Title: WHO / GI
Tags: GI::Pancreas::Neoplastic GI::Stomach::Neoplastic GI::Liver::Neoplastic GI::Small_Intestine::Neoplastic GI::Appendix::Neoplastic GI::Unclassified GI::Esophagus::Neoplastic GI::Mesenchymal::Vascular GI::Stomach::Polyp GI::Biliary::Neoplastic GI::Mesenchymal::Miscellaneous GI::Anus::Neoplastic GI::Mesenchymal::Neural GI::General::Neoplastic GI::Hematolymphoid::T_Cell_Lymphoma GI::Mesenchymal::Adipocytic GI::Syndrome::Polyposis GI::Colon::Polyp GI::Syndrome::Cancer_Predisposition

Q: A biopsy of a mucosal-type anal adenocarcinoma (pictured) shows a stratified mucin-producing pattern with hybrid glandular and [...] components.
Adenocarcinoma, mucosal; HPV-associated. A stratified mucin-producing carcinoma showing hybrid mucin-producing glandular (left) and squamoid components (right).
A: squamoid
Back Extra: Anal adenocarcinoma
- Clinical: Rare neoplasm (5–10% of anal cancers) occurring in three main subtypes: mucosal (luminal), anal gland (extramucosal), and fistula-associated (often linked to longstanding Crohn disease).
- Microscopic: Mucosal-type can be HPV-independent (intestinal-type, resembling rectal adenocarcinoma) or HPV-associated (stratified mucin-producing or endocervical-like patterns).
- Microscopic: Anal gland adenocarcinoma typically presents as haphazardly dispersed glands with cuboidal cells and scant mucin, lacking a luminal in situ component.
- Ancillary: HPV-associated cases show diffuse p16 positivity; Anal gland adenocarcinomas are usually CK7+/CK20-/CDX2-, helping distinguish them from intestinal-type tumors.
- Prognosis: Generally worse than anal squamous cell carcinoma; staging is based on tumor size (TNM), though depth of invasion is also clinically significant.
Adenocarcinoma, mucosal; HPV-associated. A stratified mucin-producing carcinoma showing hybrid mucin-producing glandular (left) and squamoid components (right).

Q: Unlike primary Paget disease of the anus, secondary pagetoid spread from an underlying anal adenocarcinoma is typically [...] positive.
Adenocarcinoma, mucosal; HPV-independent. B Pagetoid spread of anal adenocarcinoma into the adjacent squamous epithelium.
A: CK20
Back Extra: Anal adenocarcinoma
- Clinical: Rare neoplasm (5–10% of anal cancers) occurring in three main subtypes: mucosal (luminal), anal gland (extramucosal), and fistula-associated (often linked to longstanding Crohn disease).
- Microscopic: Mucosal-type can be HPV-independent (intestinal-type, resembling rectal adenocarcinoma) or HPV-associated (stratified mucin-producing or endocervical-like patterns).
- Microscopic: Anal gland adenocarcinoma typically presents as haphazardly dispersed glands with cuboidal cells and scant mucin, lacking a luminal in situ component.
- Ancillary: HPV-associated cases show diffuse p16 positivity; Anal gland adenocarcinomas are usually CK7+/CK20-/CDX2-, helping distinguish them from intestinal-type tumors.
- Prognosis: Generally worse than anal squamous cell carcinoma; staging is based on tumor size (TNM), though depth of invasion is also clinically significant.
Adenocarcinoma, mucosal; HPV-independent. B Pagetoid spread of anal adenocarcinoma into the adjacent squamous epithelium.

Q: The HPV-associated subtype of anal adenocarcinoma is characterized by strong and diffuse immunohistochemical expression of [...].
Adenocarcinoma, mucosal; HPV-associated. A stratified mucin-producing carcinoma showing hybrid mucin-producing glandular (left) and squamoid components (right).
Adenocarcinoma, mucosal; HPV-associated. B Villoglandular adenocarcinoma featuring delicate, long villiform exophytic architecture.
Adenocarcinoma, mucosal; HPV-associated. C Higher magnification shows cigar-shaped nuclei, variable intracytoplasmic mucin, and apical mitoses.
A: p16
Back Extra: Anal adenocarcinoma
- Clinical: Rare neoplasm (5–10% of anal cancers) occurring in three main subtypes: mucosal (luminal), anal gland (extramucosal), and fistula-associated (often linked to longstanding Crohn disease).
- Microscopic: Mucosal-type can be HPV-independent (intestinal-type, resembling rectal adenocarcinoma) or HPV-associated (stratified mucin-producing or endocervical-like patterns).
- Microscopic: Anal gland adenocarcinoma typically presents as haphazardly dispersed glands with cuboidal cells and scant mucin, lacking a luminal in situ component.
- Ancillary: HPV-associated cases show diffuse p16 positivity; Anal gland adenocarcinomas are usually CK7+/CK20-/CDX2-, helping distinguish them from intestinal-type tumors.
- Prognosis: Generally worse than anal squamous cell carcinoma; staging is based on tumor size (TNM), though depth of invasion is also clinically significant.
Adenocarcinoma, mucosal; HPV-associated. A stratified mucin-producing carcinoma showing hybrid mucin-producing glandular (left) and squamoid components (right).
Adenocarcinoma, mucosal; HPV-associated. B Villoglandular adenocarcinoma featuring delicate, long villiform exophytic architecture.
Adenocarcinoma, mucosal; HPV-associated. C Higher magnification shows cigar-shaped nuclei, variable intracytoplasmic mucin, and apical mitoses.

Q: In the context of Anal neuroendocrine neoplasms, a diagnosis of [...] is supported by the visual finding of small tumour cells with high N:C ratios and nuclear moulding.
High-power view of SCNEC showing small tumour cells with a high N:C ratio and nuclear moulding.
Anal small cell neuroendocrine carcinoma (SCNEC) biopsy specimen showing hyperchromatic nuclei and scant cytoplasm.
A: small cell neuroendocrine carcinoma (SCNEC)
Back Extra: Anal neuroendocrine neoplasms
- Clinical: Anal neuroendocrine neoplasms (NENs) are rare (1% of anal cancers), with poorly differentiated neuroendocrine carcinomas (NECs) being far more common than well-differentiated NETs; SCNEC is notably associated with HIV infection.
- Microscopic: SCNEC shows small cells with high N:C ratios and nuclear moulding, while LCNEC shows large cells with vesicular chromatin and prominent nucleoli; MiNEN requires each component (neuroendocrine and non-neuroendocrine) to comprise ≥30% of the neoplasm.
- Ancillary: NECs typically express synaptophysin and INSM1, show a very high Ki-67 proliferation index, and often demonstrate abnormal p53 (overexpression or loss) and loss of RB1.
- Differential Diagnosis: Basaloid squamous cell carcinoma (SCC) is a key mimic but is distinguished from anal NEC by its strong expression of p63 and p40.
High-power view of SCNEC showing small tumour cells with a high N:C ratio and nuclear moulding.
Anal small cell neuroendocrine carcinoma (SCNEC) biopsy specimen showing hyperchromatic nuclei and scant cytoplasm.

Q: To distinguish anal neuroendocrine carcinoma from its morphologic mimic, basaloid squamous cell carcinoma, a pathologist should look for immunoreactivity for [...] or [...], which are negative in true neuroendocrine neoplasms.
High-power view of SCNEC showing small tumour cells with a high N:C ratio and nuclear moulding.
Positive p63 immunohistochemical staining in basaloid squamous cell carcinoma, distinguishing it from neuroendocrine carcinoma.
A: p63; p40
Back Extra: Anal neuroendocrine neoplasms
- Clinical: Anal neuroendocrine neoplasms (NENs) are rare (1% of anal cancers), with poorly differentiated neuroendocrine carcinomas (NECs) being far more common than well-differentiated NETs; SCNEC is notably associated with HIV infection.
- Microscopic: SCNEC shows small cells with high N:C ratios and nuclear moulding, while LCNEC shows large cells with vesicular chromatin and prominent nucleoli; MiNEN requires each component (neuroendocrine and non-neuroendocrine) to comprise ≥30% of the neoplasm.
- Ancillary: NECs typically express synaptophysin and INSM1, show a very high Ki-67 proliferation index, and often demonstrate abnormal p53 (overexpression or loss) and loss of RB1.
- Differential Diagnosis: Basaloid squamous cell carcinoma (SCC) is a key mimic but is distinguished from anal NEC by its strong expression of p63 and p40.
High-power view of SCNEC showing small tumour cells with a high N:C ratio and nuclear moulding.
Positive p63 immunohistochemical staining in basaloid squamous cell carcinoma, distinguishing it from neuroendocrine carcinoma.

Q: Anal neuroendocrine neoplasms categorized as [...] must have both components represent at least [...]% of the tumor.
Anal mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) with small cell neuroendocrine carcinoma (SCNEC) and squamous cell carcinoma.
Combined/biphasic-type MiNEN with distinct regions of SCNEC and adenocarcinoma.
A: mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs); 30
Back Extra: Anal neuroendocrine neoplasms
- Clinical: Anal neuroendocrine neoplasms (NENs) are rare (1% of anal cancers), with poorly differentiated neuroendocrine carcinomas (NECs) being far more common than well-differentiated NETs; SCNEC is notably associated with HIV infection.
- Microscopic: SCNEC shows small cells with high N:C ratios and nuclear moulding, while LCNEC shows large cells with vesicular chromatin and prominent nucleoli; MiNEN requires each component (neuroendocrine and non-neuroendocrine) to comprise ≥30% of the neoplasm.
- Ancillary: NECs typically express synaptophysin and INSM1, show a very high Ki-67 proliferation index, and often demonstrate abnormal p53 (overexpression or loss) and loss of RB1.
- Differential Diagnosis: Basaloid squamous cell carcinoma (SCC) is a key mimic but is distinguished from anal NEC by its strong expression of p63 and p40.
Anal mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) with small cell neuroendocrine carcinoma (SCNEC) and squamous cell carcinoma.
Combined/biphasic-type MiNEN with distinct regions of SCNEC and adenocarcinoma.

Q: The loss of [...] expression and the aberrant expression of [...] are immunohistochemical features commonly seen in poorly differentiated Anal neuroendocrine neoplasms (NECs).
Anal large cell neuroendocrine carcinoma (LCNEC) with large nuclei, vesicular chromatin, and rosette-like arrangements.
Immunohistochemical staining of p53 aberrant expression in anal small cell neuroendocrine carcinoma (SCNEC).
Loss of RB1 expression by immunohistochemistry in anal large cell neuroendocrine carcinoma (LCNEC).
A: RB1; p53
Back Extra: Anal neuroendocrine neoplasms
- Clinical: Anal neuroendocrine neoplasms (NENs) are rare (1% of anal cancers), with poorly differentiated neuroendocrine carcinomas (NECs) being far more common than well-differentiated NETs; SCNEC is notably associated with HIV infection.
- Microscopic: SCNEC shows small cells with high N:C ratios and nuclear moulding, while LCNEC shows large cells with vesicular chromatin and prominent nucleoli; MiNEN requires each component (neuroendocrine and non-neuroendocrine) to comprise ≥30% of the neoplasm.
- Ancillary: NECs typically express synaptophysin and INSM1, show a very high Ki-67 proliferation index, and often demonstrate abnormal p53 (overexpression or loss) and loss of RB1.
- Differential Diagnosis: Basaloid squamous cell carcinoma (SCC) is a key mimic but is distinguished from anal NEC by its strong expression of p63 and p40.
Anal large cell neuroendocrine carcinoma (LCNEC) with large nuclei, vesicular chromatin, and rosette-like arrangements.
Immunohistochemical staining of p53 aberrant expression in anal small cell neuroendocrine carcinoma (SCNEC).
Loss of RB1 expression by immunohistochemistry in anal large cell neuroendocrine carcinoma (LCNEC).

Q: An endoscopic examination revealing a whitish, constricting mass at the anal verge and histology showing infiltrative nests of squamous cells with either eosinophilic cytoplasm or basaloid features is diagnostic of [...].
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.
Anal squamous cell carcinoma. Malignant squamous cells with solid pattern of infiltration featuring abundant eosinophilic cytoplasm.
Invasive squamous cell carcinoma with basaloid features. The tumour shows a combination of basaloid and well-differentiated features.
A: anal squamous cell carcinoma
Back Extra: Anal squamous cell carcinoma
- Clinical: Most common anal malignancy, strongly associated with high-risk HPV infection (predominantly HPV16) and immunodeficiency states such as HIV.
- Microscopic: Displays histological heterogeneity, ranging from keratinizing (large eosinophilic cells) to basaloid (scant cytoplasm, peripheral palisading) and rare urothelial-like or verrucous patterns.
- Ancillary: Characterized by strong, diffuse p16 and p40 expression; high-risk HPV oncoproteins E6 and E7 drive pathogenesis by inactivating p53 and RB1.
- Prognosis: Poor outcomes are associated with male sex, tumor size > 50 mm, and nodal metastasis; PD-L1 expression in ~50% of cases may support checkpoint inhibitor therapy.
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.
Anal squamous cell carcinoma. Malignant squamous cells with solid pattern of infiltration featuring abundant eosinophilic cytoplasm.
Invasive squamous cell carcinoma with basaloid features. The tumour shows a combination of basaloid and well-differentiated features.

Q: In the context of anal squamous cell carcinoma, strong and diffuse nuclear and cytoplasmic immunohistochemical staining for [...] is used as a surrogate marker for high-risk HPV infection.
Invasive squamous cell carcinoma. p16 immunohistochemistry is strongly and diffusely positive.
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.
A: p16
Back Extra: Anal squamous cell carcinoma
- Clinical: Most common anal malignancy, strongly associated with high-risk HPV infection (predominantly HPV16) and immunodeficiency states such as HIV.
- Microscopic: Displays histological heterogeneity, ranging from keratinizing (large eosinophilic cells) to basaloid (scant cytoplasm, peripheral palisading) and rare urothelial-like or verrucous patterns.
- Ancillary: Characterized by strong, diffuse p16 and p40 expression; high-risk HPV oncoproteins E6 and E7 drive pathogenesis by inactivating p53 and RB1.
- Prognosis: Poor outcomes are associated with male sex, tumor size > 50 mm, and nodal metastasis; PD-L1 expression in ~50% of cases may support checkpoint inhibitor therapy.
Invasive squamous cell carcinoma. p16 immunohistochemistry is strongly and diffusely positive.
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.

Q: The pathogenesis of approximately 90% of anal squamous cell carcinoma cases involves high-risk HPV, where the viral oncoprotein E6 inactivates [...] and E7 inactivates [...].
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.
Anal squamous cell carcinoma. Malignant squamous cells with solid pattern of infiltration featuring abundant eosinophilic cytoplasm.
A: p53; RB1
Back Extra: Anal squamous cell carcinoma
- Clinical: Most common anal malignancy, strongly associated with high-risk HPV infection (predominantly HPV16) and immunodeficiency states such as HIV.
- Microscopic: Displays histological heterogeneity, ranging from keratinizing (large eosinophilic cells) to basaloid (scant cytoplasm, peripheral palisading) and rare urothelial-like or verrucous patterns.
- Ancillary: Characterized by strong, diffuse p16 and p40 expression; high-risk HPV oncoproteins E6 and E7 drive pathogenesis by inactivating p53 and RB1.
- Prognosis: Poor outcomes are associated with male sex, tumor size > 50 mm, and nodal metastasis; PD-L1 expression in ~50% of cases may support checkpoint inhibitor therapy.
Anal squamous cell carcinoma. Low magnification showing nests of squamous cell carcinoma underneath the anal epithelium with ulceration.
Anal squamous cell carcinoma. Malignant squamous cells with solid pattern of infiltration featuring abundant eosinophilic cytoplasm.

Q: The [...] subtype of anal squamous cell carcinoma is rare, typically HPV-negative, and is characterized by a pushing interface of broad bulbous fronds and a lack of significant cytological atypia.
Verrucous carcinoma. The carcinoma featuring mostly endophytic growth of broad bulbous fronds of thickened epithelium with a pushing interface.
A: verrucous
Back Extra: Anal squamous cell carcinoma
- Clinical: Most common anal malignancy, strongly associated with high-risk HPV infection (predominantly HPV16) and immunodeficiency states such as HIV.
- Microscopic: Displays histological heterogeneity, ranging from keratinizing (large eosinophilic cells) to basaloid (scant cytoplasm, peripheral palisading) and rare urothelial-like or verrucous patterns.
- Ancillary: Characterized by strong, diffuse p16 and p40 expression; high-risk HPV oncoproteins E6 and E7 drive pathogenesis by inactivating p53 and RB1.
- Prognosis: Poor outcomes are associated with male sex, tumor size > 50 mm, and nodal metastasis; PD-L1 expression in ~50% of cases may support checkpoint inhibitor therapy.
Verrucous carcinoma. The carcinoma featuring mostly endophytic growth of broad bulbous fronds of thickened epithelium with a pushing interface.

Q: A key histological feature distinguishing mucinous [...] from Low-grade Appendiceal Mucinous Neoplasm (LAMN) is the presence of [...] invasion rather than a broad pushing front.
Mucinous adenocarcinoma of the appendix. A The adenocarcinoma is composed of > 50% extracellular mucin with dissecting pools of mucin containing floating neoplastic glands and nests of tumour cells.
Mucinous adenocarcinoma of the appendix. B Small mucin pools containing neoplastic glands, single cells, and nests of tumour cells with high-grade cytological features.
A: appendiceal adenocarcinoma; infiltrative
Back Extra: Appendiceal adenocarcinoma
- Clinical: Rare primary malignancy (incidence ~1 per 100,000) typically presenting in the 5th-7th decades with symptoms mimicking acute appendicitis or a palpable abdominal mass.
- Microscopic (Mucinous): Defined by >50% extracellular mucin and distinguished from LAMN/HAMN by the presence of infiltrative invasion (e.g., cribriform glands or single cells) and desmoplastic response.
- Microscopic (Non-mucinous/Signet-ring): Non-mucinous types resemble colorectal adenocarcinoma with jagged glands and luminal necrosis; signet-ring cell types require >50% signet-ring cell morphology and carry a worse prognosis.
- Ancillary: Frequent mutations in KRAS (55–80%) and GNAS (30–70%); TP53 mutations or 'triple-negative' status (lacking RAS/GNAS/TP53 mutations) are associated with worse clinical outcomes.
Mucinous adenocarcinoma of the appendix. A The adenocarcinoma is composed of > 50% extracellular mucin with dissecting pools of mucin containing floating neoplastic glands and nests of tumour cells.
Mucinous adenocarcinoma of the appendix. B Small mucin pools containing neoplastic glands, single cells, and nests of tumour cells with high-grade cytological features.

Q: In the context of [...], the non-mucinous subtype typically histologically resembles [...] adenocarcinoma, featuring invasive glands with columnar cells and intraluminal necrosis.
Non-mucinous adenocarcinoma of the appendix. A The adenocarcinoma is composed of invasive glands lined by columnar cells without associated extracellular mucin.
Non-mucinous adenocarcinoma of the appendix. B The invasive glands exhibit luminal necrosis and resemble conventional colorectal adenocarcinoma.
A: appendiceal adenocarcinoma; colorectal
Back Extra: Appendiceal adenocarcinoma
- Clinical: Rare primary malignancy (incidence ~1 per 100,000) typically presenting in the 5th-7th decades with symptoms mimicking acute appendicitis or a palpable abdominal mass.
- Microscopic (Mucinous): Defined by >50% extracellular mucin and distinguished from LAMN/HAMN by the presence of infiltrative invasion (e.g., cribriform glands or single cells) and desmoplastic response.
- Microscopic (Non-mucinous/Signet-ring): Non-mucinous types resemble colorectal adenocarcinoma with jagged glands and luminal necrosis; signet-ring cell types require >50% signet-ring cell morphology and carry a worse prognosis.
- Ancillary: Frequent mutations in KRAS (55–80%) and GNAS (30–70%); TP53 mutations or 'triple-negative' status (lacking RAS/GNAS/TP53 mutations) are associated with worse clinical outcomes.
Non-mucinous adenocarcinoma of the appendix. A The adenocarcinoma is composed of invasive glands lined by columnar cells without associated extracellular mucin.
Non-mucinous adenocarcinoma of the appendix. B The invasive glands exhibit luminal necrosis and resemble conventional colorectal adenocarcinoma.

Q: A malignant glandular neoplasm of the appendix characterized by more than 50% cells with eccentric nuclei and intracytoplasmic mucin is diagnosed as [...].
Signet-ring cell adenocarcinoma of the appendix. A The adenocarcinoma is composed of > 50% signet-ring cells present within mucin pools. This signet-ring cell adenocarcinoma is associated with a precursor dysplastic lesion (left side of the image).
Signet-ring cell adenocarcinoma of the appendix. B Signet-ring cells forming complex anastomosing aggregates within mucin pools.
Signet-ring cell adenocarcinoma of the appendix. C Infiltrating single neoplastic cells without associated extracellular mucin.
A: signet-ring cell appendiceal adenocarcinoma
Back Extra: Appendiceal adenocarcinoma
- Clinical: Rare primary malignancy (incidence ~1 per 100,000) typically presenting in the 5th-7th decades with symptoms mimicking acute appendicitis or a palpable abdominal mass.
- Microscopic (Mucinous): Defined by >50% extracellular mucin and distinguished from LAMN/HAMN by the presence of infiltrative invasion (e.g., cribriform glands or single cells) and desmoplastic response.
- Microscopic (Non-mucinous/Signet-ring): Non-mucinous types resemble colorectal adenocarcinoma with jagged glands and luminal necrosis; signet-ring cell types require >50% signet-ring cell morphology and carry a worse prognosis.
- Ancillary: Frequent mutations in KRAS (55–80%) and GNAS (30–70%); TP53 mutations or 'triple-negative' status (lacking RAS/GNAS/TP53 mutations) are associated with worse clinical outcomes.
Signet-ring cell adenocarcinoma of the appendix. A The adenocarcinoma is composed of > 50% signet-ring cells present within mucin pools. This signet-ring cell adenocarcinoma is associated with a precursor dysplastic lesion (left side of the image).
Signet-ring cell adenocarcinoma of the appendix. B Signet-ring cells forming complex anastomosing aggregates within mucin pools.
Signet-ring cell adenocarcinoma of the appendix. C Infiltrating single neoplastic cells without associated extracellular mucin.

Q: A 56-year-old presents with acute appendicitis. Histology shows cohesive clusters of cells with goblet-like mucin and eosinophilic granular cytoplasm resembling intestinal crypts. The most likely diagnosis is [...].
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).
A: Appendiceal goblet cell adenocarcinoma
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: An uncommon amphicrine-like tumor (0.05–0.3 cases/100,000) that typically affects adults (mean age 56) and most frequently presents as acute appendicitis.
- Microscopic (Architecture): Low-grade tumors form cohesive tubules and nests resembling intestinal crypts; high-grade tumors exhibit loss of cohesion, single-cell infiltration (signet-ring-like), and prominent stromal desmoplasia.
- Grading & Prognosis: Prognosis is highly dependent on stage and grade; the 5-year survival is ~76–81%, but high-grade and disseminated tumors show significantly worse outcomes.
- Molecular: Characterized by a lack of common colorectal drivers like KRAS, APC, and BRAF; instead, it often involves mutations in the WNT pathway (USP9X, NOTCH1) or chromatin-remodeling genes (ARID1A).
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).

Q: Unlike conventional appendiceal adenocarcinoma, [...] rarely contains mutations in the genes [...].
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).
A: Appendiceal goblet cell adenocarcinoma; KRAS, APC, or BRAF
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: An uncommon amphicrine-like tumor (0.05–0.3 cases/100,000) that typically affects adults (mean age 56) and most frequently presents as acute appendicitis.
- Microscopic (Architecture): Low-grade tumors form cohesive tubules and nests resembling intestinal crypts; high-grade tumors exhibit loss of cohesion, single-cell infiltration (signet-ring-like), and prominent stromal desmoplasia.
- Grading & Prognosis: Prognosis is highly dependent on stage and grade; the 5-year survival is ~76–81%, but high-grade and disseminated tumors show significantly worse outcomes.
- Molecular: Characterized by a lack of common colorectal drivers like KRAS, APC, and BRAF; instead, it often involves mutations in the WNT pathway (USP9X, NOTCH1) or chromatin-remodeling genes (ARID1A).
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).

Q: In high-grade [...], the tumor frequently displays a loss of cohesive clusters and may grow as [...] of single atypical cells or confluent sheets.
Goblet cell carcinoma, high-grade pattern showing linear arrays of single, highly atypical cells.
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).
A: Appendiceal goblet cell adenocarcinoma; linear arrays
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: An uncommon amphicrine-like tumor (0.05–0.3 cases/100,000) that typically affects adults (mean age 56) and most frequently presents as acute appendicitis.
- Microscopic (Architecture): Low-grade tumors form cohesive tubules and nests resembling intestinal crypts; high-grade tumors exhibit loss of cohesion, single-cell infiltration (signet-ring-like), and prominent stromal desmoplasia.
- Grading & Prognosis: Prognosis is highly dependent on stage and grade; the 5-year survival is ~76–81%, but high-grade and disseminated tumors show significantly worse outcomes.
- Molecular: Characterized by a lack of common colorectal drivers like KRAS, APC, and BRAF; instead, it often involves mutations in the WNT pathway (USP9X, NOTCH1) or chromatin-remodeling genes (ARID1A).
Goblet cell carcinoma, high-grade pattern showing linear arrays of single, highly atypical cells.
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).

Q: The presence of variable neuroendocrine differentiation (marked by [...]) is characteristic but not required for the diagnosis of [...].
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).
A: synaptophysin or chromogranin; Appendiceal goblet cell adenocarcinoma
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: An uncommon amphicrine-like tumor (0.05–0.3 cases/100,000) that typically affects adults (mean age 56) and most frequently presents as acute appendicitis.
- Microscopic (Architecture): Low-grade tumors form cohesive tubules and nests resembling intestinal crypts; high-grade tumors exhibit loss of cohesion, single-cell infiltration (signet-ring-like), and prominent stromal desmoplasia.
- Grading & Prognosis: Prognosis is highly dependent on stage and grade; the 5-year survival is ~76–81%, but high-grade and disseminated tumors show significantly worse outcomes.
- Molecular: Characterized by a lack of common colorectal drivers like KRAS, APC, and BRAF; instead, it often involves mutations in the WNT pathway (USP9X, NOTCH1) or chromatin-remodeling genes (ARID1A).
Comparison of low-grade (G1) goblet cell adenocarcinoma with cohesive clusters (upper panel) versus high-grade (G3) with loss of cohesion and stromal desmoplasia (lower panel).

Q: A 55-year-old patient presents with acute appendicitis. Histology shows cohesive clusters of goblet-like cells infiltrating the appendiceal wall without surface dysplasia. This morphology is diagnostic of [...].
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).
A: Appendiceal goblet cell adenocarcinoma
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: Often presents as acute appendicitis or an incidental finding; common metastatic sites include the peritoneum and ovaries (often mimicking primary ovarian tumors).
- Microscopic (Low-Grade): Characterized by cohesive, smooth-contoured tubules or nests of cells with goblet-like mucin and small, peripheral nuclei; notably lacks precursor surface dysplasia.
- Microscopic (High-Grade): Shows infiltrating single cells, complex/irregular tubules, stromal desmoplasia, marked nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Exhibits amphicrine differentiation with variable expression of neuroendocrine markers (Synaptophysin, Chromogranin) and mucin; grading is determined by the percentage of high-grade components.
- Prognosis: Outcome is stage- and grade-dependent, with 5-year survival rates around 76-80%; high-grade tumors typically present at stage IV.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).

Q: In Appendiceal goblet cell adenocarcinoma, the presence of [...] and [...] are indicative of a high-grade component.
Goblet cell carcinoma, high-grade pattern. In this high-grade area, the tumour is growing as linear arrays of single, highly atypical cells, with no attempt to form tubular or clustered groups. The overall grade of the tumour is determined by the tumour percentage that shows high-grade features.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).
A: single-cell infiltration; stromal desmoplasia
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: Often presents as acute appendicitis or an incidental finding; common metastatic sites include the peritoneum and ovaries (often mimicking primary ovarian tumors).
- Microscopic (Low-Grade): Characterized by cohesive, smooth-contoured tubules or nests of cells with goblet-like mucin and small, peripheral nuclei; notably lacks precursor surface dysplasia.
- Microscopic (High-Grade): Shows infiltrating single cells, complex/irregular tubules, stromal desmoplasia, marked nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Exhibits amphicrine differentiation with variable expression of neuroendocrine markers (Synaptophysin, Chromogranin) and mucin; grading is determined by the percentage of high-grade components.
- Prognosis: Outcome is stage- and grade-dependent, with 5-year survival rates around 76-80%; high-grade tumors typically present at stage IV.
Goblet cell carcinoma, high-grade pattern. In this high-grade area, the tumour is growing as linear arrays of single, highly atypical cells, with no attempt to form tubular or clustered groups. The overall grade of the tumour is determined by the tumour percentage that shows high-grade features.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).

Q: Unlike conventional appendiceal adenocarcinoma, Appendiceal goblet cell adenocarcinoma is characteristically associated with an [...] of precursor dysplasia in the surface epithelium.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).
A: absence
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: Often presents as acute appendicitis or an incidental finding; common metastatic sites include the peritoneum and ovaries (often mimicking primary ovarian tumors).
- Microscopic (Low-Grade): Characterized by cohesive, smooth-contoured tubules or nests of cells with goblet-like mucin and small, peripheral nuclei; notably lacks precursor surface dysplasia.
- Microscopic (High-Grade): Shows infiltrating single cells, complex/irregular tubules, stromal desmoplasia, marked nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Exhibits amphicrine differentiation with variable expression of neuroendocrine markers (Synaptophysin, Chromogranin) and mucin; grading is determined by the percentage of high-grade components.
- Prognosis: Outcome is stage- and grade-dependent, with 5-year survival rates around 76-80%; high-grade tumors typically present at stage IV.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).

Q: In the molecular pathology of Appendiceal goblet cell adenocarcinoma, high-grade tumors and poor clinical outcomes are frequently associated with mutations in the [...] gene.
Goblet cell carcinoma, high-grade pattern. In this high-grade area, the tumour is growing as linear arrays of single, highly atypical cells, with no attempt to form tubular or clustered groups. The overall grade of the tumour is determined by the tumour percentage that shows high-grade features.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).
A: TP53
Back Extra: Appendiceal goblet cell adenocarcinoma
- Clinical: Often presents as acute appendicitis or an incidental finding; common metastatic sites include the peritoneum and ovaries (often mimicking primary ovarian tumors).
- Microscopic (Low-Grade): Characterized by cohesive, smooth-contoured tubules or nests of cells with goblet-like mucin and small, peripheral nuclei; notably lacks precursor surface dysplasia.
- Microscopic (High-Grade): Shows infiltrating single cells, complex/irregular tubules, stromal desmoplasia, marked nuclear pleomorphism, and increased mitotic activity.
- Ancillary: Exhibits amphicrine differentiation with variable expression of neuroendocrine markers (Synaptophysin, Chromogranin) and mucin; grading is determined by the percentage of high-grade components.
- Prognosis: Outcome is stage- and grade-dependent, with 5-year survival rates around 76-80%; high-grade tumors typically present at stage IV.
Goblet cell carcinoma, high-grade pattern. In this high-grade area, the tumour is growing as linear arrays of single, highly atypical cells, with no attempt to form tubular or clustered groups. The overall grade of the tumour is determined by the tumour percentage that shows high-grade features.
Goblet cell adenocarcinoma of appendix. Low-grade (G1) goblet cell adenocarcinoma shows cohesive and smooth-contoured clusters of tumour cells with goblet-like intracellular mucin resembling intestinal crypts (upper panel). High-grade (G3) goblet cell adenocarcinoma shows loss of most cohesive clusters with aggregates of tumour cells having irregular contours, single-cell infiltration, stromal desmoplasia, with marked nuclear atypia, and pleomorphism (lower panel).

Q: A benign appendiceal lesion characterized by a villous or tubular glandular neoplasm with conventional intestinal dysplasia, but which lacks the mural remodeling and mucin pools of LAMN, is diagnosed as [...].
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.
Conventional appendiceal adenoma. The adenoma incompletely involves the appendiceal circumference and projects into the lumen as a polyp.
A: conventional appendiceal adenoma
Back Extra: Conventional appendiceal adenoma
- Clinical: Rare (0.03–0.06% incidence) benign neoplasm, usually found incidentally; may be associated with familial adenomatous polyposis (FAP).
- Microscopic: Resembles colorectal counterparts with tubular, villous, or tubulovillous architecture and conventional intestinal dysplasia (elongated, hyperchromatic nuclei).
- Exclusion Criteria: Unlike LAMN or HAMN, conventional appendiceal adenoma lacks mural changes like lymphoid atrophy, submucosal fibromuscularization, or hyalinization.
- Grading: High-grade dysplasia (HGD) is defined by architectural complexity (cribriforming), loss of cell polarity, and round nuclei with open chromatin (staged as pTis).
- Molecular: Commonly harbor mutations in KRAS and WNT pathway genes (APC or RNF43); TP53 mutations may be present in cases with high-grade dysplasia.
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.
Conventional appendiceal adenoma. The adenoma incompletely involves the appendiceal circumference and projects into the lumen as a polyp.

Q: While most cases are sporadic, [...] can be seen in patients with heritable syndromes, particularly [...].
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. The adenoma incompletely involves the appendiceal circumference and projects into the lumen as a polyp.
A: conventional appendiceal adenoma; familial adenomatous polyposis (FAP)
Back Extra: Conventional appendiceal adenoma
- Clinical: Rare (0.03–0.06% incidence) benign neoplasm, usually found incidentally; may be associated with familial adenomatous polyposis (FAP).
- Microscopic: Resembles colorectal counterparts with tubular, villous, or tubulovillous architecture and conventional intestinal dysplasia (elongated, hyperchromatic nuclei).
- Exclusion Criteria: Unlike LAMN or HAMN, conventional appendiceal adenoma lacks mural changes like lymphoid atrophy, submucosal fibromuscularization, or hyalinization.
- Grading: High-grade dysplasia (HGD) is defined by architectural complexity (cribriforming), loss of cell polarity, and round nuclei with open chromatin (staged as pTis).
- Molecular: Commonly harbor mutations in KRAS and WNT pathway genes (APC or RNF43); TP53 mutations may be present in cases with high-grade dysplasia.
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. The adenoma incompletely involves the appendiceal circumference and projects into the lumen as a polyp.

Q: In the context of a [...], the development of [...] is indicated by architectural complexity, loss of nuclear stratification, and a loss of cell polarity.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.
A: conventional appendiceal adenoma; high-grade dysplasia (HGD)
Back Extra: Conventional appendiceal adenoma
- Clinical: Rare (0.03–0.06% incidence) benign neoplasm, usually found incidentally; may be associated with familial adenomatous polyposis (FAP).
- Microscopic: Resembles colorectal counterparts with tubular, villous, or tubulovillous architecture and conventional intestinal dysplasia (elongated, hyperchromatic nuclei).
- Exclusion Criteria: Unlike LAMN or HAMN, conventional appendiceal adenoma lacks mural changes like lymphoid atrophy, submucosal fibromuscularization, or hyalinization.
- Grading: High-grade dysplasia (HGD) is defined by architectural complexity (cribriforming), loss of cell polarity, and round nuclei with open chromatin (staged as pTis).
- Molecular: Commonly harbor mutations in KRAS and WNT pathway genes (APC or RNF43); TP53 mutations may be present in cases with high-grade dysplasia.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.

Q: The molecular pathogenesis of [...] frequently involves mutations in the [...] gene and activation of the [...] pathway (via APC or RNF43 mutations).
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.
A: conventional appendiceal adenoma; KRAS; WNT
Back Extra: Conventional appendiceal adenoma
- Clinical: Rare (0.03–0.06% incidence) benign neoplasm, usually found incidentally; may be associated with familial adenomatous polyposis (FAP).
- Microscopic: Resembles colorectal counterparts with tubular, villous, or tubulovillous architecture and conventional intestinal dysplasia (elongated, hyperchromatic nuclei).
- Exclusion Criteria: Unlike LAMN or HAMN, conventional appendiceal adenoma lacks mural changes like lymphoid atrophy, submucosal fibromuscularization, or hyalinization.
- Grading: High-grade dysplasia (HGD) is defined by architectural complexity (cribriforming), loss of cell polarity, and round nuclei with open chromatin (staged as pTis).
- Molecular: Commonly harbor mutations in KRAS and WNT pathway genes (APC or RNF43); TP53 mutations may be present in cases with high-grade dysplasia.
Conventional appendiceal adenoma. Irregularly shaped crypts show low-grade architectural and cytological features. Elongated, basally located nuclei are hyperchromatic with small nucleoli. Apoptotic debris and mitotic figures are present.
Conventional appendiceal adenoma. Areas of high-grade dysplasia expand the mucosa and display cribriform growth with foci of luminal necrosis and loss of cell polarity.

Q: A circumferential proliferation of neoplastic mucinous epithelium confined to the mucosa with an intact muscularis mucosae is the hallmark of [...].
Mucinous adenoma of the appendix. The neoplasm circumferentially involves the appendiceal mucosa.
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.
A: Appendiceal mucinous adenoma
Back Extra: Appendiceal mucinous adenoma
- Clinical: Benign lesion occurring in the sixth decade of life; typically asymptomatic or discovered incidentally during imaging or appendectomy for unrelated symptoms.
- Microscopic: Characterized by a circumferential proliferation of neoplastic mucinous epithelium (filiform, villous, or flat) confined to the mucosa.
- Key Diagnostic Feature: The muscularis mucosae must remain intact, which distinguishes this lesion from low-grade appendiceal mucinous neoplasms (LAMN).
- Prognosis: Excellent prognosis; appendectomy is considered curative, and even involvement of the resection margin does not typically influence outcome.
- Differential: Distinguished from reactive hyperplasia by its neoplastic cytology and from serrated lesions by its lack of complex serration patterns.
Mucinous adenoma of the appendix. The neoplasm circumferentially involves the appendiceal mucosa.
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.

Q: The primary histological feature that distinguishes [...] from a low-grade appendiceal mucinous neoplasm (LAMN) is the presence of an [...].
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.
A: Appendiceal mucinous adenoma; intact muscularis mucosae
Back Extra: Appendiceal mucinous adenoma
- Clinical: Benign lesion occurring in the sixth decade of life; typically asymptomatic or discovered incidentally during imaging or appendectomy for unrelated symptoms.
- Microscopic: Characterized by a circumferential proliferation of neoplastic mucinous epithelium (filiform, villous, or flat) confined to the mucosa.
- Key Diagnostic Feature: The muscularis mucosae must remain intact, which distinguishes this lesion from low-grade appendiceal mucinous neoplasms (LAMN).
- Prognosis: Excellent prognosis; appendectomy is considered curative, and even involvement of the resection margin does not typically influence outcome.
- Differential: Distinguished from reactive hyperplasia by its neoplastic cytology and from serrated lesions by its lack of complex serration patterns.
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.

Q: Regarding the clinical management of [...], the lesion is considered cured by [...] alone.
Mucinous adenoma of the appendix. The neoplasm circumferentially involves the appendiceal mucosa.
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.
Mucinous adenoma of the appendix. The neoplastic epithelial cells are uniform and contain abundant cytoplasmic mucin. The nuclei are polarized to the basement membrane and are pseudostratified with mild atypia.
A: Appendiceal mucinous adenoma; appendectomy
Back Extra: Appendiceal mucinous adenoma
- Clinical: Benign lesion occurring in the sixth decade of life; typically asymptomatic or discovered incidentally during imaging or appendectomy for unrelated symptoms.
- Microscopic: Characterized by a circumferential proliferation of neoplastic mucinous epithelium (filiform, villous, or flat) confined to the mucosa.
- Key Diagnostic Feature: The muscularis mucosae must remain intact, which distinguishes this lesion from low-grade appendiceal mucinous neoplasms (LAMN).
- Prognosis: Excellent prognosis; appendectomy is considered curative, and even involvement of the resection margin does not typically influence outcome.
- Differential: Distinguished from reactive hyperplasia by its neoplastic cytology and from serrated lesions by its lack of complex serration patterns.
Mucinous adenoma of the appendix. The neoplasm circumferentially involves the appendiceal mucosa.
Mucinous adenoma of the appendix. Tall villous projections are lined by neoplastic epithelium and contain lamina propria. The muscularis mucosae are intact. A few residual lymphoid aggregates are present.
Mucinous adenoma of the appendix. The neoplastic epithelial cells are uniform and contain abundant cytoplasmic mucin. The nuclei are polarized to the basement membrane and are pseudostratified with mild atypia.

Q: A dilated appendix showing a circumferential proliferation of low-grade mucinous epithelium with pushing, diverticulum-like growth into the wall and loss of the muscularis mucosae is diagnostic of [...].
Low-grade appendiceal mucinous neoplasm. A Low-grade appendiceal mucinous neoplasms show pushing, diverticulum-like growth in the wall with extension into the periappendiceal soft tissue. Fibromuscularization of the muscularis mucosae and submucosa obscure the separation between layers of the appendiceal wall.
Low-grade appendiceal mucinous neoplasm. B The lamina propria is diminished, and the muscularis mucosae are disrupted with areas of fibrosis. The epithelium is arranged in villous projections without true crypt formation.
A: low-grade appendiceal mucinous neoplasm (LAMN)
Back Extra: Appendiceal mucinous neoplasms
- Clinical: Often incidental findings or mimic acute appendicitis; peritoneal dissemination (pseudomyxoma peritonei) can cause progressive abdominal distension.
- Micro (LAMN): Characterized by circumferential replacement of epithelium by low-grade mucinous cells, pushing/diverticulum-like growth, and loss of the muscularis mucosae and lamina propria.
- Micro (HAMN): Requires unequivocal high-grade cytologic features (pleomorphism, loss of polarity, high mitotic activity) in ≥10% of the tumor, while maintaining an expansile growth pattern.
- Ancillary: Highly associated with KRAS (60-90%) and GNAS (50-60%) mutations; typically microsatellite stable (MSS) and BRAF wild-type.
- Prognosis: Stage-dependent; tumors confined to the appendix have an excellent prognosis, whereas peritoneal spread requires cytoreductive surgery and HIPEC.
Low-grade appendiceal mucinous neoplasm. A Low-grade appendiceal mucinous neoplasms show pushing, diverticulum-like growth in the wall with extension into the periappendiceal soft tissue. Fibromuscularization of the muscularis mucosae and submucosa obscure the separation between layers of the appendiceal wall.
Low-grade appendiceal mucinous neoplasm. B The lamina propria is diminished, and the muscularis mucosae are disrupted with areas of fibrosis. The epithelium is arranged in villous projections without true crypt formation.

Q: In the category of Appendiceal mucinous neoplasms, a diagnosis of HAMN requires high-grade cytological features to be present in at least [percentage]% of the tumor cells.
High-grade appendiceal mucinous neoplasm. B The neoplastic epithelium is arranged in slender papillary projections with focal cribriform growth.
High-grade appendiceal mucinous neoplasm. C Small tufts of necrotic tumour cells have sloughed into the lumen. The tumour cells are supported by scant lamina propria, are arranged in a single layer, lack polarity, and show increased mitotic activity.
A: 10
Back Extra: Appendiceal mucinous neoplasms
- Clinical: Often incidental findings or mimic acute appendicitis; peritoneal dissemination (pseudomyxoma peritonei) can cause progressive abdominal distension.
- Micro (LAMN): Characterized by circumferential replacement of epithelium by low-grade mucinous cells, pushing/diverticulum-like growth, and loss of the muscularis mucosae and lamina propria.
- Micro (HAMN): Requires unequivocal high-grade cytologic features (pleomorphism, loss of polarity, high mitotic activity) in ≥10% of the tumor, while maintaining an expansile growth pattern.
- Ancillary: Highly associated with KRAS (60-90%) and GNAS (50-60%) mutations; typically microsatellite stable (MSS) and BRAF wild-type.
- Prognosis: Stage-dependent; tumors confined to the appendix have an excellent prognosis, whereas peritoneal spread requires cytoreductive surgery and HIPEC.
High-grade appendiceal mucinous neoplasm. B The neoplastic epithelium is arranged in slender papillary projections with focal cribriform growth.
High-grade appendiceal mucinous neoplasm. C Small tufts of necrotic tumour cells have sloughed into the lumen. The tumour cells are supported by scant lamina propria, are arranged in a single layer, lack polarity, and show increased mitotic activity.

Q: The molecular profile of Appendiceal mucinous neoplasms frequently features co-occurring mutations in the [...] and [...] genes.
Low-grade appendiceal mucinous neoplasm. The typical appearance, with slender villi lined by tall mucinous epithelial cells with low-grade cytological atypia.
High-grade appendiceal mucinous neoplasm. A This example shows fibromuscularization of the submucosa that obscures the separation between layers of the appendiceal wall. The tumour circumferentially involves the appendiceal mucosa.
A: KRAS; GNAS
Back Extra: Appendiceal mucinous neoplasms
- Clinical: Often incidental findings or mimic acute appendicitis; peritoneal dissemination (pseudomyxoma peritonei) can cause progressive abdominal distension.
- Micro (LAMN): Characterized by circumferential replacement of epithelium by low-grade mucinous cells, pushing/diverticulum-like growth, and loss of the muscularis mucosae and lamina propria.
- Micro (HAMN): Requires unequivocal high-grade cytologic features (pleomorphism, loss of polarity, high mitotic activity) in ≥10% of the tumor, while maintaining an expansile growth pattern.
- Ancillary: Highly associated with KRAS (60-90%) and GNAS (50-60%) mutations; typically microsatellite stable (MSS) and BRAF wild-type.
- Prognosis: Stage-dependent; tumors confined to the appendix have an excellent prognosis, whereas peritoneal spread requires cytoreductive surgery and HIPEC.
Low-grade appendiceal mucinous neoplasm. The typical appearance, with slender villi lined by tall mucinous epithelial cells with low-grade cytological atypia.
High-grade appendiceal mucinous neoplasm. A This example shows fibromuscularization of the submucosa that obscures the separation between layers of the appendiceal wall. The tumour circumferentially involves the appendiceal mucosa.

Q: Unlike mucinous adenocarcinoma, Appendiceal mucinous neoplasms (both LAMN and HAMN) are defined by a lack of [type] invasion.
Low-grade appendiceal mucinous neoplasm. A Low-grade appendiceal mucinous neoplasms show pushing, diverticulum-like growth in the wall with extension into the periappendiceal soft tissue. Fibromuscularization of the muscularis mucosae and submucosa obscure the separation between layers of the appendiceal wall.
High-grade appendiceal mucinous neoplasm. A This example shows fibromuscularization of the submucosa that obscures the separation between layers of the appendiceal wall. The tumour circumferentially involves the appendiceal mucosa.
A: destructive/infiltrative
Back Extra: Appendiceal mucinous neoplasms
- Clinical: Often incidental findings or mimic acute appendicitis; peritoneal dissemination (pseudomyxoma peritonei) can cause progressive abdominal distension.
- Micro (LAMN): Characterized by circumferential replacement of epithelium by low-grade mucinous cells, pushing/diverticulum-like growth, and loss of the muscularis mucosae and lamina propria.
- Micro (HAMN): Requires unequivocal high-grade cytologic features (pleomorphism, loss of polarity, high mitotic activity) in ≥10% of the tumor, while maintaining an expansile growth pattern.
- Ancillary: Highly associated with KRAS (60-90%) and GNAS (50-60%) mutations; typically microsatellite stable (MSS) and BRAF wild-type.
- Prognosis: Stage-dependent; tumors confined to the appendix have an excellent prognosis, whereas peritoneal spread requires cytoreductive surgery and HIPEC.
Low-grade appendiceal mucinous neoplasm. A Low-grade appendiceal mucinous neoplasms show pushing, diverticulum-like growth in the wall with extension into the periappendiceal soft tissue. Fibromuscularization of the muscularis mucosae and submucosa obscure the separation between layers of the appendiceal wall.
High-grade appendiceal mucinous neoplasm. A This example shows fibromuscularization of the submucosa that obscures the separation between layers of the appendiceal wall. The tumour circumferentially involves the appendiceal mucosa.

Q: An incidental appendiceal specimen showing circumferential proliferation of serrated crypts with persistent basal dilatation and lateral budding is diagnostic of [...].
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Sessile serrated lesion of the appendix. The serrated crypts are lined by mature goblet cells and non-goblet columnar cells with small cytoplasmic vesicles of mucin. Mild cytological atypia is evident in the deep mucosa.
A: Appendiceal Sessile Serrated Lesion
Back Extra: Appendiceal Sessile Serrated Lesion
- Clinical: Appendiceal Sessile Serrated Lesions (SSLs) are typically incidental findings in older adults (60–80 years); their presence signals an increased risk for colorectal neoplasia.
- Microscopic Architecture: Characterized by circumferential mucosal involvement with crypts that are variably dilated at the base, often forming 'L' or 'T' shapes (lateral budding) with serration extending to the crypt base.
- Microscopic Cytology: Lined by goblet cells and non-goblet columnar cells with tiny mucin vesicles; unlike LAMN, these lesions typically retain normal lamina propria and an intact muscularis mucosae.
- Ancillary: Differing from colonic SSLs, appendiceal SSLs harbor a higher frequency of KRAS mutations and a lower frequency of BRAF mutations; mismatch repair deficiency is rare.
- Differential: Distinguished from hyperplastic polyps by circumferential involvement and basal crypt architectural distortion (dilatation and branching).
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Sessile serrated lesion of the appendix. The serrated crypts are lined by mature goblet cells and non-goblet columnar cells with small cytoplasmic vesicles of mucin. Mild cytological atypia is evident in the deep mucosa.

Q: Unlike sessile serrated lesions of the colon, Appendiceal Sessile Serrated Lesions demonstrate a higher frequency of [...] mutations and a lower frequency of [...] mutations.
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Sessile serrated lesion of the appendix. The serrated crypts are lined by mature goblet cells and non-goblet columnar cells with small cytoplasmic vesicles of mucin. Mild cytological atypia is evident in the deep mucosa.
A: KRAS; BRAF
Back Extra: Appendiceal Sessile Serrated Lesion
- Clinical: Appendiceal Sessile Serrated Lesions (SSLs) are typically incidental findings in older adults (60–80 years); their presence signals an increased risk for colorectal neoplasia.
- Microscopic Architecture: Characterized by circumferential mucosal involvement with crypts that are variably dilated at the base, often forming 'L' or 'T' shapes (lateral budding) with serration extending to the crypt base.
- Microscopic Cytology: Lined by goblet cells and non-goblet columnar cells with tiny mucin vesicles; unlike LAMN, these lesions typically retain normal lamina propria and an intact muscularis mucosae.
- Ancillary: Differing from colonic SSLs, appendiceal SSLs harbor a higher frequency of KRAS mutations and a lower frequency of BRAF mutations; mismatch repair deficiency is rare.
- Differential: Distinguished from hyperplastic polyps by circumferential involvement and basal crypt architectural distortion (dilatation and branching).
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Sessile serrated lesion of the appendix. The serrated crypts are lined by mature goblet cells and non-goblet columnar cells with small cytoplasmic vesicles of mucin. Mild cytological atypia is evident in the deep mucosa.

Q: A key feature to distinguish Appendiceal Sessile Serrated Lesion from Low-grade Appendiceal Mucinous Neoplasm (LAMN) is that SSLs typically maintain a(n) [...] and have preserved lamina propria.
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Serrated dysplasia of the appendix. Serrated dysplasia circumferentially involves the appendiceal mucosa. The neoplasm is associated with preserved lamina propria, muscularis mucosae, and submucosa.
A: intact muscularis mucosae
Back Extra: Appendiceal Sessile Serrated Lesion
- Clinical: Appendiceal Sessile Serrated Lesions (SSLs) are typically incidental findings in older adults (60–80 years); their presence signals an increased risk for colorectal neoplasia.
- Microscopic Architecture: Characterized by circumferential mucosal involvement with crypts that are variably dilated at the base, often forming 'L' or 'T' shapes (lateral budding) with serration extending to the crypt base.
- Microscopic Cytology: Lined by goblet cells and non-goblet columnar cells with tiny mucin vesicles; unlike LAMN, these lesions typically retain normal lamina propria and an intact muscularis mucosae.
- Ancillary: Differing from colonic SSLs, appendiceal SSLs harbor a higher frequency of KRAS mutations and a lower frequency of BRAF mutations; mismatch repair deficiency is rare.
- Differential: Distinguished from hyperplastic polyps by circumferential involvement and basal crypt architectural distortion (dilatation and branching).
Sessile serrated lesion of the appendix. The lesion is composed of a circumferential proliferation of architecturally abnormal serrated crypts supported by normal amounts of lamina propria. The crypts show persistent dilatation at the crypt bases with lateral buds and branching.
Serrated dysplasia of the appendix. Serrated dysplasia circumferentially involves the appendiceal mucosa. The neoplasm is associated with preserved lamina propria, muscularis mucosae, and submucosa.

Q: In the context of histological variants, [...] may show clear cell changes characterized by optically clear cytoplasm and distinct cell borders that mimic renal cell carcinoma.
Carcinoma of the gallbladder. Clear cell carcinoma change characterized by optically clear cytoplasm and distinct cell borders, mimicking renal cell carcinoma.
A: Carcinoma of the gallbladder
Back Extra: Carcinoma of the gallbladder
- Clinical: Often clinically inapparent and diagnosed incidentally after cholecystectomy (~50% of cases); risk factors include gallstones, pancreaticobiliary maljunction, and high incidence in Chile, India, and eastern Asia.
- Microscopic: The most common type is biliary-type adenocarcinoma showing tubular differentiation; variants include clear cell, mucinous, adenosquamous, and undifferentiated (sarcomatoid) types.
- Ancillary: TP53 alterations occur in >50% of cases; ERBB2 (HER2) amplification is found in approximately 16% and may have therapeutic implications.
- Prognosis: Stage is the most relevant factor; 5-year survival for T2 is 45%, but drops below 15% for T3 disease.
Carcinoma of the gallbladder. Clear cell carcinoma change characterized by optically clear cytoplasm and distinct cell borders, mimicking renal cell carcinoma.

Q: Approximately [...] of cases of Carcinoma of the gallbladder are diagnosed incidentally after cholecystectomy for gallstones because signs and symptoms are often non-specific.
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.
A: 50%
Back Extra: Carcinoma of the gallbladder
- Clinical: Often clinically inapparent and diagnosed incidentally after cholecystectomy (~50% of cases); risk factors include gallstones, pancreaticobiliary maljunction, and high incidence in Chile, India, and eastern Asia.
- Microscopic: The most common type is biliary-type adenocarcinoma showing tubular differentiation; variants include clear cell, mucinous, adenosquamous, and undifferentiated (sarcomatoid) types.
- Ancillary: TP53 alterations occur in >50% of cases; ERBB2 (HER2) amplification is found in approximately 16% and may have therapeutic implications.
- Prognosis: Stage is the most relevant factor; 5-year survival for T2 is 45%, but drops below 15% for T3 disease.
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.

Q: A potential molecular target for therapy in Carcinoma of the gallbladder is [...], which is amplified in approximately 16% of cases.
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.
A: ERBB2 (HER2)
Back Extra: Carcinoma of the gallbladder
- Clinical: Often clinically inapparent and diagnosed incidentally after cholecystectomy (~50% of cases); risk factors include gallstones, pancreaticobiliary maljunction, and high incidence in Chile, India, and eastern Asia.
- Microscopic: The most common type is biliary-type adenocarcinoma showing tubular differentiation; variants include clear cell, mucinous, adenosquamous, and undifferentiated (sarcomatoid) types.
- Ancillary: TP53 alterations occur in >50% of cases; ERBB2 (HER2) amplification is found in approximately 16% and may have therapeutic implications.
- Prognosis: Stage is the most relevant factor; 5-year survival for T2 is 45%, but drops below 15% for T3 disease.
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.

Q: Identify the malignancy in the gallbladder showing low-grade glands with a haphazard pattern of infiltration: [...].
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.
A: Carcinoma of the gallbladder (biliary-type adenocarcinoma)
Back Extra: Carcinoma of the gallbladder
- Clinical: Often clinically inapparent and diagnosed incidentally after cholecystectomy (~50% of cases); risk factors include gallstones, pancreaticobiliary maljunction, and high incidence in Chile, India, and eastern Asia.
- Microscopic: The most common type is biliary-type adenocarcinoma showing tubular differentiation; variants include clear cell, mucinous, adenosquamous, and undifferentiated (sarcomatoid) types.
- Ancillary: TP53 alterations occur in >50% of cases; ERBB2 (HER2) amplification is found in approximately 16% and may have therapeutic implications.
- Prognosis: Stage is the most relevant factor; 5-year survival for T2 is 45%, but drops below 15% for T3 disease.
Carcinoma of the gallbladder. The well-differentiated adenocarcinoma, biliary type, displays low-grade glands with haphazard pattern of infiltration.

Q: In Neuroendocrine neoplasms of the gallbladder, the subtype characterized by small cells with hyperchromatic nuclei, nuclear moulding, and scant cytoplasm is known as [...].
Small cell neuroendocrine carcinoma (SCNEC) presenting as a hypercellular mass lesion in the gallbladder.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.
A: small cell neuroendocrine carcinoma (SCNEC)
Back Extra: Neuroendocrine neoplasms of the gallbladder
- Clinical: Neuroendocrine carcinomas (NECs) are significantly more common in the gallbladder than neuroendocrine tumours (NETs), often presenting as advanced disease with symptoms like abdominal pain and weight loss.
- Microscopic (NEC): Small cell NECs feature nuclear moulding and scant cytoplasm, while Large cell NECs show organoid growth, large vesicular nuclei, and prominent nucleoli; both types exhibit brisk mitotic activity and geographical necrosis.
- Microscopic (MiNEN): These neoplasms contain both neuroendocrine and non-neuroendocrine (usually adenocarcinoma) components, each of which must comprise at least 30% of the tumor.
- Ancillary: NETs typically express synaptophysin and chromogranin A, whereas NECs may only show focal chromogranin A but frequently demonstrate loss of RB1 and aberrant p53 expression.
- Prognosis: Gallbladder NECs have a very poor prognosis with a median survival time of less than 1 year, frequently presenting with disseminated disease at the time of diagnosis.
Small cell neuroendocrine carcinoma (SCNEC) presenting as a hypercellular mass lesion in the gallbladder.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.

Q: To diagnose a Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) of the gallbladder, each morphologically distinguishable component must represent at least [...]% of the total neoplasm.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) showing high-grade biliary intraepithelial neoplasia, adenocarcinoma, and NEC components.
A: 30
Back Extra: Neuroendocrine neoplasms of the gallbladder
- Clinical: Neuroendocrine carcinomas (NECs) are significantly more common in the gallbladder than neuroendocrine tumours (NETs), often presenting as advanced disease with symptoms like abdominal pain and weight loss.
- Microscopic (NEC): Small cell NECs feature nuclear moulding and scant cytoplasm, while Large cell NECs show organoid growth, large vesicular nuclei, and prominent nucleoli; both types exhibit brisk mitotic activity and geographical necrosis.
- Microscopic (MiNEN): These neoplasms contain both neuroendocrine and non-neuroendocrine (usually adenocarcinoma) components, each of which must comprise at least 30% of the tumor.
- Ancillary: NETs typically express synaptophysin and chromogranin A, whereas NECs may only show focal chromogranin A but frequently demonstrate loss of RB1 and aberrant p53 expression.
- Prognosis: Gallbladder NECs have a very poor prognosis with a median survival time of less than 1 year, frequently presenting with disseminated disease at the time of diagnosis.
Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) showing high-grade biliary intraepithelial neoplasia, adenocarcinoma, and NEC components.

Q: Poorly differentiated Neuroendocrine neoplasms of the gallbladder (NECs) often share molecular pathways with adenocarcinoma, frequently exhibiting loss of [...] and abnormal expression of [...].
Large cell neuroendocrine carcinoma (LCNEC) of the gallbladder showing infiltration of nests and chords of poorly differentiated neuroendocrine cells.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.
A: RB1; p53
Back Extra: Neuroendocrine neoplasms of the gallbladder
- Clinical: Neuroendocrine carcinomas (NECs) are significantly more common in the gallbladder than neuroendocrine tumours (NETs), often presenting as advanced disease with symptoms like abdominal pain and weight loss.
- Microscopic (NEC): Small cell NECs feature nuclear moulding and scant cytoplasm, while Large cell NECs show organoid growth, large vesicular nuclei, and prominent nucleoli; both types exhibit brisk mitotic activity and geographical necrosis.
- Microscopic (MiNEN): These neoplasms contain both neuroendocrine and non-neuroendocrine (usually adenocarcinoma) components, each of which must comprise at least 30% of the tumor.
- Ancillary: NETs typically express synaptophysin and chromogranin A, whereas NECs may only show focal chromogranin A but frequently demonstrate loss of RB1 and aberrant p53 expression.
- Prognosis: Gallbladder NECs have a very poor prognosis with a median survival time of less than 1 year, frequently presenting with disseminated disease at the time of diagnosis.
Large cell neuroendocrine carcinoma (LCNEC) of the gallbladder showing infiltration of nests and chords of poorly differentiated neuroendocrine cells.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.

Q: While gallbladder NETs are often incidental, Neuroendocrine neoplasms of the gallbladder of the [...] type frequently present with advanced symptoms such as jaundice and ascites, and have a 5-year survival rate of approximately [...]%.
Large cell neuroendocrine carcinoma (LCNEC) of the gallbladder showing infiltration of nests and chords of poorly differentiated neuroendocrine cells.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.
A: NEC; 20
Back Extra: Neuroendocrine neoplasms of the gallbladder
- Clinical: Neuroendocrine carcinomas (NECs) are significantly more common in the gallbladder than neuroendocrine tumours (NETs), often presenting as advanced disease with symptoms like abdominal pain and weight loss.
- Microscopic (NEC): Small cell NECs feature nuclear moulding and scant cytoplasm, while Large cell NECs show organoid growth, large vesicular nuclei, and prominent nucleoli; both types exhibit brisk mitotic activity and geographical necrosis.
- Microscopic (MiNEN): These neoplasms contain both neuroendocrine and non-neuroendocrine (usually adenocarcinoma) components, each of which must comprise at least 30% of the tumor.
- Ancillary: NETs typically express synaptophysin and chromogranin A, whereas NECs may only show focal chromogranin A but frequently demonstrate loss of RB1 and aberrant p53 expression.
- Prognosis: Gallbladder NECs have a very poor prognosis with a median survival time of less than 1 year, frequently presenting with disseminated disease at the time of diagnosis.
Large cell neuroendocrine carcinoma (LCNEC) of the gallbladder showing infiltration of nests and chords of poorly differentiated neuroendocrine cells.
Small cell neuroendocrine carcinoma (SCNEC) composed of small cells with scant cytoplasm, nuclear moulding, and frequent apoptosis.

Q: A grossly visible tan-brown lesion protruding into an intrahepatic duct that microscopically shows complex papillae lined by cells with dense, eosinophilic cytoplasm is diagnostic of [...].
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The eosinophilic neoplastic cells have large, relatively uniform nuclei with a single prominent nucleolus. Intraepithelial luminal structures are frequently observed.
A: intraductal oncocytic papillary neoplasm of the bile ducts
Back Extra: Intraductal oncocytic papillary neoplasm of the bile ducts
- Definition: A non-invasive cystic precursor lesion characterized by exophytic papillary projections of cells with abundant eosinophilic, granular (oncocytic) cytoplasm.
- Microscopic: Features thick, arborizing papillae with high-grade dysplasia (Tis) and cells containing large, uniform nuclei with single prominent nucleoli.
- Ancillary: Shows diffuse expression of MUC5AC and MUC6; notably positive for HepPar1 and KIT (CD117).
- Molecular: Driven by translocations resulting in PRKACA or PRKACB gene fusions (e.g., DNAJB1::PRKACA), leading to mitochondrial hyperplasia.
- Prognosis: Progression to invasive carcinoma occurs in ~30–40% of cases, but survival is generally better than in invasive carcinomas arising from conventional IPNB.
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The eosinophilic neoplastic cells have large, relatively uniform nuclei with a single prominent nucleolus. Intraepithelial luminal structures are frequently observed.

Q: Unlike typical pancreaticobiliary IPNBs, intraductal oncocytic papillary neoplasm of the bile ducts exhibits diffuse immunohistochemical labelling for [...] and [...].
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The vast majority are positive for MUC6.
A: MUC6; HepPar1
Back Extra: Intraductal oncocytic papillary neoplasm of the bile ducts
- Definition: A non-invasive cystic precursor lesion characterized by exophytic papillary projections of cells with abundant eosinophilic, granular (oncocytic) cytoplasm.
- Microscopic: Features thick, arborizing papillae with high-grade dysplasia (Tis) and cells containing large, uniform nuclei with single prominent nucleoli.
- Ancillary: Shows diffuse expression of MUC5AC and MUC6; notably positive for HepPar1 and KIT (CD117).
- Molecular: Driven by translocations resulting in PRKACA or PRKACB gene fusions (e.g., DNAJB1::PRKACA), leading to mitochondrial hyperplasia.
- Prognosis: Progression to invasive carcinoma occurs in ~30–40% of cases, but survival is generally better than in invasive carcinomas arising from conventional IPNB.
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The vast majority are positive for MUC6.

