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Site
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Macroscopic appearance
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Histopathology
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IHC
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Grading
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Cytology
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Diagnostic molecular pathology
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Diagnostic criteria
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Staging
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Prognosis
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Head and neck
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|
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Middle ear
{30001283; 30069842; 26622884; 22777694; 28547535; 33044790}
|
Reddish bulging mass
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Classic NE patterns intermingled with glandular mucous secretion
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Pancytokeratin, chromogranin A, synaptophysin; hindgut NET (including PP, glucagon-related peptides, serotonin, SATB2); luminal PAS and Alcian blue positivity
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G1: < 2 mitoses/2 mm2; no necrosis
G2: not defined yet, but 2–10 mitoses/2 mm2 and/or foci of necrosis
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Not clinically relevant
|
No
|
Essential: NE morphology; diffuse and intense expression of cytokeratin(s) and chromogranin A, synaptophysin, and many peptide hormones or two other NE markers
Desirable: Ki-67 and SSTR2–5
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Not performed
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5-year survival rate, G1: 80–100%; too few but lower for G2
|
|
|
Sinonasal tract
{30001239; 16526967; 29103747; 32138448; 16526967; 19321468; 20961443; 22740238; 23772319; 24944702; 24327102; 24944702}
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Polypoid or fungating, friable, sometimes ulcerated or haemorrhagic mass
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IP: histological features of IP
ITAC: histological features of conventional ITAC
SCC: histological features of conventional SCC
SCNEC: histological features of conventional SCNEC
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ITAC: CK20, CDX2, CEA
SCC: CK5/6, p63, p40
SCNEC: synaptophysin, chromogranin A, TTF1
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ITAC and SCC components: graded as when present as pure forms
NEC component: high-grade by definition
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (CK20, CDX2 or p63, and CK5/6) and ≥ 2 NE markers for the NEC component
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Same as for sinonasal cancer
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3-year OS rate: 40%
3-year DFS rate 26.6%
5-year OS and DFS rate: 0%
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|
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Oropharynx, oral cavity, and salivary glands
{21997688; 27496009}
|
Ulcerated mass
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SCC: histological features of HPV-associated SCC
SCNEC: histological features of conventional SCNEC
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SCC: CK5/6, p63, p40, p16
SCNEC: synaptophysin, chromogranin A, TTF1, p16
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HPV-associated SCC component: histological grading not currently advocated
SCNEC component: high-grade by definition
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (p63, p40, CK5/6, p16) and ≥ 2 NE markers for the NEC component
|
Same as for HPV-positive oropharyngeal cancer
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Mean survival time: 8.4 months (range: 2–12 months)
|
|
|
Larynx, hypopharynx, trachea, and parapharyngeal space
{214939; 6299507; 6295589; 2994505; 3033580; 2838769; 1315242; 11130578; 15504064; 16718502; 19930775; 21228933; 32335641}
|
Same as SCC
|
SCC: histological features of conventional SCC
SCNEC: histological features of conventional SCNEC
NET: histological features of well-differentiated NET
|
SCC: CK5/6, p63, p40
SCNEC: synaptophysin, chromogranin A, calcitonin
NET: synaptophysin, chromogranin A, INSM1, TTF1 (variable)
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SCC component: graded as the done when presented as pure form
SCNEC component: high-grade by definition
NET component: G2: 2–10 mitoses/2 mm2 often with foci of necrosis; Ki-67 generally 3–20%
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (p63, p40, CK5/6) and ≥ 2 NE markers for the NEC component
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Same as for laryngeal cancer
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5-year survival rate: 5–20%
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Thorax
|
|
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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.]]
