancy.
- Micro: Ectopic thyroid tissue shows normal follicular architecture intermixed with surrounding structures (skeletal muscle, adipose) native to the location. Thyroid nodules in dyshormonogenetic goitre (DG) are hypercellular and can show papillary, trabecular/solid, microfollicular, and microcystic architecture.
- Ancillary: Molecular testing on specimens from ectopic locations can help differentiate between reactive and neoplastic thyroid conditions.
Reference Gallery:
Ectopic thyroid. Lingual thyroid demonstrates an intact squamous epithelium with subepithelial minor mucoserous glands in addition to the follicles of unremarkable thyroid gland parenchyma.
Ectopic thyroid. Islands and follicles of normal-appearing thyroid gland tissue are noted in the adipose tissue and within the parathyroid gland parenchyma.
Ectopic thyroid. Normal-appearing thyroid and parathyroid tissue are noted in the adipose tissue of the mediastinum, along with thymic tissue.
Ectopic thyroid tissue in the larynx. Laryngectomy specimen showing ectopic thyroid tissue in soft tissue and muscle, infiltrated by squamous cell carcinoma (arrow).
Ectopic thyroid. Ectopic thyroid tissue in the thymus.
Dyshormonogenetic goitre. The thyroid is composed of nodules (usually hypercellular) separated by internodular fibrous tissue.
Dyshormonogenetic goitre. Random nuclear atypia, concentrated in the internodular regions, is one characteristic feature of this disease.
Dyshormonogenetic goitre. The nuclear atypia consists of irregularly shaped enlarged and hyperchromatic nuclei.

Q: A patient presents with a cold thyroid nodule, anemia, and hypergammaglobulinemia. Biopsy reveals large histiocytes with abundant pale cytoplasm and prominent emperipolesis (intact lymphocytes and plasma cells within the cytoplasm). These findings are highly characteristic of [...].
Rosai–Dorfman disease involving the thyroid. The distinctive histiocytes are very large. They have round nuclei with distinct nucleoli and abundant pale-staining cytoplasm. Some contain lymphocytes or plasma cells in the cytoplasm. Abundant intermingled plasma cells are noticeable.
A: Rosai–Dorfman Disease
Back Extra: Rosai–Dorfman Disease
- Clinical: Patients with thyroid Rosai–Dorfman Disease (RDD) often present with a cold thyroid nodule and systemic symptoms such as anaemia, leukocytosis, and hypergammaglobulinaemia.
- Micro: Histopathologically, RDD is characterized by large histiocytes with round vesicular nuclei, distinct nucleoli, and abundant pale cytoplasm, which exhibit emperipolesis of lymphocytes, neutrophils, and plasma cells.
- Ancillary: Approximately 50% of thyroid RDD cases carry gain-of-function mutations in MAPK/ERK pathway genes, including KRAS, NRAS, and MAP2K1.
Reference Gallery:
Rosai–Dorfman disease of the thyroid. FNA. Large histiocytes with abundant pale cytoplasm showing pronounced emperipolesis.
Rosai–Dorfman disease involving the thyroid. The distinctive histiocytes are very large. They have round nuclei with distinct nucleoli and abundant pale-staining cytoplasm. Some contain lymphocytes or plasma cells in the cytoplasm. Abundant intermingled plasma cells are noticeable.
Rosai–Dorfman disease involving the thyroid. The large histiocytes express S100. Emperipolesis is also obvious.

Q: The hallmark histologic feature of Rosai–Dorfman Disease is the presence of large histiocytes engulfing intact lymphocytes, neutrophils, and plasma cells, a phenomenon termed [...].
Rosai–Dorfman disease of the thyroid. FNA. Large histiocytes with abundant pale cytoplasm showing pronounced emperipolesis.
Rosai–Dorfman disease involving the thyroid. The distinctive histiocytes are very large. They have round nuclei with distinct nucleoli and abundant pale-staining cytoplasm. Some contain lymphocytes or plasma cells in the cytoplasm. Abundant intermingled plasma cells are noticeable.
A: emperipolesis
Back Extra: Rosai–Dorfman Disease
- Clinical: Patients with thyroid Rosai–Dorfman Disease (RDD) often present with a cold thyroid nodule and systemic symptoms such as anaemia, leukocytosis, and hypergammaglobulinaemia.
- Micro: Histopathologically, RDD is characterized by large histiocytes with round vesicular nuclei, distinct nucleoli, and abundant pale cytoplasm, which exhibit emperipolesis of lymphocytes, neutrophils, and plasma cells.
- Ancillary: Approximately 50% of thyroid RDD cases carry gain-of-function mutations in MAPK/ERK pathway genes, including KRAS, NRAS, and MAP2K1.
Reference Gallery:
Rosai–Dorfman disease of the thyroid. FNA. Large histiocytes with abundant pale cytoplasm showing pronounced emperipolesis.
Rosai–Dorfman disease involving the thyroid. The distinctive histiocytes are very large. They have round nuclei with distinct nucleoli and abundant pale-staining cytoplasm. Some contain lymphocytes or plasma cells in the cytoplasm. Abundant intermingled plasma cells are noticeable.
Rosai–Dorfman disease involving the thyroid. The large histiocytes express S100. Emperipolesis is also obvious.

Q: In Rosai–Dorfman Disease, the characteristic large histiocytes that exhibit emperipolesis typically strongly express the immunohistochemical marker [...].
Rosai–Dorfman disease involving the thyroid. The large histiocytes express S100. Emperipolesis is also obvious.
A: S100
Back Extra: Rosai–Dorfman Disease
- Clinical: Patients with thyroid Rosai–Dorfman Disease (RDD) often present with a cold thyroid nodule and systemic symptoms such as anaemia, leukocytosis, and hypergammaglobulinaemia.
- Micro: Histopathologically, RDD is characterized by large histiocytes with round vesicular nuclei, distinct nucleoli, and abundant pale cytoplasm, which exhibit emperipolesis of lymphocytes, neutrophils, and plasma cells.
- Ancillary: Approximately 50% of thyroid RDD cases carry gain-of-function mutations in MAPK/ERK pathway genes, including KRAS, NRAS, and MAP2K1.
Reference Gallery:
Rosai–Dorfman disease of the thyroid. FNA. Large histiocytes with abundant pale cytoplasm showing pronounced emperipolesis.
Rosai–Dorfman disease involving the thyroid. The distinctive histiocytes are very large. They have round nuclei with distinct nucleoli and abundant pale-staining cytoplasm. Some contain lymphocytes or plasma cells in the cytoplasm. Abundant intermingled plasma cells are noticeable.
Rosai–Dorfman disease involving the thyroid. The large histiocytes express S100. Emperipolesis is also obvious.

Q: Histologically, IgG4-Related Disease is classically characterized by a dense lymphoplasmacytic infiltrate, obliterative phlebitis, and a distinctive pattern of fibrosis described as [...].
IgG4-related disease. IgG4-related pancreatitis shows a lymphoplasmacytic infiltrate associated with fibrosis, often in a storiform pattern.
A: storiform
Back Extra: IgG4-Related Disease
- Clinical: IgG4-Related Disease in the thyroid can present with hypothyroidism or painless thyroid enlargement, often mimicking Riedel-like thyroiditis.
- Micro: Characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Eosinophils are often present, but neutrophils and granulomas are not.
- Ancillary: Diagnosis is supported by an IgG4+:IgG+ plasma cell ratio > 40%, elevated serum IgG4 (> 140 mg/dL), and response to glucocorticoid therapy.
Reference Gallery:
IgG4-related disease. IgG4-related pancreatitis shows a lymphoplasmacytic infiltrate associated with fibrosis, often in a storiform pattern.
IgG4-related disease. IgG4-related pancreatitis with obliterative phlebitis.
IgG4-related disease. IgG immunostain in a case of IgG4-related pancreatitis.
IgG4-related disease. IgG4 immunostain in a case of IgG4-related pancreatitis.

Q: A hallmark vascular finding in the histologic evaluation of IgG4-Related Disease is [...], which often accompanies dense lymphoplasmacytic infiltrates and fibrosis.
IgG4-related disease. IgG4-related pancreatitis with obliterative phlebitis.
A: obliterative phlebitis
Back Extra: IgG4-Related Disease
- Clinical: IgG4-Related Disease in the thyroid can present with hypothyroidism or painless thyroid enlargement, often mimicking Riedel-like thyroiditis.
- Micro: Characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Eosinophils are often present, but neutrophils and granulomas are not.
- Ancillary: Diagnosis is supported by an IgG4+:IgG+ plasma cell ratio > 40%, elevated serum IgG4 (> 140 mg/dL), and response to glucocorticoid therapy.
Reference Gallery:
IgG4-related disease. IgG4-related pancreatitis shows a lymphoplasmacytic infiltrate associated with fibrosis, often in a storiform pattern.
IgG4-related disease. IgG4-related pancreatitis with obliterative phlebitis.
IgG4-related disease. IgG immunostain in a case of IgG4-related pancreatitis.
IgG4-related disease. IgG4 immunostain in a case of IgG4-related pancreatitis.

Q: Immunohistochemical evaluation of IgG4-Related Disease typically demonstrates an IgG4+ to IgG+ plasma cell ratio of greater than [...]%.
IgG4-related disease. IgG immunostain in a case of IgG4-related pancreatitis.
IgG4-related disease. IgG4 immunostain in a case of IgG4-related pancreatitis.
A: 40
Back Extra: IgG4-Related Disease
- Clinical: IgG4-Related Disease in the thyroid can present with hypothyroidism or painless thyroid enlargement, often mimicking Riedel-like thyroiditis.
- Micro: Characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Eosinophils are often present, but neutrophils and granulomas are not.
- Ancillary: Diagnosis is supported by an IgG4+:IgG+ plasma cell ratio > 40%, elevated serum IgG4 (> 140 mg/dL), and response to glucocorticoid therapy.
Reference Gallery:
IgG4-related disease. IgG4-related pancreatitis shows a lymphoplasmacytic infiltrate associated with fibrosis, often in a storiform pattern.
IgG4-related disease. IgG4-related pancreatitis with obliterative phlebitis.
IgG4-related disease. IgG immunostain in a case of IgG4-related pancreatitis.
IgG4-related disease. IgG4 immunostain in a case of IgG4-related pancreatitis.

Q: Histologically, a Follicular Adenoma is a completely encapsulated, follicular-patterned tumor that specifically lacks [...].
Follicular adenoma. Low-power photomicrograph.
Follicular adenoma. Microfollicular architecture composed of cells with round nuclei with variably coarse chromatin.
A: capsular or vascular invasion
Back Extra: Follicular Adenoma
- Clinical: Follicular adenomas typically present as painless, palpable thyroid masses in adults, with a mean age of diagnosis between 45–55 years.
- Micro: Follicular adenomas are encapsulated, follicular-patterned tumours with a microfollicular, normofollicular, or macrofollicular growth pattern, lacking capsular or vascular invasion.
- Ancillary: RAS point mutations are the most common genetic alteration in follicular adenomas, occurring in about 25% of cases.
Reference Gallery:
Follicular adenoma. Low-power photomicrograph.
Follicular adenoma. Microfollicular architecture composed of cells with round nuclei with variably coarse chromatin.
Follicular adenoma. Scattered cells demonstrating endocrine atypia.
Follicular adenoma. Myxoid stroma.
Follicular adenoma. Clear cell pattern. Rare follicular adenomas are composed of cells with clear cytoplasm.
Follicular adenoma. Signet-ring cell pattern. This tumour is composed of cells with a signet-ring cell morphology.
Follicular adenoma. This FNA specimen from a follicular adenoma was diagnosed as suspicious for a follicular neoplasm. Note the microfollicular architecture and round nuclei. Follicular adenomas and follicular thyroid carcinomas cannot be distinguished in FNA specimens because the distinction is based on assessment of invasion (Pap).
Follicular adenoma. FNA specimen of a follicular adenoma diagnosed as suspicious for a follicular neoplasm because of the presence of a monotonous population of follicular cells arranged in microfollicles (Giemsa stain).

Q: On fine needle aspiration (FNA), a Follicular Adenoma typically presents as a monotonous microfollicular proliferation that cannot be reliably distinguished from a [...] because invasion cannot be assessed cytologically.
Follicular adenoma. This FNA specimen from a follicular adenoma was diagnosed as suspicious for a follicular neoplasm. Note the microfollicular architecture and round nuclei. Follicular adenomas and follicular thyroid carcinomas cannot be distinguished in FNA specimens because the distinction is based on assessment of invasion (Pap).
Follicular adenoma. FNA specimen of a follicular adenoma diagnosed as suspicious for a follicular neoplasm because of the presence of a monotonous population of follicular cells arranged in microfollicles (Giemsa stain).
A: follicular thyroid carcinoma
Back Extra: Follicular Adenoma
- Clinical: Follicular adenomas typically present as painless, palpable thyroid masses in adults, with a mean age of diagnosis between 45–55 years.
- Micro: Follicular adenomas are encapsulated, follicular-patterned tumours with a microfollicular, normofollicular, or macrofollicular growth pattern, lacking capsular or vascular invasion.
- Ancillary: RAS point mutations are the most common genetic alteration in follicular adenomas, occurring in about 25% of cases.
Reference Gallery:
Follicular adenoma. Low-power photomicrograph.
Follicular adenoma. Microfollicular architecture composed of cells with round nuclei with variably coarse chromatin.
Follicular adenoma. Scattered cells demonstrating endocrine atypia.
Follicular adenoma. Myxoid stroma.
Follicular adenoma. Clear cell pattern. Rare follicular adenomas are composed of cells with clear cytoplasm.
Follicular adenoma. Signet-ring cell pattern. This tumour is composed of cells with a signet-ring cell morphology.
Follicular adenoma. This FNA specimen from a follicular adenoma was diagnosed as suspicious for a follicular neoplasm. Note the microfollicular architecture and round nuclei. Follicular adenomas and follicular thyroid carcinomas cannot be distinguished in FNA specimens because the distinction is based on assessment of invasion (Pap).
Follicular adenoma. FNA specimen of a follicular adenoma diagnosed as suspicious for a follicular neoplasm because of the presence of a monotonous population of follicular cells arranged in microfollicles (Giemsa stain).

Q: Occasional scattered cells demonstrating enlarged, hyperchromatic nuclei within a Follicular Adenoma represent [...], a benign degenerative change that does not indicate malignancy.
Follicular adenoma. Scattered cells demonstrating endocrine atypia.
A: endocrine atypia
Back Extra: Follicular Adenoma
- Clinical: Follicular adenomas typically present as painless, palpable thyroid masses in adults, with a mean age of diagnosis between 45–55 years.
- Micro: Follicular adenomas are encapsulated, follicular-patterned tumours with a microfollicular, normofollicular, or macrofollicular growth pattern, lacking capsular or vascular invasion.
- Ancillary: RAS point mutations are the most common genetic alteration in follicular adenomas, occurring in about 25% of cases.
Reference Gallery:
Follicular adenoma. Low-power photomicrograph.
Follicular adenoma. Microfollicular architecture composed of cells with round nuclei with variably coarse chromatin.
Follicular adenoma. Scattered cells demonstrating endocrine atypia.
Follicular adenoma. Myxoid stroma.
Follicular adenoma. Clear cell pattern. Rare follicular adenomas are composed of cells with clear cytoplasm.
Follicular adenoma. Signet-ring cell pattern. This tumour is composed of cells with a signet-ring cell morphology.
Follicular adenoma. This FNA specimen from a follicular adenoma was diagnosed as suspicious for a follicular neoplasm. Note the microfollicular architecture and round nuclei. Follicular adenomas and follicular thyroid carcinomas cannot be distinguished in FNA specimens because the distinction is based on assessment of invasion (Pap).
Follicular adenoma. FNA specimen of a follicular adenoma diagnosed as suspicious for a follicular neoplasm because of the presence of a monotonous population of follicular cells arranged in microfollicles (Giemsa stain).

Q: Histologically, [...] is characterized by large follicles with complex papillary infoldings and edematous fibrovascular cores, strictly lacking the nuclear features of papillary thyroid carcinoma.
Follicular adenoma with papillary architecture. Low-power view showing large colloid-filled follicles and complex papillary infoldings of the lining epithelium.
Follicular adenoma with papillary architecture. At high magnification the cells are often columnar. The nuclei are basally located and are small, round, and dark. Nuclear features of papillary thyroid carcinoma are always absent. The oedematous fibrovascular cores show embedded follicles.
A: Follicular Thyroid Adenoma with Papillary Architecture
Back Extra: Follicular Thyroid Adenoma with Papillary Architecture
- Clinical: Solitary autonomous hyperfunctioning follicular adenomas with papillary architecture predominantly occur in women and are often associated with subclinical or overt hyperthyroidism.
- Micro: The tumours are characterized by large follicles with complex papillary infoldings, lacking nuclear features of papillary thyroid carcinoma (PTC), and often show a monotonous population of columnar cells with basally located nuclei.
- Ancillary: TSHR, DICER1, and GNAS mutations are commonly detected in these neoplasms, leading to increased intracellular cAMP and thyroid cell proliferation.
Reference Gallery:
Follicular adenoma with papillary architecture. Low-power view showing large colloid-filled follicles and complex papillary infoldings of the lining epithelium.
Follicular adenoma with papillary architecture. This example is from a patient with McCune–Albright syndrome.
Follicular adenoma with papillary architecture. At high magnification the cells are often columnar. The nuclei are basally located and are small, round, and dark. Nuclear features of papillary thyroid carcinoma are always absent. The oedematous fibrovascular cores show embedded follicles.
Follicular adenoma with papillary architecture. Pap-stained FNA specimen showing a monotonous population of follicular cells arranged in non-branching papillary groups in a background of thin colloid and macrophages.
Follicular adenoma with papillary architecture. Giemsa-stained FNA showing a monotonous population of follicular cells arranged in non-branching papillary groups.
Follicular adenoma with papillary architecture. Cytological features. The papillae are lined by follicular epithelial cells that have uniform round basophilic nuclei.

Q: On fine-needle aspiration, [...] displays a monotonous population of follicular cells arranged in non-branching papillary groups with uniform, round basophilic nuclei in a background of thin colloid.
Follicular adenoma with papillary architecture. Pap-stained FNA specimen showing a monotonous population of follicular cells arranged in non-branching papillary groups in a background of thin colloid and macrophages.
Follicular adenoma with papillary architecture. Giemsa-stained FNA showing a monotonous population of follicular cells arranged in non-branching papillary groups.
Follicular adenoma with papillary architecture. Cytological features. The papillae are lined by follicular epithelial cells that have uniform round basophilic nuclei.
A: Follicular Thyroid Adenoma with Papillary Architecture
Back Extra: Follicular Thyroid Adenoma with Papillary Architecture
- Clinical: Solitary autonomous hyperfunctioning follicular adenomas with papillary architecture predominantly occur in women and are often associated with subclinical or overt hyperthyroidism.
- Micro: The tumours are characterized by large follicles with complex papillary infoldings, lacking nuclear features of papillary thyroid carcinoma (PTC), and often show a monotonous population of columnar cells with basally located nuclei.
- Ancillary: TSHR, DICER1, and GNAS mutations are commonly detected in these neoplasms, leading to increased intracellular cAMP and thyroid cell proliferation.
Reference Gallery:
Follicular adenoma with papillary architecture. Low-power view showing large colloid-filled follicles and complex papillary infoldings of the lining epithelium.
Follicular adenoma with papillary architecture. This example is from a patient with McCune–Albright syndrome.
Follicular adenoma with papillary architecture. At high magnification the cells are often columnar. The nuclei are basally located and are small, round, and dark. Nuclear features of papillary thyroid carcinoma are always absent. The oedematous fibrovascular cores show embedded follicles.
Follicular adenoma with papillary architecture. Pap-stained FNA specimen showing a monotonous population of follicular cells arranged in non-branching papillary groups in a background of thin colloid and macrophages.
Follicular adenoma with papillary architecture. Giemsa-stained FNA showing a monotonous population of follicular cells arranged in non-branching papillary groups.
Follicular adenoma with papillary architecture. Cytological features. The papillae are lined by follicular epithelial cells that have uniform round basophilic nuclei.

Q: Follicular Thyroid Adenoma with Papillary Architecture frequently presents as an autonomous hyperfunctioning tumor and may be driven by GNAS mutations, an association classically linked to [...].
Follicular adenoma with papillary architecture. This example is from a patient with McCune–Albright syndrome.
A: McCune-Albright syndrome
Back Extra: Follicular Thyroid Adenoma with Papillary Architecture
- Clinical: Solitary autonomous hyperfunctioning follicular adenomas with papillary architecture predominantly occur in women and are often associated with subclinical or overt hyperthyroidism.
- Micro: The tumours are characterized by large follicles with complex papillary infoldings, lacking nuclear features of papillary thyroid carcinoma (PTC), and often show a monotonous population of columnar cells with basally located nuclei.
- Ancillary: TSHR, DICER1, and GNAS mutations are commonly detected in these neoplasms, leading to increased intracellular cAMP and thyroid cell proliferation.
Reference Gallery:
Follicular adenoma with papillary architecture. Low-power view showing large colloid-filled follicles and complex papillary infoldings of the lining epithelium.
Follicular adenoma with papillary architecture. This example is from a patient with McCune–Albright syndrome.
Follicular adenoma with papillary architecture. At high magnification the cells are often columnar. The nuclei are basally located and are small, round, and dark. Nuclear features of papillary thyroid carcinoma are always absent. The oedematous fibrovascular cores show embedded follicles.
Follicular adenoma with papillary architecture. Pap-stained FNA specimen showing a monotonous population of follicular cells arranged in non-branching papillary groups in a background of thin colloid and macrophages.
Follicular adenoma with papillary architecture. Giemsa-stained FNA showing a monotonous population of follicular cells arranged in non-branching papillary groups.
Follicular adenoma with papillary architecture. Cytological features. The papillae are lined by follicular epithelial cells that have uniform round basophilic nuclei.

Q: A thyroid gland [...] (a major entity among Germ Cell Tumors in Endocrine Organs) classically presents in neonates as a large, mixed solid and cystic neck mass capable of causing severe airway compression.
Thyroid gland teratoma. Sagittal T1-weighted MRI showing a large mass in the neck of a neonate, resulting in compression of vital structures. Internal solid structures (calcifications) and cystic structures are seen.
A: teratoma
Back Extra: Germ Cell Tumours in Endocrine Organs
- Clinical: Thyroid gland teratomas can present as large neck masses causing airway compression and respiratory distress, particularly in neonates.
- Micro: Teratomas contain tissues from all three germ cell layers, including epithelial, neural, and mesenchymal elements.
- Ancillary: Immunohistochemistry is usually unnecessary, but the absence of DICER1 hotspot mutations can help distinguish benign or immature teratomas from malignant tumours.
Reference Gallery:
Thyroid gland teratoma. Sagittal T1-weighted MRI showing a large mass in the neck of a neonate, resulting in compression of vital structures. Internal solid structures (calcifications) and cystic structures are seen.
Thyroid gland teratoma. Thyroid gland tissue is noted (top), and various elements of the germ cell layers are seen, including cartilage and glands. Immature neural elements are noted (immature teratoma).
Thyroid gland teratoma. A large cyst is lined by goblet-type epithelium, and more primitive stroma is seen around other glandular elements, in this mature teratoma.
Thyroid gland teratoma. Both mature and immature elements are noted in this teratoma. Pigmented retinal anlage epithelium is noted adjacent to glandular epithelium and immature skeletal muscle. Islands of immature neuroectodermal elements are seen.

Q: Microscopically, a thyroid gland teratoma (a classic example of Germ Cell Tumors in Endocrine Organs) is characterized by an admixture of tissues derived from all three [...], displaying diverse elements such as mature cartilage, glandular epithelium, and immature neuroectoderm.
Thyroid gland teratoma. Thyroid gland tissue is noted (top), and various elements of the germ cell layers are seen, including cartilage and glands. Immature neural elements are noted (immature teratoma).
Thyroid gland teratoma. A large cyst is lined by goblet-type epithelium, and more primitive stroma is seen around other glandular elements, in this mature teratoma.
Thyroid gland teratoma. Both mature and immature elements are noted in this teratoma. Pigmented retinal anlage epithelium is noted adjacent to glandular epithelium and immature skeletal muscle. Islands of immature neuroectodermal elements are seen.
A: germ cell layers
Back Extra: Germ Cell Tumours in Endocrine Organs
- Clinical: Thyroid gland teratomas can present as large neck masses causing airway compression and respiratory distress, particularly in neonates.
- Micro: Teratomas contain tissues from all three germ cell layers, including epithelial, neural, and mesenchymal elements.
- Ancillary: Immunohistochemistry is usually unnecessary, but the absence of DICER1 hotspot mutations can help distinguish benign or immature teratomas from malignant tumours.
Reference Gallery:
Thyroid gland teratoma. Sagittal T1-weighted MRI showing a large mass in the neck of a neonate, resulting in compression of vital structures. Internal solid structures (calcifications) and cystic structures are seen.
Thyroid gland teratoma. Thyroid gland tissue is noted (top), and various elements of the germ cell layers are seen, including cartilage and glands. Immature neural elements are noted (immature teratoma).
Thyroid gland teratoma. A large cyst is lined by goblet-type epithelium, and more primitive stroma is seen around other glandular elements, in this mature teratoma.
Thyroid gland teratoma. Both mature and immature elements are noted in this teratoma. Pigmented retinal anlage epithelium is noted adjacent to glandular epithelium and immature skeletal muscle. Islands of immature neuroectodermal elements are seen.

