Major pathological features and prognosis of small cell neuroendocrine carcinoma (SCNEC) at various anatomical sitesa
Source:Marco Volante|
Site |
Macroscopic appearance |
Histopathology |
IHC |
Grading |
Cytology |
Diagnostic molecular pathology |
Diagnostic criteria |
Staging |
Prognosis |
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Head and neck |
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Middle ear / external auditory canal {32851892} |
Polypoid mass |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, INSM1 |
High-grade by definition Mitoses not defined |
Not clinically relevant for diagnosis on primary site; for SCNEC classic |
No established role |
Essential: NE morphology, with high-grade cytology, tumour necrosis, and high mitotic count; expression of cytokeratin(s) and NE markers (> 1) in strong and diffuse pattern Desirable: SSTR2–5; high Ki-67 labelling index |
None |
Poor prognosis; no large studies available |
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Sinonasal tract {19157501; 19685359; 21794118; 23740425; 24980293; 25457524; 25727332; 26880574; 27392929; 27529044; 27859290; 27938993; 28932042; 29438167; 29734873; 30248495; 30475447; 31161776; 31186531; 31763323; 32358042; 33090899; 33371727; 33433884} |
Large and destructive mass with haemorrhage and necrosis |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, p16 Variable: chromogranin A, synaptophysin, INSM1 |
High-grade by definition Mitoses not defined |
Not clinically relevant for diagnosis on primary site; SCNEC classic |
No established role |
Essential: NE morphology, with high-grade cytology, tumour necrosis, and high mitotic count; expression of cytokeratin(s) and NE markers (> 1) in strong and diffuse pattern Desirable: SSTR2–5; Ki-67 labelling index |
Non-NE carcinoma |
5-year survival rates as low as 13%; median survival time: 15 months |
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Oropharynx, oral cavity, and salivary glands {18038886; 22430343; 22301491; 23838856; 2421566; 24966986; 27392929; 27496009; 27818885; 29093415; 30475447; 31161776; 31463946; 31523135; 31920384; 33694290} |
Ulcerated mass, rapid clinical presentation Salivary glands: large, infiltrative nodules with necrosis and haemorrhage |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, p16 Variable chromogranin A, synaptophysin, INSM1 Salivary glands: CK20+, MCPyV− |
High-grade by definition Mitoses not defined |
Not clinically relevant for diagnosis on primary site Salivary glands and metastasis deposit: SCNEC classic |
No established role No UV radiation signature ISH for high-risk HPV is helpful |
Essential: NE morphology, with high-grade cytology, tumour necrosis, and high mitotic count; expression of cytokeratin(s) and NE markers (> 1) in strong and diffuse pattern Desirable: SSTR2–5; Ki-67 labelling index |
Non-NE carcinoma |
Most have a poor prognosis, but few cases reported Oral cavity: median OS time of 21 months; 5-year OS rate of 27% Salivary glands: median OS time of 25 months, 5-year OS rate of 33% |
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Hypopharynx, larynx, trachea, and parapharyngeal space {22430343; 22433139; 23397781; 23397787; 24596175; 24980293; 25351497; 25457524; 25606844; 26173932; 26611246; 27392929; 27859290; 28559027; 29557536; 29909787; 31161776; 31437725} |
Fleshy, ulcerated submucosal mass |
SCNEC classic |
Positive: p16 in HPV-associated cases |
High-grade by definition Mitoses not defined |
Not clinically relevant for diagnosis on primary site; for SCNEC classic |
No established role |
Essential: NE morphology, with high-grade cytology, tumour necrosis, and high mitotic count; expression of cytokeratin(s) and NE markers (> 1) in strong and diffuse pattern Desirable: SSTR2–5; Ki-67 labelling index |
Non-NE carcinoma |
70% advanced disease; 5-year OS rate of 5–20% |
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Thorax |
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Lung {27873319; 33209646} |
Typically perihilar mass but peripheral lesions may occur |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, TTF1, INSM1 Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate > 10 mitoses/2 mm2 (average: 60 mitoses/2 mm2); Ki-67: > 50% (average: > 80%) |
SCNEC classic (FNAB, bronchial aspirates and/or brushing) |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: one/two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
2-year OS rate: 10% in metastatic disease; 5-year OS rate: 25% in non-metastatic disease; median OS time: 12.7 months |
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Thymus {31042566; 20485130; 29201448} |
Grossly invasive with frequent necrosis and haemorrhage |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, TTF1 Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate > 10 mitoses/2 mm2 (average: 110 mitoses/2 mm2) |
SCNEC classic (FNAB) |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Epithelial tumours of the thymus |
Median survival time: 13.75 months (range: 13–26 months) |
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Digestive system |
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Oesophagus {33847642; 33686305; 33980813} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, TTF1 in 70% Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
SCNEC classic |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median OS time range: 8–15 months; older age, upper third location, advanced stage, and no surgery or radiotherapy or chemotherapy are adverse prognostic factors |
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Stomach {33686305; 15226341; 28239029; 33359239; 25465415} |
Large fungating masses deeply infiltrating the wall |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, TTF1 in 70% Variable: chromogranin A, synaptophysin, CDX2 |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
SCNEC classic |
Rare MMR-deficient status but potential clinical utility |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Poor prognosis; survival time: a few months (no large studies available) |
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Small intestine and ampulla |
Large and invasive mass (median size: 25 mm) |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Poor prognosis; survival time: a few months (no large studies available) |
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Appendix {18197972} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, TTF1 |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Poor prognosis; no large studies available |
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Colorectum {33135938; 28059096; 17063080; 29354876; 25465415} |
Grossly similar to conventional adenocarcinoma |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, CDX2 (usually) Variable: chromogranin A, synaptophysin, TTF1 |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
Usually not performed / not clinically relevant |
Rare MMR-deficient status but potential clinical utility |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median OS times for patients with extensive and limited disease: 4.04 months and 21.82 months, respectively; administration of chemotherapy and radiotherapy but not surgery are associated with improved survival |