Q: The mitochondrial hyperplasia seen in intraductal oncocytic papillary neoplasm of the bile ducts is caused by gene fusions involving the genes [PRKACA/PRKACB] or [PRKACA/PRKACB].
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The eosinophilic neoplastic cells have large, relatively uniform nuclei with a single prominent nucleolus. Intraepithelial luminal structures are frequently observed.
A: PRKACA; PRKACB
Back Extra: Intraductal oncocytic papillary neoplasm of the bile ducts
- Definition: A non-invasive cystic precursor lesion characterized by exophytic papillary projections of cells with abundant eosinophilic, granular (oncocytic) cytoplasm.
- Microscopic: Features thick, arborizing papillae with high-grade dysplasia (Tis) and cells containing large, uniform nuclei with single prominent nucleoli.
- Ancillary: Shows diffuse expression of MUC5AC and MUC6; notably positive for HepPar1 and KIT (CD117).
- Molecular: Driven by translocations resulting in PRKACA or PRKACB gene fusions (e.g., DNAJB1::PRKACA), leading to mitochondrial hyperplasia.
- Prognosis: Progression to invasive carcinoma occurs in ~30–40% of cases, but survival is generally better than in invasive carcinomas arising from conventional IPNB.
Biliary intraductal oncocytic papillary neoplasm. Complex, branching papillae supported by fibrovascular cores. The eosinophilic cytoplasm can be appreciated.
Biliary intraductal oncocytic papillary neoplasm. The eosinophilic neoplastic cells have large, relatively uniform nuclei with a single prominent nucleolus. Intraepithelial luminal structures are frequently observed.

Q: A solid-appearing nodular proliferation filling a dilated bile duct and composed of back-to-back small tubules without visible mucin production is the classic macroscopic and low-power appearance of [...].
Biliary intraductal tubulopapillary neoplasm. A Dilated duct filled with a solid-appearing nodular proliferation.
Biliary intraductal tubulopapillary neoplasm. B Back-to-back small tubular structures fill the lumen of a bile duct lined by pre-existent biliary epithelium.
Biliary intraductal tubulopapillary neoplasm. D Small, back-to-back tubules lined by cuboidal to columnar epithelial cells with large, round nuclei with prominent nucleoli. Mucin and papillae are not seen.
A: intraductal tubulopapillary neoplasm of the bile ducts
Back Extra: Intraductal tubulopapillary neoplasm of the bile ducts
- Clinical: Predominantly intrahepatic (70%) and perihilar (20%) neoplasm affecting women more frequently (2:1) with a median age of 63 years; typically presents as a solid, non-mucin-secreting mass within a dilated duct.
- Microscopic: Characterized by a solid-nodular growth of back-to-back tubular glands forming cribriform structures with minimal stroma, uniform high-grade dysplasia, and frequent (85%) comedo-like necrosis.
- Invasive Component: Associated invasive tubular adenocarcinoma is seen in 80% of cases, yet patients still exhibit better survival rates (75% at 5 years) than those with conventional cholangiocarcinoma.
- Immunohistochemistry: Typically positive for CK7, CK19, and MUC1 (80%), while characteristically negative for MUC2 and MUC5AC.
- Molecular: Genetically distinct from intraductal papillary neoplasm of the bile duct (IPNB) as it lacks hotspot mutations in KRAS, GNAS, and IDH1/2.
Biliary intraductal tubulopapillary neoplasm. A Dilated duct filled with a solid-appearing nodular proliferation.
Biliary intraductal tubulopapillary neoplasm. B Back-to-back small tubular structures fill the lumen of a bile duct lined by pre-existent biliary epithelium.
Biliary intraductal tubulopapillary neoplasm. D Small, back-to-back tubules lined by cuboidal to columnar epithelial cells with large, round nuclei with prominent nucleoli. Mucin and papillae are not seen.

Q: In contrast to IPNB, the [...] is characteristically negative for the mucin marker [...].
Biliary intraductal tubulopapillary neoplasm. B Back-to-back small tubular structures fill the lumen of a bile duct lined by pre-existent biliary epithelium.
Biliary intraductal tubulopapillary neoplasm. D Small, back-to-back tubules lined by cuboidal to columnar epithelial cells with large, round nuclei with prominent nucleoli. Mucin and papillae are not seen.
A: intraductal tubulopapillary neoplasm of the bile ducts; MUC5AC
Back Extra: Intraductal tubulopapillary neoplasm of the bile ducts
- Clinical: Predominantly intrahepatic (70%) and perihilar (20%) neoplasm affecting women more frequently (2:1) with a median age of 63 years; typically presents as a solid, non-mucin-secreting mass within a dilated duct.
- Microscopic: Characterized by a solid-nodular growth of back-to-back tubular glands forming cribriform structures with minimal stroma, uniform high-grade dysplasia, and frequent (85%) comedo-like necrosis.
- Invasive Component: Associated invasive tubular adenocarcinoma is seen in 80% of cases, yet patients still exhibit better survival rates (75% at 5 years) than those with conventional cholangiocarcinoma.
- Immunohistochemistry: Typically positive for CK7, CK19, and MUC1 (80%), while characteristically negative for MUC2 and MUC5AC.
- Molecular: Genetically distinct from intraductal papillary neoplasm of the bile duct (IPNB) as it lacks hotspot mutations in KRAS, GNAS, and IDH1/2.
Biliary intraductal tubulopapillary neoplasm. B Back-to-back small tubular structures fill the lumen of a bile duct lined by pre-existent biliary epithelium.
Biliary intraductal tubulopapillary neoplasm. D Small, back-to-back tubules lined by cuboidal to columnar epithelial cells with large, round nuclei with prominent nucleoli. Mucin and papillae are not seen.

Q: In approximately 85% of cases, [...] shows a distinctive [...] pattern of necrosis within the nodular proliferation.
Biliary intraductal tubulopapillary neoplasm. A Dilated duct filled with a solid-appearing nodular proliferation.
Biliary intraductal tubulopapillary neoplasm. C A comedo-like necrosis is seen in the centre of the nodular proliferation.
A: intraductal tubulopapillary neoplasm of the bile ducts; comedo-like
Back Extra: Intraductal tubulopapillary neoplasm of the bile ducts
- Clinical: Predominantly intrahepatic (70%) and perihilar (20%) neoplasm affecting women more frequently (2:1) with a median age of 63 years; typically presents as a solid, non-mucin-secreting mass within a dilated duct.
- Microscopic: Characterized by a solid-nodular growth of back-to-back tubular glands forming cribriform structures with minimal stroma, uniform high-grade dysplasia, and frequent (85%) comedo-like necrosis.
- Invasive Component: Associated invasive tubular adenocarcinoma is seen in 80% of cases, yet patients still exhibit better survival rates (75% at 5 years) than those with conventional cholangiocarcinoma.
- Immunohistochemistry: Typically positive for CK7, CK19, and MUC1 (80%), while characteristically negative for MUC2 and MUC5AC.
- Molecular: Genetically distinct from intraductal papillary neoplasm of the bile duct (IPNB) as it lacks hotspot mutations in KRAS, GNAS, and IDH1/2.
Biliary intraductal tubulopapillary neoplasm. A Dilated duct filled with a solid-appearing nodular proliferation.
Biliary intraductal tubulopapillary neoplasm. C A comedo-like necrosis is seen in the centre of the nodular proliferation.

Q: A microscopic, non-invasive epithelial lesion in the gallbladder showing complete loss of nuclear polarity and budding of cell clusters is diagnostic of [...].
High-grade biliary intraepithelial neoplasia. There is complete loss of nuclear polarity and budding of cell clusters into the lumen. The nuclei are markedly pleomorphic.
Progression of biliary intraepithelial neoplasia. High-grade BilIN.
A: high-grade biliary intraepithelial neoplasia (BilIN)
Back Extra: Biliary intraepithelial neoplasia
- Clinical: Microscopic, non-invasive precursor lesion often found incidentally in gallbladders resected for cholecystolithiasis or in mucosa adjacent to invasive carcinoma.
- Microscopic: Classified into a two-tiered system; low-grade shows maintained polarity and mild atypia, while high-grade (Tis) shows complete loss of polarity and complex architecture (micropapillae).
- Pitfalls: High-grade lesions can involve Rokitansky–Aschoff sinuses, which may mimic invasive adenocarcinoma, necessitating thorough sampling.
- Ancillary: p53 overexpression is a helpful feature to distinguish neoplastic dysplasia from reactive/inflammatory epithelial atypia.
High-grade biliary intraepithelial neoplasia. There is complete loss of nuclear polarity and budding of cell clusters into the lumen. The nuclei are markedly pleomorphic.
Progression of biliary intraepithelial neoplasia. High-grade BilIN.

Q: A pediatric patient presents with a solitary rectosigmoid lesion showing cystically dilated glands and an expanded inflammatory stroma; this is the classic appearance of a [...].
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.
A: Juvenile polyp
Back Extra: Juvenile polyp
- Clinical: Most common in children <10 years as solitary rectosigmoid lesions; typically presents with painless rectal bleeding, rectal prolapse, or autoamputation.
- Microscopic: Characterized by cystically dilated glands filled with inspissated mucin, embedded in an expanded, edematous lamina propria rich in inflammatory cells.
- Syndromic Association: Juvenile Polyposis Syndrome (JPS) involves multiple polyps and is associated with germline mutations in SMAD4, BMPR1A, or PTEN.
- Differential: Morphologically similar to inflammatory or retention polyps; however, inflammatory polyps in IBD usually lack the prominent cystic dilatation of a Juvenile polyp.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.

Q: In the context of Juvenile Polyposis Syndrome, germline mutations are most commonly found in the [...] or [...] genes.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.
A: SMAD4; BMPR1A
Back Extra: Juvenile polyp
- Clinical: Most common in children <10 years as solitary rectosigmoid lesions; typically presents with painless rectal bleeding, rectal prolapse, or autoamputation.
- Microscopic: Characterized by cystically dilated glands filled with inspissated mucin, embedded in an expanded, edematous lamina propria rich in inflammatory cells.
- Syndromic Association: Juvenile Polyposis Syndrome (JPS) involves multiple polyps and is associated with germline mutations in SMAD4, BMPR1A, or PTEN.
- Differential: Morphologically similar to inflammatory or retention polyps; however, inflammatory polyps in IBD usually lack the prominent cystic dilatation of a Juvenile polyp.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.

Q: While sporadic [...] carry no increased cancer risk, syndromic cases require monitoring as they can develop [...] and subsequent malignancy.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.
A: Juvenile polyps; dysplasia
Back Extra: Juvenile polyp
- Clinical: Most common in children <10 years as solitary rectosigmoid lesions; typically presents with painless rectal bleeding, rectal prolapse, or autoamputation.
- Microscopic: Characterized by cystically dilated glands filled with inspissated mucin, embedded in an expanded, edematous lamina propria rich in inflammatory cells.
- Syndromic Association: Juvenile Polyposis Syndrome (JPS) involves multiple polyps and is associated with germline mutations in SMAD4, BMPR1A, or PTEN.
- Differential: Morphologically similar to inflammatory or retention polyps; however, inflammatory polyps in IBD usually lack the prominent cystic dilatation of a Juvenile polyp.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.

Q: A clinical phenomenon where a [...] detaches and is passed spontaneously through the rectum is known as [...].
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.
A: Juvenile polyp; autoamputation
Back Extra: Juvenile polyp
- Clinical: Most common in children <10 years as solitary rectosigmoid lesions; typically presents with painless rectal bleeding, rectal prolapse, or autoamputation.
- Microscopic: Characterized by cystically dilated glands filled with inspissated mucin, embedded in an expanded, edematous lamina propria rich in inflammatory cells.
- Syndromic Association: Juvenile Polyposis Syndrome (JPS) involves multiple polyps and is associated with germline mutations in SMAD4, BMPR1A, or PTEN.
- Differential: Morphologically similar to inflammatory or retention polyps; however, inflammatory polyps in IBD usually lack the prominent cystic dilatation of a Juvenile polyp.
Juvenile polyp. In this large, multilobulated syndromic juvenile polyp, the surface shows erosion and granulation tissue. The epithelial compartment shows marked disarray and cystic change. The lamina propria also harbours a prominent smooth muscle component that is broad and haphazard, unlike a typical Peutz–Jeghers polyp.
Juvenile polyp. Small juvenile polyps, even when syndromic, are morphologically indistinguishable from a sporadic one. The polyp here shows an expanded lamina propria with inflammation and slight crypt disarray. The patient had a known germline SMAD4 mutation.

Q: The presence of [...] in colonic polyps, as shown in the provided image, serves as a major diagnostic clue for [...].
Colonic ganglioneuroma in PTEN hamartoma tumour syndrome (PHTS). The presence of ganglioneuromatous components is a specific diagnostic clue for this syndrome.
A: ganglioneuromas; PTEN hamartoma tumour syndrome (PHTS)
Back Extra: PTEN hamartoma tumour syndrome (PHTS)
- Clinical: Autosomal dominant disorder (PTEN germline variant) characterized by macrocephaly, mucocutaneous lesions (trichilemmomas, acral keratoses), and a high risk of breast, endometrial, and thyroid cancers.
- Microscopic: GI polyps are diverse, most commonly hamartomatous with mixed features including juvenile-type components, ganglioneuromas, lymphoid aggregates, and lipomas.
- Diagnostic Clues: The presence of ganglioneuromas or diffuse esophageal glycogenic acanthosis in the setting of polyposis is highly suggestive of PHTS.
- Ancillary: Germline pathogenic variants in PTEN (10q23.3) are found in ~85% of cases; PTEN functions as a lipid phosphatase that antagonizes the PI3K/AKT/mTOR pathway.
- Prognosis: Requires intensive surveillance due to significantly elevated cancer risks; breast and endometrial cancer are the leading concerns in female patients.
Colonic ganglioneuroma in PTEN hamartoma tumour syndrome (PHTS). The presence of ganglioneuromatous components is a specific diagnostic clue for this syndrome.

Q: Beyond the gastrointestinal tract, patients with [...] have a markedly increased risk for [...], breast, and endometrial cancers.
Hamartomatous gastric polyp in a patient with PHTS. These polyps often exhibit juvenile characteristics, including expanded stromal components and irregular, hyperplastic glands.
Hamartomatous duodenal polyp. Fully developed polyps associated with PHTS are often histologically similar to juvenile polyps.
A: PTEN hamartoma tumour syndrome (PHTS); thyroid
Back Extra: PTEN hamartoma tumour syndrome (PHTS)
- Clinical: Autosomal dominant disorder (PTEN germline variant) characterized by macrocephaly, mucocutaneous lesions (trichilemmomas, acral keratoses), and a high risk of breast, endometrial, and thyroid cancers.
- Microscopic: GI polyps are diverse, most commonly hamartomatous with mixed features including juvenile-type components, ganglioneuromas, lymphoid aggregates, and lipomas.
- Diagnostic Clues: The presence of ganglioneuromas or diffuse esophageal glycogenic acanthosis in the setting of polyposis is highly suggestive of PHTS.
- Ancillary: Germline pathogenic variants in PTEN (10q23.3) are found in ~85% of cases; PTEN functions as a lipid phosphatase that antagonizes the PI3K/AKT/mTOR pathway.
- Prognosis: Requires intensive surveillance due to significantly elevated cancer risks; breast and endometrial cancer are the leading concerns in female patients.
Hamartomatous gastric polyp in a patient with PHTS. These polyps often exhibit juvenile characteristics, including expanded stromal components and irregular, hyperplastic glands.
Hamartomatous duodenal polyp. Fully developed polyps associated with PHTS are often histologically similar to juvenile polyps.

Q: In [...], the loss of PTEN lipid phosphatase activity leads to the hyperactivation of the [...] signaling pathway.
Hamartomatous colon polyp showing expanded stroma and cystic glandular components typical of PHTS-associated lesions.
A: PTEN hamartoma tumour syndrome (PHTS); PI3K/AKT/mTOR
Back Extra: PTEN hamartoma tumour syndrome (PHTS)
- Clinical: Autosomal dominant disorder (PTEN germline variant) characterized by macrocephaly, mucocutaneous lesions (trichilemmomas, acral keratoses), and a high risk of breast, endometrial, and thyroid cancers.
- Microscopic: GI polyps are diverse, most commonly hamartomatous with mixed features including juvenile-type components, ganglioneuromas, lymphoid aggregates, and lipomas.
- Diagnostic Clues: The presence of ganglioneuromas or diffuse esophageal glycogenic acanthosis in the setting of polyposis is highly suggestive of PHTS.
- Ancillary: Germline pathogenic variants in PTEN (10q23.3) are found in ~85% of cases; PTEN functions as a lipid phosphatase that antagonizes the PI3K/AKT/mTOR pathway.
- Prognosis: Requires intensive surveillance due to significantly elevated cancer risks; breast and endometrial cancer are the leading concerns in female patients.
Hamartomatous colon polyp showing expanded stroma and cystic glandular components typical of PHTS-associated lesions.

Q: In the esophagus, the presence of a prominent granular layer and compact hyperorthokeratosis as seen in this image is diagnostic of [...].
Epidermoid metaplasia. Characteristic granular layer with overlying hyper-orthokeratosis
Esophageal Epidermoid Metaplasia. Lesions are composed of a prominent granular layer and an overlying, compact hyperorthokeratotic layer.
Epidermoid metaplasia. Distinctive granular cell layer with overlying hyperorthokeratosis.
A: epidermoid metaplasia
Back Extra: Epidermoid metaplasia
- Clinical: Rare finding (0.18% of specimens) most common in the 7th decade; often associated with tobacco, alcohol, or chronic GERD and can present with dysphagia or as an incidental finding.
- Microscopic: Characterized by sharply demarcated undulating mucosa with flattened rete pegs, a prominent granular cell layer (hypergranulosis), and compact superficial hyperorthokeratosis.
- Risk Factors: Considered a premalignant precursor with a significant (3.5–17%) prevalence of associated squamous dysplasia or squamous cell carcinoma.
- Ancillary: TP53 mutations have been identified in cases of epidermoid metaplasia and its associated neoplastic progression.
Epidermoid metaplasia. Characteristic granular layer with overlying hyper-orthokeratosis
Esophageal Epidermoid Metaplasia. Lesions are composed of a prominent granular layer and an overlying, compact hyperorthokeratotic layer.
Epidermoid metaplasia. Distinctive granular cell layer with overlying hyperorthokeratosis.

Q: Epidemiological evidence suggests that [...] serves as a precursor lesion for esophageal [...].
Oesophageal squamous cell carcinoma arising in association with epidermoid metaplasia. B Histologically, oesophageal squamous cell carcinoma arising in association with epidermoid metaplasia is often well to moderately differentiated and keratinizing.
Epidermoid metaplasia with associated low-grade squamous dysplasia. A Cytological abnormalities in the lower half of the epithelium with overlying epidermoid metaplasia.
A: epidermoid metaplasia; squamous cell carcinoma
Back Extra: Epidermoid metaplasia
- Clinical: Rare finding (0.18% of specimens) most common in the 7th decade; often associated with tobacco, alcohol, or chronic GERD and can present with dysphagia or as an incidental finding.
- Microscopic: Characterized by sharply demarcated undulating mucosa with flattened rete pegs, a prominent granular cell layer (hypergranulosis), and compact superficial hyperorthokeratosis.
- Risk Factors: Considered a premalignant precursor with a significant (3.5–17%) prevalence of associated squamous dysplasia or squamous cell carcinoma.
- Ancillary: TP53 mutations have been identified in cases of epidermoid metaplasia and its associated neoplastic progression.
Oesophageal squamous cell carcinoma arising in association with epidermoid metaplasia. B Histologically, oesophageal squamous cell carcinoma arising in association with epidermoid metaplasia is often well to moderately differentiated and keratinizing.
Epidermoid metaplasia with associated low-grade squamous dysplasia. A Cytological abnormalities in the lower half of the epithelium with overlying epidermoid metaplasia.

Q: Mutations in the [...] gene have been identified in both [...] and its synchronous squamous neoplasia.
Epidermoid metaplasia with associated low-grade squamous dysplasia. A Cytological abnormalities in the lower half of the epithelium with overlying epidermoid metaplasia.
Epidermoid metaplasia with associated low-grade squamous dysplasia. B Note p53 expansion/overexpression in the area of low-grade dysplasia.
A: TP53; epidermoid metaplasia
Back Extra: Epidermoid metaplasia
- Clinical: Rare finding (0.18% of specimens) most common in the 7th decade; often associated with tobacco, alcohol, or chronic GERD and can present with dysphagia or as an incidental finding.
- Microscopic: Characterized by sharply demarcated undulating mucosa with flattened rete pegs, a prominent granular cell layer (hypergranulosis), and compact superficial hyperorthokeratosis.
- Risk Factors: Considered a premalignant precursor with a significant (3.5–17%) prevalence of associated squamous dysplasia or squamous cell carcinoma.
- Ancillary: TP53 mutations have been identified in cases of epidermoid metaplasia and its associated neoplastic progression.
Epidermoid metaplasia with associated low-grade squamous dysplasia. A Cytological abnormalities in the lower half of the epithelium with overlying epidermoid metaplasia.
Epidermoid metaplasia with associated low-grade squamous dysplasia. B Note p53 expansion/overexpression in the area of low-grade dysplasia.

Q: In Adenocarcinoma of the oesophagus and oesophagogastric junction, a tumor showing sheets of cells and less than 50% gland formation is graded as [...].
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.
Poorly differentiated adenocarcinoma with sheets of tumour cells showing marked nuclear atypia and scattered foci of abortive gland formation.
A: poorly differentiated (high grade)
Back Extra: Adenocarcinoma of the oesophagus and oesophagogastric junction
- Clinical: Predominantly affects men (6:1 ratio) in the seventh decade; strongly associated with gastro-oesophageal reflux disease (GERD), obesity, Barrett oesophagus, and smoking.
- Microscopic: Histological patterns include tubular, papillary, mucinous, or poorly cohesive (including signet-ring) types. Grading is two-tiered: well/moderately differentiated (≥50% glands) and poorly differentiated (<50% glands).
- Ancillary: Classically CK7+, CK19+, and CDX2+ positive, while typically negative for CK20 and squamous markers like p40 or CK5/6.
- Biomarkers: Routine testing for HER2 (ERBB2), MSI/MMR status, and PD-L1 (CPS) is essential for guiding targeted and immunotherapy.
- Prognosis: Stage pT1a (intramucosal) is frequently managed by endoscopic resection, whereas pT1b (submucosal) carries a higher risk of nodal metastasis requiring surgical intervention.
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.
Poorly differentiated adenocarcinoma with sheets of tumour cells showing marked nuclear atypia and scattered foci of abortive gland formation.

Q: Molecular progression to Adenocarcinoma of the oesophagus and oesophagogastric junction from Barrett oesophagus is most critically driven by mutations in the [...] gene.
Molecular underpinnings of the development of oesophageal adenocarcinoma. Progression to adenocarcinoma from non-dysplastic Barrett oesophagus is driven by a synergistic cascade of TP53 mutations, epigenetic modifications, and increasing chromosomal structural alterations.
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.
A: TP53
Back Extra: Adenocarcinoma of the oesophagus and oesophagogastric junction
- Clinical: Predominantly affects men (6:1 ratio) in the seventh decade; strongly associated with gastro-oesophageal reflux disease (GERD), obesity, Barrett oesophagus, and smoking.
- Microscopic: Histological patterns include tubular, papillary, mucinous, or poorly cohesive (including signet-ring) types. Grading is two-tiered: well/moderately differentiated (≥50% glands) and poorly differentiated (<50% glands).
- Ancillary: Classically CK7+, CK19+, and CDX2+ positive, while typically negative for CK20 and squamous markers like p40 or CK5/6.
- Biomarkers: Routine testing for HER2 (ERBB2), MSI/MMR status, and PD-L1 (CPS) is essential for guiding targeted and immunotherapy.
- Prognosis: Stage pT1a (intramucosal) is frequently managed by endoscopic resection, whereas pT1b (submucosal) carries a higher risk of nodal metastasis requiring surgical intervention.
Molecular underpinnings of the development of oesophageal adenocarcinoma. Progression to adenocarcinoma from non-dysplastic Barrett oesophagus is driven by a synergistic cascade of TP53 mutations, epigenetic modifications, and increasing chromosomal structural alterations.
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.

Q: Testing for [...] is standard for Adenocarcinoma of the oesophagus and oesophagogastric junction, where an IHC score of 3+ or a 2+ score with ISH amplification predicts response to targeted therapy.
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.
Silver-enhanced in situ hybridization (SISH) confirms ERBB2 (HER2) amplification (black dots) in an oesophageal adenocarcinoma.
A: HER2 (ERBB2)
Back Extra: Adenocarcinoma of the oesophagus and oesophagogastric junction
- Clinical: Predominantly affects men (6:1 ratio) in the seventh decade; strongly associated with gastro-oesophageal reflux disease (GERD), obesity, Barrett oesophagus, and smoking.
- Microscopic: Histological patterns include tubular, papillary, mucinous, or poorly cohesive (including signet-ring) types. Grading is two-tiered: well/moderately differentiated (≥50% glands) and poorly differentiated (<50% glands).
- Ancillary: Classically CK7+, CK19+, and CDX2+ positive, while typically negative for CK20 and squamous markers like p40 or CK5/6.
- Biomarkers: Routine testing for HER2 (ERBB2), MSI/MMR status, and PD-L1 (CPS) is essential for guiding targeted and immunotherapy.
- Prognosis: Stage pT1a (intramucosal) is frequently managed by endoscopic resection, whereas pT1b (submucosal) carries a higher risk of nodal metastasis requiring surgical intervention.
Well-differentiated adenocarcinoma. Note the irregular haphazard infiltrative glandular architecture diagnostic of adenocarcinoma infiltrating through the muscularis mucosae.
Silver-enhanced in situ hybridization (SISH) confirms ERBB2 (HER2) amplification (black dots) in an oesophageal adenocarcinoma.

Q: Rare cases of Adenocarcinoma of the oesophagus and oesophagogastric junction showing fetal-gut-like morphology and positivity for SALL4 and AFP are known as tumors with [...].
Adenocarcinoma with enteroblastic differentiation (SALL4/AFP positive) showing tubulopapillary architecture and clear cytoplasmic vacuoles mimicking fetal gut.
A: enteroblastic differentiation
Back Extra: Adenocarcinoma of the oesophagus and oesophagogastric junction
- Clinical: Predominantly affects men (6:1 ratio) in the seventh decade; strongly associated with gastro-oesophageal reflux disease (GERD), obesity, Barrett oesophagus, and smoking.
- Microscopic: Histological patterns include tubular, papillary, mucinous, or poorly cohesive (including signet-ring) types. Grading is two-tiered: well/moderately differentiated (≥50% glands) and poorly differentiated (<50% glands).
- Ancillary: Classically CK7+, CK19+, and CDX2+ positive, while typically negative for CK20 and squamous markers like p40 or CK5/6.
- Biomarkers: Routine testing for HER2 (ERBB2), MSI/MMR status, and PD-L1 (CPS) is essential for guiding targeted and immunotherapy.
- Prognosis: Stage pT1a (intramucosal) is frequently managed by endoscopic resection, whereas pT1b (submucosal) carries a higher risk of nodal metastasis requiring surgical intervention.
Adenocarcinoma with enteroblastic differentiation (SALL4/AFP positive) showing tubulopapillary architecture and clear cytoplasmic vacuoles mimicking fetal gut.

Q: An esophageal biopsy reveals a poorly circumscribed nest of large cells with abundant eosinophilic granular cytoplasm and overlying squamous hyperplasia; the most likely diagnosis is [...].
Granular cell tumour involving the lamina propria and extending into the muscularis mucosae.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
Granular cell tumour resulting in marked reactive squamous mucosal changes (pseudoepitheliomatous hyperplasia).
A: Granular cell tumour
Back Extra: Granular cell tumour
- Clinical: Benign neoplasm of Schwannian derivation; the esophagus is the most common gastrointestinal site (predominantly the distal third).
- Microscopic: Characterized by nests or sheets of large epithelioid cells with abundant, eosinophilic, lysosome-rich granular cytoplasm and small, hyperchromatic nuclei.
- Architecture: Typically located in the lamina propria or submucosa; esophageal cases frequently induce striking pseudoepitheliomatous hyperplasia in the overlying squamous epithelium.
- Ancillary: Consistently positive for S100, SOX10, and lysosomal markers such as CD68 and CD63 (NKI/C3).
- Molecular: Most cases (72%) harbor inactivating somatic mutations in endosomal pH regulators ATP6AP1 and ATP6AP2.
Granular cell tumour involving the lamina propria and extending into the muscularis mucosae.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
Granular cell tumour resulting in marked reactive squamous mucosal changes (pseudoepitheliomatous hyperplasia).

Q: The reactive squamous change often seen overlying an esophageal [...] is called [...], which can occasionally be mistaken for squamous cell carcinoma.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
Granular cell tumour resulting in marked reactive squamous mucosal changes (pseudoepitheliomatous hyperplasia).
A: Granular cell tumour; pseudoepitheliomatous hyperplasia
Back Extra: Granular cell tumour
- Clinical: Benign neoplasm of Schwannian derivation; the esophagus is the most common gastrointestinal site (predominantly the distal third).
- Microscopic: Characterized by nests or sheets of large epithelioid cells with abundant, eosinophilic, lysosome-rich granular cytoplasm and small, hyperchromatic nuclei.
- Architecture: Typically located in the lamina propria or submucosa; esophageal cases frequently induce striking pseudoepitheliomatous hyperplasia in the overlying squamous epithelium.
- Ancillary: Consistently positive for S100, SOX10, and lysosomal markers such as CD68 and CD63 (NKI/C3).
- Molecular: Most cases (72%) harbor inactivating somatic mutations in endosomal pH regulators ATP6AP1 and ATP6AP2.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
Granular cell tumour resulting in marked reactive squamous mucosal changes (pseudoepitheliomatous hyperplasia).

Q: Granular cell tumours characteristically show strong, diffuse expression of [...] and [...] due to their neuroectodermal/Schwannian differentiation.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
S100 protein stain is strongly and diffusely reactive in granular cell tumours.
A: S100; SOX10
Back Extra: Granular cell tumour
- Clinical: Benign neoplasm of Schwannian derivation; the esophagus is the most common gastrointestinal site (predominantly the distal third).
- Microscopic: Characterized by nests or sheets of large epithelioid cells with abundant, eosinophilic, lysosome-rich granular cytoplasm and small, hyperchromatic nuclei.
- Architecture: Typically located in the lamina propria or submucosa; esophageal cases frequently induce striking pseudoepitheliomatous hyperplasia in the overlying squamous epithelium.
- Ancillary: Consistently positive for S100, SOX10, and lysosomal markers such as CD68 and CD63 (NKI/C3).
- Molecular: Most cases (72%) harbor inactivating somatic mutations in endosomal pH regulators ATP6AP1 and ATP6AP2.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
S100 protein stain is strongly and diffusely reactive in granular cell tumours.

Q: Molecular studies of [...] have identified mutations in the endosomal pH regulators [...] as likely oncogenic drivers.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.
A: Granular cell tumour; ATP6AP1 or ATP6AP2
Back Extra: Granular cell tumour
- Clinical: Benign neoplasm of Schwannian derivation; the esophagus is the most common gastrointestinal site (predominantly the distal third).
- Microscopic: Characterized by nests or sheets of large epithelioid cells with abundant, eosinophilic, lysosome-rich granular cytoplasm and small, hyperchromatic nuclei.
- Architecture: Typically located in the lamina propria or submucosa; esophageal cases frequently induce striking pseudoepitheliomatous hyperplasia in the overlying squamous epithelium.
- Ancillary: Consistently positive for S100, SOX10, and lysosomal markers such as CD68 and CD63 (NKI/C3).
- Molecular: Most cases (72%) harbor inactivating somatic mutations in endosomal pH regulators ATP6AP1 and ATP6AP2.
High magnification showing polygonal cells with hyperchromatic nuclei and abundant granular eosinophilic cytoplasm.

Q: An esophageal mass biopsy showing poorly defined nests of small cells with hyperchromatic nuclei and scant cytoplasm (as seen in the provided image) is diagnostic of [...].
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
A: Small cell neuroendocrine carcinoma
Back Extra: Small cell neuroendocrine carcinoma
- Clinical: Aggressive malignancy presenting in the 6th-7th decades with dysphagia and weight loss; often metastatic at diagnosis with a median survival of only 8-15 months.
- Microscopic: Characterized by small to medium cells with high N:C ratios, scant cytoplasm, finely dispersed chromatin (without prominent nucleoli), and frequent necrosis/brisk mitoses.
- Ancillary: Consistently positive for synaptophysin and INSM1 (highly sensitive); TTF1 is positive in ~70% of cases and does not imply a lung primary.
- Molecular: High frequency of inactivating mutations in TP53 and RB1, similar to small cell carcinomas in other organ systems.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).

Q: In the context of [...] of the esophagus, a Ki-67 labeling index greater than [...]% is associated with a significantly worse prognosis (median survival of 5.3 months).
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
A: Small cell neuroendocrine carcinoma; 55
Back Extra: Small cell neuroendocrine carcinoma
- Clinical: Aggressive malignancy presenting in the 6th-7th decades with dysphagia and weight loss; often metastatic at diagnosis with a median survival of only 8-15 months.
- Microscopic: Characterized by small to medium cells with high N:C ratios, scant cytoplasm, finely dispersed chromatin (without prominent nucleoli), and frequent necrosis/brisk mitoses.
- Ancillary: Consistently positive for synaptophysin and INSM1 (highly sensitive); TTF1 is positive in ~70% of cases and does not imply a lung primary.
- Molecular: High frequency of inactivating mutations in TP53 and RB1, similar to small cell carcinomas in other organ systems.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).

Q: While [Marker] is positive in 70% of cases, it cannot be used to differentiate [...] of the esophagus from a metastasis originating in the lung.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
A: TTF1; Small cell neuroendocrine carcinoma
Back Extra: Small cell neuroendocrine carcinoma
- Clinical: Aggressive malignancy presenting in the 6th-7th decades with dysphagia and weight loss; often metastatic at diagnosis with a median survival of only 8-15 months.
- Microscopic: Characterized by small to medium cells with high N:C ratios, scant cytoplasm, finely dispersed chromatin (without prominent nucleoli), and frequent necrosis/brisk mitoses.
- Ancillary: Consistently positive for synaptophysin and INSM1 (highly sensitive); TTF1 is positive in ~70% of cases and does not imply a lung primary.
- Molecular: High frequency of inactivating mutations in TP53 and RB1, similar to small cell carcinomas in other organ systems.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).

Q: The differential diagnosis for [...] includes basaloid squamous cell carcinoma, which can be distinguished by its expression of [...] and lack of neuroendocrine markers.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
Neuroendocrine carcinoma typically shows strong and diffuse positivity for synaptophysin.
A: Small cell neuroendocrine carcinoma; p40 or CK5/6
Back Extra: Small cell neuroendocrine carcinoma
- Clinical: Aggressive malignancy presenting in the 6th-7th decades with dysphagia and weight loss; often metastatic at diagnosis with a median survival of only 8-15 months.
- Microscopic: Characterized by small to medium cells with high N:C ratios, scant cytoplasm, finely dispersed chromatin (without prominent nucleoli), and frequent necrosis/brisk mitoses.
- Ancillary: Consistently positive for synaptophysin and INSM1 (highly sensitive); TTF1 is positive in ~70% of cases and does not imply a lung primary.
- Molecular: High frequency of inactivating mutations in TP53 and RB1, similar to small cell carcinomas in other organ systems.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
Neuroendocrine carcinoma typically shows strong and diffuse positivity for synaptophysin.

Q: Like its pulmonary counterpart, esophageal [...] consistently shows high rates of inactivating mutations in [...].
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).
A: Small cell neuroendocrine carcinoma; TP53 and RB1
Back Extra: Small cell neuroendocrine carcinoma
- Clinical: Aggressive malignancy presenting in the 6th-7th decades with dysphagia and weight loss; often metastatic at diagnosis with a median survival of only 8-15 months.
- Microscopic: Characterized by small to medium cells with high N:C ratios, scant cytoplasm, finely dispersed chromatin (without prominent nucleoli), and frequent necrosis/brisk mitoses.
- Ancillary: Consistently positive for synaptophysin and INSM1 (highly sensitive); TTF1 is positive in ~70% of cases and does not imply a lung primary.
- Molecular: High frequency of inactivating mutations in TP53 and RB1, similar to small cell carcinomas in other organ systems.
Oesophageal MiNEN: Small cell neuroendocrine carcinoma (SCNEC) appearing as poorly defined nests of malignant cells with scant cytoplasm and hyperchromatic nuclei (bottom) associated with areas of adenocarcinoma (top).

Q: The diagnosis of [...] is characterized histologically by a biphasic cell population and the presence of punched-out spaces containing [...] material.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Adenoid cystic carcinoma of the oesophagus. A The neoplasm is composed of cells with monotonous nuclei, and abundant basement membrane material is present.
A: Esophageal adenoid cystic carcinoma; hyaline/basement membrane
Back Extra: Esophageal adenoid cystic carcinoma
- Clinical: Extremely rare esophageal malignancy (< 1%) typically arising in the mid-esophagus from submucosal glands; most common in men around age 60.
- Microscopic: Characterized by a biphasic population of epithelial and myoepithelial cells forming cribriform, tubular, or solid patterns with punched-out spaces containing Alcian blue-positive glycosaminoglycans or PASD-positive basement membrane material.
- Ancillary Studies: Myoepithelial cells express p63, p40, S100, and SMA, while luminal epithelial cells express CK and KIT (CD117); the tumor is often driven by MYB gene rearrangements.
- Differential Diagnosis: Must be distinguished from basaloid squamous cell carcinoma, which lacks the dual neoplastic cell population (epithelial and myoepithelial) seen in adenoid cystic carcinoma.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Adenoid cystic carcinoma of the oesophagus. A The neoplasm is composed of cells with monotonous nuclei, and abundant basement membrane material is present.

Q: In the molecular diagnosis of [...], the detection of [...] gene rearrangements or fusions is a highly characteristic finding.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
A: Esophageal adenoid cystic carcinoma; MYB
Back Extra: Esophageal adenoid cystic carcinoma
- Clinical: Extremely rare esophageal malignancy (< 1%) typically arising in the mid-esophagus from submucosal glands; most common in men around age 60.
- Microscopic: Characterized by a biphasic population of epithelial and myoepithelial cells forming cribriform, tubular, or solid patterns with punched-out spaces containing Alcian blue-positive glycosaminoglycans or PASD-positive basement membrane material.
- Ancillary Studies: Myoepithelial cells express p63, p40, S100, and SMA, while luminal epithelial cells express CK and KIT (CD117); the tumor is often driven by MYB gene rearrangements.
- Differential Diagnosis: Must be distinguished from basaloid squamous cell carcinoma, which lacks the dual neoplastic cell population (epithelial and myoepithelial) seen in adenoid cystic carcinoma.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.

Q: Immunohistochemical staining for [...] typically highlights the luminal epithelial cells in [...], while p63/p40 highlight the myoepithelial cells.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Oesophageal adenoid cystic carcinoma. p63 staining highlights the myoepithelial cells.
Oesophageal adenoid cystic carcinoma. KIT staining highlights the luminal cells.
A: KIT (CD117); Esophageal adenoid cystic carcinoma
Back Extra: Esophageal adenoid cystic carcinoma
- Clinical: Extremely rare esophageal malignancy (< 1%) typically arising in the mid-esophagus from submucosal glands; most common in men around age 60.
- Microscopic: Characterized by a biphasic population of epithelial and myoepithelial cells forming cribriform, tubular, or solid patterns with punched-out spaces containing Alcian blue-positive glycosaminoglycans or PASD-positive basement membrane material.
- Ancillary Studies: Myoepithelial cells express p63, p40, S100, and SMA, while luminal epithelial cells express CK and KIT (CD117); the tumor is often driven by MYB gene rearrangements.
- Differential Diagnosis: Must be distinguished from basaloid squamous cell carcinoma, which lacks the dual neoplastic cell population (epithelial and myoepithelial) seen in adenoid cystic carcinoma.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Oesophageal adenoid cystic carcinoma. p63 staining highlights the myoepithelial cells.
Oesophageal adenoid cystic carcinoma. KIT staining highlights the luminal cells.

Q: A key feature distinguishing [...] from basaloid squamous cell carcinoma is that the latter is composed of only [...] cell type.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Adenoid cystic carcinoma of the oesophagus. A The neoplasm is composed of cells with monotonous nuclei, and abundant basement membrane material is present.
A: Esophageal adenoid cystic carcinoma; one
Back Extra: Esophageal adenoid cystic carcinoma
- Clinical: Extremely rare esophageal malignancy (< 1%) typically arising in the mid-esophagus from submucosal glands; most common in men around age 60.
- Microscopic: Characterized by a biphasic population of epithelial and myoepithelial cells forming cribriform, tubular, or solid patterns with punched-out spaces containing Alcian blue-positive glycosaminoglycans or PASD-positive basement membrane material.
- Ancillary Studies: Myoepithelial cells express p63, p40, S100, and SMA, while luminal epithelial cells express CK and KIT (CD117); the tumor is often driven by MYB gene rearrangements.
- Differential Diagnosis: Must be distinguished from basaloid squamous cell carcinoma, which lacks the dual neoplastic cell population (epithelial and myoepithelial) seen in adenoid cystic carcinoma.
Oesophageal adenoid cystic carcinoma. The cribriform pattern.
Adenoid cystic carcinoma of the oesophagus. A The neoplasm is composed of cells with monotonous nuclei, and abundant basement membrane material is present.

Q: Endoscopically, an [...] presents as a small, white exophytic growth with a [...] surface.
Oesophageal squamous papilloma. These lesions are usually not associated with human papillomavirus despite their wart-like appearance.
Oesophageal squamous papilloma. Exophytic pattern of growth; the papillary fibrovascular core is surrounded by hyperplastic squamous epithelium with parakeratosis. Each individual papilla contains capillaries.
A: Oesophageal squamous papilloma; wart-like
Back Extra: Oesophageal squamous papilloma
- Clinical: Uncommon benign lesion (prevalence 0.01-0.45%) most often found in the lower (Western) or middle (Asian) esophagus; frequently associated with chronic irritation like GERD.
- Endoscopy: Characteristically appears as a small, white exophytic growth with a wart-like surface.
- Microscopic: Characterized by a papillary/exophytic proliferation of hyperplastic squamous epithelium supported by central fibrovascular cores of lamina propria.
- Pathogenesis: Although morphology may show vacuolated cells mimicking koilocytes, most cases are not associated with Human Papillomavirus (HPV).
Oesophageal squamous papilloma. These lesions are usually not associated with human papillomavirus despite their wart-like appearance.
Oesophageal squamous papilloma. Exophytic pattern of growth; the papillary fibrovascular core is surrounded by hyperplastic squamous epithelium with parakeratosis. Each individual papilla contains capillaries.

Q: Microscopically, the [...] consists of hyperplastic squamous epithelium surrounding a central [...] of lamina propria.
Squamous papilloma. Papillary proliferation lined by squamous epithelium
Squamous papilloma. A papillomatous lesion lined by squamous epithelium
Oesophageal squamous papilloma. Exophytic pattern of growth; the papillary fibrovascular core is surrounded by hyperplastic squamous epithelium with parakeratosis. Each individual papilla contains capillaries.
A: Oesophageal squamous papilloma; fibrovascular core
Back Extra: Oesophageal squamous papilloma
- Clinical: Uncommon benign lesion (prevalence 0.01-0.45%) most often found in the lower (Western) or middle (Asian) esophagus; frequently associated with chronic irritation like GERD.
- Endoscopy: Characteristically appears as a small, white exophytic growth with a wart-like surface.
- Microscopic: Characterized by a papillary/exophytic proliferation of hyperplastic squamous epithelium supported by central fibrovascular cores of lamina propria.
- Pathogenesis: Although morphology may show vacuolated cells mimicking koilocytes, most cases are not associated with Human Papillomavirus (HPV).
Squamous papilloma. Papillary proliferation lined by squamous epithelium
Squamous papilloma. A papillomatous lesion lined by squamous epithelium
Oesophageal squamous papilloma. Exophytic pattern of growth; the papillary fibrovascular core is surrounded by hyperplastic squamous epithelium with parakeratosis. Each individual papilla contains capillaries.

Q: Despite the presence of vacuolated cells mimicking [...], the [...] is typically not associated with Human Papillomavirus (HPV).
Oesophageal squamous papilloma. These lesions are usually not associated with human papillomavirus despite their wart-like appearance.
A: koilocytes; Oesophageal squamous papilloma
Back Extra: Oesophageal squamous papilloma
- Clinical: Uncommon benign lesion (prevalence 0.01-0.45%) most often found in the lower (Western) or middle (Asian) esophagus; frequently associated with chronic irritation like GERD.
- Endoscopy: Characteristically appears as a small, white exophytic growth with a wart-like surface.
- Microscopic: Characterized by a papillary/exophytic proliferation of hyperplastic squamous epithelium supported by central fibrovascular cores of lamina propria.
- Pathogenesis: Although morphology may show vacuolated cells mimicking koilocytes, most cases are not associated with Human Papillomavirus (HPV).
Oesophageal squamous papilloma. These lesions are usually not associated with human papillomavirus despite their wart-like appearance.

Q: In Western populations, the etiology of [...] in the lower esophagus is frequently linked to chronic mucosal irritation from [...].
Squamous papilloma in an endoscopic biopsy. This patient had a previous diagnosis of eosinophilic oesophagitis
Squamous papilloma. Papillary proliferation lined by squamous epithelium
A: Oesophageal squamous papilloma; gastro-oesophageal reflux (GERD)
Back Extra: Oesophageal squamous papilloma
- Clinical: Uncommon benign lesion (prevalence 0.01-0.45%) most often found in the lower (Western) or middle (Asian) esophagus; frequently associated with chronic irritation like GERD.
- Endoscopy: Characteristically appears as a small, white exophytic growth with a wart-like surface.
- Microscopic: Characterized by a papillary/exophytic proliferation of hyperplastic squamous epithelium supported by central fibrovascular cores of lamina propria.
- Pathogenesis: Although morphology may show vacuolated cells mimicking koilocytes, most cases are not associated with Human Papillomavirus (HPV).
Squamous papilloma in an endoscopic biopsy. This patient had a previous diagnosis of eosinophilic oesophagitis
Squamous papilloma. Papillary proliferation lined by squamous epithelium

Q: In a 9-year-old girl with a liver hilum mass and a serum AFP of 4000 µg/L, the diagnosis of [...] (specifically a primary yolk sac tumour or mixed germ cell tumour) should be considered.
Germ cell tumour of the liver. A liver hilum germ cell tumour centred around the common hepatic/bile duct in a 9-year-old girl. Serum AFP = 4000 µg/L. A mature hepatocellular component (centre) is admixed with an immature epithelial (left) and mesenchymal (right) component.
A: germ cell tumours of the digestive system
Back Extra: Germ cell tumours of the digestive system
- Clinical: These are extremely rare midline tumours; primary liver occurrences may present with obstructive jaundice (porta hepatis) or a palpable mass. Serum AFP is markedly elevated in yolk sac components, while high β-hCG suggests choriocarcinoma.
- Microscopic: Most germ cell tumours in the GI tract are metastatic from gonadal sites. Primary liver tumours are most commonly teratomas or yolk sac tumours, often showing a mixture of mature and immature components.
- Ancillary: SALL4 is a sensitive marker across germ cell types; yolk sac tumours express AFP and glypican-3 (GPC3), while seminomas express PLAP, KIT, and OCT3/4.
- Differential: Key differentials include somatic carcinomas with germ cell-like differentiation (e.g., enteroblastic adenocarcinoma of the stomach), SMARCA4-deficient carcinomas, and hepatoblastoma (distinguished by nuclear β-catenin).
Germ cell tumour of the liver. A liver hilum germ cell tumour centred around the common hepatic/bile duct in a 9-year-old girl. Serum AFP = 4000 µg/L. A mature hepatocellular component (centre) is admixed with an immature epithelial (left) and mesenchymal (right) component.

Q: Before confirming a diagnosis of primary germ cell tumours of the digestive system, pathologists must first exclude a [...] from an occult gonadal primary.
Metastatic seminoma to small bowel. This patient presented with small bowel obstruction, and a regressed testicular seminoma was later discovered.
Metastatic seminoma to the small intestine. The tumour is predominantly within the submucosa with mucosal ulceration and composed of neoplastic cells in a backdrop of lymphocytes and plasma cells.
A: metastatic germ cell tumour
Back Extra: Germ cell tumours of the digestive system
- Clinical: These are extremely rare midline tumours; primary liver occurrences may present with obstructive jaundice (porta hepatis) or a palpable mass. Serum AFP is markedly elevated in yolk sac components, while high β-hCG suggests choriocarcinoma.
- Microscopic: Most germ cell tumours in the GI tract are metastatic from gonadal sites. Primary liver tumours are most commonly teratomas or yolk sac tumours, often showing a mixture of mature and immature components.
- Ancillary: SALL4 is a sensitive marker across germ cell types; yolk sac tumours express AFP and glypican-3 (GPC3), while seminomas express PLAP, KIT, and OCT3/4.
- Differential: Key differentials include somatic carcinomas with germ cell-like differentiation (e.g., enteroblastic adenocarcinoma of the stomach), SMARCA4-deficient carcinomas, and hepatoblastoma (distinguished by nuclear β-catenin).
Metastatic seminoma to small bowel. This patient presented with small bowel obstruction, and a regressed testicular seminoma was later discovered.
Metastatic seminoma to the small intestine. The tumour is predominantly within the submucosa with mucosal ulceration and composed of neoplastic cells in a backdrop of lymphocytes and plasma cells.

Q: In the context of germ cell tumours of the digestive system, yolk sac elements are characteristically positive for AFP and [...], but can be confused with enteroblastic adenocarcinomas which also express these markers.
Enteroblastic adenocarcinoma of the stomach showing morphological features of conventional adenocarcinoma and sheet-like growth.
Enteroblastic adenocarcinoma of the stomach. The tumour shows a mixture of primitive (germ cell tumour–like) elements (A) and conventional adenocarcinoma (B).
Enteroblastic adenocarcinoma of the stomach showing patchy AFP expression in both conventional adenocarcinoma and germ cell tumour-like areas.
A: glypican-3 (GPC3)
Back Extra: Germ cell tumours of the digestive system
- Clinical: These are extremely rare midline tumours; primary liver occurrences may present with obstructive jaundice (porta hepatis) or a palpable mass. Serum AFP is markedly elevated in yolk sac components, while high β-hCG suggests choriocarcinoma.
- Microscopic: Most germ cell tumours in the GI tract are metastatic from gonadal sites. Primary liver tumours are most commonly teratomas or yolk sac tumours, often showing a mixture of mature and immature components.
- Ancillary: SALL4 is a sensitive marker across germ cell types; yolk sac tumours express AFP and glypican-3 (GPC3), while seminomas express PLAP, KIT, and OCT3/4.
- Differential: Key differentials include somatic carcinomas with germ cell-like differentiation (e.g., enteroblastic adenocarcinoma of the stomach), SMARCA4-deficient carcinomas, and hepatoblastoma (distinguished by nuclear β-catenin).
Enteroblastic adenocarcinoma of the stomach showing morphological features of conventional adenocarcinoma and sheet-like growth.
Enteroblastic adenocarcinoma of the stomach. The tumour shows a mixture of primitive (germ cell tumour–like) elements (A) and conventional adenocarcinoma (B).
Enteroblastic adenocarcinoma of the stomach showing patchy AFP expression in both conventional adenocarcinoma and germ cell tumour-like areas.

Q: An anorectal mass biopsy showing lentiginous growth at the squamocolumnar junction and diffuse SOX10 positivity is diagnostic of [...].
Anorectal melanoma showing lentiginous growth involving the squamocolumnar junctional epithelium highlighted by SOX10 immunostain.
Anorectal melanoma. Diffusely infiltrating neoplastic cells showing strong immunoreactivity for SOX10.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.
A: Mucosal melanoma of the digestive system
Back Extra: Mucosal melanoma of the digestive system
- Clinical: Rare primary malignancy occurring most often in the anorectal region (median age ~65) or distal esophagus; frequently misdiagnosed as hemorrhoids due to dark pigmentation and location.
- Microscopic: Characterized by pleomorphic epithelioid or spindle cells with vesicular chromatin and prominent nucleoli; associated squamous epithelium often shows a lentiginous growth pattern (melanoma in situ).
- Pathogenesis: Distinct from cutaneous melanoma by lacking UV radiation signatures; instead characterized by high copy-number changes and frequent mutations in KIT (24%) or NRAS (18%).
- Prognosis: Poor overall 5-year survival (~20% for anorectal), significantly affected by tumor thickness and presence of regional or distant metastases at diagnosis.
Anorectal melanoma showing lentiginous growth involving the squamocolumnar junctional epithelium highlighted by SOX10 immunostain.
Anorectal melanoma. Diffusely infiltrating neoplastic cells showing strong immunoreactivity for SOX10.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.

Q: Unlike its cutaneous counterpart, [...] lacks a UV signature and most commonly harbors somatic mutations in the [...] gene (24%).
Anorectal melanoma. Polypoid invasive anorectal melanoma with satellitosis in submucosa.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.
A: Mucosal melanoma of the digestive system; KIT
Back Extra: Mucosal melanoma of the digestive system
- Clinical: Rare primary malignancy occurring most often in the anorectal region (median age ~65) or distal esophagus; frequently misdiagnosed as hemorrhoids due to dark pigmentation and location.
- Microscopic: Characterized by pleomorphic epithelioid or spindle cells with vesicular chromatin and prominent nucleoli; associated squamous epithelium often shows a lentiginous growth pattern (melanoma in situ).
- Pathogenesis: Distinct from cutaneous melanoma by lacking UV radiation signatures; instead characterized by high copy-number changes and frequent mutations in KIT (24%) or NRAS (18%).
- Prognosis: Poor overall 5-year survival (~20% for anorectal), significantly affected by tumor thickness and presence of regional or distant metastases at diagnosis.
Anorectal melanoma. Polypoid invasive anorectal melanoma with satellitosis in submucosa.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.

Q: In the clinical setting, the dark pigmentation of [...] in the anorectal region often leads to it being misdiagnosed as [...].
Anorectal melanoma. Polypoid invasive anorectal melanoma with satellitosis in submucosa.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.
A: Mucosal melanoma of the digestive system; haemorrhoids
Back Extra: Mucosal melanoma of the digestive system
- Clinical: Rare primary malignancy occurring most often in the anorectal region (median age ~65) or distal esophagus; frequently misdiagnosed as hemorrhoids due to dark pigmentation and location.
- Microscopic: Characterized by pleomorphic epithelioid or spindle cells with vesicular chromatin and prominent nucleoli; associated squamous epithelium often shows a lentiginous growth pattern (melanoma in situ).
- Pathogenesis: Distinct from cutaneous melanoma by lacking UV radiation signatures; instead characterized by high copy-number changes and frequent mutations in KIT (24%) or NRAS (18%).
- Prognosis: Poor overall 5-year survival (~20% for anorectal), significantly affected by tumor thickness and presence of regional or distant metastases at diagnosis.
Anorectal melanoma. Polypoid invasive anorectal melanoma with satellitosis in submucosa.
Anorectal Melanoma. Polypoid anorectal melanoma where malignant cells infiltrate between benign glands.

Q: In cases of Metastases to other digestive system sites, metastatic [...] to the stomach can histologically and macroscopically mimic [...].
Metastatic lobular breast carcinoma in a gastric biopsy, mimicking diffuse infiltrating gastric carcinoma; highlighted by ER immunohistochemistry.
A: lobular breast carcinoma; primary diffuse infiltrating gastric carcinoma (linitis plastica)
Back Extra: Metastases to other digestive system sites
- Clinical: Metastatic tumors outnumber primary tumors in the small intestine; common origins include breast (lobular) and lung cancer.
- Specific Sites: Renal cell carcinoma is the most common metastasis to the pancreas, while gallbladder metastases are frequently from melanoma, RCC, or colorectal cancer.
- Morphologic Mimicry: Metastatic lobular breast carcinoma can diffusely infiltrate the gastric wall, mimicking the 'linitis plastica' appearance of primary diffuse gastric adenocarcinoma.
- Diagnostic Strategy: Identification requires a high index of clinical suspicion and immunohistochemical correlation (e.g., HepPar1 for HCC, ER for breast, SALL4 for germ cell tumors).
- Prognosis: Usually indicates Stage IV disease, though oligometastatic disease (especially pancreatic metastases from RCC) may have a better survival profile.
Metastatic lobular breast carcinoma in a gastric biopsy, mimicking diffuse infiltrating gastric carcinoma; highlighted by ER immunohistochemistry.

Q: For Metastases to other digestive system sites involving the gallbladder, a lesion showing abundant eosinophilic cytoplasm and prominent nucleoli that is [...] positive is diagnostic of metastatic [...].
Metastatic hepatocellular carcinoma to gallbladder: cells show abundant eosinophilic cytoplasm with prominent nucleoli.
HepPar1 immunohistochemical staining showing diffuse positivity in metastatic hepatocellular carcinoma to the gallbladder.
A: HepPar1; hepatocellular carcinoma
Back Extra: Metastases to other digestive system sites
- Clinical: Metastatic tumors outnumber primary tumors in the small intestine; common origins include breast (lobular) and lung cancer.
- Specific Sites: Renal cell carcinoma is the most common metastasis to the pancreas, while gallbladder metastases are frequently from melanoma, RCC, or colorectal cancer.
- Morphologic Mimicry: Metastatic lobular breast carcinoma can diffusely infiltrate the gastric wall, mimicking the 'linitis plastica' appearance of primary diffuse gastric adenocarcinoma.
- Diagnostic Strategy: Identification requires a high index of clinical suspicion and immunohistochemical correlation (e.g., HepPar1 for HCC, ER for breast, SALL4 for germ cell tumors).
- Prognosis: Usually indicates Stage IV disease, though oligometastatic disease (especially pancreatic metastases from RCC) may have a better survival profile.
Metastatic hepatocellular carcinoma to gallbladder: cells show abundant eosinophilic cytoplasm with prominent nucleoli.
HepPar1 immunohistochemical staining showing diffuse positivity in metastatic hepatocellular carcinoma to the gallbladder.

Q: In the small intestine, Metastases to other digestive system sites actually [...] primary tumors in terms of frequency.
Metastatic seminoma to the small intestine; note the presence of a granuloma in the lower center.
A: outnumber
Back Extra: Metastases to other digestive system sites
- Clinical: Metastatic tumors outnumber primary tumors in the small intestine; common origins include breast (lobular) and lung cancer.
- Specific Sites: Renal cell carcinoma is the most common metastasis to the pancreas, while gallbladder metastases are frequently from melanoma, RCC, or colorectal cancer.
- Morphologic Mimicry: Metastatic lobular breast carcinoma can diffusely infiltrate the gastric wall, mimicking the 'linitis plastica' appearance of primary diffuse gastric adenocarcinoma.
- Diagnostic Strategy: Identification requires a high index of clinical suspicion and immunohistochemical correlation (e.g., HepPar1 for HCC, ER for breast, SALL4 for germ cell tumors).
- Prognosis: Usually indicates Stage IV disease, though oligometastatic disease (especially pancreatic metastases from RCC) may have a better survival profile.
Metastatic seminoma to the small intestine; note the presence of a granuloma in the lower center.

Q: Metastatic seminoma is a rare cause of Metastases to other digestive system sites (e.g., small bowel); diagnostic IHC markers include [...] and OCT3/4.
Metastatic seminoma to the small intestine; note the presence of a granuloma in the lower center.
Strong SALL4 expression in metastatic seminoma to the small intestine.
A: SALL4
Back Extra: Metastases to other digestive system sites
- Clinical: Metastatic tumors outnumber primary tumors in the small intestine; common origins include breast (lobular) and lung cancer.
- Specific Sites: Renal cell carcinoma is the most common metastasis to the pancreas, while gallbladder metastases are frequently from melanoma, RCC, or colorectal cancer.
- Morphologic Mimicry: Metastatic lobular breast carcinoma can diffusely infiltrate the gastric wall, mimicking the 'linitis plastica' appearance of primary diffuse gastric adenocarcinoma.
- Diagnostic Strategy: Identification requires a high index of clinical suspicion and immunohistochemical correlation (e.g., HepPar1 for HCC, ER for breast, SALL4 for germ cell tumors).
- Prognosis: Usually indicates Stage IV disease, though oligometastatic disease (especially pancreatic metastases from RCC) may have a better survival profile.
Metastatic seminoma to the small intestine; note the presence of a granuloma in the lower center.
Strong SALL4 expression in metastatic seminoma to the small intestine.

Q: A 7-year-old child presents with intussusception and a small bowel mass. Histology shows a monotonous medium-sized lymphoid infiltrate with a 'starry-sky' pattern. What is the most likely diagnosis? [...]
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. High-power view shows the remaining Lieberkühn crypts separated by the neoplastic lymphocytes.
A: Burkitt lymphoma
Back Extra: Burkitt lymphoma
- Clinical: Aggressive B-cell neoplasm that commonly involves the ileocaecal region; it frequently presents as a rapidly growing mass often causing intussusception or bowel obstruction in children.
- Microscopic: Characterized by a diffuse, monotonous infiltrate of medium-sized lymphoid cells with a 'starry-sky' pattern created by tingible body macrophages; cells often show 'squared-off' cytoplasmic borders.
- Ancillary: Typical immunophenotype is CD10+, BCL6+, BCL2 negative (or very weak), and a Ki-67 proliferation index of nearly 100%.
- Molecular: Essential diagnostic feature is the demonstration of an IG::MYC rearrangement; EBV association is seen in >95% of endemic cases and 20–30% of sporadic cases.
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. High-power view shows the remaining Lieberkühn crypts separated by the neoplastic lymphocytes.

Q: In the diagnosis of [...], immunohistochemistry typically shows strong positivity for germinal center markers like CD10 and BCL6, but characteristically lacks expression of [...].
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Burkitt lymphoma cells are BCL2-negative (C) and MYC-positive (D).
A: Burkitt lymphoma; BCL2
Back Extra: Burkitt lymphoma
- Clinical: Aggressive B-cell neoplasm that commonly involves the ileocaecal region; it frequently presents as a rapidly growing mass often causing intussusception or bowel obstruction in children.
- Microscopic: Characterized by a diffuse, monotonous infiltrate of medium-sized lymphoid cells with a 'starry-sky' pattern created by tingible body macrophages; cells often show 'squared-off' cytoplasmic borders.
- Ancillary: Typical immunophenotype is CD10+, BCL6+, BCL2 negative (or very weak), and a Ki-67 proliferation index of nearly 100%.
- Molecular: Essential diagnostic feature is the demonstration of an IG::MYC rearrangement; EBV association is seen in >95% of endemic cases and 20–30% of sporadic cases.
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Burkitt lymphoma cells are BCL2-negative (C) and MYC-positive (D).

Q: The definitive molecular hallmark of [...] is a translocation or rearrangement involving the [...] gene.
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Break-apart FISH probes for MYC show one allele with colocalization of both probes (red and green) and one allele with separation of the probes.
A: Burkitt lymphoma; MYC
Back Extra: Burkitt lymphoma
- Clinical: Aggressive B-cell neoplasm that commonly involves the ileocaecal region; it frequently presents as a rapidly growing mass often causing intussusception or bowel obstruction in children.
- Microscopic: Characterized by a diffuse, monotonous infiltrate of medium-sized lymphoid cells with a 'starry-sky' pattern created by tingible body macrophages; cells often show 'squared-off' cytoplasmic borders.
- Ancillary: Typical immunophenotype is CD10+, BCL6+, BCL2 negative (or very weak), and a Ki-67 proliferation index of nearly 100%.
- Molecular: Essential diagnostic feature is the demonstration of an IG::MYC rearrangement; EBV association is seen in >95% of endemic cases and 20–30% of sporadic cases.
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Break-apart FISH probes for MYC show one allele with colocalization of both probes (red and green) and one allele with separation of the probes.

Q: Cytologic touch imprints of [...] highlight cells with deeply basophilic cytoplasm containing numerous [...].
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Touch imprint. The deeply basophilic cytoplasm, and abundant lipid vacuoles within it, can be appreciated.
A: Burkitt lymphoma; lipid vacuoles
Back Extra: Burkitt lymphoma
- Clinical: Aggressive B-cell neoplasm that commonly involves the ileocaecal region; it frequently presents as a rapidly growing mass often causing intussusception or bowel obstruction in children.
- Microscopic: Characterized by a diffuse, monotonous infiltrate of medium-sized lymphoid cells with a 'starry-sky' pattern created by tingible body macrophages; cells often show 'squared-off' cytoplasmic borders.
- Ancillary: Typical immunophenotype is CD10+, BCL6+, BCL2 negative (or very weak), and a Ki-67 proliferation index of nearly 100%.
- Molecular: Essential diagnostic feature is the demonstration of an IG::MYC rearrangement; EBV association is seen in >95% of endemic cases and 20–30% of sporadic cases.
Burkitt lymphoma. A diffuse proliferation of regular, cohesive cells with a starry-sky pattern is present. Adipophilin staining (inset) highlights the lipid vacuoles in paraffin sections. B The neoplastic cells are CD10-positive.
Burkitt lymphoma. Touch imprint. The deeply basophilic cytoplasm, and abundant lipid vacuoles within it, can be appreciated.