Q: A well-circumscribed thyroid neoplasm characterized by large cells with abundant hyaline cytoplasm arranged in wide trabeculae, prominent eosinophilic intratrabecular hyaline material, and nuclei with grooves and pseudoinclusions is diagnostic of a [...].
Hyalinizing trabecular tumour with metachronous lymph node metastases. A circumscribed but unencapsulated neoplasm composed of nests and cords of elongated cells with hyaline cytoplasm and prominent eosinophilic hyaline amorphous material in the stroma.
Hyalinizing trabecular tumour. Typical trabecular growth, marked cytoplasmic hyalinization, and irregular nuclei with irregular contours and pseudoinclusions.
A: hyalinizing trabecular tumor
Back Extra: Hyalinizing Trabecular Tumour
- Clinical: Hyalinizing Trabecular Tumour (HTT) is often found incidentally on ultrasonography and is usually hypoechoic and solid with peripheral or poor vascularity.
- Micro: HTT is characterized by wide trabeculae of large polygonal or elongated cells with abundant hyaline cytoplasm and prominent eosinophilic intratrabecular hyaline material.
- Ancillary: Thyroglobulin and TTF1 are invariably positive in HTT, and the presence of a PAX8::GLIS3 fusion can be detected by GLIS3 expression.
Reference Gallery:
Hyalinizing trabecular tumour with metachronous lymph node metastases. A circumscribed but unencapsulated neoplasm composed of nests and cords of elongated cells with hyaline cytoplasm and prominent eosinophilic hyaline amorphous material in the stroma.
Hyalinizing trabecular tumour with metachronous lymph node metastases. Large polygonal or elongated tumour cells have abundant eosinophilic cytoplasm.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cells have abundant hyaline cytoplasm and bizarre convoluted nuclei.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cell nuclei are convoluted with prominent membrane irregularities that form grooves and pseudoinclusions (arrow).
Hyalinizing trabecular tumour. Cytological features. Sheets of cells with a trabecular arrangement (Pap).
Hyalinizing trabecular tumour. A well-circumscribed nodule with a thin capsule.
Hyalinizing trabecular tumour. Typical trabecular growth, marked cytoplasmic hyalinization, and irregular nuclei with irregular contours and pseudoinclusions.
Hyalinizing trabecular tumour. PASD-positive intratrabecular material, with cells oriented perpendicularly to the trabeculae.
Hyalinizing trabecular tumour. Membranous Ki-67 staining using the MIB1 clone in a histological sample. Immunoperoxidase with DAB staining.
Hyalinizing trabecular tumour. Cytoplasmic and nuclear expression of GLIS3 in the presence of a PAX8::GLIS3 rearrangement.

Q: In hyalinizing trabecular tumor, a highly characteristic molecular alteration is the presence of a [GLIS3] gene fusion, which correlates with positive cytoplasmic and nuclear expression of GLIS3.
Hyalinizing trabecular tumour. Cytoplasmic and nuclear expression of GLIS3 in the presence of a PAX8::GLIS3 rearrangement.
A: PAX8
Back Extra: Hyalinizing Trabecular Tumour
- Clinical: Hyalinizing Trabecular Tumour (HTT) is often found incidentally on ultrasonography and is usually hypoechoic and solid with peripheral or poor vascularity.
- Micro: HTT is characterized by wide trabeculae of large polygonal or elongated cells with abundant hyaline cytoplasm and prominent eosinophilic intratrabecular hyaline material.
- Ancillary: Thyroglobulin and TTF1 are invariably positive in HTT, and the presence of a PAX8::GLIS3 fusion can be detected by GLIS3 expression.
Reference Gallery:
Hyalinizing trabecular tumour with metachronous lymph node metastases. A circumscribed but unencapsulated neoplasm composed of nests and cords of elongated cells with hyaline cytoplasm and prominent eosinophilic hyaline amorphous material in the stroma.
Hyalinizing trabecular tumour with metachronous lymph node metastases. Large polygonal or elongated tumour cells have abundant eosinophilic cytoplasm.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cells have abundant hyaline cytoplasm and bizarre convoluted nuclei.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cell nuclei are convoluted with prominent membrane irregularities that form grooves and pseudoinclusions (arrow).
Hyalinizing trabecular tumour. Cytological features. Sheets of cells with a trabecular arrangement (Pap).
Hyalinizing trabecular tumour. A well-circumscribed nodule with a thin capsule.
Hyalinizing trabecular tumour. Typical trabecular growth, marked cytoplasmic hyalinization, and irregular nuclei with irregular contours and pseudoinclusions.
Hyalinizing trabecular tumour. PASD-positive intratrabecular material, with cells oriented perpendicularly to the trabeculae.
Hyalinizing trabecular tumour. Membranous Ki-67 staining using the MIB1 clone in a histological sample. Immunoperoxidase with DAB staining.
Hyalinizing trabecular tumour. Cytoplasmic and nuclear expression of GLIS3 in the presence of a PAX8::GLIS3 rearrangement.

Q: A unique and diagnostically useful immunohistochemical artifact frequently observed in hyalinizing trabecular tumor is anomalous [...] staining when evaluating the Ki-67 index using the MIB1 clone.
Hyalinizing trabecular tumour. Membranous Ki-67 staining using the MIB1 clone in a histological sample. Immunoperoxidase with DAB staining.
A: membranous
Back Extra: Hyalinizing Trabecular Tumour
- Clinical: Hyalinizing Trabecular Tumour (HTT) is often found incidentally on ultrasonography and is usually hypoechoic and solid with peripheral or poor vascularity.
- Micro: HTT is characterized by wide trabeculae of large polygonal or elongated cells with abundant hyaline cytoplasm and prominent eosinophilic intratrabecular hyaline material.
- Ancillary: Thyroglobulin and TTF1 are invariably positive in HTT, and the presence of a PAX8::GLIS3 fusion can be detected by GLIS3 expression.
Reference Gallery:
Hyalinizing trabecular tumour with metachronous lymph node metastases. A circumscribed but unencapsulated neoplasm composed of nests and cords of elongated cells with hyaline cytoplasm and prominent eosinophilic hyaline amorphous material in the stroma.
Hyalinizing trabecular tumour with metachronous lymph node metastases. Large polygonal or elongated tumour cells have abundant eosinophilic cytoplasm.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cells have abundant hyaline cytoplasm and bizarre convoluted nuclei.
Hyalinizing trabecular tumour with metachronous lymph node metastases. The tumour cell nuclei are convoluted with prominent membrane irregularities that form grooves and pseudoinclusions (arrow).
Hyalinizing trabecular tumour. Cytological features. Sheets of cells with a trabecular arrangement (Pap).
Hyalinizing trabecular tumour. A well-circumscribed nodule with a thin capsule.
Hyalinizing trabecular tumour. Typical trabecular growth, marked cytoplasmic hyalinization, and irregular nuclei with irregular contours and pseudoinclusions.
Hyalinizing trabecular tumour. PASD-positive intratrabecular material, with cells oriented perpendicularly to the trabeculae.
Hyalinizing trabecular tumour. Membranous Ki-67 staining using the MIB1 clone in a histological sample. Immunoperoxidase with DAB staining.
Hyalinizing trabecular tumour. Cytoplasmic and nuclear expression of GLIS3 in the presence of a PAX8::GLIS3 rearrangement.

Q: To establish the histologic diagnosis of an Oncocytic Adenoma of the Thyroid Gland, the encapsulated, follicular-patterned tumor must be composed of > 75% [...], which are characterized by abundant granular eosinophilic cytoplasm and prominent nucleoli.
Oncocytic adenoma. Tumour cells with abundant eosinophilic cytoplasm and nuclei with prominent nucleoli. Focal nuclear atypia is frequently seen in oncocytic tumours.
Oncocytic adenoma. The tumour has a follicular architecture, and the cells lining the follicles have bland round uniform nuclei with evenly distributed chromatin; they lack nuclear irregularity including overlap, moulding, grooves, and clearing of nucleoplasm.
A: oncocytic cells
Back Extra: Oncocytic Adenoma of the Thyroid Gland
- Clinical: Oncocytic adenomas of the thyroid gland are typically solitary, well-demarcated nodules with smooth borders and variable echogenicity on ultrasound. They are often detected incidentally and can present as painless, palpable masses.
- Micro: On histology, oncocytic adenomas are encapsulated, follicular-patterned tumours composed of > 75% oncocytic cells with abundant granular eosinophilic cytoplasm and uniform central round nuclei with prominent nucleoli.
- Ancillary: Immunohistochemistry in oncocytic adenomas shows positivity for PAX8 and TTF1, and negativity for calcitonin. The cytoplasm and associated colloid are positive for thyroglobulin.
Reference Gallery:
Oncocytic adenoma. An ultrasound image of an oncocytic adenoma showing a well-demarcated, solid, ovoid nodule with smooth borders, variable echogenicity (isoechoic to hypoechoic and hyperechoic), and no associated calcifications.
Oncocytic adenoma. A low-power photomicrograph of an oncocytic adenoma showing extensive infarction secondary to FNA.
Oncocytic adenoma. Lipomatous metaplasia.
Oncocytic adenoma. A Giemsa-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A Pap-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A minor subset of oncocytic adenomas has areas of papillary architecture. However, in contrast to the oncocytic subtype of papillary thyroid carcinoma, this tumour lacks the nuclear features of papillary thyroid carcinoma.
Oncocytic adenoma. Tumour cells with abundant eosinophilic cytoplasm and nuclei with prominent nucleoli. Focal nuclear atypia is frequently seen in oncocytic tumours.
Oncocytic adenoma. An oncocytic adenoma with calcifications. Note that the calcifications are within follicles and are associated with colloid.
Oncocytic adenoma. The tumour has a follicular architecture, and the cells lining the follicles have bland round uniform nuclei with evenly distributed chromatin; they lack nuclear irregularity including overlap, moulding, grooves, and clearing of nucleoplasm.

Q: Fine needle aspiration (FNA) cytologic smears demonstrating clusters of cells with abundant coarsely granular cytoplasm, uniform central round nuclei, and prominent single nucleoli are highly indicative of an [...].
Oncocytic adenoma. A Giemsa-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A Pap-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
A: Oncocytic Adenoma of the Thyroid Gland
Back Extra: Oncocytic Adenoma of the Thyroid Gland
- Clinical: Oncocytic adenomas of the thyroid gland are typically solitary, well-demarcated nodules with smooth borders and variable echogenicity on ultrasound. They are often detected incidentally and can present as painless, palpable masses.
- Micro: On histology, oncocytic adenomas are encapsulated, follicular-patterned tumours composed of > 75% oncocytic cells with abundant granular eosinophilic cytoplasm and uniform central round nuclei with prominent nucleoli.
- Ancillary: Immunohistochemistry in oncocytic adenomas shows positivity for PAX8 and TTF1, and negativity for calcitonin. The cytoplasm and associated colloid are positive for thyroglobulin.
Reference Gallery:
Oncocytic adenoma. An ultrasound image of an oncocytic adenoma showing a well-demarcated, solid, ovoid nodule with smooth borders, variable echogenicity (isoechoic to hypoechoic and hyperechoic), and no associated calcifications.
Oncocytic adenoma. A low-power photomicrograph of an oncocytic adenoma showing extensive infarction secondary to FNA.
Oncocytic adenoma. Lipomatous metaplasia.
Oncocytic adenoma. A Giemsa-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A Pap-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A minor subset of oncocytic adenomas has areas of papillary architecture. However, in contrast to the oncocytic subtype of papillary thyroid carcinoma, this tumour lacks the nuclear features of papillary thyroid carcinoma.
Oncocytic adenoma. Tumour cells with abundant eosinophilic cytoplasm and nuclei with prominent nucleoli. Focal nuclear atypia is frequently seen in oncocytic tumours.
Oncocytic adenoma. An oncocytic adenoma with calcifications. Note that the calcifications are within follicles and are associated with colloid.
Oncocytic adenoma. The tumour has a follicular architecture, and the cells lining the follicles have bland round uniform nuclei with evenly distributed chromatin; they lack nuclear irregularity including overlap, moulding, grooves, and clearing of nucleoplasm.

Q: While a minor subset of Oncocytic Adenoma of the Thyroid Gland may exhibit areas of papillary architecture, the tumor is readily distinguished from papillary thyroid carcinoma (PTC) because it lacks the classic [...] (e.g., clearing, grooves, pseudo-inclusions) associated with PTC.
Oncocytic adenoma. A minor subset of oncocytic adenomas has areas of papillary architecture. However, in contrast to the oncocytic subtype of papillary thyroid carcinoma, this tumour lacks the nuclear features of papillary thyroid carcinoma.
A: nuclear features
Back Extra: Oncocytic Adenoma of the Thyroid Gland
- Clinical: Oncocytic adenomas of the thyroid gland are typically solitary, well-demarcated nodules with smooth borders and variable echogenicity on ultrasound. They are often detected incidentally and can present as painless, palpable masses.
- Micro: On histology, oncocytic adenomas are encapsulated, follicular-patterned tumours composed of > 75% oncocytic cells with abundant granular eosinophilic cytoplasm and uniform central round nuclei with prominent nucleoli.
- Ancillary: Immunohistochemistry in oncocytic adenomas shows positivity for PAX8 and TTF1, and negativity for calcitonin. The cytoplasm and associated colloid are positive for thyroglobulin.
Reference Gallery:
Oncocytic adenoma. An ultrasound image of an oncocytic adenoma showing a well-demarcated, solid, ovoid nodule with smooth borders, variable echogenicity (isoechoic to hypoechoic and hyperechoic), and no associated calcifications.
Oncocytic adenoma. A low-power photomicrograph of an oncocytic adenoma showing extensive infarction secondary to FNA.
Oncocytic adenoma. Lipomatous metaplasia.
Oncocytic adenoma. A Giemsa-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A Pap-stained FNA specimen showing a cluster of cells exhibiting abundant coarsely granular cytoplasm and uniform central round nuclei with prominent single nucleoli. Intracytoplasmic lumina can be seen.
Oncocytic adenoma. A minor subset of oncocytic adenomas has areas of papillary architecture. However, in contrast to the oncocytic subtype of papillary thyroid carcinoma, this tumour lacks the nuclear features of papillary thyroid carcinoma.
Oncocytic adenoma. Tumour cells with abundant eosinophilic cytoplasm and nuclei with prominent nucleoli. Focal nuclear atypia is frequently seen in oncocytic tumours.
Oncocytic adenoma. An oncocytic adenoma with calcifications. Note that the calcifications are within follicles and are associated with colloid.
Oncocytic adenoma. The tumour has a follicular architecture, and the cells lining the follicles have bland round uniform nuclei with evenly distributed chromatin; they lack nuclear irregularity including overlap, moulding, grooves, and clearing of nucleoplasm.

Q: Cytologic smears and histologic sections of Anaplastic Thyroid Carcinoma typically show highly pleomorphic, high-grade tumor cells mixed with marked necrosis and a heavy background infiltrate of [...].
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (left) consisting of markedly pleomorphic cells is identified in association with a papillary thyroid carcinoma (right). A heavy neutrophilic infiltrate is not uncommon in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma. FNA specimen (air-dried smear stained with Diff-Quik) showing epithelioid tumour cells with pleomorphic nuclei intermixed with necrotic debris containing neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (alcohol-fixed, Pap-stained smear preparation) showing a cohesive tissue fragment of epithelioid and spindle-shaped cells with marked cellular pleomorphism and interspersed neutrophils.
A: neutrophils
Back Extra: Anaplastic Thyroid Carcinoma
- Clinical: ATC often presents as a rapidly enlarging, fixed, and widely infiltrative neck mass that may be associated with compressive symptoms, pain, hoarseness, and dyspnoea. Paraneoplastic hypercalcaemia, leukocytosis, neutrophi…
- Micro: ATCs are highly infiltrative malignancies with frequent extrathyroidal growth, necrosis, prominent mitotic activity, atypical mitoses, significant nuclear pleomorphism, and angiolymphatic invasion. ATCs are high-grade tu…
- Cyto: Smears show variable (sparse to marked) cellularity, with frequent necrosis and neutrophils in the background. Individual polygonal, plasmacytoid, spindle, or rhabdoid tumour cells predominate, with a variable number of …
- Ancillary: ATC has more complex molecular changes than poorly differentiated carcinoma or well-differentiated (papillary and follicular) thyroid carcinomas. A wide variety of genetic alterations are found in ATCs. RAS (10–50%) and …
Reference Gallery:
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (left) consisting of markedly pleomorphic cells is identified in association with a papillary thyroid carcinoma (right). A heavy neutrophilic infiltrate is not uncommon in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (right) is identified with an oncocytic thyroid carcinoma (left).
Anaplastic thyroid carcinoma. Paucicellular subtype. This paucicellular anaplastic thyroid carcinoma shows a prominent hyalinized/sclerotic background and could be mistaken for a reactive process such as Riedel thyroiditis.
Anaplastic thyroid carcinoma. Rhabdomyoblastic differentiation. This anaplastic thyroid carcinoma has foci of rhabdomyoblastic differentiation positive for desmin and myogenin.
Anaplastic thyroid carcinoma. Spindle subtype. This anaplastic thyroid carcinoma shows prominent spindling of markedly atypical cells.
Molecular profile of anaplastic thyroid carcinoma. Mutation count and frequency of genetic alterations in 102 anaplastic thyroid carcinomas sequenced using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing platform.
Anaplastic thyroid carcinoma, squamous pattern. This anaplastic thyroid carcinoma has a squamous cell carcinoma phenotype. These tumours can be primary to the thyroid and must be differentiated from secondary involvement by a squamous cell carcinoma from another site.
Anaplastic thyroid carcinoma. FNA specimen (air-dried smear stained with Diff-Quik) showing epithelioid tumour cells with pleomorphic nuclei intermixed with necrotic debris containing neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (alcohol-fixed, Pap-stained smear preparation) showing a cohesive tissue fragment of epithelioid and spindle-shaped cells with marked cellular pleomorphism and interspersed neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (liquid-based cytology preparation) showing pleomorphic tumour cells with necrotic debris (arrow).
Anaplastic thyroid carcinoma. This anaplastic thyroid carcinoma has foci of osteosarcomatous differentiation. A few residual thyroid follicles are present.
Anaplastic thyroid carcinoma. This tumour has a rhabdoid morphology characterized by cells with eccentric nuclei and abundant eosinophilic cytoplasm.

Q: Because it frequently arises from dedifferentiation, Anaplastic Thyroid Carcinoma is often found intimately admixed with a preexisting well-differentiated tumor, most commonly [...] thyroid carcinoma.
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (left) consisting of markedly pleomorphic cells is identified in association with a papillary thyroid carcinoma (right). A heavy neutrophilic infiltrate is not uncommon in anaplastic thyroid carcinoma.
A: papillary
Back Extra: Anaplastic Thyroid Carcinoma
- Clinical: ATC often presents as a rapidly enlarging, fixed, and widely infiltrative neck mass that may be associated with compressive symptoms, pain, hoarseness, and dyspnoea. Paraneoplastic hypercalcaemia, leukocytosis, neutrophi…
- Micro: ATCs are highly infiltrative malignancies with frequent extrathyroidal growth, necrosis, prominent mitotic activity, atypical mitoses, significant nuclear pleomorphism, and angiolymphatic invasion. ATCs are high-grade tu…
- Cyto: Smears show variable (sparse to marked) cellularity, with frequent necrosis and neutrophils in the background. Individual polygonal, plasmacytoid, spindle, or rhabdoid tumour cells predominate, with a variable number of …
- Ancillary: ATC has more complex molecular changes than poorly differentiated carcinoma or well-differentiated (papillary and follicular) thyroid carcinomas. A wide variety of genetic alterations are found in ATCs. RAS (10–50%) and …
Reference Gallery:
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (left) consisting of markedly pleomorphic cells is identified in association with a papillary thyroid carcinoma (right). A heavy neutrophilic infiltrate is not uncommon in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (right) is identified with an oncocytic thyroid carcinoma (left).
Anaplastic thyroid carcinoma. Paucicellular subtype. This paucicellular anaplastic thyroid carcinoma shows a prominent hyalinized/sclerotic background and could be mistaken for a reactive process such as Riedel thyroiditis.
Anaplastic thyroid carcinoma. Rhabdomyoblastic differentiation. This anaplastic thyroid carcinoma has foci of rhabdomyoblastic differentiation positive for desmin and myogenin.
Anaplastic thyroid carcinoma. Spindle subtype. This anaplastic thyroid carcinoma shows prominent spindling of markedly atypical cells.
Molecular profile of anaplastic thyroid carcinoma. Mutation count and frequency of genetic alterations in 102 anaplastic thyroid carcinomas sequenced using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing platform.
Anaplastic thyroid carcinoma, squamous pattern. This anaplastic thyroid carcinoma has a squamous cell carcinoma phenotype. These tumours can be primary to the thyroid and must be differentiated from secondary involvement by a squamous cell carcinoma from another site.
Anaplastic thyroid carcinoma. FNA specimen (air-dried smear stained with Diff-Quik) showing epithelioid tumour cells with pleomorphic nuclei intermixed with necrotic debris containing neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (alcohol-fixed, Pap-stained smear preparation) showing a cohesive tissue fragment of epithelioid and spindle-shaped cells with marked cellular pleomorphism and interspersed neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (liquid-based cytology preparation) showing pleomorphic tumour cells with necrotic debris (arrow).
Anaplastic thyroid carcinoma. This anaplastic thyroid carcinoma has foci of osteosarcomatous differentiation. A few residual thyroid follicles are present.
Anaplastic thyroid carcinoma. This tumour has a rhabdoid morphology characterized by cells with eccentric nuclei and abundant eosinophilic cytoplasm.

Q: The rare paucicellular variant of Anaplastic Thyroid Carcinoma features a prominent hyalinized and sclerotic background, which can histologically mimic the extensive fibrotic process seen in [...].
Anaplastic thyroid carcinoma. Paucicellular subtype. This paucicellular anaplastic thyroid carcinoma shows a prominent hyalinized/sclerotic background and could be mistaken for a reactive process such as Riedel thyroiditis.
A: Riedel thyroiditis
Back Extra: Anaplastic Thyroid Carcinoma
- Clinical: ATC often presents as a rapidly enlarging, fixed, and widely infiltrative neck mass that may be associated with compressive symptoms, pain, hoarseness, and dyspnoea. Paraneoplastic hypercalcaemia, leukocytosis, neutrophi…
- Micro: ATCs are highly infiltrative malignancies with frequent extrathyroidal growth, necrosis, prominent mitotic activity, atypical mitoses, significant nuclear pleomorphism, and angiolymphatic invasion. ATCs are high-grade tu…
- Cyto: Smears show variable (sparse to marked) cellularity, with frequent necrosis and neutrophils in the background. Individual polygonal, plasmacytoid, spindle, or rhabdoid tumour cells predominate, with a variable number of …
- Ancillary: ATC has more complex molecular changes than poorly differentiated carcinoma or well-differentiated (papillary and follicular) thyroid carcinomas. A wide variety of genetic alterations are found in ATCs. RAS (10–50%) and …
Reference Gallery:
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (left) consisting of markedly pleomorphic cells is identified in association with a papillary thyroid carcinoma (right). A heavy neutrophilic infiltrate is not uncommon in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma. An anaplastic thyroid carcinoma (right) is identified with an oncocytic thyroid carcinoma (left).
Anaplastic thyroid carcinoma. Paucicellular subtype. This paucicellular anaplastic thyroid carcinoma shows a prominent hyalinized/sclerotic background and could be mistaken for a reactive process such as Riedel thyroiditis.
Anaplastic thyroid carcinoma. Rhabdomyoblastic differentiation. This anaplastic thyroid carcinoma has foci of rhabdomyoblastic differentiation positive for desmin and myogenin.
Anaplastic thyroid carcinoma. Spindle subtype. This anaplastic thyroid carcinoma shows prominent spindling of markedly atypical cells.
Molecular profile of anaplastic thyroid carcinoma. Mutation count and frequency of genetic alterations in 102 anaplastic thyroid carcinomas sequenced using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) next-generation sequencing platform.
Anaplastic thyroid carcinoma, squamous pattern. This anaplastic thyroid carcinoma has a squamous cell carcinoma phenotype. These tumours can be primary to the thyroid and must be differentiated from secondary involvement by a squamous cell carcinoma from another site.
Anaplastic thyroid carcinoma. FNA specimen (air-dried smear stained with Diff-Quik) showing epithelioid tumour cells with pleomorphic nuclei intermixed with necrotic debris containing neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (alcohol-fixed, Pap-stained smear preparation) showing a cohesive tissue fragment of epithelioid and spindle-shaped cells with marked cellular pleomorphism and interspersed neutrophils.
Anaplastic thyroid carcinoma. FNA specimen (liquid-based cytology preparation) showing pleomorphic tumour cells with necrotic debris (arrow).
Anaplastic thyroid carcinoma. This anaplastic thyroid carcinoma has foci of osteosarcomatous differentiation. A few residual thyroid follicles are present.
Anaplastic thyroid carcinoma. This tumour has a rhabdoid morphology characterized by cells with eccentric nuclei and abundant eosinophilic cytoplasm.

