Site

Macroscopic appearance

Histopathology

IHC

Grading

Cytology

Diagnostic molecular pathology

Diagnostic criteria

Staging

Prognosis

Head and neck

Middle ear

{30069842; 22964339; 27166275}

Reddish bulging mass

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1: < 2 mitoses/2 mm²; no necrosis

G2: 2–10 mitoses/2 mm² and/or foci of necrosis

Not clinically relevant

No

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

Desirable: Ki-67 and SSTR2–5

Not performed

Few cases

Sinonasal tract, nasopharynx

{17481837; 29103747; 26830400; 26622884; 30332658; 33474978; 33770323}

n/a

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin, S100

Negative: TTF1

n/a

n/a

No

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

Desirable: Ki-67, SSTR2, and SSTR5

Not performed

Not sufficiently reported

Oropharynx, oral cavity, and salivary glands

{14720139; 21493041; 27840746; 28116178; 22614165; 23456649}

Bulging/palpable mass, 10–50 mm

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

n/a

n/a

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinomas

Not sufficiently reported

Hypopharynx, larynx, trachea, and parapharyngeal space

{12071530; 15053292; 15098009; 15995505; 18617341; 19172557; 20580173; 20961285; 23397781; 24220389; 24596175; 26622884; 26854777; 26886629; 30974468; 31012344; 33167723}

Submucosal polypoid or sessile mass

Classic NE patterns for G1

G2: epithelioid; nested, moulded in some cases; surface involvement; focal necrosis may be seen; mitoses are not defined; spotty necrosis for atypical carcinoid

Positive: pancytokeratin, chromogranin A, synaptophysin, INSM1, various hormones (calcitonin, serotonin, bombesin [GRP], somatostatin)

Negative: TTF1

Mitoses not used at present; tumour necrosis places in G2

n/a

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinomas

5-year survival rates: 80% for G1 typical carcinoid, 50% for G2 atypical carcinoid

Thorax

Lung

Well-circumscribed round to ovoid lesion

Classic NE patterns; spotty necrosis for atypical carcinoid

Positive: pancytokeratin, chromogranin A, synaptophysin, INSM1

TTF1+ in peripheral tumours, TTF1− in central tumours

Typical carcinoid: < 2 mitoses/2 mm²; no necrosis

Atypical carcinoid: 2–10 mitoses/2 mm² and/or foci of necrosis

Tumour cells are discohesive and small, with round, oval, or spindle-shaped nuclei with finely granular chromatin and inconspicuous nucleoli; background is clean

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE lung carcinomas

5-year survival rates: > 90% for typical carcinoid, 60% for atypical carcinoid

Thymus

Most are unencapsulated and either circumscribed or grossly invasive; mean size: 80–100 mm; calcifications are frequent

Classic NE patterns; spotty necrosis for atypical carcinoid

Positive: pancytokeratin, chromogranin A, synaptophysin

Negative: often TTF1

Hormones can be detected

Typical carcinoid: < 2 mitoses/2 mm²; no necrosis

Atypical carcinoid: 2–10 mitoses/2 mm² and/or foci of necrosis

Loose clusters or small strands of tumour cells with indistinct cell borders; cells are uniformly small and round to oval, with scant cytoplasm

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for other non-NE thymic carcinomas

5-year survival rates: 50–70% for typical carcinoid, 20–70% for atypical carcinoid

Digestive system

Oesophagus

Polypoid or nodular submucosal mass; mean size: 24 mm

Classic NE patterns; spotty necrosis rare

Positive: cytokeratin, chromogranin A, synaptophysin, hormones (serotonin, PP, gastrin, enteroglucagon), VMAT2

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Usually not performed / not clinically relevant

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

The same as for non-NE carcinoma

Good prognosis (few reports)

Stomach

Polypoid or nodular lesions; type I and type II ECL -cell NETs are mostly multiple; type III are single

Classic NE patterns; spotty necrosis rare

Positive: pancytokeratin, chromogranin A, synaptophysin, CDX2, SSTR2

ECL-cell NET: VMAT2+ and ghrelin

G-cell NET: gastrin

EC-cell NET: serotonin

D-cell NET: somatostatin

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Usually not performed / not clinically relevant

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

Gastric NET–specific

Largely depends on stage and grade; variable according to type: type I, excellent prognosis; type III, worst; type II, intermediate

Small intestine and ampulla

Submucosal nodules; often multiple; small in the duodenum; larger in the ileum, with muscular wall invasion

Classic NE patterns; usually solid islets; spotty necrosis rare; glandular pattern with psammoma bodies in duodenum (D-cell NETs)

Positive: pancytokeratin, chromogranin A, synaptophysin, CDX2, and SSTR2–5

G-cell NET: gastrin

EC-cell NET: VMAT1 and serotonin

D-cell NET: somatostatin

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Usually not performed / not clinically relevant

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

Duodenal-ileal NET–specific

Largely depends on stage and grade

Ampullary NET: 10-year survival rate of 71%

Benign NET of ileum: 5-year survival rates of 70–100% when localized, 35–60% with distant metastases

Appendix

Well-demarcated yellowish nodules, mostly < 20 mm

Classic NE patterns; usually solid islets (EC-cell NET); trabeculae/glands (L-cell NET)

Positive: pancytokeratin, chromogranin A, synaptophysin, CDX2, and SSTR2

EC-cell NET: serotonin+

L-cell NET: chromogranin A− and enteroglucagon/PYY+

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Usually not performed / not clinically relevant

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

Appendiceal NET–specific

Largely depends on stage and grade; excellent outcome (10-year survival rate of 92%)

Colorectum

Well-demarcated submucosal nodules

Classic NE patterns; usually solid islets (EC-cell NET); trabeculae/glands (L-cell NET)