Q: In adults with Systemic mastocytosis, more than 90% of cases harbor a somatic gain-of-function mutation in [...].
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Immunostaining with an antibody against CD117 (KIT) reveals a compact mast cell infiltrate in an intravillous position.
A: KIT (specifically p.Asp816Val)
Back Extra: Systemic mastocytosis
- Clinical: Characterized by clonal mast cell proliferation in at least one extracutaneous site; >90% of adults harbor the somatic gain-of-function KIT p.Asp816Val mutation.
- Microscopic: Features intramucosal aggregates or band-like subepithelial infiltrates of plump/ovoid mast cells, often accompanied by numerous eosinophils that may obscure the neoplasm.
- Ancillary: Neoplastic mast cells are KIT (CD117) and tryptase positive, and they frequently show aberrant expression of CD25, CD2, or CD30 (unlike normal mast cells).
- Prognosis: Highly variable; indolent systemic mastocytosis (ISM) has a near-normal life expectancy, whereas advanced systemic mastocytosis (ASM) is associated with significant morbidity and decreased survival.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Immunostaining with an antibody against CD117 (KIT) reveals a compact mast cell infiltrate in an intravillous position.

Q: In the GI tract, Systemic mastocytosis frequently presents histologically as a [...] subepithelial infiltrate or compact aggregates of plump cells with pale cytoplasm.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Indolent systemic mastocytosis: Ovoid mast cells contain hyperchromatic nuclei and faintly eosinophilic cytoplasm.
A: band-like
Back Extra: Systemic mastocytosis
- Clinical: Characterized by clonal mast cell proliferation in at least one extracutaneous site; >90% of adults harbor the somatic gain-of-function KIT p.Asp816Val mutation.
- Microscopic: Features intramucosal aggregates or band-like subepithelial infiltrates of plump/ovoid mast cells, often accompanied by numerous eosinophils that may obscure the neoplasm.
- Ancillary: Neoplastic mast cells are KIT (CD117) and tryptase positive, and they frequently show aberrant expression of CD25, CD2, or CD30 (unlike normal mast cells).
- Prognosis: Highly variable; indolent systemic mastocytosis (ISM) has a near-normal life expectancy, whereas advanced systemic mastocytosis (ASM) is associated with significant morbidity and decreased survival.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Indolent systemic mastocytosis: Ovoid mast cells contain hyperchromatic nuclei and faintly eosinophilic cytoplasm.

Q: Diagnostic criteria for Systemic mastocytosis include the aberrant expression of [...] (or CD2/CD30) by mast cells, which is not seen in normal mast cell populations.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Indolent systemic mastocytosis: Ovoid mast cells contain hyperchromatic nuclei and faintly eosinophilic cytoplasm.
A: CD25
Back Extra: Systemic mastocytosis
- Clinical: Characterized by clonal mast cell proliferation in at least one extracutaneous site; >90% of adults harbor the somatic gain-of-function KIT p.Asp816Val mutation.
- Microscopic: Features intramucosal aggregates or band-like subepithelial infiltrates of plump/ovoid mast cells, often accompanied by numerous eosinophils that may obscure the neoplasm.
- Ancillary: Neoplastic mast cells are KIT (CD117) and tryptase positive, and they frequently show aberrant expression of CD25, CD2, or CD30 (unlike normal mast cells).
- Prognosis: Highly variable; indolent systemic mastocytosis (ISM) has a near-normal life expectancy, whereas advanced systemic mastocytosis (ASM) is associated with significant morbidity and decreased survival.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Indolent systemic mastocytosis: Ovoid mast cells contain hyperchromatic nuclei and faintly eosinophilic cytoplasm.

Q: A mucosal biopsy from the small intestine (as seen in this image) shows effacement of architecture by atypical mast cells and eosinophils, confirming a diagnosis of [...].
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Aggressive systemic mastocytosis: Numerous eosinophils accompany neoplastic mast cells and expand the mucosa.
A: Systemic mastocytosis
Back Extra: Systemic mastocytosis
- Clinical: Characterized by clonal mast cell proliferation in at least one extracutaneous site; >90% of adults harbor the somatic gain-of-function KIT p.Asp816Val mutation.
- Microscopic: Features intramucosal aggregates or band-like subepithelial infiltrates of plump/ovoid mast cells, often accompanied by numerous eosinophils that may obscure the neoplasm.
- Ancillary: Neoplastic mast cells are KIT (CD117) and tryptase positive, and they frequently show aberrant expression of CD25, CD2, or CD30 (unlike normal mast cells).
- Prognosis: Highly variable; indolent systemic mastocytosis (ISM) has a near-normal life expectancy, whereas advanced systemic mastocytosis (ASM) is associated with significant morbidity and decreased survival.
Systemic mastocytosis involving the digestive tract showing compact infiltration and broadening of a duodenal villus by medium-sized cells with ample pale cytoplasm.
Aggressive systemic mastocytosis: Numerous eosinophils accompany neoplastic mast cells and expand the mucosa.

Q: The characteristically low proliferation index seen in [...] is defined by a Ki-67 score of less than [...].
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Indolent T-cell lymphoma of the GI tract (ileum) showing an extremely low Ki-67 proliferative rate.
Low-power view of the small lymphocytic infiltrate.
A: Indolent T-cell lymphoma of the GI tract; 10%
Back Extra: Indolent T-cell lymphoma of the GI tract
- Clinical: Affects adults (median age ~50) with a chronic course (diarrhea, abdominal pain) often mimicking inflammatory bowel disease or coeliac disease.
- Microscopic: Characterized by a dense, non-destructive infiltrate of small mature lymphocytes in the lamina propria, usually lacking significant epitheliotropism and showing preserved villous architecture.
- Immunophenotype: Mature T-cells (CD3+, TCRαβ+) that are typically either CD4+ or CD8+ (TIA1+); EBER is characteristically negative, and the Ki-67 index is extremely low (<10%).
- Molecular: Clonal T-cell receptor (TRB/TRG) rearrangements are present in all cases, often associated with JAK/STAT pathway alterations.
- Prognosis: Very indolent course with high survival rates, though the disease is often refractory to standard chemotherapy and may rarely transform after decades.
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Indolent T-cell lymphoma of the GI tract (ileum) showing an extremely low Ki-67 proliferative rate.
Low-power view of the small lymphocytic infiltrate.

Q: Unlike more aggressive intestinal T-cell lymphomas, [...] typically shows a dense lamina propria infiltrate that lacks significant [growth pattern] and spares the overall architecture.
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Indolent T-cell lymphoma of the GI tract, CD8 immunophenotype: broadened villi with expanded lamina propria.
A: Indolent T-cell lymphoma of the GI tract; epitheliotropism
Back Extra: Indolent T-cell lymphoma of the GI tract
- Clinical: Affects adults (median age ~50) with a chronic course (diarrhea, abdominal pain) often mimicking inflammatory bowel disease or coeliac disease.
- Microscopic: Characterized by a dense, non-destructive infiltrate of small mature lymphocytes in the lamina propria, usually lacking significant epitheliotropism and showing preserved villous architecture.
- Immunophenotype: Mature T-cells (CD3+, TCRαβ+) that are typically either CD4+ or CD8+ (TIA1+); EBER is characteristically negative, and the Ki-67 index is extremely low (<10%).
- Molecular: Clonal T-cell receptor (TRB/TRG) rearrangements are present in all cases, often associated with JAK/STAT pathway alterations.
- Prognosis: Very indolent course with high survival rates, though the disease is often refractory to standard chemotherapy and may rarely transform after decades.
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Indolent T-cell lymphoma of the GI tract, CD8 immunophenotype: broadened villi with expanded lamina propria.

Q: Indolent T-cell lymphoma of the GI tract frequently involves alterations in the [...] signaling pathway, including recurrent STAT3::JAK2 fusions in the CD4+ subset.
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
CD4 immunohistochemistry highlighting the lymphoid infiltrate in the lamina propria.
A: JAK/STAT
Back Extra: Indolent T-cell lymphoma of the GI tract
- Clinical: Affects adults (median age ~50) with a chronic course (diarrhea, abdominal pain) often mimicking inflammatory bowel disease or coeliac disease.
- Microscopic: Characterized by a dense, non-destructive infiltrate of small mature lymphocytes in the lamina propria, usually lacking significant epitheliotropism and showing preserved villous architecture.
- Immunophenotype: Mature T-cells (CD3+, TCRαβ+) that are typically either CD4+ or CD8+ (TIA1+); EBER is characteristically negative, and the Ki-67 index is extremely low (<10%).
- Molecular: Clonal T-cell receptor (TRB/TRG) rearrangements are present in all cases, often associated with JAK/STAT pathway alterations.
- Prognosis: Very indolent course with high survival rates, though the disease is often refractory to standard chemotherapy and may rarely transform after decades.
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
CD4 immunohistochemistry highlighting the lymphoid infiltrate in the lamina propria.

Q: A duodenal biopsy demonstrating a dense infiltrate of small, mature T-lymphocytes in the lamina propria and a clonal TRB rearrangement in a patient with chronic diarrhea is most suggestive of the diagnosis [...].
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Small lymphocytes with round/oval nuclei and scant cytoplasm, typical of the CD8+ subset.
A: Indolent T-cell lymphoma of the GI tract
Back Extra: Indolent T-cell lymphoma of the GI tract
- Clinical: Affects adults (median age ~50) with a chronic course (diarrhea, abdominal pain) often mimicking inflammatory bowel disease or coeliac disease.
- Microscopic: Characterized by a dense, non-destructive infiltrate of small mature lymphocytes in the lamina propria, usually lacking significant epitheliotropism and showing preserved villous architecture.
- Immunophenotype: Mature T-cells (CD3+, TCRαβ+) that are typically either CD4+ or CD8+ (TIA1+); EBER is characteristically negative, and the Ki-67 index is extremely low (<10%).
- Molecular: Clonal T-cell receptor (TRB/TRG) rearrangements are present in all cases, often associated with JAK/STAT pathway alterations.
- Prognosis: Very indolent course with high survival rates, though the disease is often refractory to standard chemotherapy and may rarely transform after decades.
Duodenal biopsy showing villus atrophy and expansion of the lamina propria by an infiltrate of small lymphocytes in a CD4+ case of indolent T-cell lymphoma.
Higher magnification showing a dense infiltrate of small mature lymphocytes in the lamina propria.
Small lymphocytes with round/oval nuclei and scant cytoplasm, typical of the CD8+ subset.

Q: A 60-year-old patient presents with an aggressive, ulcerated colonic mass composed of large pleomorphic T-cells that are CD3+, TIA1+, and EBV (EBER) negative. This entity, which lacks the specific features of EATL or MEITL, is best diagnosed as [...].
Intestinal T-cell lymphoma NOS: Large pleomorphic lymphocytes with vesicular nuclei and prominent nucleoli.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing CD3.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing TIA1.
A: Intestinal T-cell lymphoma NOS
Back Extra: Intestinal T-cell lymphoma NOS
- Clinical: Aggressive primary GI lymphoma and a diagnosis of exclusion for cases that do not meet criteria for EATL or MEITL; commonly presents in middle-aged/elderly adults, with up to 20% experiencing perforation.
- Micro: Characterized by mucosal or transmural infiltration of pleomorphic medium-to-large lymphocytes, often presenting as ulcerated or plaque-like masses.
- Ancillary: Neoplastic cells are CD3+, typically negative for EBER (EBV), and often express cytotoxic markers such as TIA1 or granzyme B.
- Genetics: Genetic landscape is heterogeneous, but JAK/STAT pathway mutations are frequently identified, though SETD2 mutations are less common than in MEITL.
Intestinal T-cell lymphoma NOS: Large pleomorphic lymphocytes with vesicular nuclei and prominent nucleoli.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing CD3.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing TIA1.

Q: In the diagnosis of Intestinal T-cell lymphoma NOS, a critical essential criterion is the exclusion of EBV, as the neoplastic cells must be [...].
Intestinal T-cell lymphoma NOS: High magnification showing medium-sized to large pleomorphic lymphocytes with dispersed chromatin and prominent nucleoli.
A: EBER negative
Back Extra: Intestinal T-cell lymphoma NOS
- Clinical: Aggressive primary GI lymphoma and a diagnosis of exclusion for cases that do not meet criteria for EATL or MEITL; commonly presents in middle-aged/elderly adults, with up to 20% experiencing perforation.
- Micro: Characterized by mucosal or transmural infiltration of pleomorphic medium-to-large lymphocytes, often presenting as ulcerated or plaque-like masses.
- Ancillary: Neoplastic cells are CD3+, typically negative for EBER (EBV), and often express cytotoxic markers such as TIA1 or granzyme B.
- Genetics: Genetic landscape is heterogeneous, but JAK/STAT pathway mutations are frequently identified, though SETD2 mutations are less common than in MEITL.
Intestinal T-cell lymphoma NOS: High magnification showing medium-sized to large pleomorphic lymphocytes with dispersed chromatin and prominent nucleoli.

Q: Approximately [...] of patients diagnosed with Intestinal T-cell lymphoma NOS present with the acute clinical complication of intestinal perforation.
Intestinal T-cell lymphoma NOS in the colon showing transmural infiltration.
A: 20%
Back Extra: Intestinal T-cell lymphoma NOS
- Clinical: Aggressive primary GI lymphoma and a diagnosis of exclusion for cases that do not meet criteria for EATL or MEITL; commonly presents in middle-aged/elderly adults, with up to 20% experiencing perforation.
- Micro: Characterized by mucosal or transmural infiltration of pleomorphic medium-to-large lymphocytes, often presenting as ulcerated or plaque-like masses.
- Ancillary: Neoplastic cells are CD3+, typically negative for EBER (EBV), and often express cytotoxic markers such as TIA1 or granzyme B.
- Genetics: Genetic landscape is heterogeneous, but JAK/STAT pathway mutations are frequently identified, though SETD2 mutations are less common than in MEITL.
Intestinal T-cell lymphoma NOS in the colon showing transmural infiltration.

Q: While the immunophenotype is variable, the neoplastic cells in Intestinal T-cell lymphoma NOS frequently express the cytotoxic marker [...].
Intestinal T-cell lymphoma NOS: Large pleomorphic lymphocytes with vesicular nuclei and prominent nucleoli.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing TIA1.
A: TIA1
Back Extra: Intestinal T-cell lymphoma NOS
- Clinical: Aggressive primary GI lymphoma and a diagnosis of exclusion for cases that do not meet criteria for EATL or MEITL; commonly presents in middle-aged/elderly adults, with up to 20% experiencing perforation.
- Micro: Characterized by mucosal or transmural infiltration of pleomorphic medium-to-large lymphocytes, often presenting as ulcerated or plaque-like masses.
- Ancillary: Neoplastic cells are CD3+, typically negative for EBER (EBV), and often express cytotoxic markers such as TIA1 or granzyme B.
- Genetics: Genetic landscape is heterogeneous, but JAK/STAT pathway mutations are frequently identified, though SETD2 mutations are less common than in MEITL.
Intestinal T-cell lymphoma NOS: Large pleomorphic lymphocytes with vesicular nuclei and prominent nucleoli.
Intestinal T-cell lymphoma NOS: Neoplastic cells expressing TIA1.

Q: A small (< 1 cm), white, subcapsular liver nodule is found incidentally during a cholecystectomy. Histology shows uniform small tubules and an enclosed portal tract, supporting a diagnosis of [...].
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.
A: Bile duct adenoma
Back Extra: Bile duct adenoma
- Clinical: Typically an incidental, solitary subcapsular nodule (< 10 mm) found during surgery or autopsy; it appears as a firm, white, unencapsulated mass.
- Microscopic: Characterized by a well-circumscribed but non-encapsulated proliferation of small, uniform tubules lined by cuboidal cells; a key feature is the inclusion of native portal tracts within the lesion.
- Variants: Rare patterns include clear cell and oncocytic variants, the latter featuring abundant eosinophilic cytoplasm and dilated tubules.
- Ancillary: Often positive for CK7, CK19, and p16 (INK4a); molecular studies show BRAF p.Val600Glu mutations in ~53% of cases, supporting a neoplastic origin.
- Differential Diagnosis: Differentiated from small duct intrahepatic cholangiocarcinoma by its smaller size, lack of infiltrative growth, low Ki-67 (< 10%), and retained p16 expression.
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.

Q: Regarding molecular findings, approximately 53% of [...] cases harbor the [...] mutation.
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.
A: Bile duct adenoma; BRAF p.Val600Glu
Back Extra: Bile duct adenoma
- Clinical: Typically an incidental, solitary subcapsular nodule (< 10 mm) found during surgery or autopsy; it appears as a firm, white, unencapsulated mass.
- Microscopic: Characterized by a well-circumscribed but non-encapsulated proliferation of small, uniform tubules lined by cuboidal cells; a key feature is the inclusion of native portal tracts within the lesion.
- Variants: Rare patterns include clear cell and oncocytic variants, the latter featuring abundant eosinophilic cytoplasm and dilated tubules.
- Ancillary: Often positive for CK7, CK19, and p16 (INK4a); molecular studies show BRAF p.Val600Glu mutations in ~53% of cases, supporting a neoplastic origin.
- Differential Diagnosis: Differentiated from small duct intrahepatic cholangiocarcinoma by its smaller size, lack of infiltrative growth, low Ki-67 (< 10%), and retained p16 expression.
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.

Q: In the differential diagnosis between [...] and small duct intrahepatic cholangiocarcinoma, the adenoma is characterized by a [...] Ki-67 index and the preservation of [...] expression.
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.
A: Bile duct adenoma; low (average 2%); p16 (INK4a)
Back Extra: Bile duct adenoma
- Clinical: Typically an incidental, solitary subcapsular nodule (< 10 mm) found during surgery or autopsy; it appears as a firm, white, unencapsulated mass.
- Microscopic: Characterized by a well-circumscribed but non-encapsulated proliferation of small, uniform tubules lined by cuboidal cells; a key feature is the inclusion of native portal tracts within the lesion.
- Variants: Rare patterns include clear cell and oncocytic variants, the latter featuring abundant eosinophilic cytoplasm and dilated tubules.
- Ancillary: Often positive for CK7, CK19, and p16 (INK4a); molecular studies show BRAF p.Val600Glu mutations in ~53% of cases, supporting a neoplastic origin.
- Differential Diagnosis: Differentiated from small duct intrahepatic cholangiocarcinoma by its smaller size, lack of infiltrative growth, low Ki-67 (< 10%), and retained p16 expression.
Bile duct adenoma. The lesion consists of evenly distributed ducts and fibrotic stroma. It is well circumscribed with little mass effects in the adjacent parenchyma. A portal tract is present within the lesion (arrow).
Bile duct adenoma. The partly anastomosing ducts are lined by a non-dysplastic, cuboidal epithelium.

Q: The oncocytic variant of [...] is distinguished by neoplastic cells with abundant [...] cytoplasm and dilated tubules.
Oncocytic bile duct adenoma. The lining epithelium has abundant eosinophilic cytoplasm, and tubules are dilated. Other findings are similar to those of usual bile duct adenoma.
A: Bile duct adenoma; eosinophilic
Back Extra: Bile duct adenoma
- Clinical: Typically an incidental, solitary subcapsular nodule (< 10 mm) found during surgery or autopsy; it appears as a firm, white, unencapsulated mass.
- Microscopic: Characterized by a well-circumscribed but non-encapsulated proliferation of small, uniform tubules lined by cuboidal cells; a key feature is the inclusion of native portal tracts within the lesion.
- Variants: Rare patterns include clear cell and oncocytic variants, the latter featuring abundant eosinophilic cytoplasm and dilated tubules.
- Ancillary: Often positive for CK7, CK19, and p16 (INK4a); molecular studies show BRAF p.Val600Glu mutations in ~53% of cases, supporting a neoplastic origin.
- Differential Diagnosis: Differentiated from small duct intrahepatic cholangiocarcinoma by its smaller size, lack of infiltrative growth, low Ki-67 (< 10%), and retained p16 expression.
Oncocytic bile duct adenoma. The lining epithelium has abundant eosinophilic cytoplasm, and tubules are dilated. Other findings are similar to those of usual bile duct adenoma.

Q: The microscopic hallmark of [...] is a solid-microcystic architecture where tubules and cysts are embedded in a [...] stroma.
Biliary adenofibroma showing microcysts of various sizes separated by fibrous stroma.
High-power view of biliary adenofibroma demonstrating lining epithelium with minimal cytological atypia.
A: biliary adenofibroma; fibrotic/collagenous
Back Extra: Biliary adenofibroma
- Clinical: A rare, benign but potentially pre-malignant intrahepatic neoplasm typically presenting in adults (median age 57) as a solitary, solid-microcystic mass.
- Microscopic: Characterized by complex tubuloacinar and microcystic structures lined by a single layer of bland, non-mucin-secreting biliary epithelium supported by dense, hypocellular fibrotic stroma.
- Malignant Transformation: High clinical significance as ~50% of cases undergo malignant transformation into conventional adenocarcinomas (typically small duct-type intrahepatic cholangiocarcinoma).
- Ancillary: Expresses a biliary phenotype (CK7, CK19, EMA, CA19-9) with a low Ki-67 proliferation index (<10% in epithelium).
- Molecular: Mutations in chromatin-remodeling genes (e.g., ARID1A, BAP1) or FGFR2 fusions favor a diagnosis of intrahepatic cholangiocarcinoma over benign biliary adenofibroma.
Biliary adenofibroma showing microcysts of various sizes separated by fibrous stroma.
High-power view of biliary adenofibroma demonstrating lining epithelium with minimal cytological atypia.

Q: Approximately [...] of reported cases of [...] exhibit malignant transformation into adenocarcinoma.
Biliary adenofibroma with malignant change, showing the transition from benign microcystic areas to tubular adenocarcinoma.
A: 50%; biliary adenofibroma
Back Extra: Biliary adenofibroma
- Clinical: A rare, benign but potentially pre-malignant intrahepatic neoplasm typically presenting in adults (median age 57) as a solitary, solid-microcystic mass.
- Microscopic: Characterized by complex tubuloacinar and microcystic structures lined by a single layer of bland, non-mucin-secreting biliary epithelium supported by dense, hypocellular fibrotic stroma.
- Malignant Transformation: High clinical significance as ~50% of cases undergo malignant transformation into conventional adenocarcinomas (typically small duct-type intrahepatic cholangiocarcinoma).
- Ancillary: Expresses a biliary phenotype (CK7, CK19, EMA, CA19-9) with a low Ki-67 proliferation index (<10% in epithelium).
- Molecular: Mutations in chromatin-remodeling genes (e.g., ARID1A, BAP1) or FGFR2 fusions favor a diagnosis of intrahepatic cholangiocarcinoma over benign biliary adenofibroma.
Biliary adenofibroma with malignant change, showing the transition from benign microcystic areas to tubular adenocarcinoma.

Q: When differentiating [...] from small duct-type intrahepatic cholangiocarcinoma (SD-iCCA), the presence of mutations in [...] strongly favors a malignant diagnosis.
Biliary adenofibroma showing microcysts of various sizes separated by fibrous stroma.
Biliary adenofibroma with malignant change, showing the transition from benign microcystic areas to tubular adenocarcinoma.
A: biliary adenofibroma; ARID1A or BAP1
Back Extra: Biliary adenofibroma
- Clinical: A rare, benign but potentially pre-malignant intrahepatic neoplasm typically presenting in adults (median age 57) as a solitary, solid-microcystic mass.
- Microscopic: Characterized by complex tubuloacinar and microcystic structures lined by a single layer of bland, non-mucin-secreting biliary epithelium supported by dense, hypocellular fibrotic stroma.
- Malignant Transformation: High clinical significance as ~50% of cases undergo malignant transformation into conventional adenocarcinomas (typically small duct-type intrahepatic cholangiocarcinoma).
- Ancillary: Expresses a biliary phenotype (CK7, CK19, EMA, CA19-9) with a low Ki-67 proliferation index (<10% in epithelium).
- Molecular: Mutations in chromatin-remodeling genes (e.g., ARID1A, BAP1) or FGFR2 fusions favor a diagnosis of intrahepatic cholangiocarcinoma over benign biliary adenofibroma.
Biliary adenofibroma showing microcysts of various sizes separated by fibrous stroma.
Biliary adenofibroma with malignant change, showing the transition from benign microcystic areas to tubular adenocarcinoma.

Q: A well-delineated liver mass showing nodular architecture with a central stellate scar and a map-like staining pattern on glutamine synthetase is diagnostic of [...].
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.
Focal nodular hyperplasia, glutamine synthetase stain. Typical map-like (geographical) pattern of staining comprising strong staining in large anastomosing groups of lesional hepatocytes.
A: focal nodular hyperplasia of the liver
Back Extra: Focal nodular hyperplasia of the liver
- Clinical: Predominantly affects females aged 20–50 years; typically a solitary, asymptomatic lesion discovered incidentally as a hyperplastic response to localized vascular abnormalities.
- Macroscopic: Classic appearance is an ochre, firm, lobulated mass with a central stellate fibrous scar and radiating extensions.
- Microscopic: Characterized by nodules of benign hepatocytes, a central scar containing large dystrophic vessels (lacking portal veins/bile ducts), and a prominent ductular reaction at the septal interface.
- Ancillary: Glutamine synthetase (GS) immunohistochemistry shows a pathognomonic map-like (geographical) staining pattern; the lesion is polyclonal and shows focal WNT pathway activation without CTNNB1 mutations.
- Differential: Distinguish from inflammatory hepatocellular adenoma (diffuse CRP/SAA+) and beta-catenin-mutated adenoma (diffuse GS+ and nuclear beta-catenin).
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.
Focal nodular hyperplasia, glutamine synthetase stain. Typical map-like (geographical) pattern of staining comprising strong staining in large anastomosing groups of lesional hepatocytes.

Q: In focal nodular hyperplasia of the liver, the prominent ductular reaction occurring at the interface of fibrous regions and nodules can be highlighted by [stains].
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.
A: CK7 or CK19
Back Extra: Focal nodular hyperplasia of the liver
- Clinical: Predominantly affects females aged 20–50 years; typically a solitary, asymptomatic lesion discovered incidentally as a hyperplastic response to localized vascular abnormalities.
- Macroscopic: Classic appearance is an ochre, firm, lobulated mass with a central stellate fibrous scar and radiating extensions.
- Microscopic: Characterized by nodules of benign hepatocytes, a central scar containing large dystrophic vessels (lacking portal veins/bile ducts), and a prominent ductular reaction at the septal interface.
- Ancillary: Glutamine synthetase (GS) immunohistochemistry shows a pathognomonic map-like (geographical) staining pattern; the lesion is polyclonal and shows focal WNT pathway activation without CTNNB1 mutations.
- Differential: Distinguish from inflammatory hepatocellular adenoma (diffuse CRP/SAA+) and beta-catenin-mutated adenoma (diffuse GS+ and nuclear beta-catenin).
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.

Q: Unlike hepatocellular adenomas, focal nodular hyperplasia of the liver is characterized by a [clonality] cell population according to HUMARA testing.
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.
A: polyclonal
Back Extra: Focal nodular hyperplasia of the liver
- Clinical: Predominantly affects females aged 20–50 years; typically a solitary, asymptomatic lesion discovered incidentally as a hyperplastic response to localized vascular abnormalities.
- Macroscopic: Classic appearance is an ochre, firm, lobulated mass with a central stellate fibrous scar and radiating extensions.
- Microscopic: Characterized by nodules of benign hepatocytes, a central scar containing large dystrophic vessels (lacking portal veins/bile ducts), and a prominent ductular reaction at the septal interface.
- Ancillary: Glutamine synthetase (GS) immunohistochemistry shows a pathognomonic map-like (geographical) staining pattern; the lesion is polyclonal and shows focal WNT pathway activation without CTNNB1 mutations.
- Differential: Distinguish from inflammatory hepatocellular adenoma (diffuse CRP/SAA+) and beta-catenin-mutated adenoma (diffuse GS+ and nuclear beta-catenin).
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.

Q: Focal nodular hyperplasia of the liver is considered a non-neoplastic hepatocellular lesion caused by localized [pathophysiology].
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.
A: vascular abnormalities
Back Extra: Focal nodular hyperplasia of the liver
- Clinical: Predominantly affects females aged 20–50 years; typically a solitary, asymptomatic lesion discovered incidentally as a hyperplastic response to localized vascular abnormalities.
- Macroscopic: Classic appearance is an ochre, firm, lobulated mass with a central stellate fibrous scar and radiating extensions.
- Microscopic: Characterized by nodules of benign hepatocytes, a central scar containing large dystrophic vessels (lacking portal veins/bile ducts), and a prominent ductular reaction at the septal interface.
- Ancillary: Glutamine synthetase (GS) immunohistochemistry shows a pathognomonic map-like (geographical) staining pattern; the lesion is polyclonal and shows focal WNT pathway activation without CTNNB1 mutations.
- Differential: Distinguish from inflammatory hepatocellular adenoma (diffuse CRP/SAA+) and beta-catenin-mutated adenoma (diffuse GS+ and nuclear beta-catenin).
Focal nodular hyperplasia. Nodular architecture and fibrous septum with aberrant arterioles and ductular reaction.

Q: A patient with a history of primary sclerosing cholangitis presents with a periductal-infiltrating central liver mass. Histology reveals large glands lined by tall columnar cells in a desmoplastic stroma (see image), consistent with [...].
Intrahepatic cholangiocarcinoma, large duct. A well-differentiated tumour with formation of round or slightly angulated large glands lined by tall columnar cancer cells.
Intrahepatic cholangiocarcinoma, large duct. B The tumour shows an infiltrative growth with a desmoplastic stroma.
A: Intrahepatic cholangiocarcinoma, large duct
Back Extra: Intrahepatic cholangiocarcinoma, large duct
- Clinical: Typically arises centrally near segmental bile ducts in patients over 50; strong associations with primary sclerosing cholangitis (PSC), liver flukes, and hepatolithiasis.
- Micro: Often presents as a pancreaticobiliary-type adenocarcinoma with large irregular glands, tall columnar cells, mucin production, and prominent desmoplastic stroma.
- Ancillary: Typically CK7(+), CK19(+), and CA19-9(+); the enteroblastic subtype may aberrantly express HepPar1, AFP, and SALL4, mimicking hepatocellular carcinoma.
- Molecular: Frequently harbors mutations in KRAS, TP53, and SMAD4, while notably lacking the IDH1/2 mutations or FGFR2 fusions seen in the small duct variant.
Intrahepatic cholangiocarcinoma, large duct. A well-differentiated tumour with formation of round or slightly angulated large glands lined by tall columnar cancer cells.
Intrahepatic cholangiocarcinoma, large duct. B The tumour shows an infiltrative growth with a desmoplastic stroma.

Q: Unlike small duct variants, [...] is characterized by the absence of [...] mutations and [...] fusions.
Intrahepatic cholangiocarcinoma, large duct. A well-differentiated tumour with formation of round or slightly angulated large glands lined by tall columnar cancer cells.
Intrahepatic cholangiocarcinoma, large duct. C A moderately differentiated tumour demonstrating fused irregular glands.
A: Intrahepatic cholangiocarcinoma, large duct; IDH1/2; FGFR2
Back Extra: Intrahepatic cholangiocarcinoma, large duct
- Clinical: Typically arises centrally near segmental bile ducts in patients over 50; strong associations with primary sclerosing cholangitis (PSC), liver flukes, and hepatolithiasis.
- Micro: Often presents as a pancreaticobiliary-type adenocarcinoma with large irregular glands, tall columnar cells, mucin production, and prominent desmoplastic stroma.
- Ancillary: Typically CK7(+), CK19(+), and CA19-9(+); the enteroblastic subtype may aberrantly express HepPar1, AFP, and SALL4, mimicking hepatocellular carcinoma.
- Molecular: Frequently harbors mutations in KRAS, TP53, and SMAD4, while notably lacking the IDH1/2 mutations or FGFR2 fusions seen in the small duct variant.
Intrahepatic cholangiocarcinoma, large duct. A well-differentiated tumour with formation of round or slightly angulated large glands lined by tall columnar cancer cells.
Intrahepatic cholangiocarcinoma, large duct. C A moderately differentiated tumour demonstrating fused irregular glands.

Q: The [...] subtype of [...] features columnar cells with clear cytoplasm and sub/supranuclear vacuoles, which can mimic hepatocellular carcinoma by expressing markers like HepPar1 and AFP.
Enteroblastic subtype of large duct intrahepatic cholangiocarcinoma. Columnar cancer cells with clear cytoplasm; intracytoplasmic vacuoles and blastic nuclei are arranged in a tubulopapillary architecture.
A: enteroblastic; Intrahepatic cholangiocarcinoma, large duct
Back Extra: Intrahepatic cholangiocarcinoma, large duct
- Clinical: Typically arises centrally near segmental bile ducts in patients over 50; strong associations with primary sclerosing cholangitis (PSC), liver flukes, and hepatolithiasis.
- Micro: Often presents as a pancreaticobiliary-type adenocarcinoma with large irregular glands, tall columnar cells, mucin production, and prominent desmoplastic stroma.
- Ancillary: Typically CK7(+), CK19(+), and CA19-9(+); the enteroblastic subtype may aberrantly express HepPar1, AFP, and SALL4, mimicking hepatocellular carcinoma.
- Molecular: Frequently harbors mutations in KRAS, TP53, and SMAD4, while notably lacking the IDH1/2 mutations or FGFR2 fusions seen in the small duct variant.
Enteroblastic subtype of large duct intrahepatic cholangiocarcinoma. Columnar cancer cells with clear cytoplasm; intracytoplasmic vacuoles and blastic nuclei are arranged in a tubulopapillary architecture.

Q: In a 10-year-old child with a liver mass showing pleomorphic spindle cells and characteristic eosinophilic hyaline globules, the most likely diagnosis is [...].
Embryonal sarcoma of the liver. The tumour is composed of variably spindled, stellate, and pleomorphic cells embedded in a myxoid stroma.
Embryonal sarcoma of the liver. Eosinophilic globules within the cytoplasm of tumour cells are a characteristic finding.
Embryonal sarcoma. Pleomorphic cells with cytoplasmic granules and globules.
A: Embryonal sarcoma of the liver
Back Extra: Embryonal sarcoma of the liver
- Clinical: Rare primary malignant sarcoma typically affecting children (aged 5–15 years); it is associated with abdominal pain, distension, and occasionally Li–Fraumeni syndrome.
- Microscopic: Characterized by pleomorphic, spindled, or stellate cells in a myxoid stroma, often containing diagnostic PAS-positive eosinophilic hyaline (lysosomal) globules.
- Histologic Features: Often displays peripheral entrapment of bile ducts, extramedullary haematopoiesis, and high mitotic activity with atypical figures.
- Molecular: Commonly shares C19MC microRNA cluster alterations (e.g., MALAT1::C19MC fusion) with mesenchymal hamartoma, but uniquely features complex copy-number alterations and TP53 mutations in 90% of cases.
Embryonal sarcoma of the liver. The tumour is composed of variably spindled, stellate, and pleomorphic cells embedded in a myxoid stroma.
Embryonal sarcoma of the liver. Eosinophilic globules within the cytoplasm of tumour cells are a characteristic finding.
Embryonal sarcoma. Pleomorphic cells with cytoplasmic granules and globules.

Q: A characteristic histologic finding in [...] is the presence of cytoplasmic, PAS-positive [...].
Embryonal sarcoma of the liver. Eosinophilic globules within the cytoplasm of tumour cells are a characteristic finding.
Embryonal sarcoma. Pleomorphic cells with cytoplasmic granules and globules.
A: Embryonal sarcoma of the liver; eosinophilic hyaline globules
Back Extra: Embryonal sarcoma of the liver
- Clinical: Rare primary malignant sarcoma typically affecting children (aged 5–15 years); it is associated with abdominal pain, distension, and occasionally Li–Fraumeni syndrome.
- Microscopic: Characterized by pleomorphic, spindled, or stellate cells in a myxoid stroma, often containing diagnostic PAS-positive eosinophilic hyaline (lysosomal) globules.
- Histologic Features: Often displays peripheral entrapment of bile ducts, extramedullary haematopoiesis, and high mitotic activity with atypical figures.
- Molecular: Commonly shares C19MC microRNA cluster alterations (e.g., MALAT1::C19MC fusion) with mesenchymal hamartoma, but uniquely features complex copy-number alterations and TP53 mutations in 90% of cases.
Embryonal sarcoma of the liver. Eosinophilic globules within the cytoplasm of tumour cells are a characteristic finding.
Embryonal sarcoma. Pleomorphic cells with cytoplasmic granules and globules.

Q: Unlike its benign counterpart, mesenchymal hamartoma, [...] uniformly harbours complex copy-number alterations and mutations in [...] (found in 90% of cases).
Embryonal sarcoma of the liver. There is a haphazard growth pattern. Note the multinucleated tumour giant cells and mitotic activity, including atypical mitotic figures.
Embryonal sarcoma. A tumour comprising spindle cells in sheets with some nuclear variability and frequent mitoses.
A: Embryonal sarcoma of the liver; TP53
Back Extra: Embryonal sarcoma of the liver
- Clinical: Rare primary malignant sarcoma typically affecting children (aged 5–15 years); it is associated with abdominal pain, distension, and occasionally Li–Fraumeni syndrome.
- Microscopic: Characterized by pleomorphic, spindled, or stellate cells in a myxoid stroma, often containing diagnostic PAS-positive eosinophilic hyaline (lysosomal) globules.
- Histologic Features: Often displays peripheral entrapment of bile ducts, extramedullary haematopoiesis, and high mitotic activity with atypical figures.
- Molecular: Commonly shares C19MC microRNA cluster alterations (e.g., MALAT1::C19MC fusion) with mesenchymal hamartoma, but uniquely features complex copy-number alterations and TP53 mutations in 90% of cases.
Embryonal sarcoma of the liver. There is a haphazard growth pattern. Note the multinucleated tumour giant cells and mitotic activity, including atypical mitotic figures.
Embryonal sarcoma. A tumour comprising spindle cells in sheets with some nuclear variability and frequent mitoses.

Q: Both mesenchymal hamartoma and [...] share alterations in the large microRNA cluster [...], such as the MALAT1 fusion.
Embryonal sarcoma of the liver. The tumour is composed of variably spindled, stellate, and pleomorphic cells embedded in a myxoid stroma.
Embryonal sarcoma. A tumour comprising spindle cells in sheets with some nuclear variability and frequent mitoses.
A: Embryonal sarcoma of the liver; C19MC
Back Extra: Embryonal sarcoma of the liver
- Clinical: Rare primary malignant sarcoma typically affecting children (aged 5–15 years); it is associated with abdominal pain, distension, and occasionally Li–Fraumeni syndrome.
- Microscopic: Characterized by pleomorphic, spindled, or stellate cells in a myxoid stroma, often containing diagnostic PAS-positive eosinophilic hyaline (lysosomal) globules.
- Histologic Features: Often displays peripheral entrapment of bile ducts, extramedullary haematopoiesis, and high mitotic activity with atypical figures.
- Molecular: Commonly shares C19MC microRNA cluster alterations (e.g., MALAT1::C19MC fusion) with mesenchymal hamartoma, but uniquely features complex copy-number alterations and TP53 mutations in 90% of cases.
Embryonal sarcoma of the liver. The tumour is composed of variably spindled, stellate, and pleomorphic cells embedded in a myxoid stroma.
Embryonal sarcoma. A tumour comprising spindle cells in sheets with some nuclear variability and frequent mitoses.

Q: At the periphery of the tumour, [...] often demonstrates the entrapment of [...] within the myxoid stroma.
Embryonal sarcoma of the liver. Entrapment of bile ducts is often seen at the periphery of the tumour. Note the myxoid stroma.
A: Embryonal sarcoma of the liver; bile ducts
Back Extra: Embryonal sarcoma of the liver
- Clinical: Rare primary malignant sarcoma typically affecting children (aged 5–15 years); it is associated with abdominal pain, distension, and occasionally Li–Fraumeni syndrome.
- Microscopic: Characterized by pleomorphic, spindled, or stellate cells in a myxoid stroma, often containing diagnostic PAS-positive eosinophilic hyaline (lysosomal) globules.
- Histologic Features: Often displays peripheral entrapment of bile ducts, extramedullary haematopoiesis, and high mitotic activity with atypical figures.
- Molecular: Commonly shares C19MC microRNA cluster alterations (e.g., MALAT1::C19MC fusion) with mesenchymal hamartoma, but uniquely features complex copy-number alterations and TP53 mutations in 90% of cases.
Embryonal sarcoma of the liver. Entrapment of bile ducts is often seen at the periphery of the tumour. Note the myxoid stroma.

Q: A 2-year-old child presents with a large, multicystic hepatic mass that grossly shows solid and cystic areas (see image). The most likely diagnosis is [...].
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal hamartoma. Dilated and branched bile duct–like structures in a loose mesenchymal stroma containing bland spindle-shaped cells.
Mesenchymal Hamartoma. Mesenchymal hamartoma showing a lobulated appearance and comprised of loose mesenchyme containing tortuous anastomosing and branching duct-like structures.
A: Mesenchymal hamartoma of the liver
Back Extra: Mesenchymal hamartoma of the liver
- Clinical: The third most common pediatric liver tumor; usually presents before age 3 with abdominal distention and is associated with Beckwith–Wiedemann syndrome and placental mesenchymal dysplasia.
- Microscopic: Characterized by a lobulated mass of hypocellular myxoid stroma containing stellate cells, branching/cystically dilated bile duct-like structures (often with a concentric collagen collar), and extramedullary hematopoiesis (>85% of cases).
- Ancillary: Spindle cells express vimentin and actin, while ductal structures are CK7/CK19 positive; Glypican-3 (GPC3) may be positive in both hepatocytes and tumor components.
- Genetics: Demonstrates characteristic chromosomal rearrangements at 19q13.4 (MHLB1), commonly t(19q13;11q13), and may rarely transform into undifferentiated embryonal sarcoma.
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal hamartoma. Dilated and branched bile duct–like structures in a loose mesenchymal stroma containing bland spindle-shaped cells.
Mesenchymal Hamartoma. Mesenchymal hamartoma showing a lobulated appearance and comprised of loose mesenchyme containing tortuous anastomosing and branching duct-like structures.

Q: Mesenchymal hamartoma of the liver characteristically demonstrates a molecular signature involving chromosomal rearrangements at the breakpoint [...].
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal Hamartoma. Mesenchymal hamartoma has a lobulated appearance with the lobules made up of loose mesenchyme containing islands of hepatocytes, bile duct-like structures and blood vessels.
A: 19q13.4
Back Extra: Mesenchymal hamartoma of the liver
- Clinical: The third most common pediatric liver tumor; usually presents before age 3 with abdominal distention and is associated with Beckwith–Wiedemann syndrome and placental mesenchymal dysplasia.
- Microscopic: Characterized by a lobulated mass of hypocellular myxoid stroma containing stellate cells, branching/cystically dilated bile duct-like structures (often with a concentric collagen collar), and extramedullary hematopoiesis (>85% of cases).
- Ancillary: Spindle cells express vimentin and actin, while ductal structures are CK7/CK19 positive; Glypican-3 (GPC3) may be positive in both hepatocytes and tumor components.
- Genetics: Demonstrates characteristic chromosomal rearrangements at 19q13.4 (MHLB1), commonly t(19q13;11q13), and may rarely transform into undifferentiated embryonal sarcoma.
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal Hamartoma. Mesenchymal hamartoma has a lobulated appearance with the lobules made up of loose mesenchyme containing islands of hepatocytes, bile duct-like structures and blood vessels.

Q: In Mesenchymal hamartoma of the liver, the bile duct–like structures are frequently surrounded by a diagnostic [fibrotic pattern] of collagenous tissue.
Mesenchymal hamartoma. Dilated bile duct–like structures surrounded by a concentric cuff of collagenous tissue.
Mesenchymal hamartoma. Dense collagenous stroma arranged concentrically around bile duct-like structures.
Mesenchymal hamartoma of the liver. Bile duct-like structures surrounded by a concentric cuff of collagenous tissue in a loose mesenchymal stroma.
A: concentric cuff
Back Extra: Mesenchymal hamartoma of the liver
- Clinical: The third most common pediatric liver tumor; usually presents before age 3 with abdominal distention and is associated with Beckwith–Wiedemann syndrome and placental mesenchymal dysplasia.
- Microscopic: Characterized by a lobulated mass of hypocellular myxoid stroma containing stellate cells, branching/cystically dilated bile duct-like structures (often with a concentric collagen collar), and extramedullary hematopoiesis (>85% of cases).
- Ancillary: Spindle cells express vimentin and actin, while ductal structures are CK7/CK19 positive; Glypican-3 (GPC3) may be positive in both hepatocytes and tumor components.
- Genetics: Demonstrates characteristic chromosomal rearrangements at 19q13.4 (MHLB1), commonly t(19q13;11q13), and may rarely transform into undifferentiated embryonal sarcoma.
Mesenchymal hamartoma. Dilated bile duct–like structures surrounded by a concentric cuff of collagenous tissue.
Mesenchymal hamartoma. Dense collagenous stroma arranged concentrically around bile duct-like structures.
Mesenchymal hamartoma of the liver. Bile duct-like structures surrounded by a concentric cuff of collagenous tissue in a loose mesenchymal stroma.

Q: Which pediatric overgrowth syndrome is most commonly associated with Mesenchymal hamartoma of the liver? [...]
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal hamartoma. Dilated and branched bile duct–like structures in a loose mesenchymal stroma containing bland spindle-shaped cells.
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct- like structures in abnormal configuration and interposed islands of hepatocytes.
A: Beckwith–Wiedemann syndrome
Back Extra: Mesenchymal hamartoma of the liver
- Clinical: The third most common pediatric liver tumor; usually presents before age 3 with abdominal distention and is associated with Beckwith–Wiedemann syndrome and placental mesenchymal dysplasia.
- Microscopic: Characterized by a lobulated mass of hypocellular myxoid stroma containing stellate cells, branching/cystically dilated bile duct-like structures (often with a concentric collagen collar), and extramedullary hematopoiesis (>85% of cases).
- Ancillary: Spindle cells express vimentin and actin, while ductal structures are CK7/CK19 positive; Glypican-3 (GPC3) may be positive in both hepatocytes and tumor components.
- Genetics: Demonstrates characteristic chromosomal rearrangements at 19q13.4 (MHLB1), commonly t(19q13;11q13), and may rarely transform into undifferentiated embryonal sarcoma.
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct-like structures in abnormal configuration and interposed islands of hepatocytes.
Mesenchymal hamartoma. Dilated and branched bile duct–like structures in a loose mesenchymal stroma containing bland spindle-shaped cells.
Mesenchymal hamartoma. Abundant mesenchymal stroma surrounding bile duct- like structures in abnormal configuration and interposed islands of hepatocytes.

Q: In [...] from a colorectal adenocarcinoma, the characteristic histologic pattern of necrotic debris within malignant glandular spaces is referred to as [...].
Metastatic colorectal adenocarcinoma to the liver showing tall columnar cells with characteristic dirty necrosis.
Metachronous liver metastasis from colorectal adenocarcinoma showing smooth borders accompanied by a cuff of chronic inflammatory cells.
A: Liver metastases; dirty necrosis
Back Extra: Liver metastases
- Clinical: The liver is the most common site for haematogenous metastasis from portal-drained organs, with colorectal (46%), pancreatic (10%), and breast (8%) cancers being the most frequent primaries.
- Microscopic: Grossly, metastases often present as multiple nodules, sometimes with central umbilication; histologically, they typically resemble the primary tumor, such as the tall columnar cells and 'dirty necrosis' seen in colorectal metastases.
- Ancillary: In cases of adenocarcinoma of unknown primary (CUP), molecular markers like FGFR2 rearrangements or IDH-family mutations may help reclassify a lesion as a small duct intrahepatic cholangiocarcinoma rather than a metastasis.
- Prognosis: While generally poor, outcomes improve with resectability (oligometastatic disease) and favorable molecular features like Microsatellite Instability (MSI), which predicts response to immunotherapy.
- Differential Diagnosis: For any liver metastasis/CUP, primary intrahepatic cholangiocarcinoma (for adenocarcinoma) or primary hepatic neuroendocrine tumour (for NET) must be excluded.
Metastatic colorectal adenocarcinoma to the liver showing tall columnar cells with characteristic dirty necrosis.
Metachronous liver metastasis from colorectal adenocarcinoma showing smooth borders accompanied by a cuff of chronic inflammatory cells.

Q: High-grade neuroendocrine [...] (e.g., small cell carcinoma) typically demonstrate nuclear moulding and a characteristic [...] pattern of cytokeratin expression.
Metastatic small cell carcinoma in the liver showing malignant cells with prominent nuclear moulding.
Metastatic small cell carcinoma in the liver: Dot-like cytokeratin expression.
A: Liver metastases; dot-like
Back Extra: Liver metastases
- Clinical: The liver is the most common site for haematogenous metastasis from portal-drained organs, with colorectal (46%), pancreatic (10%), and breast (8%) cancers being the most frequent primaries.
- Microscopic: Grossly, metastases often present as multiple nodules, sometimes with central umbilication; histologically, they typically resemble the primary tumor, such as the tall columnar cells and 'dirty necrosis' seen in colorectal metastases.
- Ancillary: In cases of adenocarcinoma of unknown primary (CUP), molecular markers like FGFR2 rearrangements or IDH-family mutations may help reclassify a lesion as a small duct intrahepatic cholangiocarcinoma rather than a metastasis.
- Prognosis: While generally poor, outcomes improve with resectability (oligometastatic disease) and favorable molecular features like Microsatellite Instability (MSI), which predicts response to immunotherapy.
- Differential Diagnosis: For any liver metastasis/CUP, primary intrahepatic cholangiocarcinoma (for adenocarcinoma) or primary hepatic neuroendocrine tumour (for NET) must be excluded.
Metastatic small cell carcinoma in the liver showing malignant cells with prominent nuclear moulding.
Metastatic small cell carcinoma in the liver: Dot-like cytokeratin expression.

Q: A hepatic mass in a 15-year-old female showing nested epithelioid cells, myofibroblastic stroma, and prominent psammomatous calcifications is most likely a [...].
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Psammomatous calcifications within the nested architecture and cellular stroma.
Higher power view showing both psammomatous calcifications and osseous metaplasia (H&E stain).
A: calcifying nested stromal-epithelial tumour of the liver
Back Extra: Calcifying nested stromal-epithelial tumour of the liver
- Clinical: Rare, low-grade hepatic neoplasm primarily affecting children, adolescents, and young adults with a female predominance; occasionally associated with Beckwith–Wiedemann syndrome.
- Microscopic: Characterized by a distinctive nested architecture of bland, uniform epithelioid to spindled cells surrounded by a cellular myofibroblastic stroma; hallmarks include psammomatous calcifications and/or osseous metaplasia.
- Ancillary Studies: Tumor cells characteristically show nuclear and cytoplasmic β-catenin expression and nuclear WT1; the surrounding myofibroblastic stroma expresses SMA and lacks nuclear β-catenin.
- Molecular: Consistently demonstrates somatic activating mutations or deletions in exon 3 of the CTNNB1 gene, alongside TERT promoter mutations.
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Psammomatous calcifications within the nested architecture and cellular stroma.
Higher power view showing both psammomatous calcifications and osseous metaplasia (H&E stain).

Q: In calcifying nested stromal-epithelial tumour of the liver, the tumor cells characteristically show aberrant nuclear and cytoplasmic staining for [...].
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Immunohistochemistry for β-catenin showing aberrant nuclear and cytoplasmic staining.
Nuclear and cytoplasmic expression of β-catenin within the nests.
A: β-catenin
Back Extra: Calcifying nested stromal-epithelial tumour of the liver
- Clinical: Rare, low-grade hepatic neoplasm primarily affecting children, adolescents, and young adults with a female predominance; occasionally associated with Beckwith–Wiedemann syndrome.
- Microscopic: Characterized by a distinctive nested architecture of bland, uniform epithelioid to spindled cells surrounded by a cellular myofibroblastic stroma; hallmarks include psammomatous calcifications and/or osseous metaplasia.
- Ancillary Studies: Tumor cells characteristically show nuclear and cytoplasmic β-catenin expression and nuclear WT1; the surrounding myofibroblastic stroma expresses SMA and lacks nuclear β-catenin.
- Molecular: Consistently demonstrates somatic activating mutations or deletions in exon 3 of the CTNNB1 gene, alongside TERT promoter mutations.
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Immunohistochemistry for β-catenin showing aberrant nuclear and cytoplasmic staining.
Nuclear and cytoplasmic expression of β-catenin within the nests.

Q: The nested cells in calcifying nested stromal-epithelial tumour of the liver frequently demonstrate nuclear expression of [...] (Wilms tumor 1).
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Scattered nuclear expression of WT-1 within the tumor nests.
A: WT1
Back Extra: Calcifying nested stromal-epithelial tumour of the liver
- Clinical: Rare, low-grade hepatic neoplasm primarily affecting children, adolescents, and young adults with a female predominance; occasionally associated with Beckwith–Wiedemann syndrome.
- Microscopic: Characterized by a distinctive nested architecture of bland, uniform epithelioid to spindled cells surrounded by a cellular myofibroblastic stroma; hallmarks include psammomatous calcifications and/or osseous metaplasia.
- Ancillary Studies: Tumor cells characteristically show nuclear and cytoplasmic β-catenin expression and nuclear WT1; the surrounding myofibroblastic stroma expresses SMA and lacks nuclear β-catenin.
- Molecular: Consistently demonstrates somatic activating mutations or deletions in exon 3 of the CTNNB1 gene, alongside TERT promoter mutations.
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Scattered nuclear expression of WT-1 within the tumor nests.

Q: The driver mutation typically identified in calcifying nested stromal-epithelial tumour of the liver involves the [...] gene.
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Nodular lesion with ovoid to irregular nests of neoplastic cells, separated by myofibroblastic stroma.
Bland and uniform cells with vesicular chromatin and eosinophilic cytoplasm arranged in irregular nests.
A: CTNNB1
Back Extra: Calcifying nested stromal-epithelial tumour of the liver
- Clinical: Rare, low-grade hepatic neoplasm primarily affecting children, adolescents, and young adults with a female predominance; occasionally associated with Beckwith–Wiedemann syndrome.
- Microscopic: Characterized by a distinctive nested architecture of bland, uniform epithelioid to spindled cells surrounded by a cellular myofibroblastic stroma; hallmarks include psammomatous calcifications and/or osseous metaplasia.
- Ancillary Studies: Tumor cells characteristically show nuclear and cytoplasmic β-catenin expression and nuclear WT1; the surrounding myofibroblastic stroma expresses SMA and lacks nuclear β-catenin.
- Molecular: Consistently demonstrates somatic activating mutations or deletions in exon 3 of the CTNNB1 gene, alongside TERT promoter mutations.
Nests of epithelioid and spindle cells surrounded by a cellular stroma containing a bile ductular proliferation (H&E stain).
Nodular lesion with ovoid to irregular nests of neoplastic cells, separated by myofibroblastic stroma.
Bland and uniform cells with vesicular chromatin and eosinophilic cytoplasm arranged in irregular nests.

Q: A liver biopsy reveals a malignant epithelial neoplasm with neuroendocrine differentiation. Before diagnosing a primary [...], clinicians must rigorously exclude [...] from an occult extrahepatic site.
Primary neuroendocrine tumour (NET) of the liver.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.
A: Hepatic neuroendocrine neoplasm; metastatic disease
Back Extra: Hepatic neuroendocrine neoplasms
- Clinical: Hepatic neuroendocrine neoplasms (NENs) are extremely rare (< 1% of hepatic primaries); metastatic disease from extrahepatic sites (e.g., small intestine, pancreas) must be rigorously excluded before confirming a liver primary.
- Microscopic (NET vs. NEC): Primary hepatic NETs are typically G1 or G2 (G3 NETs have not yet been reported in the liver), whereas NECs are poorly differentiated with a Ki-67 index typically > 50%.
- Mixed Neoplasms: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) most commonly consist of a combination of neuroendocrine carcinoma and hepatocellular carcinoma (HCC).
- Ancillary: Neoplastic cells express neuroendocrine markers (synaptophysin, chromogranin A, INSM1). NECs often show aberrant p53 expression and loss of RB1.
Primary neuroendocrine tumour (NET) of the liver.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.

Q: In the classification of primary [...], grade 1 and grade 2 neuroendocrine tumors (NETs) are recognized, but [...] NETs have not yet been reported in the liver.
Primary neuroendocrine tumour (NET) of the liver.
A: Hepatic neuroendocrine neoplasms; Grade 3 (G3)
Back Extra: Hepatic neuroendocrine neoplasms
- Clinical: Hepatic neuroendocrine neoplasms (NENs) are extremely rare (< 1% of hepatic primaries); metastatic disease from extrahepatic sites (e.g., small intestine, pancreas) must be rigorously excluded before confirming a liver primary.
- Microscopic (NET vs. NEC): Primary hepatic NETs are typically G1 or G2 (G3 NETs have not yet been reported in the liver), whereas NECs are poorly differentiated with a Ki-67 index typically > 50%.
- Mixed Neoplasms: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) most commonly consist of a combination of neuroendocrine carcinoma and hepatocellular carcinoma (HCC).
- Ancillary: Neoplastic cells express neuroendocrine markers (synaptophysin, chromogranin A, INSM1). NECs often show aberrant p53 expression and loss of RB1.
Primary neuroendocrine tumour (NET) of the liver.

Q: This image of a primary [...] shows a Ki-67 proliferation index of nearly 100%, which is characteristic of the [...] subtype.
Hepatic small cell neuroendocrine carcinoma (SCNEC) with a Ki-67 proliferation index near 100%.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.
A: Hepatic neuroendocrine neoplasm; neuroendocrine carcinoma (NEC)
Back Extra: Hepatic neuroendocrine neoplasms
- Clinical: Hepatic neuroendocrine neoplasms (NENs) are extremely rare (< 1% of hepatic primaries); metastatic disease from extrahepatic sites (e.g., small intestine, pancreas) must be rigorously excluded before confirming a liver primary.
- Microscopic (NET vs. NEC): Primary hepatic NETs are typically G1 or G2 (G3 NETs have not yet been reported in the liver), whereas NECs are poorly differentiated with a Ki-67 index typically > 50%.
- Mixed Neoplasms: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) most commonly consist of a combination of neuroendocrine carcinoma and hepatocellular carcinoma (HCC).
- Ancillary: Neoplastic cells express neuroendocrine markers (synaptophysin, chromogranin A, INSM1). NECs often show aberrant p53 expression and loss of RB1.
Hepatic small cell neuroendocrine carcinoma (SCNEC) with a Ki-67 proliferation index near 100%.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.

Q: A hepatic MiNEN (Mixed neuroendocrine-non-neuroendocrine neoplasm) most commonly shows a neuroendocrine component intermingled with or separate from a [...] component.
Mixed neuroendocrine and hepatocellular carcinoma showing two distinct morphological components.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.
A: hepatocellular carcinoma (HCC)
Back Extra: Hepatic neuroendocrine neoplasms
- Clinical: Hepatic neuroendocrine neoplasms (NENs) are extremely rare (< 1% of hepatic primaries); metastatic disease from extrahepatic sites (e.g., small intestine, pancreas) must be rigorously excluded before confirming a liver primary.
- Microscopic (NET vs. NEC): Primary hepatic NETs are typically G1 or G2 (G3 NETs have not yet been reported in the liver), whereas NECs are poorly differentiated with a Ki-67 index typically > 50%.
- Mixed Neoplasms: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) most commonly consist of a combination of neuroendocrine carcinoma and hepatocellular carcinoma (HCC).
- Ancillary: Neoplastic cells express neuroendocrine markers (synaptophysin, chromogranin A, INSM1). NECs often show aberrant p53 expression and loss of RB1.
Mixed neuroendocrine and hepatocellular carcinoma showing two distinct morphological components.
Hepatic mixed neuroendocrine and hepatocellular carcinoma showing neuroendocrine cells with scant cytoplasm and hyperchromatic chromatin.

Q: An endoscopic finding of a yellow submucosal mass (as seen in Figure 51479) that histologically shows mature adipocytes without atypia is diagnostic of a [...].
Lipoma. Note the mucosa coating the lesion, which is centred in the submucosa.
Lipoma. The lesion, centred in the submucosa, is composed of mature adipose tissue that forms a mass.
A: Lipoma
Back Extra: Lipoma
- Clinical: Most common in the large intestine (caecum and ascending colon), typically arising in the submucosa; large lesions may cause obstruction or colocolic intussusception.
- Microscopic: Composed of mature adipocytes of uniform size lacking cytological atypia or atypical hyperchromatic stromal cells.
- Syndromic Association: While rare, the presence of intramucosal gastrointestinal lipomas can be a herald for Cowden syndrome (PTEN hamartoma tumour syndrome).
- Ancillary/Pathogenesis: Approximately 75% harbor chromosomal aberrations, most frequently involving 12q13-q14 and rearrangements of the HMGA2 gene.
- Differential Diagnosis: Intramucosal variants must be distinguished from pseudolipomatosis, which is an artifact caused by insufflated gas during endoscopy.
Lipoma. Note the mucosa coating the lesion, which is centred in the submucosa.
Lipoma. The lesion, centred in the submucosa, is composed of mature adipose tissue that forms a mass.

Q: The pathogenesis of a [...] frequently involves simple chromosomal aberrations at 12q13-q14, often resulting in rearrangements of the [...] gene.
Lipoma. The lesion, centred in the submucosa, is composed of mature adipose tissue that forms a mass.
A: Lipoma; HMGA2
Back Extra: Lipoma
- Clinical: Most common in the large intestine (caecum and ascending colon), typically arising in the submucosa; large lesions may cause obstruction or colocolic intussusception.
- Microscopic: Composed of mature adipocytes of uniform size lacking cytological atypia or atypical hyperchromatic stromal cells.
- Syndromic Association: While rare, the presence of intramucosal gastrointestinal lipomas can be a herald for Cowden syndrome (PTEN hamartoma tumour syndrome).
- Ancillary/Pathogenesis: Approximately 75% harbor chromosomal aberrations, most frequently involving 12q13-q14 and rearrangements of the HMGA2 gene.
- Differential Diagnosis: Intramucosal variants must be distinguished from pseudolipomatosis, which is an artifact caused by insufflated gas during endoscopy.
Lipoma. The lesion, centred in the submucosa, is composed of mature adipose tissue that forms a mass.

Q: While usually an incidental finding, a gastrointestinal [...] can rarely present as a part of [...] syndrome, particularly if it is located within the mucosa.
Lipoma. A bit of the lesion is present in the mucosa, pressing the deep lamina propria to the side.
A: Lipoma; Cowden
Back Extra: Lipoma
- Clinical: Most common in the large intestine (caecum and ascending colon), typically arising in the submucosa; large lesions may cause obstruction or colocolic intussusception.
- Microscopic: Composed of mature adipocytes of uniform size lacking cytological atypia or atypical hyperchromatic stromal cells.
- Syndromic Association: While rare, the presence of intramucosal gastrointestinal lipomas can be a herald for Cowden syndrome (PTEN hamartoma tumour syndrome).
- Ancillary/Pathogenesis: Approximately 75% harbor chromosomal aberrations, most frequently involving 12q13-q14 and rearrangements of the HMGA2 gene.
- Differential Diagnosis: Intramucosal variants must be distinguished from pseudolipomatosis, which is an artifact caused by insufflated gas during endoscopy.
Lipoma. A bit of the lesion is present in the mucosa, pressing the deep lamina propria to the side.

Q: When evaluating a suspected intramucosal [...], the pathologist must distinguish it from [...], which is caused by the infiltration of air into the mucosa during endoscopy.
Lipoma. A bit of the lesion is present in the mucosa, pressing the deep lamina propria to the side.
A: Lipoma; pseudolipomatosis
Back Extra: Lipoma
- Clinical: Most common in the large intestine (caecum and ascending colon), typically arising in the submucosa; large lesions may cause obstruction or colocolic intussusception.
- Microscopic: Composed of mature adipocytes of uniform size lacking cytological atypia or atypical hyperchromatic stromal cells.
- Syndromic Association: While rare, the presence of intramucosal gastrointestinal lipomas can be a herald for Cowden syndrome (PTEN hamartoma tumour syndrome).
- Ancillary/Pathogenesis: Approximately 75% harbor chromosomal aberrations, most frequently involving 12q13-q14 and rearrangements of the HMGA2 gene.
- Differential Diagnosis: Intramucosal variants must be distinguished from pseudolipomatosis, which is an artifact caused by insufflated gas during endoscopy.
Lipoma. A bit of the lesion is present in the mucosa, pressing the deep lamina propria to the side.