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Liver {23280574} |
Typically a solitary circumscribed mass with gross necrosis |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
SCNEC classic |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median survival time: 2 months |
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Gallbladder and bile ducts {29548338; 28040546; 26208508} |
Solid mass with necrotic areas |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition Mitotic rate: > 20 mitoses/2 mm2; Ki-67: > 20% |
SCNEC classic (brushing) |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median survival time: 3 months |
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Female genital tract |
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Ovary {24875120; 29621125} |
Nonspecific; mean size: 130 mm |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, TTF1 |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
5-year OS rates of 48.6%, 30.7%, 18%, and 12.3% for stages I, II, III, and IV; earlier disease stage and use of CT are associated with lower mortality |
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Fallopian tube {10053109} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Unknown |
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Endometrium {24875120; 32773531} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, p16 MMR abnormalities in 50% |
High-grade by definition |
SCNEC classic (both on smears and on liquid-based cytology samples) |
Rare MMR-deficient status but potential clinical utility |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Mean OS times of 22 and 12 months in early and late stages, respectively |
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Cervix {24875120; 33888337; 30355937; 33830625} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, p16 (in the majority of cases), TTF1 (often) Variable: chromogranin A, synaptophysin, CDX2, p63 |
High-grade by definition |
SCNEC classic (both on smears and on liquid-based cytology samples) |
HPV typing useful |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median OS time of 22–25 months; 5-year OS rate of 35%; adverse prognostic indicators are advanced FIGO stage, larger tumour size, lymph node metastasis, lymphovascular space involvement, parametrial involvement, depth of stromal invasion > 2/3, radiotherapy but not chemotherapy |
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Vagina {33792412; 24875120} |
Nonspecific, also submucosal |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition |
SCNEC classic (both on smears and on liquid-based cytology samples) |
HPV typing useful |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Poor prognosis (mean OS time: 10 months); no large studies available |
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Vulva {24875120} |
Nodules usually predominantly intradermal with areas of haemorrhage, necrosis, and ulceration |
SCNEC classic or MCC morphology |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin TTF1+ in SCNEC classic CK20+ and MCPyV+ in MCC |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Unknown for SCNEC classic; see below for MCC |
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Breast |
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Breast {32336623; 33135938; 33584543; 32613538} |
No distinctive macroscopic appearance compared with other breast carcinomas |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse, ER, PR, AR, GATA3, GCDFP-15 Variable: chromogranin A, synaptophysin Negative: ERBB2 |
High-grade by definition |
SCNEC classic |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median OS time: 3–5 years; 5-year survival rate: 42% |
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Urinary and male genital tracts |
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Kidney {33477429} |
Solid mass with frequent necrosis |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
Median OS time: of 9.3 months |
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Urinary tract {21567387; 33561506; 31664527; 27698324} |
Large, solid, solitary, polypoid, nodular mass with or without ulceration |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, GATA3 (in ~30% of cases), TTF1 (in 40% of cases) |
High-grade by definition |
SCNEC classic (both on smears and on liquid-based cytology samples) |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
5-year OS rate: 8–25% Organ-confined disease and chemotherapy are favourable prognostic factors |
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Prostate {33664492; 21336263; 18162772; 24323898; 33847621; 33582100} |
Nonspecific (rarely surgically resectable) |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin, TTF1 (in 50% of cases), PSA, AR, NKX3-1 (in a minority of cases) |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE carcinoma |
5-year OS rate: 14%; median OS time: 12 months in cases with pure histology |
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Testis {25207197} |
No specific features |
SCNEC classic |
Positive: AE1/AE3, CAM5.2 dot-like or diffuse Variable: chromogranin A, synaptophysin |
High-grade by definition |
Usually not performed / not clinically relevant |
No established role |
Essential: small cell epithelial neoplasm with high-grade features, finely granular nuclear chromatin, and no prominent nucleoli Desirable: two positive NE marker(s); high proliferation index (> 30%, most frequently > 75%); p53 overexpression and/or RB1 loss; SSTR2–5 |
Non-NE tumours |
Poor prognosis |
IHC, immunohistochemistry; ISH, in situ hybridization; LCNEC, large cell neuroendocrine carcinoma; MCC, Merkel cell carcinoma; MCPyV, Merkel cell polyomavirus; MMR, mismatch repair; NE, neuroendocrine; OS, overall survival; TTF1, thyroid transcription factor 1; UV, ultraviolet.
aSee also the relevant site-specific volumes of the WHO Classification of Tumours series: Head and neck tumours [[WHO Classification of Tumours Editorial Board. Head and neck tumours. Lyon (France): International Agency for Research on Cancer; 2024. (WHO classification of tumours series, 5th ed.; vol. 9). https://publications.iarc.who.int/629.]], Thoracic tumours [[WHO Classification of Tumours Editorial Board. Thoracic tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 5). https://publications.iarc.who.int/595.]], Digestive system tumours [[WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1). https://publications.iarc.who.int/579.]], Female genital tumours [[WHO Classification of Tumours Editorial Board. Female genital tumours. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 4). https://publications.iarc.who.int/592.]], Breast tumours [[WHO Classification of Tumours Editorial Board. Breast tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 2). https://publications.iarc.who.int/581.]], Urinary and male genital tumours [[WHO Classification of Tumours Editorial Board. Urinary and male genital tumours. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 8). https://publications.iarc.who.int/610.]], and Skin tumours [[WHO Classification of Tumours Editorial Board. Skin tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed.; vol. 12). https://tumourclassification.iarc.who.int/chapters/64.]].