Q: Histologically, Cribriform Morular Thyroid Carcinoma features an admixture of growth patterns, most notably cribriform structures that lack intervening stroma and squamoid nests known as [...].
Cribriform-morular thyroid carcinoma. There is a morule in the upper-left corner and cribriform tubular growth in the lower-right corner.
Cribriform-morular thyroid carcinoma. The cribriform structures lack intervening fibrous stroma and merge with tubular follicles that lack colloid.
A: morules
Back Extra: Cribriform Morular Thyroid Carcinoma
- Clinical: Cribriform Morular Thyroid Carcinoma (CMTC) is almost exclusively found in young women (97%), with 89% of cases occurring in individuals aged < 40 years. It often presents as a painless mass, hoarseness, or dysphagia.
- Micro: CMTC is characterized by an admixture of growth patterns including cribriform, follicular, papillary, trabecular, and solid patterns with morular (squamoid) areas. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified cells.
- Ancillary: Strong nuclear and cytoplasmic β-catenin staining is a hallmark of CMTC. The tumour is also positive for TTF1, various keratins, EMA, ER, and PR, but negative for CK20, calcitonin, and WT1.
Reference Gallery:
Pathogenesis of cribriform-morular thyroid carcinoma. Under normal conditions, in the absence of WNT binding to Frizzled receptors, β-catenin interacts with the destruction complex (CK1, GSK3B, APC, and AXIN1), resulting in its phosphorylation by CK1 and GSK3B and its subsequent degradation by the proteasome. In sporadic cribriform-morular thyroid carcinoma, somatic mutations in APC, CTNNB1, and/or AXIN1 alter the destruction complex, impairing β-catenin phosphorylation and degradation. β-Catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF proteins that lead to the constitutive expression of WNT target genes. In cribriform-morular thyroid carcinomas associated with familial adenomatous polyposis, there are germline APC mutations.
Cribriform-morular thyroid carcinoma. β-Catenin immunostaining shows characteristic aberrant positivity in the nuclei and in the cytoplasm of the tumour cells.
Cribriform-morular thyroid carcinoma. There is a morule in the upper-left corner and cribriform tubular growth in the lower-right corner.
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.
Cribriform-morular thyroid carcinoma. The cribriform structures lack intervening fibrous stroma and merge with tubular follicles that lack colloid.
Cribriform-morular thyroid carcinoma. These tumours are usually circumscribed or encapsulated but can have fibrous bands imparting a multilobulated appearance.
Cribriform-morular thyroid carcinoma. The morular component is positive for CK5.
Cribriform-morular thyroid carcinoma. Immunostaining for CD5 highlights the morular component of these tumours, as well as scattered CD5+ T lymphocytes.
Cribriform-morular thyroid carcinoma. This tumour is diffusely positive for ER.
Cribriform-morular thyroid carcinoma. The tumour is immunopositive for thyroid transcription factor 1 (TTF1) except in the morules (arrows).
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.

Q: A hallmark diagnostic feature of Cribriform Morular Thyroid Carcinoma is strong, aberrant nuclear and cytoplasmic immunohistochemical staining for [...].
Pathogenesis of cribriform-morular thyroid carcinoma. Under normal conditions, in the absence of WNT binding to Frizzled receptors, β-catenin interacts with the destruction complex (CK1, GSK3B, APC, and AXIN1), resulting in its phosphorylation by CK1 and GSK3B and its subsequent degradation by the proteasome. In sporadic cribriform-morular thyroid carcinoma, somatic mutations in APC, CTNNB1, and/or AXIN1 alter the destruction complex, impairing β-catenin phosphorylation and degradation. β-Catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF proteins that lead to the constitutive expression of WNT target genes. In cribriform-morular thyroid carcinomas associated with familial adenomatous polyposis, there are germline APC mutations.
Cribriform-morular thyroid carcinoma. β-Catenin immunostaining shows characteristic aberrant positivity in the nuclei and in the cytoplasm of the tumour cells.
A: β-catenin
Back Extra: Cribriform Morular Thyroid Carcinoma
- Clinical: Cribriform Morular Thyroid Carcinoma (CMTC) is almost exclusively found in young women (97%), with 89% of cases occurring in individuals aged < 40 years. It often presents as a painless mass, hoarseness, or dysphagia.
- Micro: CMTC is characterized by an admixture of growth patterns including cribriform, follicular, papillary, trabecular, and solid patterns with morular (squamoid) areas. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified cells.
- Ancillary: Strong nuclear and cytoplasmic β-catenin staining is a hallmark of CMTC. The tumour is also positive for TTF1, various keratins, EMA, ER, and PR, but negative for CK20, calcitonin, and WT1.
Reference Gallery:
Pathogenesis of cribriform-morular thyroid carcinoma. Under normal conditions, in the absence of WNT binding to Frizzled receptors, β-catenin interacts with the destruction complex (CK1, GSK3B, APC, and AXIN1), resulting in its phosphorylation by CK1 and GSK3B and its subsequent degradation by the proteasome. In sporadic cribriform-morular thyroid carcinoma, somatic mutations in APC, CTNNB1, and/or AXIN1 alter the destruction complex, impairing β-catenin phosphorylation and degradation. β-Catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF proteins that lead to the constitutive expression of WNT target genes. In cribriform-morular thyroid carcinomas associated with familial adenomatous polyposis, there are germline APC mutations.
Cribriform-morular thyroid carcinoma. β-Catenin immunostaining shows characteristic aberrant positivity in the nuclei and in the cytoplasm of the tumour cells.
Cribriform-morular thyroid carcinoma. There is a morule in the upper-left corner and cribriform tubular growth in the lower-right corner.
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.
Cribriform-morular thyroid carcinoma. The cribriform structures lack intervening fibrous stroma and merge with tubular follicles that lack colloid.
Cribriform-morular thyroid carcinoma. These tumours are usually circumscribed or encapsulated but can have fibrous bands imparting a multilobulated appearance.
Cribriform-morular thyroid carcinoma. The morular component is positive for CK5.
Cribriform-morular thyroid carcinoma. Immunostaining for CD5 highlights the morular component of these tumours, as well as scattered CD5+ T lymphocytes.
Cribriform-morular thyroid carcinoma. This tumour is diffusely positive for ER.
Cribriform-morular thyroid carcinoma. The tumour is immunopositive for thyroid transcription factor 1 (TTF1) except in the morules (arrows).
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.

Q: Immunohistochemically, Cribriform Morular Thyroid Carcinoma typically shows widespread nuclear positivity for [...], although expression of this marker is characteristically absent within the morular components.
Cribriform-morular thyroid carcinoma. The tumour is immunopositive for thyroid transcription factor 1 (TTF1) except in the morules (arrows).
A: TTF1
Back Extra: Cribriform Morular Thyroid Carcinoma
- Clinical: Cribriform Morular Thyroid Carcinoma (CMTC) is almost exclusively found in young women (97%), with 89% of cases occurring in individuals aged < 40 years. It often presents as a painless mass, hoarseness, or dysphagia.
- Micro: CMTC is characterized by an admixture of growth patterns including cribriform, follicular, papillary, trabecular, and solid patterns with morular (squamoid) areas. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified cells.
- Ancillary: Strong nuclear and cytoplasmic β-catenin staining is a hallmark of CMTC. The tumour is also positive for TTF1, various keratins, EMA, ER, and PR, but negative for CK20, calcitonin, and WT1.
Reference Gallery:
Pathogenesis of cribriform-morular thyroid carcinoma. Under normal conditions, in the absence of WNT binding to Frizzled receptors, β-catenin interacts with the destruction complex (CK1, GSK3B, APC, and AXIN1), resulting in its phosphorylation by CK1 and GSK3B and its subsequent degradation by the proteasome. In sporadic cribriform-morular thyroid carcinoma, somatic mutations in APC, CTNNB1, and/or AXIN1 alter the destruction complex, impairing β-catenin phosphorylation and degradation. β-Catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it acts as an activator of TCF/LEF proteins that lead to the constitutive expression of WNT target genes. In cribriform-morular thyroid carcinomas associated with familial adenomatous polyposis, there are germline APC mutations.
Cribriform-morular thyroid carcinoma. β-Catenin immunostaining shows characteristic aberrant positivity in the nuclei and in the cytoplasm of the tumour cells.
Cribriform-morular thyroid carcinoma. There is a morule in the upper-left corner and cribriform tubular growth in the lower-right corner.
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.
Cribriform-morular thyroid carcinoma. The cribriform structures lack intervening fibrous stroma and merge with tubular follicles that lack colloid.
Cribriform-morular thyroid carcinoma. These tumours are usually circumscribed or encapsulated but can have fibrous bands imparting a multilobulated appearance.
Cribriform-morular thyroid carcinoma. The morular component is positive for CK5.
Cribriform-morular thyroid carcinoma. Immunostaining for CD5 highlights the morular component of these tumours, as well as scattered CD5+ T lymphocytes.
Cribriform-morular thyroid carcinoma. This tumour is diffusely positive for ER.
Cribriform-morular thyroid carcinoma. The tumour is immunopositive for thyroid transcription factor 1 (TTF1) except in the morules (arrows).
Cribriform-morular thyroid carcinoma. Papillae and pseudopapillae are lined by tall, cuboidal or pseudostratified columnar cells. Tubular follicles lacking colloid are seen.

Q: The defining histologic features of High-grade follicular cell-derived non-anaplastic thyroid carcinoma include an elevated mitotic count and/or the presence of [...].
High-grade differentiated thyroid carcinoma. This papillary tumour shows papillae lined by cells with the nuclear alterations of papillary carcinoma and abundant tumour necrosis.
Poorly differentiated thyroid carcinoma. This tumour is composed of large cells with a solid growth pattern and tumour necrosis in the centre.
High-grade differentiated thyroid carcinoma. This tumour shows solid growth, the nuclear alterations of papillary carcinoma, and comedo-type necrosis.
A: tumor necrosis
Back Extra: High-grade follicular cell-derived non-anaplastic thyroid carcinoma
- Clinical: High-grade follicular cell-derived non-anaplastic thyroid carcinoma typically presents as a large, rapidly growing mass and is often associated with distant metastases in 20–25% of cases at diagnosis.
- Micro: These tumours are characterized by a solid/trabecular/insular growth pattern, tumour necrosis, and a mitotic count of ≥ 3 mitoses/2 mm² in poorly differentiated thyroid carcinoma, or ≥ 5 mitoses/2 mm² in high-grade differentiated thyroid carcinoma.
- Ancillary: Immunohistochemically, neoplastic cells are positive for keratins, thyroglobulin, TTF1, and PAX8, with reduced and focal thyroglobulin expression and an elevated Ki-67 (MIB1) labelling index (10–30%).
Reference Gallery:
High-grade differentiated thyroid carcinoma. This papillary tumour shows papillae lined by cells with the nuclear alterations of papillary carcinoma and abundant tumour necrosis.
High-grade differentiated thyroid carcinoma. This tumour shows a large focus of tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade differentiated thyroid carcinoma. Tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a widely invasive poorly differentiated carcinoma showing a variegated cut surface with foci of haemorrhage and necrosis.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a high-grade differentiated thyroid carcinoma that infiltrates the trachea.
Poorly differentiated thyroid carcinoma. This tumour is composed of large cells with a solid growth pattern and tumour necrosis in the centre.
Poorly differentiated thyroid carcinoma. Peritheliomatous growth due to large areas of necrosis with surviving tumour cells grouped around blood vessels.
Poorly differentiated thyroid carcinoma. This carcinoma is composed of oncocytic cells growing in a solid pattern with tumour necrosis.
Poorly differentiated thyroid carcinoma. The tumour is composed of solid nests of cells with hyperchromatic round nuclei with mitoses (centre).
High-grade differentiated thyroid carcinoma. This tumour shows solid growth, the nuclear alterations of papillary carcinoma, and comedo-type necrosis.
Poorly differentiated thyroid carcinoma. Thyroglobulin expression is reduced and there is distinctive dot-like paranuclear immunoreactivity.
Poorly differentiated thyroid carcinoma. Preoperative fine-needle aspirate showing uniform cells with round, hyperchromatic nuclei; scant, fragile, and poorly defined cytoplasm; and a few microfollicles (lower left).

Q: A major histologic subtype of High-grade follicular cell-derived non-anaplastic thyroid carcinoma is poorly differentiated thyroid carcinoma, which is morphologically characterized by a [...] architectural growth pattern.
Poorly differentiated thyroid carcinoma. This tumour is composed of large cells with a solid growth pattern and tumour necrosis in the centre.
Poorly differentiated thyroid carcinoma. The tumour is composed of solid nests of cells with hyperchromatic round nuclei with mitoses (centre).
A: solid, trabecular, or insular
Back Extra: High-grade follicular cell-derived non-anaplastic thyroid carcinoma
- Clinical: High-grade follicular cell-derived non-anaplastic thyroid carcinoma typically presents as a large, rapidly growing mass and is often associated with distant metastases in 20–25% of cases at diagnosis.
- Micro: These tumours are characterized by a solid/trabecular/insular growth pattern, tumour necrosis, and a mitotic count of ≥ 3 mitoses/2 mm² in poorly differentiated thyroid carcinoma, or ≥ 5 mitoses/2 mm² in high-grade differentiated thyroid carcinoma.
- Ancillary: Immunohistochemically, neoplastic cells are positive for keratins, thyroglobulin, TTF1, and PAX8, with reduced and focal thyroglobulin expression and an elevated Ki-67 (MIB1) labelling index (10–30%).
Reference Gallery:
High-grade differentiated thyroid carcinoma. This papillary tumour shows papillae lined by cells with the nuclear alterations of papillary carcinoma and abundant tumour necrosis.
High-grade differentiated thyroid carcinoma. This tumour shows a large focus of tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade differentiated thyroid carcinoma. Tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a widely invasive poorly differentiated carcinoma showing a variegated cut surface with foci of haemorrhage and necrosis.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a high-grade differentiated thyroid carcinoma that infiltrates the trachea.
Poorly differentiated thyroid carcinoma. This tumour is composed of large cells with a solid growth pattern and tumour necrosis in the centre.
Poorly differentiated thyroid carcinoma. Peritheliomatous growth due to large areas of necrosis with surviving tumour cells grouped around blood vessels.
Poorly differentiated thyroid carcinoma. This carcinoma is composed of oncocytic cells growing in a solid pattern with tumour necrosis.
Poorly differentiated thyroid carcinoma. The tumour is composed of solid nests of cells with hyperchromatic round nuclei with mitoses (centre).
High-grade differentiated thyroid carcinoma. This tumour shows solid growth, the nuclear alterations of papillary carcinoma, and comedo-type necrosis.
Poorly differentiated thyroid carcinoma. Thyroglobulin expression is reduced and there is distinctive dot-like paranuclear immunoreactivity.
Poorly differentiated thyroid carcinoma. Preoperative fine-needle aspirate showing uniform cells with round, hyperchromatic nuclei; scant, fragile, and poorly defined cytoplasm; and a few microfollicles (lower left).

Q: In poorly differentiated cases of High-grade follicular cell-derived non-anaplastic thyroid carcinoma, immunohistochemical expression of [...] is typically reduced and often exhibits a distinctive dot-like paranuclear pattern.
Poorly differentiated thyroid carcinoma. Thyroglobulin expression is reduced and there is distinctive dot-like paranuclear immunoreactivity.
A: thyroglobulin
Back Extra: High-grade follicular cell-derived non-anaplastic thyroid carcinoma
- Clinical: High-grade follicular cell-derived non-anaplastic thyroid carcinoma typically presents as a large, rapidly growing mass and is often associated with distant metastases in 20–25% of cases at diagnosis.
- Micro: These tumours are characterized by a solid/trabecular/insular growth pattern, tumour necrosis, and a mitotic count of ≥ 3 mitoses/2 mm² in poorly differentiated thyroid carcinoma, or ≥ 5 mitoses/2 mm² in high-grade differentiated thyroid carcinoma.
- Ancillary: Immunohistochemically, neoplastic cells are positive for keratins, thyroglobulin, TTF1, and PAX8, with reduced and focal thyroglobulin expression and an elevated Ki-67 (MIB1) labelling index (10–30%).
Reference Gallery:
High-grade differentiated thyroid carcinoma. This papillary tumour shows papillae lined by cells with the nuclear alterations of papillary carcinoma and abundant tumour necrosis.
High-grade differentiated thyroid carcinoma. This tumour shows a large focus of tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade differentiated thyroid carcinoma. Tumour necrosis in the centre of a follicular tumour lacking the nuclear features of papillary carcinoma.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a widely invasive poorly differentiated carcinoma showing a variegated cut surface with foci of haemorrhage and necrosis.
High-grade follicular cell–derived non-anaplastic thyroid carcinoma. Macroscopic appearance of a high-grade differentiated thyroid carcinoma that infiltrates the trachea.
Poorly differentiated thyroid carcinoma. This tumour is composed of large cells with a solid growth pattern and tumour necrosis in the centre.
Poorly differentiated thyroid carcinoma. Peritheliomatous growth due to large areas of necrosis with surviving tumour cells grouped around blood vessels.
Poorly differentiated thyroid carcinoma. This carcinoma is composed of oncocytic cells growing in a solid pattern with tumour necrosis.
Poorly differentiated thyroid carcinoma. The tumour is composed of solid nests of cells with hyperchromatic round nuclei with mitoses (centre).
High-grade differentiated thyroid carcinoma. This tumour shows solid growth, the nuclear alterations of papillary carcinoma, and comedo-type necrosis.
Poorly differentiated thyroid carcinoma. Thyroglobulin expression is reduced and there is distinctive dot-like paranuclear immunoreactivity.
Poorly differentiated thyroid carcinoma. Preoperative fine-needle aspirate showing uniform cells with round, hyperchromatic nuclei; scant, fragile, and poorly defined cytoplasm; and a few microfollicles (lower left).

Q: Histologically, [...] typically shows expansile irregular lobules and anastomosing cords of epithelial tumor cells set within a desmoplastic stroma heavily infiltrated by lymphocytes and plasma cells.
Intrathyroidal thymic carcinoma. Anastomosing islands of tumour cells surrounded by fibrous stroma.
Intrathyroidal thymic carcinoma. Stromal infiltration by atypical tumour cells accompanied by numerous lymphocytes and plasma cells.
A: Intrathyroidal Thymic Carcinoma
Back Extra: Intrathyroidal Thymic Carcinoma
- Clinical: Intrathyroidal Thymic Carcinoma typically presents as a firm, painless neck mass in euthyroid patients, often with hoarseness and/or dysphagia.
- Micro: Histopathologically, ITC shows expansile irregular lobules and cords of epithelial tumour cells, accompanied by sclerohyaline to desmoplastic stroma infiltrated by lymphocytes and plasma cells.
- Ancillary: ITC cells are immunoreactive for CD5, KIT (CD117), p63, and p40, and often express BCL2, calretinin, CEA, and p53, but are negative for TTF1 and thyroglobulin.
Reference Gallery:
Intrathyroidal thymic carcinoma. Anastomosing islands of tumour cells surrounded by fibrous stroma.
Intrathyroidal thymic carcinoma. Well-circumscribed but unencapsulated tumour with the surrounding thyroid parenchyma.
Intrathyroidal thymic carcinoma. Stromal infiltration by atypical tumour cells accompanied by numerous lymphocytes and plasma cells.
Intrathyroidal thymic carcinoma. The nuclear chromatin is vesicular, with small and easily identifiable nucleoli.
Intrathyroidal thymic carcinoma. Perineural invasion.
Intrathyroidal thymic carcinoma. Tumour islands invade into an adjacent parathyroid gland.
Intrathyroidal thymic carcinoma. Immunostaining for CD5 shows membrane positivity in tumour cells and in the cytoplasm of T lymphocytes.
Intrathyroidal thymic carcinoma. Tumour cells are positive for KIT (CD117).
Intrathyroidal thymic carcinoma. Anastomosed tumour islands are highlighted by their positivity for CK19.
Intrathyroidal thymic carcinoma. Nuclear positivity for p63.
Intrathyroidal thymic carcinoma. Nuclear staining for Ki-67.

Q: Immunohistochemistry for Intrathyroidal Thymic Carcinoma characteristically demonstrates negativity for TTF-1 and thyroglobulin, but shows defining positivity for CD5, p63, and [...].
Intrathyroidal thymic carcinoma. Immunostaining for CD5 shows membrane positivity in tumour cells and in the cytoplasm of T lymphocytes.
Intrathyroidal thymic carcinoma. Tumour cells are positive for KIT (CD117).
Intrathyroidal thymic carcinoma. Nuclear positivity for p63.
A: CD117 (KIT)
Back Extra: Intrathyroidal Thymic Carcinoma
- Clinical: Intrathyroidal Thymic Carcinoma typically presents as a firm, painless neck mass in euthyroid patients, often with hoarseness and/or dysphagia.
- Micro: Histopathologically, ITC shows expansile irregular lobules and cords of epithelial tumour cells, accompanied by sclerohyaline to desmoplastic stroma infiltrated by lymphocytes and plasma cells.
- Ancillary: ITC cells are immunoreactive for CD5, KIT (CD117), p63, and p40, and often express BCL2, calretinin, CEA, and p53, but are negative for TTF1 and thyroglobulin.
Reference Gallery:
Intrathyroidal thymic carcinoma. Anastomosing islands of tumour cells surrounded by fibrous stroma.
Intrathyroidal thymic carcinoma. Well-circumscribed but unencapsulated tumour with the surrounding thyroid parenchyma.
Intrathyroidal thymic carcinoma. Stromal infiltration by atypical tumour cells accompanied by numerous lymphocytes and plasma cells.
Intrathyroidal thymic carcinoma. The nuclear chromatin is vesicular, with small and easily identifiable nucleoli.
Intrathyroidal thymic carcinoma. Perineural invasion.
Intrathyroidal thymic carcinoma. Tumour islands invade into an adjacent parathyroid gland.
Intrathyroidal thymic carcinoma. Immunostaining for CD5 shows membrane positivity in tumour cells and in the cytoplasm of T lymphocytes.
Intrathyroidal thymic carcinoma. Tumour cells are positive for KIT (CD117).
Intrathyroidal thymic carcinoma. Anastomosed tumour islands are highlighted by their positivity for CK19.
Intrathyroidal thymic carcinoma. Nuclear positivity for p63.
Intrathyroidal thymic carcinoma. Nuclear staining for Ki-67.

Q: Histologically, [...] typically presents as a tumor with a lobulated architecture featuring scattered epithelial cells in a background of small lymphoid cells, often compressing adjacent normal thyroid follicles.
Intrathyroidal thymoma. Residual compressed thyroid tissue is seen in the left field. The tumour exhibits a lobulated architecture, and the various tumour lobules exhibit different morphologies.
Intrathyroidal thymoma. High-power view of an ectopic thymoma in the thyroid, featuring scattered single or grouped epithelial cells in a background of small lymphoid cells.
A: Intrathyroidal Thymoma
Back Extra: Intrathyroidal Thymoma
- Clinical: Intrathyroidal thymoma usually presents as an asymptomatic euthyroid mass, but can also cause pain, compressive symptoms, and tracheal deviation.
- Micro: The tumour typically forms jigsaw puzzle-like lobules with a mix of epithelial and lymphoid cells, and may show entrapment of thyroid follicles.
- Ancillary: FNA smears can show both lymphocytic and epithelial cells, which can lead to misdiagnosis without additional immunohistochemical studies.
Reference Gallery:
Intrathyroidal thymoma. Residual compressed thyroid tissue is seen in the left field. The tumour exhibits a lobulated architecture, and the various tumour lobules exhibit different morphologies.
Intrathyroidal thymoma. High-power view of an ectopic thymoma in the thyroid, featuring scattered single or grouped epithelial cells in a background of small lymphoid cells.

Q: On high-power examination of an Intrathyroidal Thymoma, the tumor features a characteristic biphasic population consisting of a background of small lymphoid cells and scattered single or grouped [...] cells.
Intrathyroidal thymoma. High-power view of an ectopic thymoma in the thyroid, featuring scattered single or grouped epithelial cells in a background of small lymphoid cells.
A: epithelial
Back Extra: Intrathyroidal Thymoma
- Clinical: Intrathyroidal thymoma usually presents as an asymptomatic euthyroid mass, but can also cause pain, compressive symptoms, and tracheal deviation.
- Micro: The tumour typically forms jigsaw puzzle-like lobules with a mix of epithelial and lymphoid cells, and may show entrapment of thyroid follicles.
- Ancillary: FNA smears can show both lymphocytic and epithelial cells, which can lead to misdiagnosis without additional immunohistochemical studies.
Reference Gallery:
Intrathyroidal thymoma. Residual compressed thyroid tissue is seen in the left field. The tumour exhibits a lobulated architecture, and the various tumour lobules exhibit different morphologies.
Intrathyroidal thymoma. High-power view of an ectopic thymoma in the thyroid, featuring scattered single or grouped epithelial cells in a background of small lymphoid cells.

Q: The histopathological hallmark of [...] is the intimate admixture of distinct tumor cell populations showing features of both medullary carcinoma and follicular cell-derived neoplasms.
Mixed medullary and follicular cell–derived thyroid carcinoma. The papillary carcinoma component has a follicular growth and shows squamous metaplasia. It is intimately admixed with the medullary carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (in the middle) growing in an otherwise oncocytic carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (predominant on the left) admixed with a papillary carcinoma component with solid growth (predominant at the upper right).
A: Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma
Back Extra: Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma
- Clinical: Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma (MMFCC) often presents as a solitary thyroid nodule, with up to 25% of cases showing lymph node metastases at diagnosis.
- Micro: The histopathological hallmark of MMFCC is the coexistence of distinct tumour cell populations showing features of both medullary carcinoma and follicular cell–derived neoplasms, such as papillary, follicular, or oncocytic carcinomas.
- Ancillary: Immunohistochemistry is crucial for diagnosis, with positive staining for calcitonin in the medullary component and thyroglobulin in the follicular cell–derived component.
Reference Gallery:
Mixed medullary and follicular cell–derived thyroid carcinoma. The papillary carcinoma component has a follicular growth and shows squamous metaplasia. It is intimately admixed with the medullary carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. Calcitonin immunostaining highlights the intimate admixture between the two components.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (in the middle) growing in an otherwise oncocytic carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (predominant on the left) admixed with a papillary carcinoma component with solid growth (predominant at the upper right).
Mixed medullary and follicular cell–derived thyroid carcinoma. Tumour analysed using targeted next-generation sequencing after manual microdissection of medullary carcinoma–predominant (MTC, brown box) and papillary carcinoma with follicular/solid growth–predominant (FOLL, red box) areas. The medullary carcinoma component showed HRAS mutation and RET fusion, whereas the papillary carcinoma component had an NRAS mutation associated with PIK3CA mutation with low allelic frequency (AF).