Q: A large, polypoid mass in the esophagus, historically termed a 'giant fibrovascular polyp', that histologically shows mature fat with hyperchromatic stromal cells is diagnostic of [...].
Polypoid WDL. Scanning magnification view of a polypoid esophageal well-differentiated liposarcoma.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal well-differentiated liposarcoma. Higher-power view of hyperchromatic stromal cells and a mixed inflammatory cell infiltrate in an oesophageal well-differentiated liposarcoma.
A: well-differentiated liposarcoma
Back Extra: Liposarcoma
- Clinical: Primarily occurs in the esophagus as large, polypoid masses previously known as "giant fibrovascular polyps"; patients may present with dramatic symptoms like tumor regurgitation.
- Microscopic (WDL): Characterized by mature adipocytic tissue with significant size variation, transected by fibrous septa containing enlarged, hyperchromatic stromal spindle cells; lipoblasts are not required for diagnosis.
- Microscopic (DL): Defined by an abrupt transition from well-differentiated liposarcoma to a high-grade, mitotically active spindle cell sarcoma.
- Ancillary: Driven by MDM2 (12q15) amplification, which leads to MDM2 and/or CDK4 nuclear immunopositivity and serves as a critical diagnostic marker to distinguish it from benign lipomas.
Polypoid WDL. Scanning magnification view of a polypoid esophageal well-differentiated liposarcoma.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal well-differentiated liposarcoma. Higher-power view of hyperchromatic stromal cells and a mixed inflammatory cell infiltrate in an oesophageal well-differentiated liposarcoma.

Q: The hallmark molecular driver of both well-differentiated and dedifferentiated [...] is the amplification of the [...] gene on chromosome 12q15.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal dedifferentiated liposarcoma. B Undifferentiated spindle cell sarcoma in oesophageal dedifferentiated liposarcoma.
A: liposarcoma; MDM2
Back Extra: Liposarcoma
- Clinical: Primarily occurs in the esophagus as large, polypoid masses previously known as "giant fibrovascular polyps"; patients may present with dramatic symptoms like tumor regurgitation.
- Microscopic (WDL): Characterized by mature adipocytic tissue with significant size variation, transected by fibrous septa containing enlarged, hyperchromatic stromal spindle cells; lipoblasts are not required for diagnosis.
- Microscopic (DL): Defined by an abrupt transition from well-differentiated liposarcoma to a high-grade, mitotically active spindle cell sarcoma.
- Ancillary: Driven by MDM2 (12q15) amplification, which leads to MDM2 and/or CDK4 nuclear immunopositivity and serves as a critical diagnostic marker to distinguish it from benign lipomas.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal dedifferentiated liposarcoma. B Undifferentiated spindle cell sarcoma in oesophageal dedifferentiated liposarcoma.

Q: In [...], while mature adipocytes and hyperchromatic stromal cells are defining features, the presence of [...] is not strictly required for the diagnosis.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal well-differentiated liposarcoma. Higher-power view of hyperchromatic stromal cells and a mixed inflammatory cell infiltrate in an oesophageal well-differentiated liposarcoma.
A: well-differentiated liposarcoma; lipoblasts
Back Extra: Liposarcoma
- Clinical: Primarily occurs in the esophagus as large, polypoid masses previously known as "giant fibrovascular polyps"; patients may present with dramatic symptoms like tumor regurgitation.
- Microscopic (WDL): Characterized by mature adipocytic tissue with significant size variation, transected by fibrous septa containing enlarged, hyperchromatic stromal spindle cells; lipoblasts are not required for diagnosis.
- Microscopic (DL): Defined by an abrupt transition from well-differentiated liposarcoma to a high-grade, mitotically active spindle cell sarcoma.
- Ancillary: Driven by MDM2 (12q15) amplification, which leads to MDM2 and/or CDK4 nuclear immunopositivity and serves as a critical diagnostic marker to distinguish it from benign lipomas.
Oesophageal well-differentiated liposarcoma. Low-power view of a polypoid oesophageal liposarcoma, with overlying squamous mucosa. As in other locations, the tumour consists of mature fat transected by irregular fibrous septa containing enlarged, hyperchromatic stromal cells.
Oesophageal well-differentiated liposarcoma. Higher-power view of hyperchromatic stromal cells and a mixed inflammatory cell infiltrate in an oesophageal well-differentiated liposarcoma.

Q: The [...] subtype of GI [...] is characterized by an abrupt transition to high-grade spindle cell sarcoma and may result in distant metastasis.
Dedifferentiated oesophageal liposarcoma. A Dedifferentiated liposarcoma involving the oesophagus.
Oesophageal dedifferentiated liposarcoma. B Undifferentiated spindle cell sarcoma in oesophageal dedifferentiated liposarcoma.
A: dedifferentiated; liposarcoma
Back Extra: Liposarcoma
- Clinical: Primarily occurs in the esophagus as large, polypoid masses previously known as "giant fibrovascular polyps"; patients may present with dramatic symptoms like tumor regurgitation.
- Microscopic (WDL): Characterized by mature adipocytic tissue with significant size variation, transected by fibrous septa containing enlarged, hyperchromatic stromal spindle cells; lipoblasts are not required for diagnosis.
- Microscopic (DL): Defined by an abrupt transition from well-differentiated liposarcoma to a high-grade, mitotically active spindle cell sarcoma.
- Ancillary: Driven by MDM2 (12q15) amplification, which leads to MDM2 and/or CDK4 nuclear immunopositivity and serves as a critical diagnostic marker to distinguish it from benign lipomas.
Dedifferentiated oesophageal liposarcoma. A Dedifferentiated liposarcoma involving the oesophagus.
Oesophageal dedifferentiated liposarcoma. B Undifferentiated spindle cell sarcoma in oesophageal dedifferentiated liposarcoma.

Q: A well-circumscribed, hypocellular, densely collagenous mass in the gastric submucosa containing numerous psammomatous calcifications and plasma cells is most characteristic of [...].
Calcifying fibrous tumour. Calcifying fibrous tumour arising within the submucosa of the small intestine.
Calcifying fibrous tumour. Calcifying fibrous tumour with prominent psammomatous calcification.
Calcifying fibrous tumour. High-power view highlights the prominent plasma cells and dense collagenous stroma.
A: Calcifying fibrous tumour
Back Extra: Calcifying fibrous tumour
- Clinical: A benign, anatomically ubiquitous lesion with a predilection for the GI tract (stomach, small intestine) and peritoneum, typically presenting as a firm, gritty, well-circumscribed mass in young adults.
- Microscopic: Characterized by a hypocellular proliferation of slender spindle cells embedded in dense, hyalinized collagenous stroma with a sparse lymphoplasmacytic infiltrate.
- Diagnostic Features: Essential criteria include the presence of dystrophic or psammomatous calcifications within a dense collagenous background.
- Ancillary: Lesional cells are characteristically positive for CD34, while KIT (CD117), DOG1, STAT6, and ALK are negative.
- Prognosis: Entirely benign with no metastatic potential, though local recurrence occurs in approximately 10% of cases.
Calcifying fibrous tumour. Calcifying fibrous tumour arising within the submucosa of the small intestine.
Calcifying fibrous tumour. Calcifying fibrous tumour with prominent psammomatous calcification.
Calcifying fibrous tumour. High-power view highlights the prominent plasma cells and dense collagenous stroma.

Q: Although [...] is a benign entity with no metastatic potential, it carries a local recurrence rate of approximately [...]%.
Calcifying fibrous tumour. Calcifying fibrous tumour with prominent psammomatous calcification.
Calcifying fibrous tumour. Calcifying fibrous tumour with a lymphoplasmacytic infiltrate including a lymphoid follicle.
Calcifying fibrous tumour. High-power view highlights the prominent plasma cells and dense collagenous stroma.
A: Calcifying fibrous tumour; 10
Back Extra: Calcifying fibrous tumour
- Clinical: A benign, anatomically ubiquitous lesion with a predilection for the GI tract (stomach, small intestine) and peritoneum, typically presenting as a firm, gritty, well-circumscribed mass in young adults.
- Microscopic: Characterized by a hypocellular proliferation of slender spindle cells embedded in dense, hyalinized collagenous stroma with a sparse lymphoplasmacytic infiltrate.
- Diagnostic Features: Essential criteria include the presence of dystrophic or psammomatous calcifications within a dense collagenous background.
- Ancillary: Lesional cells are characteristically positive for CD34, while KIT (CD117), DOG1, STAT6, and ALK are negative.
- Prognosis: Entirely benign with no metastatic potential, though local recurrence occurs in approximately 10% of cases.
Calcifying fibrous tumour. Calcifying fibrous tumour with prominent psammomatous calcification.
Calcifying fibrous tumour. Calcifying fibrous tumour with a lymphoplasmacytic infiltrate including a lymphoid follicle.
Calcifying fibrous tumour. High-power view highlights the prominent plasma cells and dense collagenous stroma.

Q: A mesenteric mass demonstrating long, sweeping fascicles of myofibroblasts and showing nuclear [...] expression by immunohistochemistry is characteristic of [...].
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.
Fibromatosis. A subset of the tumour cell nuclei stains using β-catenin immunohistochemistry.
A: β-catenin; Desmoid fibromatosis
Back Extra: Desmoid fibromatosis
- Clinical: Locally aggressive, non-metastasizing spindle cell neoplasm most commonly arising in the small bowel mesentery; 10–15% of cases are associated with Familial Adenomatous Polyposis (FAP)/Gardner syndrome.
- Microscopic: Characterized by monomorphic, slender spindle cells arranged in long sweeping fascicles with an infiltrative growth pattern; the matrix may range from myxoid to hyalinized (keloid-like) collagen.
- Ancillary: Nuclear expression of β-catenin is seen in ≥ 80% of cases; somatic CTNNB1 mutations are common in sporadic cases, while APC mutations characterize FAP-related cases.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.
Fibromatosis. A subset of the tumour cell nuclei stains using β-catenin immunohistochemistry.

Q: Approximately 10–15% of patients with [...] have germline mutations in the [...] gene, which is often associated with Gardner syndrome.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.
A: Desmoid fibromatosis; APC
Back Extra: Desmoid fibromatosis
- Clinical: Locally aggressive, non-metastasizing spindle cell neoplasm most commonly arising in the small bowel mesentery; 10–15% of cases are associated with Familial Adenomatous Polyposis (FAP)/Gardner syndrome.
- Microscopic: Characterized by monomorphic, slender spindle cells arranged in long sweeping fascicles with an infiltrative growth pattern; the matrix may range from myxoid to hyalinized (keloid-like) collagen.
- Ancillary: Nuclear expression of β-catenin is seen in ≥ 80% of cases; somatic CTNNB1 mutations are common in sporadic cases, while APC mutations characterize FAP-related cases.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.

Q: In sporadic cases of [...], somatic activating mutations are most frequently found in exon 3 of the [...] gene.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.
A: Desmoid fibromatosis; CTNNB1
Back Extra: Desmoid fibromatosis
- Clinical: Locally aggressive, non-metastasizing spindle cell neoplasm most commonly arising in the small bowel mesentery; 10–15% of cases are associated with Familial Adenomatous Polyposis (FAP)/Gardner syndrome.
- Microscopic: Characterized by monomorphic, slender spindle cells arranged in long sweeping fascicles with an infiltrative growth pattern; the matrix may range from myxoid to hyalinized (keloid-like) collagen.
- Ancillary: Nuclear expression of β-catenin is seen in ≥ 80% of cases; somatic CTNNB1 mutations are common in sporadic cases, while APC mutations characterize FAP-related cases.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.

Q: Regarding the prognosis of [...], the presence of the [...] mutation in CTNNB1 is specifically considered a risk factor for local recurrence after surgery.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.
A: Desmoid fibromatosis; p.Ser45Phe
Back Extra: Desmoid fibromatosis
- Clinical: Locally aggressive, non-metastasizing spindle cell neoplasm most commonly arising in the small bowel mesentery; 10–15% of cases are associated with Familial Adenomatous Polyposis (FAP)/Gardner syndrome.
- Microscopic: Characterized by monomorphic, slender spindle cells arranged in long sweeping fascicles with an infiltrative growth pattern; the matrix may range from myxoid to hyalinized (keloid-like) collagen.
- Ancillary: Nuclear expression of β-catenin is seen in ≥ 80% of cases; somatic CTNNB1 mutations are common in sporadic cases, while APC mutations characterize FAP-related cases.
Desmoid fibromatosis with involvement of the small intestine. Medium power shows irregular fascicles of hypocellular fibrous tissue with small vessels.
Desmoid fibromatosis with involvement of the small intestine. The cells are spindle-shaped with minimal nuclear irregularity.

Q: An aggressive GI mesenchymal neoplasm showing nuclear [...] protein expression and rearrangements of the chromosome 15q gene is diagnostic of NUT-rearranged sarcoma.
NUTM1 sarcoma. A NUTM1-rearranged colonic sarcoma.
Epithelioid to rhabdoid cells in colonic NUTM1-rearranged sarcoma.
NUT protein expression in colonic NUTM1-rearranged sarcoma.
A: NUT
Back Extra: NUT-rearranged sarcoma
- Clinical: Extremely rare, highly aggressive mesenchymal tumors with a striking female predilection (94% of GI cases) and frequent metastasis to the liver, peritoneum, and lungs at presentation.
- Microscopic: Composed of monomorphic spindled cells, epithelioid to rhabdoid cells, or primitive round cells in a hyalinized background; amianthoid-like fibers are a characteristic feature.
- Ancillary: Diagnostic confirmation requires NUT protein IHC (nuclear positivity) and identification of NUTM1 or NUTM2 rearrangements, most commonly MXD4::NUTM1 or MXI1::NUTM1.
- Differential: Distinguished from SMARCB1-deficient tumors by the retained expression of SMARCB1 and SMARCA4, despite often sharing rhabdoid morphology.
NUTM1 sarcoma. A NUTM1-rearranged colonic sarcoma.
Epithelioid to rhabdoid cells in colonic NUTM1-rearranged sarcoma.
NUT protein expression in colonic NUTM1-rearranged sarcoma.

Q: In the gastrointestinal tract, NUT-rearranged sarcoma shows a strong predilection for the [...] sex (approximately 94% of reported cases).
NUTM1 sarcoma. A NUTM1-rearranged colonic sarcoma.
NUTM1 sarcoma involving the colonic muscularis propria and serosa.
A: female
Back Extra: NUT-rearranged sarcoma
- Clinical: Extremely rare, highly aggressive mesenchymal tumors with a striking female predilection (94% of GI cases) and frequent metastasis to the liver, peritoneum, and lungs at presentation.
- Microscopic: Composed of monomorphic spindled cells, epithelioid to rhabdoid cells, or primitive round cells in a hyalinized background; amianthoid-like fibers are a characteristic feature.
- Ancillary: Diagnostic confirmation requires NUT protein IHC (nuclear positivity) and identification of NUTM1 or NUTM2 rearrangements, most commonly MXD4::NUTM1 or MXI1::NUTM1.
- Differential: Distinguished from SMARCB1-deficient tumors by the retained expression of SMARCB1 and SMARCA4, despite often sharing rhabdoid morphology.
NUTM1 sarcoma. A NUTM1-rearranged colonic sarcoma.
NUTM1 sarcoma involving the colonic muscularis propria and serosa.

Q: Despite the presence of rhabdoid morphology in many cases of NUT-rearranged sarcoma, the immunohistochemical expression of [...] is characteristically retained.
Epithelioid to rhabdoid cells in colonic NUTM1-rearranged sarcoma.
Gastric NUTM1-rearranged sarcoma showing rhabdoid to round cells.
A: SMARCB1 (INI1)
Back Extra: NUT-rearranged sarcoma
- Clinical: Extremely rare, highly aggressive mesenchymal tumors with a striking female predilection (94% of GI cases) and frequent metastasis to the liver, peritoneum, and lungs at presentation.
- Microscopic: Composed of monomorphic spindled cells, epithelioid to rhabdoid cells, or primitive round cells in a hyalinized background; amianthoid-like fibers are a characteristic feature.
- Ancillary: Diagnostic confirmation requires NUT protein IHC (nuclear positivity) and identification of NUTM1 or NUTM2 rearrangements, most commonly MXD4::NUTM1 or MXI1::NUTM1.
- Differential: Distinguished from SMARCB1-deficient tumors by the retained expression of SMARCB1 and SMARCA4, despite often sharing rhabdoid morphology.
Epithelioid to rhabdoid cells in colonic NUTM1-rearranged sarcoma.
Gastric NUTM1-rearranged sarcoma showing rhabdoid to round cells.

Q: The most common genetic fusion partner for NUTM1 in NUT-rearranged sarcomas of the GI tract is [...].
Monomorphic spindled cells in a colonic NUTM1-rearranged sarcoma.
Nested and hyalinized architecture with amianthoid-like fibers in colonic NUTM1-rearranged sarcoma.
A: MXD4
Back Extra: NUT-rearranged sarcoma
- Clinical: Extremely rare, highly aggressive mesenchymal tumors with a striking female predilection (94% of GI cases) and frequent metastasis to the liver, peritoneum, and lungs at presentation.
- Microscopic: Composed of monomorphic spindled cells, epithelioid to rhabdoid cells, or primitive round cells in a hyalinized background; amianthoid-like fibers are a characteristic feature.
- Ancillary: Diagnostic confirmation requires NUT protein IHC (nuclear positivity) and identification of NUTM1 or NUTM2 rearrangements, most commonly MXD4::NUTM1 or MXI1::NUTM1.
- Differential: Distinguished from SMARCB1-deficient tumors by the retained expression of SMARCB1 and SMARCA4, despite often sharing rhabdoid morphology.
Monomorphic spindled cells in a colonic NUTM1-rearranged sarcoma.
Nested and hyalinized architecture with amianthoid-like fibers in colonic NUTM1-rearranged sarcoma.

Q: Synovial sarcoma of the GI tract is genetically defined by a translocation involving the [...] gene, most commonly fused with [...] or [...].
Synovial sarcoma. A monophasic synovial sarcoma with extension into the overlying mucosa.
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.
A: SS18; SSX1; SSX2
Back Extra: Synovial sarcoma
- Clinical: Rare in the GI tract, most commonly arising in the stomach; typically presents in middle age (median 50 years).
- Micro: Most cases are monophasic spindle cell tumours with uniform cytomorphology and scant matrix; a minority are biphasic (spindle cells + glandular elements).
- Ancillary: Characterized by SS18 gene rearrangements (usually SS18::SSX1 or SS18::SSX2).
- Immunohistochemistry: Diffuse strong nuclear expression of SS18::SSX is highly specific; focal positivity for Keratin, EMA, and CD99 is common.
- Differential: Can mimic GIST (rare KIT/DOG1 focal expression) or Ewing sarcoma (CD99 expression).
Synovial sarcoma. A monophasic synovial sarcoma with extension into the overlying mucosa.
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.

Q: A spindle cell neoplasm of the stomach that exhibits [pattern of expression] staining with an [SSX] monoclonal antibody is diagnostic of Synovial sarcoma.
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.
Synovial sarcoma. Distinct immunohistochemical nuclear expression of SS18::SSX.
A: diffuse strong nuclear; SS18
Back Extra: Synovial sarcoma
- Clinical: Rare in the GI tract, most commonly arising in the stomach; typically presents in middle age (median 50 years).
- Micro: Most cases are monophasic spindle cell tumours with uniform cytomorphology and scant matrix; a minority are biphasic (spindle cells + glandular elements).
- Ancillary: Characterized by SS18 gene rearrangements (usually SS18::SSX1 or SS18::SSX2).
- Immunohistochemistry: Diffuse strong nuclear expression of SS18::SSX is highly specific; focal positivity for Keratin, EMA, and CD99 is common.
- Differential: Can mimic GIST (rare KIT/DOG1 focal expression) or Ewing sarcoma (CD99 expression).
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.
Synovial sarcoma. Distinct immunohistochemical nuclear expression of SS18::SSX.

Q: In the monophasic spindle cell variant of Synovial sarcoma, epithelial markers such as [...] and [...] typically show only [distribution] positivity.
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.
Synovial sarcoma. Gastric synovial sarcoma showing infiltration into the overlying gastric mucosa and uniform cytomorphology (H&E).
A: Keratin; EMA; patchy or focal
Back Extra: Synovial sarcoma
- Clinical: Rare in the GI tract, most commonly arising in the stomach; typically presents in middle age (median 50 years).
- Micro: Most cases are monophasic spindle cell tumours with uniform cytomorphology and scant matrix; a minority are biphasic (spindle cells + glandular elements).
- Ancillary: Characterized by SS18 gene rearrangements (usually SS18::SSX1 or SS18::SSX2).
- Immunohistochemistry: Diffuse strong nuclear expression of SS18::SSX is highly specific; focal positivity for Keratin, EMA, and CD99 is common.
- Differential: Can mimic GIST (rare KIT/DOG1 focal expression) or Ewing sarcoma (CD99 expression).
Synovial Sarcoma. This monophasic tumour shows classic low-grade appearance with uniform cytomorphology and scant matrix.
Synovial sarcoma. Gastric synovial sarcoma showing infiltration into the overlying gastric mucosa and uniform cytomorphology (H&E).

Q: Synovial sarcoma can be confused with GIST because it may occasionally show focal immunoreactivity for [...] and [...].
Synovial sarcoma. A monophasic synovial sarcoma with extension into the overlying mucosa.
Synovial sarcoma. Gastric synovial sarcoma showing infiltration into the overlying gastric mucosa and uniform cytomorphology (H&E).
A: KIT (CD117); DOG1
Back Extra: Synovial sarcoma
- Clinical: Rare in the GI tract, most commonly arising in the stomach; typically presents in middle age (median 50 years).
- Micro: Most cases are monophasic spindle cell tumours with uniform cytomorphology and scant matrix; a minority are biphasic (spindle cells + glandular elements).
- Ancillary: Characterized by SS18 gene rearrangements (usually SS18::SSX1 or SS18::SSX2).
- Immunohistochemistry: Diffuse strong nuclear expression of SS18::SSX is highly specific; focal positivity for Keratin, EMA, and CD99 is common.
- Differential: Can mimic GIST (rare KIT/DOG1 focal expression) or Ewing sarcoma (CD99 expression).
Synovial sarcoma. A monophasic synovial sarcoma with extension into the overlying mucosa.
Synovial sarcoma. Gastric synovial sarcoma showing infiltration into the overlying gastric mucosa and uniform cytomorphology (H&E).

Q: A colonic biopsy showing spindled Schwann cells and clusters of ganglion cells with amphophilic cytoplasm expanding the lamina propria (as seen in the provided image) is diagnostic of [...].
Polypoid ganglioneuroma. The colonic crypts are surrounded by spindled Schwann cells and scattered ganglion cells.
Polypoid ganglioneuroma. Clusters of ganglion cells with amphophilic cytoplasm dispersed among Schwann cells.
Ganglioneuroma. At low magnification, a spindle cell proliferation expands the colonic lamina propria and submucosa.
A: Ganglioneuroma
Back Extra: Ganglioneuroma and ganglioneuromatosis
- Clinical: Presents in three settings: solitary (incidental), multiple polypoid (associated with PTEN hamartoma/Cowden syndrome), and diffuse ganglioneuromatosis (associated with MEN2B or NF1).
- Microscopic: Characterized by a benign mixture of mature ganglion cells, spindled Schwann cells, and unmyelinated axons expanding the lamina propria or distorting the myenteric plexus.
- Ancillary: Ganglion cells are positive for neurofilament, NSE, synaptophysin, and PHOX2B; Schwann cells are diffusely positive for S100.
- Prognosis: Benign course, but diagnosis is critical to trigger genetic screening for associated syndromes (PTEN, RET, or NF1 mutations).
Polypoid ganglioneuroma. The colonic crypts are surrounded by spindled Schwann cells and scattered ganglion cells.
Polypoid ganglioneuroma. Clusters of ganglion cells with amphophilic cytoplasm dispersed among Schwann cells.
Ganglioneuroma. At low magnification, a spindle cell proliferation expands the colonic lamina propria and submucosa.

Q: In the setting of Ganglioneuroma and ganglioneuromatosis, multiple polypoid lesions (ganglioneuromatous polyposis) are most frequently associated with [...] syndrome.
Polypoid ganglioneuroma. The colonic crypts are surrounded by spindled Schwann cells and scattered ganglion cells.
Polypoid ganglioneuroma. Clusters of ganglion cells with amphophilic cytoplasm dispersed among Schwann cells.
A: PTEN hamartoma (Cowden)
Back Extra: Ganglioneuroma and ganglioneuromatosis
- Clinical: Presents in three settings: solitary (incidental), multiple polypoid (associated with PTEN hamartoma/Cowden syndrome), and diffuse ganglioneuromatosis (associated with MEN2B or NF1).
- Microscopic: Characterized by a benign mixture of mature ganglion cells, spindled Schwann cells, and unmyelinated axons expanding the lamina propria or distorting the myenteric plexus.
- Ancillary: Ganglion cells are positive for neurofilament, NSE, synaptophysin, and PHOX2B; Schwann cells are diffusely positive for S100.
- Prognosis: Benign course, but diagnosis is critical to trigger genetic screening for associated syndromes (PTEN, RET, or NF1 mutations).
Polypoid ganglioneuroma. The colonic crypts are surrounded by spindled Schwann cells and scattered ganglion cells.
Polypoid ganglioneuroma. Clusters of ganglion cells with amphophilic cytoplasm dispersed among Schwann cells.

Q: Diffuse ganglioneuromatosis presenting with megacolon or motility disorders in infancy is a characteristic gastrointestinal manifestation of [...].
Ganglioneuroma. At low magnification, a spindle cell proliferation expands the colonic lamina propria and submucosa.
Ganglioneuroma. The lesion presses apart glands. It is composed of spindled Schwann cells and ganglion cells; the latter have mildly abnormal morphology.
A: MEN2B (Multiple Endocrine Neoplasia type 2B)
Back Extra: Ganglioneuroma and ganglioneuromatosis
- Clinical: Presents in three settings: solitary (incidental), multiple polypoid (associated with PTEN hamartoma/Cowden syndrome), and diffuse ganglioneuromatosis (associated with MEN2B or NF1).
- Microscopic: Characterized by a benign mixture of mature ganglion cells, spindled Schwann cells, and unmyelinated axons expanding the lamina propria or distorting the myenteric plexus.
- Ancillary: Ganglion cells are positive for neurofilament, NSE, synaptophysin, and PHOX2B; Schwann cells are diffusely positive for S100.
- Prognosis: Benign course, but diagnosis is critical to trigger genetic screening for associated syndromes (PTEN, RET, or NF1 mutations).
Ganglioneuroma. At low magnification, a spindle cell proliferation expands the colonic lamina propria and submucosa.
Ganglioneuroma. The lesion presses apart glands. It is composed of spindled Schwann cells and ganglion cells; the latter have mildly abnormal morphology.

Q: A small colonic polyp shows spindle cells in the lamina propria with a distinctive whorled architecture around mucosal crypts. This morphological pattern is characteristic of [...].
Perineurioma. The spindle cells whorl around crypts. Note the adjacent dilated crypts with serrated architecture.
Perineurioma. This colonic tumour is composed of elongated spindle cells with slender nuclei arranged in a whorled growth pattern. Mural perineuriomas of the GI tract are identical to soft tissue perineuriomas.
Perineurioma. The lesion replaces the lamina propria between colon glands.
A: Perineurioma
Back Extra: Perineurioma
- Clinical: Benign peripheral nerve sheath tumor, most common in the rectosigmoid colon as small (2–6 mm) incidental polyps; mural types are larger and non-polypoid.
- Microscopic: Characterized by a proliferation of uniform spindle cells with slender, tapering nuclei and long, bipolar cytoplasmic processes, typically showing a whorled growth pattern around crypts.
- Associations: Intramucosal lesions (formerly 'benign fibroblastic polyps') are frequently associated with serrated epithelial polyps, including hyperplastic polyps and sessile serrated lesions.
- Ancillary: Positive for EMA (delicate staining), claudin-1, and GLUT1; characteristically S100-negative, distinguishing it from other neural tumors.
- Molecular: Mural/submucosal variants often harbor chromosome 22 deletions (NF2); mucosal lesions are molecularly distinct and often coexist with BRAF-mutated serrated polyps.
Perineurioma. The spindle cells whorl around crypts. Note the adjacent dilated crypts with serrated architecture.
Perineurioma. This colonic tumour is composed of elongated spindle cells with slender nuclei arranged in a whorled growth pattern. Mural perineuriomas of the GI tract are identical to soft tissue perineuriomas.
Perineurioma. The lesion replaces the lamina propria between colon glands.

Q: Immunohistochemistry for [...] and [...] is typically positive in [...], while S100 is characteristically negative.
Perineurioma. The lesional cells contain slender nuclei and indistinct cytoplasm and are dispersed within a fine collagenous stroma.
Mucosal perineurioma. Immunohistochemistry for EMA is positive. Note the delicate pattern of staining.
Perineurioma. This example shows strong GLUT1 staining.
A: EMA; GLUT1; Perineurioma
Back Extra: Perineurioma
- Clinical: Benign peripheral nerve sheath tumor, most common in the rectosigmoid colon as small (2–6 mm) incidental polyps; mural types are larger and non-polypoid.
- Microscopic: Characterized by a proliferation of uniform spindle cells with slender, tapering nuclei and long, bipolar cytoplasmic processes, typically showing a whorled growth pattern around crypts.
- Associations: Intramucosal lesions (formerly 'benign fibroblastic polyps') are frequently associated with serrated epithelial polyps, including hyperplastic polyps and sessile serrated lesions.
- Ancillary: Positive for EMA (delicate staining), claudin-1, and GLUT1; characteristically S100-negative, distinguishing it from other neural tumors.
- Molecular: Mural/submucosal variants often harbor chromosome 22 deletions (NF2); mucosal lesions are molecularly distinct and often coexist with BRAF-mutated serrated polyps.
Perineurioma. The lesional cells contain slender nuclei and indistinct cytoplasm and are dispersed within a fine collagenous stroma.
Mucosal perineurioma. Immunohistochemistry for EMA is positive. Note the delicate pattern of staining.
Perineurioma. This example shows strong GLUT1 staining.

Q: Intramucosal [...] is frequently found associated with [...] polyps, which often harbor BRAF p.Val600Glu mutations.
Perineurioma. Mucosal lesions involve the lamina propria and are often associated with serrated epithelial polyps.
Perineurioma. The spindle cells whorl around crypts. Note the adjacent dilated crypts with serrated architecture.
A: Perineurioma; serrated epithelial
Back Extra: Perineurioma
- Clinical: Benign peripheral nerve sheath tumor, most common in the rectosigmoid colon as small (2–6 mm) incidental polyps; mural types are larger and non-polypoid.
- Microscopic: Characterized by a proliferation of uniform spindle cells with slender, tapering nuclei and long, bipolar cytoplasmic processes, typically showing a whorled growth pattern around crypts.
- Associations: Intramucosal lesions (formerly 'benign fibroblastic polyps') are frequently associated with serrated epithelial polyps, including hyperplastic polyps and sessile serrated lesions.
- Ancillary: Positive for EMA (delicate staining), claudin-1, and GLUT1; characteristically S100-negative, distinguishing it from other neural tumors.
- Molecular: Mural/submucosal variants often harbor chromosome 22 deletions (NF2); mucosal lesions are molecularly distinct and often coexist with BRAF-mutated serrated polyps.
Perineurioma. Mucosal lesions involve the lamina propria and are often associated with serrated epithelial polyps.
Perineurioma. The spindle cells whorl around crypts. Note the adjacent dilated crypts with serrated architecture.

Q: Mural/submucosal [...] are known to harbor deletions or monosomies of [...], likely targeting the NF2 tumor suppressor gene.
Perineurioma. This colonic tumour is composed of elongated spindle cells with slender nuclei arranged in a whorled growth pattern. Mural perineuriomas of the GI tract are identical to soft tissue perineuriomas.
A: Perineuriomas; chromosome 22
Back Extra: Perineurioma
- Clinical: Benign peripheral nerve sheath tumor, most common in the rectosigmoid colon as small (2–6 mm) incidental polyps; mural types are larger and non-polypoid.
- Microscopic: Characterized by a proliferation of uniform spindle cells with slender, tapering nuclei and long, bipolar cytoplasmic processes, typically showing a whorled growth pattern around crypts.
- Associations: Intramucosal lesions (formerly 'benign fibroblastic polyps') are frequently associated with serrated epithelial polyps, including hyperplastic polyps and sessile serrated lesions.
- Ancillary: Positive for EMA (delicate staining), claudin-1, and GLUT1; characteristically S100-negative, distinguishing it from other neural tumors.
- Molecular: Mural/submucosal variants often harbor chromosome 22 deletions (NF2); mucosal lesions are molecularly distinct and often coexist with BRAF-mutated serrated polyps.
Perineurioma. This colonic tumour is composed of elongated spindle cells with slender nuclei arranged in a whorled growth pattern. Mural perineuriomas of the GI tract are identical to soft tissue perineuriomas.

Q: The presence of a well-circumscribed spindle cell tumor in the gastric wall with a prominent [...] is highly characteristic of a gastrointestinal Schwannoma.
Gastric schwannoma. This well-circumscribed tumour involves the muscularis propria and has a prominent peripheral lymphoid cuff.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.
A: peripheral lymphoid cuff
Back Extra: Schwannoma
- Clinical: Gastrointestinal schwannomas are rare, benign mural masses most commonly found in the stomach of older adults (marked female predominance).
- Histopathology: Characterized by unencapsulated spindled cells with tapering nuclei arranged in short fascicles, typically surrounded by a prominent peripheral lymphoid cuff (with or without germinal centers).
- Subtypes: The microcystic reticular schwannoma is a distinct subtype featuring a net-like or lace-like architecture with a myxoid stroma.
- Ancillary: Strong and diffuse positivity for S100 and SOX10; notably negative for KIT, DOG1, and SMA, distinguishing it from GIST and leiomyoma.
- Genetics: Unlike soft tissue schwannomas, GI variants lack NF2 gene alterations and show distinct polysomy of chromosomes 22, 2, and 18.
Gastric schwannoma. This well-circumscribed tumour involves the muscularis propria and has a prominent peripheral lymphoid cuff.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.

Q: To differentiate a Schwannoma from a Gastrointestinal Stromal Tumor (GIST), a pathologist would expect the tumor cells to be strongly and diffusely positive for [...].
Schwannoma. B A SOX10 stain is strongly positive in the lesional cell nuclei, emphasizing the subtle nuclear palisading.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.
Gastric schwannoma. Some tumors show nuclear pallisading.
A: S100 and/or SOX10
Back Extra: Schwannoma
- Clinical: Gastrointestinal schwannomas are rare, benign mural masses most commonly found in the stomach of older adults (marked female predominance).
- Histopathology: Characterized by unencapsulated spindled cells with tapering nuclei arranged in short fascicles, typically surrounded by a prominent peripheral lymphoid cuff (with or without germinal centers).
- Subtypes: The microcystic reticular schwannoma is a distinct subtype featuring a net-like or lace-like architecture with a myxoid stroma.
- Ancillary: Strong and diffuse positivity for S100 and SOX10; notably negative for KIT, DOG1, and SMA, distinguishing it from GIST and leiomyoma.
- Genetics: Unlike soft tissue schwannomas, GI variants lack NF2 gene alterations and show distinct polysomy of chromosomes 22, 2, and 18.
Schwannoma. B A SOX10 stain is strongly positive in the lesional cell nuclei, emphasizing the subtle nuclear palisading.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.
Gastric schwannoma. Some tumors show nuclear pallisading.

Q: Gastrointestinal Schwannomas are genetically distinct from conventional soft tissue schwannomas because they typically lack [...] gene alterations.
Gastric schwannoma. This well-circumscribed tumour involves the muscularis propria and has a prominent peripheral lymphoid cuff.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.
A: NF2
Back Extra: Schwannoma
- Clinical: Gastrointestinal schwannomas are rare, benign mural masses most commonly found in the stomach of older adults (marked female predominance).
- Histopathology: Characterized by unencapsulated spindled cells with tapering nuclei arranged in short fascicles, typically surrounded by a prominent peripheral lymphoid cuff (with or without germinal centers).
- Subtypes: The microcystic reticular schwannoma is a distinct subtype featuring a net-like or lace-like architecture with a myxoid stroma.
- Ancillary: Strong and diffuse positivity for S100 and SOX10; notably negative for KIT, DOG1, and SMA, distinguishing it from GIST and leiomyoma.
- Genetics: Unlike soft tissue schwannomas, GI variants lack NF2 gene alterations and show distinct polysomy of chromosomes 22, 2, and 18.
Gastric schwannoma. This well-circumscribed tumour involves the muscularis propria and has a prominent peripheral lymphoid cuff.
Gastric schwannoma. The tumour is composed of loose fascicles of spindle cells with tapering nuclei and eosinophilic cytoplasm. Note the stromal collagen and lymphocytes.

Q: The [...] variant of Schwannoma is characterized by a net-like architecture and myxoid stroma, occurring as a submucosal lesion in the stomach or colon.
Microcystic reticular schwannoma. The tumour has a lace-like configuration.
A: microcystic reticular
Back Extra: Schwannoma
- Clinical: Gastrointestinal schwannomas are rare, benign mural masses most commonly found in the stomach of older adults (marked female predominance).
- Histopathology: Characterized by unencapsulated spindled cells with tapering nuclei arranged in short fascicles, typically surrounded by a prominent peripheral lymphoid cuff (with or without germinal centers).
- Subtypes: The microcystic reticular schwannoma is a distinct subtype featuring a net-like or lace-like architecture with a myxoid stroma.
- Ancillary: Strong and diffuse positivity for S100 and SOX10; notably negative for KIT, DOG1, and SMA, distinguishing it from GIST and leiomyoma.
- Genetics: Unlike soft tissue schwannomas, GI variants lack NF2 gene alterations and show distinct polysomy of chromosomes 22, 2, and 18.
Microcystic reticular schwannoma. The tumour has a lace-like configuration.

Q: A polypoid "grape-like" mass in the biliary tree showing a condensation of neoplastic cells beneath the epithelial surface (the cambium layer) is characteristic of [...].
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.
A: Botryoid embryonal rhabdomyosarcoma
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma (RMS) is exceptionally rare in the GI tract; the embryonal subtype (ERMS) is the most frequent, typically involving the biliary tree (presenting with jaundice) and associated with syndromes like DICER1, NF1, and Costello syndrome.
- Microscopic: Botryoid-type ERMS is characterized by a "grape-like" gross appearance and a histologic "cambium layer" (subepithelial condensation of primitive cells) beneath intact mucosa.
- Microscopic Details: Tumors exhibit a mix of primitive round cells and rhabdomyoblasts (strap cells) which may show diagnostic cross-striations within a myxoid or myxocollagenous stroma.
- Ancillary: Diagnosis is confirmed by skeletal muscle markers, including cytoplasmic Desmin and nuclear Myogenin (diffuse in Alveolar RMS, patchy in Embryonal RMS) and MYOD1.
- Molecular: Alveolar RMS is defined by PAX3 or PAX7 fusions with FOXO1; Spindle cell variants may harbor MYOD1 mutations (p.Leu122Arg) or NCOA2 fusions.
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.

Q: In Rhabdomyosarcoma, the most specific nuclear transcription factors used for immunohistochemical confirmation are [...] and [...].
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.
A: Myogenin; MYOD1
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma (RMS) is exceptionally rare in the GI tract; the embryonal subtype (ERMS) is the most frequent, typically involving the biliary tree (presenting with jaundice) and associated with syndromes like DICER1, NF1, and Costello syndrome.
- Microscopic: Botryoid-type ERMS is characterized by a "grape-like" gross appearance and a histologic "cambium layer" (subepithelial condensation of primitive cells) beneath intact mucosa.
- Microscopic Details: Tumors exhibit a mix of primitive round cells and rhabdomyoblasts (strap cells) which may show diagnostic cross-striations within a myxoid or myxocollagenous stroma.
- Ancillary: Diagnosis is confirmed by skeletal muscle markers, including cytoplasmic Desmin and nuclear Myogenin (diffuse in Alveolar RMS, patchy in Embryonal RMS) and MYOD1.
- Molecular: Alveolar RMS is defined by PAX3 or PAX7 fusions with FOXO1; Spindle cell variants may harbor MYOD1 mutations (p.Leu122Arg) or NCOA2 fusions.
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.

Q: Biliary embryonal Rhabdomyosarcoma is frequently associated with germline mutations in the [...] gene.
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.
A: DICER1
Back Extra: Rhabdomyosarcoma
- Clinical: Rhabdomyosarcoma (RMS) is exceptionally rare in the GI tract; the embryonal subtype (ERMS) is the most frequent, typically involving the biliary tree (presenting with jaundice) and associated with syndromes like DICER1, NF1, and Costello syndrome.
- Microscopic: Botryoid-type ERMS is characterized by a "grape-like" gross appearance and a histologic "cambium layer" (subepithelial condensation of primitive cells) beneath intact mucosa.
- Microscopic Details: Tumors exhibit a mix of primitive round cells and rhabdomyoblasts (strap cells) which may show diagnostic cross-striations within a myxoid or myxocollagenous stroma.
- Ancillary: Diagnosis is confirmed by skeletal muscle markers, including cytoplasmic Desmin and nuclear Myogenin (diffuse in Alveolar RMS, patchy in Embryonal RMS) and MYOD1.
- Molecular: Alveolar RMS is defined by PAX3 or PAX7 fusions with FOXO1; Spindle cell variants may harbor MYOD1 mutations (p.Leu122Arg) or NCOA2 fusions.
Embryonal rhabdomyosarcoma. There is a condensation of tumour cells under the epithelial surface (cambium layer) and cells in a myxoid matrix.
Embryonal rhabdomyosarcoma. The tumour is composed of a combination of round cells, spindled cells, and pleomorphic cells. The spindled strap cells in the centre show cross-striations.

Q: Gastric GISTs in young patients that demonstrate a [...] growth pattern and [...] morphology are highly suggestive of a [...].
Succinate dehydrogenase–deficient stromal tumour arising in the stomach showing a multinodular/multilobulated growth pattern.
High-power view showing the characteristic multinodular, multilobulated or plexiform growth pattern.
SDH-deficient gastrointestinal stromal tumours are usually epithelioid predominant.
A: multinodular or plexiform; epithelioid; SDH-deficient gastrointestinal stromal tumour
Back Extra: SDH-deficient gastrointestinal stromal tumour
- Clinical: Arises almost exclusively in the stomach; typically affects children and young adults (median age 22) with a 3:1 female predominance.
- Micro: Characteristically displays a multinodular, multilobulated, or plexiform growth pattern with an epithelioid-predominant morphology.
- Ancillary: Diagnostic hallmark is the immunohistochemical loss of SDHB expression; tumours are typically wild-type for somatic KIT and PDGFRA mutations.
- Genetics: Associated with germline SDH mutations (SDHA/B/C/D) or SDHC promoter hypermethylation (Carney triad); genetic counseling is mandatory.
- Prognosis: Conventional GIST risk stratification (size/mitosis) is unreliable; high rate of lymph node and liver metastasis, but often follows an indolent course.
Succinate dehydrogenase–deficient stromal tumour arising in the stomach showing a multinodular/multilobulated growth pattern.
High-power view showing the characteristic multinodular, multilobulated or plexiform growth pattern.
SDH-deficient gastrointestinal stromal tumours are usually epithelioid predominant.

Q: The essential immunohistochemical finding for a diagnosis of SDH-deficient gastrointestinal stromal tumour is the loss of [...] expression.
Immunohistochemistry for SDHB shows loss of staining in tumour cells, with endothelial cells serving as an internal positive control.
Typical epithelioid-predominant histology of SDH-deficient GIST.
A: SDHB
Back Extra: SDH-deficient gastrointestinal stromal tumour
- Clinical: Arises almost exclusively in the stomach; typically affects children and young adults (median age 22) with a 3:1 female predominance.
- Micro: Characteristically displays a multinodular, multilobulated, or plexiform growth pattern with an epithelioid-predominant morphology.
- Ancillary: Diagnostic hallmark is the immunohistochemical loss of SDHB expression; tumours are typically wild-type for somatic KIT and PDGFRA mutations.
- Genetics: Associated with germline SDH mutations (SDHA/B/C/D) or SDHC promoter hypermethylation (Carney triad); genetic counseling is mandatory.
- Prognosis: Conventional GIST risk stratification (size/mitosis) is unreliable; high rate of lymph node and liver metastasis, but often follows an indolent course.
Immunohistochemistry for SDHB shows loss of staining in tumour cells, with endothelial cells serving as an internal positive control.
Typical epithelioid-predominant histology of SDH-deficient GIST.

Q: Unlike the majority of adult GISTs, the [...] frequently metastasizes to [...].
Succinate dehydrogenase–deficient stromal tumour arising in the stomach showing a multinodular/multilobulated growth pattern.
Individual lobules of the SDH-deficient GIST separated by bands of non-neoplastic smooth muscle.
A: SDH-deficient gastrointestinal stromal tumour; lymph nodes
Back Extra: SDH-deficient gastrointestinal stromal tumour
- Clinical: Arises almost exclusively in the stomach; typically affects children and young adults (median age 22) with a 3:1 female predominance.
- Micro: Characteristically displays a multinodular, multilobulated, or plexiform growth pattern with an epithelioid-predominant morphology.
- Ancillary: Diagnostic hallmark is the immunohistochemical loss of SDHB expression; tumours are typically wild-type for somatic KIT and PDGFRA mutations.
- Genetics: Associated with germline SDH mutations (SDHA/B/C/D) or SDHC promoter hypermethylation (Carney triad); genetic counseling is mandatory.
- Prognosis: Conventional GIST risk stratification (size/mitosis) is unreliable; high rate of lymph node and liver metastasis, but often follows an indolent course.
Succinate dehydrogenase–deficient stromal tumour arising in the stomach showing a multinodular/multilobulated growth pattern.
Individual lobules of the SDH-deficient GIST separated by bands of non-neoplastic smooth muscle.

Q: SDH-deficient gastrointestinal stromal tumour associated with pulmonary chondroma and extra-adrenal paraganglioma is known as the [...].
Epithelioid predominant morphology with subtle nesting of the neoplastic cells.
A: Carney triad
Back Extra: SDH-deficient gastrointestinal stromal tumour
- Clinical: Arises almost exclusively in the stomach; typically affects children and young adults (median age 22) with a 3:1 female predominance.
- Micro: Characteristically displays a multinodular, multilobulated, or plexiform growth pattern with an epithelioid-predominant morphology.
- Ancillary: Diagnostic hallmark is the immunohistochemical loss of SDHB expression; tumours are typically wild-type for somatic KIT and PDGFRA mutations.
- Genetics: Associated with germline SDH mutations (SDHA/B/C/D) or SDHC promoter hypermethylation (Carney triad); genetic counseling is mandatory.
- Prognosis: Conventional GIST risk stratification (size/mitosis) is unreliable; high rate of lymph node and liver metastasis, but often follows an indolent course.
Epithelioid predominant morphology with subtle nesting of the neoplastic cells.

Q: The diagnosis of PEComa (including hepatic angiomyolipoma) is supported by the co-expression of smooth muscle markers and [...] markers, of which [...] is considered the most reliable.
Angiomyolipoma. HMB45 is the best confirmatory diagnostic marker.
Angiomyolipoma. The epithelioid tumour cells contain abundant granular eosinophilic to clear cytoplasm with admixed adipocytes.
A: melanocytic; HMB45
Back Extra: PEComa
- Clinical: Mesenchymal neoplasms arising in the liver, colon, and small intestine; 5–10% of hepatic cases are associated with Tuberous Sclerosis.
- Micro: Composed of perivascular epithelioid cells (PECs) with granular eosinophilic/clear cytoplasm; Angiomyolipomas characteristically contain adipocytes, thick-walled vessels, and epithelioid cells.
- Ancillary: Co-expression of melanocytic (HMB45, Melan-A, PNL2) and smooth muscle markers (SMA, desmin); Cathepsin K is frequently positive.
- Molecular: Most harbor biallelic inactivation of TSC2 (or rarely TSC1), leading to mTOR activation; a subset contains TFE3 gene fusions (e.g., SFPQ::TFE3).
- Prognosis: Malignancy in GI PEComas is suggested by size >5cm, mitotic activity >1/mm², necrosis, and marked nuclear pleomorphism.
Angiomyolipoma. HMB45 is the best confirmatory diagnostic marker.
Angiomyolipoma. The epithelioid tumour cells contain abundant granular eosinophilic to clear cytoplasm with admixed adipocytes.

Q: In the liver, this lesion composed of adipocytes, thick-walled blood vessels, and epithelioid cells (as seen in Figure 1026) is a specialized form of PEComa known as [...].
Angiomyolipoma. Hepatic angiomyolipoma showing characteristic components: adipocytes, thick-walled blood vessels, and epithelioid cells.
Hepatic epithelioid angiomyolipoma. Epithelioid cells with clear to lightly eosinophilic cytoplasm arranged around a thick-walled blood vessel.
A: angiomyolipoma
Back Extra: PEComa
- Clinical: Mesenchymal neoplasms arising in the liver, colon, and small intestine; 5–10% of hepatic cases are associated with Tuberous Sclerosis.
- Micro: Composed of perivascular epithelioid cells (PECs) with granular eosinophilic/clear cytoplasm; Angiomyolipomas characteristically contain adipocytes, thick-walled vessels, and epithelioid cells.
- Ancillary: Co-expression of melanocytic (HMB45, Melan-A, PNL2) and smooth muscle markers (SMA, desmin); Cathepsin K is frequently positive.
- Molecular: Most harbor biallelic inactivation of TSC2 (or rarely TSC1), leading to mTOR activation; a subset contains TFE3 gene fusions (e.g., SFPQ::TFE3).
- Prognosis: Malignancy in GI PEComas is suggested by size >5cm, mitotic activity >1/mm², necrosis, and marked nuclear pleomorphism.
Angiomyolipoma. Hepatic angiomyolipoma showing characteristic components: adipocytes, thick-walled blood vessels, and epithelioid cells.
Hepatic epithelioid angiomyolipoma. Epithelioid cells with clear to lightly eosinophilic cytoplasm arranged around a thick-walled blood vessel.

Q: Most GI tract and hepatic PEComas harbor mutations in the [...] gene, which results in the constitutive activation of the [...] signaling pathway.
Angiomyolipoma. Hepatic angiomyolipoma showing characteristic components: adipocytes, thick-walled blood vessels, and epithelioid cells.
Angiomyolipoma. The epithelioid tumour cells contain abundant granular eosinophilic to clear cytoplasm with admixed adipocytes.
A: TSC2; mTOR
Back Extra: PEComa
- Clinical: Mesenchymal neoplasms arising in the liver, colon, and small intestine; 5–10% of hepatic cases are associated with Tuberous Sclerosis.
- Micro: Composed of perivascular epithelioid cells (PECs) with granular eosinophilic/clear cytoplasm; Angiomyolipomas characteristically contain adipocytes, thick-walled vessels, and epithelioid cells.
- Ancillary: Co-expression of melanocytic (HMB45, Melan-A, PNL2) and smooth muscle markers (SMA, desmin); Cathepsin K is frequently positive.
- Molecular: Most harbor biallelic inactivation of TSC2 (or rarely TSC1), leading to mTOR activation; a subset contains TFE3 gene fusions (e.g., SFPQ::TFE3).
- Prognosis: Malignancy in GI PEComas is suggested by size >5cm, mitotic activity >1/mm², necrosis, and marked nuclear pleomorphism.
Angiomyolipoma. Hepatic angiomyolipoma showing characteristic components: adipocytes, thick-walled blood vessels, and epithelioid cells.
Angiomyolipoma. The epithelioid tumour cells contain abundant granular eosinophilic to clear cytoplasm with admixed adipocytes.

Q: For gastrointestinal PEComas, a mitotic count of greater than [...] per mm² is a major risk factor for metastatic behavior and malignant classification.
Malignant colonic PEComa involving the colon of an adult female.
Malignant colonic PEComa showing marked nuclear atypia and an atypical mitotic figure (center).
A: 1
Back Extra: PEComa
- Clinical: Mesenchymal neoplasms arising in the liver, colon, and small intestine; 5–10% of hepatic cases are associated with Tuberous Sclerosis.
- Micro: Composed of perivascular epithelioid cells (PECs) with granular eosinophilic/clear cytoplasm; Angiomyolipomas characteristically contain adipocytes, thick-walled vessels, and epithelioid cells.
- Ancillary: Co-expression of melanocytic (HMB45, Melan-A, PNL2) and smooth muscle markers (SMA, desmin); Cathepsin K is frequently positive.
- Molecular: Most harbor biallelic inactivation of TSC2 (or rarely TSC1), leading to mTOR activation; a subset contains TFE3 gene fusions (e.g., SFPQ::TFE3).
- Prognosis: Malignancy in GI PEComas is suggested by size >5cm, mitotic activity >1/mm², necrosis, and marked nuclear pleomorphism.
Malignant colonic PEComa involving the colon of an adult female.
Malignant colonic PEComa showing marked nuclear atypia and an atypical mitotic figure (center).

Q: PEComas harbor gene fusions involving [...] often show a nested/alveolar architecture and lack typical melanocytic marker expression like SOX10.
SFPQ::TFE3-fused colonic PEComa presenting in the colon of an adolescent girl.
A: TFE3
Back Extra: PEComa
- Clinical: Mesenchymal neoplasms arising in the liver, colon, and small intestine; 5–10% of hepatic cases are associated with Tuberous Sclerosis.
- Micro: Composed of perivascular epithelioid cells (PECs) with granular eosinophilic/clear cytoplasm; Angiomyolipomas characteristically contain adipocytes, thick-walled vessels, and epithelioid cells.
- Ancillary: Co-expression of melanocytic (HMB45, Melan-A, PNL2) and smooth muscle markers (SMA, desmin); Cathepsin K is frequently positive.
- Molecular: Most harbor biallelic inactivation of TSC2 (or rarely TSC1), leading to mTOR activation; a subset contains TFE3 gene fusions (e.g., SFPQ::TFE3).
- Prognosis: Malignancy in GI PEComas is suggested by size >5cm, mitotic activity >1/mm², necrosis, and marked nuclear pleomorphism.
SFPQ::TFE3-fused colonic PEComa presenting in the colon of an adolescent girl.

Q: Hepatic [...] is classically associated with historical exposure to the contrast agent [...] or industrial exposure to [...] monomers.
Angiosarcoma. A well-differentiated angiosarcoma infiltrating hepatic parenchyma. Note the irregular vascular channels lined by endothelial cells with hyperchromatic nuclei showing a hobnail appearance.
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.
Angiosarcoma. The tumour cells surround hepatic cords and form solid sheets of spindle cells.
A: Angiosarcoma; Thorotrast; vinyl chloride
Back Extra: Angiosarcoma
- Clinical: Highly aggressive malignancy with a male predominance (7th decade); primary hepatic cases are four times more common than intestinal ones and are linked to vinyl chloride, arsenic, Thorotrast, and radiation exposure.
- Microscopic: High-grade neoplasm showing spindled, vasoformative, or epithelioid growth; characteristic features include hobnail-like endothelial cells, sinusoidal infiltration, and marked nuclear atypia with coagulative necrosis.
- Ancillary: Consistently positive for ERG (nuclear), CD31, and CD34; epithelioid variants may show aberrant expression of keratins and EMA, potentially mimicking carcinoma.
- Differential Diagnosis: Must be distinguished from epithelioid haemangioendothelioma, which is characterized by the WWTR1::CAMTA1 fusion and CAMTA1 immunoreactivity.
Angiosarcoma. A well-differentiated angiosarcoma infiltrating hepatic parenchyma. Note the irregular vascular channels lined by endothelial cells with hyperchromatic nuclei showing a hobnail appearance.
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.
Angiosarcoma. The tumour cells surround hepatic cords and form solid sheets of spindle cells.

Q: While [...] can mimic carcinoma due to aberrant [...] or EMA expression, it is reliably identified by nuclear staining for the vascular marker [...].
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.
A: Angiosarcoma; keratin; ERG
Back Extra: Angiosarcoma
- Clinical: Highly aggressive malignancy with a male predominance (7th decade); primary hepatic cases are four times more common than intestinal ones and are linked to vinyl chloride, arsenic, Thorotrast, and radiation exposure.
- Microscopic: High-grade neoplasm showing spindled, vasoformative, or epithelioid growth; characteristic features include hobnail-like endothelial cells, sinusoidal infiltration, and marked nuclear atypia with coagulative necrosis.
- Ancillary: Consistently positive for ERG (nuclear), CD31, and CD34; epithelioid variants may show aberrant expression of keratins and EMA, potentially mimicking carcinoma.
- Differential Diagnosis: Must be distinguished from epithelioid haemangioendothelioma, which is characterized by the WWTR1::CAMTA1 fusion and CAMTA1 immunoreactivity.
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.

Q: Based on the microscopic image showing irregular vascular channels with hyperchromatic, atypical cells in the liver, the diagnosis is [...].
Angiosarcoma. A well-differentiated angiosarcoma infiltrating hepatic parenchyma. Note the irregular vascular channels lined by endothelial cells with hyperchromatic nuclei showing a hobnail appearance.
A: Angiosarcoma
Back Extra: Angiosarcoma
- Clinical: Highly aggressive malignancy with a male predominance (7th decade); primary hepatic cases are four times more common than intestinal ones and are linked to vinyl chloride, arsenic, Thorotrast, and radiation exposure.
- Microscopic: High-grade neoplasm showing spindled, vasoformative, or epithelioid growth; characteristic features include hobnail-like endothelial cells, sinusoidal infiltration, and marked nuclear atypia with coagulative necrosis.
- Ancillary: Consistently positive for ERG (nuclear), CD31, and CD34; epithelioid variants may show aberrant expression of keratins and EMA, potentially mimicking carcinoma.
- Differential Diagnosis: Must be distinguished from epithelioid haemangioendothelioma, which is characterized by the WWTR1::CAMTA1 fusion and CAMTA1 immunoreactivity.
Angiosarcoma. A well-differentiated angiosarcoma infiltrating hepatic parenchyma. Note the irregular vascular channels lined by endothelial cells with hyperchromatic nuclei showing a hobnail appearance.

Q: To differentiate a high-grade [...] from epithelioid haemangioendothelioma, molecular or immunohistochemical testing for [...] (representing the WWTR1::CAMTA1 fusion) should be performed.
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.
A: Angiosarcoma; CAMTA1
Back Extra: Angiosarcoma
- Clinical: Highly aggressive malignancy with a male predominance (7th decade); primary hepatic cases are four times more common than intestinal ones and are linked to vinyl chloride, arsenic, Thorotrast, and radiation exposure.
- Microscopic: High-grade neoplasm showing spindled, vasoformative, or epithelioid growth; characteristic features include hobnail-like endothelial cells, sinusoidal infiltration, and marked nuclear atypia with coagulative necrosis.
- Ancillary: Consistently positive for ERG (nuclear), CD31, and CD34; epithelioid variants may show aberrant expression of keratins and EMA, potentially mimicking carcinoma.
- Differential Diagnosis: Must be distinguished from epithelioid haemangioendothelioma, which is characterized by the WWTR1::CAMTA1 fusion and CAMTA1 immunoreactivity.
Angiosarcoma. A poorly differentiated angiosarcoma showing marked nuclear atypia. The tumour infiltrates hepatic parenchyma and forms micropapillary structures.

Q: In the category of Benign vascular anomalies and vascular tumours, a liver lesion characterized by multilocular blood-filled structures and large, thin-walled spaces lined by flattened endothelium is a [...].
Cavernous haemangioma. Note the large, thin-walled vascular spaces.
A: hepatic cavernous haemangioma
Back Extra: Benign vascular anomalies and vascular tumours
- Clinical: Hepatic cavernous haemangiomas are the most common benign liver tumours in adults; Infantile haemangiomas (HIHs) can present with cardiac failure or coagulopathy.
- Microscopic: Features range from large, thin-walled spaces in cavernous haemangiomas to capillary-like vessels with endothelial hobnailing and hyaline globules in anastomosing haemangiomas.
- Ancillary: GLUT1 immunohistochemistry is the gold standard diagnostic tool to distinguish infantile haemangioma (positive) from hepatic congenital haemangioma (negative).
- Differential: Benign lesions like hepatic small vessel neoplasms lack the severe atypia, multilayering, and high Ki-67 index (>10%) seen in angiosarcoma.
Cavernous haemangioma. Note the large, thin-walled vascular spaces.

Q: When evaluating Benign vascular anomalies and vascular tumours of the liver, the marker [...] shows diffuse strong positivity in infantile haemangiomas (HIH) but is negative in congenital haemangiomas (HCH).
Infantile haemangioma (infantile haemangioendothelioma). Vessels are lined by a single layer of plump endothelial cells surrounded by a scant fibrous stroma; note the scattered bile ducts (Masson trichrome staining).
A: GLUT1
Back Extra: Benign vascular anomalies and vascular tumours
- Clinical: Hepatic cavernous haemangiomas are the most common benign liver tumours in adults; Infantile haemangiomas (HIHs) can present with cardiac failure or coagulopathy.
- Microscopic: Features range from large, thin-walled spaces in cavernous haemangiomas to capillary-like vessels with endothelial hobnailing and hyaline globules in anastomosing haemangiomas.
- Ancillary: GLUT1 immunohistochemistry is the gold standard diagnostic tool to distinguish infantile haemangioma (positive) from hepatic congenital haemangioma (negative).
- Differential: Benign lesions like hepatic small vessel neoplasms lack the severe atypia, multilayering, and high Ki-67 index (>10%) seen in angiosarcoma.
Infantile haemangioma (infantile haemangioendothelioma). Vessels are lined by a single layer of plump endothelial cells surrounded by a scant fibrous stroma; note the scattered bile ducts (Masson trichrome staining).

Q: Anastomosing haemangiomas, which are Benign vascular anomalies and vascular tumours, are characterized microscopically by endothelial cell [...] and the presence of [...].
Anastomosing haemangioma. Anastomosing haemangioma involving colonic mucosa.
Anastomosing haemangioma. Endothelial cell hobnailing can be seen with only mild cytological atypia. Hyaline globules are also seen in some cases.
A: hobnailing; hyaline globules
Back Extra: Benign vascular anomalies and vascular tumours
- Clinical: Hepatic cavernous haemangiomas are the most common benign liver tumours in adults; Infantile haemangiomas (HIHs) can present with cardiac failure or coagulopathy.
- Microscopic: Features range from large, thin-walled spaces in cavernous haemangiomas to capillary-like vessels with endothelial hobnailing and hyaline globules in anastomosing haemangiomas.
- Ancillary: GLUT1 immunohistochemistry is the gold standard diagnostic tool to distinguish infantile haemangioma (positive) from hepatic congenital haemangioma (negative).
- Differential: Benign lesions like hepatic small vessel neoplasms lack the severe atypia, multilayering, and high Ki-67 index (>10%) seen in angiosarcoma.
Anastomosing haemangioma. Anastomosing haemangioma involving colonic mucosa.
Anastomosing haemangioma. Endothelial cell hobnailing can be seen with only mild cytological atypia. Hyaline globules are also seen in some cases.

Q: A key molecular finding in several Benign vascular anomalies and vascular tumours, including hepatic congenital haemangiomas and anastomosing haemangiomas, is a mutation in either [...] or GNA11.
Anastomosing haemangioma. Anastomosing haemangioma involving colonic mucosa.
Anastomosing haemangioma. Endothelial cell hobnailing can be seen with only mild cytological atypia. Hyaline globules are also seen in some cases.
A: GNAQ
Back Extra: Benign vascular anomalies and vascular tumours
- Clinical: Hepatic cavernous haemangiomas are the most common benign liver tumours in adults; Infantile haemangiomas (HIHs) can present with cardiac failure or coagulopathy.
- Microscopic: Features range from large, thin-walled spaces in cavernous haemangiomas to capillary-like vessels with endothelial hobnailing and hyaline globules in anastomosing haemangiomas.
- Ancillary: GLUT1 immunohistochemistry is the gold standard diagnostic tool to distinguish infantile haemangioma (positive) from hepatic congenital haemangioma (negative).
- Differential: Benign lesions like hepatic small vessel neoplasms lack the severe atypia, multilayering, and high Ki-67 index (>10%) seen in angiosarcoma.
Anastomosing haemangioma. Anastomosing haemangioma involving colonic mucosa.
Anastomosing haemangioma. Endothelial cell hobnailing can be seen with only mild cytological atypia. Hyaline globules are also seen in some cases.

Q: Which immunohistochemical marker is typically positive in the endothelial cells of [...] but may show only focal or absent expression compared to other vascular lesions? [...]
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Lymphatic malformation. This lesion extended from the mesentery into the mucosa.
A: lymphatic anomalies; CD34
Back Extra: Lymphatic anomalies
- Classification: Categorized into localized (common lymphatic malformations [CLMs]) or generalized/complex (complex lymphatic anomalies [CLAs]), encompassing entities formerly known as lymphangiomas and lymphangiomatosis.
- Microscopic: Characterized by dilated, malformed lymphatic channels lined by a single layer of attenuated endothelial cells lacking cytological atypia; walls are irregularly muscularized and spaces may contain clear fluid, lymphocytes, or chyle.
- Ancillary Studies: Endothelial cells express D2-40, PROX1, CD31, ERG, and FLI1; notably, CD34 expression is often only focal or negative compared to blood vessel endothelium.
- Molecular Pathology: Associated with somatic mosaicism in the PIK3CA/AKT/mTOR and RAS/MAPK/MEK pathways; PIK3CA mutations are frequent in CLMs, while RAS-pathway mutations (e.g., NRAS, KRAS) are found in complex subtypes like KLA and Gorham–Stout disease.
- Differential Diagnosis: Distinguished from lymphangioleiomyomatosis (PEComa) by the absence of melanocytic markers (HMB45, Melan-A) in the smooth muscle component.
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Lymphatic malformation. This lesion extended from the mesentery into the mucosa.

