Site

ICD-O coding

Subtype(s)

Localization

Clinical features

Epidemiology

Etiology

Pathogenesis

Head and neck

Middle ear

{12011260; 15053292; 15825200; 16148713; 19303146; 20111612; 22623086; 22935814; 24766278; 25400805; 25992031; 26622884; 27761737; 28611057; 29438167; 30001283; 30069842; 34041698}

8154/3 (MiNEN)

Glandular (adenoma)

Middle ear

Hearing loss, aural fullness, and tonal tinnitus

Rare (< 2% of ear tumours)

Fifth decade of life

Equal sex distribution

Unknown

Unknown

Sinonasal tract

{30001239; 16526967; 29103747; 32138448; 16526967; 19321468; 20961443; 22740238; 23772319; 24944702; 24327102; 24944702}

8154/3 (MiNEN)

IP-SCNEC

ITAC-SCNEC

SCC-SCNEC

AdSC-SCNEC

Nasal cavity, ethmoid sinus, maxillary sinus

Stuffiness, rhinorrhoea, epistaxis, obstruction, pain, mucoid discharge; inappropriate hormone secretion (SIAD) is rare

16% of sinonasal NENs

M > F

Mean age: 58.8 years (range: 22–85 years)

Unknown; no professional exposure to carcinogens

ITAC-NEC: copy-number changes at TP53, MLH3, and KLK3 regions; additional gains and losses at APC, CDK6, DAPK1, TNFRSF1A, CDKN1B, BRCA2, HIC1, BCL2, KLK3, and TIMP3 regions, and aberrant methylation of APC and DAPK1 in the NEC component; no KRAS, BRAF, or TP53 mutations

SCC-NEC: TP53 missense mutation in exon 7, restricted to the NEC component

Oropharynx, oral cavity, and salivary glands

{21997688; 26735857; 27496009; 29556964; 31093350; 33709305}

8154/3 (MiNEN)

SCC-SCNEC

Tonsil

Oropharyngeal mass, neck mass (lymph node metastases)

Very rare

M > F

Mean age: 65.8 years (range: 55–83 years)

High-risk HPV identified in carcinoma

History of smoking in some cases

Unknown

Larynx, hypopharynx, trachea, and parapharyngeal space

{214939; 6299507; 6295589; 2994505; 3033580; 2838769; 1315242; 11130578; 15504064; 16718502; 19930775; 21228933; 24596175; 28430347; 32335641}

8154/3 (MiNEN)

SCC-SCNEC

SCC-NET

More frequently supraglottic

Hoarseness, dysphagia

Very rare

M > F

Mean age: 65.8 years (range: 55–83 years)

Smoking in most patients

Unknown

Thorax

Lung

{2540288; 12218575; 23010092; 23792008; 28203418; 32592985; 33718010; 31775086; 23792008; 26960398; 27507618; 29535388; 32365350; 23689091; 9792054; 29248665; 26027992; 30429033; 33718010; 14652820; 19179901; 21210145; 17784875; 18829487; 27507618; 26960398; 28884744; 33011388; 22103903; 29101056; 6291745; 3002587; 26273331; 9792054; 21427100; 26027992} [[La Rosa S, Simbolo M, Franzi F, et al. Combined adenocarcinoma–atypical carcinoid of the lung. Targeted next-generation sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopathol. 2018 Mar;24(3):120–3. doi:10.1016/j.mpdhp.2018.02.002.]]

8013/3 (combined LCNEC)

8045/3 (combined SCNEC)

8154/3 (MiNEN)

ADC-NEC (SCNEC or LCNEC)

SCC-NEC (SCNEC or LCNEC)

Large cell carcinoma–NEC (SCNEC or LCNEC)

Spindle/giant cell carcinoma–NEC (SCNEC or LCNEC)

ADC-NET

SCC-NET

Similar to pure non-NE types

ADC or SCC-NEC (LCNEC or SCNEC): similar to pure LCNEC (peripheral or central) or SCNEC

Paraneoplastic syndrome described (SIAD, Cushing, etc.)

