Site

Macroscopic appearance

Histopathology

IHC

Grading

Cytology

Diagnostic molecular pathology

Diagnostic criteria

Staging

Prognosis

Head and neck

Sinonasal tract and nasopharynx

{30191506; 31186531; 33433884; 22082601; 30191506; 27392929; 26735857; 25727332; 2208260}

Large and destructive mass with haemorrhage and necrosis

LCNEC classic

AE1/AE3, CAM5.2 dot-like or diffuse; variable chromogranin A, synaptophysin, INSM1; p16+

High-grade by definition

Mitotic count not determined

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

To be defined; reported 5-year DFS rate: 50–65%

Oropharynx, oral cavity, salivary glands

{22082601; 22024350; 26735857; 31463946; 30475447; 27818885; 22718848; 33544384; 23953500}

Large and ulcerated mass

Salivary glands: large infiltrative nodules with necrosis and haemorrhage

LCNEC classic

AE1/AE3, CAM5.2 dot-like or diffuse; variable chromogranin A, synaptophysin; p16+

Salivary glands: AE1/AE3, CAM5.2 dot-like or diffuse, high-molecular-weight cytokeratins negative; variable chromogranin A, synaptophysin; p16+, p63−; may be focally CK20+ but always MCPyV−

High-grade by definition

Mitotic count not determined

ISH for high-risk HPV is helpful in the oropharynx and oral cavity

Salivary glands: LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor prognosis

Salivary glands: 5-year DFS rate: 5–20%

Hypopharynx, larynx, trachea, and parapharyngeal space

{22082601; 31437725; 22024350; 24596175; 26611246; 22718848; 22433139; 22430343; 20679623; 20589486}

Fleshy, ulcerated submucosal mass

LCNEC classic

AE1/AE3, CAM5.2 dot-like or diffuse; variable chromogranin A, synaptophysin; p16+

High-grade by definition

Mitotic count > 10 mitoses/2 mm²

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

5-year DFS rate: 15%

Thorax

Lung

Large (average: 30–40 mm) masses, well circumscribed, with necrotic areas

LCNEC classic; combined forms with small cell carcinoma

AE1/AE3, CAM5.2 dot-like or diffuse; variable chromogranin A, synaptophysin; TTF1+ (50% of cases); KIT (CD117) (70%); INSM1

High-grade by definition

Mitotic count > 10 mitoses/2 mm²

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

2-year OS rate: 10% in metastatic disease; 5-year OS rate: 25% in non-metastatic disease; median OS time: 10 months

Thymus

{33555458; 31042566}

Grossly invasive with frequent necrosis and haemorrhage

LCNEC classic; combined forms with small cell carcinoma

AE1/AE3, CAM5.2 dot-like or diffuse; variable chromogranin A, synaptophysin; TTF1 and CD5 generally negative

High-grade by definition

Mitotic count > 10 mitoses/2 mm² (average: 110 mitoses/2 mm²)

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

5-year OS rate: 0–66%

Digestive system

Oesophagus

{23426118}

Exophytic/polypoid or ulcerated

LCNEC classic; may be associated with a non-NE component (squamous cell carcinoma or adenocarcinoma)

AE1/AE3, CAM5.2 dot-like or diffuse; synaptophysin (100%), chromogranin A (60%), p63 (40%), TTF1 (40%), CK8/18 (100%), KIT (CD117) (60%), and p16 (60%)

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Median OS time: 8–15 months

Stomach

{32985687; 28239029; 32985687; 23759931; 33142079}

Large fungating masses deeply infiltrating the wall

LCNEC classic; frequently associated with adenocarcinoma; may be associated with an SCNEC component

AE1/AE3, CAM5.2 dot-like or diffuse; synaptophysin (90%); chromogranin A (85%); ASH1L (32%); TTF1 (35%)

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor prognosis, overlapping with SCNEC; 5-year OS rate: 8–66%

Small intestine and ampulla

{15832081; 22964952}

Large and invasive mass (median size: 25 mm)

LCNEC classic; may be associated with an adenoma or adenocarcinoma

Cytokeratins and general NE markers (no systematic study)

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Median OS time: 11.8 months

Appendix

Not specifically investigated

Not specifically investigated

Not specifically investigated

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Not specifically investigated

Colorectum

{18360283; 24763982; 33197299; 27586204; 31672771; 27048246; 30237525; 25465415; 30022911; 30990915}

Large and invasive mass

LCNEC classic; about half associated with an adenoma and/or adenocarcinoma, rare cases with a squamous cell carcinoma component

91–100% of cases positive for chromogranin and/or synaptophysin

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Ominous outcome related to Ki-67 PI: < 55%, median OS: 25.4 months; > 55%, median OS: 5.3 months; LCNECs with MSI-H may have better OS than non–MSI-H counterparts

Liver

{33726764; 27881473; 26184027}

Typically solitary circumscribed mass with gross necrosis (mean size: 58 mm)

LCNEC classic; typically mixed with non-NEC components (HCC)

Synaptophysin+, chromogranin+/−, hepatocyte markers −, albumin (ISH) −, Ki-67 PI > 80%

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Worse than pure HCC; analysis of a small number of reported cases revealed a 1-year cumulative survival rate of 53%

Gallbladder and EHBDs

{32739935; 27888490; 19917473}

Solid mass with necrotic areas; diameter: 2.2–30 mm in EHBDs, 35–56 mm in gallbladder NENs

LCNEC classic; one third of cases mixed with adenocarcinoma or SCNEC

AE1/AE3, CAM5.2 dot-like or diffuse; synaptophysin (100%), chromogranin A (53%)

