Site

ICD-O coding

Subtype(s)

Localization

Clinical features

Epidemiology

Etiology

Pathogenesis

Head and neck

Sinonasal tract and nasopharynx

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

8031/3

None

Paranasal sinuses > nasal cavity > nasopharynx

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

< 10 cases reported

Smoking; rare association with HR-HPV and previous irradiation; nasopharyngeal cases EBV-associated (3 cases)

TP53 mutation; loss of various members of SWI/SNF complex (ARID1A, SMARCA4, and, to a lesser extent, SMARCB1) and of IDH2 have been described; among sinonasal NECs, IDH2-mutated cases are LCNECs and ARID1A-proficient, whereas SCNECs are preferentially ARID1A-mutated and IDH2-proficient

Oropharynx, oral cavity, and salivary glands

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

8031/3

None

Most frequent in tonsil and oropharynx; major salivary glands

Nonspecific symptoms; advanced local and distant disease

< 10 cases reported

Salivary glands: 13 cases reported, all in the parotid and submandibular glands; M > F; mean age: 68 years

Smoking; rare association with HR-HPV and previous irradiation

Salivary glands: unknown

Unknown; salivary glands: some data on p53 and RB1 losses

Hypopharynx, larynx, trachea, and parapharyngeal space

{22082601; 31437725; 22024350; 24596175}

8031/3

None

Larynx (supraglottis/ epiglottis); very rare in other sites

Mostly hoarseness and/or dysphagia

< 50 cases reported (far less common than SCNEC); M > F; mean age: 63 years

90% cigarette smokers; questionable HR-HPV association

Not known

Thorax

Lung

8031/3

None

Most frequent in the peripheral lung

Similar to those of non-small cell lung carcinoma

3% of resected lung carcinomas; M > F; mean age: > 65 years

Highly related to smoking

p53 and RB1 inactivation; mutation of CREBBP, EP300, KMT2A (MLL), FGFR1, STK11, and KEAP1

Thymus

{33555458; 31042566}

8031/3

None

Anterior mediastinum

Half of patients are asymptomatic; symptoms may be chest pain, dyspnoea, superior vena cava syndrome

1 case/20 million individuals; 14–26% of thymic NENs; M > F; median age: 57 years

Unknown

p53 and RB1 inactivation; intermediate or high copy-number instability score is associated with LCNEC

Digestive system

Oesophagus

{23426118}

8031/3

None

Mostly in lower third

Nonspecific mass-related symptoms (dysphagia) and weight loss

Rare; as many as half of all oesophageal NECs; M > F; mean age: 70 years

Possible risk factors: tobacco smoking, alcohol drinking; specifically LCNEC related: gastroesophageal reflux disease

Common TP53 and RB1 mutations

Stomach

{32985687; 28239029; 32985687; 23759931; 33142079}

8031/3

None

Anywhere

Nonspecific mass-related symptoms (dyspepsia) and weight loss

Rare; reported to be more frequent than SCNEC; M > F; median age: 70 years

Possible risk factor: Helicobacter pylori–related atrophic gastritis

Common TP53 mutations; RB1 mutations virtually absent; TP53-wildtype cases may have MSI-H; higher frequency of APC mutations than pulmonary NECs, and lower frequency of KRAS and BRAF mutations than colonic NECs; monoclonal origin in cases with a non-NEC component / MiNEN (sharing altered p53 pathway or MMR defect)

Small intestine and ampulla

{15832081; 22964952}

8031/3

None

Almost exclusively in the ampullary region

Mostly obstructive jaundice in ampullary mass

Rare; reported to be more frequent than SCNEC; M > F; median age: 70 years

Unknown

To be defined; may be related to non-NE epithelial neoplasms of the same anatomical site

Appendix

8031/3

None

Not specifically investigated

Not specifically investigated

These neoplasms are poorly defined in this location and only anecdotal cases are reported

Unknown

Unknown

Colorectum

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

8031/3

None

Roughly equal distribution between right colon and rectosigmoid, rare in left/descending colon

Nonspecific mass-related symptoms

< 1% of all colorectal cancers; no reported sex differences

Possible risk factors: family history of cancer, tobacco smoking, alcohol consumption, and increased body mass index, with the adjusted summary effect estimate of risk (odds ratio) ranging from 0.67 (increased body mass index) to 1.6 (alcohol consumption)

Common mutations in KRAS, TP53, and APC; compared with CRC: higher rate of BRAF p.V600E and distinct methylome; EGFR methylated in NECs but not in CRC (different patterns of response and resistance to targeted therapies); possible deregulation of the RB1/p16 pathway and mutations in FHIT, DCC, SMAD4, and MEN1; a subset of LCNECs have MSI-H; monoclonal origin in cases with a non-NEC component / MiNEN