Q: In Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma, immunohistochemistry is crucial to highlight the biphasic population, characteristically showing positive staining for thyroglobulin in the follicular-derived component and [...] in the medullary component.
Mixed medullary and follicular cell–derived thyroid carcinoma. Calcitonin immunostaining highlights the intimate admixture between the two components.
A: calcitonin
Back Extra: Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma
- Clinical: Mixed Medullary and Follicular Cell-Derived Thyroid Carcinoma (MMFCC) often presents as a solitary thyroid nodule, with up to 25% of cases showing lymph node metastases at diagnosis.
- Micro: The histopathological hallmark of MMFCC is the coexistence of distinct tumour cell populations showing features of both medullary carcinoma and follicular cell–derived neoplasms, such as papillary, follicular, or oncocytic carcinomas.
- Ancillary: Immunohistochemistry is crucial for diagnosis, with positive staining for calcitonin in the medullary component and thyroglobulin in the follicular cell–derived component.
Reference Gallery:
Mixed medullary and follicular cell–derived thyroid carcinoma. The papillary carcinoma component has a follicular growth and shows squamous metaplasia. It is intimately admixed with the medullary carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. Calcitonin immunostaining highlights the intimate admixture between the two components.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (in the middle) growing in an otherwise oncocytic carcinoma.
Mixed medullary and follicular cell–derived thyroid carcinoma. A medullary carcinoma component (predominant on the left) admixed with a papillary carcinoma component with solid growth (predominant at the upper right).
Mixed medullary and follicular cell–derived thyroid carcinoma. Tumour analysed using targeted next-generation sequencing after manual microdissection of medullary carcinoma–predominant (MTC, brown box) and papillary carcinoma with follicular/solid growth–predominant (FOLL, red box) areas. The medullary carcinoma component showed HRAS mutation and RET fusion, whereas the papillary carcinoma component had an NRAS mutation associated with PIK3CA mutation with low allelic frequency (AF).

Q: Histologically, Mucoepidermoid Carcinoma of the Thyroid features large solid nests of epidermoid cells intermixed with glandular spaces and mucous cells, which are also known as [...].
Mucoepidermoid carcinoma of the thyroid. Solid sheets of tumour cells composed of epidermoid cells, mucous cells, and glandular spaces.
Mucoepidermoid carcinoma of the thyroid. Mucocytes and glandular spaces are intermixed with epidermoid cells.
A: mucocytes
Back Extra: Mucoepidermoid Carcinoma of the Thyroid
- Clinical: Mucoepidermoid carcinoma of the thyroid typically presents as a unilateral painless nodule in euthyroid patients, and it is more common in females with a mean age of 46 years.
- Micro: The tumour consists of large nests of epidermoid cells, mucocytes, and glandular spaces, often with a fibrotic stroma and intermixed cysts.
- Ancillary: Immunohistochemistry shows positivity for cytokeratins, p63, PAX8, TTF1, and thyroglobulin, while being negative for calcitonin and neuroendocrine markers.
Reference Gallery:
Mucoepidermoid carcinoma of the thyroid. A mucoepidermoid carcinoma (left and centre) associated with a papillary thyroid carcinoma (upper right).
Mucoepidermoid carcinoma of the thyroid. Solid sheets of tumour cells composed of epidermoid cells, mucous cells, and glandular spaces.
Mucoepidermoid carcinoma of the thyroid. Mucin is present in glandular spaces and mucocytes (goblet cells) (mucicarmine stain).
Mucoepidermoid carcinoma of the thyroid. PAX8 immunopositivity is seen in the mucoepidermoid carcinoma and in the concurrent papillary thyroid carcinoma.
Mucoepidermoid carcinoma of the thyroid. Both the mucoepidermoid carcinoma and the concurrent papillary thyroid carcinoma are positive for thyroid transcription factor 1 (TTF1).
Mucoepidermoid carcinoma of the thyroid. The tumour can express thyroglobulin.
Mucoepidermoid carcinoma of the thyroid. Mucocytes and glandular spaces are intermixed with epidermoid cells.

Q: To confirm a primary thyroid origin over a salivary gland metastasis, Mucoepidermoid Carcinoma of the Thyroid demonstrates characteristic immunohistochemical positivity for TTF1, PAX8, and [...].
Mucoepidermoid carcinoma of the thyroid. PAX8 immunopositivity is seen in the mucoepidermoid carcinoma and in the concurrent papillary thyroid carcinoma.
Mucoepidermoid carcinoma of the thyroid. Both the mucoepidermoid carcinoma and the concurrent papillary thyroid carcinoma are positive for thyroid transcription factor 1 (TTF1).
Mucoepidermoid carcinoma of the thyroid. The tumour can express thyroglobulin.
A: thyroglobulin
Back Extra: Mucoepidermoid Carcinoma of the Thyroid
- Clinical: Mucoepidermoid carcinoma of the thyroid typically presents as a unilateral painless nodule in euthyroid patients, and it is more common in females with a mean age of 46 years.
- Micro: The tumour consists of large nests of epidermoid cells, mucocytes, and glandular spaces, often with a fibrotic stroma and intermixed cysts.
- Ancillary: Immunohistochemistry shows positivity for cytokeratins, p63, PAX8, TTF1, and thyroglobulin, while being negative for calcitonin and neuroendocrine markers.
Reference Gallery:
Mucoepidermoid carcinoma of the thyroid. A mucoepidermoid carcinoma (left and centre) associated with a papillary thyroid carcinoma (upper right).
Mucoepidermoid carcinoma of the thyroid. Solid sheets of tumour cells composed of epidermoid cells, mucous cells, and glandular spaces.
Mucoepidermoid carcinoma of the thyroid. Mucin is present in glandular spaces and mucocytes (goblet cells) (mucicarmine stain).
Mucoepidermoid carcinoma of the thyroid. PAX8 immunopositivity is seen in the mucoepidermoid carcinoma and in the concurrent papillary thyroid carcinoma.
Mucoepidermoid carcinoma of the thyroid. Both the mucoepidermoid carcinoma and the concurrent papillary thyroid carcinoma are positive for thyroid transcription factor 1 (TTF1).
Mucoepidermoid carcinoma of the thyroid. The tumour can express thyroglobulin.
Mucoepidermoid carcinoma of the thyroid. Mucocytes and glandular spaces are intermixed with epidermoid cells.

Q: In Mucoepidermoid Carcinoma of the Thyroid, the intracytoplasmic and glandular mucin can be effectively highlighted using a [...] stain.
Mucoepidermoid carcinoma of the thyroid. Mucin is present in glandular spaces and mucocytes (goblet cells) (mucicarmine stain).
A: mucicarmine
Back Extra: Mucoepidermoid Carcinoma of the Thyroid
- Clinical: Mucoepidermoid carcinoma of the thyroid typically presents as a unilateral painless nodule in euthyroid patients, and it is more common in females with a mean age of 46 years.
- Micro: The tumour consists of large nests of epidermoid cells, mucocytes, and glandular spaces, often with a fibrotic stroma and intermixed cysts.
- Ancillary: Immunohistochemistry shows positivity for cytokeratins, p63, PAX8, TTF1, and thyroglobulin, while being negative for calcitonin and neuroendocrine markers.
Reference Gallery:
Mucoepidermoid carcinoma of the thyroid. A mucoepidermoid carcinoma (left and centre) associated with a papillary thyroid carcinoma (upper right).
Mucoepidermoid carcinoma of the thyroid. Solid sheets of tumour cells composed of epidermoid cells, mucous cells, and glandular spaces.
Mucoepidermoid carcinoma of the thyroid. Mucin is present in glandular spaces and mucocytes (goblet cells) (mucicarmine stain).
Mucoepidermoid carcinoma of the thyroid. PAX8 immunopositivity is seen in the mucoepidermoid carcinoma and in the concurrent papillary thyroid carcinoma.
Mucoepidermoid carcinoma of the thyroid. Both the mucoepidermoid carcinoma and the concurrent papillary thyroid carcinoma are positive for thyroid transcription factor 1 (TTF1).
Mucoepidermoid carcinoma of the thyroid. The tumour can express thyroglobulin.
Mucoepidermoid carcinoma of the thyroid. Mucocytes and glandular spaces are intermixed with epidermoid cells.

Q: True malignancy in Oncocytic Carcinoma of the Thyroid Gland can be established by transcapsular growth, classically appearing as a full-thickness "[...]" invasion through the thick tumor capsule.
Oncocytic carcinoma. Mushroom invasion of the full thickness of the tumour capsule.
A: mushroom
Back Extra: Oncocytic Carcinoma of the Thyroid Gland
- Clinical: Oncocytic carcinoma of the thyroid gland usually presents as a slowly enlarging, painless solitary thyroid nodule. Distant metastasis at the time of presentation is seen in 15–27% of cases, especially with extensive vascular invasion.
- Micro: Oncocytic carcinoma is a thickly encapsulated neoplasm with a monotonous population of oncocytic follicular cells, often showing capsular and/or vascular invasion. The cytoplasm is voluminous and granular, with centrally located nuclei and prominent nucleoli.
- Ancillary: No immunostains can distinguish oncocytic carcinoma from oncocytic adenoma. However, the presence of capsular and vascular invasion, along with clinical context, helps in making the diagnosis.
Reference Gallery:
Oncocytic carcinoma. Giemsa-stained air-dried smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Pap-stained alcohol-fixed smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Mushroom invasion of the full thickness of the tumour capsule.
Oncocytic carcinoma. Venous invasion in the tumour capsule. At the lower left, partial cystic change was noted in the tumour.
Oncocytic carcinoma, encapsulated with angioinvasion. Encapsulated tumour with a lesional bud penetrating the capsule and hanging in the lumen of an intracapsular vessel.
Oncocytic carcinoma, encapsulated with angioinvasion. Several tumour plugs are hanging in the lumen of an intracapsular vessel and covered by endothelial cells.
Oncocytic carcinoma, encapsulated with angioinvasion. Intravascular tumour plugs of oncocytic cells with vesicular nuclei and central nucleoli covered by endothelial cells.
Oncocytic neoplasm diagnostic paradigm. Legend text not found

Q: Histologic evaluation of Oncocytic Carcinoma of the Thyroid Gland often reveals [...] invasion, characterized by tumor plugs hanging within the lumen of intracapsular vessels that are typically covered by a layer of endothelial cells.
Oncocytic carcinoma, encapsulated with angioinvasion. Encapsulated tumour with a lesional bud penetrating the capsule and hanging in the lumen of an intracapsular vessel.
Oncocytic carcinoma, encapsulated with angioinvasion. Several tumour plugs are hanging in the lumen of an intracapsular vessel and covered by endothelial cells.
Oncocytic carcinoma, encapsulated with angioinvasion. Intravascular tumour plugs of oncocytic cells with vesicular nuclei and central nucleoli covered by endothelial cells.
A: vascular
Back Extra: Oncocytic Carcinoma of the Thyroid Gland
- Clinical: Oncocytic carcinoma of the thyroid gland usually presents as a slowly enlarging, painless solitary thyroid nodule. Distant metastasis at the time of presentation is seen in 15–27% of cases, especially with extensive vascular invasion.
- Micro: Oncocytic carcinoma is a thickly encapsulated neoplasm with a monotonous population of oncocytic follicular cells, often showing capsular and/or vascular invasion. The cytoplasm is voluminous and granular, with centrally located nuclei and prominent nucleoli.
- Ancillary: No immunostains can distinguish oncocytic carcinoma from oncocytic adenoma. However, the presence of capsular and vascular invasion, along with clinical context, helps in making the diagnosis.
Reference Gallery:
Oncocytic carcinoma. Giemsa-stained air-dried smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Pap-stained alcohol-fixed smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Mushroom invasion of the full thickness of the tumour capsule.
Oncocytic carcinoma. Venous invasion in the tumour capsule. At the lower left, partial cystic change was noted in the tumour.
Oncocytic carcinoma, encapsulated with angioinvasion. Encapsulated tumour with a lesional bud penetrating the capsule and hanging in the lumen of an intracapsular vessel.
Oncocytic carcinoma, encapsulated with angioinvasion. Several tumour plugs are hanging in the lumen of an intracapsular vessel and covered by endothelial cells.
Oncocytic carcinoma, encapsulated with angioinvasion. Intravascular tumour plugs of oncocytic cells with vesicular nuclei and central nucleoli covered by endothelial cells.
Oncocytic neoplasm diagnostic paradigm. Legend text not found

Q: Fine needle aspiration of Oncocytic Carcinoma of the Thyroid Gland yields a monotonous population of loosely cohesive oncocytic cells; however, cytology cannot definitively distinguish this carcinoma from a benign [...].
Oncocytic carcinoma. Giemsa-stained air-dried smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Pap-stained alcohol-fixed smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
A: oncocytic adenoma
Back Extra: Oncocytic Carcinoma of the Thyroid Gland
- Clinical: Oncocytic carcinoma of the thyroid gland usually presents as a slowly enlarging, painless solitary thyroid nodule. Distant metastasis at the time of presentation is seen in 15–27% of cases, especially with extensive vascular invasion.
- Micro: Oncocytic carcinoma is a thickly encapsulated neoplasm with a monotonous population of oncocytic follicular cells, often showing capsular and/or vascular invasion. The cytoplasm is voluminous and granular, with centrally located nuclei and prominent nucleoli.
- Ancillary: No immunostains can distinguish oncocytic carcinoma from oncocytic adenoma. However, the presence of capsular and vascular invasion, along with clinical context, helps in making the diagnosis.
Reference Gallery:
Oncocytic carcinoma. Giemsa-stained air-dried smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Pap-stained alcohol-fixed smear from an FNA specimen of oncocytic carcinoma showing a monotonous population of oncocytic cells arranged in loosely cohesive groups.
Oncocytic carcinoma. Mushroom invasion of the full thickness of the tumour capsule.
Oncocytic carcinoma. Venous invasion in the tumour capsule. At the lower left, partial cystic change was noted in the tumour.
Oncocytic carcinoma, encapsulated with angioinvasion. Encapsulated tumour with a lesional bud penetrating the capsule and hanging in the lumen of an intracapsular vessel.
Oncocytic carcinoma, encapsulated with angioinvasion. Several tumour plugs are hanging in the lumen of an intracapsular vessel and covered by endothelial cells.
Oncocytic carcinoma, encapsulated with angioinvasion. Intravascular tumour plugs of oncocytic cells with vesicular nuclei and central nucleoli covered by endothelial cells.
Oncocytic neoplasm diagnostic paradigm. Legend text not found

Q: The definitive diagnosis of Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma requires an exclusive follicular architecture, characteristic nuclear features, and the histopathologic presence of [...].
Invasive encapsulated follicular variant of papillary thyroid carcinoma. Low-power photomicrograph showing capsular invasion.
Invasive encapsulated follicular variant of papillary thyroid carcinoma, angioinvasive. Vascular invasion.
A: capsular or vascular invasion
Back Extra: Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma
- Clinical: Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC) predominantly occurs in adults with a median age of 40-50 years, and it presents as a painless thyroid mass.
- Micro: IEFVPTC is characterized by an exclusive or almost exclusive follicular architecture with enlarged, elongated nuclei, contour irregularities, and longitudinal grooves.
- Ancillary: IEFVPTC is positive for CAM5.2, EMA, CK7, PAX8, TTF1, and thyroglobulin. RAS point mutations are present in up to two-thirds of cases.
Reference Gallery:
Invasive encapsulated follicular variant of papillary thyroid carcinoma. Low-power photomicrograph showing capsular invasion.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour demonstrates foci with more well-developed nuclear features of papillary thyroid carcinoma. This phenomenon, known as the sprinkling sign, can be appreciated at low magnification.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour is characterized by a follicular architecture and nuclei that demonstrate enlargement, clearing, contour irregularities, and grooves.
Invasive encapsulated follicular variant of papillary thyroid carcinoma, angioinvasive. Vascular invasion.
Follicular neoplasm. FNA specimen diagnosed as suspicious for follicular neoplasm. Note the microfollicular architecture. Additionally, there is nuclear pallor and there are mild contour irregularities. The cytological findings are not diagnostic of malignancy, because malignancy is based on the assessment of invasion in the resection specimen. The resection specimen was an encapsulated follicular-variant papillary thyroid carcinoma with invasion.

Q: At low magnification, Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma can demonstrate patchy foci with more well-developed classic nuclear features, a visual phenomenon known as the [...].
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour demonstrates foci with more well-developed nuclear features of papillary thyroid carcinoma. This phenomenon, known as the sprinkling sign, can be appreciated at low magnification.
A: sprinkling sign
Back Extra: Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma
- Clinical: Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC) predominantly occurs in adults with a median age of 40-50 years, and it presents as a painless thyroid mass.
- Micro: IEFVPTC is characterized by an exclusive or almost exclusive follicular architecture with enlarged, elongated nuclei, contour irregularities, and longitudinal grooves.
- Ancillary: IEFVPTC is positive for CAM5.2, EMA, CK7, PAX8, TTF1, and thyroglobulin. RAS point mutations are present in up to two-thirds of cases.
Reference Gallery:
Invasive encapsulated follicular variant of papillary thyroid carcinoma. Low-power photomicrograph showing capsular invasion.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour demonstrates foci with more well-developed nuclear features of papillary thyroid carcinoma. This phenomenon, known as the sprinkling sign, can be appreciated at low magnification.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour is characterized by a follicular architecture and nuclei that demonstrate enlargement, clearing, contour irregularities, and grooves.
Invasive encapsulated follicular variant of papillary thyroid carcinoma, angioinvasive. Vascular invasion.
Follicular neoplasm. FNA specimen diagnosed as suspicious for follicular neoplasm. Note the microfollicular architecture. Additionally, there is nuclear pallor and there are mild contour irregularities. The cytological findings are not diagnostic of malignancy, because malignancy is based on the assessment of invasion in the resection specimen. The resection specimen was an encapsulated follicular-variant papillary thyroid carcinoma with invasion.

Q: The characteristic cytomorphology of Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma includes enlarged, cleared nuclei with contour irregularities and longitudinal [...].
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour is characterized by a follicular architecture and nuclei that demonstrate enlargement, clearing, contour irregularities, and grooves.
A: grooves
Back Extra: Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma
- Clinical: Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC) predominantly occurs in adults with a median age of 40-50 years, and it presents as a painless thyroid mass.
- Micro: IEFVPTC is characterized by an exclusive or almost exclusive follicular architecture with enlarged, elongated nuclei, contour irregularities, and longitudinal grooves.
- Ancillary: IEFVPTC is positive for CAM5.2, EMA, CK7, PAX8, TTF1, and thyroglobulin. RAS point mutations are present in up to two-thirds of cases.
Reference Gallery:
Invasive encapsulated follicular variant of papillary thyroid carcinoma. Low-power photomicrograph showing capsular invasion.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour demonstrates foci with more well-developed nuclear features of papillary thyroid carcinoma. This phenomenon, known as the sprinkling sign, can be appreciated at low magnification.
Invasive encapsulated follicular variant of papillary thyroid carcinoma. The tumour is characterized by a follicular architecture and nuclei that demonstrate enlargement, clearing, contour irregularities, and grooves.
Invasive encapsulated follicular variant of papillary thyroid carcinoma, angioinvasive. Vascular invasion.
Follicular neoplasm. FNA specimen diagnosed as suspicious for follicular neoplasm. Note the microfollicular architecture. Additionally, there is nuclear pallor and there are mild contour irregularities. The cytological findings are not diagnostic of malignancy, because malignancy is based on the assessment of invasion in the resection specimen. The resection specimen was an encapsulated follicular-variant papillary thyroid carcinoma with invasion.

Q: Histologically, Non-invasive follicular thyroid neoplasm with papillary-like nuclear features is defined by a completely encapsulated or well-demarcated tumor that exhibits a predominantly [...] growth pattern lacking well-formed papillae.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour can display a thick capsule. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The capsule can be thin. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour lacks a capsule but is well demarcated from adjacent non-neoplastic thyroid. The neoplasm shows a predominantly follicular growth pattern.
A: follicular
Back Extra: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features
- Clinical: Patients typically present with an asymptomatic nodule detected during routine physical examination or by imaging, often appearing as a solid, mildly hypoechoic or isoechoic mass with smooth borders and lacking calcifications.
- Micro: NIFTPs must be totally encapsulated or completely demarcated from the surrounding non-neoplastic parenchyma. The tumour shows a predominantly follicular growth pattern with enlarged, irregular nuclei and minimal papillae.
- Ancillary: RAS mutations are the main molecular drivers, occurring in 52% of cases, with most located in NRAS. BRAF p.V600E mutation excludes the diagnosis.
Reference Gallery:
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour can display a thick capsule. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The capsule can be thin. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour lacks a capsule but is well demarcated from adjacent non-neoplastic thyroid. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour shows follicles with papillary carcinoma–like nuclei intermixed with follicles lined by normal-appearing follicular cells.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour has a diffuse distribution of papillary carcinoma–like nuclei, and the neoplastic cell cytoplasm is oncocytic (oncocytic non-invasive follicular thyroid neoplasm with papillary-like nuclear features).
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Normal follicles lined by cells with small round normochromatic nuclei are adjacent to a non-invasive follicular thyroid neoplasm with papillary-like nuclear features and are used as a reference.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 1. The cells in this field are enlarged as compared with normal thyroid but lack significant nuclear irregularity and chromatin clearing. These features are insufficient for a diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 2. The cells of this non-invasive follicular thyroid neoplasm with papillary-like nuclear features have enlarged nuclei (as compared with normal thyroid) and irregular nuclear membranes but no substantial chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 3. The cells in this example have enlarged nuclei (as compared with normal thyroid), irregular nuclear membranes, and chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Grossly, the tumour is well demarcated, with smooth borders, a homogeneous yellow-tan cut surface, and focal areas of haemorrhage.

Q: To establish the diagnosis of Non-invasive follicular thyroid neoplasm with papillary-like nuclear features, the tumor cells must demonstrate sufficient nuclear atypia, including enlargement, irregular nuclear membranes, and [...].
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 2. The cells of this non-invasive follicular thyroid neoplasm with papillary-like nuclear features have enlarged nuclei (as compared with normal thyroid) and irregular nuclear membranes but no substantial chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 3. The cells in this example have enlarged nuclei (as compared with normal thyroid), irregular nuclear membranes, and chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
A: chromatin clearing
Back Extra: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features
- Clinical: Patients typically present with an asymptomatic nodule detected during routine physical examination or by imaging, often appearing as a solid, mildly hypoechoic or isoechoic mass with smooth borders and lacking calcifications.
- Micro: NIFTPs must be totally encapsulated or completely demarcated from the surrounding non-neoplastic parenchyma. The tumour shows a predominantly follicular growth pattern with enlarged, irregular nuclei and minimal papillae.
- Ancillary: RAS mutations are the main molecular drivers, occurring in 52% of cases, with most located in NRAS. BRAF p.V600E mutation excludes the diagnosis.
Reference Gallery:
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour can display a thick capsule. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The capsule can be thin. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour lacks a capsule but is well demarcated from adjacent non-neoplastic thyroid. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour shows follicles with papillary carcinoma–like nuclei intermixed with follicles lined by normal-appearing follicular cells.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour has a diffuse distribution of papillary carcinoma–like nuclei, and the neoplastic cell cytoplasm is oncocytic (oncocytic non-invasive follicular thyroid neoplasm with papillary-like nuclear features).
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Normal follicles lined by cells with small round normochromatic nuclei are adjacent to a non-invasive follicular thyroid neoplasm with papillary-like nuclear features and are used as a reference.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 1. The cells in this field are enlarged as compared with normal thyroid but lack significant nuclear irregularity and chromatin clearing. These features are insufficient for a diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 2. The cells of this non-invasive follicular thyroid neoplasm with papillary-like nuclear features have enlarged nuclei (as compared with normal thyroid) and irregular nuclear membranes but no substantial chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 3. The cells in this example have enlarged nuclei (as compared with normal thyroid), irregular nuclear membranes, and chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Grossly, the tumour is well demarcated, with smooth borders, a homogeneous yellow-tan cut surface, and focal areas of haemorrhage.

Q: On gross examination, Non-invasive follicular thyroid neoplasm with papillary-like nuclear features typically presents as a well-demarcated tumor with smooth borders and a homogeneous [...] cut surface.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Grossly, the tumour is well demarcated, with smooth borders, a homogeneous yellow-tan cut surface, and focal areas of haemorrhage.
A: yellow-tan
Back Extra: Non-invasive follicular thyroid neoplasm with papillary-like nuclear features
- Clinical: Patients typically present with an asymptomatic nodule detected during routine physical examination or by imaging, often appearing as a solid, mildly hypoechoic or isoechoic mass with smooth borders and lacking calcifications.
- Micro: NIFTPs must be totally encapsulated or completely demarcated from the surrounding non-neoplastic parenchyma. The tumour shows a predominantly follicular growth pattern with enlarged, irregular nuclei and minimal papillae.
- Ancillary: RAS mutations are the main molecular drivers, occurring in 52% of cases, with most located in NRAS. BRAF p.V600E mutation excludes the diagnosis.
Reference Gallery:
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour can display a thick capsule. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The capsule can be thin. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. The tumour lacks a capsule but is well demarcated from adjacent non-neoplastic thyroid. The neoplasm shows a predominantly follicular growth pattern.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour shows follicles with papillary carcinoma–like nuclei intermixed with follicles lined by normal-appearing follicular cells.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. This tumour has a diffuse distribution of papillary carcinoma–like nuclei, and the neoplastic cell cytoplasm is oncocytic (oncocytic non-invasive follicular thyroid neoplasm with papillary-like nuclear features).
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Normal follicles lined by cells with small round normochromatic nuclei are adjacent to a non-invasive follicular thyroid neoplasm with papillary-like nuclear features and are used as a reference.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 1. The cells in this field are enlarged as compared with normal thyroid but lack significant nuclear irregularity and chromatin clearing. These features are insufficient for a diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 2. The cells of this non-invasive follicular thyroid neoplasm with papillary-like nuclear features have enlarged nuclei (as compared with normal thyroid) and irregular nuclear membranes but no substantial chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Nuclear score of 3. The cells in this example have enlarged nuclei (as compared with normal thyroid), irregular nuclear membranes, and chromatin clearing. These features meet the criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features.
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Grossly, the tumour is well demarcated, with smooth borders, a homogeneous yellow-tan cut surface, and focal areas of haemorrhage.