High-grade by definition

Mitotic count > 20 mitoses/2 mm²; Ki-67 PI > 20%

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Median survival time: < 1 year; 5-year OS rate: 20%; 10-year OS rate: 0%

Female genital tract

Ovary

{33194158}

No distinctive macroscopic appearance vs other ovarian carcinomas

LCNEC classic; usually associated with surface epithelial tumours, rarely with teratoma

Variable expression of NE markers and pancytokeratin; PAX8 and WT1 may be positive; ER and PR usually negative

High-grade by definition

Mitotic count > 10 mitoses/2 mm² and frequent necrosis; Ki-67: no cut-off point defined

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor; median OS time: 10 months

Fallopian tube

{33194158}

No distinctive macroscopic appearance vs other carcinomas

LCNEC classic

Variable expression of NE markers and pancytokeratin; PAX8, WT1, ER, and PR usually negative

High-grade by definition

Mitotic count > 10 mitoses/2 mm² and frequent necrosis; Ki-67: no cut-off point defined

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor

Endometrium

{33194158; 26945341; 32773531}

No distinctive macroscopic appearance vs other endometrial carcinomas

LCNEC classic; frequent association with other endometrial cancers (endometrioid, serous)

Variable expression of NE markers and pancytokeratin; p16+/−; MMR abnormalities in 50%

High-grade by definition

Mitotic count > 10 mitoses/2 mm² and frequent necrosis; Ki-67: no cut-off point defined

Pap smear: large cells with prominent nucleoli dispersed as single cells or arranged as loosely cohesive sheets

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor

Cervix

{33194158; 20182342; 32408525; 29728073}

No distinctive macroscopic appearance vs other cervical neoplasms

LCNEC classic; in situ or invasive minor glandular or squamous component

Variable expression of NE markers and pancytokeratin; p16+; CDX2, TTF1, p63, SSTR2A, and SSTR5 may be expressed

High-grade by definition

Mitotic count > 10 mitoses/2 mm² and frequent necrosis; Ki-67: no cut-off point defined

Pap smear: large cells with prominent nucleoli dispersed as single cells or arranged as loosely cohesive sheets

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

5-year survival rate: 14–39%; mean OS time: 40 months

Vagina

{33194158}

No distinctive macroscopic appearance vs other vaginal carcinomas

LCNEC classic

Variable expression of NE markers and pancytokeratin; p16+

High-grade by definition

Mitotic count > 10 mitoses/2 mm² and frequent necrosis; Ki-67: no cut-off point defined

Pap smear: large cells with prominent nucleoli dispersed as single cells or arranged as loosely cohesive sheets

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor

Vulva

{33194158; 32826525}

Nodules with areas of haemorrhage, necrosis, and ulceration

LCNEC classic; MCC

Variable expression of NE markers; TTF1+; CK20−

High-grade by definition

Not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor

Breast

Breast

No distinctive macroscopic appearance vs other breast carcinomas

LCNEC classic

Variable expression of NE markers; GATA3+; variable expression of ER and PR; ERBB2−

High-grade by definition

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Not specifically investigated

Urinary and male genital tracts

Kidney

{32366387; 29848671}

Large, solid mass with frequent necrosis

LCNEC classic

Not specifically investigated

High-grade by definition

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Aggressive with frequent distant metastases

Urinary tract

{32366387; 28638669; 29180607; 33454836; 20164052; 29763719; 33454836; 26308137}

Large, solid, solitary, polypoid, nodular mass with or without ulceration

LCNEC classic; frequently associated with urothelial-derived components

Synaptophysin (92%), chromogranin A (85%), epithelial markers (pancytokeratin, CAM5.2, EMA), p16; TTF1 (< 70%); negative for p63 and GATA3

High-grade by definition

LCNEC classic

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Dismal prognosis, similar to stage-matched urothelial carcinoma

Prostate

{16723845; 30965328; 26885643; 30918106}

Nonspecific

LCNEC classic; sometimes in association with squamous cell carcinoma and adenocarcinoma

Synaptophysin, chromogranin A, epithelial markers (pancytokeratin, CAM5.2, EMA), p16; negative for PSA and AR; AMACR may be positive

High-grade by definition

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; large cells; expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: high Ki-67 PI (> 55%), SSTR2–5

As epithelial malignancies of the site

Poor prognosis; patients with de novo LCNEC mixed with prostatic adenocarcinoma may respond to adjuvant therapy and have a better outcome than those with pure de novo or post–adjuvant therapy LCNEC

Skin

Merkel cell carcinoma

{19395876; 11486166; 30067951; 31233624; 33760021; 33932460; 30349028; 31399473}

Nodule in dermis and/or subcutis with haemorrhage, necrosis, and ulceration

A spectrum of cytological features from small to intermediate and large cells has been described; fine granular salt-and-pepper chromatin pattern; nuclear moulding is uncommon but may be observed; nucleoli are inconspicuous; rosette-like structures may be seen; mitotic figures and apoptotic bodies are numerous

Positive for CK20, AE1/AE3, CAM5.2; negative for CK7; frequently positive for NFP, INSM1; variable expression of other NE markers; positive for CM2B4, if positive for MCPyV; consistently positive for SATB2 and negative for TTF1; may express PAX5

High-grade by definition

Usually not performed / not clinically relevant

No

Essential: poorly differentiated NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers

Desirable: CK20+, NFP+, TTF1−, CK7−; MCPyV+/−

In the skin, specific staging for MCC according to the size of the neoplasm

5-year OS: 51% localized; 35% regional; 14% distant; 5-year disease-specific survival: 30%