Q: A 2-year-old girl presents with a large omental cyst; histology shows large dilated spaces lined by a single layer of simple endothelium (as seen in the provided figures). The most likely diagnosis for this [...] is [...] (formerly cystic lymphangioma).
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Macrocystic lymphatic malformation. Panoramic view of a large omental cyst in a 2-year-old girl. A lesion was formerly called cystic lymphangioma.
A: lymphatic anomaly; macrocystic lymphatic malformation
Back Extra: Lymphatic anomalies
- Classification: Categorized into localized (common lymphatic malformations [CLMs]) or generalized/complex (complex lymphatic anomalies [CLAs]), encompassing entities formerly known as lymphangiomas and lymphangiomatosis.
- Microscopic: Characterized by dilated, malformed lymphatic channels lined by a single layer of attenuated endothelial cells lacking cytological atypia; walls are irregularly muscularized and spaces may contain clear fluid, lymphocytes, or chyle.
- Ancillary Studies: Endothelial cells express D2-40, PROX1, CD31, ERG, and FLI1; notably, CD34 expression is often only focal or negative compared to blood vessel endothelium.
- Molecular Pathology: Associated with somatic mosaicism in the PIK3CA/AKT/mTOR and RAS/MAPK/MEK pathways; PIK3CA mutations are frequent in CLMs, while RAS-pathway mutations (e.g., NRAS, KRAS) are found in complex subtypes like KLA and Gorham–Stout disease.
- Differential Diagnosis: Distinguished from lymphangioleiomyomatosis (PEComa) by the absence of melanocytic markers (HMB45, Melan-A) in the smooth muscle component.
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Macrocystic lymphatic malformation. Panoramic view of a large omental cyst in a 2-year-old girl. A lesion was formerly called cystic lymphangioma.

Q: Localized common [...] (CLMs) are most frequently associated with somatic mosaic mutations in the [...] gene.
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Lymphatic malformation. This lesion extended from the mesentery into the mucosa.
A: lymphatic anomalies; PIK3CA
Back Extra: Lymphatic anomalies
- Classification: Categorized into localized (common lymphatic malformations [CLMs]) or generalized/complex (complex lymphatic anomalies [CLAs]), encompassing entities formerly known as lymphangiomas and lymphangiomatosis.
- Microscopic: Characterized by dilated, malformed lymphatic channels lined by a single layer of attenuated endothelial cells lacking cytological atypia; walls are irregularly muscularized and spaces may contain clear fluid, lymphocytes, or chyle.
- Ancillary Studies: Endothelial cells express D2-40, PROX1, CD31, ERG, and FLI1; notably, CD34 expression is often only focal or negative compared to blood vessel endothelium.
- Molecular Pathology: Associated with somatic mosaicism in the PIK3CA/AKT/mTOR and RAS/MAPK/MEK pathways; PIK3CA mutations are frequent in CLMs, while RAS-pathway mutations (e.g., NRAS, KRAS) are found in complex subtypes like KLA and Gorham–Stout disease.
- Differential Diagnosis: Distinguished from lymphangioleiomyomatosis (PEComa) by the absence of melanocytic markers (HMB45, Melan-A) in the smooth muscle component.
Macrocystic lymphatic malformation. Low power view of an omental cyst measuring 17 cm in a 2-year-old girl with abdominal pain.[https://www.issva.org/UserFiles/file/ISSVA-Classification-2018.pdf] A lesion formerly called "cystic lymphangioma".
Lymphatic malformation. This lesion extended from the mesentery into the mucosa.

Q: The pathognomonic molecular driver found in >90% of cases of epithelioid haemangioendothelioma is the [CAMTA1] gene fusion.
Epithelioid haemangioendothelioma of the liver showing nuclear atypia, myxohyaline stroma, and prominent cytoplasmic vacuoles.
Diffuse and strong nuclear expression of CAMTA1 in epithelioid haemangioendothelioma.
A: WWTR1
Back Extra: Epithelioid haemangioendothelioma
- Clinical: Malignant vascular neoplasm that primarily arises in the liver (often multifocal); approximately 70% of patients have metastatic disease (lungs, bone) at presentation.
- Microscopic: Characterized by epithelioid cells in a distinctive myxohyaline or sclerotic stroma. Cells often contain pathognomonic intracytoplasmic vacuoles ('blister cells') that may contain erythrocytes.
- Ancillary: Strongly positive for endothelial markers (CD31, CD34, ERG) and demonstrates diffuse nuclear expression of CAMTA1 (~90%). Keratins can be positive in a subset of cells.
- Molecular: Driven by the characteristic WWTR1::CAMTA1 gene fusion (t(1;3)(p36;q25)) in >90% of cases; a small subset harbors YAP1::TFE3 fusions.
- Differential: Frequently mistaken for carcinoma (e.g., cholangiocarcinoma) due to epithelioid morphology and keratin expression; distinguished by vascular markers and CAMTA1/molecular testing.
Epithelioid haemangioendothelioma of the liver showing nuclear atypia, myxohyaline stroma, and prominent cytoplasmic vacuoles.
Diffuse and strong nuclear expression of CAMTA1 in epithelioid haemangioendothelioma.

Q: In epithelioid haemangioendothelioma, the presence of [...] (also known as blister cells) containing erythrocytes is a classic microscopic finding representing primitive vascular lumina.
Epithelioid haemangioendothelioma of the liver showing nuclear atypia, myxohyaline stroma, and prominent cytoplasmic vacuoles.
Single cell infiltration in hepatic epithelioid haemangioendothelioma; arrows indicate intracytoplasmic lumina containing erythrocytes.
A: intracytoplasmic vacuoles
Back Extra: Epithelioid haemangioendothelioma
- Clinical: Malignant vascular neoplasm that primarily arises in the liver (often multifocal); approximately 70% of patients have metastatic disease (lungs, bone) at presentation.
- Microscopic: Characterized by epithelioid cells in a distinctive myxohyaline or sclerotic stroma. Cells often contain pathognomonic intracytoplasmic vacuoles ('blister cells') that may contain erythrocytes.
- Ancillary: Strongly positive for endothelial markers (CD31, CD34, ERG) and demonstrates diffuse nuclear expression of CAMTA1 (~90%). Keratins can be positive in a subset of cells.
- Molecular: Driven by the characteristic WWTR1::CAMTA1 gene fusion (t(1;3)(p36;q25)) in >90% of cases; a small subset harbors YAP1::TFE3 fusions.
- Differential: Frequently mistaken for carcinoma (e.g., cholangiocarcinoma) due to epithelioid morphology and keratin expression; distinguished by vascular markers and CAMTA1/molecular testing.
Epithelioid haemangioendothelioma of the liver showing nuclear atypia, myxohyaline stroma, and prominent cytoplasmic vacuoles.
Single cell infiltration in hepatic epithelioid haemangioendothelioma; arrows indicate intracytoplasmic lumina containing erythrocytes.

Q: Hepatic epithelioid haemangioendothelioma is often misdiagnosed as [...] due to its epithelioid morphology, sclerotic stroma, and potential positivity for [...].
The infiltrative growth of hepatic epithelioid haemangioendothelioma may superficially mimic fibrosis on needle biopsy.
Sclerotic appearance of hepatic epithelioid haemangioendothelioma, which may lead to misdiagnosis as sclerosing cholangiocarcinoma.
A: sclerosing cholangiocarcinoma; keratins
Back Extra: Epithelioid haemangioendothelioma
- Clinical: Malignant vascular neoplasm that primarily arises in the liver (often multifocal); approximately 70% of patients have metastatic disease (lungs, bone) at presentation.
- Microscopic: Characterized by epithelioid cells in a distinctive myxohyaline or sclerotic stroma. Cells often contain pathognomonic intracytoplasmic vacuoles ('blister cells') that may contain erythrocytes.
- Ancillary: Strongly positive for endothelial markers (CD31, CD34, ERG) and demonstrates diffuse nuclear expression of CAMTA1 (~90%). Keratins can be positive in a subset of cells.
- Molecular: Driven by the characteristic WWTR1::CAMTA1 gene fusion (t(1;3)(p36;q25)) in >90% of cases; a small subset harbors YAP1::TFE3 fusions.
- Differential: Frequently mistaken for carcinoma (e.g., cholangiocarcinoma) due to epithelioid morphology and keratin expression; distinguished by vascular markers and CAMTA1/molecular testing.
The infiltrative growth of hepatic epithelioid haemangioendothelioma may superficially mimic fibrosis on needle biopsy.
Sclerotic appearance of hepatic epithelioid haemangioendothelioma, which may lead to misdiagnosis as sclerosing cholangiocarcinoma.

Q: Kaposi sarcoma is a vascular neoplasm of the GI tract caused by infection with [...], particularly in the setting of immunosuppression.
Rectal involvement by Kaposi sarcoma in an HIV-positive individual. This example is florid, with interlacing fascicles of spindly cells, accompanied by extravasation of red cells and haemorrhage.
Iatrogenic Kaposi sarcoma in an immunosuppressed patient with ulcerative colitis, showing fascicles of monomorphic spindled cells with erythrocyte extravasation.
A: HHV8 (KSHV)
Back Extra: Kaposi sarcoma
- Clinical: Most common AIDS-associated extracutaneous site; usually involves the stomach/duodenum and can be multifocal; also seen in iatrogenic (post-transplant) settings.
- Etiology: Caused by KSHV/HHV8 infection; genetic and immunological factors (immunosuppression) are necessary for progression.
- Microscopic: Characterized by infiltrative fascicles of monomorphic spindle cells, slit-like vascular spaces containing erythrocytes, hyaline globules, and haemosiderin.
- Morphologic Variants: Includes spindle cell (classic), lymphangioma-like (dilated spaces), and granulation-tissue-like/inflammatory (masked by inflammation).
- Ancillary: Diffuse nuclear expression of HHV8 (LANA1) is the gold standard and essential for diagnosis to differentiate from mimics like GIST or granulation tissue.
Rectal involvement by Kaposi sarcoma in an HIV-positive individual. This example is florid, with interlacing fascicles of spindly cells, accompanied by extravasation of red cells and haemorrhage.
Iatrogenic Kaposi sarcoma in an immunosuppressed patient with ulcerative colitis, showing fascicles of monomorphic spindled cells with erythrocyte extravasation.

Q: In a biopsy of a reddish rectal macule, the presence of spindle cell fascicles with [...] and hyaline globules is diagnostic for [...].
Rectal involvement by Kaposi sarcoma in an HIV-positive individual. This example is florid, with interlacing fascicles of spindly cells, accompanied by extravasation of red cells and haemorrhage.
Iatrogenic Kaposi sarcoma in an immunosuppressed patient with ulcerative colitis, showing fascicles of monomorphic spindled cells with erythrocyte extravasation.
A: erythrocyte extravasation (slit-like spaces); Kaposi sarcoma
Back Extra: Kaposi sarcoma
- Clinical: Most common AIDS-associated extracutaneous site; usually involves the stomach/duodenum and can be multifocal; also seen in iatrogenic (post-transplant) settings.
- Etiology: Caused by KSHV/HHV8 infection; genetic and immunological factors (immunosuppression) are necessary for progression.
- Microscopic: Characterized by infiltrative fascicles of monomorphic spindle cells, slit-like vascular spaces containing erythrocytes, hyaline globules, and haemosiderin.
- Morphologic Variants: Includes spindle cell (classic), lymphangioma-like (dilated spaces), and granulation-tissue-like/inflammatory (masked by inflammation).
- Ancillary: Diffuse nuclear expression of HHV8 (LANA1) is the gold standard and essential for diagnosis to differentiate from mimics like GIST or granulation tissue.
Rectal involvement by Kaposi sarcoma in an HIV-positive individual. This example is florid, with interlacing fascicles of spindly cells, accompanied by extravasation of red cells and haemorrhage.
Iatrogenic Kaposi sarcoma in an immunosuppressed patient with ulcerative colitis, showing fascicles of monomorphic spindled cells with erythrocyte extravasation.

Q: The [...] variant of Kaposi sarcoma consists of dilated vascular channels that may lack obvious spindle cells but demonstrate nuclear positivity for [...].
Lymphangioma-like rectal Kaposi sarcoma in an AIDS patient. In this variant, lesional cells form small dilated vessels.
HHV8 immunohistochemical stain confirming lymphangioma-like rectal Kaposi sarcoma; the small lymphatic channels are positive.
A: lymphangioma-like; HHV8 (LANA1)
Back Extra: Kaposi sarcoma
- Clinical: Most common AIDS-associated extracutaneous site; usually involves the stomach/duodenum and can be multifocal; also seen in iatrogenic (post-transplant) settings.
- Etiology: Caused by KSHV/HHV8 infection; genetic and immunological factors (immunosuppression) are necessary for progression.
- Microscopic: Characterized by infiltrative fascicles of monomorphic spindle cells, slit-like vascular spaces containing erythrocytes, hyaline globules, and haemosiderin.
- Morphologic Variants: Includes spindle cell (classic), lymphangioma-like (dilated spaces), and granulation-tissue-like/inflammatory (masked by inflammation).
- Ancillary: Diffuse nuclear expression of HHV8 (LANA1) is the gold standard and essential for diagnosis to differentiate from mimics like GIST or granulation tissue.
Lymphangioma-like rectal Kaposi sarcoma in an AIDS patient. In this variant, lesional cells form small dilated vessels.
HHV8 immunohistochemical stain confirming lymphangioma-like rectal Kaposi sarcoma; the small lymphatic channels are positive.

Q: To differentiate Kaposi sarcoma from mimics such as granulation tissue or GIST, the most reliable immunohistochemical stain is [...], which shows a [...] pattern of expression.
Gastric Kaposi sarcoma in a patient with HIV. The typical features can be masked by inflammation, resembling granulation tissue.
Rectal involvement by Kaposi sarcoma showing strong HHV8 nuclear positivity.
A: HHV8; nuclear
Back Extra: Kaposi sarcoma
- Clinical: Most common AIDS-associated extracutaneous site; usually involves the stomach/duodenum and can be multifocal; also seen in iatrogenic (post-transplant) settings.
- Etiology: Caused by KSHV/HHV8 infection; genetic and immunological factors (immunosuppression) are necessary for progression.
- Microscopic: Characterized by infiltrative fascicles of monomorphic spindle cells, slit-like vascular spaces containing erythrocytes, hyaline globules, and haemosiderin.
- Morphologic Variants: Includes spindle cell (classic), lymphangioma-like (dilated spaces), and granulation-tissue-like/inflammatory (masked by inflammation).
- Ancillary: Diffuse nuclear expression of HHV8 (LANA1) is the gold standard and essential for diagnosis to differentiate from mimics like GIST or granulation tissue.
Gastric Kaposi sarcoma in a patient with HIV. The typical features can be masked by inflammation, resembling granulation tissue.
Rectal involvement by Kaposi sarcoma showing strong HHV8 nuclear positivity.

Q: Pancreatoblastoma is a malignant neoplasm of the pancreas characterized by predominantly [...] differentiation and the pathognomonic presence of [...].
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. D Prominent squamoid nest.
A: acinar; squamoid nests
Back Extra: Pancreatoblastoma
- Clinical: Rare malignant neoplasm but the most common pancreatic tumor in childhood (median age 5 years); often associated with elevated serum alpha-fetoprotein (AFP).
- Microscopic: Characterized by highly cellular lobules with acinar differentiation (polarized cells with PASD+ granules) separated by dense fibrous bands.
- Diagnostic Feature: The pathognomonic finding in Pancreatoblastoma is the presence of squamoid nests (islands of epithelioid/spindle cells, sometimes with biotin-related clear nuclei).
- Ancillary: Acinar components are positive for BCL10 and trypsin; squamoid nests show nuclear beta-catenin and EMA expression.
- Molecular: Frequently involves loss of heterozygosity of chromosome 11p and WNT/beta-catenin pathway alterations (CTNNB1 mutations).
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. D Prominent squamoid nest.

Q: In approximately two-thirds of children with Pancreatoblastoma, the serum level of [...] is elevated and can be used to track response to therapy.
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. D Prominent squamoid nest.
A: alpha-fetoprotein (AFP)
Back Extra: Pancreatoblastoma
- Clinical: Rare malignant neoplasm but the most common pancreatic tumor in childhood (median age 5 years); often associated with elevated serum alpha-fetoprotein (AFP).
- Microscopic: Characterized by highly cellular lobules with acinar differentiation (polarized cells with PASD+ granules) separated by dense fibrous bands.
- Diagnostic Feature: The pathognomonic finding in Pancreatoblastoma is the presence of squamoid nests (islands of epithelioid/spindle cells, sometimes with biotin-related clear nuclei).
- Ancillary: Acinar components are positive for BCL10 and trypsin; squamoid nests show nuclear beta-catenin and EMA expression.
- Molecular: Frequently involves loss of heterozygosity of chromosome 11p and WNT/beta-catenin pathway alterations (CTNNB1 mutations).
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. D Prominent squamoid nest.

Q: The squamoid nests in Pancreatoblastoma typically demonstrate nuclear accumulation of [...], which is associated with mutations in the [...] gene.
Pancreatoblastoma. D Prominent squamoid nest.
Pancreatoblastoma. Mosaic pattern of immunolabelling for β-catenin.
A: beta-catenin; CTNNB1
Back Extra: Pancreatoblastoma
- Clinical: Rare malignant neoplasm but the most common pancreatic tumor in childhood (median age 5 years); often associated with elevated serum alpha-fetoprotein (AFP).
- Microscopic: Characterized by highly cellular lobules with acinar differentiation (polarized cells with PASD+ granules) separated by dense fibrous bands.
- Diagnostic Feature: The pathognomonic finding in Pancreatoblastoma is the presence of squamoid nests (islands of epithelioid/spindle cells, sometimes with biotin-related clear nuclei).
- Ancillary: Acinar components are positive for BCL10 and trypsin; squamoid nests show nuclear beta-catenin and EMA expression.
- Molecular: Frequently involves loss of heterozygosity of chromosome 11p and WNT/beta-catenin pathway alterations (CTNNB1 mutations).
Pancreatoblastoma. D Prominent squamoid nest.
Pancreatoblastoma. Mosaic pattern of immunolabelling for β-catenin.

Q: The acinar component of Pancreatoblastoma can be highlighted by immunohistochemistry for pancreatic enzymes or the marker [...].
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. Immunolabelling using the BCL10 antibody highlights neoplastic cells with acinar differentiation while sparing the squamoid nests.
A: BCL10
Back Extra: Pancreatoblastoma
- Clinical: Rare malignant neoplasm but the most common pancreatic tumor in childhood (median age 5 years); often associated with elevated serum alpha-fetoprotein (AFP).
- Microscopic: Characterized by highly cellular lobules with acinar differentiation (polarized cells with PASD+ granules) separated by dense fibrous bands.
- Diagnostic Feature: The pathognomonic finding in Pancreatoblastoma is the presence of squamoid nests (islands of epithelioid/spindle cells, sometimes with biotin-related clear nuclei).
- Ancillary: Acinar components are positive for BCL10 and trypsin; squamoid nests show nuclear beta-catenin and EMA expression.
- Molecular: Frequently involves loss of heterozygosity of chromosome 11p and WNT/beta-catenin pathway alterations (CTNNB1 mutations).
Pancreatoblastoma. B Fibrous stroma separates islands of neoplastic cells.
Pancreatoblastoma. Immunolabelling using the BCL10 antibody highlights neoplastic cells with acinar differentiation while sparing the squamoid nests.

Q: A solid, fleshy intraductal pancreatic mass characterized histologically by back-to-back glands with high-grade dysplasia and minimal mucin is diagnostic of [...].
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.
Intraductal tubulopapillary neoplasm. B The lesion shows an associated invasive carcinoma.
A: intraductal tubulopapillary neoplasm (ITPN)
Back Extra: Intraductal tubulopapillary neoplasm of the pancreas
- Clinical: Rare neoplasm (<1% of exocrine pancreatic tumors) occurring at a mean age of 60; presents with abdominal pain or as an incidental finding, and carries a significantly better 5-year survival rate (~70%) than ductal adenocarcinoma.
- Microscopic: Characterized by non-invasive intraductal growth of back-to-back glands forming large cribriform structures with homogeneous high-grade dysplasia and a notable absence of overt mucin production.
- Ancillary Studies: Typically positive for CK7, MUC1, and MUC6, while characteristically negative for MUC5AC, MUC2, and acinar markers (e.g., BCL10, trypsin).
- Molecular Pathology: Distinct from IPMN and ductal adenocarcinoma due to the rarity of KRAS mutations and the frequent presence of gene fusions (e.g., BRAF, FGFR2, NRG1).
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.
Intraductal tubulopapillary neoplasm. B The lesion shows an associated invasive carcinoma.

Q: Unlike intraductal papillary mucinous neoplasms (IPMN), the [...] of the pancreas is usually negative for the immunostain [...].
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.
A: intraductal tubulopapillary neoplasm (ITPN); MUC5AC
Back Extra: Intraductal tubulopapillary neoplasm of the pancreas
- Clinical: Rare neoplasm (<1% of exocrine pancreatic tumors) occurring at a mean age of 60; presents with abdominal pain or as an incidental finding, and carries a significantly better 5-year survival rate (~70%) than ductal adenocarcinoma.
- Microscopic: Characterized by non-invasive intraductal growth of back-to-back glands forming large cribriform structures with homogeneous high-grade dysplasia and a notable absence of overt mucin production.
- Ancillary Studies: Typically positive for CK7, MUC1, and MUC6, while characteristically negative for MUC5AC, MUC2, and acinar markers (e.g., BCL10, trypsin).
- Molecular Pathology: Distinct from IPMN and ductal adenocarcinoma due to the rarity of KRAS mutations and the frequent presence of gene fusions (e.g., BRAF, FGFR2, NRG1).
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.

Q: In the differential diagnosis of [...], the absence of [...] mutations is a key molecular feature that distinguishes it from pancreaticobiliary-type IPMN.
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.
A: intraductal tubulopapillary neoplasm (ITPN); KRAS
Back Extra: Intraductal tubulopapillary neoplasm of the pancreas
- Clinical: Rare neoplasm (<1% of exocrine pancreatic tumors) occurring at a mean age of 60; presents with abdominal pain or as an incidental finding, and carries a significantly better 5-year survival rate (~70%) than ductal adenocarcinoma.
- Microscopic: Characterized by non-invasive intraductal growth of back-to-back glands forming large cribriform structures with homogeneous high-grade dysplasia and a notable absence of overt mucin production.
- Ancillary Studies: Typically positive for CK7, MUC1, and MUC6, while characteristically negative for MUC5AC, MUC2, and acinar markers (e.g., BCL10, trypsin).
- Molecular Pathology: Distinct from IPMN and ductal adenocarcinoma due to the rarity of KRAS mutations and the frequent presence of gene fusions (e.g., BRAF, FGFR2, NRG1).
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.

Q: To distinguish [...] from acinar cell carcinoma growing within ducts, immunohistochemistry for acinar markers such as [...] should be performed.
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.
A: intraductal tubulopapillary neoplasm (ITPN); BCL10 (or trypsin/chymotrypsin)
Back Extra: Intraductal tubulopapillary neoplasm of the pancreas
- Clinical: Rare neoplasm (<1% of exocrine pancreatic tumors) occurring at a mean age of 60; presents with abdominal pain or as an incidental finding, and carries a significantly better 5-year survival rate (~70%) than ductal adenocarcinoma.
- Microscopic: Characterized by non-invasive intraductal growth of back-to-back glands forming large cribriform structures with homogeneous high-grade dysplasia and a notable absence of overt mucin production.
- Ancillary Studies: Typically positive for CK7, MUC1, and MUC6, while characteristically negative for MUC5AC, MUC2, and acinar markers (e.g., BCL10, trypsin).
- Molecular Pathology: Distinct from IPMN and ductal adenocarcinoma due to the rarity of KRAS mutations and the frequent presence of gene fusions (e.g., BRAF, FGFR2, NRG1).
Intraductal tubulopapillary neoplasm. A Nodules of back-to-back glands forming cribriform structures with occasional papillae.

Q: A 45-year-old female presents with a multilocular cystic lesion in the pancreatic tail that does not communicate with the ducts; histological examination reveals mucinous epithelium and spindle-cell stroma, confirming a diagnosis of [...].
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.
Mucinous cystic neoplasm. The upper locule is lined by epithelium with low-grade dysplasia, while an adjacent locule (below) is lined by epithelium with high-grade dysplasia.
A: Mucinous cystic neoplasm of the pancreas
Back Extra: Mucinous cystic neoplasm of the pancreas
- Clinical: Occurs almost exclusively in women (> 95%, mean age 48) and is typically located in the body or tail of the pancreas.
- Microscopic: Characterized by mucin-producing columnar epithelium supported by a diagnostic, hypercellular subepithelial band of "ovarian-type" stroma.
- Differential Diagnosis: Distinguished from IPMN by its lack of communication with the pancreatic duct system and the presence of ovarian-type stroma.
- Ancillary: The ovarian-type stroma is characteristically positive for PR (60–90%) and ER (30%); molecularly, KRAS and RNF43 mutations are common.
- Prognosis: Non-invasive lesions carry an excellent 100% 5-year survival rate after complete resection; however, ~15% of cases harbor an associated invasive carcinoma.
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.
Mucinous cystic neoplasm. The upper locule is lined by epithelium with low-grade dysplasia, while an adjacent locule (below) is lined by epithelium with high-grade dysplasia.

Q: The pathognomonic histologic feature required for the diagnosis of [...] is the presence of subepithelial [...] stroma.
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.
A: Mucinous cystic neoplasm of the pancreas; ovarian-type
Back Extra: Mucinous cystic neoplasm of the pancreas
- Clinical: Occurs almost exclusively in women (> 95%, mean age 48) and is typically located in the body or tail of the pancreas.
- Microscopic: Characterized by mucin-producing columnar epithelium supported by a diagnostic, hypercellular subepithelial band of "ovarian-type" stroma.
- Differential Diagnosis: Distinguished from IPMN by its lack of communication with the pancreatic duct system and the presence of ovarian-type stroma.
- Ancillary: The ovarian-type stroma is characteristically positive for PR (60–90%) and ER (30%); molecularly, KRAS and RNF43 mutations are common.
- Prognosis: Non-invasive lesions carry an excellent 100% 5-year survival rate after complete resection; however, ~15% of cases harbor an associated invasive carcinoma.
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.

Q: While both are mucinous, [...] is distinguished from branch-duct IPMN because MCNs characteristically [...] with the pancreatic duct system.
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.
A: Mucinous cystic neoplasm of the pancreas; do not communicate
Back Extra: Mucinous cystic neoplasm of the pancreas
- Clinical: Occurs almost exclusively in women (> 95%, mean age 48) and is typically located in the body or tail of the pancreas.
- Microscopic: Characterized by mucin-producing columnar epithelium supported by a diagnostic, hypercellular subepithelial band of "ovarian-type" stroma.
- Differential Diagnosis: Distinguished from IPMN by its lack of communication with the pancreatic duct system and the presence of ovarian-type stroma.
- Ancillary: The ovarian-type stroma is characteristically positive for PR (60–90%) and ER (30%); molecularly, KRAS and RNF43 mutations are common.
- Prognosis: Non-invasive lesions carry an excellent 100% 5-year survival rate after complete resection; however, ~15% of cases harbor an associated invasive carcinoma.
Mucinous cystic neoplasm. The locules are lined by columnar mucinous epithelium. Note the subepithelial band of hypercellular ovarian-type stroma.
Mucinous cystic neoplasm with an associated invasive carcinoma. The non-invasive component (top) is composed of cysts lined by mucinous epithelium with high-grade dysplasia and subepithelial ovarian-type stroma. The glands of an associated invasive carcinoma are at the bottom.

Q: A > 10 mm unilocular pancreatic cyst lined by a single layer of gastric-type epithelium (MUC5AC+) that lacks both papillary architecture and ovarian-type stroma is most consistent with a [...].
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.
A: simple mucinous cyst
Back Extra: Simple mucinous cyst
- Definition: A neoplastic, unilocular or paucilocular pancreatic cyst (> 10 mm) lined by a single layer of gastric-type mucinous epithelium without papillary architecture.
- Clinical: Most common in females (70%) with a mean age of 57; preoperative cyst fluid often shows high CEA levels and KRAS mutations.
- Microscopic: Lined by cuboidal to columnar epithelium with mild atypia; the underlying wall is paucicellular and fibrotic.
- Differential Diagnosis: Distinguished from Mucinous Cystic Neoplasm (MCN) by the absolute absence of ovarian-type stroma and lack of ER/PR expression.
- Ancillary: Consistently expresses gastric mucins (MUC5AC and MUC6) and cytokeratins (CK7, CK19).
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.

Q: The primary histological feature used to distinguish a [...] from a mucinous cystic neoplasm (MCN) is the absence of [...] in the cyst wall.
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.
A: simple mucinous cyst; ovarian-type stroma
Back Extra: Simple mucinous cyst
- Definition: A neoplastic, unilocular or paucilocular pancreatic cyst (> 10 mm) lined by a single layer of gastric-type mucinous epithelium without papillary architecture.
- Clinical: Most common in females (70%) with a mean age of 57; preoperative cyst fluid often shows high CEA levels and KRAS mutations.
- Microscopic: Lined by cuboidal to columnar epithelium with mild atypia; the underlying wall is paucicellular and fibrotic.
- Differential Diagnosis: Distinguished from Mucinous Cystic Neoplasm (MCN) by the absolute absence of ovarian-type stroma and lack of ER/PR expression.
- Ancillary: Consistently expresses gastric mucins (MUC5AC and MUC6) and cytokeratins (CK7, CK19).
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.

Q: While both contain pale mucin, a [...] must be at least [...] mm in size to be distinguished from a microscopic pancreatic intraepithelial neoplasia (PanIN).
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.
A: simple mucinous cyst; 10
Back Extra: Simple mucinous cyst
- Definition: A neoplastic, unilocular or paucilocular pancreatic cyst (> 10 mm) lined by a single layer of gastric-type mucinous epithelium without papillary architecture.
- Clinical: Most common in females (70%) with a mean age of 57; preoperative cyst fluid often shows high CEA levels and KRAS mutations.
- Microscopic: Lined by cuboidal to columnar epithelium with mild atypia; the underlying wall is paucicellular and fibrotic.
- Differential Diagnosis: Distinguished from Mucinous Cystic Neoplasm (MCN) by the absolute absence of ovarian-type stroma and lack of ER/PR expression.
- Ancillary: Consistently expresses gastric mucins (MUC5AC and MUC6) and cytokeratins (CK7, CK19).
Simple mucinous cyst. Unilocular cyst with a thickened, fibrotic wall and lacking a papillary architecture and ovarian-type stroma.
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.

Q: Immunohistochemical staining in a [...] typically shows diffuse expression of the gastric-type mucins [...].
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.
A: simple mucinous cyst; MUC5AC and MUC6
Back Extra: Simple mucinous cyst
- Definition: A neoplastic, unilocular or paucilocular pancreatic cyst (> 10 mm) lined by a single layer of gastric-type mucinous epithelium without papillary architecture.
- Clinical: Most common in females (70%) with a mean age of 57; preoperative cyst fluid often shows high CEA levels and KRAS mutations.
- Microscopic: Lined by cuboidal to columnar epithelium with mild atypia; the underlying wall is paucicellular and fibrotic.
- Differential Diagnosis: Distinguished from Mucinous Cystic Neoplasm (MCN) by the absolute absence of ovarian-type stroma and lack of ER/PR expression.
- Ancillary: Consistently expresses gastric mucins (MUC5AC and MUC6) and cytokeratins (CK7, CK19).
Simple mucinous cyst. The cyst lining is composed of a single layer of cuboidal to columnar epithelium with gastric-type mucin and minimal nuclear atypia. Underlying the epithelium is a paucicellular fibrotic wall of variable thickness, with no evidence of ovarian-type stroma.

Q: For a diagnosis of Pancreatic mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN), what is the required minimum percentage for each component?
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).
Mixed acinar-neuroendocrine carcinoma. The acinar and neuroendocrine components are distinguishable histologically.
Mixed acinar carcinoma–neuroendocrine carcinoma showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
A: Pancreatic mixed neuroendocrine–non-neuroendocrine neoplasms
- Definition: Rare neoplasms (MiNENs) composed of morphologically and immunohistochemically distinct neuroendocrine and non-neuroendocrine (ductal or acinar) components, each comprising ≥ 30% of the tumor.
- Microscopic: Mixed ductal-neuroendocrine carcinomas (most common) feature a ductal component and a neuroendocrine component that is typically a high-grade neuroendocrine carcinoma (NEC) with > 20 mitoses/2 mm².
- Ancillary Studies: The non-neuroendocrine component stains for markers like CEA/EMA (ductal) or Trypsin/BCL10 (acinar), while the neuroendocrine component is positive for synaptophysin or chromogranin A.
- Molecular Pathology: Unlike pure PanNETs, the mixed ductal adenocarcinoma–NEC subtype frequently harbors KRAS mutations (58.3%) and loss of RB1.
- Prognosis: Mixed ductal-NEC is highly aggressive with a median overall survival of approximately 12 months, whereas acinar-NEN cases typically follow the clinical course of acinar cell carcinoma.
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).
Mixed acinar-neuroendocrine carcinoma. The acinar and neuroendocrine components are distinguishable histologically.
Mixed acinar carcinoma–neuroendocrine carcinoma showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.

Q: In Pancreatic mixed ductal adenocarcinoma–neuroendocrine carcinoma, the non-neuroendocrine component typically stains for [...], while the neuroendocrine component stains for [...].
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).
Mixed ductal-neuroendocrine carcinoma. Immunostaining for synaptophysin reveals the neuroendocrine component.
A: CEA and EMA; synaptophysin or chromogranin A
Back Extra: Pancreatic mixed neuroendocrine–non-neuroendocrine neoplasms
- Definition: Rare neoplasms (MiNENs) composed of morphologically and immunohistochemically distinct neuroendocrine and non-neuroendocrine (ductal or acinar) components, each comprising ≥ 30% of the tumor.
- Microscopic: Mixed ductal-neuroendocrine carcinomas (most common) feature a ductal component and a neuroendocrine component that is typically a high-grade neuroendocrine carcinoma (NEC) with > 20 mitoses/2 mm².
- Ancillary Studies: The non-neuroendocrine component stains for markers like CEA/EMA (ductal) or Trypsin/BCL10 (acinar), while the neuroendocrine component is positive for synaptophysin or chromogranin A.
- Molecular Pathology: Unlike pure PanNETs, the mixed ductal adenocarcinoma–NEC subtype frequently harbors KRAS mutations (58.3%) and loss of RB1.
- Prognosis: Mixed ductal-NEC is highly aggressive with a median overall survival of approximately 12 months, whereas acinar-NEN cases typically follow the clinical course of acinar cell carcinoma.
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).
Mixed ductal-neuroendocrine carcinoma. Immunostaining for synaptophysin reveals the neuroendocrine component.

Q: Which genetic mutation, common in ductal adenocarcinomas, is found in over half of Pancreatic mixed ductal adenocarcinoma–NEC cases but is rare in conventional well-differentiated PanNETs?
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).
A: Pancreatic mixed neuroendocrine–non-neuroendocrine neoplasms
- Definition: Rare neoplasms (MiNENs) composed of morphologically and immunohistochemically distinct neuroendocrine and non-neuroendocrine (ductal or acinar) components, each comprising ≥ 30% of the tumor.
- Microscopic: Mixed ductal-neuroendocrine carcinomas (most common) feature a ductal component and a neuroendocrine component that is typically a high-grade neuroendocrine carcinoma (NEC) with > 20 mitoses/2 mm².
- Ancillary Studies: The non-neuroendocrine component stains for markers like CEA/EMA (ductal) or Trypsin/BCL10 (acinar), while the neuroendocrine component is positive for synaptophysin or chromogranin A.
- Molecular Pathology: Unlike pure PanNETs, the mixed ductal adenocarcinoma–NEC subtype frequently harbors KRAS mutations (58.3%) and loss of RB1.
- Prognosis: Mixed ductal-NEC is highly aggressive with a median overall survival of approximately 12 months, whereas acinar-NEN cases typically follow the clinical course of acinar cell carcinoma.
Mixed ductal–neuroendocrine carcinoma. The ductal component (left) is intimately admixed with the neuroendocrine component (right).

Q: A pancreatic tumor showing a distinct component positive for [...] and a second distinct component positive for [...] (each > 30%) is best classified as a Pancreatic mixed acinar carcinoma–neuroendocrine neoplasm.
Mixed acinar carcinoma–neuroendocrine carcinoma showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
Mixed acinar carcinoma–neuroendocrine carcinoma. Trypsin immunoreactivity is observed in the acinar carcinoma component.
Mixed acinar carcinoma–neuroendocrine carcinoma. Chromogranin A immunoreactivity is observed in the neuroendocrine component.
A: trypsin; chromogranin A
Back Extra: Pancreatic mixed neuroendocrine–non-neuroendocrine neoplasms
- Definition: Rare neoplasms (MiNENs) composed of morphologically and immunohistochemically distinct neuroendocrine and non-neuroendocrine (ductal or acinar) components, each comprising ≥ 30% of the tumor.
- Microscopic: Mixed ductal-neuroendocrine carcinomas (most common) feature a ductal component and a neuroendocrine component that is typically a high-grade neuroendocrine carcinoma (NEC) with > 20 mitoses/2 mm².
- Ancillary Studies: The non-neuroendocrine component stains for markers like CEA/EMA (ductal) or Trypsin/BCL10 (acinar), while the neuroendocrine component is positive for synaptophysin or chromogranin A.
- Molecular Pathology: Unlike pure PanNETs, the mixed ductal adenocarcinoma–NEC subtype frequently harbors KRAS mutations (58.3%) and loss of RB1.
- Prognosis: Mixed ductal-NEC is highly aggressive with a median overall survival of approximately 12 months, whereas acinar-NEN cases typically follow the clinical course of acinar cell carcinoma.
Mixed acinar carcinoma–neuroendocrine carcinoma showing morphologically distinguishable solid acinar (left) and trabecular neuroendocrine (right) components.
Mixed acinar carcinoma–neuroendocrine carcinoma. Trypsin immunoreactivity is observed in the acinar carcinoma component.
Mixed acinar carcinoma–neuroendocrine carcinoma. Chromogranin A immunoreactivity is observed in the neuroendocrine component.

Q: Glucagon cell hyperplasia and neoplasia (Mahvash disease) is caused by autosomal recessive germline mutations in the [gene] gene.
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.
A: GCGR
Back Extra: Glucagon cell hyperplasia and neoplasia
- Clinical: Glucagon cell hyperplasia and neoplasia (GCHN), also known as Mahvash disease, is an autosomal recessive syndrome caused by biallelic mutations in the GCGR gene, leading to hyperglucagonemia (often >10,000 pg/mL) without the classic glucagonoma syndrome.
- Microscopic: The disease is characterized by a diffuse distribution of normal-sized islets, hypertrophic islets, and multiple microadenomas (PanNETs) throughout the pancreas, which may show cystic transformation.
- Ancillary: Immunohistochemistry shows nearly exclusive expression of glucagon in the hypertrophic islets and tumors, universal SSTR2A expression, and typically very low Ki-67 proliferation indices (<1%).
- Pathogenesis: The syndrome arises from deficient glucagon signaling in the liver, which triggers a feedback loop (likely amino-acid mediated) resulting in compensatory α-cell hyperplasia and eventual neoplastic transformation.
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.

Q: Despite extremely high serum glucagon levels, patients with Glucagon cell hyperplasia and neoplasia typically lack the clinical finding of [skin finding].
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.
A: necrolytic migratory erythema
Back Extra: Glucagon cell hyperplasia and neoplasia
- Clinical: Glucagon cell hyperplasia and neoplasia (GCHN), also known as Mahvash disease, is an autosomal recessive syndrome caused by biallelic mutations in the GCGR gene, leading to hyperglucagonemia (often >10,000 pg/mL) without the classic glucagonoma syndrome.
- Microscopic: The disease is characterized by a diffuse distribution of normal-sized islets, hypertrophic islets, and multiple microadenomas (PanNETs) throughout the pancreas, which may show cystic transformation.
- Ancillary: Immunohistochemistry shows nearly exclusive expression of glucagon in the hypertrophic islets and tumors, universal SSTR2A expression, and typically very low Ki-67 proliferation indices (<1%).
- Pathogenesis: The syndrome arises from deficient glucagon signaling in the liver, which triggers a feedback loop (likely amino-acid mediated) resulting in compensatory α-cell hyperplasia and eventual neoplastic transformation.
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.

Q: In Glucagon cell hyperplasia and neoplasia, the hypertrophic islets and microtumors are predominantly composed of cells expressing [hormone] by immunohistochemistry.
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.
Glucagon cell hyperplasia and neoplasia. B Hypertrophic islets and tumours exhibit almost exclusive glucagon expression by immunohistochemistry (bar marks: 2 mm).
A: glucagon
Back Extra: Glucagon cell hyperplasia and neoplasia
- Clinical: Glucagon cell hyperplasia and neoplasia (GCHN), also known as Mahvash disease, is an autosomal recessive syndrome caused by biallelic mutations in the GCGR gene, leading to hyperglucagonemia (often >10,000 pg/mL) without the classic glucagonoma syndrome.
- Microscopic: The disease is characterized by a diffuse distribution of normal-sized islets, hypertrophic islets, and multiple microadenomas (PanNETs) throughout the pancreas, which may show cystic transformation.
- Ancillary: Immunohistochemistry shows nearly exclusive expression of glucagon in the hypertrophic islets and tumors, universal SSTR2A expression, and typically very low Ki-67 proliferation indices (<1%).
- Pathogenesis: The syndrome arises from deficient glucagon signaling in the liver, which triggers a feedback loop (likely amino-acid mediated) resulting in compensatory α-cell hyperplasia and eventual neoplastic transformation.
Glucagon cell hyperplasia and neoplasia. A Numerous enlarged endocrine islets and microtumours are unevenly distributed throughout the entire pancreas.
Glucagon cell hyperplasia and neoplasia. B Hypertrophic islets and tumours exhibit almost exclusive glucagon expression by immunohistochemistry (bar marks: 2 mm).

Q: A patient presents with diabetes mellitus and the skin rash shown in clinical history. On biopsy, a pancreatic NET is found. The diffuse staining pattern seen in this image confirms the diagnosis of [...].
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
Glucagonoma of the pancreas. Immunostain of glucagon is diffusely positive in tumour cells.
A: Glucagonoma
Back Extra: Glucagonoma
- Clinical: Characterized by the 'glucagonoma syndrome' triad: necrolytic migratory erythema (NME), diabetes mellitus, and weight loss; it predominantly involves the tail of the pancreas.
- Microscopic: Usually large (30–70 mm), solitary, well-demarcated tumors with classic well-differentiated neuroendocrine morphology (nests, cords, or trabeculae) and most commonly G1 or G2 grade.
- Ancillary (IHC): Diffusely positive for glucagon and SSTR2; characteristically expresses the transcription factor ARX and often co-expresses PDX1.
- Genetics: Often associated with mutations in MEN1, DAXX, or ATRX and alternative lengthening of telomeres (ALT).
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
Glucagonoma of the pancreas. Immunostain of glucagon is diffusely positive in tumour cells.

Q: The pathognomonic skin rash associated with the clinical syndrome of a Glucagonoma is called [...].
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
A: necrolytic migratory erythema
Back Extra: Glucagonoma
- Clinical: Characterized by the 'glucagonoma syndrome' triad: necrolytic migratory erythema (NME), diabetes mellitus, and weight loss; it predominantly involves the tail of the pancreas.
- Microscopic: Usually large (30–70 mm), solitary, well-demarcated tumors with classic well-differentiated neuroendocrine morphology (nests, cords, or trabeculae) and most commonly G1 or G2 grade.
- Ancillary (IHC): Diffusely positive for glucagon and SSTR2; characteristically expresses the transcription factor ARX and often co-expresses PDX1.
- Genetics: Often associated with mutations in MEN1, DAXX, or ATRX and alternative lengthening of telomeres (ALT).
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.

Q: In addition to glucagon and SSTR2, Glucagonoma cells typically express the transcription factor [...].
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
Glucagonoma of the pancreas. Immunostain of glucagon is diffusely positive in tumour cells.
Glucagonoma, functioning neuroendocrine tumour (NET) showing diffuse SSTR2 expression with membrane reinforcement.
A: ARX
Back Extra: Glucagonoma
- Clinical: Characterized by the 'glucagonoma syndrome' triad: necrolytic migratory erythema (NME), diabetes mellitus, and weight loss; it predominantly involves the tail of the pancreas.
- Microscopic: Usually large (30–70 mm), solitary, well-demarcated tumors with classic well-differentiated neuroendocrine morphology (nests, cords, or trabeculae) and most commonly G1 or G2 grade.
- Ancillary (IHC): Diffusely positive for glucagon and SSTR2; characteristically expresses the transcription factor ARX and often co-expresses PDX1.
- Genetics: Often associated with mutations in MEN1, DAXX, or ATRX and alternative lengthening of telomeres (ALT).
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
Glucagonoma of the pancreas. Immunostain of glucagon is diffusely positive in tumour cells.
Glucagonoma, functioning neuroendocrine tumour (NET) showing diffuse SSTR2 expression with membrane reinforcement.

Q: While most Glucagonoma cases are sporadic, they are rarely associated with the hereditary syndrome [Multiple Endocrine Neoplasia Type 1].
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.
A: MEN1
Back Extra: Glucagonoma
- Clinical: Characterized by the 'glucagonoma syndrome' triad: necrolytic migratory erythema (NME), diabetes mellitus, and weight loss; it predominantly involves the tail of the pancreas.
- Microscopic: Usually large (30–70 mm), solitary, well-demarcated tumors with classic well-differentiated neuroendocrine morphology (nests, cords, or trabeculae) and most commonly G1 or G2 grade.
- Ancillary (IHC): Diffusely positive for glucagon and SSTR2; characteristically expresses the transcription factor ARX and often co-expresses PDX1.
- Genetics: Often associated with mutations in MEN1, DAXX, or ATRX and alternative lengthening of telomeres (ALT).
Glucagonoma of the pancreas. A typical well-differentiated neuroendocrine tumour (NET) with tumour cells arranged in nests and short cords.

Q: A well-differentiated neuroendocrine tumor of the pancreas that displays a trabecular architecture and prominent stromal amyloid as shown in the images is highly suggestive of [...].
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: Insulinoma
Q: Insulinoma
- Clinical: Most common functioning PanNET; presents with the Whipple triad (hypoglycaemic symptoms, plasma glucose < 3.0 mmol/L, and resolution with glucose administration).
- Microscopic: Well-differentiated neuroendocrine morphology, typically small (< 20 mm) and solitary; characteristic stromal amyloid (IAPP/amylin) deposits are present in 50% of cases.
- Genetics: Most cases are sporadic and harbor a hotspot mutation in [...] (p.Thr372Arg); familial cases may be associated with MEN1 or familial insulinomatosis (MAFA).
- Prognosis: Generally indolent and cured by surgery; aggressive behavior (10–15%) is linked to size > 20-30 mm, chromosomal instability, and mutations in ATRX or DAXX.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: YY1

Q: The clinical diagnosis of [...] is based on the [...], which includes symptoms of hypoglycemia, low plasma glucose, and relief of symptoms after glucose administration.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: Insulinoma; Whipple triad
Q: Insulinoma
- Clinical: Most common functioning PanNET; presents with the Whipple triad (hypoglycaemic symptoms, plasma glucose < 3.0 mmol/L, and resolution with glucose administration).
- Microscopic: Well-differentiated neuroendocrine morphology, typically small (< 20 mm) and solitary; characteristic stromal amyloid (IAPP/amylin) deposits are present in 50% of cases.
- Genetics: Most cases are sporadic and harbor a hotspot mutation in [...] (p.Thr372Arg); familial cases may be associated with MEN1 or familial insulinomatosis (MAFA).
- Prognosis: Generally indolent and cured by surgery; aggressive behavior (10–15%) is linked to size > 20-30 mm, chromosomal instability, and mutations in ATRX or DAXX.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: YY1

Q: In the setting of multiple pancreatic neuroendocrine tumors (e.g., MEN1), immunohistochemistry for [...] is essential to identify the culprit lesion responsible for the [...] syndrome.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
Pancreatic insulinoma. Insulin expression.
A: Insulin; Insulinoma
Q: Insulinoma
- Clinical: Most common functioning PanNET; presents with the Whipple triad (hypoglycaemic symptoms, plasma glucose < 3.0 mmol/L, and resolution with glucose administration).
- Microscopic: Well-differentiated neuroendocrine morphology, typically small (< 20 mm) and solitary; characteristic stromal amyloid (IAPP/amylin) deposits are present in 50% of cases.
- Genetics: Most cases are sporadic and harbor a hotspot mutation in [...] (p.Thr372Arg); familial cases may be associated with MEN1 or familial insulinomatosis (MAFA).
- Prognosis: Generally indolent and cured by surgery; aggressive behavior (10–15%) is linked to size > 20-30 mm, chromosomal instability, and mutations in ATRX or DAXX.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
Pancreatic insulinoma. Insulin expression.
A: YY1

Q: A specific hotspot mutation in the gene [...] is found in approximately 30% of cases of [...] and is nearly exclusive to this tumor type.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: YY1; Insulinoma
Q: Insulinoma
- Clinical: Most common functioning PanNET; presents with the Whipple triad (hypoglycaemic symptoms, plasma glucose < 3.0 mmol/L, and resolution with glucose administration).
- Microscopic: Well-differentiated neuroendocrine morphology, typically small (< 20 mm) and solitary; characteristic stromal amyloid (IAPP/amylin) deposits are present in 50% of cases.
- Genetics: Most cases are sporadic and harbor a hotspot mutation in [...] (p.Thr372Arg); familial cases may be associated with MEN1 or familial insulinomatosis (MAFA).
- Prognosis: Generally indolent and cured by surgery; aggressive behavior (10–15%) is linked to size > 20-30 mm, chromosomal instability, and mutations in ATRX or DAXX.
Pancreatic insulinoma. Trabecular architecture with stromal amyloid.
A: YY1

Q: The diagnosis for an adult patient with multicentric pancreatic neuroendocrine proliferations staining exclusively for insulin and a germline mutation in the transcription factor gene [...] is [...].
MAFA-related familial insulinomatosis. The pancreas contains innumerable multicentric beta cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microadenomas (< 5 mm) and well-differentiated beta cell neuroendocrine tumours (NETs) (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric beta cell proliferations range from dysplastic beta cell cords to microadenomas and well-differentiated tumours, all staining intensely and exclusively for insulin.
A: MAFA; MAFA-related familial insulinomatosis
Back Extra: MAFA-related familial insulinomatosis
- Clinical: Autosomal dominant syndrome caused by germline MAFA variants; presents in adulthood with recurrent hyperinsulinaemic hypoglycaemia (more common in females) or MODY-like diabetes (more common in males).
- Microscopic: Characterized by multicentric β-cell proliferations ranging from dysplastic cords to trabecular microadenomas (< 5 mm) and larger macrotumours (> 5 mm) with low Ki-67 (< 2%).
- Ancillary: Neoplastic cells show exclusive immunohistochemical expression of insulin, whereas normal islets contain a mix of insulin, glucagon, somatostatin, and pancreatic polypeptide.
- Prognosis: High recurrence rate after partial pancreatectomy due to the multicentric nature; total pancreatectomy may be required for definitive treatment.
MAFA-related familial insulinomatosis. The pancreas contains innumerable multicentric beta cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microadenomas (< 5 mm) and well-differentiated beta cell neuroendocrine tumours (NETs) (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric beta cell proliferations range from dysplastic beta cell cords to microadenomas and well-differentiated tumours, all staining intensely and exclusively for insulin.

Q: In MAFA-related familial insulinomatosis, the dysplastic cell clusters and trabecular tumours are [...] positive for [...] immunohistochemistry, unlike normal islets which show a normal distribution of various hormones.
MAFA-related familial insulinomatosis. The pancreas contains innumerable multicentric beta cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microadenomas (< 5 mm) and well-differentiated beta cell neuroendocrine tumours (NETs) (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric beta cell proliferations range from dysplastic beta cell cords to microadenomas and well-differentiated tumours, all staining intensely and exclusively for insulin.
A: exclusively; insulin
Back Extra: MAFA-related familial insulinomatosis
- Clinical: Autosomal dominant syndrome caused by germline MAFA variants; presents in adulthood with recurrent hyperinsulinaemic hypoglycaemia (more common in females) or MODY-like diabetes (more common in males).
- Microscopic: Characterized by multicentric β-cell proliferations ranging from dysplastic cords to trabecular microadenomas (< 5 mm) and larger macrotumours (> 5 mm) with low Ki-67 (< 2%).
- Ancillary: Neoplastic cells show exclusive immunohistochemical expression of insulin, whereas normal islets contain a mix of insulin, glucagon, somatostatin, and pancreatic polypeptide.
- Prognosis: High recurrence rate after partial pancreatectomy due to the multicentric nature; total pancreatectomy may be required for definitive treatment.
MAFA-related familial insulinomatosis. The pancreas contains innumerable multicentric beta cell proliferations that stain for insulin.
MAFA-related familial insulinomatosis. There are multiple neuroendocrine trabecular microadenomas (< 5 mm) and well-differentiated beta cell neuroendocrine tumours (NETs) (> 5 mm) that are composed exclusively of insulin-positive cells.
MAFA-related familial insulinomatosis. Multicentric beta cell proliferations range from dysplastic beta cell cords to microadenomas and well-differentiated tumours, all staining intensely and exclusively for insulin.

Q: A well-differentiated pancreatic neoplasm measuring 3 cm that is not associated with a hormonal syndrome and shows an organoid growth pattern is best diagnosed as a [...].
Non-functioning pancreatic neuroendocrine tumour (PanNET) demonstrating a classic gyriform-trabecular pattern.
Non-functioning neuroendocrine tumour (NET) with a paraganglioma-like pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET) with glandular morphology.
A: Non-functioning pancreatic neuroendocrine tumour
Back Extra: Non-functioning pancreatic neuroendocrine tumours
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) are well-differentiated neoplasms ≥ 5 mm that lack a clinical hormonal syndrome; they are frequently associated with MEN1 and Von Hippel-Lindau (VHL) syndromes.
- Microscopic: Features organoid growth (trabecular, gyriform, or solid) with cells showing characteristic 'salt-and-pepper' chromatin; histologic variants include clear cell (VHL-associated), oncocytic, and pleomorphic types.
- Ancillary: Strong diffuse expression of synaptophysin and ISL1 is typical; immunohistochemical loss of DAXX or ATRX (seen in ~45%) is associated with the ALT phenotype and a worse prognosis.
- Prognosis: Proliferative rate (Ki-67 index and mitotic count) is the most critical histological predictor of outcome, as all NF-PanNETs are considered to have malignant potential.
Non-functioning pancreatic neuroendocrine tumour (PanNET) demonstrating a classic gyriform-trabecular pattern.
Non-functioning neuroendocrine tumour (NET) with a paraganglioma-like pattern.
Non-functioning pancreatic neuroendocrine tumour (PanNET) with glandular morphology.

Q: In the context of [...], the loss of immunohistochemical expression for [...] is a marker for the Alternative Lengthening of Telomeres (ALT) and predicts a more aggressive course.
Non-functioning pancreatic neuroendocrine tumour (PanNET) demonstrating a classic gyriform-trabecular pattern.
A: Non-functioning pancreatic neuroendocrine tumours; DAXX or ATRX
Back Extra: Non-functioning pancreatic neuroendocrine tumours
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) are well-differentiated neoplasms ≥ 5 mm that lack a clinical hormonal syndrome; they are frequently associated with MEN1 and Von Hippel-Lindau (VHL) syndromes.
- Microscopic: Features organoid growth (trabecular, gyriform, or solid) with cells showing characteristic 'salt-and-pepper' chromatin; histologic variants include clear cell (VHL-associated), oncocytic, and pleomorphic types.
- Ancillary: Strong diffuse expression of synaptophysin and ISL1 is typical; immunohistochemical loss of DAXX or ATRX (seen in ~45%) is associated with the ALT phenotype and a worse prognosis.
- Prognosis: Proliferative rate (Ki-67 index and mitotic count) is the most critical histological predictor of outcome, as all NF-PanNETs are considered to have malignant potential.
Non-functioning pancreatic neuroendocrine tumour (PanNET) demonstrating a classic gyriform-trabecular pattern.

Q: The [...] histologic variant of [...] features lipid vacuoles and is frequently associated with Von Hippel–Lindau syndrome.
Non-functioning pancreatic neuroendocrine tumour (PanNET) with clear cell features, often associated with VHL.
A: clear cell; Non-functioning pancreatic neuroendocrine tumours
Back Extra: Non-functioning pancreatic neuroendocrine tumours
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) are well-differentiated neoplasms ≥ 5 mm that lack a clinical hormonal syndrome; they are frequently associated with MEN1 and Von Hippel-Lindau (VHL) syndromes.
- Microscopic: Features organoid growth (trabecular, gyriform, or solid) with cells showing characteristic 'salt-and-pepper' chromatin; histologic variants include clear cell (VHL-associated), oncocytic, and pleomorphic types.
- Ancillary: Strong diffuse expression of synaptophysin and ISL1 is typical; immunohistochemical loss of DAXX or ATRX (seen in ~45%) is associated with the ALT phenotype and a worse prognosis.
- Prognosis: Proliferative rate (Ki-67 index and mitotic count) is the most critical histological predictor of outcome, as all NF-PanNETs are considered to have malignant potential.
Non-functioning pancreatic neuroendocrine tumour (PanNET) with clear cell features, often associated with VHL.

Q: According to the WHO classification, a [...] is distinguished from a microtumour primarily by a size threshold of [...].
A neuroendocrine microtumour (< 5 mm) and adjacent NET from a patient with MEN1.
A: Non-functioning pancreatic neuroendocrine tumour; 5 mm
Back Extra: Non-functioning pancreatic neuroendocrine tumours
- Clinical: Non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) are well-differentiated neoplasms ≥ 5 mm that lack a clinical hormonal syndrome; they are frequently associated with MEN1 and Von Hippel-Lindau (VHL) syndromes.
- Microscopic: Features organoid growth (trabecular, gyriform, or solid) with cells showing characteristic 'salt-and-pepper' chromatin; histologic variants include clear cell (VHL-associated), oncocytic, and pleomorphic types.
- Ancillary: Strong diffuse expression of synaptophysin and ISL1 is typical; immunohistochemical loss of DAXX or ATRX (seen in ~45%) is associated with the ALT phenotype and a worse prognosis.
- Prognosis: Proliferative rate (Ki-67 index and mitotic count) is the most critical histological predictor of outcome, as all NF-PanNETs are considered to have malignant potential.
A neuroendocrine microtumour (< 5 mm) and adjacent NET from a patient with MEN1.

Q: A pancreatic mass with a well-circumscribed gross appearance and a trabecular histologic pattern (as seen in Figure 51714) that shows diffuse [...] expression is diagnostic of a [...].
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) demonstrating diffuse serotonin expression by immunohistochemistry.
A: serotonin; Serotonin-producing neuroendocrine tumour
Back Extra: Serotonin-producing neuroendocrine tumour
- Clinical: Extremely rare (<1% of PanNETs); functioning tumors often present with atypical carcinoid syndrome (abdominal pain, diarrhea, flushing) and elevated urinary 5-HIAA.
- Microscopic: Characterized by well-differentiated (G1/G2) neuroendocrine cells, frequently arranged in a trabecular pattern with variable, sometimes prominent, stroma.
- Ancillary: Consistently positive for serotonin, VMAT2, and PDX1 (confirming pancreatic origin); usually negative for CDX2 and Substance P.
- Prognosis: Non-functioning tumors are typically indolent, while functioning tumors carry a poorer prognosis as they are almost always metastatic at presentation.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) demonstrating diffuse serotonin expression by immunohistochemistry.

Q: Functioning [...] of the pancreas are confirmed by demonstrating high levels of [...] excretion.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.
A: Serotonin-producing neuroendocrine tumours; urinary 5-HIAA
Back Extra: Serotonin-producing neuroendocrine tumour
- Clinical: Extremely rare (<1% of PanNETs); functioning tumors often present with atypical carcinoid syndrome (abdominal pain, diarrhea, flushing) and elevated urinary 5-HIAA.
- Microscopic: Characterized by well-differentiated (G1/G2) neuroendocrine cells, frequently arranged in a trabecular pattern with variable, sometimes prominent, stroma.
- Ancillary: Consistently positive for serotonin, VMAT2, and PDX1 (confirming pancreatic origin); usually negative for CDX2 and Substance P.
- Prognosis: Non-functioning tumors are typically indolent, while functioning tumors carry a poorer prognosis as they are almost always metastatic at presentation.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.

Q: To differentiate a [...] from an intestinal carcinoid, the marker [...] is used because it is always positive in the pancreatic primary.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.
A: Serotonin-producing neuroendocrine tumour; PDX1
Back Extra: Serotonin-producing neuroendocrine tumour
- Clinical: Extremely rare (<1% of PanNETs); functioning tumors often present with atypical carcinoid syndrome (abdominal pain, diarrhea, flushing) and elevated urinary 5-HIAA.
- Microscopic: Characterized by well-differentiated (G1/G2) neuroendocrine cells, frequently arranged in a trabecular pattern with variable, sometimes prominent, stroma.
- Ancillary: Consistently positive for serotonin, VMAT2, and PDX1 (confirming pancreatic origin); usually negative for CDX2 and Substance P.
- Prognosis: Non-functioning tumors are typically indolent, while functioning tumors carry a poorer prognosis as they are almost always metastatic at presentation.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.

Q: Unlike intestinal counterparts, the [...] of the pancreas typically tests negative for the markers [...] and [...].
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.
A: Serotonin-producing neuroendocrine tumour; Substance P; CDX2
Back Extra: Serotonin-producing neuroendocrine tumour
- Clinical: Extremely rare (<1% of PanNETs); functioning tumors often present with atypical carcinoid syndrome (abdominal pain, diarrhea, flushing) and elevated urinary 5-HIAA.
- Microscopic: Characterized by well-differentiated (G1/G2) neuroendocrine cells, frequently arranged in a trabecular pattern with variable, sometimes prominent, stroma.
- Ancillary: Consistently positive for serotonin, VMAT2, and PDX1 (confirming pancreatic origin); usually negative for CDX2 and Substance P.
- Prognosis: Non-functioning tumors are typically indolent, while functioning tumors carry a poorer prognosis as they are almost always metastatic at presentation.
Serotonin-producing pancreatic neuroendocrine tumour (PanNET) showing a trabecular pattern with prominent stroma and no significant atypia.

Q: The classic clinical triad associated with a functioning Somatostatinoma includes [...], [...], and [...].
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.
A: diabetes/glucose intolerance; cholelithiasis; diarrhea/steatorrhea
Back Extra: Somatostatinoma
- Clinical: Functioning pancreatic neuroendocrine tumor (PanNET) presenting with the classic clinical triad of diabetes/glucose intolerance, cholelithiasis, and diarrhea/steatorrhea.
- Microscopic: Well-differentiated neuroendocrine morphology typically demonstrating trabecular, solid, or acinar architectures; unlike duodenal variants, pancreatic primary tumors usually lack psammoma bodies.
- Diagnosis: Requires biochemical evidence of fasting plasma somatostatin level ≥ 3 times the upper reference limit (> 25 pmol/L) in conjunction with compatible morphology.
- Ancillary Studies: Characterized by diffuse somatostatin immunoreactivity and expression of neuroendocrine markers (Synaptophysin, INSM1); SSTR2 expression is also frequently present.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.

Q: Biochemical diagnosis of a Somatostatinoma requires a fasting plasma somatostatin level that is at least [...] times the upper reference limit.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.
A: 3
Back Extra: Somatostatinoma
- Clinical: Functioning pancreatic neuroendocrine tumor (PanNET) presenting with the classic clinical triad of diabetes/glucose intolerance, cholelithiasis, and diarrhea/steatorrhea.
- Microscopic: Well-differentiated neuroendocrine morphology typically demonstrating trabecular, solid, or acinar architectures; unlike duodenal variants, pancreatic primary tumors usually lack psammoma bodies.
- Diagnosis: Requires biochemical evidence of fasting plasma somatostatin level ≥ 3 times the upper reference limit (> 25 pmol/L) in conjunction with compatible morphology.
- Ancillary Studies: Characterized by diffuse somatostatin immunoreactivity and expression of neuroendocrine markers (Synaptophysin, INSM1); SSTR2 expression is also frequently present.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.

Q: While duodenal somatostatin-producing tumors often contain [...], these are typically absent in pancreatic Somatostatinoma.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.
A: psammomatous calcifications (psammoma bodies)
Back Extra: Somatostatinoma
- Clinical: Functioning pancreatic neuroendocrine tumor (PanNET) presenting with the classic clinical triad of diabetes/glucose intolerance, cholelithiasis, and diarrhea/steatorrhea.
- Microscopic: Well-differentiated neuroendocrine morphology typically demonstrating trabecular, solid, or acinar architectures; unlike duodenal variants, pancreatic primary tumors usually lack psammoma bodies.
- Diagnosis: Requires biochemical evidence of fasting plasma somatostatin level ≥ 3 times the upper reference limit (> 25 pmol/L) in conjunction with compatible morphology.
- Ancillary Studies: Characterized by diffuse somatostatin immunoreactivity and expression of neuroendocrine markers (Synaptophysin, INSM1); SSTR2 expression is also frequently present.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.

