Site

ICD-O coding

Subtype(s)

Localization

Clinical features

Epidemiology

Etiology

Pathogenesis

Head and neck

Middle ear / external auditory canal

{32851892}

8041/3

None

Middle ear / temporal bone / mastoid

Purulent discharge, pain, haemorrhage

Extremely rare (few case reports)

Unknown

Unknown

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}

8041/3

None

Ethmoid sinus > nasal cavity > maxillary and sphenoidal sinuses > nasopharynx

Nonspecific symptoms; advanced local and distant disease; rare paraneoplastic syndromes; 70% present at stage IV

3% of sinonasal tumours (< 100 case reports); male predominance; sixth decade of life (mean age: 53 years)

Rare association with HR-HPV and previous irradiation; smoking; EBV in nasopharynx (3 cases)

TP53 mutation; loss of members of SWI/SNF complex (ARID1A, SMARCA4, and [less often] SMARCB1) and of IDH2; preferentially ARID1A-mutated and IDH2-proficient; MAML3 and GAS6 mutations (case reports)

Oropharynx, oral cavity and salivary glands

{18038886; 22430343; 22301491; 23838856; 2421566; 24966986; 27392929; 27496009; 27818885; 29093415; 30475447; 31161776; 31463946; 31523135; 31920384; 33694290}

8041/3

None

Tonsil >>> tongue base, tongue

Salivary glands: most frequently in the parotid

Painful mass, nonspecific symptoms; metastases at presentation in 20% of cases

Salivary glands: advanced disease at presentation

Oral cavity: M:F ratio: 1.5:1; mean age: 59 years

Salivary glands: M:F ratio: 3.4:1; mean age: 73 years

Oropharynx: HPV; previous irradiation

Oral cavity: smoking history in 50% of cases

Salivary glands: unknown

Some data on p53 and RB1 loss (salivary glands)

Hypopharynx, larynx, trachea and parapharyngeal space

{22430343; 22433139; 23397781; 23397787; 24596175; 24980293; 25351497; 25457524; 25606844; 26173932; 26611246; 27392929; 27859290; 28559027; 29557536; 29909787; 31161776; 31437725}

8041/3

None

Most frequent in the larynx, supraglottis most commonly

Mostly hoarseness and/or dysphagia

Male predominance (80% of patients are male); mean age: 59 years

90% cigarette smokers; HR-HPV association rare

More commonly TP53 and RB1 alterations

Thorax

Lung

{27873319; 33209646}

8041/3

None

Most frequently central; peripheral in ~5%

Rapid-onset signs and symptoms due to local growth and/or distant spread and/or paraneoplastic syndromes

13% of all lung cancers; most frequent lung NEN; male predominance; seventh decade of life

Strong association with cigarette smoking; secondary forms due to histological transformation of oncogene-addicted non-small cell cancers treated with tyrosine kinase inhibitors

Most frequently mutations and/or deletions in TP53, RB1, LRP1B, KMT2D, and CSMD3; copy-number gains of TERT, SDHA, RICTOR, PIK3CA, and MYC; four major classes based on predominant transcriptional activation of ASCL1, NEUROD1, YAP1, and POU2F3

Thymus

{31042566; 20485130; 29201448}

8041/3

None

Anterior mediastinum

Weight loss, sweating, chest pain, cough, superior vena cava syndrome

1 case/50 million individuals; < 10% of thymus NENs; no sex bias; median age 58 years

Unknown

High chromosomal instability score (vs carcinoids)

Digestive system

Oesophagus

{33847642; 33686305; 33980813}

8041/3

None

> 50% of cases in the lower third

Nonspecific mass-related symptoms (dysphagia) and weight loss

<1% of all digestive NENs; together with LCNEC, 90% of oesophageal NENs; LCNEC/SCNEC prevalence variable; male predominance; mean age: 56 years

Possible risk factors are tobacco smoking, alcohol drinking (no definitive data)

Most frequently TP53 and RB1 (60% and 54%, respectively); NOTCH1/3, PIK3CA, and ATM mutations more frequently than pulmonary SCNEC

Stomach

{33686305; 15226341; 28239029; 33359239; 25465415}

8041/3

None

Potentially arise in any part of stomach, usually in antral and cardiac regions

Nonspecific mass-related symptoms (dyspepsia) and weight loss

20.5% of all digestive NECs; 21% of all gastric NENs; male predominance; mean age: 63 years

More frequent in Japanese people; rare gastric primary MCC associated with MCPyV

Most frequently TP53; other mutations in TSHZ3, SEMA5A, TPH2, SDK1, PLXNA1; RB1 mutations are rare; microsatellite instability in ~10%

Small intestine and ampulla

8041/3

None

Almost exclusively ampullary region

Obstructive effect of mass (mostly obstructive jaundice in ampullary mass)

Rare

Unknown

No studies available

Appendix

{18197972}

8041/3

None

No specific localization

Pain, nausea, and vomiting (simulating appendicitis), or nonspecific mass-related symptoms

Very rare (case reports)

Unknown

No studies available

Colorectum

{33135938; 28059096; 17063080; 29354876; 25465415}

8041/3

None

Colon and rectum, with similar frequency

Nonspecific mass-related symptoms, bleeding, or metastasis-related symptoms; majority of cases are at an advanced metastatic stage at diagnosis

Increasing incidence; ~10% of all extrapulmonary small cell carcinomas; slight male predominance; sixth or seventh decade of life