Q: Characteristically exhibiting no distinct morphological findings to differentiate them from sporadic counterparts, [...] most commonly present as multifocal papillary carcinomas at a younger age (approximately 5 years earlier) than sporadic cases.
Familial papillary thyroid carcinoma. Gross appearance of the gland of a patient with four foci of familial papillary carcinoma, one oncocytic adenoma, and lymphocytic thyroiditis.
Familial papillary thyroid carcinoma. Small papillary thyroid carcinoma. Both familial papillary thyroid carcinomas are not morphologically different from sporadic papillary thyroid carcinomas.
A: Non-syndromic familial follicular cell-derived thyroid tumors
Back Extra: Non-syndromic familial follicular cell-derived thyroid tumours
- Clinical: Patients with non-syndromic familial follicular cell-derived thyroid tumours (NSFNMTC) typically present at a younger age (on average 5 years younger) than those with sporadic thyroid cancer.
- Micro: NSAFTC is mainly of the papillary type, including subcentimetre cases and the classic and follicular-type subtypes, but no distinct morphological findings differentiate these carcinomas from their sporadic counterparts.
- Ancillary: Overexpression of PLCB1, HABP2, EGFR, and NOP53, with lower immunostaining for CHK2, has been detected in thyroid tumour cells, associated with pathogenic germline variants of the genes PLCB1, HABP2, BROX, NOP53, and CHEK2.
Reference Gallery:
Familial papillary thyroid carcinoma. Gross appearance of the gland of a patient with four foci of familial papillary carcinoma, one oncocytic adenoma, and lymphocytic thyroiditis.
Familial papillary thyroid carcinoma. This papillary thyroid carcinoma includes oncocytic tall cells with a heavy lymphoid infiltrate (Warthin-like pattern).
Familial papillary thyroid carcinoma. Small papillary thyroid carcinoma. Both familial papillary thyroid carcinomas are not morphologically different from sporadic papillary thyroid carcinomas.
Thyroid tumour associated with the CHEK2 gene mutation. This papillary thyroid carcinoma consists of large follicular cells with oncocytic cytoplasm and large irregular nuclei.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. This familial papillary thyroid carcinoma, associated with chromosomal region 1q21 (fPTC/PRN), shows a papillary arrangement with a glomeruloid appearance.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. This hereditary papillary thyroid carcinoma is morphologically similar to renal papillary carcinoma.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. The positivity for thyroid transcription factor 1 (TTF1) confirms the thyroid nature of the papillary tumour.

Q: Among the pathogenic germline variants associated with Non-syndromic familial follicular cell-derived thyroid tumors, mutations in the [...] gene can produce tumors consisting of large follicular cells with oncocytic cytoplasm and large irregular nuclei.
Thyroid tumour associated with the CHEK2 gene mutation. This papillary thyroid carcinoma consists of large follicular cells with oncocytic cytoplasm and large irregular nuclei.
A: CHEK2
Back Extra: Non-syndromic familial follicular cell-derived thyroid tumours
- Clinical: Patients with non-syndromic familial follicular cell-derived thyroid tumours (NSFNMTC) typically present at a younger age (on average 5 years younger) than those with sporadic thyroid cancer.
- Micro: NSAFTC is mainly of the papillary type, including subcentimetre cases and the classic and follicular-type subtypes, but no distinct morphological findings differentiate these carcinomas from their sporadic counterparts.
- Ancillary: Overexpression of PLCB1, HABP2, EGFR, and NOP53, with lower immunostaining for CHK2, has been detected in thyroid tumour cells, associated with pathogenic germline variants of the genes PLCB1, HABP2, BROX, NOP53, and CHEK2.
Reference Gallery:
Familial papillary thyroid carcinoma. Gross appearance of the gland of a patient with four foci of familial papillary carcinoma, one oncocytic adenoma, and lymphocytic thyroiditis.
Familial papillary thyroid carcinoma. This papillary thyroid carcinoma includes oncocytic tall cells with a heavy lymphoid infiltrate (Warthin-like pattern).
Familial papillary thyroid carcinoma. Small papillary thyroid carcinoma. Both familial papillary thyroid carcinomas are not morphologically different from sporadic papillary thyroid carcinomas.
Thyroid tumour associated with the CHEK2 gene mutation. This papillary thyroid carcinoma consists of large follicular cells with oncocytic cytoplasm and large irregular nuclei.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. This familial papillary thyroid carcinoma, associated with chromosomal region 1q21 (fPTC/PRN), shows a papillary arrangement with a glomeruloid appearance.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. This hereditary papillary thyroid carcinoma is morphologically similar to renal papillary carcinoma.
Familial papillary thyroid carcinoma associated with renal papillary neoplasia. The positivity for thyroid transcription factor 1 (TTF1) confirms the thyroid nature of the papillary tumour.

Q: In Teratomas with endocrine differentiation, a lesion is classified as [...] when the teratoma is composed of > 50% thyroid tissue, typically showing mature colloid-filled follicles.
Struma ovarii. Mature follicles of various sizes with abundant colloid.
A: struma ovarii
Back Extra: Teratomas with endocrine differentiation
- Clinical: Up to one third of patients with struma ovarii have ascites, and 5% show clinical evidence of hyperthyroidism.
- Micro: Struma ovarii is classified when teratomas are composed of > 50% thyroid tissue, showing mature colloid-filled follicles, and can have a solid or microfollicular architecture.
- Ancillary: Thyroid carcinomas arising in struma ovarii frequently demonstrate BRAF, KRAS, and NRAS mutations, similar to thyroid carcinomas.
Reference Gallery:
Struma ovarii. Mature follicles of various sizes with abundant colloid.
Papillary thyroid carcinoma arising in struma ovarii. Diagnostic papillary nuclear features, including chromatin clearing, nuclear grooves, nuclear elongation, and intranuclear pseudoinclusions, are identified.
Ovarian neuroendocrine tumour (NET). Ribbons and cords of uniform cells with pink cytoplasm and centrally located nuclei with salt-and-pepper chromatin.

Q: In the context of Teratomas with endocrine differentiation, malignant transformation can occur, such as a [...] arising in struma ovarii, which microscopically displays diagnostic nuclear grooves, chromatin clearing, and intranuclear pseudoinclusions.
Papillary thyroid carcinoma arising in struma ovarii. Diagnostic papillary nuclear features, including chromatin clearing, nuclear grooves, nuclear elongation, and intranuclear pseudoinclusions, are identified.
A: papillary thyroid carcinoma
Back Extra: Teratomas with endocrine differentiation
- Clinical: Up to one third of patients with struma ovarii have ascites, and 5% show clinical evidence of hyperthyroidism.
- Micro: Struma ovarii is classified when teratomas are composed of > 50% thyroid tissue, showing mature colloid-filled follicles, and can have a solid or microfollicular architecture.
- Ancillary: Thyroid carcinomas arising in struma ovarii frequently demonstrate BRAF, KRAS, and NRAS mutations, similar to thyroid carcinomas.
Reference Gallery:
Struma ovarii. Mature follicles of various sizes with abundant colloid.
Papillary thyroid carcinoma arising in struma ovarii. Diagnostic papillary nuclear features, including chromatin clearing, nuclear grooves, nuclear elongation, and intranuclear pseudoinclusions, are identified.
Ovarian neuroendocrine tumour (NET). Ribbons and cords of uniform cells with pink cytoplasm and centrally located nuclei with salt-and-pepper chromatin.

Q: Another manifestation of Teratomas with endocrine differentiation is the ovarian [...], characterized microscopically by ribbons and cords of uniform cells containing nuclei with classic salt-and-pepper chromatin.
Ovarian neuroendocrine tumour (NET). Ribbons and cords of uniform cells with pink cytoplasm and centrally located nuclei with salt-and-pepper chromatin.
A: neuroendocrine tumor
Back Extra: Teratomas with endocrine differentiation
- Clinical: Up to one third of patients with struma ovarii have ascites, and 5% show clinical evidence of hyperthyroidism.
- Micro: Struma ovarii is classified when teratomas are composed of > 50% thyroid tissue, showing mature colloid-filled follicles, and can have a solid or microfollicular architecture.
- Ancillary: Thyroid carcinomas arising in struma ovarii frequently demonstrate BRAF, KRAS, and NRAS mutations, similar to thyroid carcinomas.
Reference Gallery:
Struma ovarii. Mature follicles of various sizes with abundant colloid.
Papillary thyroid carcinoma arising in struma ovarii. Diagnostic papillary nuclear features, including chromatin clearing, nuclear grooves, nuclear elongation, and intranuclear pseudoinclusions, are identified.
Ovarian neuroendocrine tumour (NET). Ribbons and cords of uniform cells with pink cytoplasm and centrally located nuclei with salt-and-pepper chromatin.

Q: Histologically, [...] is characterized by cords and nests of squamoid tumor cells set within a dense sclerotic stroma that is heavily infiltrated by eosinophils and lymphocytes.
Sclerosing mucoepidermoid carcinoma with eosinophilia. The squamoid tumour cells are associated with a dense sclerotic stroma infiltrated by lymphocytes and eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Large malignant cells are within a sclerotic stroma with numerous eosinophils.
A: Sclerosing Mucoepidermoid Carcinoma with Eosinophilia
Back Extra: Sclerosing Mucoepidermoid Carcinoma with Eosinophilia
- Clinical: Sclerosing mucoepidermoid carcinoma with eosinophilia typically presents as a slow-growing, unilateral painless mass in euthyroid or hypothyroid patients.
- Micro: The tumour cells form cords, strands, and nests within a densely sclerotic stroma, often with eosinophils and lymphocytes.
- Ancillary: Immunohistochemistry shows consistent reactivity for p63 and cytokeratins in the squamoid tumour cells, with focal TTF1 expression in about 50% of cases.
Reference Gallery:
Sclerosing mucoepidermoid carcinoma with eosinophilia. The sclerotic tumour (left) appears to merge with associated underlying chronic lymphocytic thyroiditis (right).
Sclerosing mucoepidermoid carcinoma with eosinophilia. The squamoid tumour cells are associated with a dense sclerotic stroma infiltrated by lymphocytes and eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A mucicarmine special stain highlights intracellular mucin within the neoplastic mucocytes.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A lymph node metastasis recapitulates the morphological features characteristic of the primary tumour.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Large malignant cells are within a sclerotic stroma with numerous eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Nests of tumour cells intermixed with eosinophils with an adjacent area of tumour necrosis.

Q: In Sclerosing Mucoepidermoid Carcinoma with Eosinophilia, the presence of intracellular mucin within scattered neoplastic mucocytes can be confirmed using a [...] special stain.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A mucicarmine special stain highlights intracellular mucin within the neoplastic mucocytes.
A: mucicarmine
Back Extra: Sclerosing Mucoepidermoid Carcinoma with Eosinophilia
- Clinical: Sclerosing mucoepidermoid carcinoma with eosinophilia typically presents as a slow-growing, unilateral painless mass in euthyroid or hypothyroid patients.
- Micro: The tumour cells form cords, strands, and nests within a densely sclerotic stroma, often with eosinophils and lymphocytes.
- Ancillary: Immunohistochemistry shows consistent reactivity for p63 and cytokeratins in the squamoid tumour cells, with focal TTF1 expression in about 50% of cases.
Reference Gallery:
Sclerosing mucoepidermoid carcinoma with eosinophilia. The sclerotic tumour (left) appears to merge with associated underlying chronic lymphocytic thyroiditis (right).
Sclerosing mucoepidermoid carcinoma with eosinophilia. The squamoid tumour cells are associated with a dense sclerotic stroma infiltrated by lymphocytes and eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A mucicarmine special stain highlights intracellular mucin within the neoplastic mucocytes.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A lymph node metastasis recapitulates the morphological features characteristic of the primary tumour.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Large malignant cells are within a sclerotic stroma with numerous eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Nests of tumour cells intermixed with eosinophils with an adjacent area of tumour necrosis.

Q: A characteristic feature of Sclerosing Mucoepidermoid Carcinoma with Eosinophilia is that the sclerotic tumor frequently arises in the background of, and morphologically merges with, underlying [...].
Sclerosing mucoepidermoid carcinoma with eosinophilia. The sclerotic tumour (left) appears to merge with associated underlying chronic lymphocytic thyroiditis (right).
A: chronic lymphocytic thyroiditis
Back Extra: Sclerosing Mucoepidermoid Carcinoma with Eosinophilia
- Clinical: Sclerosing mucoepidermoid carcinoma with eosinophilia typically presents as a slow-growing, unilateral painless mass in euthyroid or hypothyroid patients.
- Micro: The tumour cells form cords, strands, and nests within a densely sclerotic stroma, often with eosinophils and lymphocytes.
- Ancillary: Immunohistochemistry shows consistent reactivity for p63 and cytokeratins in the squamoid tumour cells, with focal TTF1 expression in about 50% of cases.
Reference Gallery:
Sclerosing mucoepidermoid carcinoma with eosinophilia. The sclerotic tumour (left) appears to merge with associated underlying chronic lymphocytic thyroiditis (right).
Sclerosing mucoepidermoid carcinoma with eosinophilia. The squamoid tumour cells are associated with a dense sclerotic stroma infiltrated by lymphocytes and eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A mucicarmine special stain highlights intracellular mucin within the neoplastic mucocytes.
Sclerosing mucoepidermoid carcinoma with eosinophilia. A lymph node metastasis recapitulates the morphological features characteristic of the primary tumour.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Large malignant cells are within a sclerotic stroma with numerous eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophilia. Nests of tumour cells intermixed with eosinophils with an adjacent area of tumour necrosis.

Q: Microscopically, Secretory Carcinoma features cells with eosinophilic to vacuolated cytoplasm and characteristic [...] composed of dense eosinophilic substance and mucin.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Nuclei are often cleared and ovoid, with prominent nucleoli.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Foci with elongation and grooves reminiscent of papillary thyroid carcinoma may be noted.
A: bubbly luminal secretions
Back Extra: Secretory Carcinoma
- Clinical: Secretory carcinoma typically presents as a uninodular mass in the thyroid, with a female predilection and an average age at presentation of 61.5 years.
- Micro: The microscopic appearance includes cells with eosinophilic, vacuolated cytoplasm arranged in papillary, tubular, microcystic, and solid patterns, with characteristic bubbly luminal secretions.
- Ancillary: Diagnostic confirmation is achieved through ETV6 translocation detection, and immunohistochemistry shows positivity for S100, mammaglobin, and GATA3, with negativity for TTF1.
Reference Gallery:
Secretory carcinoma. Sclerosis and infiltration of adjacent thyroid.
Secretory carcinoma. A mixture of cribriform and micropapillary growth patterns is common.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Nuclei are often cleared and ovoid, with prominent nucleoli.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Foci with elongation and grooves reminiscent of papillary thyroid carcinoma may be noted.
Secretory carcinoma. Thyroid transcription factor 1 (TTF1) negativity.
Secretory carcinoma. S100 positivity.
Secretory carcinoma. Break-apart FISH for ETV6 confirms the translocation status.

Q: Diagnostic confirmation of Secretory Carcinoma of the thyroid is achieved by detecting a translocation involving the [...] gene.
Secretory carcinoma. Break-apart FISH for ETV6 confirms the translocation status.
A: ETV6
Back Extra: Secretory Carcinoma
- Clinical: Secretory carcinoma typically presents as a uninodular mass in the thyroid, with a female predilection and an average age at presentation of 61.5 years.
- Micro: The microscopic appearance includes cells with eosinophilic, vacuolated cytoplasm arranged in papillary, tubular, microcystic, and solid patterns, with characteristic bubbly luminal secretions.
- Ancillary: Diagnostic confirmation is achieved through ETV6 translocation detection, and immunohistochemistry shows positivity for S100, mammaglobin, and GATA3, with negativity for TTF1.
Reference Gallery:
Secretory carcinoma. Sclerosis and infiltration of adjacent thyroid.
Secretory carcinoma. A mixture of cribriform and micropapillary growth patterns is common.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Nuclei are often cleared and ovoid, with prominent nucleoli.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Foci with elongation and grooves reminiscent of papillary thyroid carcinoma may be noted.
Secretory carcinoma. Thyroid transcription factor 1 (TTF1) negativity.
Secretory carcinoma. S100 positivity.
Secretory carcinoma. Break-apart FISH for ETV6 confirms the translocation status.

Q: By immunohistochemistry, Secretory Carcinoma in the thyroid is typically positive for S100 but classically negative for [...], helping to differentiate it from primary thyroid follicular-derived neoplasms.
Secretory carcinoma. Thyroid transcription factor 1 (TTF1) negativity.
Secretory carcinoma. S100 positivity.
A: TTF1
Back Extra: Secretory Carcinoma
- Clinical: Secretory carcinoma typically presents as a uninodular mass in the thyroid, with a female predilection and an average age at presentation of 61.5 years.
- Micro: The microscopic appearance includes cells with eosinophilic, vacuolated cytoplasm arranged in papillary, tubular, microcystic, and solid patterns, with characteristic bubbly luminal secretions.
- Ancillary: Diagnostic confirmation is achieved through ETV6 translocation detection, and immunohistochemistry shows positivity for S100, mammaglobin, and GATA3, with negativity for TTF1.
Reference Gallery:
Secretory carcinoma. Sclerosis and infiltration of adjacent thyroid.
Secretory carcinoma. A mixture of cribriform and micropapillary growth patterns is common.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Nuclei are often cleared and ovoid, with prominent nucleoli.
Secretory carcinoma. Eosinophilic to vacuolated cytoplasm with bubbly luminal secretions composed of a mixture of dense eosinophilic substance and mucin. Foci with elongation and grooves reminiscent of papillary thyroid carcinoma may be noted.
Secretory carcinoma. Thyroid transcription factor 1 (TTF1) negativity.
Secretory carcinoma. S100 positivity.
Secretory carcinoma. Break-apart FISH for ETV6 confirms the translocation status.

Q: Microscopically, Spindle Epithelial Tumor with Thymus-Like Elements exhibits a lobulated growth pattern with bundles of spindle cells intermixed with epithelial nests, which can sometimes structurally resemble [...].
Spindle epithelial tumour with thymus-like elements. Note the lobulated growth pattern with a dominance of spindle cells. The capsule of the tumour at the right shows no invasion.
Spindle epithelial tumour with thymus-like elements. Epithelial nests appear near spindle cell bundles.
Spindle epithelial tumour with thymus-like elements. Epithelial nest resembling a glomeruloid body.
A: glomeruloid bodies
Back Extra: Spindle Epithelial Tumour with Thymus-Like Elements
- Clinical: SETTLE usually presents as a painless thyroid mass, more common in children and young adults, with a median age of 19 years and a male predilection.
- Micro: SETTLE is characterized by a lobulated architecture with spindle and epithelial cells merging into glandular structures, often showing cleft-like spaces containing mucin.
- Ancillary: Both spindle and glandular cells express pancytokeratins, high-molecular-weight cytokeratins, and p63/p40, but lack SS18::SSX1, SS18::SSX2, or SS18::SSX4 gene fusions.
Reference Gallery:
Spindle epithelial tumour with thymus-like elements, FNAC. Air-dried, Giemsa-stained smear showing a tissue fragment of spindle cells, some with an epithelioid appearance.
Spindle epithelial tumour with thymus-like elements, FNAC. Liquid-based cytology preparation showing spindle cells with mild nuclear pleomorphism arranged in cohesive tissue fragments.
Spindle epithelial tumour with thymus-like elements. Note the lobulated growth pattern with a dominance of spindle cells. The capsule of the tumour at the right shows no invasion.
Spindle epithelial tumour with thymus-like elements. Epithelial nests appear near spindle cell bundles.
Spindle epithelial tumour with thymus-like elements. Epithelial nest resembling a glomeruloid body.
Spindle epithelial tumour with thymus-like elements. Immunohistochemistry for cytokeratin (CAM5.2) shows staining of spindle cells.

Q: In Spindle Epithelial Tumor with Thymus-Like Elements, immunohistochemistry characteristically demonstrates that both the epithelial nests and the prominent spindle cells strongly express epithelial markers, such as [...] (e.g., CAM5.2) and p63/p40.
Spindle epithelial tumour with thymus-like elements. Immunohistochemistry for cytokeratin (CAM5.2) shows staining of spindle cells.
A: cytokeratins
Back Extra: Spindle Epithelial Tumour with Thymus-Like Elements
- Clinical: SETTLE usually presents as a painless thyroid mass, more common in children and young adults, with a median age of 19 years and a male predilection.
- Micro: SETTLE is characterized by a lobulated architecture with spindle and epithelial cells merging into glandular structures, often showing cleft-like spaces containing mucin.
- Ancillary: Both spindle and glandular cells express pancytokeratins, high-molecular-weight cytokeratins, and p63/p40, but lack SS18::SSX1, SS18::SSX2, or SS18::SSX4 gene fusions.
Reference Gallery:
Spindle epithelial tumour with thymus-like elements, FNAC. Air-dried, Giemsa-stained smear showing a tissue fragment of spindle cells, some with an epithelioid appearance.
Spindle epithelial tumour with thymus-like elements, FNAC. Liquid-based cytology preparation showing spindle cells with mild nuclear pleomorphism arranged in cohesive tissue fragments.
Spindle epithelial tumour with thymus-like elements. Note the lobulated growth pattern with a dominance of spindle cells. The capsule of the tumour at the right shows no invasion.
Spindle epithelial tumour with thymus-like elements. Epithelial nests appear near spindle cell bundles.
Spindle epithelial tumour with thymus-like elements. Epithelial nest resembling a glomeruloid body.
Spindle epithelial tumour with thymus-like elements. Immunohistochemistry for cytokeratin (CAM5.2) shows staining of spindle cells.

Q: Histologically, the aggressive tumor known as Thyroblastoma is characterized by a primitive, [...] growth pattern composed of epithelial cell nests intermixed with spindle stromal cells.
Thyroblastoma. This primitive tumour has a biphasic growth pattern composed of nests and cords of primitive epithelial cells intermixed with primitive spindle stromal cells.
Thyroblastoma. The thyroid lobe is replaced by a friable, soft pink tumour mass. The gross cut surface shows the features of this aggressive tumour with complete replacement of the thyroid.
A: biphasic
Back Extra: Thyroblastoma
- Clinical: Thyroblastoma presents as a rapidly growing mid-cervical thyroid mass, often diffusely infiltrating one or both thyroid lobes and extending into perithyroid tissue.
- Micro: Histologically, thyroblastoma is characterized by a biphasic growth pattern with primitive follicles, small round to oval cells, and spindle cell stroma.
- Ancillary: Pathogenic somatic DICER1 variants are present in all tested cases, distinguishing thyroblastoma from teratomas.
Reference Gallery:
Thyroblastoma. This primitive tumour has a biphasic growth pattern composed of nests and cords of primitive epithelial cells intermixed with primitive spindle stromal cells.
Thyroblastoma. Lung metastasis from a thyroblastoma showing cartilage foci (cartilage was not detected in the primary tumour).
Thyroblastoma. SALL4 is strongly positive in the primitive solid nests.
Thyroblastoma cytology. Mixed cell population.
Thyroblastoma. Thyroglobulin in a few primitive follicles.
Thyroblastoma. The primitive follicles stain for thyroid transcription factor 1 (TTF1) and PAX8. The stroma is negative.
Thyroblastoma. The primitive stromal cells stain for desmin, whereas the primitive follicles are negative.
Thyroblastoma. The thyroid lobe is replaced by a friable, soft pink tumour mass. The gross cut surface shows the features of this aggressive tumour with complete replacement of the thyroid.

Q: In the immunohistochemical workup of Thyroblastoma, the primitive spindle stromal cells characteristically express [...], distinguishing them from the TTF1/PAX8-positive primitive follicles.
Thyroblastoma. The primitive follicles stain for thyroid transcription factor 1 (TTF1) and PAX8. The stroma is negative.
Thyroblastoma. The primitive stromal cells stain for desmin, whereas the primitive follicles are negative.
A: desmin
Back Extra: Thyroblastoma
- Clinical: Thyroblastoma presents as a rapidly growing mid-cervical thyroid mass, often diffusely infiltrating one or both thyroid lobes and extending into perithyroid tissue.
- Micro: Histologically, thyroblastoma is characterized by a biphasic growth pattern with primitive follicles, small round to oval cells, and spindle cell stroma.
- Ancillary: Pathogenic somatic DICER1 variants are present in all tested cases, distinguishing thyroblastoma from teratomas.
Reference Gallery:
Thyroblastoma. This primitive tumour has a biphasic growth pattern composed of nests and cords of primitive epithelial cells intermixed with primitive spindle stromal cells.
Thyroblastoma. Lung metastasis from a thyroblastoma showing cartilage foci (cartilage was not detected in the primary tumour).
Thyroblastoma. SALL4 is strongly positive in the primitive solid nests.
Thyroblastoma cytology. Mixed cell population.
Thyroblastoma. Thyroglobulin in a few primitive follicles.
Thyroblastoma. The primitive follicles stain for thyroid transcription factor 1 (TTF1) and PAX8. The stroma is negative.
Thyroblastoma. The primitive stromal cells stain for desmin, whereas the primitive follicles are negative.
Thyroblastoma. The thyroid lobe is replaced by a friable, soft pink tumour mass. The gross cut surface shows the features of this aggressive tumour with complete replacement of the thyroid.

Q: In Thyroblastoma, the primitive solid nests often exhibit strong immunohistochemical positivity for the stem cell marker [...].
Thyroblastoma. SALL4 is strongly positive in the primitive solid nests.
A: SALL4
Back Extra: Thyroblastoma
- Clinical: Thyroblastoma presents as a rapidly growing mid-cervical thyroid mass, often diffusely infiltrating one or both thyroid lobes and extending into perithyroid tissue.
- Micro: Histologically, thyroblastoma is characterized by a biphasic growth pattern with primitive follicles, small round to oval cells, and spindle cell stroma.
- Ancillary: Pathogenic somatic DICER1 variants are present in all tested cases, distinguishing thyroblastoma from teratomas.
Reference Gallery:
Thyroblastoma. This primitive tumour has a biphasic growth pattern composed of nests and cords of primitive epithelial cells intermixed with primitive spindle stromal cells.
Thyroblastoma. Lung metastasis from a thyroblastoma showing cartilage foci (cartilage was not detected in the primary tumour).
Thyroblastoma. SALL4 is strongly positive in the primitive solid nests.
Thyroblastoma cytology. Mixed cell population.
Thyroblastoma. Thyroglobulin in a few primitive follicles.
Thyroblastoma. The primitive follicles stain for thyroid transcription factor 1 (TTF1) and PAX8. The stroma is negative.
Thyroblastoma. The primitive stromal cells stain for desmin, whereas the primitive follicles are negative.
Thyroblastoma. The thyroid lobe is replaced by a friable, soft pink tumour mass. The gross cut surface shows the features of this aggressive tumour with complete replacement of the thyroid.