Q: Based on the provided figures, a pancreatic neuroendocrine tumor showing a [...] architecture and diffuse [...] immunoreactivity is diagnostic of a Somatostatinoma.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.
Somatostatinoma. Diffuse somatostatin immunoreactivity.
A: trabecular; somatostatin
Back Extra: Somatostatinoma
- Clinical: Functioning pancreatic neuroendocrine tumor (PanNET) presenting with the classic clinical triad of diabetes/glucose intolerance, cholelithiasis, and diarrhea/steatorrhea.
- Microscopic: Well-differentiated neuroendocrine morphology typically demonstrating trabecular, solid, or acinar architectures; unlike duodenal variants, pancreatic primary tumors usually lack psammoma bodies.
- Diagnosis: Requires biochemical evidence of fasting plasma somatostatin level ≥ 3 times the upper reference limit (> 25 pmol/L) in conjunction with compatible morphology.
- Ancillary Studies: Characterized by diffuse somatostatin immunoreactivity and expression of neuroendocrine markers (Synaptophysin, INSM1); SSTR2 expression is also frequently present.
Somatostatinoma. Tumour showing a mainly trabecular architecture with focal pseudoglandular features.
Somatostatinoma. Diffuse somatostatin immunoreactivity.

Q: A patient presenting with the 'WDHA syndrome' constellation of symptoms and a hypervascular pancreatic mass on imaging most likely has a [...].
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.
A: VIPoma
Back Extra: VIPoma
- Clinical: Presents with WDHA syndrome: Watery Diarrhea, Hypokalemia, and Achlorhydria (also known as Verner–Morrison syndrome); stool volume typically exceeds 700 mL/day and persists during fasting.
- Macroscopic: Usually solitary, well-circumscribed, large (mean 44-54 mm) tan lesions, typically located in the pancreatic body or tail.
- Microscopic: Displays classic well-differentiated neuroendocrine morphology (organoid, trabecular, or tubuloacinar patterns) with stippled (salt-and-pepper) nuclei and granular cytoplasm.
- Ancillary: Characterized by positive staining for neuroendocrine markers (Synaptophysin, Chromogranin A, INSM1), nuclear PDX1, and specific VIP immunolabelling in approximately 90% of cases.
- Prognosis: High metastatic potential at diagnosis (50-80%), primarily to the liver and ovary; management of VIP-induced electrolyte imbalance is critical.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.

The WDHA syndrome associated with a VIPoma stands for Watery Diarrhea, Hypokalemia, and Achlorhydria.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.
Back Extra: VIPoma
- Clinical: Presents with WDHA syndrome: Watery Diarrhea, Hypokalemia, and Achlorhydria (also known as Verner–Morrison syndrome); stool volume typically exceeds 700 mL/day and persists during fasting.
- Macroscopic: Usually solitary, well-circumscribed, large (mean 44-54 mm) tan lesions, typically located in the pancreatic body or tail.
- Microscopic: Displays classic well-differentiated neuroendocrine morphology (organoid, trabecular, or tubuloacinar patterns) with stippled (salt-and-pepper) nuclei and granular cytoplasm.
- Ancillary: Characterized by positive staining for neuroendocrine markers (Synaptophysin, Chromogranin A, INSM1), nuclear PDX1, and specific VIP immunolabelling in approximately 90% of cases.
- Prognosis: High metastatic potential at diagnosis (50-80%), primarily to the liver and ovary; management of VIP-induced electrolyte imbalance is critical.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.

Q: Microscopically, a [...] is indistinguishable from other well-differentiated PanNETs, showing cells with [...] nuclei and granular cytoplasm arranged in an organoid pattern.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.
A: VIPoma; stippled (salt-and-pepper)
Back Extra: VIPoma
- Clinical: Presents with WDHA syndrome: Watery Diarrhea, Hypokalemia, and Achlorhydria (also known as Verner–Morrison syndrome); stool volume typically exceeds 700 mL/day and persists during fasting.
- Macroscopic: Usually solitary, well-circumscribed, large (mean 44-54 mm) tan lesions, typically located in the pancreatic body or tail.
- Microscopic: Displays classic well-differentiated neuroendocrine morphology (organoid, trabecular, or tubuloacinar patterns) with stippled (salt-and-pepper) nuclei and granular cytoplasm.
- Ancillary: Characterized by positive staining for neuroendocrine markers (Synaptophysin, Chromogranin A, INSM1), nuclear PDX1, and specific VIP immunolabelling in approximately 90% of cases.
- Prognosis: High metastatic potential at diagnosis (50-80%), primarily to the liver and ovary; management of VIP-induced electrolyte imbalance is critical.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.

Q: In addition to general neuroendocrine markers, the [...] typically shows nuclear expression of the transcription factor [...] by immunohistochemistry.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.
A: VIPoma; PDX1
Back Extra: VIPoma
- Clinical: Presents with WDHA syndrome: Watery Diarrhea, Hypokalemia, and Achlorhydria (also known as Verner–Morrison syndrome); stool volume typically exceeds 700 mL/day and persists during fasting.
- Macroscopic: Usually solitary, well-circumscribed, large (mean 44-54 mm) tan lesions, typically located in the pancreatic body or tail.
- Microscopic: Displays classic well-differentiated neuroendocrine morphology (organoid, trabecular, or tubuloacinar patterns) with stippled (salt-and-pepper) nuclei and granular cytoplasm.
- Ancillary: Characterized by positive staining for neuroendocrine markers (Synaptophysin, Chromogranin A, INSM1), nuclear PDX1, and specific VIP immunolabelling in approximately 90% of cases.
- Prognosis: High metastatic potential at diagnosis (50-80%), primarily to the liver and ovary; management of VIP-induced electrolyte imbalance is critical.
VIPoma. C Microscopically, VIPomas are indistinguishable from other well-differentiated pancreatic neuroendocrine tumours (PanNENs). The neoplastic cells are arranged in an organoid pattern with granular cytoplasm and stippled nuclei.

Q: A pancreatic mass showing small cells with scant cytoplasm, nuclear moulding, and a Ki-67 index >70% (as seen in the provided SCNEC images) is diagnostic of [...].
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). B Tumour necrosis is seen.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). C Ki-67 proliferation index > 70%.
A: Pancreatic neuroendocrine carcinoma
Back Extra: Pancreatic neuroendocrine carcinoma
- Definition: A high-grade, poorly differentiated malignant epithelial neoplasm subdivided into small cell (SCNEC) and large cell (LCNEC) subtypes.
- Microscopic: Characterized by brisk mitotic activity (>20 mitoses/2 mm²), extensive necrosis, and a Ki-67 proliferation index usually exceeding 60%.
- Ancillary: Characterized by abnormal p53 expression (95%) and loss of RB1 (74%); usually lacks SSTR2 expression and DAXX/ATRX mutations.
- Clinical: Highly aggressive with a median survival <1 year; unlike well-differentiated PanNETs, these are typically positive on 18F-FDG PET-CT and negative on SSTR imaging.
- Differential: Distinguished from PanNET G3 by the presence of TP53/RB1 alterations and the absence of DAXX/ATRX mutations.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). B Tumour necrosis is seen.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). C Ki-67 proliferation index > 70%.

Q: Unlike well-differentiated neuroendocrine tumours, Pancreatic neuroendocrine carcinoma frequently demonstrates mutations in [...] and loss of expression of [...].
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.
A: TP53; RB1
Back Extra: Pancreatic neuroendocrine carcinoma
- Definition: A high-grade, poorly differentiated malignant epithelial neoplasm subdivided into small cell (SCNEC) and large cell (LCNEC) subtypes.
- Microscopic: Characterized by brisk mitotic activity (>20 mitoses/2 mm²), extensive necrosis, and a Ki-67 proliferation index usually exceeding 60%.
- Ancillary: Characterized by abnormal p53 expression (95%) and loss of RB1 (74%); usually lacks SSTR2 expression and DAXX/ATRX mutations.
- Clinical: Highly aggressive with a median survival <1 year; unlike well-differentiated PanNETs, these are typically positive on 18F-FDG PET-CT and negative on SSTR imaging.
- Differential: Distinguished from PanNET G3 by the presence of TP53/RB1 alterations and the absence of DAXX/ATRX mutations.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.

Q: In the differential diagnosis of a high-grade pancreatic NEN, the presence of DAXX or ATRX mutations would favor a [...] over a Pancreatic neuroendocrine carcinoma.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.
A: PanNET G3
Back Extra: Pancreatic neuroendocrine carcinoma
- Definition: A high-grade, poorly differentiated malignant epithelial neoplasm subdivided into small cell (SCNEC) and large cell (LCNEC) subtypes.
- Microscopic: Characterized by brisk mitotic activity (>20 mitoses/2 mm²), extensive necrosis, and a Ki-67 proliferation index usually exceeding 60%.
- Ancillary: Characterized by abnormal p53 expression (95%) and loss of RB1 (74%); usually lacks SSTR2 expression and DAXX/ATRX mutations.
- Clinical: Highly aggressive with a median survival <1 year; unlike well-differentiated PanNETs, these are typically positive on 18F-FDG PET-CT and negative on SSTR imaging.
- Differential: Distinguished from PanNET G3 by the presence of TP53/RB1 alterations and the absence of DAXX/ATRX mutations.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.

Q: Clinically, Pancreatic neuroendocrine carcinoma is typically non-functional and shows high uptake on [...] PET-CT, while usually being negative on [...] imaging.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.
A: 18F-FDG; SSTR (e.g., DOTATATE)
Back Extra: Pancreatic neuroendocrine carcinoma
- Definition: A high-grade, poorly differentiated malignant epithelial neoplasm subdivided into small cell (SCNEC) and large cell (LCNEC) subtypes.
- Microscopic: Characterized by brisk mitotic activity (>20 mitoses/2 mm²), extensive necrosis, and a Ki-67 proliferation index usually exceeding 60%.
- Ancillary: Characterized by abnormal p53 expression (95%) and loss of RB1 (74%); usually lacks SSTR2 expression and DAXX/ATRX mutations.
- Clinical: Highly aggressive with a median survival <1 year; unlike well-differentiated PanNETs, these are typically positive on 18F-FDG PET-CT and negative on SSTR imaging.
- Differential: Distinguished from PanNET G3 by the presence of TP53/RB1 alterations and the absence of DAXX/ATRX mutations.
Pancreatic small cell neuroendocrine carcinoma (SCNEC). A The carcinoma is composed of small cells with scant cytoplasm.
Pancreatic large cell neuroendocrine carcinoma (LCNEC). A Large tumour cells with abundant cytoplasm and frequent mitoses.

Q: A microscopic, non-invasive lesion measuring 3 mm in the pancreatic duct with micropapillary architecture and loss of cellular polarity (seen in figure) is most consistent with [...].
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
High-grade pancreatic intraepithelial neoplasia (PanIN). Overview of pancreatic ducts with high-grade PanIN.
High-grade pancreatic intraepithelial neoplasia. Low power view showing a duct lined by columnar epithelium micropapillary architecture.
A: High-grade Pancreatic intraepithelial neoplasia
Back Extra: Pancreatic intraepithelial neoplasia (PanIN)
- Clinical: Microscopic, asymptomatic lesions typically found incidentally; strong association with age, obesity, and familial risk for pancreatic ductal adenocarcinoma (PDAC).
- Microscopic: Non-invasive epithelial neoplasm graded by atypia; Low-grade shows flat/papillary mucinous epithelium with mild atypia, while High-grade shows micropapillary/cribriform architecture and severe cytological atypia.
- Differential Diagnosis: Distinguished from IPMN by size (PanIN <5 mm vs. IPMN >10 mm) and from 'cancerization' (intraductal spread of invasive cancer) by SMAD4 retention and lack of abrupt transition.
- Molecular: KRAS mutations (>90%) and telomere shortening are early events; TP53 and CDKN2A alterations are late events typically seen in high-grade lesions.
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
High-grade pancreatic intraepithelial neoplasia (PanIN). Overview of pancreatic ducts with high-grade PanIN.
High-grade pancreatic intraepithelial neoplasia. Low power view showing a duct lined by columnar epithelium micropapillary architecture.

Q: Regarding the differential diagnosis of Pancreatic intraepithelial neoplasia, Intraductal Papillary Mucinous Neoplasms (IPMNs) are typically distinguished by a size greater than [...].
High-grade pancreatic intraepithelial neoplasia (PanIN). Overview of pancreatic ducts with high-grade PanIN.
A: 10 mm
Back Extra: Pancreatic intraepithelial neoplasia (PanIN)
- Clinical: Microscopic, asymptomatic lesions typically found incidentally; strong association with age, obesity, and familial risk for pancreatic ductal adenocarcinoma (PDAC).
- Microscopic: Non-invasive epithelial neoplasm graded by atypia; Low-grade shows flat/papillary mucinous epithelium with mild atypia, while High-grade shows micropapillary/cribriform architecture and severe cytological atypia.
- Differential Diagnosis: Distinguished from IPMN by size (PanIN <5 mm vs. IPMN >10 mm) and from 'cancerization' (intraductal spread of invasive cancer) by SMAD4 retention and lack of abrupt transition.
- Molecular: KRAS mutations (>90%) and telomere shortening are early events; TP53 and CDKN2A alterations are late events typically seen in high-grade lesions.
High-grade pancreatic intraepithelial neoplasia (PanIN). Overview of pancreatic ducts with high-grade PanIN.

Q: In Pancreatic intraepithelial neoplasia, mutations in the [...] gene are considered early events, while biallelic inactivation of [...] or CDKN2A are typically late events found in high-grade lesions.
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
Low-grade pancreatic intraepithelial neoplasia. Although there is some nuclear enlargement and scattered prominent nucleoli, the nuclei remain well oriented, and mitoses are not seen.
A: KRAS; TP53
Back Extra: Pancreatic intraepithelial neoplasia (PanIN)
- Clinical: Microscopic, asymptomatic lesions typically found incidentally; strong association with age, obesity, and familial risk for pancreatic ductal adenocarcinoma (PDAC).
- Microscopic: Non-invasive epithelial neoplasm graded by atypia; Low-grade shows flat/papillary mucinous epithelium with mild atypia, while High-grade shows micropapillary/cribriform architecture and severe cytological atypia.
- Differential Diagnosis: Distinguished from IPMN by size (PanIN <5 mm vs. IPMN >10 mm) and from 'cancerization' (intraductal spread of invasive cancer) by SMAD4 retention and lack of abrupt transition.
- Molecular: KRAS mutations (>90%) and telomere shortening are early events; TP53 and CDKN2A alterations are late events typically seen in high-grade lesions.
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
Low-grade pancreatic intraepithelial neoplasia. Although there is some nuclear enlargement and scattered prominent nucleoli, the nuclei remain well oriented, and mitoses are not seen.

Q: Unlike the intraductal spread of invasive carcinoma (cancerization), high-grade Pancreatic intraepithelial neoplasia typically shows [...] SMAD4 expression by immunohistochemistry.
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
Differential diagnosis: Intraductal spread of invasive carcinoma (cancerization) mimicking pancreatic intraepithelial neoplasia.
A: retained
Back Extra: Pancreatic intraepithelial neoplasia (PanIN)
- Clinical: Microscopic, asymptomatic lesions typically found incidentally; strong association with age, obesity, and familial risk for pancreatic ductal adenocarcinoma (PDAC).
- Microscopic: Non-invasive epithelial neoplasm graded by atypia; Low-grade shows flat/papillary mucinous epithelium with mild atypia, while High-grade shows micropapillary/cribriform architecture and severe cytological atypia.
- Differential Diagnosis: Distinguished from IPMN by size (PanIN <5 mm vs. IPMN >10 mm) and from 'cancerization' (intraductal spread of invasive cancer) by SMAD4 retention and lack of abrupt transition.
- Molecular: KRAS mutations (>90%) and telomere shortening are early events; TP53 and CDKN2A alterations are late events typically seen in high-grade lesions.
High-grade pancreatic intraepithelial neoplasia (PanIN). High magnification showing the micropapillary and cribriform architecture and the nuclear polymorphism.
Differential diagnosis: Intraductal spread of invasive carcinoma (cancerization) mimicking pancreatic intraepithelial neoplasia.

Q: A tumor at the ampulla of Vater composed of tall columnar cells with pseudostratified nuclei and goblet cells, mimicking a colonic primary, is best diagnosed as [...].
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.
A: Ampullary adenocarcinoma, intestinal type
Back Extra: Ampullary adenocarcinoma, intestinal type
- Clinical: Presents earlier than other small bowel cancers due to biliary obstruction/jaundice; 10–15% are mismatch repair (MMR) deficient.
- Microscopic: Characterized by neoplastic glands lined by tall columnar cells with pseudostratified nuclei, closely mimicking colonic adenocarcinoma; often associated with a pre-existing intestinal-type adenoma.
- Ancillary: Typically shows an intestinal immunophenotype: CDX2(+), MUC2(+); unlike colonic primary, often co-expresses CK7 and CK20.
- Prognosis: Five-year survival is 40–70%; independent prognostic factors include lymph node status, margin status, and depth of pancreatic invasion.
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.

Q: While morphologically similar to colonic primaries, [...] often differs by showing immunohistochemical co-expression of [...] and CK20.
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.
A: Ampullary adenocarcinoma, intestinal type; CK7
Back Extra: Ampullary adenocarcinoma, intestinal type
- Clinical: Presents earlier than other small bowel cancers due to biliary obstruction/jaundice; 10–15% are mismatch repair (MMR) deficient.
- Microscopic: Characterized by neoplastic glands lined by tall columnar cells with pseudostratified nuclei, closely mimicking colonic adenocarcinoma; often associated with a pre-existing intestinal-type adenoma.
- Ancillary: Typically shows an intestinal immunophenotype: CDX2(+), MUC2(+); unlike colonic primary, often co-expresses CK7 and CK20.
- Prognosis: Five-year survival is 40–70%; independent prognostic factors include lymph node status, margin status, and depth of pancreatic invasion.
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.

Q: Approximately [...]% of cases of [...] are mismatch repair (MMR) protein deficient, necessitating routine screening.
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.
A: 10–15; Ampullary adenocarcinoma, intestinal type
Back Extra: Ampullary adenocarcinoma, intestinal type
- Clinical: Presents earlier than other small bowel cancers due to biliary obstruction/jaundice; 10–15% are mismatch repair (MMR) deficient.
- Microscopic: Characterized by neoplastic glands lined by tall columnar cells with pseudostratified nuclei, closely mimicking colonic adenocarcinoma; often associated with a pre-existing intestinal-type adenoma.
- Ancillary: Typically shows an intestinal immunophenotype: CDX2(+), MUC2(+); unlike colonic primary, often co-expresses CK7 and CK20.
- Prognosis: Five-year survival is 40–70%; independent prognostic factors include lymph node status, margin status, and depth of pancreatic invasion.
Gland-forming (tubular) adenocarcinoma. Note the mixed pattern, predominantly intestinal type (right and lower) with transition to more gastropancreatobiliary phenotype in the upper left.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.

Q: [...] often presents with the clinical sign of [...] due to its location, which typically results in a lower stage at diagnosis compared to other small intestinal adenocarcinomas.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.
A: Ampullary adenocarcinoma, intestinal type; jaundice
Back Extra: Ampullary adenocarcinoma, intestinal type
- Clinical: Presents earlier than other small bowel cancers due to biliary obstruction/jaundice; 10–15% are mismatch repair (MMR) deficient.
- Microscopic: Characterized by neoplastic glands lined by tall columnar cells with pseudostratified nuclei, closely mimicking colonic adenocarcinoma; often associated with a pre-existing intestinal-type adenoma.
- Ancillary: Typically shows an intestinal immunophenotype: CDX2(+), MUC2(+); unlike colonic primary, often co-expresses CK7 and CK20.
- Prognosis: Five-year survival is 40–70%; independent prognostic factors include lymph node status, margin status, and depth of pancreatic invasion.
Ampullary carcinoma of ampullary-ductal origin. Low-power histological view of carcinoma at the ampullary orifice.
Ampullary carcinoma: Area of invasive adenocarcinoma infiltrating the ampullary duodenal submucosa.

Q: A duodenal mass that spares the ampulla and shows malignant glands with foveolar-type morphology (MUC5AC+) is best classified as [...] with [...] histomorphology.
Infiltrating adenocarcinoma of the duodenum demonstrating the characteristic sparing of the ampulla of Vater.
Duodenal adenocarcinoma with gastric histomorphology, characterized by foveolar-type or pyloric-type columnar neoplastic cells.
A: Non-ampullary adenocarcinoma; gastric
Back Extra: Non-ampullary adenocarcinoma
- Clinical: The duodenum is the most common site for small intestine adenocarcinoma (50–60%); it is associated with hereditary syndromes like Lynch (1–12% risk) and FAP (5% risk), as well as celiac and Crohn disease.
- Microscopic: Key histomorphological patterns include gastric (MUC5AC/MUC6+), pancreatobiliary (EMA/MUC1+), and intestinal (CDX2/MUC2+). Subtypes include medullary (MSI-H association) and undifferentiated (often SMARCB1/INI1 deficient).
- Ancillary: MMR deficiency is identified in 7.6–21.6% of cases (higher in celiac-associated) and serves as a predictor for PD1 inhibitor therapy; ERBB2 (HER2) amplification or mutation occurs in ~10–16% of cases.
- Prognosis: Survival is generally worse than colorectal cancer but better than pancreaticobiliary tract cancers; retrieval of at least 8 lymph nodes is a critical prognostic factor.
Infiltrating adenocarcinoma of the duodenum demonstrating the characteristic sparing of the ampulla of Vater.
Duodenal adenocarcinoma with gastric histomorphology, characterized by foveolar-type or pyloric-type columnar neoplastic cells.

Q: In the setting of [...], the presence of [...] (often seen in medullary variants) is a predictive marker for response to [...] immunotherapy.
Duodenal medullary carcinoma with solid sheets of malignant cells, prominent nucleoli, and increased tumour-infiltrating lymphocytes (often associated with MMR deficiency).
A: Non-ampullary adenocarcinoma; MSI-H / MMR deficiency; PD1 inhibitor
Back Extra: Non-ampullary adenocarcinoma
- Clinical: The duodenum is the most common site for small intestine adenocarcinoma (50–60%); it is associated with hereditary syndromes like Lynch (1–12% risk) and FAP (5% risk), as well as celiac and Crohn disease.
- Microscopic: Key histomorphological patterns include gastric (MUC5AC/MUC6+), pancreatobiliary (EMA/MUC1+), and intestinal (CDX2/MUC2+). Subtypes include medullary (MSI-H association) and undifferentiated (often SMARCB1/INI1 deficient).
- Ancillary: MMR deficiency is identified in 7.6–21.6% of cases (higher in celiac-associated) and serves as a predictor for PD1 inhibitor therapy; ERBB2 (HER2) amplification or mutation occurs in ~10–16% of cases.
- Prognosis: Survival is generally worse than colorectal cancer but better than pancreaticobiliary tract cancers; retrieval of at least 8 lymph nodes is a critical prognostic factor.
Duodenal medullary carcinoma with solid sheets of malignant cells, prominent nucleoli, and increased tumour-infiltrating lymphocytes (often associated with MMR deficiency).

Q: Undifferentiated variants of [...] that exhibit rhabdoid morphology should be evaluated for the loss of [...] via immunohistochemistry.
Duodenal undifferentiated carcinoma showing sheets of large discohesive cells with abundant eosinophilic cytoplasm.
Undifferentiated carcinoma of the duodenum demonstrating loss of SMARCB1/INI1 expression.
A: Non-ampullary adenocarcinoma; SMARCB1 (INI1)
Back Extra: Non-ampullary adenocarcinoma
- Clinical: The duodenum is the most common site for small intestine adenocarcinoma (50–60%); it is associated with hereditary syndromes like Lynch (1–12% risk) and FAP (5% risk), as well as celiac and Crohn disease.
- Microscopic: Key histomorphological patterns include gastric (MUC5AC/MUC6+), pancreatobiliary (EMA/MUC1+), and intestinal (CDX2/MUC2+). Subtypes include medullary (MSI-H association) and undifferentiated (often SMARCB1/INI1 deficient).
- Ancillary: MMR deficiency is identified in 7.6–21.6% of cases (higher in celiac-associated) and serves as a predictor for PD1 inhibitor therapy; ERBB2 (HER2) amplification or mutation occurs in ~10–16% of cases.
- Prognosis: Survival is generally worse than colorectal cancer but better than pancreaticobiliary tract cancers; retrieval of at least 8 lymph nodes is a critical prognostic factor.
Duodenal undifferentiated carcinoma showing sheets of large discohesive cells with abundant eosinophilic cytoplasm.
Undifferentiated carcinoma of the duodenum demonstrating loss of SMARCB1/INI1 expression.

Q: A 65-year-old male presents with jaundice, and imaging reveals an exophytic granular polypoid mass filling the intra-ampullary distal common bile duct while sparing the duodenal surface. This findings is characteristic of a type of ampullary adenomatous neoplasm known as [...].
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.
A: intra-ampullary papillary-tubular neoplasm (IAPN)
Back Extra: Ampullary adenomatous neoplasm
- Clinical: These neoplasms include surface lesions (ampullary duodenal adenoma) and channel lesions (intra-ampullary papillary-tubular neoplasm [IAPN]); FAP-associated cases present much younger (mean age 39) than sporadic cases.
- Microscopic: Ampullary duodenal adenomas typically show intestinal differentiation (CDX2+, MUC2+), whereas IAPNs are exophytic, non-invasive tumors filling the distal common bile or pancreatic duct, often containing mixed intestinal and pancreatobiliary phenotypes.
- Prognosis: While surface adenomas are often endoscopically managed, IAPNs carry a higher risk of malignancy, with invasive carcinoma found in approximately 75% of resected specimens.
- Molecular: APC mutations are characteristic of both sporadic and FAP-associated ampullary adenomatous neoplasms, with KRAS mutations present in 30–40% of cases.
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.

Q: In the setting of ampullary adenomatous neoplasms, the presence of multiple lesions at a young age (mean age 39) should specifically raise suspicion for the syndromic association of [...].
Ampullary duodenal adenoma. This adenoma involves the duodenal mucosa (far left) overlying the ampulla.
Ampullary duodenal adenoma. High-power view of intestinal-type adenoma with low-grade dysplasia.
Ampullary duodenal adenoma. The adenoma has high-grade dysplasia in this region.
A: familial adenomatous polyposis (FAP)
Back Extra: Ampullary adenomatous neoplasm
- Clinical: These neoplasms include surface lesions (ampullary duodenal adenoma) and channel lesions (intra-ampullary papillary-tubular neoplasm [IAPN]); FAP-associated cases present much younger (mean age 39) than sporadic cases.
- Microscopic: Ampullary duodenal adenomas typically show intestinal differentiation (CDX2+, MUC2+), whereas IAPNs are exophytic, non-invasive tumors filling the distal common bile or pancreatic duct, often containing mixed intestinal and pancreatobiliary phenotypes.
- Prognosis: While surface adenomas are often endoscopically managed, IAPNs carry a higher risk of malignancy, with invasive carcinoma found in approximately 75% of resected specimens.
- Molecular: APC mutations are characteristic of both sporadic and FAP-associated ampullary adenomatous neoplasms, with KRAS mutations present in 30–40% of cases.
Ampullary duodenal adenoma. This adenoma involves the duodenal mucosa (far left) overlying the ampulla.
Ampullary duodenal adenoma. High-power view of intestinal-type adenoma with low-grade dysplasia.
Ampullary duodenal adenoma. The adenoma has high-grade dysplasia in this region.

Q: Regarding ampullary adenomatous neoplasms, the intestinal-type areas typically express [...], while pancreatobiliary-type areas often express [...].
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.
A: CDX2 and MUC2; MUC1 (EMA) and MUC6
Back Extra: Ampullary adenomatous neoplasm
- Clinical: These neoplasms include surface lesions (ampullary duodenal adenoma) and channel lesions (intra-ampullary papillary-tubular neoplasm [IAPN]); FAP-associated cases present much younger (mean age 39) than sporadic cases.
- Microscopic: Ampullary duodenal adenomas typically show intestinal differentiation (CDX2+, MUC2+), whereas IAPNs are exophytic, non-invasive tumors filling the distal common bile or pancreatic duct, often containing mixed intestinal and pancreatobiliary phenotypes.
- Prognosis: While surface adenomas are often endoscopically managed, IAPNs carry a higher risk of malignancy, with invasive carcinoma found in approximately 75% of resected specimens.
- Molecular: APC mutations are characteristic of both sporadic and FAP-associated ampullary adenomatous neoplasms, with KRAS mutations present in 30–40% of cases.
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.

Q: Among ampullary adenomatous neoplasms, the variant known as [...] is notably more aggressive than surface adenomas, with invasive carcinoma present in approximately [...]% of resected cases.
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.
A: intra-ampullary papillary-tubular neoplasm (IAPN); 75
Back Extra: Ampullary adenomatous neoplasm
- Clinical: These neoplasms include surface lesions (ampullary duodenal adenoma) and channel lesions (intra-ampullary papillary-tubular neoplasm [IAPN]); FAP-associated cases present much younger (mean age 39) than sporadic cases.
- Microscopic: Ampullary duodenal adenomas typically show intestinal differentiation (CDX2+, MUC2+), whereas IAPNs are exophytic, non-invasive tumors filling the distal common bile or pancreatic duct, often containing mixed intestinal and pancreatobiliary phenotypes.
- Prognosis: While surface adenomas are often endoscopically managed, IAPNs carry a higher risk of malignancy, with invasive carcinoma found in approximately 75% of resected specimens.
- Molecular: APC mutations are characteristic of both sporadic and FAP-associated ampullary adenomatous neoplasms, with KRAS mutations present in 30–40% of cases.
Intra-ampullary papillary-tubular neoplasm. Intestinal type with low-grade (left) and high-grade (right) dysplasia.
Intra-ampullary papillary-tubular neoplasm. Pancreatobiliary type with high-grade dysplasia.

Q: A polypoid Non-ampullary adenoma is identified in the proximal duodenum showing closely packed glands with foamy, ground-glass cytoplasm; this morphology is diagnostic of a [...].
Pyloric gland adenoma of the duodenum. A Low magnification of a pyloric gland adenoma showing its lobular contour.
Pyloric gland adenoma of the duodenum. B Gastric (pyloric) differentiation is evident at higher magnification.
A: Pyloric gland adenoma (PGA)
Back Extra: Non-ampullary adenoma
- Clinical: Most common in the duodenum; approximately 25% are syndromic, primarily associated with Familial Adenomatous Polyposis (FAP) or MUTYH-associated polyposis.
- Micro (Intestinal-type): The most common subtype (9:1 over PGA); presents with tubular or tubulovillous patterns, elongated nuclei, and intestinal markers (CDX2+, MUC2+).
- Micro (Pyloric Gland Adenoma): Composed of closely packed glands lined by cells with characteristic foamy, ground-glass cytoplasm and MUC6 expression.
- Prognosis: Progression risk is linked to size (> 20 mm), villous architecture, and high-grade dysplasia; FAP patients are graded using the Spigelman classification.
- Molecular: Intestinal-type adenomas frequently show APC mutations/WNT activation, while Pyloric Gland Adenomas are associated with GNAS and KRAS mutations.
Pyloric gland adenoma of the duodenum. A Low magnification of a pyloric gland adenoma showing its lobular contour.
Pyloric gland adenoma of the duodenum. B Gastric (pyloric) differentiation is evident at higher magnification.

Q: In the setting of Familial Adenomatous Polyposis (FAP), the risk of adenocarcinoma arising from Non-ampullary adenomas is estimated using the [...] classification.
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.
A: Spigelman
Back Extra: Non-ampullary adenoma
- Clinical: Most common in the duodenum; approximately 25% are syndromic, primarily associated with Familial Adenomatous Polyposis (FAP) or MUTYH-associated polyposis.
- Micro (Intestinal-type): The most common subtype (9:1 over PGA); presents with tubular or tubulovillous patterns, elongated nuclei, and intestinal markers (CDX2+, MUC2+).
- Micro (Pyloric Gland Adenoma): Composed of closely packed glands lined by cells with characteristic foamy, ground-glass cytoplasm and MUC6 expression.
- Prognosis: Progression risk is linked to size (> 20 mm), villous architecture, and high-grade dysplasia; FAP patients are graded using the Spigelman classification.
- Molecular: Intestinal-type adenomas frequently show APC mutations/WNT activation, while Pyloric Gland Adenomas are associated with GNAS and KRAS mutations.
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.

Q: While intestinal-type Non-ampullary adenomas commonly harbor APC mutations, the Pyloric Gland Adenoma (PGA) subtype is characteristically associated with mutations in [...] and [...].
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.
Pyloric gland adenoma of the duodenum. B Gastric (pyloric) differentiation is evident at higher magnification.
A: GNAS; KRAS
Back Extra: Non-ampullary adenoma
- Clinical: Most common in the duodenum; approximately 25% are syndromic, primarily associated with Familial Adenomatous Polyposis (FAP) or MUTYH-associated polyposis.
- Micro (Intestinal-type): The most common subtype (9:1 over PGA); presents with tubular or tubulovillous patterns, elongated nuclei, and intestinal markers (CDX2+, MUC2+).
- Micro (Pyloric Gland Adenoma): Composed of closely packed glands lined by cells with characteristic foamy, ground-glass cytoplasm and MUC6 expression.
- Prognosis: Progression risk is linked to size (> 20 mm), villous architecture, and high-grade dysplasia; FAP patients are graded using the Spigelman classification.
- Molecular: Intestinal-type adenomas frequently show APC mutations/WNT activation, while Pyloric Gland Adenomas are associated with GNAS and KRAS mutations.
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.
Pyloric gland adenoma of the duodenum. B Gastric (pyloric) differentiation is evident at higher magnification.

Q: The intestinal-type Non-ampullary adenoma typically shows positive immunohistochemical staining for the intestinal transcription factor [...] and the mucin [...].
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.
A: CDX2; MUC2
Back Extra: Non-ampullary adenoma
- Clinical: Most common in the duodenum; approximately 25% are syndromic, primarily associated with Familial Adenomatous Polyposis (FAP) or MUTYH-associated polyposis.
- Micro (Intestinal-type): The most common subtype (9:1 over PGA); presents with tubular or tubulovillous patterns, elongated nuclei, and intestinal markers (CDX2+, MUC2+).
- Micro (Pyloric Gland Adenoma): Composed of closely packed glands lined by cells with characteristic foamy, ground-glass cytoplasm and MUC6 expression.
- Prognosis: Progression risk is linked to size (> 20 mm), villous architecture, and high-grade dysplasia; FAP patients are graded using the Spigelman classification.
- Molecular: Intestinal-type adenomas frequently show APC mutations/WNT activation, while Pyloric Gland Adenomas are associated with GNAS and KRAS mutations.
Non-ampullary adenoma. Intestinal-type adenoma with a tubular growth pattern. The tubules are lined by tall columnar cells with elongated nuclei and inconspicuous nucleoli.

Q: A [...] is histologically defined by a predominantly tubular architecture with a villous component consisting of less than [...] of the lesion.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.
A: Tubular Adenoma of the Jejunum and Ileum; 25%
Back Extra: Tubular Adenoma of the Jejunum and Ileum
- Clinical: Rare compared to colorectal adenomas; frequently associated with genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome.
- Presentation: Often larger than duodenal counterparts at diagnosis as they are typically identified during surgery for small bowel obstruction or intussusception.
- Microscopic: Characterized by glandular epithelial dysplasia with elongated, hyperchromatic nuclei and nuclear stratification; tubular subtype is defined by a villous component < 25%.
- Grading: Divided into low-grade and high-grade dysplasia based on architectural complexity (e.g., cribriforming, intraluminal necrosis) and degree of cytologic atypia.
- Ancillary: Pathogenesis mirrors the colorectal adenoma-carcinoma pathway, involving mutations in APC (WNT/β-catenin activation) and KRAS.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.

Q: In the context of genetic syndromes, up to 87% of patients with [...] are found to have a [...] via video capsule endoscopy.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.
A: Familial Adenomatous Polyposis (FAP); Tubular Adenoma of the Jejunum and Ileum
Back Extra: Tubular Adenoma of the Jejunum and Ileum
- Clinical: Rare compared to colorectal adenomas; frequently associated with genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome.
- Presentation: Often larger than duodenal counterparts at diagnosis as they are typically identified during surgery for small bowel obstruction or intussusception.
- Microscopic: Characterized by glandular epithelial dysplasia with elongated, hyperchromatic nuclei and nuclear stratification; tubular subtype is defined by a villous component < 25%.
- Grading: Divided into low-grade and high-grade dysplasia based on architectural complexity (e.g., cribriforming, intraluminal necrosis) and degree of cytologic atypia.
- Ancillary: Pathogenesis mirrors the colorectal adenoma-carcinoma pathway, involving mutations in APC (WNT/β-catenin activation) and KRAS.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.

Q: The diagnosis of a [...] is often made later than duodenal or colonic adenomas, frequently presenting with clinical symptoms such as [...] or small bowel obstruction.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.
A: Tubular Adenoma of the Jejunum and Ileum; intussusception
Back Extra: Tubular Adenoma of the Jejunum and Ileum
- Clinical: Rare compared to colorectal adenomas; frequently associated with genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome.
- Presentation: Often larger than duodenal counterparts at diagnosis as they are typically identified during surgery for small bowel obstruction or intussusception.
- Microscopic: Characterized by glandular epithelial dysplasia with elongated, hyperchromatic nuclei and nuclear stratification; tubular subtype is defined by a villous component < 25%.
- Grading: Divided into low-grade and high-grade dysplasia based on architectural complexity (e.g., cribriforming, intraluminal necrosis) and degree of cytologic atypia.
- Ancillary: Pathogenesis mirrors the colorectal adenoma-carcinoma pathway, involving mutations in APC (WNT/β-catenin activation) and KRAS.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.

Q: High-grade dysplasia in a [...] is characterized by complex architectural findings such as [...] glands and intraluminal necrosis.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.
A: Tubular Adenoma of the Jejunum and Ileum; cribriform
Back Extra: Tubular Adenoma of the Jejunum and Ileum
- Clinical: Rare compared to colorectal adenomas; frequently associated with genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome.
- Presentation: Often larger than duodenal counterparts at diagnosis as they are typically identified during surgery for small bowel obstruction or intussusception.
- Microscopic: Characterized by glandular epithelial dysplasia with elongated, hyperchromatic nuclei and nuclear stratification; tubular subtype is defined by a villous component < 25%.
- Grading: Divided into low-grade and high-grade dysplasia based on architectural complexity (e.g., cribriforming, intraluminal necrosis) and degree of cytologic atypia.
- Ancillary: Pathogenesis mirrors the colorectal adenoma-carcinoma pathway, involving mutations in APC (WNT/β-catenin activation) and KRAS.
Tubular adenoma of the ileum. Tubular adenoma exhibiting low-grade dysplasia arising the ileum.

Q: A small bowel mass showing a nested architecture of monotonous epithelioid cells that are S100/SOX10 positive but HMB45 negative is diagnostic of [...].
Malignant gastrointestinal neuroectodermal tumour showing a dominant nested architecture.
High power demonstrating nested architecture with epithelioid features in a Malignant gastrointestinal neuroectodermal tumour (GNET).
Characteristic SOX10 immunoreactivity in Malignant gastrointestinal neuroectodermal tumour (GNET); note that specific melanocytic markers like HMB45 are negative.
A: Malignant gastrointestinal neuroectodermal tumour (GNET)
Back Extra: Malignant gastrointestinal neuroectodermal tumour
- Clinical: An aggressive, rare malignant neoplasm typically affecting young to middle-aged adults (median 33 years), most commonly presenting in the small intestine with symptoms of bowel obstruction or intussusception.
- Microscopic: Characterized by epithelioid and/or spindle cells arranged in nests, sheets, or pseudopapillary patterns; focal multinucleated osteoclast-type giant cells are present in up to 50% of cases.
- Ancillary: Typically S100 and SOX10 positive, but crucially negative for specific melanocytic markers (HMB45, Melan-A) and KIT (CD117).
- Molecular: The defining molecular genetic hallmark is an EWSR1 gene rearrangement, most frequently involving ATF1 or CREB1 fusion partners.
Malignant gastrointestinal neuroectodermal tumour showing a dominant nested architecture.
High power demonstrating nested architecture with epithelioid features in a Malignant gastrointestinal neuroectodermal tumour (GNET).
Characteristic SOX10 immunoreactivity in Malignant gastrointestinal neuroectodermal tumour (GNET); note that specific melanocytic markers like HMB45 are negative.

Q: The molecular genetic hallmark of [...] is a rearrangement involving the [...] gene.
Malignant gastrointestinal neuroectodermal tumour showing a dominant nested architecture.
High power view of GNET cells with monotonous rounded nuclei and small nucleoli.
A: Malignant gastrointestinal neuroectodermal tumour; EWSR1
Back Extra: Malignant gastrointestinal neuroectodermal tumour
- Clinical: An aggressive, rare malignant neoplasm typically affecting young to middle-aged adults (median 33 years), most commonly presenting in the small intestine with symptoms of bowel obstruction or intussusception.
- Microscopic: Characterized by epithelioid and/or spindle cells arranged in nests, sheets, or pseudopapillary patterns; focal multinucleated osteoclast-type giant cells are present in up to 50% of cases.
- Ancillary: Typically S100 and SOX10 positive, but crucially negative for specific melanocytic markers (HMB45, Melan-A) and KIT (CD117).
- Molecular: The defining molecular genetic hallmark is an EWSR1 gene rearrangement, most frequently involving ATF1 or CREB1 fusion partners.
Malignant gastrointestinal neuroectodermal tumour showing a dominant nested architecture.
High power view of GNET cells with monotonous rounded nuclei and small nucleoli.

Q: Unlike gastrointestinal clear cell sarcoma, [...] lacks evidence of melanocytic differentiation and is consistently negative for [...].
Characteristic SOX10 immunoreactivity in Malignant gastrointestinal neuroectodermal tumour (GNET); note that specific melanocytic markers like HMB45 are negative.
Epithelioid cells arranged in a vague nested pattern in Malignant gastrointestinal neuroectodermal tumour.
A: Malignant gastrointestinal neuroectodermal tumour; HMB45 and Melan-A
Back Extra: Malignant gastrointestinal neuroectodermal tumour
- Clinical: An aggressive, rare malignant neoplasm typically affecting young to middle-aged adults (median 33 years), most commonly presenting in the small intestine with symptoms of bowel obstruction or intussusception.
- Microscopic: Characterized by epithelioid and/or spindle cells arranged in nests, sheets, or pseudopapillary patterns; focal multinucleated osteoclast-type giant cells are present in up to 50% of cases.
- Ancillary: Typically S100 and SOX10 positive, but crucially negative for specific melanocytic markers (HMB45, Melan-A) and KIT (CD117).
- Molecular: The defining molecular genetic hallmark is an EWSR1 gene rearrangement, most frequently involving ATF1 or CREB1 fusion partners.
Characteristic SOX10 immunoreactivity in Malignant gastrointestinal neuroectodermal tumour (GNET); note that specific melanocytic markers like HMB45 are negative.
Epithelioid cells arranged in a vague nested pattern in Malignant gastrointestinal neuroectodermal tumour.

Q: A periampullary submucosal mass showing a triphasic population of neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells is diagnostic of [...].
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.
A: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
Back Extra: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Characteristically arises in the second part of the duodenum (periampullary) as a polypoid, submucosal lesion; patients often present with GI bleeding due to mucosal ulceration.
- Micro: Triphasic morphology consisting of neuroendocrine epithelial nests (gland-like), Schwannian spindle cells (fascicular), and scattered ganglion cells.
- Ancillary: Epithelial cells express cytokeratins and PR; spindle cells express S100/SOX10; and ganglion cells express synaptophysin/NSE but are SOX10 negative.
- Prognosis: While most are indolent, CoGNET is considered malignant due to reported lymph node (10–14.5%) and liver (1.8%) metastases.
- Molecular: Approximately 20% of cases harbor somatic gain-of-function pathogenic variants in EPAS1 (HIF2A).
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.

Q: In Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET), the spindle cell component characteristically expresses [...], reflecting its Schwannian differentiation.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 immunohistochemistry highlights Schwannian spindle cells.
A: S100 (or SOX10)
Back Extra: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Characteristically arises in the second part of the duodenum (periampullary) as a polypoid, submucosal lesion; patients often present with GI bleeding due to mucosal ulceration.
- Micro: Triphasic morphology consisting of neuroendocrine epithelial nests (gland-like), Schwannian spindle cells (fascicular), and scattered ganglion cells.
- Ancillary: Epithelial cells express cytokeratins and PR; spindle cells express S100/SOX10; and ganglion cells express synaptophysin/NSE but are SOX10 negative.
- Prognosis: While most are indolent, CoGNET is considered malignant due to reported lymph node (10–14.5%) and liver (1.8%) metastases.
- Molecular: Approximately 20% of cases harbor somatic gain-of-function pathogenic variants in EPAS1 (HIF2A).
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). S100 immunohistochemistry highlights Schwannian spindle cells.

Q: About 20% of patients with Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET) harbor somatic gain-of-function variants in the gene [...].
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.
A: EPAS1 (HIF2A)
Back Extra: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Characteristically arises in the second part of the duodenum (periampullary) as a polypoid, submucosal lesion; patients often present with GI bleeding due to mucosal ulceration.
- Micro: Triphasic morphology consisting of neuroendocrine epithelial nests (gland-like), Schwannian spindle cells (fascicular), and scattered ganglion cells.
- Ancillary: Epithelial cells express cytokeratins and PR; spindle cells express S100/SOX10; and ganglion cells express synaptophysin/NSE but are SOX10 negative.
- Prognosis: While most are indolent, CoGNET is considered malignant due to reported lymph node (10–14.5%) and liver (1.8%) metastases.
- Molecular: Approximately 20% of cases harbor somatic gain-of-function pathogenic variants in EPAS1 (HIF2A).
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.

Q: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET) is primarily classified as malignant because [...] occur in up to 14.5% of cases.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.
A: lymph node metastases
Back Extra: Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET)
- Clinical: Characteristically arises in the second part of the duodenum (periampullary) as a polypoid, submucosal lesion; patients often present with GI bleeding due to mucosal ulceration.
- Micro: Triphasic morphology consisting of neuroendocrine epithelial nests (gland-like), Schwannian spindle cells (fascicular), and scattered ganglion cells.
- Ancillary: Epithelial cells express cytokeratins and PR; spindle cells express S100/SOX10; and ganglion cells express synaptophysin/NSE but are SOX10 negative.
- Prognosis: While most are indolent, CoGNET is considered malignant due to reported lymph node (10–14.5%) and liver (1.8%) metastases.
- Molecular: Approximately 20% of cases harbor somatic gain-of-function pathogenic variants in EPAS1 (HIF2A).
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). CoGNET is composed of three components: neuroendocrine epithelial cells, Schwannian spindle cells, and ganglion cells.
Composite gangliocytoma/neuroma and neuroendocrine tumour (CoGNET). Ganglion cells characterized by dense peripheral cytoplasm are intimately intermixed with the spindled cell component.

Q: In the ampullary region, a well-differentiated [...] is the most common subtype, often characterized histologically by a tubuloglandular pattern and the presence of [...].
Ampullary non-functioning somatostatin cell NET showing a predominantly tubular/glandular pattern with intraluminal psammomatous calcifications.
Ampullary somatostatin cell NET: Tumour cells are diffusely positive for somatostatin immunostain.
A: somatostatin cell neuroendocrine tumour; psammoma bodies
Back Extra: Duodenal and ampullary neuroendocrine neoplasms
- Clinical: Most duodenal and ampullary neuroendocrine neoplasms (NENs) are non-functioning; however, gastrinomas are a significant subtype associated with Zollinger–Ellison syndrome (peptic ulcers and diarrhea).
- Genetics: Strongly associated with hereditary syndromes: MEN1 is linked to multiple duodenal gastrinomas (up to 1/3 of cases), while NF1 is specifically associated with ampullary somatostatin cell NETs.
- Microscopic: Well-differentiated NETs show organoid, trabecular, or pseudoglandular patterns with 'salt-and-pepper' chromatin. Ampullary somatostatin cell NETs uniquely feature a tubuloglandular pattern and frequently contain psammoma bodies.
- Ancillary: Neoplastic cells express general neuroendocrine markers (synaptophysin, chromogranin A) and transcription factors ISL1 and PDX1. Unlike ileal NETs, CDX2 is typically negative or only focal.
Ampullary non-functioning somatostatin cell NET showing a predominantly tubular/glandular pattern with intraluminal psammomatous calcifications.
Ampullary somatostatin cell NET: Tumour cells are diffusely positive for somatostatin immunostain.

Q: Roughly 1/3 of duodenal gastrinomas in the context of [...] are associated with the autosomal dominant syndrome [...].
Gastrinoma (functioning gastrin cell tumour) of the duodenum presenting as a well-differentiated NET in the submucosa.
High-power view of a duodenal gastrinoma showing tumour cells arranged in characteristic trabecular structures.
A: Duodenal and ampullary neuroendocrine neoplasms; MEN1
Back Extra: Duodenal and ampullary neuroendocrine neoplasms
- Clinical: Most duodenal and ampullary neuroendocrine neoplasms (NENs) are non-functioning; however, gastrinomas are a significant subtype associated with Zollinger–Ellison syndrome (peptic ulcers and diarrhea).
- Genetics: Strongly associated with hereditary syndromes: MEN1 is linked to multiple duodenal gastrinomas (up to 1/3 of cases), while NF1 is specifically associated with ampullary somatostatin cell NETs.
- Microscopic: Well-differentiated NETs show organoid, trabecular, or pseudoglandular patterns with 'salt-and-pepper' chromatin. Ampullary somatostatin cell NETs uniquely feature a tubuloglandular pattern and frequently contain psammoma bodies.
- Ancillary: Neoplastic cells express general neuroendocrine markers (synaptophysin, chromogranin A) and transcription factors ISL1 and PDX1. Unlike ileal NETs, CDX2 is typically negative or only focal.
Gastrinoma (functioning gastrin cell tumour) of the duodenum presenting as a well-differentiated NET in the submucosa.
High-power view of a duodenal gastrinoma showing tumour cells arranged in characteristic trabecular structures.

Q: Regarding IHC in [...], the transcription factors [...] and PDX1 are typically positive, while [...] is usually negative or only focal (unlike distal small bowel NETs).
Duodenal neuroendocrine tumour (NET) displaying classic organoid/trabecular architecture.
A: Duodenal and ampullary neuroendocrine neoplasms; ISL1; CDX2
Back Extra: Duodenal and ampullary neuroendocrine neoplasms
- Clinical: Most duodenal and ampullary neuroendocrine neoplasms (NENs) are non-functioning; however, gastrinomas are a significant subtype associated with Zollinger–Ellison syndrome (peptic ulcers and diarrhea).
- Genetics: Strongly associated with hereditary syndromes: MEN1 is linked to multiple duodenal gastrinomas (up to 1/3 of cases), while NF1 is specifically associated with ampullary somatostatin cell NETs.
- Microscopic: Well-differentiated NETs show organoid, trabecular, or pseudoglandular patterns with 'salt-and-pepper' chromatin. Ampullary somatostatin cell NETs uniquely feature a tubuloglandular pattern and frequently contain psammoma bodies.
- Ancillary: Neoplastic cells express general neuroendocrine markers (synaptophysin, chromogranin A) and transcription factors ISL1 and PDX1. Unlike ileal NETs, CDX2 is typically negative or only focal.
Duodenal neuroendocrine tumour (NET) displaying classic organoid/trabecular architecture.

Q: An ileal tumor showing nests of uniform cells with 'salt-and-pepper' chromatin and peripheral palisading, associated with an intense desmoplastic reaction in the mesentery, is diagnostic of [...].
Ileal neuroendocrine tumour (NET). A G1 NET showing neuroendocrine cell clusters with little pleomorphism. They are composed of nests of tumour cells with peripheral palisading.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Neuroendocrine cell nests with little pleomorphism and a sclerotic background.
A: Jejunal and ileal neuroendocrine tumour (NET)
Back Extra: Jejunal and ileal neuroendocrine tumour (NET)
- Clinical: Often presents at advanced stages with small bowel obstruction or carcinoid syndrome (diarrhea, flushing); multifocality is observed in approximately 40% of cases.
- Microscopic: Well-differentiated morphology featuring uniform cells with 'salt-and-pepper' chromatin, peripheral palisading, and a significant desmoplastic reaction often causing mesenteric kinking.
- Ancillary: Strong positivity for Synaptophysin, Chromogranin A, and Serotonin (ileal cases); CDX2 is typically positive, while SSTR2 shows membranous expression in >90%.
- Molecular: Characterized by deletion of chromosome 18 in 60–90% of cases; chromosome 14 gains are associated with disease progression and unfavorable prognosis.
Ileal neuroendocrine tumour (NET). A G1 NET showing neuroendocrine cell clusters with little pleomorphism. They are composed of nests of tumour cells with peripheral palisading.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Neuroendocrine cell nests with little pleomorphism and a sclerotic background.

Q: Carcinoid syndrome in the context of a [...] most frequently occurs in patients with [...].
Ileal neuroendocrine tumour (NET). A G1 NET showing neuroendocrine cell clusters with little pleomorphism. They are composed of nests of tumour cells with peripheral palisading.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
A: Jejunal and ileal neuroendocrine tumour (NET); liver metastases
Back Extra: Jejunal and ileal neuroendocrine tumour (NET)
- Clinical: Often presents at advanced stages with small bowel obstruction or carcinoid syndrome (diarrhea, flushing); multifocality is observed in approximately 40% of cases.
- Microscopic: Well-differentiated morphology featuring uniform cells with 'salt-and-pepper' chromatin, peripheral palisading, and a significant desmoplastic reaction often causing mesenteric kinking.
- Ancillary: Strong positivity for Synaptophysin, Chromogranin A, and Serotonin (ileal cases); CDX2 is typically positive, while SSTR2 shows membranous expression in >90%.
- Molecular: Characterized by deletion of chromosome 18 in 60–90% of cases; chromosome 14 gains are associated with disease progression and unfavorable prognosis.
Ileal neuroendocrine tumour (NET). A G1 NET showing neuroendocrine cell clusters with little pleomorphism. They are composed of nests of tumour cells with peripheral palisading.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.

Q: The most characteristic chromosomal abnormality found in 60–90% of cases of [...] is loss of [...].
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Neuroendocrine cell nests with little pleomorphism and a sclerotic background.
A: Jejunal and ileal neuroendocrine tumour (NET); chromosome 18
Back Extra: Jejunal and ileal neuroendocrine tumour (NET)
- Clinical: Often presents at advanced stages with small bowel obstruction or carcinoid syndrome (diarrhea, flushing); multifocality is observed in approximately 40% of cases.
- Microscopic: Well-differentiated morphology featuring uniform cells with 'salt-and-pepper' chromatin, peripheral palisading, and a significant desmoplastic reaction often causing mesenteric kinking.
- Ancillary: Strong positivity for Synaptophysin, Chromogranin A, and Serotonin (ileal cases); CDX2 is typically positive, while SSTR2 shows membranous expression in >90%.
- Molecular: Characterized by deletion of chromosome 18 in 60–90% of cases; chromosome 14 gains are associated with disease progression and unfavorable prognosis.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Neuroendocrine cell nests with little pleomorphism and a sclerotic background.

Q: Regarding ancillary studies for [...], ileal tumors typically show nuclear expression of [...] and cytoplasmic expression of [...].
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Nuclear expression of CDX2.
Neuroendocrine tumour (NET), G2 of the small intestine. Diffuse serotonin expression.
A: Jejunal and ileal neuroendocrine tumour (NET); CDX2; serotonin
Back Extra: Jejunal and ileal neuroendocrine tumour (NET)
- Clinical: Often presents at advanced stages with small bowel obstruction or carcinoid syndrome (diarrhea, flushing); multifocality is observed in approximately 40% of cases.
- Microscopic: Well-differentiated morphology featuring uniform cells with 'salt-and-pepper' chromatin, peripheral palisading, and a significant desmoplastic reaction often causing mesenteric kinking.
- Ancillary: Strong positivity for Synaptophysin, Chromogranin A, and Serotonin (ileal cases); CDX2 is typically positive, while SSTR2 shows membranous expression in >90%.
- Molecular: Characterized by deletion of chromosome 18 in 60–90% of cases; chromosome 14 gains are associated with disease progression and unfavorable prognosis.
Ileal neuroendocrine tumour (NET). Uniform tumour cells with round to oval nuclei with finely granular (salt-and-pepper) chromatin and plentiful amphophilic cytoplasm arranged in nests.
Ileal neuroendocrine tumour (NET). Nuclear expression of CDX2.
Neuroendocrine tumour (NET), G2 of the small intestine. Diffuse serotonin expression.

Q: The diagnosis for a hamartomatous polyp with a characteristic [...] pattern of smooth muscle bundles in a patient with mucocutaneous pigmentation is [...].
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.
A: arborizing; Peutz-Jeghers syndrome (STK11)
Back Extra: Peutz-Jeghers syndrome (STK11)
- Clinical: Autosomal dominant syndrome caused by germline mutations in STK11 (LKB1); characterized by mucocutaneous melanin pigmentation and hamartomatous gastrointestinal polyps.
- Microscopic: Classic polyps exhibit a distinctive arborizing pattern of smooth muscle bundles within the stroma, covered by near-normal appearing mucosa.
- Pitfalls: Epithelial misplacement (pseudoinvasion) into the stalk or serosa is common due to prolapse/peristalsis and can be mistaken for well-differentiated adenocarcinoma.
- Complications: High risk for small bowel intussusception in childhood/adolescence; long-term prognosis is limited by a significantly increased risk of GI, breast, and pancreatic cancers.
- Ancillary: Germline pathogenic variants in STK11 are detectable in >90% of patients via next-generation sequencing.
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.

Q: In Peutz-Jeghers syndrome (STK11), the displacement of epithelium into the bowel wall that mimics adenocarcinoma is known as [...] (or epithelial misplacement).
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.
A: pseudoinvasion
Back Extra: Peutz-Jeghers syndrome (STK11)
- Clinical: Autosomal dominant syndrome caused by germline mutations in STK11 (LKB1); characterized by mucocutaneous melanin pigmentation and hamartomatous gastrointestinal polyps.
- Microscopic: Classic polyps exhibit a distinctive arborizing pattern of smooth muscle bundles within the stroma, covered by near-normal appearing mucosa.
- Pitfalls: Epithelial misplacement (pseudoinvasion) into the stalk or serosa is common due to prolapse/peristalsis and can be mistaken for well-differentiated adenocarcinoma.
- Complications: High risk for small bowel intussusception in childhood/adolescence; long-term prognosis is limited by a significantly increased risk of GI, breast, and pancreatic cancers.
- Ancillary: Germline pathogenic variants in STK11 are detectable in >90% of patients via next-generation sequencing.
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.

Q: Peutz-Jeghers syndrome (STK11) is caused by a germline mutation in the [...] gene, which was formerly known as [...].
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.
A: STK11; LKB1
Back Extra: Peutz-Jeghers syndrome (STK11)
- Clinical: Autosomal dominant syndrome caused by germline mutations in STK11 (LKB1); characterized by mucocutaneous melanin pigmentation and hamartomatous gastrointestinal polyps.
- Microscopic: Classic polyps exhibit a distinctive arborizing pattern of smooth muscle bundles within the stroma, covered by near-normal appearing mucosa.
- Pitfalls: Epithelial misplacement (pseudoinvasion) into the stalk or serosa is common due to prolapse/peristalsis and can be mistaken for well-differentiated adenocarcinoma.
- Complications: High risk for small bowel intussusception in childhood/adolescence; long-term prognosis is limited by a significantly increased risk of GI, breast, and pancreatic cancers.
- Ancillary: Germline pathogenic variants in STK11 are detectable in >90% of patients via next-generation sequencing.
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.

Q: Patients with Peutz-Jeghers syndrome (STK11) have a 6-fold increased risk of cancer, with the highest cumulative risk (up to 54%) for [...] cancer in older patients.
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.
A: breast
Back Extra: Peutz-Jeghers syndrome (STK11)
- Clinical: Autosomal dominant syndrome caused by germline mutations in STK11 (LKB1); characterized by mucocutaneous melanin pigmentation and hamartomatous gastrointestinal polyps.
- Microscopic: Classic polyps exhibit a distinctive arborizing pattern of smooth muscle bundles within the stroma, covered by near-normal appearing mucosa.
- Pitfalls: Epithelial misplacement (pseudoinvasion) into the stalk or serosa is common due to prolapse/peristalsis and can be mistaken for well-differentiated adenocarcinoma.
- Complications: High risk for small bowel intussusception in childhood/adolescence; long-term prognosis is limited by a significantly increased risk of GI, breast, and pancreatic cancers.
- Ancillary: Germline pathogenic variants in STK11 are detectable in >90% of patients via next-generation sequencing.
Peutz–Jeghers polyp. Panoramic view of a Peutz–Jeghers polyp presenting as a jejunal intussusception in a 9-year-old boy.
Peutz–Jeghers polyp. Low magnification showing the characteristic arborizing pattern of the smooth muscle bundles.

Q: The primary genetic defect in the majority of families with Hereditary gastric and breast cancer syndrome involves germline mutations in the [...] gene, which encodes the protein [...].
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
High-power view of pagetoid spread; this finding is strongly associated with hereditary gastric and breast cancer syndrome.
A: CDH1; E-cadherin
Back Extra: Hereditary gastric and breast cancer syndrome (CDH1, CTNNA1)
- Clinical: Autosomal dominant syndrome caused by germline mutations in CDH1 (E-cadherin) or CTNNA1 (alpha-catenin), resulting in high lifetime risks for diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC).
- Microscopic Early: Prophylactic gastrectomies appear grossly normal but harbor multiple sub-millimeter foci of intramucosal signet-ring cell carcinoma (SRCC), often localized to the neck-zone of the mucosa; these pT1a lesions are usually indolent.
- Precursor Lesions: Characterized by 'signet-ring cell carcinoma in situ' (replacement of normal cells within basement membrane) and 'pagetoid spread' (neoplastic cells spreading beneath normal epithelium), which are highly specific for this syndrome.
- Pathogenesis: Loss of E-cadherin function (via a 'second hit' such as promoter methylation) leads to mitotic spindle orientation defects, causing daughter cells to detach and invade the matrix as signet-ring cells.
- Prognosis: Early intramucosal lesions are indolent with low dissemination risk, justifying prophylactic total gastrectomy; however, advanced diffuse-type cancers are highly aggressive with poor outcomes.
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
High-power view of pagetoid spread; this finding is strongly associated with hereditary gastric and breast cancer syndrome.

Q: In prophylactic gastrectomy specimens for Hereditary gastric and breast cancer syndrome (CDH1), the specific finding of neoplastic signet-ring cells spreading as a second row beneath the normal epithelial cells within the basement membrane is termed [...].
Pagetoid spread of signet-ring cells beneath normal epithelial cells within the basement membrane of a gastric gland.
High-power view of pagetoid spread; this finding is strongly associated with hereditary gastric and breast cancer syndrome.
Precursor complex in situ pagetoid lesion exhibiting a spectrum of signet-ring cell progression.
A: pagetoid spread
Back Extra: Hereditary gastric and breast cancer syndrome (CDH1, CTNNA1)
- Clinical: Autosomal dominant syndrome caused by germline mutations in CDH1 (E-cadherin) or CTNNA1 (alpha-catenin), resulting in high lifetime risks for diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC).
- Microscopic Early: Prophylactic gastrectomies appear grossly normal but harbor multiple sub-millimeter foci of intramucosal signet-ring cell carcinoma (SRCC), often localized to the neck-zone of the mucosa; these pT1a lesions are usually indolent.
- Precursor Lesions: Characterized by 'signet-ring cell carcinoma in situ' (replacement of normal cells within basement membrane) and 'pagetoid spread' (neoplastic cells spreading beneath normal epithelium), which are highly specific for this syndrome.
- Pathogenesis: Loss of E-cadherin function (via a 'second hit' such as promoter methylation) leads to mitotic spindle orientation defects, causing daughter cells to detach and invade the matrix as signet-ring cells.
- Prognosis: Early intramucosal lesions are indolent with low dissemination risk, justifying prophylactic total gastrectomy; however, advanced diffuse-type cancers are highly aggressive with poor outcomes.
Pagetoid spread of signet-ring cells beneath normal epithelial cells within the basement membrane of a gastric gland.
High-power view of pagetoid spread; this finding is strongly associated with hereditary gastric and breast cancer syndrome.
Precursor complex in situ pagetoid lesion exhibiting a spectrum of signet-ring cell progression.

Q: Beyond diffuse gastric cancer, female carriers of CDH1 mutations in Hereditary gastric and breast cancer syndrome have a 37–55% lifetime risk of [...].
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
A: lobular breast cancer
Back Extra: Hereditary gastric and breast cancer syndrome (CDH1, CTNNA1)
- Clinical: Autosomal dominant syndrome caused by germline mutations in CDH1 (E-cadherin) or CTNNA1 (alpha-catenin), resulting in high lifetime risks for diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC).
- Microscopic Early: Prophylactic gastrectomies appear grossly normal but harbor multiple sub-millimeter foci of intramucosal signet-ring cell carcinoma (SRCC), often localized to the neck-zone of the mucosa; these pT1a lesions are usually indolent.
- Precursor Lesions: Characterized by 'signet-ring cell carcinoma in situ' (replacement of normal cells within basement membrane) and 'pagetoid spread' (neoplastic cells spreading beneath normal epithelium), which are highly specific for this syndrome.
- Pathogenesis: Loss of E-cadherin function (via a 'second hit' such as promoter methylation) leads to mitotic spindle orientation defects, causing daughter cells to detach and invade the matrix as signet-ring cells.
- Prognosis: Early intramucosal lesions are indolent with low dissemination risk, justifying prophylactic total gastrectomy; however, advanced diffuse-type cancers are highly aggressive with poor outcomes.
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.