ADC or SCC-NET: similar pure ADC or SCC

MiNEN with SCNEC component: 2–30% of all SCNECs

MiNEN with LCNEC component: 12–37% of all LCNECs

MiNEN with NET component: only case reports

Similar to that of pure counterparts, with strong association with smoking history

ADC or SCC-NEC (SCNEC or LCNEC): RB1, TP53, KRAS, STK11, KEAP1, and (in SCNEC) EGFR mutations

ADC-NET: KRAS, PAPPA2, NF1, and SMARCA4 mutations

Thymus

[[Travis WD, Brambilla E, Burke AP, et al., editors. WHO classification of tumours of the lung, pleura, thymus and heart. Lyon (France): International Agency for Research on Cancer; 2015. (WHO classification of tumours series, 4th ed.; vol. 7). https://publications.iarc.who.int/17.]] {2222057; 8265883; 18996790}

8013/3 (combined LCNEC)

8045/3 (combined SCNEC)

Thymoma–NEC (SCNEC or LCNEC)

Thymic carcinoma–NEC (SCNEC or LCNEC)

Thymoma–NET

Thymic carcinoma–NET

Similar to pure non-NE types

Thymic epithelial tumour (including thymoma and thymic carcinoma)–NEC (SCNEC or LCNEC) similar to pure LCNEC or SCNEC

Unknown; very rare

Similar to that of pure counterparts, with no established role of smoking in the development

Not properly assessed; probably superimposable to pathogenesis of each counterpart

Digestive system

Oesophagus

{11914632; 28288180; 31963850; 31660035; 31014519; 29050228; 18670347; 29872597; 31134449; 33686305; 32036480}

8154/3

ADC-NEC (SCNEC or LCNEC)

SCC-NEC (SCNEC or LCNEC)

ADC-NET

ADC-NEC: distal oesophagus

SCC-NEC: any location

ADC-NET: distal oesophagus

Same as those of ADC and SCC

0.2–4% of all oesophageal malignancies; 6–16% of all digestive MiNENs

Mean age: 67 years

Probably the same as that of ADC and SCC

TP53 and RB1 mutations, RB1 deletion or LOH, and amplification of PIK3CA, PTEN, KRAS, SOX2, DVL3, and TP63

Stomach

{29592868; 31660035; 16218931; 2776113; 6176315; 2031532; 15792127; 12861036; 11942581; 25342539; 25633872; 9822131; 16167538; 20530158; 21531442; 33142079; 33642833; 32670540}

8140/3

ADC-NEC (SCNEC or LCNEC)

ADC-NET

Anywhere in the stomach

Same as those of ADC

Paraneoplastic symptoms are uncommon

0.16–1.48% of all gastric malignancies; 6–20% of all digestive MiNENs

Mean age: 69 years

Probably the same as that of ADC

ADC-NEC: similar to that of pure ADC

ADC-NET: unknown

Small intestine and ampulla

{32538468}

8154/3

ADC-NEC (SCNEC or LCNEC)

ADC-NET

Most common in duodenum and ampullar region

Same as those of ADC

Paraneoplastic hormonal symptoms are uncommon

5.6% of all digestive MiNENs

Probably the same as that of ADC

ADC-NEC: similar to that of pure ADC

ADC-NET: similar to that of pure ADC (KRAS and TP53 mutation demonstrated in 1 case)

Appendix (goblet cell adenocarcinoma excluded)

{32903647}

8154/3

ADC-NEC (SCNEC or LCNEC)

Anywhere in the appendix

Same as those of ADC, appendicitis

1% of all appendiceal epithelial malignancies

Median age: 57 years (range: 10–89 years)

M:F ratio: 1:1

Majority (86.7%) of patients are White

Probably the same as that of ADC

ADC-NEC: similar to that of pure ADC

Colorectum

{32538468; 25465415; 27586204; 28059096; 25342539; 25633872; 29592868} [[La Rosa S, Simbolo M, Luchini C, et al. MiNENs composed of adenocarcinoma and well differentiated neuroendocrine tumor have a monoclonal origin. Abstracts from USCAP 2020: Endocrine Pathology (565–611). Mod Pathol. 2020;33:720–63.]]