Q: A classic histologic feature of Medullary Thyroid Carcinoma is the presence of solid tumor cell nests separated by fibrous septa that frequently contain extracellular [...] deposits.
Medullary thyroid carcinoma. The tumour cells in this classic medullary thyroid carcinoma are arranged in solid nests separated by fibrous septa with stromal amyloid deposition.
Medullary thyroid carcinoma. This tumour shows extensive amyloid deposition with calcification.
A: amyloid
Back Extra: Medullary Thyroid Carcinoma
- Clinical: Medullary Thyroid Carcinoma typically presents as a solitary palpable thyroid nodule, often with invasion of surrounding structures leading to dysphagia or respiratory difficulty.
- Micro: Medullary Thyroid Carcinoma shows a broad morphological spectrum, including solid, nested, insular, or trabecular growth patterns with frequent stromal amyloid deposition.
- Ancillary: Medullary Thyroid Carcinoma is strongly positive for calcitonin and neuroendocrine markers, and typically negative for thyroglobulin. RET mutations are common and can influence prognosis and treatment.
Reference Gallery:
Medullary thyroid carcinoma. The tumour cells in this classic medullary thyroid carcinoma are arranged in solid nests separated by fibrous septa with stromal amyloid deposition.
Medullary thyroid carcinoma. This tumour shows extensive amyloid deposition with calcification.
Medullary thyroid carcinoma. The tumour is strongly and diffusely positive with calcitonin immunoperoxidase staining.
Medullary thyroid carcinoma. This tumour shows central tumour necrosis within nests of neoplastic cells.
Medullary thyroid carcinoma. The tumour cells have a distinctive plasmacytoid morphology.
Medullary thyroid carcinoma. In the follicular (tubular/glandular) pattern, the tumour cells are arranged in follicular structures.
Medullary thyroid carcinoma. This tumour is composed of spindle cells arranged in short intersecting fascicles.
Medullary thyroid carcinoma. Clear cell pattern of medullary thyroid carcinoma.
Medullary thyroid carcinoma. Some cases show scattered markedly pleomorphic cells with bizarre nuclei, multinucleated forms, and nuclear pseudoinclusions.
Medullary thyroid carcinoma. The oncocytic pattern of medullary thyroid carcinoma is composed of sheets of polygonal cells with abundant granular eosinophilic cytoplasm that may mimic oncocytic cells.
Medullary thyroid carcinoma. In the papillary pattern, tumour cells are aligned along true fibrovascular cores that are often hyalinized and contain amyloid deposits.
Medullary thyroid carcinoma. This tumour has a predominantly trabecular growth pattern.

Q: Because Medullary Thyroid Carcinoma originates from parafollicular C cells, it is classically strongly positive for the immunohistochemical marker [...] and usually negative for thyroglobulin.
Medullary thyroid carcinoma. The tumour is strongly and diffusely positive with calcitonin immunoperoxidase staining.
A: calcitonin
Back Extra: Medullary Thyroid Carcinoma
- Clinical: Medullary Thyroid Carcinoma typically presents as a solitary palpable thyroid nodule, often with invasion of surrounding structures leading to dysphagia or respiratory difficulty.
- Micro: Medullary Thyroid Carcinoma shows a broad morphological spectrum, including solid, nested, insular, or trabecular growth patterns with frequent stromal amyloid deposition.
- Ancillary: Medullary Thyroid Carcinoma is strongly positive for calcitonin and neuroendocrine markers, and typically negative for thyroglobulin. RET mutations are common and can influence prognosis and treatment.
Reference Gallery:
Medullary thyroid carcinoma. The tumour cells in this classic medullary thyroid carcinoma are arranged in solid nests separated by fibrous septa with stromal amyloid deposition.
Medullary thyroid carcinoma. This tumour shows extensive amyloid deposition with calcification.
Medullary thyroid carcinoma. The tumour is strongly and diffusely positive with calcitonin immunoperoxidase staining.
Medullary thyroid carcinoma. This tumour shows central tumour necrosis within nests of neoplastic cells.
Medullary thyroid carcinoma. The tumour cells have a distinctive plasmacytoid morphology.
Medullary thyroid carcinoma. In the follicular (tubular/glandular) pattern, the tumour cells are arranged in follicular structures.
Medullary thyroid carcinoma. This tumour is composed of spindle cells arranged in short intersecting fascicles.
Medullary thyroid carcinoma. Clear cell pattern of medullary thyroid carcinoma.
Medullary thyroid carcinoma. Some cases show scattered markedly pleomorphic cells with bizarre nuclei, multinucleated forms, and nuclear pseudoinclusions.
Medullary thyroid carcinoma. The oncocytic pattern of medullary thyroid carcinoma is composed of sheets of polygonal cells with abundant granular eosinophilic cytoplasm that may mimic oncocytic cells.
Medullary thyroid carcinoma. In the papillary pattern, tumour cells are aligned along true fibrovascular cores that are often hyalinized and contain amyloid deposits.
Medullary thyroid carcinoma. This tumour has a predominantly trabecular growth pattern.

Q: A slow-growing tumor composed of syncytial-appearing spindled cells with a storiform or whorled growth pattern and intermingled small lymphocytes is highly characteristic of [...].
Follicular dendritic cell sarcoma of the thyroid. Spindly cells show a storiform to whorled growth pattern. There are admixed small lymphocytes.
Follicular dendritic cell sarcoma of the thyroid. The syncytial-appearing spindly tumour cells have elongated nuclei with pale chromatin and distinct nucleoli. There are intermingled small lymphocytes.
A: Follicular Dendritic Cell Sarcoma
Back Extra: Follicular Dendritic Cell Sarcoma
- Clinical: Patients with thyroid follicular dendritic cell sarcoma (FDCS) present with a slow-growing, painless thyroid mass, sometimes accompanied by cervical lymph node metastasis.
- Micro: FDCS is composed of syncytial-appearing spindled to oval cells exhibiting a storiform, fascicular, whorled, or vague nodular pattern. The neoplastic cells have oval or elongated vesicular nuclei with a delicate nuclear membrane and distinct nucleoli.
- Ancillary: The neoplastic cells are positive for one or more of the FDC markers CD21, CD23, CD35, CXCL13, and podoplanin. Genomic analysis has revealed recurrent alterations in NF-κB pathway genes, CDKN2A, and TP53.
Reference Gallery:
Follicular dendritic cell sarcoma of the thyroid. Spindly cells show a storiform to whorled growth pattern. There are admixed small lymphocytes.
Follicular dendritic cell sarcoma of the thyroid. The syncytial-appearing spindly tumour cells have elongated nuclei with pale chromatin and distinct nucleoli. There are intermingled small lymphocytes.
Follicular dendritic cell sarcoma of the thyroid. Immunostaining for CD21 is positive. The long, interconnected cell processes are highlighted.

Q: To confirm a diagnosis of Follicular Dendritic Cell Sarcoma, immunohistochemistry is used to highlight the long, interconnected cell processes using specific FDC markers such as CD23, CD35, and [...].
Follicular dendritic cell sarcoma of the thyroid. Immunostaining for CD21 is positive. The long, interconnected cell processes are highlighted.
A: CD21
Back Extra: Follicular Dendritic Cell Sarcoma
- Clinical: Patients with thyroid follicular dendritic cell sarcoma (FDCS) present with a slow-growing, painless thyroid mass, sometimes accompanied by cervical lymph node metastasis.
- Micro: FDCS is composed of syncytial-appearing spindled to oval cells exhibiting a storiform, fascicular, whorled, or vague nodular pattern. The neoplastic cells have oval or elongated vesicular nuclei with a delicate nuclear membrane and distinct nucleoli.
- Ancillary: The neoplastic cells are positive for one or more of the FDC markers CD21, CD23, CD35, CXCL13, and podoplanin. Genomic analysis has revealed recurrent alterations in NF-κB pathway genes, CDKN2A, and TP53.
Reference Gallery:
Follicular dendritic cell sarcoma of the thyroid. Spindly cells show a storiform to whorled growth pattern. There are admixed small lymphocytes.
Follicular dendritic cell sarcoma of the thyroid. The syncytial-appearing spindly tumour cells have elongated nuclei with pale chromatin and distinct nucleoli. There are intermingled small lymphocytes.
Follicular dendritic cell sarcoma of the thyroid. Immunostaining for CD21 is positive. The long, interconnected cell processes are highlighted.

Q: Histologically, Langerhans Cell Histiocytosis is characterized by an infiltrate of histiocytoid cells possessing typical [...] (or "coffee bean") nuclei, often admixed with numerous eosinophils.
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (shown here). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. FNA. Large histiocytoid cells with convoluted nuclear membranes.
A: grooved
Q: Langerhans Cell Histiocytosis
- Clinical: Involvement of the hypothalamic–pituitary–adrenal axis in [...] often leads to diabetes insipidus and growth hormone deficiency.
- Micro: [...] is characterized by histiocytoid cells with grooved, convoluted, indented, or lobed nuclei and moderately abundant, lightly eosinophilic cytoplasm.
- Ancillary: LCH cells are positive for [...].
Reference Gallery:
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (shown here). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (shown here). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (shown here), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (shown here). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. FNA. Large histiocytoid cells with convoluted nuclear membranes.
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (shown here).
Langerhans cell histiocytosis. FDG PET of a patient with Langerhans cell histiocytosis, showing widespread disease.
Pituitary Langerhans cell histiocytosis. Langerhans cell histiocytosis cells with contorted nuclei.
Pituitary Langerhans cell histiocytosis. Eosinophils are prominent, in addition to the neoplastic Langerhans cells.
Pituitary Langerhans cell histiocytosis. The histiocytes (Langerhans cells) are CD1a-positive.
A: Langerhans Cell Histiocytosis; Langerhans Cell Histiocytosis; CD1a, S100, and CD207 (langerin)

Q: By immunohistochemistry, the neoplastic cells of Langerhans Cell Histiocytosis are characteristically positive for S100, CD1a, and [...] (langerin).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (shown here). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (shown here).
A: CD207
Q: Langerhans Cell Histiocytosis
- Clinical: Involvement of the hypothalamic–pituitary–adrenal axis in [...] often leads to diabetes insipidus and growth hormone deficiency.
- Micro: [...] is characterized by histiocytoid cells with grooved, convoluted, indented, or lobed nuclei and moderately abundant, lightly eosinophilic cytoplasm.
- Ancillary: LCH cells are positive for [...].
Reference Gallery:
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (shown here). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (shown here). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (shown here), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (shown here). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. FNA. Large histiocytoid cells with convoluted nuclear membranes.
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (shown here).
Langerhans cell histiocytosis. FDG PET of a patient with Langerhans cell histiocytosis, showing widespread disease.
Pituitary Langerhans cell histiocytosis. Langerhans cell histiocytosis cells with contorted nuclei.
Pituitary Langerhans cell histiocytosis. Eosinophils are prominent, in addition to the neoplastic Langerhans cells.
Pituitary Langerhans cell histiocytosis. The histiocytes (Langerhans cells) are CD1a-positive.
A: Langerhans Cell Histiocytosis; Langerhans Cell Histiocytosis; CD1a, S100, and CD207 (langerin)

Q: Involvement of the hypothalamic–pituitary axis in Langerhans Cell Histiocytosis frequently results in growth hormone deficiency and [...].
Pituitary Langerhans cell histiocytosis. Langerhans cell histiocytosis cells with contorted nuclei.
Pituitary Langerhans cell histiocytosis. Eosinophils are prominent, in addition to the neoplastic Langerhans cells.
A: diabetes insipidus
Q: Langerhans Cell Histiocytosis
- Clinical: Involvement of the hypothalamic–pituitary–adrenal axis in [...] often leads to diabetes insipidus and growth hormone deficiency.
- Micro: [...] is characterized by histiocytoid cells with grooved, convoluted, indented, or lobed nuclei and moderately abundant, lightly eosinophilic cytoplasm.
- Ancillary: LCH cells are positive for [...].
Reference Gallery:
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (shown here). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (shown here). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (shown here), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (shown here). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (Fig. <<25035>>).
Thyroid Langerhans cell histiocytosis. FNA. Large histiocytoid cells with convoluted nuclear membranes.
Thyroid Langerhans cell histiocytosis. The thyroid parenchyma is affected by chronic lymphocytic thyroiditis, in addition to showing a well-defined nodule of Langerhans cell histiocytosis (Fig. <<24002>>). Epithelioid histiocytes with curved, bean-shaped nuclei are associated with numerous eosinophils (Fig. <<24003>>). The neoplastic cells are strongly and diffusely immunoreactive for S100 in the nucleus and cytoplasm (Fig. <<24005>>), and strongly and diffusely immunoreactive for CD1a (Fig. <<24006>>). There is CD207 (langerin) immunoexpression in the neoplastic cells adjacent to the thyroid follicles (shown here).
Langerhans cell histiocytosis. FDG PET of a patient with Langerhans cell histiocytosis, showing widespread disease.
Pituitary Langerhans cell histiocytosis. Langerhans cell histiocytosis cells with contorted nuclei.
Pituitary Langerhans cell histiocytosis. Eosinophils are prominent, in addition to the neoplastic Langerhans cells.
Pituitary Langerhans cell histiocytosis. The histiocytes (Langerhans cells) are CD1a-positive.
A: Langerhans Cell Histiocytosis; Langerhans Cell Histiocytosis; CD1a, S100, and CD207 (langerin)

Q: In Diffuse large B-cell lymphoma NOS, histologic examination classically shows a diffuse, dense infiltrate of [...] with irregular nuclei and prominent nucleoli.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the adrenal gland. The infiltrate comprises abnormal large lymphoid cells with irregularly folded nuclei and prominent nucleoli. Mitotic figures are seen.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The infiltrate comprises atypical large lymphoid cells with small distinct nucleoli.
A: large lymphoid cells
Back Extra: Diffuse large B-cell lymphoma NOS
- Clinical: Patients with Diffuse large B-cell lymphoma NOS of the thyroid usually present with a mass, rapid enlargement, and hoarseness.
- Micro: The histology shows a diffuse, dense infiltrate of large lymphoid cells with irregular nuclei and prominent nucleoli.
- Ancillary: Immunohistochemistry shows expression of CD20, PAX5, and CD79a in the neoplastic cells.
Reference Gallery:
Diffuse large B-cell lymphoma NOS. Needle biopsy of an adrenal mass shows primary diffuse large B-cell lymphoma NOS with replacement of the normal parenchyma by a diffuse infiltrate of abnormal lymphoid cells. Focal necrosis is present. The interspersed sinusoidal blood vessels probably represent residual pre-existing vasculature of the adrenal cortex.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the adrenal gland. The infiltrate comprises abnormal large lymphoid cells with irregularly folded nuclei and prominent nucleoli. Mitotic figures are seen.
Primary adrenal diffuse large B-cell lymphoma. The abnormal large lymphoid cells are immunoreactive for CD20.
Diffuse large B-cell lymphoma NOS. Primary thyroid diffuse large B-cell lymphoma NOS shows a diffuse, dense lymphomatous infiltrate replacing the thyroid parenchyma. The residual thyroid follicles show oncocytic changes.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The infiltrate comprises atypical large lymphoid cells with small distinct nucleoli.
Diffuse large B-cell lymphoma NOS. Sometimes there can be striking infiltration of lymphoma cells into the thyroid follicular epithelium.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The lymphoma cells are immunoreactive for CD20. The infiltration into the thyroid follicular epithelium is remarkably highlighted.

Q: The neoplastic cells of Diffuse large B-cell lymphoma NOS diffusely express B-cell immunohistochemical markers, such as PAX5, CD79a, and [...].
Primary adrenal diffuse large B-cell lymphoma. The abnormal large lymphoid cells are immunoreactive for CD20.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The lymphoma cells are immunoreactive for CD20. The infiltration into the thyroid follicular epithelium is remarkably highlighted.
A: CD20
Back Extra: Diffuse large B-cell lymphoma NOS
- Clinical: Patients with Diffuse large B-cell lymphoma NOS of the thyroid usually present with a mass, rapid enlargement, and hoarseness.
- Micro: The histology shows a diffuse, dense infiltrate of large lymphoid cells with irregular nuclei and prominent nucleoli.
- Ancillary: Immunohistochemistry shows expression of CD20, PAX5, and CD79a in the neoplastic cells.
Reference Gallery:
Diffuse large B-cell lymphoma NOS. Needle biopsy of an adrenal mass shows primary diffuse large B-cell lymphoma NOS with replacement of the normal parenchyma by a diffuse infiltrate of abnormal lymphoid cells. Focal necrosis is present. The interspersed sinusoidal blood vessels probably represent residual pre-existing vasculature of the adrenal cortex.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the adrenal gland. The infiltrate comprises abnormal large lymphoid cells with irregularly folded nuclei and prominent nucleoli. Mitotic figures are seen.
Primary adrenal diffuse large B-cell lymphoma. The abnormal large lymphoid cells are immunoreactive for CD20.
Diffuse large B-cell lymphoma NOS. Primary thyroid diffuse large B-cell lymphoma NOS shows a diffuse, dense lymphomatous infiltrate replacing the thyroid parenchyma. The residual thyroid follicles show oncocytic changes.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The infiltrate comprises atypical large lymphoid cells with small distinct nucleoli.
Diffuse large B-cell lymphoma NOS. Sometimes there can be striking infiltration of lymphoma cells into the thyroid follicular epithelium.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The lymphoma cells are immunoreactive for CD20. The infiltration into the thyroid follicular epithelium is remarkably highlighted.

Q: When Diffuse large B-cell lymphoma NOS arises in the thyroid gland, the histology can show striking infiltration of lymphoma cells directly into the [...].
Diffuse large B-cell lymphoma NOS. Sometimes there can be striking infiltration of lymphoma cells into the thyroid follicular epithelium.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The lymphoma cells are immunoreactive for CD20. The infiltration into the thyroid follicular epithelium is remarkably highlighted.
A: follicular epithelium
Back Extra: Diffuse large B-cell lymphoma NOS
- Clinical: Patients with Diffuse large B-cell lymphoma NOS of the thyroid usually present with a mass, rapid enlargement, and hoarseness.
- Micro: The histology shows a diffuse, dense infiltrate of large lymphoid cells with irregular nuclei and prominent nucleoli.
- Ancillary: Immunohistochemistry shows expression of CD20, PAX5, and CD79a in the neoplastic cells.
Reference Gallery:
Diffuse large B-cell lymphoma NOS. Needle biopsy of an adrenal mass shows primary diffuse large B-cell lymphoma NOS with replacement of the normal parenchyma by a diffuse infiltrate of abnormal lymphoid cells. Focal necrosis is present. The interspersed sinusoidal blood vessels probably represent residual pre-existing vasculature of the adrenal cortex.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the adrenal gland. The infiltrate comprises abnormal large lymphoid cells with irregularly folded nuclei and prominent nucleoli. Mitotic figures are seen.
Primary adrenal diffuse large B-cell lymphoma. The abnormal large lymphoid cells are immunoreactive for CD20.
Diffuse large B-cell lymphoma NOS. Primary thyroid diffuse large B-cell lymphoma NOS shows a diffuse, dense lymphomatous infiltrate replacing the thyroid parenchyma. The residual thyroid follicles show oncocytic changes.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The infiltrate comprises atypical large lymphoid cells with small distinct nucleoli.
Diffuse large B-cell lymphoma NOS. Sometimes there can be striking infiltration of lymphoma cells into the thyroid follicular epithelium.
Diffuse large B-cell lymphoma NOS. Primary diffuse large B-cell lymphoma NOS involving the thyroid. The lymphoma cells are immunoreactive for CD20. The infiltration into the thyroid follicular epithelium is remarkably highlighted.

Q: A classic microscopic finding in Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL) is the destructive infiltration of the local epithelium by lymphoma cells, termed [...].
Extranodal marginal zone lymphoma of the thyroid. Cytokeratin highlights destructive infiltration of the thyroid follicular epithelium by lymphoma cells (lymphoepithelial lesions).
Extranodal marginal zone lymphoma of the thyroid. Lymphoepithelial lesions with squamous metaplasia of thyroid follicular cells.
A: lymphoepithelial lesions
Back Extra: Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL)
- Clinical: Extranodal Marginal Zone Lymphoma (EMZL) typically presents as an enlarging mass that is markedly hypoechoic on ultrasound and cold on scintigraphy in the thyroid.
- Micro: The histopathology shows a heterogeneous infiltrate predominantly composed of small B cells, including marginal zone-like cells and small lymphocytes, with scattered plasma cells, immunoblasts, and centroblast-like cells.
- Ancillary: The neoplastic cells are immunopositive for B-lineage markers (CD20, CD79a, PAX5) and often express IgM. BCL2 is often positive, and the marginal zone marker IRTA1 is variably expressed.
Reference Gallery:
Extranodal marginal zone lymphoma of the thyroid. Thyroid parenchyma replaced by lymphoma.
Extranodal marginal zone lymphoma of the thyroid. Cytokeratin highlights destructive infiltration of the thyroid follicular epithelium by lymphoma cells (lymphoepithelial lesions).
Extranodal marginal zone lymphoma of the thyroid. Heterogeneous infiltrate with small lymphocytes intermixed with scattered cells showing plasmacytic differentiation and a few large cells.
Extranodal marginal zone lymphoma of the thyroid. Tumour cells with pale cytoplasm, slightly irregular or indented nuclei, dispersed chromatin, and inconspicuous nucleoli, intermixed with monocyte-like cells with abundant pale cytoplasm.
Extranodal marginal zone lymphoma of the thyroid. An increased number of large cells, immunoblasts, and centroblast-like cells. Solid or sheet-like infiltrates of large cells are diagnostic of a diffuse large B-cell lymphoma component.
Extranodal marginal zone lymphoma of the thyroid. Lymphoepithelial lesions with squamous metaplasia of thyroid follicular cells.
Extranodal marginal zone lymphoma of the thyroid. Expansile, ball-like collections of lymphoma cells within thyroid follicles (MALT balls) are distinctive lymphoepithelial lesions.
Extranodal marginal zone lymphoma of the thyroid. Lymphoma cells plugging the thyroid follicle in a MALT-ball lymphoepithelial lesion (sequential section of the case shown in Fig. 26383, immunostained with CD20).

Q: When Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL) involves the thyroid, it can form highly distinctive, expansile, ball-like collections of neoplastic cells within the follicles known as [...].
Extranodal marginal zone lymphoma of the thyroid. Expansile, ball-like collections of lymphoma cells within thyroid follicles (MALT balls) are distinctive lymphoepithelial lesions.
Extranodal marginal zone lymphoma of the thyroid. Lymphoma cells plugging the thyroid follicle in a MALT-ball lymphoepithelial lesion (sequential section of the case shown in Fig. 26383, immunostained with CD20).
A: MALT balls
Back Extra: Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL)
- Clinical: Extranodal Marginal Zone Lymphoma (EMZL) typically presents as an enlarging mass that is markedly hypoechoic on ultrasound and cold on scintigraphy in the thyroid.
- Micro: The histopathology shows a heterogeneous infiltrate predominantly composed of small B cells, including marginal zone-like cells and small lymphocytes, with scattered plasma cells, immunoblasts, and centroblast-like cells.
- Ancillary: The neoplastic cells are immunopositive for B-lineage markers (CD20, CD79a, PAX5) and often express IgM. BCL2 is often positive, and the marginal zone marker IRTA1 is variably expressed.
Reference Gallery:
Extranodal marginal zone lymphoma of the thyroid. Thyroid parenchyma replaced by lymphoma.
Extranodal marginal zone lymphoma of the thyroid. Cytokeratin highlights destructive infiltration of the thyroid follicular epithelium by lymphoma cells (lymphoepithelial lesions).
Extranodal marginal zone lymphoma of the thyroid. Heterogeneous infiltrate with small lymphocytes intermixed with scattered cells showing plasmacytic differentiation and a few large cells.
Extranodal marginal zone lymphoma of the thyroid. Tumour cells with pale cytoplasm, slightly irregular or indented nuclei, dispersed chromatin, and inconspicuous nucleoli, intermixed with monocyte-like cells with abundant pale cytoplasm.
Extranodal marginal zone lymphoma of the thyroid. An increased number of large cells, immunoblasts, and centroblast-like cells. Solid or sheet-like infiltrates of large cells are diagnostic of a diffuse large B-cell lymphoma component.
Extranodal marginal zone lymphoma of the thyroid. Lymphoepithelial lesions with squamous metaplasia of thyroid follicular cells.
Extranodal marginal zone lymphoma of the thyroid. Expansile, ball-like collections of lymphoma cells within thyroid follicles (MALT balls) are distinctive lymphoepithelial lesions.
Extranodal marginal zone lymphoma of the thyroid. Lymphoma cells plugging the thyroid follicle in a MALT-ball lymphoepithelial lesion (sequential section of the case shown in Fig. 26383, immunostained with CD20).