Q: Unlike sporadic signet-ring cell carcinomas, the early intramucosal (pT1a) foci in Hereditary gastric and breast cancer syndrome (CDH1) are typically [...] and show very low proliferative activity on [...] staining.
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
A: indolent; Ki-67
Back Extra: Hereditary gastric and breast cancer syndrome (CDH1, CTNNA1)
- Clinical: Autosomal dominant syndrome caused by germline mutations in CDH1 (E-cadherin) or CTNNA1 (alpha-catenin), resulting in high lifetime risks for diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC).
- Microscopic Early: Prophylactic gastrectomies appear grossly normal but harbor multiple sub-millimeter foci of intramucosal signet-ring cell carcinoma (SRCC), often localized to the neck-zone of the mucosa; these pT1a lesions are usually indolent.
- Precursor Lesions: Characterized by 'signet-ring cell carcinoma in situ' (replacement of normal cells within basement membrane) and 'pagetoid spread' (neoplastic cells spreading beneath normal epithelium), which are highly specific for this syndrome.
- Pathogenesis: Loss of E-cadherin function (via a 'second hit' such as promoter methylation) leads to mitotic spindle orientation defects, causing daughter cells to detach and invade the matrix as signet-ring cells.
- Prognosis: Early intramucosal lesions are indolent with low dissemination risk, justifying prophylactic total gastrectomy; however, advanced diffuse-type cancers are highly aggressive with poor outcomes.
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.

Q: A prophylactic gastrectomy from a patient with a known CDH1 mutation reveals multiple foci of signet-ring cells confined to the lamina propria and in situ lesions. What is the most likely diagnosis? [...]
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
Pagetoid spread of signet-ring cells beneath normal epithelial cells within the basement membrane of a gastric gland.
A: Hereditary gastric and breast cancer syndrome
Back Extra: Hereditary gastric and breast cancer syndrome (CDH1, CTNNA1)
- Clinical: Autosomal dominant syndrome caused by germline mutations in CDH1 (E-cadherin) or CTNNA1 (alpha-catenin), resulting in high lifetime risks for diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC).
- Microscopic Early: Prophylactic gastrectomies appear grossly normal but harbor multiple sub-millimeter foci of intramucosal signet-ring cell carcinoma (SRCC), often localized to the neck-zone of the mucosa; these pT1a lesions are usually indolent.
- Precursor Lesions: Characterized by 'signet-ring cell carcinoma in situ' (replacement of normal cells within basement membrane) and 'pagetoid spread' (neoplastic cells spreading beneath normal epithelium), which are highly specific for this syndrome.
- Pathogenesis: Loss of E-cadherin function (via a 'second hit' such as promoter methylation) leads to mitotic spindle orientation defects, causing daughter cells to detach and invade the matrix as signet-ring cells.
- Prognosis: Early intramucosal lesions are indolent with low dissemination risk, justifying prophylactic total gastrectomy; however, advanced diffuse-type cancers are highly aggressive with poor outcomes.
Intramucosal signet-ring cell carcinoma (pT1a) featuring a small focus of loosely arranged signet-ring cells in the lamina propria.
Signet-ring cell carcinoma in situ (pTis) showing signet-ring cells within the basal membrane replacing normal epithelial cells.
Pagetoid spread of signet-ring cells beneath normal epithelial cells within the basement membrane of a gastric gland.

Q: A gastric biopsy reveals individual cells with eccentrically placed nuclei and intracytoplasmic mucin; this morphological pattern is characteristic of the [...] variant of Gastric adenocarcinoma.
Poorly cohesive carcinoma, signet-ring cell type: Neoplastic cells with an eccentrically placed nucleus and clear/eosinophilic cytoplasm.
A: signet-ring cell
Back Extra: Gastric adenocarcinoma
- Clinical: Often asymptomatic in early stages; advanced cases present with weight loss, epigastric pain, or evidence of metastasis (e.g., Krukenberg tumour to ovaries).
- Microscopic Subtypes: The WHO recognizes tubular (most common), papillary, poorly cohesive (including signet-ring cell), mucinous, and mixed subtypes.
- Molecular Classification: TCGA divides Gastric Adenocarcinoma into four groups: EBV-positive, Microsatellite-unstable (MSI), Genomically stable (GS), and Chromosomally unstable (CIN).
- Predictive Biomarkers: Essential testing includes HER2 status for trastuzumab, PD-L1 (CPS score) for checkpoint inhibitors, MMR/MSI for immunotherapy, and Claudin-18.2 for zolbetuximab.
Poorly cohesive carcinoma, signet-ring cell type: Neoplastic cells with an eccentrically placed nucleus and clear/eosinophilic cytoplasm.

Q: The TCGA molecular classification of Gastric adenocarcinoma includes a [...] subtype, which is frequently associated with TP53 mutations and HER2 amplification.
Tubular adenocarcinoma: Neoplasm consisting of dilated tubules with intraluminal necrotic debris.
Papillary adenocarcinoma: Finger-like processes with fibrovascular cores lined by neoplastic columnar cells.
A: Chromosomally unstable (CIN)
Back Extra: Gastric adenocarcinoma
- Clinical: Often asymptomatic in early stages; advanced cases present with weight loss, epigastric pain, or evidence of metastasis (e.g., Krukenberg tumour to ovaries).
- Microscopic Subtypes: The WHO recognizes tubular (most common), papillary, poorly cohesive (including signet-ring cell), mucinous, and mixed subtypes.
- Molecular Classification: TCGA divides Gastric Adenocarcinoma into four groups: EBV-positive, Microsatellite-unstable (MSI), Genomically stable (GS), and Chromosomally unstable (CIN).
- Predictive Biomarkers: Essential testing includes HER2 status for trastuzumab, PD-L1 (CPS score) for checkpoint inhibitors, MMR/MSI for immunotherapy, and Claudin-18.2 for zolbetuximab.
Tubular adenocarcinoma: Neoplasm consisting of dilated tubules with intraluminal necrotic debris.
Papillary adenocarcinoma: Finger-like processes with fibrovascular cores lined by neoplastic columnar cells.

Q: In the context of Gastric adenocarcinoma, diffuse thickening of the gastric wall with a 'waffle-like' appearance of folds due to scirrhous infiltration is macroscopically referred to as [...].
Poorly cohesive carcinoma, signet-ring cell type: Neoplastic cells with an eccentrically placed nucleus and clear/eosinophilic cytoplasm.
A: linitis plastica
Back Extra: Gastric adenocarcinoma
- Clinical: Often asymptomatic in early stages; advanced cases present with weight loss, epigastric pain, or evidence of metastasis (e.g., Krukenberg tumour to ovaries).
- Microscopic Subtypes: The WHO recognizes tubular (most common), papillary, poorly cohesive (including signet-ring cell), mucinous, and mixed subtypes.
- Molecular Classification: TCGA divides Gastric Adenocarcinoma into four groups: EBV-positive, Microsatellite-unstable (MSI), Genomically stable (GS), and Chromosomally unstable (CIN).
- Predictive Biomarkers: Essential testing includes HER2 status for trastuzumab, PD-L1 (CPS score) for checkpoint inhibitors, MMR/MSI for immunotherapy, and Claudin-18.2 for zolbetuximab.
Poorly cohesive carcinoma, signet-ring cell type: Neoplastic cells with an eccentrically placed nucleus and clear/eosinophilic cytoplasm.

Q: Gastric adenocarcinoma with [...] is a subtype characterized by poorly defined tubules/sheets with a prominent lymphocytic infiltrate and a strong association with [...] infection.
Gastric carcinoma with lymphoid stroma: Appearance reminiscent of lymphoepithelioma, often positive for EBV (EBER ISH).
A: lymphoid stroma; EBV
Back Extra: Gastric adenocarcinoma
- Clinical: Often asymptomatic in early stages; advanced cases present with weight loss, epigastric pain, or evidence of metastasis (e.g., Krukenberg tumour to ovaries).
- Microscopic Subtypes: The WHO recognizes tubular (most common), papillary, poorly cohesive (including signet-ring cell), mucinous, and mixed subtypes.
- Molecular Classification: TCGA divides Gastric Adenocarcinoma into four groups: EBV-positive, Microsatellite-unstable (MSI), Genomically stable (GS), and Chromosomally unstable (CIN).
- Predictive Biomarkers: Essential testing includes HER2 status for trastuzumab, PD-L1 (CPS score) for checkpoint inhibitors, MMR/MSI for immunotherapy, and Claudin-18.2 for zolbetuximab.
Gastric carcinoma with lymphoid stroma: Appearance reminiscent of lymphoepithelioma, often positive for EBV (EBER ISH).

Q: A biphasic tumor of the distal stomach (as seen in Figure 50727) composed of uniform epithelial cells and spindle cells in a myxoid background harboring a GLI1 rearrangement is diagnostic of [...].
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Spindle cell component in a myxoid background.
Gastroblastoma: Epithelial component displaying cells with rounded nuclei, inconspicuous nucleoli and scanty cytoplasm.
A: gastroblastoma (GLI1-altered neoplasm)
Back Extra: GLI1-altered neoplasms (including gastroblastoma)
- Clinical: Low-grade neoplasms most commonly arising in the distal stomach; they typically pursue an indolent clinical course despite the possibility of lymph node or visceral metastases.
- Microscopic: Characteristically biphasic, showing variable proportions of monotonous spindle cells (often in a myxoid background) and uniform epithelial cells arranged in nests, trabeculae, or pseudorosettes.
- Ancillary (IHC): The spindle component typically expresses CD10 and CD56; nuclear GLI1 expression reflects the underlying gene fusion.
- Molecular: Definitive diagnosis requires identification of a GLI1 rearrangement (e.g., MALAT1::GLI1 or ACTB::GLI1) by FISH or NGS.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Spindle cell component in a myxoid background.
Gastroblastoma: Epithelial component displaying cells with rounded nuclei, inconspicuous nucleoli and scanty cytoplasm.

Q: In the spindle component of GLI1-altered neoplasms (including gastroblastoma), immunohistochemistry characteristically shows expression of [...], while KIT and DOG1 are typically negative.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: CD10 expressed in the stromal component and variable in the epithelial component.
Gastroblastoma: The stromal component is strongly positive for CD56.
A: CD10 and CD56
Back Extra: GLI1-altered neoplasms (including gastroblastoma)
- Clinical: Low-grade neoplasms most commonly arising in the distal stomach; they typically pursue an indolent clinical course despite the possibility of lymph node or visceral metastases.
- Microscopic: Characteristically biphasic, showing variable proportions of monotonous spindle cells (often in a myxoid background) and uniform epithelial cells arranged in nests, trabeculae, or pseudorosettes.
- Ancillary (IHC): The spindle component typically expresses CD10 and CD56; nuclear GLI1 expression reflects the underlying gene fusion.
- Molecular: Definitive diagnosis requires identification of a GLI1 rearrangement (e.g., MALAT1::GLI1 or ACTB::GLI1) by FISH or NGS.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: CD10 expressed in the stromal component and variable in the epithelial component.
Gastroblastoma: The stromal component is strongly positive for CD56.

Q: The MALAT1::GLI1 and ACTB::GLI1 fusions characteristic of GLI1-altered neoplasms (including gastroblastoma) are also found in which benign mesenchymal stomach tumor? [...]
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Spindle cell component in a myxoid background.
A: Plexiform fibromyxoma
Back Extra: GLI1-altered neoplasms (including gastroblastoma)
- Clinical: Low-grade neoplasms most commonly arising in the distal stomach; they typically pursue an indolent clinical course despite the possibility of lymph node or visceral metastases.
- Microscopic: Characteristically biphasic, showing variable proportions of monotonous spindle cells (often in a myxoid background) and uniform epithelial cells arranged in nests, trabeculae, or pseudorosettes.
- Ancillary (IHC): The spindle component typically expresses CD10 and CD56; nuclear GLI1 expression reflects the underlying gene fusion.
- Molecular: Definitive diagnosis requires identification of a GLI1 rearrangement (e.g., MALAT1::GLI1 or ACTB::GLI1) by FISH or NGS.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Spindle cell component in a myxoid background.

Q: Despite presenting with potential regional lymph node or visceral metastases, GLI1-altered neoplasms (including gastroblastoma) usually follow an [...] clinical course.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Epithelial component displaying cells with rounded nuclei, inconspicuous nucleoli and scanty cytoplasm.
A: indolent
Back Extra: GLI1-altered neoplasms (including gastroblastoma)
- Clinical: Low-grade neoplasms most commonly arising in the distal stomach; they typically pursue an indolent clinical course despite the possibility of lymph node or visceral metastases.
- Microscopic: Characteristically biphasic, showing variable proportions of monotonous spindle cells (often in a myxoid background) and uniform epithelial cells arranged in nests, trabeculae, or pseudorosettes.
- Ancillary (IHC): The spindle component typically expresses CD10 and CD56; nuclear GLI1 expression reflects the underlying gene fusion.
- Molecular: Definitive diagnosis requires identification of a GLI1 rearrangement (e.g., MALAT1::GLI1 or ACTB::GLI1) by FISH or NGS.
Gastroblastoma: A biphasic tumour showing fairly uniform spindle and epithelial cells.
Gastroblastoma: Epithelial component displaying cells with rounded nuclei, inconspicuous nucleoli and scanty cytoplasm.

Q: A gastric tumor composed of both adenocarcinoma and squamous cell carcinoma components is diagnosed as [...] only if each component accounts for at least [...]% of the tumor volume.
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.
A: Gastric adenosquamous carcinoma; 25
Back Extra: Gastric adenosquamous carcinoma
- Definition: A rare gastric malignancy (< 0.4% of cases) defined by distinct components of adenocarcinoma and squamous cell carcinoma (SCC), with each component accounting for at least 25% of the tumor.
- Clinical Features: Predominantly affects men (mean age 62 years); typically presents as a large gastric mass (mean 60 mm) with an aggressive clinical course and frequent metastasis to nodes and liver.
- Histopathology: Shows variable proportions of SCC and adenocarcinoma; the SCC component resembles esophageal squamous cell carcinoma and is highlighted by p63/p40 immunohistochemistry.
- Differential Diagnosis: It is critical to exclude distal extension from a primary adenosquamous carcinoma of the lower esophagus via endoscopic or gross correlation.
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.

Q: In the context of Gastric adenosquamous carcinoma, the squamous cell component can be confirmed using immunohistochemical markers such as [...].
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.
A: p40, p63, or CK5/6
Back Extra: Gastric adenosquamous carcinoma
- Definition: A rare gastric malignancy (< 0.4% of cases) defined by distinct components of adenocarcinoma and squamous cell carcinoma (SCC), with each component accounting for at least 25% of the tumor.
- Clinical Features: Predominantly affects men (mean age 62 years); typically presents as a large gastric mass (mean 60 mm) with an aggressive clinical course and frequent metastasis to nodes and liver.
- Histopathology: Shows variable proportions of SCC and adenocarcinoma; the SCC component resembles esophageal squamous cell carcinoma and is highlighted by p63/p40 immunohistochemistry.
- Differential Diagnosis: It is critical to exclude distal extension from a primary adenosquamous carcinoma of the lower esophagus via endoscopic or gross correlation.
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.

Q: Regarding the metastatic patterns of Gastric adenosquamous carcinoma, lymph node metastases are most commonly composed of the [...] component.
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.
A: adenocarcinoma
Back Extra: Gastric adenosquamous carcinoma
- Definition: A rare gastric malignancy (< 0.4% of cases) defined by distinct components of adenocarcinoma and squamous cell carcinoma (SCC), with each component accounting for at least 25% of the tumor.
- Clinical Features: Predominantly affects men (mean age 62 years); typically presents as a large gastric mass (mean 60 mm) with an aggressive clinical course and frequent metastasis to nodes and liver.
- Histopathology: Shows variable proportions of SCC and adenocarcinoma; the SCC component resembles esophageal squamous cell carcinoma and is highlighted by p63/p40 immunohistochemistry.
- Differential Diagnosis: It is critical to exclude distal extension from a primary adenosquamous carcinoma of the lower esophagus via endoscopic or gross correlation.
Gastric adenosquamous carcinoma. A Note poorly differentiated squamous cell carcinoma (left) and well-differentiated tubular adenocarcinoma (right) components.
Gastric adenosquamous carcinoma. A Well-differentiated squamous cell carcinoma (upper left) and well-differentiated tubular adenocarcinoma (lower right) components.

Q: A diagnosis of [...] requires the demonstration of keratinization or [...] on histology, in the absence of an adenocarcinoma component.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. A,B Non-keratinizing squamous cell carcinoma.
A: gastric squamous cell carcinoma; intercellular bridges
Back Extra: Gastric squamous cell carcinoma
- Definition: A rare gastric malignancy (0.04–0.5% of cases) showing squamous differentiation (keratinization and/or intercellular bridges) without an adenocarcinoma component.
- Histopathology: Resembles squamous cell carcinoma of the esophagus; Includes a rare verrucous subtype characterized by well-differentiated keratinizing cells, papillary projections, and bulbous downgrowth.
- Differential Diagnosis: It is essential to exclude distal extension of esophageal squamous cell carcinoma and metastasis from other sites before confirming a primary gastric origin.
- Prognosis: Frequently presents at an advanced stage and is generally more aggressive than gastric adenocarcinoma of the same disease stage.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. A,B Non-keratinizing squamous cell carcinoma.

Q: To diagnose primary [...], pathologists must first rule out distal extension of [...] squamous cell carcinoma.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.
A: gastric squamous cell carcinoma; oesophageal
Back Extra: Gastric squamous cell carcinoma
- Definition: A rare gastric malignancy (0.04–0.5% of cases) showing squamous differentiation (keratinization and/or intercellular bridges) without an adenocarcinoma component.
- Histopathology: Resembles squamous cell carcinoma of the esophagus; Includes a rare verrucous subtype characterized by well-differentiated keratinizing cells, papillary projections, and bulbous downgrowth.
- Differential Diagnosis: It is essential to exclude distal extension of esophageal squamous cell carcinoma and metastasis from other sites before confirming a primary gastric origin.
- Prognosis: Frequently presents at an advanced stage and is generally more aggressive than gastric adenocarcinoma of the same disease stage.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.

Q: While common in some cases of [...], the presence of [...] changes alone does not qualify the tumor for a diagnosis of adenosquamous carcinoma.
Gastric squamous cell carcinoma. Adenoid or microcystic change is common within the otherwise pure squamous cell carcinoma and does not qualify for diagnosis of adenosquamous carcinoma.
A: gastric squamous cell carcinoma; adenoid or microcystic
Back Extra: Gastric squamous cell carcinoma
- Definition: A rare gastric malignancy (0.04–0.5% of cases) showing squamous differentiation (keratinization and/or intercellular bridges) without an adenocarcinoma component.
- Histopathology: Resembles squamous cell carcinoma of the esophagus; Includes a rare verrucous subtype characterized by well-differentiated keratinizing cells, papillary projections, and bulbous downgrowth.
- Differential Diagnosis: It is essential to exclude distal extension of esophageal squamous cell carcinoma and metastasis from other sites before confirming a primary gastric origin.
- Prognosis: Frequently presents at an advanced stage and is generally more aggressive than gastric adenocarcinoma of the same disease stage.
Gastric squamous cell carcinoma. Adenoid or microcystic change is common within the otherwise pure squamous cell carcinoma and does not qualify for diagnosis of adenosquamous carcinoma.

Q: Primary [...] is noted for often being more [...] and having a poorer outcome compared to adenocarcinoma of the same stage.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.
A: gastric squamous cell carcinoma; aggressive
Back Extra: Gastric squamous cell carcinoma
- Definition: A rare gastric malignancy (0.04–0.5% of cases) showing squamous differentiation (keratinization and/or intercellular bridges) without an adenocarcinoma component.
- Histopathology: Resembles squamous cell carcinoma of the esophagus; Includes a rare verrucous subtype characterized by well-differentiated keratinizing cells, papillary projections, and bulbous downgrowth.
- Differential Diagnosis: It is essential to exclude distal extension of esophageal squamous cell carcinoma and metastasis from other sites before confirming a primary gastric origin.
- Prognosis: Frequently presents at an advanced stage and is generally more aggressive than gastric adenocarcinoma of the same disease stage.
Gastric squamous cell carcinoma. A Well-differentiated keratinizing squamous cell carcinoma.
Gastric squamous cell carcinoma. B Poorly differentiated keratinizing squamous cell carcinoma.

Q: A rare gastric tumor showing large, pleomorphic cells in solid sheets with a focal rhabdoid pattern and loss of SMARCA4 (BRG1) expression is most consistent with [...].
Undifferentiated gastric carcinoma. A Rhabdoid pattern with enlarged vesicular nuclei and prominent macronucleoli.
Undifferentaited gastric carcinoma. Undifferentaited gastric carcinoma; loss of SMARCA4(BRG1) staining confirms the diagnosis
A: Gastric undifferentiated carcinoma
Back Extra: Gastric undifferentiated carcinoma
- Clinical: Extremely rare (0.2% of gastric carcinomas) aggressive tumor typically presenting in men (mean age 60) as a large, necrotic, and ulcerated mass.
- Microscopic: Composed of anaplastic polygonal cells in solid or discohesive sheets; common variants include rhabdoid phenotypes, spindled sarcomatoid morphology, and the presence of non-neoplastic osteoclast-like giant cells.
- Ancillary: Often shows loss of SWI/SNF complex proteins (SMARCB1/INI1, SMARCA4/BRG1); frequently expresses vimentin (often with a perinuclear dot-like pattern) and variable pankeratin.
- Prognosis: Highly aggressive with most patients dying within 1 year; outcomes are dictated by stage at diagnosis and specific SWI/SNF mutations.
Undifferentiated gastric carcinoma. A Rhabdoid pattern with enlarged vesicular nuclei and prominent macronucleoli.
Undifferentaited gastric carcinoma. Undifferentaited gastric carcinoma; loss of SMARCA4(BRG1) staining confirms the diagnosis

Q: In the molecular pathogenesis of [...], the tumor phenotype is frequently driven by mutations or loss of the [...] chromatin-remodelling complex.
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; Note solid sheets of large to medium-sized polygonal cells. Binucleated cells are recognizable
Undifferentaited gastric carcinoma. Undifferentaited gastric carcinoma; loss of SMARCA4(BRG1) staining confirms the diagnosis
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; in this case SMARCB1(INI1) staining by immunohistochemisry was preserved
A: Gastric undifferentiated carcinoma; SWI/SNF
Back Extra: Gastric undifferentiated carcinoma
- Clinical: Extremely rare (0.2% of gastric carcinomas) aggressive tumor typically presenting in men (mean age 60) as a large, necrotic, and ulcerated mass.
- Microscopic: Composed of anaplastic polygonal cells in solid or discohesive sheets; common variants include rhabdoid phenotypes, spindled sarcomatoid morphology, and the presence of non-neoplastic osteoclast-like giant cells.
- Ancillary: Often shows loss of SWI/SNF complex proteins (SMARCB1/INI1, SMARCA4/BRG1); frequently expresses vimentin (often with a perinuclear dot-like pattern) and variable pankeratin.
- Prognosis: Highly aggressive with most patients dying within 1 year; outcomes are dictated by stage at diagnosis and specific SWI/SNF mutations.
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; Note solid sheets of large to medium-sized polygonal cells. Binucleated cells are recognizable
Undifferentaited gastric carcinoma. Undifferentaited gastric carcinoma; loss of SMARCA4(BRG1) staining confirms the diagnosis
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; in this case SMARCB1(INI1) staining by immunohistochemisry was preserved

Q: Although highly anaplastic, [...] typically shows consistent expression of [...], often in a characteristic perinuclear dot-like pattern.
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; Note solid sheets of large to medium-sized polygonal cells. Binucleated cells are recognizable
A: Gastric undifferentiated carcinoma; vimentin
Back Extra: Gastric undifferentiated carcinoma
- Clinical: Extremely rare (0.2% of gastric carcinomas) aggressive tumor typically presenting in men (mean age 60) as a large, necrotic, and ulcerated mass.
- Microscopic: Composed of anaplastic polygonal cells in solid or discohesive sheets; common variants include rhabdoid phenotypes, spindled sarcomatoid morphology, and the presence of non-neoplastic osteoclast-like giant cells.
- Ancillary: Often shows loss of SWI/SNF complex proteins (SMARCB1/INI1, SMARCA4/BRG1); frequently expresses vimentin (often with a perinuclear dot-like pattern) and variable pankeratin.
- Prognosis: Highly aggressive with most patients dying within 1 year; outcomes are dictated by stage at diagnosis and specific SWI/SNF mutations.
Undifferentiated gastric carcinoma. Undifferentiated gastric carcinoma; Note solid sheets of large to medium-sized polygonal cells. Binucleated cells are recognizable

Q: Extensive sampling of a suspected [...] is critical to identify a focal component of [...], which helps confirm its epithelial origin.
Undifferentiated gastric carcinoma. D A minor glandular component is seen in most gastric undifferentiated carcinomas that are sufficiently sampled.
A: Gastric undifferentiated carcinoma; adenocarcinoma
Back Extra: Gastric undifferentiated carcinoma
- Clinical: Extremely rare (0.2% of gastric carcinomas) aggressive tumor typically presenting in men (mean age 60) as a large, necrotic, and ulcerated mass.
- Microscopic: Composed of anaplastic polygonal cells in solid or discohesive sheets; common variants include rhabdoid phenotypes, spindled sarcomatoid morphology, and the presence of non-neoplastic osteoclast-like giant cells.
- Ancillary: Often shows loss of SWI/SNF complex proteins (SMARCB1/INI1, SMARCA4/BRG1); frequently expresses vimentin (often with a perinuclear dot-like pattern) and variable pankeratin.
- Prognosis: Highly aggressive with most patients dying within 1 year; outcomes are dictated by stage at diagnosis and specific SWI/SNF mutations.
Undifferentiated gastric carcinoma. D A minor glandular component is seen in most gastric undifferentiated carcinomas that are sufficiently sampled.

Q: A gastric mesenchymal tumor showing spindle cells with [...] and strong, diffuse expression of [...] is diagnostic of a Gastrointestinal stromal tumour.
Gastrointestinal stromal tumour (GIST). GISTs are often composed of cytologically bland spindle cells that may feature distinctive paranuclear vacuolization.
Gastrointestinal stromal tumour. KIT (CD117)-positive gastrointestinal stromal tumour. Cytoplasmic immunopositivity is associated with perinuclear dot-like accentuation.
A: paranuclear vacuoles; KIT (CD117)
Back Extra: Gastrointestinal stromal tumour
- Clinical: Most common mesenchymal neoplasm of the GI tract, arising from interstitial cells of Cajal; 55% occur in the stomach and often present with GI bleeding or an incidental mass.
- Morphology: Typically presents as a spindle cell neoplasm with characteristic paranuclear vacuoles; epithelioid variants are more common in the stomach (often PDGFRA-mutated).
- Ancillary: Diagnosed via KIT (CD117) and DOG1 (ANO1) expression; KIT-negative cases are often PDGFRA-mutant and require DOG1 for confirmation.
- Molecular: Most harbor KIT (75%, mainly exon 11) or PDGFRA (10%) mutations; SDH-deficiency accounts for a subset of syndromic/pediatric cases.
- Prognosis: Risk stratification is based on mitotic rate (per 5 mm²), tumor size, and anatomical site (stomach has a more favorable prognosis than small bowel).
Gastrointestinal stromal tumour (GIST). GISTs are often composed of cytologically bland spindle cells that may feature distinctive paranuclear vacuolization.
Gastrointestinal stromal tumour. KIT (CD117)-positive gastrointestinal stromal tumour. Cytoplasmic immunopositivity is associated with perinuclear dot-like accentuation.

Q: In a Gastrointestinal stromal tumour that is immunohistochemically negative for KIT, the marker [...] is highly sensitive for confirming the diagnosis, especially in cases with [...] mutations.
Gastrointestinal stromal tumour (GIST), epithelioid type. This tumour harbours a PDGFRA mutation. Note the round nuclei and abundant eosinophilic cytoplasm.
Gastrointestinal stromal tumour (GIST), epithelioid type. Immunohistochemistry for DOG1 (ANO1) is helpful to confirm the diagnosis of PDGFRA-mutant GISTs.
Gastrointestinal stromal tumour, epithelioid type. PDGFRA-mutant GISTs typically show strong and diffuse expression of PDGFRA.
A: DOG1 (ANO1); PDGFRA
Back Extra: Gastrointestinal stromal tumour
- Clinical: Most common mesenchymal neoplasm of the GI tract, arising from interstitial cells of Cajal; 55% occur in the stomach and often present with GI bleeding or an incidental mass.
- Morphology: Typically presents as a spindle cell neoplasm with characteristic paranuclear vacuoles; epithelioid variants are more common in the stomach (often PDGFRA-mutated).
- Ancillary: Diagnosed via KIT (CD117) and DOG1 (ANO1) expression; KIT-negative cases are often PDGFRA-mutant and require DOG1 for confirmation.
- Molecular: Most harbor KIT (75%, mainly exon 11) or PDGFRA (10%) mutations; SDH-deficiency accounts for a subset of syndromic/pediatric cases.
- Prognosis: Risk stratification is based on mitotic rate (per 5 mm²), tumor size, and anatomical site (stomach has a more favorable prognosis than small bowel).
Gastrointestinal stromal tumour (GIST), epithelioid type. This tumour harbours a PDGFRA mutation. Note the round nuclei and abundant eosinophilic cytoplasm.
Gastrointestinal stromal tumour (GIST), epithelioid type. Immunohistochemistry for DOG1 (ANO1) is helpful to confirm the diagnosis of PDGFRA-mutant GISTs.
Gastrointestinal stromal tumour, epithelioid type. PDGFRA-mutant GISTs typically show strong and diffuse expression of PDGFRA.

Q: The three critical parameters for risk-stratifying a Gastrointestinal stromal tumour are tumour size, anatomical site, and [...].
Gastrointestinal stromal tumour (GIST). Rarely, GIST may feature a high-grade morphology that is associated with high mitotic count.
Gastrointestinal stromal tumour (GIST). GISTs are often composed of cytologically bland spindle cells that may feature distinctive paranuclear vacuolization.
A: mitotic activity (mitotic count)
Back Extra: Gastrointestinal stromal tumour
- Clinical: Most common mesenchymal neoplasm of the GI tract, arising from interstitial cells of Cajal; 55% occur in the stomach and often present with GI bleeding or an incidental mass.
- Morphology: Typically presents as a spindle cell neoplasm with characteristic paranuclear vacuoles; epithelioid variants are more common in the stomach (often PDGFRA-mutated).
- Ancillary: Diagnosed via KIT (CD117) and DOG1 (ANO1) expression; KIT-negative cases are often PDGFRA-mutant and require DOG1 for confirmation.
- Molecular: Most harbor KIT (75%, mainly exon 11) or PDGFRA (10%) mutations; SDH-deficiency accounts for a subset of syndromic/pediatric cases.
- Prognosis: Risk stratification is based on mitotic rate (per 5 mm²), tumor size, and anatomical site (stomach has a more favorable prognosis than small bowel).
Gastrointestinal stromal tumour (GIST). Rarely, GIST may feature a high-grade morphology that is associated with high mitotic count.
Gastrointestinal stromal tumour (GIST). GISTs are often composed of cytologically bland spindle cells that may feature distinctive paranuclear vacuolization.

Q: In the context of Gastrointestinal stromal tumour genetics, a mutation in [...] is most frequently associated with a [...] primary location.
Gastrointestinal stromal tumor, spindle cell type. GISTs of the small intestine may show extracellular aggregates of collagen, known as skenoid fibers.
A: KIT exon 9; small bowel
Back Extra: Gastrointestinal stromal tumour
- Clinical: Most common mesenchymal neoplasm of the GI tract, arising from interstitial cells of Cajal; 55% occur in the stomach and often present with GI bleeding or an incidental mass.
- Morphology: Typically presents as a spindle cell neoplasm with characteristic paranuclear vacuoles; epithelioid variants are more common in the stomach (often PDGFRA-mutated).
- Ancillary: Diagnosed via KIT (CD117) and DOG1 (ANO1) expression; KIT-negative cases are often PDGFRA-mutant and require DOG1 for confirmation.
- Molecular: Most harbor KIT (75%, mainly exon 11) or PDGFRA (10%) mutations; SDH-deficiency accounts for a subset of syndromic/pediatric cases.
- Prognosis: Risk stratification is based on mitotic rate (per 5 mm²), tumor size, and anatomical site (stomach has a more favorable prognosis than small bowel).
Gastrointestinal stromal tumor, spindle cell type. GISTs of the small intestine may show extracellular aggregates of collagen, known as skenoid fibers.

Q: A well-circumscribed intramural gastric mass showing uniform round cells with mitotic activity (as seen in the image) is consistent with a [...].
Malignant glomus tumour. Round cell features with mitotic activity.
A: malignant glomus tumour
Back Extra: Glomus tumour
- Clinical: Primarily affects the gastric antrum in females (median age 55), presenting with upper GI bleeding or symptoms of gastric outlet obstruction.
- Microscopic: Characterized by monomorphic round cells with central, dark nuclei and clear to eosinophilic cytoplasm arranged in a plexiform growth pattern within the muscularis propria.
- Ancillary: Strong, diffuse SMA expression is diagnostic; notably negative for KIT, DOG1, and chromogranin, which distinguishes it from GIST and neuroendocrine tumours.
- Malignancy: Defined in the GI tract by size > 50 mm, significant cytological atypia, and/or a mitotic count of ≥ 2 mitoses/10 HPF.
- Molecular: Recurrent gene rearrangements in the NOTCH family (e.g., MIR143::NOTCH2) are found in approximately 50% of cases.
Malignant glomus tumour. Round cell features with mitotic activity.

Q: While both may express synaptophysin, the [...] is distinguished from a neuroendocrine tumour by its diffuse expression of [...] and lack of chromogranin.
Malignant glomus tumour. Round cell features with mitotic activity.
A: Glomus tumour; SMA
Back Extra: Glomus tumour
- Clinical: Primarily affects the gastric antrum in females (median age 55), presenting with upper GI bleeding or symptoms of gastric outlet obstruction.
- Microscopic: Characterized by monomorphic round cells with central, dark nuclei and clear to eosinophilic cytoplasm arranged in a plexiform growth pattern within the muscularis propria.
- Ancillary: Strong, diffuse SMA expression is diagnostic; notably negative for KIT, DOG1, and chromogranin, which distinguishes it from GIST and neuroendocrine tumours.
- Malignancy: Defined in the GI tract by size > 50 mm, significant cytological atypia, and/or a mitotic count of ≥ 2 mitoses/10 HPF.
- Molecular: Recurrent gene rearrangements in the NOTCH family (e.g., MIR143::NOTCH2) are found in approximately 50% of cases.
Malignant glomus tumour. Round cell features with mitotic activity.

Q: Approximately half of sporadic [...] harbor gene rearrangements involving the [...] family, often resulting in MIR143::NOTCH2 fusions.
Malignant glomus tumour. Round cell features with mitotic activity.
A: Glomus tumours; NOTCH
Back Extra: Glomus tumour
- Clinical: Primarily affects the gastric antrum in females (median age 55), presenting with upper GI bleeding or symptoms of gastric outlet obstruction.
- Microscopic: Characterized by monomorphic round cells with central, dark nuclei and clear to eosinophilic cytoplasm arranged in a plexiform growth pattern within the muscularis propria.
- Ancillary: Strong, diffuse SMA expression is diagnostic; notably negative for KIT, DOG1, and chromogranin, which distinguishes it from GIST and neuroendocrine tumours.
- Malignancy: Defined in the GI tract by size > 50 mm, significant cytological atypia, and/or a mitotic count of ≥ 2 mitoses/10 HPF.
- Molecular: Recurrent gene rearrangements in the NOTCH family (e.g., MIR143::NOTCH2) are found in approximately 50% of cases.
Malignant glomus tumour. Round cell features with mitotic activity.

Q: In the upper GI tract, a [...] is considered malignant if it exceeds a size of [...] mm and/or has a mitotic count of ≥ [...] mitoses/10 HPF.
Malignant glomus tumour. Round cell features with mitotic activity.
A: Glomus tumour; 50; 2
Back Extra: Glomus tumour
- Clinical: Primarily affects the gastric antrum in females (median age 55), presenting with upper GI bleeding or symptoms of gastric outlet obstruction.
- Microscopic: Characterized by monomorphic round cells with central, dark nuclei and clear to eosinophilic cytoplasm arranged in a plexiform growth pattern within the muscularis propria.
- Ancillary: Strong, diffuse SMA expression is diagnostic; notably negative for KIT, DOG1, and chromogranin, which distinguishes it from GIST and neuroendocrine tumours.
- Malignancy: Defined in the GI tract by size > 50 mm, significant cytological atypia, and/or a mitotic count of ≥ 2 mitoses/10 HPF.
- Molecular: Recurrent gene rearrangements in the NOTCH family (e.g., MIR143::NOTCH2) are found in approximately 50% of cases.
Malignant glomus tumour. Round cell features with mitotic activity.

Q: A spindle cell lesion in the gastric antrum exhibiting a multinodular growth pattern within a myxoid matrix as seen in this image is diagnostic of [...].
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
Plexiform fibromyxoma. High-power view shows the spectrum of morphology: hypovascular (A).
A: Plexiform fibromyxoma
Back Extra: Plexiform fibromyxoma
- Clinical: A rare, benign mesenchymal neoplasm typically arising in the gastric antrum or pylorus; presents with GI bleeding, weight loss, or pyloric obstruction.
- Histopathology: Characterized by a multinodular or plexiform growth of bland spindle cells set in a myxoid, fibromyxoid, or collagenous matrix with a prominent arborizing thin-walled capillary network.
- Ancillary Studies: Tumor cells are typically SMA positive but negative for KIT (CD117), DOG1, and CD34, helping to distinguish it from GIST.
- Molecular Pathology: Recurrently features MALAT1::GLI1 fusions or PTCH1 inactivation, both of which lead to GLI1 overexpression.
- Prognosis: Excellent; the lesion is entirely benign with no reports of recurrence or metastasis.
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
Plexiform fibromyxoma. High-power view shows the spectrum of morphology: hypovascular (A).

Q: Unlike gastrointestinal stromal tumors (GIST), plexiform fibromyxoma is characteristically negative for the markers [...] and [...].
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
Plexiform fibromyxoma. High-power view shows the spectrum of morphology: hypovascular (A).
A: KIT (CD117); DOG1
Back Extra: Plexiform fibromyxoma
- Clinical: A rare, benign mesenchymal neoplasm typically arising in the gastric antrum or pylorus; presents with GI bleeding, weight loss, or pyloric obstruction.
- Histopathology: Characterized by a multinodular or plexiform growth of bland spindle cells set in a myxoid, fibromyxoid, or collagenous matrix with a prominent arborizing thin-walled capillary network.
- Ancillary Studies: Tumor cells are typically SMA positive but negative for KIT (CD117), DOG1, and CD34, helping to distinguish it from GIST.
- Molecular Pathology: Recurrently features MALAT1::GLI1 fusions or PTCH1 inactivation, both of which lead to GLI1 overexpression.
- Prognosis: Excellent; the lesion is entirely benign with no reports of recurrence or metastasis.
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
Plexiform fibromyxoma. High-power view shows the spectrum of morphology: hypovascular (A).

Q: The molecular signature of plexiform fibromyxoma frequently involves the [GLI1] fusion, resulting in the overexpression of [...].
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
A: MALAT1; GLI1
Back Extra: Plexiform fibromyxoma
- Clinical: A rare, benign mesenchymal neoplasm typically arising in the gastric antrum or pylorus; presents with GI bleeding, weight loss, or pyloric obstruction.
- Histopathology: Characterized by a multinodular or plexiform growth of bland spindle cells set in a myxoid, fibromyxoid, or collagenous matrix with a prominent arborizing thin-walled capillary network.
- Ancillary Studies: Tumor cells are typically SMA positive but negative for KIT (CD117), DOG1, and CD34, helping to distinguish it from GIST.
- Molecular Pathology: Recurrently features MALAT1::GLI1 fusions or PTCH1 inactivation, both of which lead to GLI1 overexpression.
- Prognosis: Excellent; the lesion is entirely benign with no reports of recurrence or metastasis.
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.

Q: The essential low-power architectural feature required to diagnose plexiform fibromyxoma is a [...] or [...] arrangement of spindle cells.
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.
A: multinodular; plexiform
Back Extra: Plexiform fibromyxoma
- Clinical: A rare, benign mesenchymal neoplasm typically arising in the gastric antrum or pylorus; presents with GI bleeding, weight loss, or pyloric obstruction.
- Histopathology: Characterized by a multinodular or plexiform growth of bland spindle cells set in a myxoid, fibromyxoid, or collagenous matrix with a prominent arborizing thin-walled capillary network.
- Ancillary Studies: Tumor cells are typically SMA positive but negative for KIT (CD117), DOG1, and CD34, helping to distinguish it from GIST.
- Molecular Pathology: Recurrently features MALAT1::GLI1 fusions or PTCH1 inactivation, both of which lead to GLI1 overexpression.
- Prognosis: Excellent; the lesion is entirely benign with no reports of recurrence or metastasis.
Plexiform fibromyxoma. Scanning magnification shows the plexiform pattern of arrangement.

Q: Gastric Neuroendocrine Tumor Type 1 (Autoimmune) arises due to unregulated stimulus from [...] (hypergastrinaemia) following the autoimmune-mediated loss of [...].
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.
A: gastrin; parietal cells
Back Extra: Gastric Neuroendocrine Tumor Type 1 (Autoimmune)
- Clinical: Represents 80–90% of gastric NETs; strongly associated with autoimmune chronic atrophic gastritis, hypergastrinaemia, achlorhydria, and often pernicious anaemia.
- Microscopic: Characterized by small, multiple microlobular or trabecular nests of well-differentiated cells with monomorphic nuclei and eosinophilic cytoplasm, typically found in the oxyntic mucosa.
- Background Mucosa: Essential diagnostic feature showing atrophic oxyntic glands, intestinal/pseudopyloric metaplasia, and linear or micronodular ECL-cell hyperplasia.
- Ancillary: Strong, diffuse positivity for Synaptophysin and Chromogranin A; Ki-67 index is typically low (WHO Grade 1 or 2).
- Prognosis: Excellent prognosis with an indolent clinical course; surgical or endoscopic resection is often curative.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.

Q: In the setting of Gastric Neuroendocrine Tumor Type 1 (Autoimmune), the surrounding oxyntic mucosa typically shows [...] hyperplasia, which can be highlighted by the immunohistochemical marker [...].
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). Synaptophysin immunohistochemistry highlights the background atrophic gastritis with nodular/linear enterochromaffin-like cell hyperplasia.
A: ECL-cell; synaptophysin
Back Extra: Gastric Neuroendocrine Tumor Type 1 (Autoimmune)
- Clinical: Represents 80–90% of gastric NETs; strongly associated with autoimmune chronic atrophic gastritis, hypergastrinaemia, achlorhydria, and often pernicious anaemia.
- Microscopic: Characterized by small, multiple microlobular or trabecular nests of well-differentiated cells with monomorphic nuclei and eosinophilic cytoplasm, typically found in the oxyntic mucosa.
- Background Mucosa: Essential diagnostic feature showing atrophic oxyntic glands, intestinal/pseudopyloric metaplasia, and linear or micronodular ECL-cell hyperplasia.
- Ancillary: Strong, diffuse positivity for Synaptophysin and Chromogranin A; Ki-67 index is typically low (WHO Grade 1 or 2).
- Prognosis: Excellent prognosis with an indolent clinical course; surgical or endoscopic resection is often curative.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). Synaptophysin immunohistochemistry highlights the background atrophic gastritis with nodular/linear enterochromaffin-like cell hyperplasia.

Q: Which specific location is the primary site for Gastric Neuroendocrine Tumor Type 1 (Autoimmune) within the stomach? [...]
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.
A: Corpus (Body) and Fundus
Back Extra: Gastric Neuroendocrine Tumor Type 1 (Autoimmune)
- Clinical: Represents 80–90% of gastric NETs; strongly associated with autoimmune chronic atrophic gastritis, hypergastrinaemia, achlorhydria, and often pernicious anaemia.
- Microscopic: Characterized by small, multiple microlobular or trabecular nests of well-differentiated cells with monomorphic nuclei and eosinophilic cytoplasm, typically found in the oxyntic mucosa.
- Background Mucosa: Essential diagnostic feature showing atrophic oxyntic glands, intestinal/pseudopyloric metaplasia, and linear or micronodular ECL-cell hyperplasia.
- Ancillary: Strong, diffuse positivity for Synaptophysin and Chromogranin A; Ki-67 index is typically low (WHO Grade 1 or 2).
- Prognosis: Excellent prognosis with an indolent clinical course; surgical or endoscopic resection is often curative.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.

Q: Unlike Type 1 cases, the [...] Gastric Neuroendocrine Tumor is sporadic, usually solitary, and occurs in the background of normal gastric mucosa.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.
A: Type 3
Back Extra: Gastric Neuroendocrine Tumor Type 1 (Autoimmune)
- Clinical: Represents 80–90% of gastric NETs; strongly associated with autoimmune chronic atrophic gastritis, hypergastrinaemia, achlorhydria, and often pernicious anaemia.
- Microscopic: Characterized by small, multiple microlobular or trabecular nests of well-differentiated cells with monomorphic nuclei and eosinophilic cytoplasm, typically found in the oxyntic mucosa.
- Background Mucosa: Essential diagnostic feature showing atrophic oxyntic glands, intestinal/pseudopyloric metaplasia, and linear or micronodular ECL-cell hyperplasia.
- Ancillary: Strong, diffuse positivity for Synaptophysin and Chromogranin A; Ki-67 index is typically low (WHO Grade 1 or 2).
- Prognosis: Excellent prognosis with an indolent clinical course; surgical or endoscopic resection is often curative.
Type 1 enterochromaffin-like (ECL)-cell neuroendocrine tumour (NET). High-power field showing cords/nests of well-differentiated NET cells intermixed with benign gastric glands.

Q: In an H. pylori-naïve patient, a bright red, "raspberry-like" polyp showing papillary structures lined by cells with an apical mucin cap is characteristic of [...] gastric dysplasia.
Foveolar-type dysplasia/adenoma. Columnar tumour cells have a characteristic apical mucin cap and basally oriented nuclei.
Foveolar‐type adenoma with a raspberry‐like appearance showing irregularly shaped papillary structures supported by a well-vascularized stroma.
A: foveolar-type
Back Extra: Gastric dysplasia
- Clinical: Often asymptomatic or presenting with non-specific dyspepsia; intestinal-type is strongly linked to H. pylori atrophic gastritis, while sporadic foveolar-type (raspberry-like) polyps can occur in H. pylori-naïve mucosa.
- Microscopic Subtypes: Classed into Intestinal-type (columnar cells with intestinal differentiation and elongated nuclei), Foveolar-type (papillary/serrated fronds with apical neutral mucin caps), and Crypt dysplasia (basal-limited atypia with surface maturation).
- Grading: High-grade dysplasia (HGD) is distinguished from low-grade (LGD) by architectural complexity (back-to-back/crowded glands), marked nuclear atypia, loss of cell polarity, and frequent mitoses.
- Ancillary Studies: Subtyping is supported by IHC; intestinal-type expresses MUC2, CD10, and CDX2, while foveolar-type expresses MUC5AC and/or MUC6. Strong, diffuse p53 expression is common in high-grade lesions.
- Prognosis: Progression risk correlates with grade; HGD has a very high risk (up to 69%) of progression to invasive adenocarcinoma, often requiring endoscopic resection (EMR/ESD).
Foveolar-type dysplasia/adenoma. Columnar tumour cells have a characteristic apical mucin cap and basally oriented nuclei.
Foveolar‐type adenoma with a raspberry‐like appearance showing irregularly shaped papillary structures supported by a well-vascularized stroma.

Q: The key architectural feature distinguishing [...] gastric dysplasia from low-grade is the presence of [...] and a loss of cellular polarity.
Low-grade intestinal-type gastric dysplasia showing preserved glandular architecture and neoplastic cells with moderate cytological atypia and elongated, basally located nuclei.
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.
High-grade foveolar-type dysplasia composed of tall cells with disoriented, markedly atypical, hyperchromatic, and angulated nuclei.
A: high-grade; back-to-back glands (or architectural distortion)
Back Extra: Gastric dysplasia
- Clinical: Often asymptomatic or presenting with non-specific dyspepsia; intestinal-type is strongly linked to H. pylori atrophic gastritis, while sporadic foveolar-type (raspberry-like) polyps can occur in H. pylori-naïve mucosa.
- Microscopic Subtypes: Classed into Intestinal-type (columnar cells with intestinal differentiation and elongated nuclei), Foveolar-type (papillary/serrated fronds with apical neutral mucin caps), and Crypt dysplasia (basal-limited atypia with surface maturation).
- Grading: High-grade dysplasia (HGD) is distinguished from low-grade (LGD) by architectural complexity (back-to-back/crowded glands), marked nuclear atypia, loss of cell polarity, and frequent mitoses.
- Ancillary Studies: Subtyping is supported by IHC; intestinal-type expresses MUC2, CD10, and CDX2, while foveolar-type expresses MUC5AC and/or MUC6. Strong, diffuse p53 expression is common in high-grade lesions.
- Prognosis: Progression risk correlates with grade; HGD has a very high risk (up to 69%) of progression to invasive adenocarcinoma, often requiring endoscopic resection (EMR/ESD).
Low-grade intestinal-type gastric dysplasia showing preserved glandular architecture and neoplastic cells with moderate cytological atypia and elongated, basally located nuclei.
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.
High-grade foveolar-type dysplasia composed of tall cells with disoriented, markedly atypical, hyperchromatic, and angulated nuclei.

Q: In the subtyping of gastric dysplasia, markers such as CDX2, CD10, and [...] are typically expressed in the [...]-type.
Low-grade intestinal-type gastric dysplasia showing preserved glandular architecture and neoplastic cells with moderate cytological atypia and elongated, basally located nuclei.
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.
A: MUC2; intestinal
Back Extra: Gastric dysplasia
- Clinical: Often asymptomatic or presenting with non-specific dyspepsia; intestinal-type is strongly linked to H. pylori atrophic gastritis, while sporadic foveolar-type (raspberry-like) polyps can occur in H. pylori-naïve mucosa.
- Microscopic Subtypes: Classed into Intestinal-type (columnar cells with intestinal differentiation and elongated nuclei), Foveolar-type (papillary/serrated fronds with apical neutral mucin caps), and Crypt dysplasia (basal-limited atypia with surface maturation).
- Grading: High-grade dysplasia (HGD) is distinguished from low-grade (LGD) by architectural complexity (back-to-back/crowded glands), marked nuclear atypia, loss of cell polarity, and frequent mitoses.
- Ancillary Studies: Subtyping is supported by IHC; intestinal-type expresses MUC2, CD10, and CDX2, while foveolar-type expresses MUC5AC and/or MUC6. Strong, diffuse p53 expression is common in high-grade lesions.
- Prognosis: Progression risk correlates with grade; HGD has a very high risk (up to 69%) of progression to invasive adenocarcinoma, often requiring endoscopic resection (EMR/ESD).
Low-grade intestinal-type gastric dysplasia showing preserved glandular architecture and neoplastic cells with moderate cytological atypia and elongated, basally located nuclei.
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.

Q: Distinguishing high-grade gastric dysplasia from [...] depends on identifying features like [...], irregular budding, or glandular fusion, even in the absence of desmoplasia.
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.
Differential diagnosis: Intramucosal adenocarcinoma. Note marked glandular crowding and anastomosing glands despite absence of stromal reaction.
A: intramucosal adenocarcinoma; cribriforming
Back Extra: Gastric dysplasia
- Clinical: Often asymptomatic or presenting with non-specific dyspepsia; intestinal-type is strongly linked to H. pylori atrophic gastritis, while sporadic foveolar-type (raspberry-like) polyps can occur in H. pylori-naïve mucosa.
- Microscopic Subtypes: Classed into Intestinal-type (columnar cells with intestinal differentiation and elongated nuclei), Foveolar-type (papillary/serrated fronds with apical neutral mucin caps), and Crypt dysplasia (basal-limited atypia with surface maturation).
- Grading: High-grade dysplasia (HGD) is distinguished from low-grade (LGD) by architectural complexity (back-to-back/crowded glands), marked nuclear atypia, loss of cell polarity, and frequent mitoses.
- Ancillary Studies: Subtyping is supported by IHC; intestinal-type expresses MUC2, CD10, and CDX2, while foveolar-type expresses MUC5AC and/or MUC6. Strong, diffuse p53 expression is common in high-grade lesions.
- Prognosis: Progression risk correlates with grade; HGD has a very high risk (up to 69%) of progression to invasive adenocarcinoma, often requiring endoscopic resection (EMR/ESD).
High-grade intestinal-type gastric dysplasia featuring crowded irregular glands and marked cytological atypia.
Differential diagnosis: Intramucosal adenocarcinoma. Note marked glandular crowding and anastomosing glands despite absence of stromal reaction.

Q: Gastric dysplasia limited to the basal portion of intestinalized glands with an abrupt transition to non-dysplastic surface foveolae is known as [...] dysplasia.
Gastric basal gland/crypt dysplasia. The dysplastic changes are limited to the basal portion of the intestinalized crypts with abrupt transition with the foveolae.
A: crypt (or basal gland)
Back Extra: Gastric dysplasia
- Clinical: Often asymptomatic or presenting with non-specific dyspepsia; intestinal-type is strongly linked to H. pylori atrophic gastritis, while sporadic foveolar-type (raspberry-like) polyps can occur in H. pylori-naïve mucosa.
- Microscopic Subtypes: Classed into Intestinal-type (columnar cells with intestinal differentiation and elongated nuclei), Foveolar-type (papillary/serrated fronds with apical neutral mucin caps), and Crypt dysplasia (basal-limited atypia with surface maturation).
- Grading: High-grade dysplasia (HGD) is distinguished from low-grade (LGD) by architectural complexity (back-to-back/crowded glands), marked nuclear atypia, loss of cell polarity, and frequent mitoses.
- Ancillary Studies: Subtyping is supported by IHC; intestinal-type expresses MUC2, CD10, and CDX2, while foveolar-type expresses MUC5AC and/or MUC6. Strong, diffuse p53 expression is common in high-grade lesions.
- Prognosis: Progression risk correlates with grade; HGD has a very high risk (up to 69%) of progression to invasive adenocarcinoma, often requiring endoscopic resection (EMR/ESD).
Gastric basal gland/crypt dysplasia. The dysplastic changes are limited to the basal portion of the intestinalized crypts with abrupt transition with the foveolae.

Q: An intramucosal gastric lesion composed of clusters of tightly packed glands lined by basophilic chief-like cells and eosinophilic parietal cells (seen in the image) is diagnostic of [...].
Oxyntic gland adenoma. Glandular proliferation lined by chief cell–like cells.
Oxyntic gland adenoma. High-power view; note eosinophilic cells showing parietal cell differentiation.
A: Oxyntic gland adenoma
Back Extra: Oxyntic gland adenoma
- Clinical: Rare neoplasm occurring in non-atrophic oxyntic mucosa, typically in patients aged 60–70; often presents as a subsurface polypoid lesion with surface vasodilatation.
- Micro: Intramucosal proliferation of tightly packed glands in the deeper mucosa, primarily composed of chief cell-like cells (basophilic) with variable parietal cell (eosinophilic) differentiation and a pushing interface.
- Ancillary: Characteristically shows diffuse strong nuclear expression of Cyclin D1 and cytoplasmic positivity for MUC6 and Pepsinogen I; notably negative for Chromogranin A.
- Prognosis/Genetics: Slow-growing and benign; the presence of submucosal invasion upgrades the diagnosis to gastric adenocarcinoma of fundic-gland type (GA-FG). Frequently harbors GNAS mutations.
Oxyntic gland adenoma. Glandular proliferation lined by chief cell–like cells.
Oxyntic gland adenoma. High-power view; note eosinophilic cells showing parietal cell differentiation.

Q: The diagnosis of [...] is changed to [...] once [...] is identified.
Oxyntic gland adenoma. With transition to submucosal invasive carcinoma.
A: Oxyntic gland adenoma; gastric adenocarcinoma of fundic-gland type (GA-FG); submucosal invasion
Back Extra: Oxyntic gland adenoma
- Clinical: Rare neoplasm occurring in non-atrophic oxyntic mucosa, typically in patients aged 60–70; often presents as a subsurface polypoid lesion with surface vasodilatation.
- Micro: Intramucosal proliferation of tightly packed glands in the deeper mucosa, primarily composed of chief cell-like cells (basophilic) with variable parietal cell (eosinophilic) differentiation and a pushing interface.
- Ancillary: Characteristically shows diffuse strong nuclear expression of Cyclin D1 and cytoplasmic positivity for MUC6 and Pepsinogen I; notably negative for Chromogranin A.
- Prognosis/Genetics: Slow-growing and benign; the presence of submucosal invasion upgrades the diagnosis to gastric adenocarcinoma of fundic-gland type (GA-FG). Frequently harbors GNAS mutations.
Oxyntic gland adenoma. With transition to submucosal invasive carcinoma.

Q: A [...] is a polypoid neoplasm characterized by closely packed glands with ground-glass cytoplasm that lacks the [...] found in foveolar-type lesions.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. High-power view.
Gastric pyloric gland adenoma. The tumour is composed of small to dilated glands, consisting of pyloric/mucous neck cell–type cells. The surface epithelial cells exhibit slight columnarization.
A: Gastric pyloric gland adenoma; apical mucin cap
Back Extra: Gastric pyloric gland adenoma
- Clinical: Usually occurs in the gastric body or fundus; sporadic cases are frequently associated with autoimmune gastritis (elderly women), while syndromic cases (FAP, Lynch, GAPPS) occur in younger patients.
- Microscopic: Composed of closely packed glands of pyloric/mucous neck cell differentiation; cells feature "ground-glass" cytoplasm and characteristically lack the apical mucin cap seen in foveolar-type adenomas.
- Ancillary: Consistently expresses MUC6 in the glandular component; MUC5AC is usually limited to surface epithelium.
- Molecular: Characterized by a triad of mutations in GNAS, KRAS, and APC.
- Prognosis: Progression to high-grade dysplasia or adenocarcinoma is common (up to 50% in some series), though submucosal invasion is seen in <10%.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. High-power view.
Gastric pyloric gland adenoma. The tumour is composed of small to dilated glands, consisting of pyloric/mucous neck cell–type cells. The surface epithelial cells exhibit slight columnarization.

Q: Both sporadic and syndromic forms of Gastric pyloric gland adenoma consistently harbor mutations in [...], KRAS, and APC.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. The adenoma shows an inverted growth pattern.
A: GNAS
Back Extra: Gastric pyloric gland adenoma
- Clinical: Usually occurs in the gastric body or fundus; sporadic cases are frequently associated with autoimmune gastritis (elderly women), while syndromic cases (FAP, Lynch, GAPPS) occur in younger patients.
- Microscopic: Composed of closely packed glands of pyloric/mucous neck cell differentiation; cells feature "ground-glass" cytoplasm and characteristically lack the apical mucin cap seen in foveolar-type adenomas.
- Ancillary: Consistently expresses MUC6 in the glandular component; MUC5AC is usually limited to surface epithelium.
- Molecular: Characterized by a triad of mutations in GNAS, KRAS, and APC.
- Prognosis: Progression to high-grade dysplasia or adenocarcinoma is common (up to 50% in some series), though submucosal invasion is seen in <10%.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. The adenoma shows an inverted growth pattern.

Q: In Gastric pyloric gland adenoma, the glandular component shows strong and consistent immunohistochemical expression of [...].
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. A Glandular component expresses MUC6.
A: MUC6
Back Extra: Gastric pyloric gland adenoma
- Clinical: Usually occurs in the gastric body or fundus; sporadic cases are frequently associated with autoimmune gastritis (elderly women), while syndromic cases (FAP, Lynch, GAPPS) occur in younger patients.
- Microscopic: Composed of closely packed glands of pyloric/mucous neck cell differentiation; cells feature "ground-glass" cytoplasm and characteristically lack the apical mucin cap seen in foveolar-type adenomas.
- Ancillary: Consistently expresses MUC6 in the glandular component; MUC5AC is usually limited to surface epithelium.
- Molecular: Characterized by a triad of mutations in GNAS, KRAS, and APC.
- Prognosis: Progression to high-grade dysplasia or adenocarcinoma is common (up to 50% in some series), though submucosal invasion is seen in <10%.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. A Glandular component expresses MUC6.

Q: Sporadic Gastric pyloric gland adenomas are most commonly identified in elderly female patients with a background of [...] gastritis.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. The tumour is composed of small to dilated glands, consisting of pyloric/mucous neck cell–type cells. The surface epithelial cells exhibit slight columnarization.
A: autoimmune
Back Extra: Gastric pyloric gland adenoma
- Clinical: Usually occurs in the gastric body or fundus; sporadic cases are frequently associated with autoimmune gastritis (elderly women), while syndromic cases (FAP, Lynch, GAPPS) occur in younger patients.
- Microscopic: Composed of closely packed glands of pyloric/mucous neck cell differentiation; cells feature "ground-glass" cytoplasm and characteristically lack the apical mucin cap seen in foveolar-type adenomas.
- Ancillary: Consistently expresses MUC6 in the glandular component; MUC5AC is usually limited to surface epithelium.
- Molecular: Characterized by a triad of mutations in GNAS, KRAS, and APC.
- Prognosis: Progression to high-grade dysplasia or adenocarcinoma is common (up to 50% in some series), though submucosal invasion is seen in <10%.
Gastric pyloric gland adenoma. Low-power view.
Gastric pyloric gland adenoma. The tumour is composed of small to dilated glands, consisting of pyloric/mucous neck cell–type cells. The surface epithelial cells exhibit slight columnarization.

Q: A 55-year-old female on chronic PPI therapy presents with multiple small, sessile polyps in the gastric fundus. Microscopic examination reveals cystic dilation of oxyntic glands lined by flattened parietal cells. What is the diagnosis? [...]
Fundic gland polyp. Low-power view of a typical example; there are numerous dilated oxyntic glands lined by flattened parietal cells; there are also two dilated mucous glands lined by foveolar cells.
Fundic gland polyp. Sporadic fundic gland polyp with marked cystic expansion, parietal cell protrusion, and hyperplasia in a patient taking proton-pump inhibitors.
A: Fundic gland polyps
Back Extra: Fundic gland polyps
- Clinical: Fundic gland polyps (FGPs) are the most common gastric polyps, arising exclusively in the oxyntic mucosa (body/fundus); they are strongly associated with proton-pump inhibitor (PPI) use and are negatively associated with H. pylori infection.
- Microscopic: Characterized by disordered architecture with microcystic dilation of oxyntic glands lined by flattened parietal and chief cells; PPI-associated cases often show prominent parietal cell protrusion/hyperplasia.
- Genetics: Driven by the WNT pathway; sporadic cases typically harbor CTNNB1 mutations, whereas syndromic cases (FAP or GAPPS) involve germline APC mutations.
- Prognosis: Highly benign; sporadic cases associated with PPIs may regress upon therapy cessation. While dysplasia can occur (more commonly in FAP), progression to adenocarcinoma is exceptionally rare.
Fundic gland polyp. Low-power view of a typical example; there are numerous dilated oxyntic glands lined by flattened parietal cells; there are also two dilated mucous glands lined by foveolar cells.
Fundic gland polyp. Sporadic fundic gland polyp with marked cystic expansion, parietal cell protrusion, and hyperplasia in a patient taking proton-pump inhibitors.

Q: Sporadic fundic gland polyps are typically associated with mutations in [...], whereas those arising in the context of Familial Adenomatous Polyposis (FAP) are associated with mutations in [...].
Fundic gland polyp. Sporadic fundic gland polyp without proton-pump inhibitors. Oxyntic glands exhibit a disordered architecture with crowding and cystic dilation; foveolar epithelium is hypoplastic.
Fundic gland polyp, familial adenomatous polyposis–associated. The microcysts are lined almost exclusively by fundic epithelium without overt parietal cell hyperplasia.
A: CTNNB1 (β-catenin); APC
Back Extra: Fundic gland polyps
- Clinical: Fundic gland polyps (FGPs) are the most common gastric polyps, arising exclusively in the oxyntic mucosa (body/fundus); they are strongly associated with proton-pump inhibitor (PPI) use and are negatively associated with H. pylori infection.
- Microscopic: Characterized by disordered architecture with microcystic dilation of oxyntic glands lined by flattened parietal and chief cells; PPI-associated cases often show prominent parietal cell protrusion/hyperplasia.
- Genetics: Driven by the WNT pathway; sporadic cases typically harbor CTNNB1 mutations, whereas syndromic cases (FAP or GAPPS) involve germline APC mutations.
- Prognosis: Highly benign; sporadic cases associated with PPIs may regress upon therapy cessation. While dysplasia can occur (more commonly in FAP), progression to adenocarcinoma is exceptionally rare.
Fundic gland polyp. Sporadic fundic gland polyp without proton-pump inhibitors. Oxyntic glands exhibit a disordered architecture with crowding and cystic dilation; foveolar epithelium is hypoplastic.
Fundic gland polyp, familial adenomatous polyposis–associated. The microcysts are lined almost exclusively by fundic epithelium without overt parietal cell hyperplasia.