Liver

{33726764; 27881473; 26184027}

8031/3

None

Anywhere

Nonspecific mass-related symptoms

Extremely rare (0.48% of all hepatic malignancies); metastatic nature must be excluded; almost all occur in association with HCC; combined NEC–intrahepatic cholangiocarcinoma is extremely rare

Unknown; occasional patients have history of viral hepatitis (HCV or HBV)

To be defined

Gallbladder and EHBDs

{32739935; 27888490; 19917473}

8031/3

None

Anywhere in gallbladder (44% in fundus); in EHBDs, more common in distal bile duct

Abdominal pain, jaundice, weight loss, ascites, abdominal distension or mass

< 1% of all malignant gallbladder and EHBD neoplasms; F > M; average age in sixth decade of life

Possible risk factors: gallstones, Clonorchis sinensis infection

Common TP53 and RB1 mutations; other alterations in ERBB4, HRAS, NRG1, HMCN1, and CDH10, fusions of NCAM2::SGCZ and BTG3::CCDC40, and microsatellite instability; no BRAF mutations

Female genital tract

Ovary

{33194158}

8031/3

None

Unspecified

Mass

Extremely rare

Unknown

Unknown

Fallopian tube

{33194158}

8031/3

None

Unspecified

Mass

Extremely rare

Unknown

Unknown

Endometrium

{33194158; 26945341; 32773531}

8031/3

None

Unspecified

Abnormal bleeding

Rare; perimenopausal and postmenopausal women

Unknown

Common defects of MMR; a recent study reported that endometrial NECs may be represented in all four molecular groups defined by TCGA for endometrial carcinomas (POLE; MSI; CN-H; no specific molecular profile), but LCNECs are not represented in the CN-H group

Cervix

{33194158; 20182342; 32408525; 29728073}

8031/3

None

Unspecified

Mass or abnormal bleeding

Rare; premenopausal women

HR-HPV (mostly HPV18 and HPV16)

Unknown

Vagina

{33194158}

8031/3

None

Unspecified

Mass or abnormal bleeding

Extremely rare

Unknown

Unknown

Vulva

{33194158; 32826525}

8031/3

None

Unspecified

Cutaneous nodule

Extremely rare

Unknown

Unknown

Breast

Breast

8031/3

None

Unspecified

No specific differences in presentation from other high-grade carcinomas

Extremely rare

No data on the etiology of NECs; probably the same etiology as other high-grade breast carcinomas

Lack of data

Urinary and male genital tracts

Kidney

{32366387; 29848671}

8031/3

None

Unspecified

Haematuria and/or abdominal pain

Less frequent than SCNEC, < 10 cases reported; M > F; mean age: 52 years

Unknown

Lack of data

Urinary tract

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

8031/3

None

Most frequent in urinary bladder (mostly lateral walls); 4 cases reported in the ureter

Gross haematuria, dysuria, and obstructive symptoms

Extremely rare; far less common than SCNEC; 0.5% of primary urinary bladder malignancies, < 40 cases reported; M > F; mostly elderly patients, but wide age range (20–84 years)

Possible risk factors: environmental exposure, smoking, radiation therapy for previous prostatic cancer

Data aggregated with SCNEC: common TP53 and RB1 mutations; bladder-specific mutations in the TERT promoter

Prostate

{16723845; 30965328; 26885643; 30918106}

8031/3

None

Unspecified

Nonspecific; PSA usually low

Extremely rare; 17 cases reported

Possible risk factor: androgen deprivation therapy

May arise de novo or, more frequently, as a transdifferentiation of androgen-resistant prostate carcinomas; interval between initial diagnosis of conventional prostatic adenocarcinoma and subsequent diagnosis of LCNEC: 2–12 years; biallelic loss of RB1, elevated expression levels of p16 (CDKN2A) and E2F1, loss of expression of AR and of AR-responsive genes (TMPRSS2 and NKX3-1)

Skin

Merkel cell carcinoma

{19395876; 11486166; 22204708; 30067951; 31233624; 33760021; 33932460; 30349028; 31399473}

8247/3

None

Mostly in sun-exposed areas, but can occur anywhere; primary Merkel cell carcinoma of extracutaneous sites may rarely be encountered

Nodule or plaque

Increasing incidence in the USA (2.7%), Australia (1.8%) and Europe (Scotland, 3.8%); from 0.55 to 1.3/100 000 in males and from 0.28 to 0.45/100 000 in females between 1997 and 2016 in the USA

UV radiation exposure or MCPyV

To be defined; low mutation burden in MCPyV+ cases; high mutation burden in MCPyV− cases, with mutation in TP53 (97%), RB1 (80%), NOTCH family (50%), KMT2D (26%), FAT1 (26%), LRP1B (23%), PIK3CA (21%), TERT (15%), and KMT2C (13%)