Q: The neoplastic infiltrate in Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL) is typically heterogeneous, comprising small B-cells with pale cytoplasm intermixed with scattered cells showing [...] differentiation.
Extranodal marginal zone lymphoma of the thyroid. Heterogeneous infiltrate with small lymphocytes intermixed with scattered cells showing plasmacytic differentiation and a few large cells.
Extranodal marginal zone lymphoma of the thyroid. Tumour cells with pale cytoplasm, slightly irregular or indented nuclei, dispersed chromatin, and inconspicuous nucleoli, intermixed with monocyte-like cells with abundant pale cytoplasm.
A: plasmacytic
Back Extra: Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (EMZL)
- Clinical: Extranodal Marginal Zone Lymphoma (EMZL) typically presents as an enlarging mass that is markedly hypoechoic on ultrasound and cold on scintigraphy in the thyroid.
- Micro: The histopathology shows a heterogeneous infiltrate predominantly composed of small B cells, including marginal zone-like cells and small lymphocytes, with scattered plasma cells, immunoblasts, and centroblast-like cells.
- Ancillary: The neoplastic cells are immunopositive for B-lineage markers (CD20, CD79a, PAX5) and often express IgM. BCL2 is often positive, and the marginal zone marker IRTA1 is variably expressed.
Reference Gallery:
Extranodal marginal zone lymphoma of the thyroid. Thyroid parenchyma replaced by lymphoma.
Extranodal marginal zone lymphoma of the thyroid. Cytokeratin highlights destructive infiltration of the thyroid follicular epithelium by lymphoma cells (lymphoepithelial lesions).
Extranodal marginal zone lymphoma of the thyroid. Heterogeneous infiltrate with small lymphocytes intermixed with scattered cells showing plasmacytic differentiation and a few large cells.
Extranodal marginal zone lymphoma of the thyroid. Tumour cells with pale cytoplasm, slightly irregular or indented nuclei, dispersed chromatin, and inconspicuous nucleoli, intermixed with monocyte-like cells with abundant pale cytoplasm.
Extranodal marginal zone lymphoma of the thyroid. An increased number of large cells, immunoblasts, and centroblast-like cells. Solid or sheet-like infiltrates of large cells are diagnostic of a diffuse large B-cell lymphoma component.
Extranodal marginal zone lymphoma of the thyroid. Lymphoepithelial lesions with squamous metaplasia of thyroid follicular cells.
Extranodal marginal zone lymphoma of the thyroid. Expansile, ball-like collections of lymphoma cells within thyroid follicles (MALT balls) are distinctive lymphoepithelial lesions.
Extranodal marginal zone lymphoma of the thyroid. Lymphoma cells plugging the thyroid follicle in a MALT-ball lymphoepithelial lesion (sequential section of the case shown in Fig. 26383, immunostained with CD20).

Q: Microscopically, a Leiomyoma is a well-circumscribed nodule composed of intersecting fascicles of spindle-shaped cells with eosinophilic cytoplasm and characteristic [...] nuclei.
Leiomyoma. This thyroid gland leiomyoma demonstrates hypocellular fascicles of spindled smooth muscle cells.
Leiomyoma. High-power view of a thyroid gland leiomyoma showing spindled cells without pleomorphism, necrosis, or increased mitoses.
A: blunt-ended
Back Extra: Leiomyoma
- Clinical: Thyroid leiomyoma presents as a painless, slow-growing mass that on thyroid scan appears as a cold nodule.
- Micro: Leiomyomas are well-circumscribed nodules composed of intersecting fascicles of spindle-shaped cells with eosinophilic cytoplasm and blunt-ended nuclei.
- Ancillary: Immunohistochemistry shows strong and diffuse desmin immunoreactivity, and low proliferation rates by Ki-67 or MIB1 staining.
Reference Gallery:
Leiomyoma. This thyroid gland leiomyoma demonstrates hypocellular fascicles of spindled smooth muscle cells.
Leiomyoma. High-power view of a thyroid gland leiomyoma showing spindled cells without pleomorphism, necrosis, or increased mitoses.
Leiomyoma. The neoplastic cells of a thyroid gland leiomyoma show strong and diffuse desmin immunoreactivity.

Q: Immunohistochemically, the neoplastic spindle cells of a Leiomyoma typically demonstrate strong and diffuse immunoreactivity for the muscle marker [...].
Leiomyoma. The neoplastic cells of a thyroid gland leiomyoma show strong and diffuse desmin immunoreactivity.
A: desmin
Back Extra: Leiomyoma
- Clinical: Thyroid leiomyoma presents as a painless, slow-growing mass that on thyroid scan appears as a cold nodule.
- Micro: Leiomyomas are well-circumscribed nodules composed of intersecting fascicles of spindle-shaped cells with eosinophilic cytoplasm and blunt-ended nuclei.
- Ancillary: Immunohistochemistry shows strong and diffuse desmin immunoreactivity, and low proliferation rates by Ki-67 or MIB1 staining.
Reference Gallery:
Leiomyoma. This thyroid gland leiomyoma demonstrates hypocellular fascicles of spindled smooth muscle cells.
Leiomyoma. High-power view of a thyroid gland leiomyoma showing spindled cells without pleomorphism, necrosis, or increased mitoses.
Leiomyoma. The neoplastic cells of a thyroid gland leiomyoma show strong and diffuse desmin immunoreactivity.

Q: Microscopically, a [...] is characterized by poorly defined borders with sheets and nests of large, monotonous epithelioid to polygonal cells with small, cytologically bland nuclei and intensely eosinophilic, granular cytoplasm.
Granular cell tumour. A loose collection of large tumour cells with small, cytologically bland nuclei and abundant granular cytoplasm.
A: granular cell tumor
Back Extra: Granular Cell Tumour
- Clinical: Granular cell tumours within the thyroid and pancreas may mimic malignancies, including neuroendocrine tumours (NETs).
- Micro: Characterized by poorly defined borders with sheets, nests, and trabeculae of large, monotonous epithelioid to polygonal cells with intensely eosinophilic, granular cytoplasm.
- Ancillary: Immunoreactive for S100, SOX10, nestin, inhibin, and calretinin, with pathognomonic loss-of-function mutations in V-ATPase accessory genes.
Reference Gallery:
Granular cell tumour. A loose collection of large tumour cells with small, cytologically bland nuclei and abundant granular cytoplasm.

Q: A granular cell tumor typically consists of large, cytologically bland cells with abundant granular cytoplasm and characteristically harbors pathognomonic loss-of-function mutations in [...] accessory genes.
Granular cell tumour. A loose collection of large tumour cells with small, cytologically bland nuclei and abundant granular cytoplasm.
A: V-ATPase
Back Extra: Granular Cell Tumour
- Clinical: Granular cell tumours within the thyroid and pancreas may mimic malignancies, including neuroendocrine tumours (NETs).
- Micro: Characterized by poorly defined borders with sheets, nests, and trabeculae of large, monotonous epithelioid to polygonal cells with intensely eosinophilic, granular cytoplasm.
- Ancillary: Immunoreactive for S100, SOX10, nestin, inhibin, and calretinin, with pathognomonic loss-of-function mutations in V-ATPase accessory genes.
Reference Gallery:
Granular cell tumour. A loose collection of large tumour cells with small, cytologically bland nuclei and abundant granular cytoplasm.

Q: A characteristic low-power histologic finding in a malignant peripheral nerve sheath tumor is the presence of alternating hypercellular and hypocellular zones, producing a [...] appearance.
Malignant peripheral nerve sheath tumour. Marbled appearance at low magnification, with alternating dark and pale zones.
A: marbled
Back Extra: Malignant Peripheral Nerve Sheath Tumour
- Clinical: Malignant Peripheral Nerve Sheath Tumours (MPNSTs) typically present in patients aged 20–50 years, often associated with neurofibromatosis type 1 (NF1). Symptoms include nonspecific signs such as pain, anorexia, and organ-specific findings like dyspnoea (thyroid).
- Micro: MPNSTs are characterized by a fascicular architecture of spindle-shaped cells, with wavy, buckled, and tapered nuclei. They often show geographical necrosis and a marbled appearance with alternating hypercellular and hypocellular areas.
- Ancillary: MPNSTs may be positive for S100 (< 50% of tumours), SOX10 (< 70%), and GFAP (20–30%). DNA methylation profiling and loss of H3 p.K27me3 can be diagnostically useful.
Reference Gallery:
Epithelioid malignant peripheral nerve sheath tumour. An adrenal gland tumour with destruction of the adjacent adrenal cortex.
Epithelioid malignant peripheral nerve sheath tumour. The native adrenal cortex is captured by the pleomorphic, epithelioid to spindled cell population.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear and cytoplasmic reactivity for S100.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear reactivity for SOX10.
Malignant peripheral nerve sheath tumour. This thyroid gland malignant peripheral nerve sheath tumour demonstrates the peritheliomatous growth pattern of an atypical spindled cell neoplasm, showing buckled nuclei.
Malignant peripheral nerve sheath tumour. The atypical spindled cells of this malignant peripheral nerve sheath tumour demonstrate a fascicular architecture, with wavy, buckled, pointed nuclei.
Malignant peripheral nerve sheath tumour. There is comedonecrosis adjacent to the atypical spindled cells of this thyroid gland malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Marbled appearance at low magnification, with alternating dark and pale zones.
Malignant peripheral nerve sheath tumour. Extensive geographical necrosis.

Q: A malignant peripheral nerve sheath tumor classically exhibits a fascicular architecture composed of spindle cells with wavy, tapered, and [...] nuclei.
Malignant peripheral nerve sheath tumour. The atypical spindled cells of this malignant peripheral nerve sheath tumour demonstrate a fascicular architecture, with wavy, buckled, pointed nuclei.
A: buckled
Back Extra: Malignant Peripheral Nerve Sheath Tumour
- Clinical: Malignant Peripheral Nerve Sheath Tumours (MPNSTs) typically present in patients aged 20–50 years, often associated with neurofibromatosis type 1 (NF1). Symptoms include nonspecific signs such as pain, anorexia, and organ-specific findings like dyspnoea (thyroid).
- Micro: MPNSTs are characterized by a fascicular architecture of spindle-shaped cells, with wavy, buckled, and tapered nuclei. They often show geographical necrosis and a marbled appearance with alternating hypercellular and hypocellular areas.
- Ancillary: MPNSTs may be positive for S100 (< 50% of tumours), SOX10 (< 70%), and GFAP (20–30%). DNA methylation profiling and loss of H3 p.K27me3 can be diagnostically useful.
Reference Gallery:
Epithelioid malignant peripheral nerve sheath tumour. An adrenal gland tumour with destruction of the adjacent adrenal cortex.
Epithelioid malignant peripheral nerve sheath tumour. The native adrenal cortex is captured by the pleomorphic, epithelioid to spindled cell population.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear and cytoplasmic reactivity for S100.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear reactivity for SOX10.
Malignant peripheral nerve sheath tumour. This thyroid gland malignant peripheral nerve sheath tumour demonstrates the peritheliomatous growth pattern of an atypical spindled cell neoplasm, showing buckled nuclei.
Malignant peripheral nerve sheath tumour. The atypical spindled cells of this malignant peripheral nerve sheath tumour demonstrate a fascicular architecture, with wavy, buckled, pointed nuclei.
Malignant peripheral nerve sheath tumour. There is comedonecrosis adjacent to the atypical spindled cells of this thyroid gland malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Marbled appearance at low magnification, with alternating dark and pale zones.
Malignant peripheral nerve sheath tumour. Extensive geographical necrosis.

Q: An aggressive, spindled to epithelioid neoplasm that often arises in patients with neurofibromatosis type 1 (NF1) and frequently exhibits geographical necrosis is the [...].
Malignant peripheral nerve sheath tumour. Extensive geographical necrosis.
A: malignant peripheral nerve sheath tumor
Back Extra: Malignant Peripheral Nerve Sheath Tumour
- Clinical: Malignant Peripheral Nerve Sheath Tumours (MPNSTs) typically present in patients aged 20–50 years, often associated with neurofibromatosis type 1 (NF1). Symptoms include nonspecific signs such as pain, anorexia, and organ-specific findings like dyspnoea (thyroid).
- Micro: MPNSTs are characterized by a fascicular architecture of spindle-shaped cells, with wavy, buckled, and tapered nuclei. They often show geographical necrosis and a marbled appearance with alternating hypercellular and hypocellular areas.
- Ancillary: MPNSTs may be positive for S100 (< 50% of tumours), SOX10 (< 70%), and GFAP (20–30%). DNA methylation profiling and loss of H3 p.K27me3 can be diagnostically useful.
Reference Gallery:
Epithelioid malignant peripheral nerve sheath tumour. An adrenal gland tumour with destruction of the adjacent adrenal cortex.
Epithelioid malignant peripheral nerve sheath tumour. The native adrenal cortex is captured by the pleomorphic, epithelioid to spindled cell population.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear and cytoplasmic reactivity for S100.
Epithelioid malignant peripheral nerve sheath tumour. Extensive nuclear reactivity for SOX10.
Malignant peripheral nerve sheath tumour. This thyroid gland malignant peripheral nerve sheath tumour demonstrates the peritheliomatous growth pattern of an atypical spindled cell neoplasm, showing buckled nuclei.
Malignant peripheral nerve sheath tumour. The atypical spindled cells of this malignant peripheral nerve sheath tumour demonstrate a fascicular architecture, with wavy, buckled, pointed nuclei.
Malignant peripheral nerve sheath tumour. There is comedonecrosis adjacent to the atypical spindled cells of this thyroid gland malignant peripheral nerve sheath tumour.
Malignant peripheral nerve sheath tumour. Marbled appearance at low magnification, with alternating dark and pale zones.
Malignant peripheral nerve sheath tumour. Extensive geographical necrosis.

Q: Grossly, a Schwannoma is a well-circumscribed, slowly growing tumor that often exhibits a [...] appearance corresponding to hypocellular regions on the cut surface.
Schwannoma. There is a well-defined, gelatinous to myxoid neoplasm within the adrenal gland, identified as a schwannoma histologically.
A: gelatinous to myxoid
Back Extra: Schwannoma
- Clinical: Schwannomas are slowly growing, often asymptomatic or incidental tumours, typically found in the fourth to sixth decade of life, with no sex predilection.
- Micro: Schwannomas are well-circumscribed spindle cell tumours with biphasic patterns (Antoni A and B zones) and characteristic Verocay bodies.
- Ancillary: Immunohistochemistry shows extensive S100 and SOX10 positivity, with CD34 typically positive only in subcapsular and septal areas.
Reference Gallery:
Schwannoma. There is a well-defined, gelatinous to myxoid neoplasm within the adrenal gland, identified as a schwannoma histologically.
Schwannoma. This thyroid gland schwannoma demonstrates perivascular hyalinization. The neoplastic cells are spindled and have a vaguely palisaded appearance.
Schwannoma. The spindled cells are bland and show bent to wavy nuclei within a syncytial-appearing cytoplasm.

Q: On high-power microscopic examination, the bland, spindled cells of a Schwannoma characteristically feature [...] nuclei set within a syncytial-appearing cytoplasm.
Schwannoma. The spindled cells are bland and show bent to wavy nuclei within a syncytial-appearing cytoplasm.
A: bent to wavy
Back Extra: Schwannoma
- Clinical: Schwannomas are slowly growing, often asymptomatic or incidental tumours, typically found in the fourth to sixth decade of life, with no sex predilection.
- Micro: Schwannomas are well-circumscribed spindle cell tumours with biphasic patterns (Antoni A and B zones) and characteristic Verocay bodies.
- Ancillary: Immunohistochemistry shows extensive S100 and SOX10 positivity, with CD34 typically positive only in subcapsular and septal areas.
Reference Gallery:
Schwannoma. There is a well-defined, gelatinous to myxoid neoplasm within the adrenal gland, identified as a schwannoma histologically.
Schwannoma. This thyroid gland schwannoma demonstrates perivascular hyalinization. The neoplastic cells are spindled and have a vaguely palisaded appearance.
Schwannoma. The spindled cells are bland and show bent to wavy nuclei within a syncytial-appearing cytoplasm.

Q: In a Schwannoma, the hypercellular Antoni A areas frequently display nuclear palisading that can form characteristic structures known as [...].
Schwannoma. This thyroid gland schwannoma demonstrates perivascular hyalinization. The neoplastic cells are spindled and have a vaguely palisaded appearance.
A: Verocay bodies
Back Extra: Schwannoma
- Clinical: Schwannomas are slowly growing, often asymptomatic or incidental tumours, typically found in the fourth to sixth decade of life, with no sex predilection.
- Micro: Schwannomas are well-circumscribed spindle cell tumours with biphasic patterns (Antoni A and B zones) and characteristic Verocay bodies.
- Ancillary: Immunohistochemistry shows extensive S100 and SOX10 positivity, with CD34 typically positive only in subcapsular and septal areas.
Reference Gallery:
Schwannoma. There is a well-defined, gelatinous to myxoid neoplasm within the adrenal gland, identified as a schwannoma histologically.
Schwannoma. This thyroid gland schwannoma demonstrates perivascular hyalinization. The neoplastic cells are spindled and have a vaguely palisaded appearance.
Schwannoma. The spindled cells are bland and show bent to wavy nuclei within a syncytial-appearing cytoplasm.

Q: In a Glomus tumor, the neoplastic cells are characteristically composed of small, uniform, round to polygonal cells arranged in nests that specifically surround [...].
Glomus tumour. Tumour composed of nests of cells surrounding capillaries and small vessels in a myxoid to hyalinized stroma.
Glomus tumour. Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm.
A: capillaries and small vessels
Back Extra: Glomus Tumour
- Clinical: Glomus tumours typically present as solitary, painful, pink to blue nodules, especially in the distal extremities, and can also occur in visceral locations such as the thyroid.
- Micro: Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm, arranged in nests surrounding capillaries and small vessels.
- Ancillary: Positive for SMA, MSA, vimentin, caldesmon, and laminin; negative for keratins, chromogranin A, CD56, S100, and KIT (CD117). NOTCH gene fusions are common, with NOTCH2 being the most frequent.
Reference Gallery:
Glomus tumour. Tumour composed of nests of cells surrounding capillaries and small vessels in a myxoid to hyalinized stroma.
Glomus tumour. Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm.

Q: A [...] typically presents clinically as a painful nodule on the distal extremities and is histologically defined by uniform, round cells with central nuclei and amphophilic cytoplasm surrounding vascular spaces, often within a myxoid to hyalinized stroma.
Glomus tumour. Tumour composed of nests of cells surrounding capillaries and small vessels in a myxoid to hyalinized stroma.
Glomus tumour. Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm.
A: Glomus tumor
Back Extra: Glomus Tumour
- Clinical: Glomus tumours typically present as solitary, painful, pink to blue nodules, especially in the distal extremities, and can also occur in visceral locations such as the thyroid.
- Micro: Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm, arranged in nests surrounding capillaries and small vessels.
- Ancillary: Positive for SMA, MSA, vimentin, caldesmon, and laminin; negative for keratins, chromogranin A, CD56, S100, and KIT (CD117). NOTCH gene fusions are common, with NOTCH2 being the most frequent.
Reference Gallery:
Glomus tumour. Tumour composed of nests of cells surrounding capillaries and small vessels in a myxoid to hyalinized stroma.
Glomus tumour. Tumours are composed of small, uniform, round or polygonal cells with a central nucleus and amphophilic or eosinophilic cytoplasm.

Q: Microscopically, a Solitary Fibrous Tumor exhibits a characteristic [...] architecture, consisting of variably cellular spindled cells in a collagenized stroma with prominent, dilated (patulous) blood vessels.
Solitary fibrous tumour. Entrapped thyroid follicles are noted at the periphery, whereas patulous, open vessels are identified in the spindled cell neoplastic proliferation. Collagenized stroma is present.
Solitary fibrous tumour. A hypercellular spindled cell proliferation associated with open, patulous vessels. Collagenized stroma is noted.
Solitary fibrous tumour. There is a hypercellular spindled cell proliferation, showing tight, short bundles, meandering between the thyroid follicles, with open, patulous vessels easily identified.
A: patternless
Back Extra: Solitary Fibrous Tumour
- Clinical: Symptoms of solitary fibrous tumour are often nonspecific, presenting as slow-growing, painless masses. Large tumours may cause mass effect or obstructive symptoms.
- Micro: Solitary fibrous tumours are unencapsulated, variably cellular, and have a patternless architecture with a collagenized or myxoid stroma. They are highly vascular with dilated blood vessels.
- Ancillary: Immunohistochemistry for solitary fibrous tumour typically shows strong and diffuse cytoplasmic expression of CD34 and nuclear STAT6.
Reference Gallery:
Solitary fibrous tumour. A well-defined mass is identified within the thyroid gland parenchyma. There is a spindled cell proliferation set within thyroid gland follicles.
Solitary fibrous tumour. Entrapped thyroid follicles are noted at the periphery, whereas patulous, open vessels are identified in the spindled cell neoplastic proliferation. Collagenized stroma is present.
Solitary fibrous tumour. A hypercellular spindled cell proliferation associated with open, patulous vessels. Collagenized stroma is noted.
Solitary fibrous tumour. There is a hypercellular spindled cell proliferation, showing tight, short bundles, meandering between the thyroid follicles, with open, patulous vessels easily identified.
Solitary fibrous tumour. Entrapped thyroid follicles are seen at the periphery of the spindled cell proliferation. There is a background collagenized stroma.
Solitary fibrous tumour. The neoplastic cells show strong and diffuse nuclear immunoreactivity for STAT6, whereas the nuclei of the native thyroid follicles are negative.
Solitary fibrous tumour. Tumour involving the pituitary.

Q: A diagnosis of Solitary Fibrous Tumor can be confirmed by immunohistochemistry showing highly specific, strong, and diffuse nuclear expression of [...].
Solitary fibrous tumour. The neoplastic cells show strong and diffuse nuclear immunoreactivity for STAT6, whereas the nuclei of the native thyroid follicles are negative.
A: STAT6
Back Extra: Solitary Fibrous Tumour
- Clinical: Symptoms of solitary fibrous tumour are often nonspecific, presenting as slow-growing, painless masses. Large tumours may cause mass effect or obstructive symptoms.
- Micro: Solitary fibrous tumours are unencapsulated, variably cellular, and have a patternless architecture with a collagenized or myxoid stroma. They are highly vascular with dilated blood vessels.
- Ancillary: Immunohistochemistry for solitary fibrous tumour typically shows strong and diffuse cytoplasmic expression of CD34 and nuclear STAT6.
Reference Gallery:
Solitary fibrous tumour. A well-defined mass is identified within the thyroid gland parenchyma. There is a spindled cell proliferation set within thyroid gland follicles.
Solitary fibrous tumour. Entrapped thyroid follicles are noted at the periphery, whereas patulous, open vessels are identified in the spindled cell neoplastic proliferation. Collagenized stroma is present.
Solitary fibrous tumour. A hypercellular spindled cell proliferation associated with open, patulous vessels. Collagenized stroma is noted.
Solitary fibrous tumour. There is a hypercellular spindled cell proliferation, showing tight, short bundles, meandering between the thyroid follicles, with open, patulous vessels easily identified.
Solitary fibrous tumour. Entrapped thyroid follicles are seen at the periphery of the spindled cell proliferation. There is a background collagenized stroma.
Solitary fibrous tumour. The neoplastic cells show strong and diffuse nuclear immunoreactivity for STAT6, whereas the nuclei of the native thyroid follicles are negative.
Solitary fibrous tumour. Tumour involving the pituitary.

Q: Microscopically, Angiosarcoma of endocrine organs typically displays either spindled or epithelioid cells that line vascular-like spaces, a diagnostic pattern known as [...] features.
Angiosarcoma. Prominent vasoformative features are present in this angiosarcoma in the thyroid.
Angiosarcoma. This primary adrenal angiosarcoma has prominent vasoformative features, helpful in recognizing the tumour as an angiosarcoma rather than an adrenal cortical carcinoma.
A: vasoformative
Back Extra: Angiosarcoma
- Clinical: Angiosarcoma of the thyroid often presents as a rapidly enlarging neck mass with compressive symptoms like dysphagia or dyspnoea.
- Micro: Angiosarcomas in endocrine organs can exhibit a spindled or epithelioid morphology with prominent vasoformative features.
- Ancillary: Angiosarcomas are positive for endothelial markers such as CD31, CD34, and CAM5.2, and may show immunopositivity for low-molecular-weight keratins.
Reference Gallery:
Angiosarcoma. This thyroid angiosarcoma is highly cellular, with a spindled growth pattern.
Angiosarcoma. This angiosarcoma has areas of sheet-like growth and marked haemorrhage.
Angiosarcoma. Prominent vasoformative features are present in this angiosarcoma in the thyroid.
Angiosarcoma. Markedly epithelioid cells are seen lining vascular-like spaces in this angiosarcoma.
Angiosarcoma, CAM5.2 immunostain. Angiosarcomas of endocrine organs are often epithelioid and frequently show immunopositivity for low-molecular-weight keratins such as CAM5.2.
Angiosarcoma. This primary adrenal angiosarcoma can be seen with residual adrenal cortical cells in the background.
Angiosarcoma, CD31 immunostain. The CD31 immunostain highlights the angiosarcoma with a background of residual adrenal cortical cells.
Angiosarcoma. Focal residual adrenal cortical cells are identified in the background of this primary adrenal angiosarcoma that shows a sheet-like growth pattern.
Angiosarcoma. This primary adrenal angiosarcoma has prominent vasoformative features, helpful in recognizing the tumour as an angiosarcoma rather than an adrenal cortical carcinoma.
Angiosarcoma. Primary angiosarcomas of endocrine organs usually have an epithelioid morphology, with epithelioid cells exhibiting large pleomorphic nuclei and prominent eosinophilic nucleoli.
Angiosarcoma. Epithelioid cells arranged in a cohesive group, showing abundant cytoplasm with enlarged nuclei and multiple nucleoli in a haemorrhagic background (Pap).
Angiosarcoma. Epithelioid cells showing abundant and delicate cytoplasm and enlarged nuclei with granular chromatin and multiple nucleoli, in a haemorrhagic background.