Unknown (possibly linked to adenocarcinoma)

Usually mutations in TP53 and RB1; other mutations in APC, KRAS, FHIT, DCC, SMAD4, MEN1, BRAF; microsatellite instability in ~10%

Liver

{23280574}

8041/3

None

No specific localization

Nonspecific

Very rare; metastatic nature must be excluded in all cases

Unknown; occasional patients have history of viral hepatitis

No studies available

Gallbladder and bile ducts

{29548338; 28040546; 26208508}

8041/3

None

No specific localization

Abdominal pain, jaundice, weight loss, ascites, abdominal distension or mass; distant metastases including in the CNS

4% of all malignant gallbladder neoplasms; female predominance; seventh decade of life

Close to that of adenocarcinoma, frequently associated with gallstones

Few data; whole-genome sequencing in a metastatic case showed alterations in ERBB4, HRAS, NRG1, HMCN1, CDH10, fusions of NCAM2::SGCZ and BTG3::CCDC40, and microsatellite instability

Female genital tract

Ovary

{24875120; 29621125}

8041/3

None

Bilateral disease in 20–50% of cases

Nonspecific (no hypercalcaemia)

Rare; mean age: 39 years (premenopausal)

Unknown; case reports of SCNEC arising in mature teratomas

No studies available

Fallopian tube

{10053109}

8041/3

None

No specific localization

Nonspecific

Extremely rare (2 out of 105 cases of fallopian tube cancers in one series)

Unknown

No studies available

Endometrium

{24875120; 32773531}

8041/3

None

No specific localization

Abnormal vaginal bleeding, metastasis-related symptoms, paraneoplastic syndromes (retinopathy, Cushing); > 50% are diagnosed at FIGO stages II–IV

Rare, 0.8% of all endometrial carcinomas

Unknown

TP53 and RB1 mutations are rare; most frequently represented among the four TCGA groups are microsatellite instability/hypermutated and no specific molecular profile

Cervix

{24875120; 33888337; 30355937; 33830625}

8041/3

None

No specific localization

Vaginal bleeding/discharge and/or detection of cervical mass; stage I in the majority of cases, but as many as 40% have positive nodal status

1–3% of all cervical malignancies; most frequent NEC of the female genital tract; mean age: 45–50 years

HR-HPV (mostly HPV18) in 50–100% of cases

Most frequently involved pathways are RTK/RAS, PI3K/AKT, p53, and MYC; RB1 loss is rare; rare cases with MSI-H / MMR deficiency; inactivation of p53 and RB1 pathways through HPV-mediated oncogenic mechanisms

Vagina

{33792412; 24875120}

8041/3

None

No specific localization

Vaginal bleeding, mass-related symptoms; Cushing syndrome in case reports

Very rare (~30 case reports); median age: 55 years

Unknown, HPV detected in some cases

NF1 or AR mutations (2 cases analysed)

Vulva

{24875120}

8041/3

SCNEC, classic; MCC

Arise from vulvar skin and rarely from Bartholin gland

Cutaneous nodule(s) with overlying skin erythematous or ulcerated

Rare

MCPyV; higher risk in immunocompromised patients

No studies available

Breast

Breast

{32336623; 33135938; 33584543; 32613538}

8041/3

None

No specific localization

No specific differences in presentation from other high-grade carcinomas

Rare, 0.1% of all breast cancers; 2–10% of all extrapulmonary SCNECs; mean age: < 60 years

Unknown

Frequent mutations in TP53 but not in RB1; PIK3CA mutations in 30%

Urinary and male genital tracts

Kidney

{33477429}

8041/3

None

No specific localization

Haematuria and/or abdominal pain; metastatic disease at diagnosis in ~50% of cases

Rare, < 1% of all renal tumours; median age: 69 years; M:F ratio: 1:1

Unknown

No studies available

Urinary tract

{21567387; 33561506; 31664527; 27698324}

8041/3

None

Most arise in the bladder

Gross haematuria, dysuria, obstructive symptoms including recurrent infections and weight loss; rare paraneoplastic syndromes (hypercalcaemia, Cushing syndrome); organ-confined disease is present in < 50% of cases

< 0.2 cases/100 000 person-years; < 1% of malignant bladder tumours; M:F ratio: 3:1; median age: ~70 years

No specific etiology; most patients report a history of smoking; additional associated factors are bladder stones and chronic cystitis

Mutations in TP53, RB1, CDKN2A, and MDM2, and in chromosome modifiers; TERT promoter mutations very frequent

Prostate

{33664492; 21336263; 18162772; 24323898; 33847621; 33582100}

8041/3

None

No specific localization

Metastatic disease is present in > 70% of patients at diagnosis in de novo cases; PSA: < 10 ng/mL in > 80%; mean age: 68 years

0.5% of all prostate cancer, but up to 10–20% in autopsies of patients who died from castration-resistant prostate cancer

Unknown; frequently occur in patients with castration-resistant prostate cancer (1–300 months after initial adenocarcinoma diagnosis)

RB1 inactivation, PTEN, ERG fusions (50%); increased activity of transcriptional regulators HOXB5, HOXB6, and NR1D2

Testis

{25207197}

8041/3

None

No specific localization

Nonspecific; may be distant metastases at diagnosis

Extremely rare

Unknown; case reports of SCNEC arising in mature teratomas

No studies available