Q: True or False: The presence of H. pylori infection is a risk factor for the development of sporadic fundic gland polyps. [...]
Fundic gland polyp. Low-power view of a typical example; there are numerous dilated oxyntic glands lined by flattened parietal cells; there are also two dilated mucous glands lined by foveolar cells.
Fundic gland polyp. High-power view; dilated glands are lined by flattened oxyntic gland cells or foveolar epithelium.
A: False
Back Extra: Fundic gland polyps
- Clinical: Fundic gland polyps (FGPs) are the most common gastric polyps, arising exclusively in the oxyntic mucosa (body/fundus); they are strongly associated with proton-pump inhibitor (PPI) use and are negatively associated with H. pylori infection.
- Microscopic: Characterized by disordered architecture with microcystic dilation of oxyntic glands lined by flattened parietal and chief cells; PPI-associated cases often show prominent parietal cell protrusion/hyperplasia.
- Genetics: Driven by the WNT pathway; sporadic cases typically harbor CTNNB1 mutations, whereas syndromic cases (FAP or GAPPS) involve germline APC mutations.
- Prognosis: Highly benign; sporadic cases associated with PPIs may regress upon therapy cessation. While dysplasia can occur (more commonly in FAP), progression to adenocarcinoma is exceptionally rare.
Fundic gland polyp. Low-power view of a typical example; there are numerous dilated oxyntic glands lined by flattened parietal cells; there are also two dilated mucous glands lined by foveolar cells.
Fundic gland polyp. High-power view; dilated glands are lined by flattened oxyntic gland cells or foveolar epithelium.

Q: When fundic gland polyps are found in high numbers in a young patient (e.g., 20s-30s), the clinician should investigate for syndromic associations such as [...] or [...].
Fundic gland polyp, familial adenomatous polyposis–associated. The microcysts are lined almost exclusively by fundic epithelium without overt parietal cell hyperplasia.
Fundic gland polyp, GAPPS-associated. The large microcysts are predominantly lined by inverted foveolar epithelium.
A: Familial Adenomatous Polyposis (FAP); Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)
Back Extra: Fundic gland polyps
- Clinical: Fundic gland polyps (FGPs) are the most common gastric polyps, arising exclusively in the oxyntic mucosa (body/fundus); they are strongly associated with proton-pump inhibitor (PPI) use and are negatively associated with H. pylori infection.
- Microscopic: Characterized by disordered architecture with microcystic dilation of oxyntic glands lined by flattened parietal and chief cells; PPI-associated cases often show prominent parietal cell protrusion/hyperplasia.
- Genetics: Driven by the WNT pathway; sporadic cases typically harbor CTNNB1 mutations, whereas syndromic cases (FAP or GAPPS) involve germline APC mutations.
- Prognosis: Highly benign; sporadic cases associated with PPIs may regress upon therapy cessation. While dysplasia can occur (more commonly in FAP), progression to adenocarcinoma is exceptionally rare.
Fundic gland polyp, familial adenomatous polyposis–associated. The microcysts are lined almost exclusively by fundic epithelium without overt parietal cell hyperplasia.
Fundic gland polyp, GAPPS-associated. The large microcysts are predominantly lined by inverted foveolar epithelium.

Q: Gastric hyperplastic polyps are histologically characterized by [...] set within an [...] lamina propria.
Gastric hyperplastic polyp. Characteristic features of gastric hyperplastic polyps include irregularly shaped, haphazardly dilated foveolae in a background of a loose oedematous stroma, with variable numbers of inflammatory cells. The surface is frequently eroded.
Gastric hyperplastic polyp. The polyp contains oedematous lamina propria and numerous thin-walled vessels in the mucosa. The surface epithelial cells contain variable amounts of mucin; some are mucin-depleted whereas others harbour large cytoplasmic vacuoles.
A: elongated and tortuous foveolae; oedematous and inflamed
Back Extra: Gastric hyperplastic polyps
- Clinical: These are benign, regenerative lesions that typically arise in the sixth or seventh decade of life in the setting of chronic mucosal injury (e.g., H. pylori gastritis, autoimmune gastritis, or chemical gastropathy).
- Microscopic: Characterized by a polypoid expansion of elongated, tortuous, and often dilated foveolae set within an intensely oedematous and inflamed lamina propria.
- Specific Variants: Includes 'globoid cells' (mucin-distended cells resembling signet rings) and subtypes like Gastritis cystica profunda (cysts extending into the submucosa) and polypoid foveolar hyperplasia.
- Prognosis: While benign, polyps > 10 mm have a 1–20% risk of dysplasia and a ~2% risk of adenocarcinoma; malignant transformation is associated with TP53 mutations.
Gastric hyperplastic polyp. Characteristic features of gastric hyperplastic polyps include irregularly shaped, haphazardly dilated foveolae in a background of a loose oedematous stroma, with variable numbers of inflammatory cells. The surface is frequently eroded.
Gastric hyperplastic polyp. The polyp contains oedematous lamina propria and numerous thin-walled vessels in the mucosa. The surface epithelial cells contain variable amounts of mucin; some are mucin-depleted whereas others harbour large cytoplasmic vacuoles.

Q: In the setting of Gastric hyperplastic polyps, the term used to describe distended, goblet cell-like mucinous cells that may mimic signet ring cells is [...].
Gastric hyperplastic polyp. Distended goblet cell–like mucinous cells in hyperplastic foveolae are called globoid cells.
A: globoid cells
Back Extra: Gastric hyperplastic polyps
- Clinical: These are benign, regenerative lesions that typically arise in the sixth or seventh decade of life in the setting of chronic mucosal injury (e.g., H. pylori gastritis, autoimmune gastritis, or chemical gastropathy).
- Microscopic: Characterized by a polypoid expansion of elongated, tortuous, and often dilated foveolae set within an intensely oedematous and inflamed lamina propria.
- Specific Variants: Includes 'globoid cells' (mucin-distended cells resembling signet rings) and subtypes like Gastritis cystica profunda (cysts extending into the submucosa) and polypoid foveolar hyperplasia.
- Prognosis: While benign, polyps > 10 mm have a 1–20% risk of dysplasia and a ~2% risk of adenocarcinoma; malignant transformation is associated with TP53 mutations.
Gastric hyperplastic polyp. Distended goblet cell–like mucinous cells in hyperplastic foveolae are called globoid cells.

Q: A subtype of Gastric hyperplastic polyps, often occurring near a gastrojejunal anastomosis and characterized by foveolar hyperplasia and cystic glands extending into the submucosa, is known as [...].
Gastritis cystica profunda. A polypoid lesion near the gastroduodenal anastomosis contains cysts extending from the deep mucosa into the submucosa.
A: gastritis cystica profunda
Back Extra: Gastric hyperplastic polyps
- Clinical: These are benign, regenerative lesions that typically arise in the sixth or seventh decade of life in the setting of chronic mucosal injury (e.g., H. pylori gastritis, autoimmune gastritis, or chemical gastropathy).
- Microscopic: Characterized by a polypoid expansion of elongated, tortuous, and often dilated foveolae set within an intensely oedematous and inflamed lamina propria.
- Specific Variants: Includes 'globoid cells' (mucin-distended cells resembling signet rings) and subtypes like Gastritis cystica profunda (cysts extending into the submucosa) and polypoid foveolar hyperplasia.
- Prognosis: While benign, polyps > 10 mm have a 1–20% risk of dysplasia and a ~2% risk of adenocarcinoma; malignant transformation is associated with TP53 mutations.
Gastritis cystica profunda. A polypoid lesion near the gastroduodenal anastomosis contains cysts extending from the deep mucosa into the submucosa.

Q: Malignant transformation of a Gastric hyperplastic polyp is most commonly associated with a mutation in [...].
Gastric hyperplastic polyp with dysplasia. High-grade dysplasia in a polyp, containing enlarged, hyperchromatic nuclei with readily apparent mitotic figures and a loss of cell polarity.
A: TP53
Back Extra: Gastric hyperplastic polyps
- Clinical: These are benign, regenerative lesions that typically arise in the sixth or seventh decade of life in the setting of chronic mucosal injury (e.g., H. pylori gastritis, autoimmune gastritis, or chemical gastropathy).
- Microscopic: Characterized by a polypoid expansion of elongated, tortuous, and often dilated foveolae set within an intensely oedematous and inflamed lamina propria.
- Specific Variants: Includes 'globoid cells' (mucin-distended cells resembling signet rings) and subtypes like Gastritis cystica profunda (cysts extending into the submucosa) and polypoid foveolar hyperplasia.
- Prognosis: While benign, polyps > 10 mm have a 1–20% risk of dysplasia and a ~2% risk of adenocarcinoma; malignant transformation is associated with TP53 mutations.
Gastric hyperplastic polyp with dysplasia. High-grade dysplasia in a polyp, containing enlarged, hyperchromatic nuclei with readily apparent mitotic figures and a loss of cell polarity.

Q: A submucosal gastric antral polyp composed of bland spindle cells forming concentric 'onion-skin' whorls around small blood vessels with a background rich in eosinophils is most likely a(n) [diagnosis].
Inflammatory fibroid polyp. The tumour cells whorl around the small blood vessel in the centre of the image (onion-skinning).
Inflammatory fibroid polyp of the stomach. Eosinophils are present in the background.
Inflammatory fibroid polyp. This example has arisen in the classic location, the gastric antral submucosa.
A: inflammatory fibroid polyp
Back Extra: Inflammatory fibroid polyp
- Clinical: Benign, rare neoplasm typically found in the gastric antrum (most common) or ileum; small intestinal lesions frequently present with intussusception.
- Microscopic: Hypocellular proliferation of spindled and stellate cells in an edematous or myxoid stroma, often showing characteristic concentric 'onion-skin' whorling around small blood vessels.
- Inflammatory Infiltrate: Characterized by a prominent mixed infiltrate, typically rich in eosinophils and lymphocytes.
- Ancillary/Molecular: Strong and diffuse immunohistochemical expression of CD34 and PDGFRA; most cases harbor activating mutations in PDGFRA (Exon 18 in stomach, Exon 12 in small intestine).
Inflammatory fibroid polyp. The tumour cells whorl around the small blood vessel in the centre of the image (onion-skinning).
Inflammatory fibroid polyp of the stomach. Eosinophils are present in the background.
Inflammatory fibroid polyp. This example has arisen in the classic location, the gastric antral submucosa.

Q: The majority of sporadic cases of [...] harbor activating mutations in the [...] gene.
Inflammatory fibroid polyp of the stomach. Polyp formed as a result of submucosal spindle cell proliferation.
Inflammatory Fibroid Polyp. The tumor cells are cytologically bland, with small nuclei.
A: inflammatory fibroid polyp; PDGFRA
Back Extra: Inflammatory fibroid polyp
- Clinical: Benign, rare neoplasm typically found in the gastric antrum (most common) or ileum; small intestinal lesions frequently present with intussusception.
- Microscopic: Hypocellular proliferation of spindled and stellate cells in an edematous or myxoid stroma, often showing characteristic concentric 'onion-skin' whorling around small blood vessels.
- Inflammatory Infiltrate: Characterized by a prominent mixed infiltrate, typically rich in eosinophils and lymphocytes.
- Ancillary/Molecular: Strong and diffuse immunohistochemical expression of CD34 and PDGFRA; most cases harbor activating mutations in PDGFRA (Exon 18 in stomach, Exon 12 in small intestine).
Inflammatory fibroid polyp of the stomach. Polyp formed as a result of submucosal spindle cell proliferation.
Inflammatory Fibroid Polyp. The tumor cells are cytologically bland, with small nuclei.

Q: In the small intestine, a(n) [...] is a well-known lead point for the clinical complication of [...].
Inflammatory fibroid polyp of the small intestine. As is characteristic of small/large bowel inflammatory fibroid polyp, this example shows transmural involvement.
A: inflammatory fibroid polyp; intussusception
Back Extra: Inflammatory fibroid polyp
- Clinical: Benign, rare neoplasm typically found in the gastric antrum (most common) or ileum; small intestinal lesions frequently present with intussusception.
- Microscopic: Hypocellular proliferation of spindled and stellate cells in an edematous or myxoid stroma, often showing characteristic concentric 'onion-skin' whorling around small blood vessels.
- Inflammatory Infiltrate: Characterized by a prominent mixed infiltrate, typically rich in eosinophils and lymphocytes.
- Ancillary/Molecular: Strong and diffuse immunohistochemical expression of CD34 and PDGFRA; most cases harbor activating mutations in PDGFRA (Exon 18 in stomach, Exon 12 in small intestine).
Inflammatory fibroid polyp of the small intestine. As is characteristic of small/large bowel inflammatory fibroid polyp, this example shows transmural involvement.

Q: Immunohistochemically, the [...] is characteristically positive for [...] and negative for KIT (CD117) and DOG1.
Inflammatory fibroid polyp of the stomach. CD34 immunostaining shows a whorled pattern of positive staining.
Inflammatory fibroid polyp. Strong CD34 expression is characteristic of inflammatory fibroid polyp, regardless of location.
Inflammatory fibroid polyp of the stomach. Polyp formed as a result of submucosal spindle cell proliferation.
A: inflammatory fibroid polyp; CD34
Back Extra: Inflammatory fibroid polyp
- Clinical: Benign, rare neoplasm typically found in the gastric antrum (most common) or ileum; small intestinal lesions frequently present with intussusception.
- Microscopic: Hypocellular proliferation of spindled and stellate cells in an edematous or myxoid stroma, often showing characteristic concentric 'onion-skin' whorling around small blood vessels.
- Inflammatory Infiltrate: Characterized by a prominent mixed infiltrate, typically rich in eosinophils and lymphocytes.
- Ancillary/Molecular: Strong and diffuse immunohistochemical expression of CD34 and PDGFRA; most cases harbor activating mutations in PDGFRA (Exon 18 in stomach, Exon 12 in small intestine).
Inflammatory fibroid polyp of the stomach. CD34 immunostaining shows a whorled pattern of positive staining.
Inflammatory fibroid polyp. Strong CD34 expression is characteristic of inflammatory fibroid polyp, regardless of location.
Inflammatory fibroid polyp of the stomach. Polyp formed as a result of submucosal spindle cell proliferation.

Q: A 45-year-old with a colorectal tumor showing medullary architecture and numerous TILs has an IHC profile showing loss of MSH2 and MSH6. The most likely diagnosis is [...].
Medullary carcinoma pattern in Lynch syndrome, characterized by nests of tumour cells with vesicular nuclei and prominent eosinophilic cytoplasm.
MMR IHC: Loss of staining for MSH2 in neoplastic epithelium (stroma serves as internal control).
MMR IHC: Loss of staining for MSH6, secondary to MSH2 loss.
A: Lynch syndrome (MLH1, PMS2, MSH2, MSH6)
Back Extra: Lynch syndrome (MLH1, PMS2, MSH2, MSH6)
- Clinical: Autosomal dominant inheritance of germline pathogenic variants in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM; accounts for ~1 in 30 colorectal carcinomas (CRC).
- Microscopic: Classically associated with 'MSI-H' histology including tumor-infiltrating lymphocytes (TILs), Crohn-like peritumoral reaction, medullary growth, and mucinous/signet-ring differentiation.
- Ancillary: Screening is via MMR immunohistochemistry (IHC) or MSI PCR/NGS; loss of MLH1 requires BRAF V600E or MLH1 promoter methylation testing to exclude sporadic origin.
- Cancer Spectrum: High risk for CRC and endometrial carcinoma (most common extra-colonic site), followed by ovary, stomach, small bowel, and urinary tract.
- Management: Surveillance colonoscopy and aspirin reduce mortality; checkpoint inhibitors (e.g., PD-1 inhibitors) are highly effective in dMMR cases.
Medullary carcinoma pattern in Lynch syndrome, characterized by nests of tumour cells with vesicular nuclei and prominent eosinophilic cytoplasm.
MMR IHC: Loss of staining for MSH2 in neoplastic epithelium (stroma serves as internal control).
MMR IHC: Loss of staining for MSH6, secondary to MSH2 loss.

Q: In the context of [...], the presence of a [...] mutation or [...] in a tumor with MLH1 loss strongly suggests a sporadic rather than germline etiology.
Microsatellite-unstable colorectal adenocarcinoma showing conventional gland-forming histology with abundant tumour-infiltrating lymphocytes (TILs).
Microsatellite-unstable colorectal adenocarcinoma with mucinous features and tumour-infiltrating lymphocytes.
A: Lynch syndrome (MLH1, PMS2, MSH2, MSH6); BRAF V600E; MLH1 promoter methylation
Back Extra: Lynch syndrome (MLH1, PMS2, MSH2, MSH6)
- Clinical: Autosomal dominant inheritance of germline pathogenic variants in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM; accounts for ~1 in 30 colorectal carcinomas (CRC).
- Microscopic: Classically associated with 'MSI-H' histology including tumor-infiltrating lymphocytes (TILs), Crohn-like peritumoral reaction, medullary growth, and mucinous/signet-ring differentiation.
- Ancillary: Screening is via MMR immunohistochemistry (IHC) or MSI PCR/NGS; loss of MLH1 requires BRAF V600E or MLH1 promoter methylation testing to exclude sporadic origin.
- Cancer Spectrum: High risk for CRC and endometrial carcinoma (most common extra-colonic site), followed by ovary, stomach, small bowel, and urinary tract.
- Management: Surveillance colonoscopy and aspirin reduce mortality; checkpoint inhibitors (e.g., PD-1 inhibitors) are highly effective in dMMR cases.
Microsatellite-unstable colorectal adenocarcinoma showing conventional gland-forming histology with abundant tumour-infiltrating lymphocytes (TILs).
Microsatellite-unstable colorectal adenocarcinoma with mucinous features and tumour-infiltrating lymphocytes.

Q: Unlike Lynch syndrome, which is autosomal dominant, [...] is inherited in an [...] pattern.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.
A: Constitutional mismatch repair deficiency syndrome (CMMRD); autosomal recessive
Back Extra: Constitutional mismatch repair deficiency syndrome (CMMRD)
- Clinical: Autosomal recessive syndrome presenting in childhood/adolescence (mean age < 10 years) with high-grade gliomas, T-cell lymphoblastic lymphomas, and early-onset colorectal cancers/adenomas.
- Phenotype: Frequently mimics Neurofibromatosis type 1 (NF1) with café-au-lait macules and other pigmentary skin changes.
- Ancillary (IHC): Unlike Lynch syndrome, CMMRD demonstrates complete loss of the affected MMR protein (MLH1, MSH2, MSH6, or PMS2) in both neoplastic and all non-neoplastic (stromal and immune) cells.
- Genetics: Caused by biallelic (homozygous or compound heterozygous) germline pathogenic variants in mismatch repair genes; tumors are often hypermutated or ultramutated.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.

Q: On immunohistochemistry, the diagnosis of [...] is supported when loss of an MMR protein is observed in [...] cells.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.
A: Constitutional mismatch repair deficiency syndrome (CMMRD); both neoplastic and non-neoplastic (normal)
Back Extra: Constitutional mismatch repair deficiency syndrome (CMMRD)
- Clinical: Autosomal recessive syndrome presenting in childhood/adolescence (mean age < 10 years) with high-grade gliomas, T-cell lymphoblastic lymphomas, and early-onset colorectal cancers/adenomas.
- Phenotype: Frequently mimics Neurofibromatosis type 1 (NF1) with café-au-lait macules and other pigmentary skin changes.
- Ancillary (IHC): Unlike Lynch syndrome, CMMRD demonstrates complete loss of the affected MMR protein (MLH1, MSH2, MSH6, or PMS2) in both neoplastic and all non-neoplastic (stromal and immune) cells.
- Genetics: Caused by biallelic (homozygous or compound heterozygous) germline pathogenic variants in mismatch repair genes; tumors are often hypermutated or ultramutated.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.

Q: Patients with [...] often present with pigmentary skin changes that mimic [...].
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.
A: Constitutional mismatch repair deficiency syndrome (CMMRD); Neurofibromatosis type 1 (NF1)
Back Extra: Constitutional mismatch repair deficiency syndrome (CMMRD)
- Clinical: Autosomal recessive syndrome presenting in childhood/adolescence (mean age < 10 years) with high-grade gliomas, T-cell lymphoblastic lymphomas, and early-onset colorectal cancers/adenomas.
- Phenotype: Frequently mimics Neurofibromatosis type 1 (NF1) with café-au-lait macules and other pigmentary skin changes.
- Ancillary (IHC): Unlike Lynch syndrome, CMMRD demonstrates complete loss of the affected MMR protein (MLH1, MSH2, MSH6, or PMS2) in both neoplastic and all non-neoplastic (stromal and immune) cells.
- Genetics: Caused by biallelic (homozygous or compound heterozygous) germline pathogenic variants in mismatch repair genes; tumors are often hypermutated or ultramutated.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.

Q: In [...], a unique IHC finding in MSH6-deficient cases is the presence of [...], which occur due to somatic reversion.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.
MSH6-proficient crypt foci in an MSH6 CMMRD patient; note the background loss of staining in most crypts and stromal cells, while specific foci show somatic reversion leading to MMR-proficient staining.
A: Constitutional mismatch repair deficiency syndrome (CMMRD); MMR-proficient crypt foci
Back Extra: Constitutional mismatch repair deficiency syndrome (CMMRD)
- Clinical: Autosomal recessive syndrome presenting in childhood/adolescence (mean age < 10 years) with high-grade gliomas, T-cell lymphoblastic lymphomas, and early-onset colorectal cancers/adenomas.
- Phenotype: Frequently mimics Neurofibromatosis type 1 (NF1) with café-au-lait macules and other pigmentary skin changes.
- Ancillary (IHC): Unlike Lynch syndrome, CMMRD demonstrates complete loss of the affected MMR protein (MLH1, MSH2, MSH6, or PMS2) in both neoplastic and all non-neoplastic (stromal and immune) cells.
- Genetics: Caused by biallelic (homozygous or compound heterozygous) germline pathogenic variants in mismatch repair genes; tumors are often hypermutated or ultramutated.
PMS2 CMMRD-associated colonic adenoma: (A) H&E, (B) MLH1 showing retained staining, (C, D) PMS2 immunohistochemistry demonstrating total absence of staining in both the adenoma and the background non-neoplastic epithelial/stromal cells.
MSH6-proficient crypt foci in an MSH6 CMMRD patient; note the background loss of staining in most crypts and stromal cells, while specific foci show somatic reversion leading to MMR-proficient staining.

Q: MUTYH-associated polyposis (MUTYH) is inherited in an [...] pattern, distinguishing it from the autosomal dominant pattern of FAP.
MUTYH-associated polyposis colonic adenocarcinoma. A,B Adenocarcinoma of the ascending colon, with prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates in a 60-year-old woman with MUTYH-associated polyposis.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.
A: autosomal recessive
Back Extra: MUTYH-associated polyposis (MUTYH)
- Clinical: An autosomal recessive disorder caused by germline biallelic pathogenic variants of MUTYH, typically presenting with 10–100 colorectal adenomas and a high lifetime risk (~70%) of colorectal cancer.
- Associated Features: Extra-colonic manifestations include duodenal polyposis (up to 40% of older patients) and sebaceous skin tumours (Muir-Torre syndrome phenotype).
- Microscopic: Colorectal adenocarcinomas in MAP often demonstrate characteristic prominent tumour-infiltrating lymphocytes (TILs) and Crohn-like lymphoid aggregates.
- Ancillary: Diagnostic signatures include somatic G:C>T:A mutations (SBS18/SBS36) and a high frequency of the somatic KRAS p.Gly12Cys variant.
MUTYH-associated polyposis colonic adenocarcinoma. A,B Adenocarcinoma of the ascending colon, with prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates in a 60-year-old woman with MUTYH-associated polyposis.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.

Q: As seen in this specimen from a patient with MUTYH-associated polyposis (MUTYH), the adenocarcinoma characteristically exhibits prominent [...] and Crohn-like lymphoid aggregates.
MUTYH-associated polyposis colonic adenocarcinoma. A,B Adenocarcinoma of the ascending colon, with prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates in a 60-year-old woman with MUTYH-associated polyposis.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.
A: tumour-infiltrating lymphocytes (TILs)
Back Extra: MUTYH-associated polyposis (MUTYH)
- Clinical: An autosomal recessive disorder caused by germline biallelic pathogenic variants of MUTYH, typically presenting with 10–100 colorectal adenomas and a high lifetime risk (~70%) of colorectal cancer.
- Associated Features: Extra-colonic manifestations include duodenal polyposis (up to 40% of older patients) and sebaceous skin tumours (Muir-Torre syndrome phenotype).
- Microscopic: Colorectal adenocarcinomas in MAP often demonstrate characteristic prominent tumour-infiltrating lymphocytes (TILs) and Crohn-like lymphoid aggregates.
- Ancillary: Diagnostic signatures include somatic G:C>T:A mutations (SBS18/SBS36) and a high frequency of the somatic KRAS p.Gly12Cys variant.
MUTYH-associated polyposis colonic adenocarcinoma. A,B Adenocarcinoma of the ascending colon, with prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates in a 60-year-old woman with MUTYH-associated polyposis.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.

Q: The somatic mutation signature characteristic of tumors in MUTYH-associated polyposis (MUTYH) is [...] transversions (SBS18 and SBS36).
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.
A: G:C>T:A
Back Extra: MUTYH-associated polyposis (MUTYH)
- Clinical: An autosomal recessive disorder caused by germline biallelic pathogenic variants of MUTYH, typically presenting with 10–100 colorectal adenomas and a high lifetime risk (~70%) of colorectal cancer.
- Associated Features: Extra-colonic manifestations include duodenal polyposis (up to 40% of older patients) and sebaceous skin tumours (Muir-Torre syndrome phenotype).
- Microscopic: Colorectal adenocarcinomas in MAP often demonstrate characteristic prominent tumour-infiltrating lymphocytes (TILs) and Crohn-like lymphoid aggregates.
- Ancillary: Diagnostic signatures include somatic G:C>T:A mutations (SBS18/SBS36) and a high frequency of the somatic KRAS p.Gly12Cys variant.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.

Q: The detection of a somatic [...] mutation in a colorectal adenocarcinoma should raise suspicion for underlying MUTYH-associated polyposis (MUTYH).
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.
A: KRAS p.Gly12Cys
Back Extra: MUTYH-associated polyposis (MUTYH)
- Clinical: An autosomal recessive disorder caused by germline biallelic pathogenic variants of MUTYH, typically presenting with 10–100 colorectal adenomas and a high lifetime risk (~70%) of colorectal cancer.
- Associated Features: Extra-colonic manifestations include duodenal polyposis (up to 40% of older patients) and sebaceous skin tumours (Muir-Torre syndrome phenotype).
- Microscopic: Colorectal adenocarcinomas in MAP often demonstrate characteristic prominent tumour-infiltrating lymphocytes (TILs) and Crohn-like lymphoid aggregates.
- Ancillary: Diagnostic signatures include somatic G:C>T:A mutations (SBS18/SBS36) and a high frequency of the somatic KRAS p.Gly12Cys variant.
MUTYH-associated polyposis colonic adenocarcinoma. High-power view showing prominent tumour-infiltrating lymphocytes and Crohn-like lymphoid aggregates.

Q: The clinical condition characterized by multiple colonic serrated polyps and an increased risk of colorectal carcinoma (CRC) is known as [...].
Serrated polyposis showing a hyperplastic polyp with preserved crypt architecture and serration in the upper part of the crypts.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
Serrated polyposis: Exophytic traditional serrated adenoma (TSA) with ectopic crypt formations and slit-like serration.
A: Serrated polyposis
Back Extra: Serrated polyposis
- Clinical: Serrated polyposis is the most common colorectal polyposis syndrome, typically diagnosed in patients aged 50–60; it is associated with smoking and high BMI but lacks extracolonic manifestations.
- Microscopic: Characterized by a spectrum of polyps including hyperplastic polyps (~45%), sessile serrated lesions (~34%), conventional adenomas (~17%), and traditional serrated adenomas (~4%).
- Ancillary: The molecular profile mirrors sporadic counterparts, with BRAF mutations present in ~73% of serrated polyps; germline RNF43 variants are identified in <2% of cases.
- Prognosis: Carries a high risk of colorectal carcinoma (CRC) with a prevalence of 16–29%; dysplastic sessile serrated lesions (SSLs) are thought to be the primary precursor for rapid malignant transformation.
Serrated polyposis showing a hyperplastic polyp with preserved crypt architecture and serration in the upper part of the crypts.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
Serrated polyposis: Exophytic traditional serrated adenoma (TSA) with ectopic crypt formations and slit-like serration.

Q: In patients with [...], approximately 73% of the serrated polyps harbor a mutation in the [...] gene.
Serrated polyposis showing a hyperplastic polyp with preserved crypt architecture and serration in the upper part of the crypts.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
A: Serrated polyposis; BRAF
Back Extra: Serrated polyposis
- Clinical: Serrated polyposis is the most common colorectal polyposis syndrome, typically diagnosed in patients aged 50–60; it is associated with smoking and high BMI but lacks extracolonic manifestations.
- Microscopic: Characterized by a spectrum of polyps including hyperplastic polyps (~45%), sessile serrated lesions (~34%), conventional adenomas (~17%), and traditional serrated adenomas (~4%).
- Ancillary: The molecular profile mirrors sporadic counterparts, with BRAF mutations present in ~73% of serrated polyps; germline RNF43 variants are identified in <2% of cases.
- Prognosis: Carries a high risk of colorectal carcinoma (CRC) with a prevalence of 16–29%; dysplastic sessile serrated lesions (SSLs) are thought to be the primary precursor for rapid malignant transformation.
Serrated polyposis showing a hyperplastic polyp with preserved crypt architecture and serration in the upper part of the crypts.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.

Q: Although most cases of [...] have an unknown etiology, rare familial clusters (<2%) are associated with pathogenic germline variants in [...].
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
Serrated polyposis: Sessile serrated lesion with dysplasia showing crowding of crypts lined by dysplastic cells.
A: Serrated polyposis; RNF43
Back Extra: Serrated polyposis
- Clinical: Serrated polyposis is the most common colorectal polyposis syndrome, typically diagnosed in patients aged 50–60; it is associated with smoking and high BMI but lacks extracolonic manifestations.
- Microscopic: Characterized by a spectrum of polyps including hyperplastic polyps (~45%), sessile serrated lesions (~34%), conventional adenomas (~17%), and traditional serrated adenomas (~4%).
- Ancillary: The molecular profile mirrors sporadic counterparts, with BRAF mutations present in ~73% of serrated polyps; germline RNF43 variants are identified in <2% of cases.
- Prognosis: Carries a high risk of colorectal carcinoma (CRC) with a prevalence of 16–29%; dysplastic sessile serrated lesions (SSLs) are thought to be the primary precursor for rapid malignant transformation.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
Serrated polyposis: Sessile serrated lesion with dysplasia showing crowding of crypts lined by dysplastic cells.

Q: The lesion shown in this image from a patient with [...] is a sessile serrated lesion, identified by its characteristically distorted crypts with [...].
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.
A: Serrated polyposis; dilatation of the base
Back Extra: Serrated polyposis
- Clinical: Serrated polyposis is the most common colorectal polyposis syndrome, typically diagnosed in patients aged 50–60; it is associated with smoking and high BMI but lacks extracolonic manifestations.
- Microscopic: Characterized by a spectrum of polyps including hyperplastic polyps (~45%), sessile serrated lesions (~34%), conventional adenomas (~17%), and traditional serrated adenomas (~4%).
- Ancillary: The molecular profile mirrors sporadic counterparts, with BRAF mutations present in ~73% of serrated polyps; germline RNF43 variants are identified in <2% of cases.
- Prognosis: Carries a high risk of colorectal carcinoma (CRC) with a prevalence of 16–29%; dysplastic sessile serrated lesions (SSLs) are thought to be the primary precursor for rapid malignant transformation.
Serrated polyposis: Sessile serrated lesion showing distorted crypts with dilatation of the base.

Q: In the context of anal squamous intraepithelial neoplasia, a large exophytic mass with pushing borders and koilocytes (as seen in giant condyloma) is distinguished from verrucous carcinoma by the presence of [...].
Giant condyloma (Buschke–Löwenstein tumour). Large condyloma with pushing border, parakeratosis, hyperkeratosis, and koilocytosis. The presence of koilocytes distinguish this large mass from verrucous carcinoma.
A: koilocytes
Back Extra: Anal squamous intraepithelial neoplasia
- Clinical: HPV-associated neoplasm of the anal canal and perianal region; low-risk HPV (6, 11) causes LSIL/condyloma, while high-risk HPV (16, 18) causes HSIL, a precursor to invasive squamous cell carcinoma.
- Micro (LSIL): Low-grade squamous intraepithelial lesion (LSIL/AIN I) is characterized by cytological atypia and mitoses limited to the lower third of the epithelium, often accompanied by koilocytotic atypia.
- Micro (HSIL): High-grade squamous intraepithelial lesion (HSIL/AIN II/III) shows marked atypia involving at least two-thirds of the epithelium, including mitoses in the upper zones and loss of nuclear polarity.
- Ancillary: Strong, continuous block-like p16 expression is an essential criterion for the diagnosis of HSIL and helps distinguish it from reactive squamous metaplasia or atrophy.
Giant condyloma (Buschke–Löwenstein tumour). Large condyloma with pushing border, parakeratosis, hyperkeratosis, and koilocytosis. The presence of koilocytes distinguish this large mass from verrucous carcinoma.

Q: To confirm a diagnosis of HSIL in anal squamous intraepithelial neoplasia, the immunohistochemical marker [...] must show strong, continuous block-like staining.
Anal high-grade squamous intraepithelial lesion (AIN II/III). It exhibits full-thickness involvement by hyperchromatic cells with a high N:C ratio and mitotic figures in the upper epithelial zones.
Anal high-grade squamous intraepithelial lesion (AIN II/III). B Immunohistochemical stain for p16 exhibits strong, diffuse block positive expression.
A: p16
Back Extra: Anal squamous intraepithelial neoplasia
- Clinical: HPV-associated neoplasm of the anal canal and perianal region; low-risk HPV (6, 11) causes LSIL/condyloma, while high-risk HPV (16, 18) causes HSIL, a precursor to invasive squamous cell carcinoma.
- Micro (LSIL): Low-grade squamous intraepithelial lesion (LSIL/AIN I) is characterized by cytological atypia and mitoses limited to the lower third of the epithelium, often accompanied by koilocytotic atypia.
- Micro (HSIL): High-grade squamous intraepithelial lesion (HSIL/AIN II/III) shows marked atypia involving at least two-thirds of the epithelium, including mitoses in the upper zones and loss of nuclear polarity.
- Ancillary: Strong, continuous block-like p16 expression is an essential criterion for the diagnosis of HSIL and helps distinguish it from reactive squamous metaplasia or atrophy.
Anal high-grade squamous intraepithelial lesion (AIN II/III). It exhibits full-thickness involvement by hyperchromatic cells with a high N:C ratio and mitotic figures in the upper epithelial zones.
Anal high-grade squamous intraepithelial lesion (AIN II/III). B Immunohistochemical stain for p16 exhibits strong, diffuse block positive expression.

Q: A biopsy of anal squamous intraepithelial neoplasia showing hyperchromatic cells with a high N:C ratio and mitoses involving the full thickness of the epithelium (as seen in image 49758) is best classified as [...].
Anal high-grade squamous intraepithelial lesion (AIN II/III). It exhibits full-thickness involvement by hyperchromatic cells with a high N:C ratio and mitotic figures in the upper epithelial zones.
A: High-grade squamous intraepithelial lesion (HSIL)
Back Extra: Anal squamous intraepithelial neoplasia
- Clinical: HPV-associated neoplasm of the anal canal and perianal region; low-risk HPV (6, 11) causes LSIL/condyloma, while high-risk HPV (16, 18) causes HSIL, a precursor to invasive squamous cell carcinoma.
- Micro (LSIL): Low-grade squamous intraepithelial lesion (LSIL/AIN I) is characterized by cytological atypia and mitoses limited to the lower third of the epithelium, often accompanied by koilocytotic atypia.
- Micro (HSIL): High-grade squamous intraepithelial lesion (HSIL/AIN II/III) shows marked atypia involving at least two-thirds of the epithelium, including mitoses in the upper zones and loss of nuclear polarity.
- Ancillary: Strong, continuous block-like p16 expression is an essential criterion for the diagnosis of HSIL and helps distinguish it from reactive squamous metaplasia or atrophy.
Anal high-grade squamous intraepithelial lesion (AIN II/III). It exhibits full-thickness involvement by hyperchromatic cells with a high N:C ratio and mitotic figures in the upper epithelial zones.

Q: The morphological hallmark of [...] that helps distinguish it from non-dysplastic metaplasia at low power is a lack of [...] and an abrupt transition between cell types.
Low-grade Barrett dysplasia, intestinal type: Evenly spaced tubules lined by hyperchromatic, elongated cells with lack of surface maturation.
Low-grade dysplasia in Barrett oesophagus: Note the abrupt transition between the dysplasia (right) and the non-dysplastic surface (left).
A: Barrett dysplasia; surface maturation
Back Extra: Barrett dysplasia
- Clinical: Barrett dysplasia occurs within metaplastic columnar epithelium of the esophagus; it is the primary determinant for the risk of progression to esophageal adenocarcinoma (OAC).
- Microscopic Features: Characterized by an abrupt transition from non-dysplastic cells, a lack of surface maturation, and variable cytological atypia including hyperchromasia and nuclear enlargement.
- Grading: Graded as Low-grade (LGD) or High-grade (HGD). HGD is defined by marked atypia, architectural complexity (e.g., cribriforming), and loss of nuclear polarity.
- Patterns: Histologic patterns include intestinal (adenoma-like) with goblet cells and gastric/foveolar (non-adenomatous) which can appear deceptively bland.
- Ancillary Studies: Aberrant p53 immunohistochemistry (overexpression or null pattern) is a key diagnostic aid, identifying patients with a significantly higher risk of progression.
Low-grade Barrett dysplasia, intestinal type: Evenly spaced tubules lined by hyperchromatic, elongated cells with lack of surface maturation.
Low-grade dysplasia in Barrett oesophagus: Note the abrupt transition between the dysplasia (right) and the non-dysplastic surface (left).

Q: In the context of [...], a finding of [...] is a critical cytological feature used to upgrade a lesion from low-grade to high-grade dysplasia.
High-grade Barrett dysplasia, intestinal type: Compact crypts with markedly enlarged, hyperchromatic nuclei showing full-thickness stratification and loss of polarity.
Low-grade intestinal-type Barrett dysplasia: Nuclei are arranged perpendicular to the basement membrane with retained polarity.
A: Barrett dysplasia; loss of nuclear polarity
Back Extra: Barrett dysplasia
- Clinical: Barrett dysplasia occurs within metaplastic columnar epithelium of the esophagus; it is the primary determinant for the risk of progression to esophageal adenocarcinoma (OAC).
- Microscopic Features: Characterized by an abrupt transition from non-dysplastic cells, a lack of surface maturation, and variable cytological atypia including hyperchromasia and nuclear enlargement.
- Grading: Graded as Low-grade (LGD) or High-grade (HGD). HGD is defined by marked atypia, architectural complexity (e.g., cribriforming), and loss of nuclear polarity.
- Patterns: Histologic patterns include intestinal (adenoma-like) with goblet cells and gastric/foveolar (non-adenomatous) which can appear deceptively bland.
- Ancillary Studies: Aberrant p53 immunohistochemistry (overexpression or null pattern) is a key diagnostic aid, identifying patients with a significantly higher risk of progression.
High-grade Barrett dysplasia, intestinal type: Compact crypts with markedly enlarged, hyperchromatic nuclei showing full-thickness stratification and loss of polarity.
Low-grade intestinal-type Barrett dysplasia: Nuclei are arranged perpendicular to the basement membrane with retained polarity.

Q: Regarding ancillary tests for [...], aberrant staining for [...] (either strong nuclear overexpression or a null pattern) correlates with TP53 mutation and an increased risk of progression to adenocarcinoma.
High-grade Barrett dysplasia: Complete loss of p53 immunostaining (null pattern).
High-grade Barrett dysplasia: Strong nuclear p53 overexpression (mutant pattern).
A: Barrett dysplasia; p53
Back Extra: Barrett dysplasia
- Clinical: Barrett dysplasia occurs within metaplastic columnar epithelium of the esophagus; it is the primary determinant for the risk of progression to esophageal adenocarcinoma (OAC).
- Microscopic Features: Characterized by an abrupt transition from non-dysplastic cells, a lack of surface maturation, and variable cytological atypia including hyperchromasia and nuclear enlargement.
- Grading: Graded as Low-grade (LGD) or High-grade (HGD). HGD is defined by marked atypia, architectural complexity (e.g., cribriforming), and loss of nuclear polarity.
- Patterns: Histologic patterns include intestinal (adenoma-like) with goblet cells and gastric/foveolar (non-adenomatous) which can appear deceptively bland.
- Ancillary Studies: Aberrant p53 immunohistochemistry (overexpression or null pattern) is a key diagnostic aid, identifying patients with a significantly higher risk of progression.
High-grade Barrett dysplasia: Complete loss of p53 immunostaining (null pattern).
High-grade Barrett dysplasia: Strong nuclear p53 overexpression (mutant pattern).

Q: Consensus diagnosis of [...] is recommended because high-grade dysplasia progresses to esophageal adenocarcinoma at a rate of approximately [...] per patient-year.
High-grade Barrett dysplasia, intestinal type: Compact crypts with markedly enlarged, hyperchromatic nuclei showing full-thickness stratification and loss of polarity.
High-grade Barrett dysplasia, foveolar type: Markedly atypical epithelium with pleomorphism, loss of polarity, and increased mitoses.
A: Barrett dysplasia; 6.6%
Back Extra: Barrett dysplasia
- Clinical: Barrett dysplasia occurs within metaplastic columnar epithelium of the esophagus; it is the primary determinant for the risk of progression to esophageal adenocarcinoma (OAC).
- Microscopic Features: Characterized by an abrupt transition from non-dysplastic cells, a lack of surface maturation, and variable cytological atypia including hyperchromasia and nuclear enlargement.
- Grading: Graded as Low-grade (LGD) or High-grade (HGD). HGD is defined by marked atypia, architectural complexity (e.g., cribriforming), and loss of nuclear polarity.
- Patterns: Histologic patterns include intestinal (adenoma-like) with goblet cells and gastric/foveolar (non-adenomatous) which can appear deceptively bland.
- Ancillary Studies: Aberrant p53 immunohistochemistry (overexpression or null pattern) is a key diagnostic aid, identifying patients with a significantly higher risk of progression.
High-grade Barrett dysplasia, intestinal type: Compact crypts with markedly enlarged, hyperchromatic nuclei showing full-thickness stratification and loss of polarity.
High-grade Barrett dysplasia, foveolar type: Markedly atypical epithelium with pleomorphism, loss of polarity, and increased mitoses.

Q: In Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA), the presence of diffuse [...] in the background of the GI tract is a specific clue suggesting a germline variant in the [...] gene.
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. These tumours are morphologically indistinguishable from their sporadic counterparts, although the presence of adjacent interstitial cell of Cajal hyperplasia (ICCH) may be a clue.
A: interstitial cell of Cajal hyperplasia (ICCH); KIT
Back Extra: Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA)
- Clinical Presentation: Autosomal dominant syndrome where KIT variants lead to GISTs, interstitial cell of Cajal hyperplasia (ICCH), and skin/mast cell disorders, while PDGFRA variants lead to gastric GISTs, inflammatory fibroid polyps (IFPs), and fibrous tumours without ICCH or pigmentation issues.
- Morphologic Clues: GISTs are morphologically identical to sporadic counterparts but are typically multifocal; the presence of diffuse background ICCH is a strong indicator of a germline KIT variant.
- Ancillary Testing: Diagnosis requires confirmation of germline pathogenic variants (GPVs) in KIT (usually exons 8, 9, 11, 13, 17) or PDGFRA (usually exons 12, 14, 18).
- Differential Diagnosis: Must be distinguished from SDH-deficient syndromes (which show loss of SDHB expression) and Neurofibromatosis type 1 (which lacks KIT/PDGFRA variants).
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. These tumours are morphologically indistinguishable from their sporadic counterparts, although the presence of adjacent interstitial cell of Cajal hyperplasia (ICCH) may be a clue.

Q: Unlike sporadic cases, the inflammatory fibroid polyps and fibrous tumours seen in the [...]-related Gastrointestinal stromal tumour predisposition syndrome often show an irregular white [...] of the submucosa that extends away from the main lesion.
Inflammatory fibroid polyp arising in the setting of a pathogenic germline variant in PDGFRA exon 18 (p.Asp846Val). The irregular white fibrous thickening of the submucosa that extends away from the inflammatory fibroid polyp is a feature that helps distinguish syndromic from sporadic inflammatory fibroid polyps.
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. A In this patient with a germline pathogenic variant, there are areas of submucosal fibrosis causing bowel wall thickening.
A: PDGFRA; fibrous thickening
Back Extra: Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA)
- Clinical Presentation: Autosomal dominant syndrome where KIT variants lead to GISTs, interstitial cell of Cajal hyperplasia (ICCH), and skin/mast cell disorders, while PDGFRA variants lead to gastric GISTs, inflammatory fibroid polyps (IFPs), and fibrous tumours without ICCH or pigmentation issues.
- Morphologic Clues: GISTs are morphologically identical to sporadic counterparts but are typically multifocal; the presence of diffuse background ICCH is a strong indicator of a germline KIT variant.
- Ancillary Testing: Diagnosis requires confirmation of germline pathogenic variants (GPVs) in KIT (usually exons 8, 9, 11, 13, 17) or PDGFRA (usually exons 12, 14, 18).
- Differential Diagnosis: Must be distinguished from SDH-deficient syndromes (which show loss of SDHB expression) and Neurofibromatosis type 1 (which lacks KIT/PDGFRA variants).
Inflammatory fibroid polyp arising in the setting of a pathogenic germline variant in PDGFRA exon 18 (p.Asp846Val). The irregular white fibrous thickening of the submucosa that extends away from the inflammatory fibroid polyp is a feature that helps distinguish syndromic from sporadic inflammatory fibroid polyps.
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. A In this patient with a germline pathogenic variant, there are areas of submucosal fibrosis causing bowel wall thickening.

Q: To differentiate Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA) from SDH-deficient GIST syndromes, one should perform [...] immunohistochemistry, which will show [...] expression in the KIT/PDGFRA-related tumours.
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. These tumours are morphologically indistinguishable from their sporadic counterparts, although the presence of adjacent interstitial cell of Cajal hyperplasia (ICCH) may be a clue.
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. B In gastrointestinal stromal tumours associated with germline variants of SDHB, expression is preserved.
A: SDHB; preserved (positive)
Back Extra: Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA)
- Clinical Presentation: Autosomal dominant syndrome where KIT variants lead to GISTs, interstitial cell of Cajal hyperplasia (ICCH), and skin/mast cell disorders, while PDGFRA variants lead to gastric GISTs, inflammatory fibroid polyps (IFPs), and fibrous tumours without ICCH or pigmentation issues.
- Morphologic Clues: GISTs are morphologically identical to sporadic counterparts but are typically multifocal; the presence of diffuse background ICCH is a strong indicator of a germline KIT variant.
- Ancillary Testing: Diagnosis requires confirmation of germline pathogenic variants (GPVs) in KIT (usually exons 8, 9, 11, 13, 17) or PDGFRA (usually exons 12, 14, 18).
- Differential Diagnosis: Must be distinguished from SDH-deficient syndromes (which show loss of SDHB expression) and Neurofibromatosis type 1 (which lacks KIT/PDGFRA variants).
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. These tumours are morphologically indistinguishable from their sporadic counterparts, although the presence of adjacent interstitial cell of Cajal hyperplasia (ICCH) may be a clue.
Gastrointestinal stromal tumour arising in the setting of a germline pathogenic variant in KIT. B In gastrointestinal stromal tumours associated with germline variants of SDHB, expression is preserved.

Q: In the context of Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA), the fibrous tumours associated with PDGFRA variants contain spindled cells (telocytes) that typically express [...] but are negative for [...].
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. A In this patient with a germline pathogenic variant, there are areas of submucosal fibrosis causing bowel wall thickening.
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. B CD34 immunohistochemistry highlights normal endothelial cells, and CD34 is positive in the sparse spindled cells (telocytes) in the region of fibrosis.
A: CD34; KIT (CD117)
Back Extra: Gastrointestinal stromal tumour predisposition syndrome (KIT, PDGFRA)
- Clinical Presentation: Autosomal dominant syndrome where KIT variants lead to GISTs, interstitial cell of Cajal hyperplasia (ICCH), and skin/mast cell disorders, while PDGFRA variants lead to gastric GISTs, inflammatory fibroid polyps (IFPs), and fibrous tumours without ICCH or pigmentation issues.
- Morphologic Clues: GISTs are morphologically identical to sporadic counterparts but are typically multifocal; the presence of diffuse background ICCH is a strong indicator of a germline KIT variant.
- Ancillary Testing: Diagnosis requires confirmation of germline pathogenic variants (GPVs) in KIT (usually exons 8, 9, 11, 13, 17) or PDGFRA (usually exons 12, 14, 18).
- Differential Diagnosis: Must be distinguished from SDH-deficient syndromes (which show loss of SDHB expression) and Neurofibromatosis type 1 (which lacks KIT/PDGFRA variants).
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. A In this patient with a germline pathogenic variant, there are areas of submucosal fibrosis causing bowel wall thickening.
Submucosal fibrosis causing areas of thickened bowel in a patient with a germline pathogenic variant in PDGFRA. B CD34 immunohistochemistry highlights normal endothelial cells, and CD34 is positive in the sparse spindled cells (telocytes) in the region of fibrosis.

Q: Multiple endocrine neoplasia type 1 (MEN1) is caused by germline mutations in the [...] gene which encodes the protein [...].
Multiple endocrine neoplasia type 1. Two neuroendocrine microtumours in a patient with multiple endocrine neoplasia type 1.
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.
A: MEN1; menin
Back Extra: Multiple endocrine neoplasia type 1 (MEN1)
- Clinical: Autosomal dominant multicentric syndrome characterized by multifocal neuroendocrine tumors of the pancreas, duodenum, parathyroids, and anterior pituitary.
- Genetics: Caused by germline pathogenic sequence variants in the MEN1 gene, which encodes the tumor suppressor protein menin.
- Microscopic: The hallmark is multifocality; the pancreas typically contains multiple microtumours (<5 mm) alongside larger grossly visible tumours, often producing glucagon, insulin, or pancreatic polypeptide.
- Duodenal/Gastric: Duodenal NETs (often gastrinomas) arise in a background of neuroendocrine cell hyperplasia, while gastric involvement presents as Type 2 ECL-cell NETs driven by gastrin hypersecretion.
- Ancillary: Loss of menin expression via IHC is common but cannot distinguish MEN1 syndrome from the ~40% of sporadic PanNETs that also show MEN1 inactivation.
Multiple endocrine neoplasia type 1. Two neuroendocrine microtumours in a patient with multiple endocrine neoplasia type 1.
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.

Q: In the pancreas of a patient with Multiple endocrine neoplasia type 1 (MEN1), the presence of multifocal neuroendocrine [...] (defined as <0.5 cm) is a pathognomonic histological finding.
Multiple endocrine neoplasia type 1. Two neuroendocrine microtumours in a patient with multiple endocrine neoplasia type 1.
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1. Pancreatic endocrine microtumors in a MEN1
A: microtumours
Back Extra: Multiple endocrine neoplasia type 1 (MEN1)
- Clinical: Autosomal dominant multicentric syndrome characterized by multifocal neuroendocrine tumors of the pancreas, duodenum, parathyroids, and anterior pituitary.
- Genetics: Caused by germline pathogenic sequence variants in the MEN1 gene, which encodes the tumor suppressor protein menin.
- Microscopic: The hallmark is multifocality; the pancreas typically contains multiple microtumours (<5 mm) alongside larger grossly visible tumours, often producing glucagon, insulin, or pancreatic polypeptide.
- Duodenal/Gastric: Duodenal NETs (often gastrinomas) arise in a background of neuroendocrine cell hyperplasia, while gastric involvement presents as Type 2 ECL-cell NETs driven by gastrin hypersecretion.
- Ancillary: Loss of menin expression via IHC is common but cannot distinguish MEN1 syndrome from the ~40% of sporadic PanNETs that also show MEN1 inactivation.
Multiple endocrine neoplasia type 1. Two neuroendocrine microtumours in a patient with multiple endocrine neoplasia type 1.
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1. Pancreatic endocrine microtumors in a MEN1

Q: A clinical diagnosis of Multiple endocrine neoplasia type 1 (MEN1) can be made if a patient presents with at least [...] MEN1-associated tumours (e.g., parathyroid, pituitary, or pancreatic).
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1. Pancreatic endocrine microtumors in a MEN1
A: two
Back Extra: Multiple endocrine neoplasia type 1 (MEN1)
- Clinical: Autosomal dominant multicentric syndrome characterized by multifocal neuroendocrine tumors of the pancreas, duodenum, parathyroids, and anterior pituitary.
- Genetics: Caused by germline pathogenic sequence variants in the MEN1 gene, which encodes the tumor suppressor protein menin.
- Microscopic: The hallmark is multifocality; the pancreas typically contains multiple microtumours (<5 mm) alongside larger grossly visible tumours, often producing glucagon, insulin, or pancreatic polypeptide.
- Duodenal/Gastric: Duodenal NETs (often gastrinomas) arise in a background of neuroendocrine cell hyperplasia, while gastric involvement presents as Type 2 ECL-cell NETs driven by gastrin hypersecretion.
- Ancillary: Loss of menin expression via IHC is common but cannot distinguish MEN1 syndrome from the ~40% of sporadic PanNETs that also show MEN1 inactivation.
Neuroendocrine tumour (NET) in multiple endocrine neoplasia type 1. A neuroendocrine microtumour adjacent to a normal islet in a patient with multiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 1. Pancreatic endocrine microtumors in a MEN1

Q: The pathognomonic histopathologic feature of a Peutz–Jeghers polyp is a(n) [...] of smooth muscle that divides the epithelial compartment into discrete lobules.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.
A: arborizing core
Back Extra: Peutz–Jeghers polyp
- Definition: A non-neoplastic hamartomatous polyp defined by a pathognomonic arborizing core of smooth muscle that organizes the mucosal epithelium into discrete lobules.
- Genetics: Strongly associated with Peutz–Jeghers syndrome (PJS) caused by germline mutations in the STK11 (LKB1) tumor suppressor gene (>90% of cases); sporadic solitary polyps lack these variants.
- Clinical: Syndromic polyps commonly involve the small intestine, often presenting with intussusception. Diagnosis of PJS requires 3+ polyps, or one polyp plus family history, mucocutaneous pigmentation, or a documented STK11 variant.
- Histopathology: Key features include near-normal mucosa divided by muscle bundles. Epithelial misplacement (pseudoinvasion) is common and may extend to the serosa, mimicking well-differentiated invasive carcinoma.
- Prognosis: Syndromic patients have a 6-fold increased risk of malignancy; however, solitary sporadic Peutz–Jeghers polyps do not carry an increased risk of death or malignancy.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.

Q: More than 90% of patients with syndromic Peutz–Jeghers polyps harbor a germline pathogenic variant in the [...] (LKB1) tumor suppressor gene.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.
A: STK11
Back Extra: Peutz–Jeghers polyp
- Definition: A non-neoplastic hamartomatous polyp defined by a pathognomonic arborizing core of smooth muscle that organizes the mucosal epithelium into discrete lobules.
- Genetics: Strongly associated with Peutz–Jeghers syndrome (PJS) caused by germline mutations in the STK11 (LKB1) tumor suppressor gene (>90% of cases); sporadic solitary polyps lack these variants.
- Clinical: Syndromic polyps commonly involve the small intestine, often presenting with intussusception. Diagnosis of PJS requires 3+ polyps, or one polyp plus family history, mucocutaneous pigmentation, or a documented STK11 variant.
- Histopathology: Key features include near-normal mucosa divided by muscle bundles. Epithelial misplacement (pseudoinvasion) is common and may extend to the serosa, mimicking well-differentiated invasive carcinoma.
- Prognosis: Syndromic patients have a 6-fold increased risk of malignancy; however, solitary sporadic Peutz–Jeghers polyps do not carry an increased risk of death or malignancy.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.

Q: In the small intestine, Peutz–Jeghers polyps frequently act as a lead point for [...], which is a clinical hallmark of the syndrome.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.
A: intussusception
Back Extra: Peutz–Jeghers polyp
- Definition: A non-neoplastic hamartomatous polyp defined by a pathognomonic arborizing core of smooth muscle that organizes the mucosal epithelium into discrete lobules.
- Genetics: Strongly associated with Peutz–Jeghers syndrome (PJS) caused by germline mutations in the STK11 (LKB1) tumor suppressor gene (>90% of cases); sporadic solitary polyps lack these variants.
- Clinical: Syndromic polyps commonly involve the small intestine, often presenting with intussusception. Diagnosis of PJS requires 3+ polyps, or one polyp plus family history, mucocutaneous pigmentation, or a documented STK11 variant.
- Histopathology: Key features include near-normal mucosa divided by muscle bundles. Epithelial misplacement (pseudoinvasion) is common and may extend to the serosa, mimicking well-differentiated invasive carcinoma.
- Prognosis: Syndromic patients have a 6-fold increased risk of malignancy; however, solitary sporadic Peutz–Jeghers polyps do not carry an increased risk of death or malignancy.
Peutz–Jeghers polyp: Small intestine lesion showing normal mucosal components organized into lobules by arborizing smooth muscle bundles.

Q: A Peutz–Jeghers polyp is distinguished from a [...] by the fact that the latter shows haphazard smooth muscle proliferation wrapping around individual glands rather than neat sectoral division.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.
Differential diagnosis: Mucosal prolapse polyp showing haphazard smooth muscle branching that wraps around individual colonic crypts.
A: mucosal prolapse polyp
Back Extra: Peutz–Jeghers polyp
- Definition: A non-neoplastic hamartomatous polyp defined by a pathognomonic arborizing core of smooth muscle that organizes the mucosal epithelium into discrete lobules.
- Genetics: Strongly associated with Peutz–Jeghers syndrome (PJS) caused by germline mutations in the STK11 (LKB1) tumor suppressor gene (>90% of cases); sporadic solitary polyps lack these variants.
- Clinical: Syndromic polyps commonly involve the small intestine, often presenting with intussusception. Diagnosis of PJS requires 3+ polyps, or one polyp plus family history, mucocutaneous pigmentation, or a documented STK11 variant.
- Histopathology: Key features include near-normal mucosa divided by muscle bundles. Epithelial misplacement (pseudoinvasion) is common and may extend to the serosa, mimicking well-differentiated invasive carcinoma.
- Prognosis: Syndromic patients have a 6-fold increased risk of malignancy; however, solitary sporadic Peutz–Jeghers polyps do not carry an increased risk of death or malignancy.
Peutz–Jeghers polyp: Higher magnification showing smooth muscle bundles dividing the polyp into discrete lobules without the haphazard entrapment seen in prolapse.
Differential diagnosis: Mucosal prolapse polyp showing haphazard smooth muscle branching that wraps around individual colonic crypts.

Q: In SDH-deficient tumour syndromes, immunohistochemical loss of [...] is the universal hallmark, regardless of which specific subunit gene is mutated.
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern
SDHB-deficient gastrointestinal stromal tumour. SDHB immunohistochemistry in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. For a tumour to be considered truly succinate dehydrogenase–deficient, there should be positive staining in the non-neoplastic endothelial cells, which act as internal positive controls.
A: SDHB
Back Extra: SDH-deficient tumour syndromes
- Genetics: Caused by germline variants in SDH subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) or SDHC promoter hypermethylation (epimutation in Carney triad).
- Clinical Presentation: Characterized by paragangliomas, phaeochromocytomas, gastric GISTs (predominantly pediatric), and renal cell carcinomas.
- Histopathology: GISTs show a characteristic plexiform/multinodular growth pattern, epithelioid morphology, and a high frequency of lymph node metastases.
- Ancillary Studies: Loss of SDHB protein expression by IHC is the diagnostic hallmark; internal positive controls (endothelial cells) are mandatory for interpretation.
- Prognosis: Clinical behavior is not reliably predicted by size or mitotic rate; metastases are common but may follow an indolent course.
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern
SDHB-deficient gastrointestinal stromal tumour. SDHB immunohistochemistry in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. For a tumour to be considered truly succinate dehydrogenase–deficient, there should be positive staining in the non-neoplastic endothelial cells, which act as internal positive controls.

Q: A key microscopic clue to SDH-deficient tumour syndromes in the stomach is the presence of a [...] growth pattern and the frequent finding of [...] metastases.
Lymph node metastasis of succinate dehydrogenase–deficient gastrointestinal stromal tumour (GIST). Lymph node metastases, uncommon in all other GISTs, are very frequent in succinate dehydrogenase–deficient GISTs and are a clue to the diagnosis.
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern
A: plexiform or multinodular; lymph node
Back Extra: SDH-deficient tumour syndromes
- Genetics: Caused by germline variants in SDH subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) or SDHC promoter hypermethylation (epimutation in Carney triad).
- Clinical Presentation: Characterized by paragangliomas, phaeochromocytomas, gastric GISTs (predominantly pediatric), and renal cell carcinomas.
- Histopathology: GISTs show a characteristic plexiform/multinodular growth pattern, epithelioid morphology, and a high frequency of lymph node metastases.
- Ancillary Studies: Loss of SDHB protein expression by IHC is the diagnostic hallmark; internal positive controls (endothelial cells) are mandatory for interpretation.
- Prognosis: Clinical behavior is not reliably predicted by size or mitotic rate; metastases are common but may follow an indolent course.
Lymph node metastasis of succinate dehydrogenase–deficient gastrointestinal stromal tumour (GIST). Lymph node metastases, uncommon in all other GISTs, are very frequent in succinate dehydrogenase–deficient GISTs and are a clue to the diagnosis.
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern

Q: The Carney triad, a component of the SDH-deficient tumour syndromes spectrum, is typically non-hereditary and is caused by postzygotic [...].
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Such tumours are usually epithelioid predominant and demonstrate a lobulated growth pattern.
A: SDHC promoter hypermethylation
Back Extra: SDH-deficient tumour syndromes
- Genetics: Caused by germline variants in SDH subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) or SDHC promoter hypermethylation (epimutation in Carney triad).
- Clinical Presentation: Characterized by paragangliomas, phaeochromocytomas, gastric GISTs (predominantly pediatric), and renal cell carcinomas.
- Histopathology: GISTs show a characteristic plexiform/multinodular growth pattern, epithelioid morphology, and a high frequency of lymph node metastases.
- Ancillary Studies: Loss of SDHB protein expression by IHC is the diagnostic hallmark; internal positive controls (endothelial cells) are mandatory for interpretation.
- Prognosis: Clinical behavior is not reliably predicted by size or mitotic rate; metastases are common but may follow an indolent course.
SDH deficient GIST. SDH deficient GISTs commonly demonstrate a plexiform or multilobulated growth pattern
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Such tumours are usually epithelioid predominant and demonstrate a lobulated growth pattern.

Q: In the context of SDH-deficient tumour syndromes, loss of [...] immunohistochemical expression is specifically seen only when the biallelic inactivation involves that specific subunit.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Such tumours are usually epithelioid predominant and demonstrate a lobulated growth pattern.
SDHB-deficient gastrointestinal stromal tumour. SDHB immunohistochemistry in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. For a tumour to be considered truly succinate dehydrogenase–deficient, there should be positive staining in the non-neoplastic endothelial cells, which act as internal positive controls.
A: SDHA
Back Extra: SDH-deficient tumour syndromes
- Genetics: Caused by germline variants in SDH subunits (SDHA, SDHB, SDHC, SDHD, SDHAF2) or SDHC promoter hypermethylation (epimutation in Carney triad).
- Clinical Presentation: Characterized by paragangliomas, phaeochromocytomas, gastric GISTs (predominantly pediatric), and renal cell carcinomas.
- Histopathology: GISTs show a characteristic plexiform/multinodular growth pattern, epithelioid morphology, and a high frequency of lymph node metastases.
- Ancillary Studies: Loss of SDHB protein expression by IHC is the diagnostic hallmark; internal positive controls (endothelial cells) are mandatory for interpretation.
- Prognosis: Clinical behavior is not reliably predicted by size or mitotic rate; metastases are common but may follow an indolent course.
Succinate dehydrogenase–deficient gastrointestinal stromal tumour. Such tumours are usually epithelioid predominant and demonstrate a lobulated growth pattern.
SDHB-deficient gastrointestinal stromal tumour. SDHB immunohistochemistry in a succinate dehydrogenase–deficient gastrointestinal stromal tumour. For a tumour to be considered truly succinate dehydrogenase–deficient, there should be positive staining in the non-neoplastic endothelial cells, which act as internal positive controls.