8154/3

ADC-NEC (SCNEC or LCNEC)

ADC-NET

Anywhere in the colon

Same as those of adenocarcinoma

Paraneoplastic hormonal symptoms are uncommon

30% all digestive MiNENs

Median age at diagnosis: 65 years

The same as that of ADC

ADC-NEC: similar to that of pure ADC

ADC-NET: similar to that of pure ADC (KRAS, AKT1, APC, PIK3CA, SMAD4, RB1, and TP53 mutations demonstrated)

Liver

{27169712}

8154/3

HCC-NEC

HCC-NET

CHC-NEC

Anywhere in the liver

Same as those of liver carcinomas

Extremely rare

Unknown

Unclear

Gallbladder and bile ducts

{31981075}

8154/3

ADC-NEC (SCNEC or LCNEC)

ADC-ICPN-NEC (SCNEC or LCNEC)

Anywhere in the gallbladder or biliary tree

Same as those of ADC

Paraneoplastic hormonal symptoms are uncommon

10% of gallbladder carcinomas; 4% of extrahepatic cholangiocarcinomas; 2.4% of all digestive MiNENs

Median age at diagnosis: 65 years (range: 34–85 years); M:F ratio: 1:3.3

Unknown

ADC-NEC: similar to that of pure ADC (TP53 mutation demonstrated)

Female genital tract

Vulva

{32826525}

8154/3

ADC-LCNEC

Labium majus (Bartolini gland)

Vulvar mass

Extremely rare (only 1 case reported)

Unknown

Undefined

Cervix and vagina

{15381906; 16730307; 21965825; 22534245; 23722515; 27532149; 28603541; 33241100}

8154/3

ADC-SCNEC

ADC-LCNEC

SCC-SCNEC

SCC-LCNEC

AdSC-SCNEC

Carcinosarcoma–SCNEC

Mesonephric adenocarcinoma–LCNEC

Adenoid-cystic adenocarcinoma–SCNEC

Mostly in the uterine cervix

Abnormal vaginal bleeding

Very rare; 12–24% of all cervical NENs

In a subset of cases, HPV is involved

Monoclonal origin for the two components has been demonstrated in a few cases

Endometrium

{26945341; 7883422; 3020961; 32773531; 31576694}

8154/3

EC-LCNEC

EC-SCNEC

HGSC-LCNEC

Carcinosarcoma–SCNEC

Everywhere in the endometrial cavity

Abnormal uterine bleeding

Rare in absolute numbers, but about three quarters of endometrial NECs

Unknown

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 MiNENs are not represented in the CN-H group

Ovary

{17460463; 19047907; 33194158; 1384368}

8154/3

MC-LCNEC

EC-LCNEC

EC-SCNEC

HGSC-LCNEC

UC-LCNEC

Both ovaries may be involved

Abdominal/pelvic pain, abdominal/pelvic mass, ascites

Rare in absolute numbers, but about three quarters of ovarian NECs

Unknown

Monoclonal origin for the two components has been demonstrated in a few cases

Urinary and male genital tracts

Kidney

{27169712}

8154/3

UrC-SCNEC

UrC-LCNEC

SCC-SCNEC

PRCC-SCNEC

CCRCC-NET

MiNENs with NEC component are usually located in the renal pelvis

MiNENs with NET (carcinoid) component are usually located in the renal parenchyma

Nonspecific symptoms; rarely, flank mass and haematuria

F > M

Mean age: 60 years (range: 32–84 years)

Unknown

Unknown

Urinary tract

{33454836; 29763719; 29535424}

8154/3

UrC (including subtypes)-SCNEC

ADC-SCNEC

ADC-LCNEC

Most frequent in urinary bladder (mostly lateral and posterior walls)

Haematuria

Rare in absolute numbers but about two thirds of urinary bladder NECs

M > F

Mean age: 68 years

Unknown

To be defined; common TP53 and RB1 mutations; bladder-specific mutations in the TERT promoter

Prostate

{30965328; 24705311; 26885643}

8154/3

Acinar ADC-LCNEC

Acinar ADC-SCNEC

Anywhere in the prostate

Nonspecific symptoms

Rare in absolute numbers; about two thirds of prostatic NECs; seventh decade of life

Unknown

To be defined; common ETS gene fusions; AR, AURKA, and MYCN amplifications

Skin

Skin

{24729037; 9027628; 9808429; 19609205; 26022453; 26099430; 26433246; 25720654; 31759946; 33533503}

8154/3

SCC-MCC

BCC-MCC

Trichoblastoma–MCC

Sebaceous carcinoma–MCC

Sun-damaged skin

SCC-MCC: M > F; mean age: 76.5 years

Rare, unknown incidence

Unknown; MCPyV usually absent

Suggested origin from precursor stem cells located in the hair follicle; TP53 and RB1 mutations