Q: Angiosarcoma is usually positive for endothelial markers such as CD31, but the epithelioid variant can also show misleading immunopositivity for low-molecular-weight keratins like [...].
Angiosarcoma, CAM5.2 immunostain. Angiosarcomas of endocrine organs are often epithelioid and frequently show immunopositivity for low-molecular-weight keratins such as CAM5.2.
Angiosarcoma, CD31 immunostain. The CD31 immunostain highlights the angiosarcoma with a background of residual adrenal cortical cells.
A: CAM5.2
Back Extra: Angiosarcoma
- Clinical: Angiosarcoma of the thyroid often presents as a rapidly enlarging neck mass with compressive symptoms like dysphagia or dyspnoea.
- Micro: Angiosarcomas in endocrine organs can exhibit a spindled or epithelioid morphology with prominent vasoformative features.
- Ancillary: Angiosarcomas are positive for endothelial markers such as CD31, CD34, and CAM5.2, and may show immunopositivity for low-molecular-weight keratins.
Reference Gallery:
Angiosarcoma. This thyroid angiosarcoma is highly cellular, with a spindled growth pattern.
Angiosarcoma. This angiosarcoma has areas of sheet-like growth and marked haemorrhage.
Angiosarcoma. Prominent vasoformative features are present in this angiosarcoma in the thyroid.
Angiosarcoma. Markedly epithelioid cells are seen lining vascular-like spaces in this angiosarcoma.
Angiosarcoma, CAM5.2 immunostain. Angiosarcomas of endocrine organs are often epithelioid and frequently show immunopositivity for low-molecular-weight keratins such as CAM5.2.
Angiosarcoma. This primary adrenal angiosarcoma can be seen with residual adrenal cortical cells in the background.
Angiosarcoma, CD31 immunostain. The CD31 immunostain highlights the angiosarcoma with a background of residual adrenal cortical cells.
Angiosarcoma. Focal residual adrenal cortical cells are identified in the background of this primary adrenal angiosarcoma that shows a sheet-like growth pattern.
Angiosarcoma. This primary adrenal angiosarcoma has prominent vasoformative features, helpful in recognizing the tumour as an angiosarcoma rather than an adrenal cortical carcinoma.
Angiosarcoma. Primary angiosarcomas of endocrine organs usually have an epithelioid morphology, with epithelioid cells exhibiting large pleomorphic nuclei and prominent eosinophilic nucleoli.
Angiosarcoma. Epithelioid cells arranged in a cohesive group, showing abundant cytoplasm with enlarged nuclei and multiple nucleoli in a haemorrhagic background (Pap).
Angiosarcoma. Epithelioid cells showing abundant and delicate cytoplasm and enlarged nuclei with granular chromatin and multiple nucleoli, in a haemorrhagic background.

Q: Primary Angiosarcoma of endocrine organs frequently demonstrates marked hemorrhage and is composed of cells with an [...] morphology, characterized by large pleomorphic nuclei and prominent eosinophilic nucleoli.
Angiosarcoma. This angiosarcoma has areas of sheet-like growth and marked haemorrhage.
Angiosarcoma. Primary angiosarcomas of endocrine organs usually have an epithelioid morphology, with epithelioid cells exhibiting large pleomorphic nuclei and prominent eosinophilic nucleoli.
Angiosarcoma. Epithelioid cells arranged in a cohesive group, showing abundant cytoplasm with enlarged nuclei and multiple nucleoli in a haemorrhagic background (Pap).
A: epithelioid
Back Extra: Angiosarcoma
- Clinical: Angiosarcoma of the thyroid often presents as a rapidly enlarging neck mass with compressive symptoms like dysphagia or dyspnoea.
- Micro: Angiosarcomas in endocrine organs can exhibit a spindled or epithelioid morphology with prominent vasoformative features.
- Ancillary: Angiosarcomas are positive for endothelial markers such as CD31, CD34, and CAM5.2, and may show immunopositivity for low-molecular-weight keratins.
Reference Gallery:
Angiosarcoma. This thyroid angiosarcoma is highly cellular, with a spindled growth pattern.
Angiosarcoma. This angiosarcoma has areas of sheet-like growth and marked haemorrhage.
Angiosarcoma. Prominent vasoformative features are present in this angiosarcoma in the thyroid.
Angiosarcoma. Markedly epithelioid cells are seen lining vascular-like spaces in this angiosarcoma.
Angiosarcoma, CAM5.2 immunostain. Angiosarcomas of endocrine organs are often epithelioid and frequently show immunopositivity for low-molecular-weight keratins such as CAM5.2.
Angiosarcoma. This primary adrenal angiosarcoma can be seen with residual adrenal cortical cells in the background.
Angiosarcoma, CD31 immunostain. The CD31 immunostain highlights the angiosarcoma with a background of residual adrenal cortical cells.
Angiosarcoma. Focal residual adrenal cortical cells are identified in the background of this primary adrenal angiosarcoma that shows a sheet-like growth pattern.
Angiosarcoma. This primary adrenal angiosarcoma has prominent vasoformative features, helpful in recognizing the tumour as an angiosarcoma rather than an adrenal cortical carcinoma.
Angiosarcoma. Primary angiosarcomas of endocrine organs usually have an epithelioid morphology, with epithelioid cells exhibiting large pleomorphic nuclei and prominent eosinophilic nucleoli.
Angiosarcoma. Epithelioid cells arranged in a cohesive group, showing abundant cytoplasm with enlarged nuclei and multiple nucleoli in a haemorrhagic background (Pap).
Angiosarcoma. Epithelioid cells showing abundant and delicate cytoplasm and enlarged nuclei with granular chromatin and multiple nucleoli, in a haemorrhagic background.

Q: Histologically, Leiomyosarcoma is characterized by highly atypical spindle cells arranged in interlacing fascicles and, unlike benign smooth muscle tumors, frequently exhibits well-developed [...].
Leiomyosarcoma. Thyroid follicles are seen at the periphery of this destructive spindled cell neoplasm. There are interlacing fascicles.
Leiomyosarcoma. There is well-developed comedonecrosis in this leiomyosarcoma, a finding not seen in benign smooth muscle tumours.
A: comedonecrosis
Back Extra: Leiomyosarcoma
- Clinical: Thyroid LMS typically presents as a painless, rapidly growing neck mass, often accompanied by hoarseness, dysphagia, dyspnoea, and weight loss.
- Micro: Histologically, LMS shows spindle cells arranged in interlacing fascicles with hypercellularity, nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Neoplastic cells in LMS are positive for SMA, MSA, desmin, and caldesmon, and show a high proliferation index by Ki-67 staining.
Reference Gallery:
Leiomyosarcoma. There is a large destructive mass within the thyroid gland, with cystic metastasis in a neck lymph node (CT).
Leiomyosarcoma. There is a large destructive mass within the thyroid gland. The neoplastic cells are spindled, showing an interlacing fascicular architecture.
Leiomyosarcoma. Thyroid follicles are seen at the periphery of this destructive spindled cell neoplasm. There are interlacing fascicles.
Leiomyosarcoma. The neoplastic cells seem to originate from the smooth muscle wall of this large vessel at the thyroid gland periphery.
Leiomyosarcoma. Destructive infiltration by a spindled cell population into adjacent parathyroid gland tissue is noted in this leiomyosarcoma.
Leiomyosarcoma. The atypical spindled cell population is more accentuated around a vessel, seen pushing aside native thyroid gland follicles.
Leiomyosarcoma. There is well-developed comedonecrosis in this leiomyosarcoma, a finding not seen in benign smooth muscle tumours.
Leiomyosarcoma. The spindled neoplastic cells have a vaguely epithelioid quality. Numerous mitotic figures are seen.
Leiomyosarcoma. The neoplastic cells show a strong and diffuse cytoplasmic reaction for SMA.
Leiomyosarcoma. There is usually a high proliferation index in leiomyosarcoma, as detected by Ki-67 labelling.
Leiomyosarcoma. Leiomyosarcomas of the adrenal gland usually arise around the central vessels. Note the destroyed adrenal cortical cells.
Leiomyosarcoma. The neoplastic cells this adrenal gland leiomyosarcoma are strongly reactive for desmin, whereas the native cortical cells are negative.

Q: A destructive spindle cell malignancy displaying nuclear pleomorphism, frequent mitoses, and strong diffuse immunoreactivity for SMA and desmin is best diagnosed as [...].
Leiomyosarcoma. There is a large destructive mass within the thyroid gland. The neoplastic cells are spindled, showing an interlacing fascicular architecture.
Leiomyosarcoma. The neoplastic cells show a strong and diffuse cytoplasmic reaction for SMA.
Leiomyosarcoma. The neoplastic cells this adrenal gland leiomyosarcoma are strongly reactive for desmin, whereas the native cortical cells are negative.
A: Leiomyosarcoma
Back Extra: Leiomyosarcoma
- Clinical: Thyroid LMS typically presents as a painless, rapidly growing neck mass, often accompanied by hoarseness, dysphagia, dyspnoea, and weight loss.
- Micro: Histologically, LMS shows spindle cells arranged in interlacing fascicles with hypercellularity, nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Neoplastic cells in LMS are positive for SMA, MSA, desmin, and caldesmon, and show a high proliferation index by Ki-67 staining.
Reference Gallery:
Leiomyosarcoma. There is a large destructive mass within the thyroid gland, with cystic metastasis in a neck lymph node (CT).
Leiomyosarcoma. There is a large destructive mass within the thyroid gland. The neoplastic cells are spindled, showing an interlacing fascicular architecture.
Leiomyosarcoma. Thyroid follicles are seen at the periphery of this destructive spindled cell neoplasm. There are interlacing fascicles.
Leiomyosarcoma. The neoplastic cells seem to originate from the smooth muscle wall of this large vessel at the thyroid gland periphery.
Leiomyosarcoma. Destructive infiltration by a spindled cell population into adjacent parathyroid gland tissue is noted in this leiomyosarcoma.
Leiomyosarcoma. The atypical spindled cell population is more accentuated around a vessel, seen pushing aside native thyroid gland follicles.
Leiomyosarcoma. There is well-developed comedonecrosis in this leiomyosarcoma, a finding not seen in benign smooth muscle tumours.
Leiomyosarcoma. The spindled neoplastic cells have a vaguely epithelioid quality. Numerous mitotic figures are seen.
Leiomyosarcoma. The neoplastic cells show a strong and diffuse cytoplasmic reaction for SMA.
Leiomyosarcoma. There is usually a high proliferation index in leiomyosarcoma, as detected by Ki-67 labelling.
Leiomyosarcoma. Leiomyosarcomas of the adrenal gland usually arise around the central vessels. Note the destroyed adrenal cortical cells.
Leiomyosarcoma. The neoplastic cells this adrenal gland leiomyosarcoma are strongly reactive for desmin, whereas the native cortical cells are negative.

Q: In the alveolar variant of Rhabdomyosarcoma, the tumor cells often exhibit central degeneration and necrosis, leaving a characteristic [...] periphery attached to the fibrovascular septa.
Alveolar rhabdomyosarcoma of the thyroid. There are nests with a dilapidated periphery, showing small blue round cells within the alveolar spaces. Tumour necrosis is present.
Alveolar rhabdomyosarcoma of the thyroid. Nests with degenerative changes in the centre are noted, composed of small neoplastic cells with eccentric, eosinophilic cytoplasm.
A: dilapidated
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma at endocrine sites, such as the thyroid, may present with palpable masses or mass effect symptoms like visual disorders or headaches.
- Micro: Alveolar rhabdomyosarcoma (ARMS) shows fibrovascular septa separating cellular nests of small monomorphic round cells with scant cytoplasm.
- Ancillary: PAX3/7::FOXO1 fusion is a characteristic molecular finding in alveolar rhabdomyosarcoma (ARMS).
Reference Gallery:
Spindle rhabdomyosarcoma of thyroid. Slightly spindled, primitive rhabdoid cells are present in this rhabdomyosarcoma.
Alveolar rhabdomyosarcoma of the thyroid. There are nests with a dilapidated periphery, showing small blue round cells within the alveolar spaces. Tumour necrosis is present.
Alveolar rhabdomyosarcoma of the thyroid. Nests with degenerative changes in the centre are noted, composed of small neoplastic cells with eccentric, eosinophilic cytoplasm.

Q: The spindle cell variant of Rhabdomyosarcoma is morphologically composed of fascicles containing slightly spindled, primitive [...] cells.
Spindle rhabdomyosarcoma of thyroid. Slightly spindled, primitive rhabdoid cells are present in this rhabdomyosarcoma.
A: rhabdoid
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma at endocrine sites, such as the thyroid, may present with palpable masses or mass effect symptoms like visual disorders or headaches.
- Micro: Alveolar rhabdomyosarcoma (ARMS) shows fibrovascular septa separating cellular nests of small monomorphic round cells with scant cytoplasm.
- Ancillary: PAX3/7::FOXO1 fusion is a characteristic molecular finding in alveolar rhabdomyosarcoma (ARMS).
Reference Gallery:
Spindle rhabdomyosarcoma of thyroid. Slightly spindled, primitive rhabdoid cells are present in this rhabdomyosarcoma.
Alveolar rhabdomyosarcoma of the thyroid. There are nests with a dilapidated periphery, showing small blue round cells within the alveolar spaces. Tumour necrosis is present.
Alveolar rhabdomyosarcoma of the thyroid. Nests with degenerative changes in the centre are noted, composed of small neoplastic cells with eccentric, eosinophilic cytoplasm.

Q: The alveolar variant of Rhabdomyosarcoma is molecularly characterized by a specific [FOXO1] gene fusion.
Alveolar rhabdomyosarcoma of the thyroid. There are nests with a dilapidated periphery, showing small blue round cells within the alveolar spaces. Tumour necrosis is present.
Alveolar rhabdomyosarcoma of the thyroid. Nests with degenerative changes in the centre are noted, composed of small neoplastic cells with eccentric, eosinophilic cytoplasm.
A: PAX3/7
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma at endocrine sites, such as the thyroid, may present with palpable masses or mass effect symptoms like visual disorders or headaches.
- Micro: Alveolar rhabdomyosarcoma (ARMS) shows fibrovascular septa separating cellular nests of small monomorphic round cells with scant cytoplasm.
- Ancillary: PAX3/7::FOXO1 fusion is a characteristic molecular finding in alveolar rhabdomyosarcoma (ARMS).
Reference Gallery:
Spindle rhabdomyosarcoma of thyroid. Slightly spindled, primitive rhabdoid cells are present in this rhabdomyosarcoma.
Alveolar rhabdomyosarcoma of the thyroid. There are nests with a dilapidated periphery, showing small blue round cells within the alveolar spaces. Tumour necrosis is present.
Alveolar rhabdomyosarcoma of the thyroid. Nests with degenerative changes in the centre are noted, composed of small neoplastic cells with eccentric, eosinophilic cytoplasm.

Q: The most frequent primary tumor histotype that presents as a Metastasis to the Thyroid Gland is [...], which often features solid nests packed with red blood cells.
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cell renal cell carcinoma is separated from the thyroid by a fibrous capsule. Some lumina and solid nests are packed with blood in the renal cell carcinoma.
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cells of the renal cell carcinoma are in contact with thyroid follicles. Some lumina and solid nests of renal cell carcinoma are packed with red blood cells.
A: clear cell renal cell carcinoma
Back Extra: Metastasis to the Thyroid Gland
- Clinical: Metastasis to the thyroid gland often presents as a palpable neck mass, with dysphonia and dysphagia in some cases. Patients are typically euthyroid, and 25% of cases are found incidentally.
- Micro: Clear cell renal cell carcinoma (RCC) is the most frequent histotype. Metastatic cells can grow into the interstitium, form nodular masses, or develop within pre-existing thyroid nodules.
- Ancillary: Immunohistochemistry is crucial for distinguishing metastatic tumours from primary thyroid neoplasms. CD10 positivity in clear cell RCC and napsin A positivity in lung adenocarcinoma are key markers.
Reference Gallery:
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cell renal cell carcinoma is separated from the thyroid by a fibrous capsule. Some lumina and solid nests are packed with blood in the renal cell carcinoma.
Metastatic clear cell renal cell carcinoma to the thyroid. The cells of the renal cell carcinoma are immunopositive for CD10.
Metastatic lung adenocarcinoma to the thyroid. This metastasis has a solid pattern.
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cells of the renal cell carcinoma are in contact with thyroid follicles. Some lumina and solid nests of renal cell carcinoma are packed with red blood cells.
Metastatic lung adenocarcinoma to the thyroid. The metastatic tumour cells are immunopositive for napsin A.
Metastatic colorectal adenocarcinoma to the thyroid. The colorectal carcinoma infiltrates in between thyroid follicles.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Romanowsky-stained air-dried smear preparation showing a tissue fragment of tumour cells with clear cytoplasm and mild nuclear pleomorphism.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Pap-stained, alcohol-fixed smear preparation showing a tissue fragment of tumour cells with clear cytoplasm, distinct cell borders, and round to oval nuclei with even chromatin.

Q: Immunohistochemistry is crucial in evaluating a Metastasis to the Thyroid Gland; for instance, a metastatic tumor that exhibits strong immunopositivity for napsin A is indicative of a primary [...].
Metastatic lung adenocarcinoma to the thyroid. This metastasis has a solid pattern.
Metastatic lung adenocarcinoma to the thyroid. The metastatic tumour cells are immunopositive for napsin A.
A: lung adenocarcinoma
Back Extra: Metastasis to the Thyroid Gland
- Clinical: Metastasis to the thyroid gland often presents as a palpable neck mass, with dysphonia and dysphagia in some cases. Patients are typically euthyroid, and 25% of cases are found incidentally.
- Micro: Clear cell renal cell carcinoma (RCC) is the most frequent histotype. Metastatic cells can grow into the interstitium, form nodular masses, or develop within pre-existing thyroid nodules.
- Ancillary: Immunohistochemistry is crucial for distinguishing metastatic tumours from primary thyroid neoplasms. CD10 positivity in clear cell RCC and napsin A positivity in lung adenocarcinoma are key markers.
Reference Gallery:
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cell renal cell carcinoma is separated from the thyroid by a fibrous capsule. Some lumina and solid nests are packed with blood in the renal cell carcinoma.
Metastatic clear cell renal cell carcinoma to the thyroid. The cells of the renal cell carcinoma are immunopositive for CD10.
Metastatic lung adenocarcinoma to the thyroid. This metastasis has a solid pattern.
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cells of the renal cell carcinoma are in contact with thyroid follicles. Some lumina and solid nests of renal cell carcinoma are packed with red blood cells.
Metastatic lung adenocarcinoma to the thyroid. The metastatic tumour cells are immunopositive for napsin A.
Metastatic colorectal adenocarcinoma to the thyroid. The colorectal carcinoma infiltrates in between thyroid follicles.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Romanowsky-stained air-dried smear preparation showing a tissue fragment of tumour cells with clear cytoplasm and mild nuclear pleomorphism.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Pap-stained, alcohol-fixed smear preparation showing a tissue fragment of tumour cells with clear cytoplasm, distinct cell borders, and round to oval nuclei with even chromatin.

Q: Fine-needle aspiration of a Metastasis to the Thyroid Gland often reveals tissue fragments of tumor cells with distinct cell borders and abundant clear cytoplasm, which is highly characteristic of a primary [...].
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Romanowsky-stained air-dried smear preparation showing a tissue fragment of tumour cells with clear cytoplasm and mild nuclear pleomorphism.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Pap-stained, alcohol-fixed smear preparation showing a tissue fragment of tumour cells with clear cytoplasm, distinct cell borders, and round to oval nuclei with even chromatin.
A: renal cell carcinoma
Back Extra: Metastasis to the Thyroid Gland
- Clinical: Metastasis to the thyroid gland often presents as a palpable neck mass, with dysphonia and dysphagia in some cases. Patients are typically euthyroid, and 25% of cases are found incidentally.
- Micro: Clear cell renal cell carcinoma (RCC) is the most frequent histotype. Metastatic cells can grow into the interstitium, form nodular masses, or develop within pre-existing thyroid nodules.
- Ancillary: Immunohistochemistry is crucial for distinguishing metastatic tumours from primary thyroid neoplasms. CD10 positivity in clear cell RCC and napsin A positivity in lung adenocarcinoma are key markers.
Reference Gallery:
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cell renal cell carcinoma is separated from the thyroid by a fibrous capsule. Some lumina and solid nests are packed with blood in the renal cell carcinoma.
Metastatic clear cell renal cell carcinoma to the thyroid. The cells of the renal cell carcinoma are immunopositive for CD10.
Metastatic lung adenocarcinoma to the thyroid. This metastasis has a solid pattern.
Metastatic clear cell renal cell carcinoma to the thyroid. The clear cells of the renal cell carcinoma are in contact with thyroid follicles. Some lumina and solid nests of renal cell carcinoma are packed with red blood cells.
Metastatic lung adenocarcinoma to the thyroid. The metastatic tumour cells are immunopositive for napsin A.
Metastatic colorectal adenocarcinoma to the thyroid. The colorectal carcinoma infiltrates in between thyroid follicles.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Romanowsky-stained air-dried smear preparation showing a tissue fragment of tumour cells with clear cytoplasm and mild nuclear pleomorphism.
FNA specimen of metastatic renal cell carcinoma to the thyroid gland. Pap-stained, alcohol-fixed smear preparation showing a tissue fragment of tumour cells with clear cytoplasm, distinct cell borders, and round to oval nuclei with even chromatin.

Q: Grossly and clinically, Thyroid Follicular Nodular Disease classically presents as a [...], an irregularly enlarged gland that may cause compressive symptoms such as dysphagia and stridor.
Multinodular goitre. Gross picture of multinodular goitre. One side of the gland is often more affected than the other.
A: multinodular goiter
Back Extra: Thyroid Follicular Nodular Disease
- Clinical: Thyroid Follicular Nodular Disease (FND) can present as a multinodular goitre (MNG), which may cause compressive symptoms such as dysphagia and stridor.
- Micro: Histopathologically, FND shows an admixture of large and small follicles, often with papillary formations, and lacks invasive growth or nuclear features of papillary thyroid carcinoma.
- Ancillary: Molecular analysis of FNA specimens in FND can reveal somatic alterations in genes like SPOP, ZNF148, and EZH1.
Reference Gallery:
Multinodular goitre. Gross picture of multinodular goitre. One side of the gland is often more affected than the other.
Hyperplastic nodule. Hyperplastic nodule with dilated macrofollicles.
Hyperplastic nodule. Hyperplastic nodule with mixed macrofollicular and microfollicular architecture.
Hyperplastic nodule. Hyperplastic nodule with degenerative changes.
Hyperplastic nodule. Hyperplastic nodule with areas of papillary architecture.
Cytology of a hyperplastic nodule of multinodular goitre. This nodule has abundant colloid showing the chicken-wire artefact (Giemsa stain).
Cytology of a hyperplastic nodule of multinodular goitre. A monolayer sheet of cells lacking nuclear atypia (Pap).
Cytology of a hyperplastic nodule of multinodular goitre. The cells are arranged in a cohesive tissue fragment (Giemsa stain).

Q: Microscopically, Thyroid Follicular Nodular Disease features hyperplastic nodules with an admixture of large and small follicles and occasional non-neoplastic papillary formations, which critically lack the nuclear features of [...].
Hyperplastic nodule. Hyperplastic nodule with dilated macrofollicles.
Hyperplastic nodule. Hyperplastic nodule with mixed macrofollicular and microfollicular architecture.
Hyperplastic nodule. Hyperplastic nodule with areas of papillary architecture.
A: papillary thyroid carcinoma
Back Extra: Thyroid Follicular Nodular Disease
- Clinical: Thyroid Follicular Nodular Disease (FND) can present as a multinodular goitre (MNG), which may cause compressive symptoms such as dysphagia and stridor.
- Micro: Histopathologically, FND shows an admixture of large and small follicles, often with papillary formations, and lacks invasive growth or nuclear features of papillary thyroid carcinoma.
- Ancillary: Molecular analysis of FNA specimens in FND can reveal somatic alterations in genes like SPOP, ZNF148, and EZH1.
Reference Gallery:
Multinodular goitre. Gross picture of multinodular goitre. One side of the gland is often more affected than the other.
Hyperplastic nodule. Hyperplastic nodule with dilated macrofollicles.
Hyperplastic nodule. Hyperplastic nodule with mixed macrofollicular and microfollicular architecture.
Hyperplastic nodule. Hyperplastic nodule with degenerative changes.
Hyperplastic nodule. Hyperplastic nodule with areas of papillary architecture.
Cytology of a hyperplastic nodule of multinodular goitre. This nodule has abundant colloid showing the chicken-wire artefact (Giemsa stain).
Cytology of a hyperplastic nodule of multinodular goitre. A monolayer sheet of cells lacking nuclear atypia (Pap).
Cytology of a hyperplastic nodule of multinodular goitre. The cells are arranged in a cohesive tissue fragment (Giemsa stain).

Q: On cytologic smears, Thyroid Follicular Nodular Disease yields monolayer sheets of benign follicular cells and abundant colloid that classically displays a [...] artifact on Giemsa staining.
Cytology of a hyperplastic nodule of multinodular goitre. This nodule has abundant colloid showing the chicken-wire artefact (Giemsa stain).
Cytology of a hyperplastic nodule of multinodular goitre. A monolayer sheet of cells lacking nuclear atypia (Pap).
A: chicken-wire
Back Extra: Thyroid Follicular Nodular Disease
- Clinical: Thyroid Follicular Nodular Disease (FND) can present as a multinodular goitre (MNG), which may cause compressive symptoms such as dysphagia and stridor.
- Micro: Histopathologically, FND shows an admixture of large and small follicles, often with papillary formations, and lacks invasive growth or nuclear features of papillary thyroid carcinoma.
- Ancillary: Molecular analysis of FNA specimens in FND can reveal somatic alterations in genes like SPOP, ZNF148, and EZH1.
Reference Gallery:
Multinodular goitre. Gross picture of multinodular goitre. One side of the gland is often more affected than the other.
Hyperplastic nodule. Hyperplastic nodule with dilated macrofollicles.
Hyperplastic nodule. Hyperplastic nodule with mixed macrofollicular and microfollicular architecture.
Hyperplastic nodule. Hyperplastic nodule with degenerative changes.
Hyperplastic nodule. Hyperplastic nodule with areas of papillary architecture.
Cytology of a hyperplastic nodule of multinodular goitre. This nodule has abundant colloid showing the chicken-wire artefact (Giemsa stain).
Cytology of a hyperplastic nodule of multinodular goitre. A monolayer sheet of cells lacking nuclear atypia (Pap).
Cytology of a hyperplastic nodule of multinodular goitre. The cells are arranged in a cohesive tissue fragment (Giemsa stain).