Site

ICD-O coding

Subtype(s)

Localization

Clinical features

Epidemiology

Etiology

Pathogenesis

Head and neck

Middle ear

{30069842; 22964339; 27166275}

8240/3

8249/3

Well-differentiated (G1) and moderately differentiated (G2)

Middle ear and external auditory canal

Hearing loss, aural fullness, tonal tinnitus {30001283}

Exceedingly rare (few reported cases); middle ear tumours account for < 2% of ear tumours; fifth decade of life; M:F ratio: 2:1

Unknown

Unknown

Sinonasal tract, nasopharynx

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

8240/3

8249/3

Well-differentiated (G1) and moderately differentiated (G2) (not recognized reproducibly)

n/a

n/a

Rare to extremely rare; metastasis from gastroenteropancreatic system or lung must be excluded

Unknown

Unknown

Oropharynx, oral cavity, and salivary glands

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

8240/3

8249/3

Well-differentiated (G1) and moderately differentiated (G2)

Base of the tongue; tonsil; uvula; floor of the mouth; retromolar region; sublingual, submandibular, and parotid glands

n/a

Exceedingly rare; 1–2% of salivary gland tumours

Unknown

Unknown

Hypopharynx, larynx, trachea, and parapharyngeal space

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

8240/3

8249/3

Grade 1: typical carcinoid

Grade 2: atypical carcinoid

Grade 3: not recognized by any criteria presently

Supraglottic larynx most commonly

Hoarseness, dysphagia, sore throat, voice changes, haemoptysis, airway obstruction

Rare (< 1% of laryngeal tumours); grade 1, 5%; grade 2, majority; male > female; fifth to seventh decade of life

Association with tobacco smoking

Unknown

Thorax

Lung

8240/3

8249/3

Typical carcinoid, atypical carcinoid

Central or peripheral airways

Asymptomatic or symptoms due to local growth; endocrine hyperfunction syndromes uncommon

< 0.1–1.5 cases/100 000 person-years; < 1% of all lung cancers; mostly typical carcinoid (70–90%); sixth decade of life; female prevalence

Not clear; some arising in DIPNECH and tumourlets; no clear association with smoking

Mutations of MEN1, CBX6 of polycomb repressive complex 1 and EZH2 of polycomb repressive complex 2; alterations of chromatin-remodelling genes

Thymus

8240/3

8249/3

Typical carcinoid, atypical carcinoid

Anterior mediastinum

Local mass symptoms: chest pain, cough, dyspnoea; Cushing syndrome and hypercalcaemia/hypophosphataemia when functioning

2–5% of thymic neoplasms; fifth to sixth decade of life; male prevalence

25% in MEN1

Chromosomal recurrent aberrations occur especially in atypical carcinoids; ATRX/DAXX mutations

Digestive system

Oesophagus

8240/3

8249/3

NET

Lower oesophagus

Incidental at endoscopy

Extremely rare (0.04–1% of all GEP-NENs); sixth to seventh decade of life; no sex bias

Unknown

Unknown

Stomach

8240/3

8249/3

8242/3

8156/3

8153/3

8241/3

ECL-cell NET (type 1 associated with CAG, type 2 associated with ZES/MEN1, type 3 sporadic), D-cell NET, G-cell NET, EC-cell NET

Corpus/fundus (ECL-cell and EC-cell NETs), antrum (G-cell and D-cell NETs)

No specific symptoms; rare ZES due to antral gastrinoma; hypergastrinaemia and low BAO and MAO

0.4 cases/100 000 person-years; seventh decade of life; female predominance; type 1 ECL-cell NETs are the most frequent

Type 1 ECL-cell NET: hypergastrinaemia due to CAG; type 2 ECL-cell NET: ZES-MEN1; type 3 ECL-cell NET: unknown

MEN1 LOH in sporadic ECL-cell NET; MEN1 mutation in type 2 ECL-cell NET

Small intestine and ampulla

8240/3

8249/3

8156/3

8153/3

8241/3

D-cell NET, G-cell NET, EC-cell NET

Duodenum/ampulla (D-cell NET, G-cell NET), ileum (EC-cell NET)

No specific mass-related symptoms; possible transit obstruction and occlusion; vague persisting pain

Hormonal syndromes: ZES by gastrinoma; somatostatinoma syndrome; carcinoid syndrome

1.2 cases/100 000 person-years; sixth to seventh decade of life; no sex bias

Unknown; a minority arise in the setting of hereditary cancer predisposition syndrome, e.g. MEN1, NF1