Positive: pancytokeratin, chromogranin A, synaptophysin, CDX2, and SSTR2

EC-cell NET: serotonin+

L-cell NET: chromogranin A− and enteroglucagon/PYY+ and PAP

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Usually not performed / not clinically relevant

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

Colorectal NET–specific

Largely depends on stage and grade; for low-stage G1–G2, median OS is 30 years (rectum) or 12 years (colon); G3 NET has poor OS (12 months)

Liver

Well-demarcated nodules

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Loose clusters or small strands of tumour cells with indistinct cell borders; cells are uniformly small and round to oval, with scant cytoplasm

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

The same as for non-NE carcinoma

Long survival when amenable for surgery; 18–47% metastatic disease (G2)

Gallbladder and bile ducts

Submucosal nodules

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1: < 2 mitoses/2 mm² and Ki-67 < 3%

G2: 2–20 mitoses/2 mm² and/or Ki-67 3–20%

G3: > 20 mitoses/2 mm² and/or Ki-67 > 20%

Lesions are seldom aspirated

No

Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A or two other NE markers; Ki-67

Desirable: SSTR2, SSTR5

The same as for non-NE carcinoma

Limited data; depends on size (larger tumours extend into the liver); 36% OS at 10 years

Female genital tract

Ovary

{28735441}

Usually a unilateral and small nodule within a dermoid cyst

Classic NE patterns admixed with thyroid follicles (strumal), associated with mucin pools with goblet cells (mucinous)

Positive: pancytokeratin, chromogranin A, synaptophysin

Strumal carcinoids: TTF1+ and thyroglobulin+

Insular carcinoids: CDX2+

Well-differentiated; grade not defined

Seldom undertaken

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Generally excellent

Fallopian tube

Polypoid/nodular lesion

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1 tumours show rare mitotic figures, whereas G2 tumours can show 2–20 mitoses/2 mm² (10 mitoses/10 HPF of 0.5 mm in diameter and 0.2 mm² in area) and foci of necrosis

Seldom undertaken

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Very few studies

Endometrium

{28735441}

Mass

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1 tumours show rare mitotic figures, whereas G2 tumours can show 2–20 mitoses/2 mm² (10 mitoses/10 HPF of 0.5 mm in diameter and 0.2 mm² in area) and foci of necrosis

Seldom undertaken

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Very few studies

Cervix

{28735441}

Polypoid/nodular lesion

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1 tumours show rare mitotic figures, whereas G2 tumours can show 2–20 mitoses/2 mm² (10 mitoses/10 HPF of 0.5 mm in diameter and 0.2 mm² in area) and foci of necrosis

Pap smear: cuboidal/columnar/polygonal cells with variable amounts of pale, granular cytoplasm and monotonous nuclei

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Very few studies

Vagina

{28735441}

Mass

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1 tumours show rare mitotic figures, whereas G2 tumours can show 2–20 mitoses/2 mm² (10 mitoses/10 HPF of 0.5 mm in diameter and 0.2 mm² in area) and foci of necrosis

Seldom undertaken

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Very few studies

Vulva

{28735441}

Mass

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

G1 tumours show rare mitotic figures, whereas G2 tumours can show 2–20 mitoses/2 mm² (10 mitoses/10 HPF of 0.5 mm in diameter and 0.2 mm² in area) and foci of necrosis

Seldom undertaken

No

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

Desirable: Ki-67

The same as for non-NE carcinoma

Very few studies

Breast

Breast

Infiltrating or expansile tumour

Densely cellular, solid nests and trabeculae of spindle to plasmacytoid cells

Positive: pancytokeratin, chromogranin A, synaptophysin, ER (> 90%)

Negative: ERBB2

Nottingham grading G1 or G2

Cell clusters with rigid borders; plasmacytoid aspect; peripheral cytoplasmic granules on Giemsa stain; synaptophysin, chromogranin A, and ER are positive

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinoma

Variable according to grade and stage

Urinary and male genital tracts

Kidney

{33613455; 30732641}

Yellow nodule usually < 80 mm with possible haemorrhage

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

Negative: TTF1

Grade not defined

Seldom undertaken

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinoma

Variable, depends on stage

Urinary tract

{27334654; 33301750}

Small polypoid masses in the bladder neck or trigone

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

Negative: WT1

Grade not defined

Not clinically relevant

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinoma

Rarely muscle-invasive

Prostate

{33301750; 31415779}

Not defined

Not defined

Positive: pancytokeratin, chromogranin A, synaptophysin

Negative: PSA

Immunohistochemistry with chromogranin A or synaptophysin is not recommended in usual prostatic adenocarcinomas

Grade not defined

Seldom undertaken

No

A combination of an NE component (characterized by synaptophysin or chromogranin A immunostaining) and a significant non-NE component

The same as for non-NE carcinoma

Undefined

Testis

{28559773; 26027014; 18316560; 22347748}

Mass; average size: 46 mm

Classic NE patterns

Positive: pancytokeratin, chromogranin A, synaptophysin

Grade not defined

Seldom undertaken

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinoma

Usually excellent; depends on tumour size and stage, and presence of syndrome

Skin

Skin

{28169866}

10–40 mm lesion

Classic NE patterns; evident mitoses; Ki-67: < 20%

Positive: pancytokeratin, chromogranin A, synaptophysin, ER, AR, GCDFP-15, GATA3

Positive/negative: mammaglobin

Grade not defined; considered low-grade

Not clinically relevant

No

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

Desirable: Ki-67, SSTR2, and SSTR5

The same as for non-NE carcinoma

Depends on stage (2 of 11 reported cases had metastases/recurrence)