Duodenum and ampulla: MEN1 mutation; small intestine: chromosome 18 deletion; CpG island methylation; CDKN1B mutation; whole-arm copy-number variations

Appendix

8240/3

8249/3

8241/3

8152/3

EC-cell NET, L-cell NET

Corpus to tip

Nonspecific symptoms; identified incidentally after surgery for appendicitis

0.5–0.6 cases/100 000 person-years; fifth most frequent GEP-NET; third to fourth decade of life, and in children; female prevalence

Unknown

Rare chromosome 18 deletions

Colorectum

8240/3

8249/3

8241/3

8152/3

L-cell NET, EC-cell NET

Anywhere

Nonspecific mass-related symptoms

1.2 cases/100 000 person-years in rectum; 0.2 cases/100 000 person-years in colon; sixth to seventh decade of life; no sex bias

Unknown

Unknown

Liver

8240/3

8249/3

NET

Anywhere

Nonspecific mass-related symptoms

Extremely rare; metastatic nature must be excluded; 0.4% of all resected hepatic primaries

Unknown; occasional patients have history of viral hepatitis

Unknown

Gallbladder and bile ducts

8240/3

NET

Gallbladder > bile ducts

Nonspecific mass-related symptoms

Extremely rare (0.21% of all NETs)

Unknown; some associated with VHL and MEN1

Unknown

Female genital tract

Ovary

{28735441}

9091/1

Carcinoid (insular, trabecular, strumal, mucinous)

Anywhere

Usually an incidental finding in a dermoid cyst

Most common site for NETs in female genital tract; account for approximately 1% of ovarian neoplasms; fifth to sixth decade of life

Usually arise within teratomas; when pure they are considered monodermal teratomas; occasionally arise within other ovarian neoplasms, such as Sertoli–Leydig cell tumour, Brenner tumour, mucinous tumour, yolk sac tumour

Unknown

Fallopian tube

8240/3

8249/3

G1 NET, G2 NET

Anywhere

Usually an incidental finding

Extremely rare

Unknown

Unknown

Endometrium

{28735441}

8240/3

8249/3

G1 NET, G2 NET

Anywhere

Abnormal vaginal bleeding

Extremely rare

Unknown

Unknown

Cervix

{28735441}

8240/3

8249/3

G1 NET, G2 NET

Anywhere

Mass or abnormal vaginal bleeding

Extremely rare

Rare cases associated with HPV infection

Occasionally associated with persistent HPV infection

Vagina

{28735441}

8240/3

8249/3

G1 NET, G2 NET

Anywhere

Mass or abnormal vaginal bleeding

Extremely rare

Unknown

Unknown

Vulva

{28735441}

8240/3

8249/3

G1 NET, G2 NET

Anywhere

Vulvar mass

Extremely rare

Unknown

Unknown

Breast

Breast

8240/3

8249/3

NET; Nottingham grading G1 or G2

Anywhere

Not different from invasive carcinoma NOS; possible ectopic hormone production

Rare (< 1% of breast carcinomas); sixth to seventh decade of life

Probably the same etiology as other ER-positive breast carcinomas

Frequent mutation of FOXA1, TBX3, GATA3, and ARID1A

Urinary and male genital tracts

Kidney

{33613455; 30732641}

8240/3

8249/3

NET

Anywhere in the kidney, with overrepresentation in horseshoe kidneys

Nonspecific mass-related symptoms

Extremely rare

Unknown

Chromosome 3p21 LOH in subsets

Urinary tract

{27334654; 33301750}

8240/3

8249/3

NET

Bladder

Haematuria, irritative voiding symptoms

Few cases described

Unknown

Unknown

Prostate

{33301750; 31415779}

8240/3

8249/3

Not defined

Prostate

Neuroendocrine differentiation frequent in prostate adenocarcinomas

Existence of pure prostate NET is debated

Unknown

Unknown

Testis

{28559773; 26027014; 18316560; 22347748}

8240/3

8249/3

Carcinoid (EC-cell NET)

Left testis; rarely bilateral

Occurs in mature teratoma; enlargement, pain, hydrocoele, and (rarely) cryptorchidism; rare carcinoid syndrome

Rare (1% of testicular tumours); third to fifth decade of life

Unknown

Isochromosome 12p overrepresentation

Skin

Skin

{28169866}

8240/3

8249/3

Carcinoid, NET

Anterior body (chest, abdomen)

Metastasis from gastroenteropancreatic system or lung must be excluded

Extremely rare; sixth to seventh decade of life (range: 40–79 years); no sex bias

Unknown

Unknown