|
Same as in pure counterparts
|
ADC: histological features of conventional ADC
SCC: histological features of conventional SCC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
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Same immunophenotype as respective pure ADC (CK7, napsin A, TTF1), SCC (p40, CK5/6), and NEC (synaptophysin, chromogranin, OTP, variable TTF1) counterparts; SCNEC component of MiNEN is more likely to be positive for YAP1 than pure SCNEC
|
ADC and SCC components: graded as when present as pure forms
NEC component: high-grade by definition
NET component: TC: < 2 mitoses/2 mm2; no necrosis; AC: 2–10 mitoses/2 mm2 and/or foci of necrosis
|
Same as in pure neoplasm counterparts
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (TTF1. napsin A, p40) and ≥ 2 NE markers for the NEC component
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Same as for other primary lung carcinomas
|
ADC or SCC-SCNEC: clinical outcome is similar to that of pure SCNEC, with some studies suggesting a worse prognosis and/or less chemosensitivity
ADC or SCC-LCNEC: appear to have a more favourable prognosis than pure LCNEC, corresponding to a lower Ki-67 proliferation index in the NE component
ADC-NET: apparently as that of ADC
SCC-NET: apparently as that of SCC
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|
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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}
|
Same as in pure counterparts
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Thymic epithelial tumours: histological features of conventional thymic epithelial tumours
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
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General NE markers (synaptophysin, chromogranin A)
Non-neuroendocrine markers (cytokeratin CAM5.2 or AE1/AE3, CD5, KIT [CD117], p40)
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Thymic epithelial tumours: graded as when present as pure forms
NEC component: high-grade by definition
NET component: TC: < 2 mitoses/2 mm2 and no necrosis; AC: 2–10 mitoses/2 mm2 and/or foci of necrosis
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Same as in pure neoplasm counterparts
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (cytokeratins CAM5.2 or AE1/AE3, CD5, KIT [CD117], p40) and ≥ 2 NE markers for the NE component
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Same as for other primary thymic carcinomas
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No specific papers on the clinical outcome of thymus MiNENs are available; poorly differentiated counterparts (LCNEC, SCNEC) could reasonably be considered to drive MiNEN prognosis
|
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Digestive system
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|
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Oesophagus
{11914632; 28288180; 31963850; 31660035; 31014519; 29050228; 18670347; 29872597; 31134449; 33686305; 32036480}
|
Same as that of SCC or ADC
|
SCC: histological features of conventional SCC
ADC: histological features of conventional ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
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SCC: CK5/6, p63, p40
ADC: CK7, CK19
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1
NET: synaptophysin, chromogranin A
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ADC and SCC components: graded as when present as pure forms
NEC component: high-grade by definition
NET component: graded as G1, G2, or G3 according to proliferative index
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (p63, p40, CK5/6 or CK7, and CK19) and ≥ 2 NE markers for the NE component
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Same as for conventional carcinoma
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Median survival about 6 months depending on tumour stage
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|
|
Stomach
{29592868; 31660035; 16218931; 2776113; 6176315; 2031532; 15792127; 12861036; 11942581; 25342539; 25633872; 9822131; 16167538; 20530158; 21531442; 33142079; 33642833; 32670540}
|
Same as that of ADC
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ADC: histological features of conventional or signet-ring cell ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
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ADC: CK7, CK19
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1+/−
NET: synaptophysin, chromogranin A
|
ADC component: graded as when present as pure forms
NEC component: high-grade by definition
NET component: graded as G1, G2, or G3 according to proliferative index
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
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Same as for gastric ADC
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ADC-NEC: median survival time: 27 months; 5-year survival rate: 8–11% with advanced-stage disease even after surgical resection
ADC-NET: better prognosis than ADC-NEC
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|
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Small intestine and ampulla
{32538468}
|
Same as that of ADC
|
ADC: histological features of conventional or signet-ring cell ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
|
ADC: CK7, CK19
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1+/−
NET: synaptophysin, chromogranin A
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ADC component: graded as when present as pure forms
NEC component: high-grade by definition
NET component: graded as G1, G2, or G3 according to proliferative index
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
|
Same as for small intestinal ADC
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ADC-NEC: mean survival time: 61 months
ADC-NET: better prognosis than ADC-NEC
|
|
|
Appendix (goblet cell adenocarcinoma excluded)
{32903647}
|
Same as that of ADC
|
ADC: histological features of conventional or signet-ring cell ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
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ADC: CK20, CDX2
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1+/−
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ADC component: graded as when present as pure forms
NEC component: high-grade by definition
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for NE component
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Same as for appendiceal ADC
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5-year OS rate: 57.4%
5-year disease-specific survival rate: 36.4%; worse than NET, NEC, and goblet cell adenocarcinoma
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|
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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.]]
|
Same as that of ADC
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ADC: histological features of conventional or signet-ring cell ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
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ADC: CK20, CDX2
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1+/−
NET: synaptophysin, chromogranin A
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ADC component: graded as when present as pure forms
NEC component: high-grade by definition
NET component: graded as G1, G2, or G3 according to proliferative index
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Not clinically relevant
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Not clinically relevant
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Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
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Same as for colonic ADC
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Median OS time: 29.6 months with localized disease
Median OS time of 9.6 months with advance disease
|
|
|
Liver
{27169712}
|
Same as that of HCC or CHC
|
HCC: histological features of conventional HCC
CHC: histological features of conventional CHC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of well-differentiated NET
|
HCC: HepPar1, arginase, GPC3, GS
CHC: CK7
|
HCC and CHC component: graded as when present as pure forms
NEC component: high-grade by definition
NET component: graded as G1, G2, or G3 according to proliferative index
|
Not clinically relevant
|
Not clinically relevant
|
Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
|
Same as for liver cancers
|
No specific information on OS, but these are aggressive neoplasms
|
|
|
Gallbladder and bile ducts
{31981075}
|
Same as that of ADC
|
ADC: histological features of conventional or signet-ring cell ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
|
ADC: EMA, CK7
ICPN: EMA, MUC5A, CK7
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 +/−
|
ADC component: graded as when present as pure forms
NEC component: high-grade by definition
|
Not clinically relevant
|
Not clinically relevant
|
Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
|
Same as for ADC
|
Median OS time of 8.6 months with localized disease
Median OS time of 4.4 months with advance disease
|
|
Female genital tract
|
|
|
Vulva
{32826525}
|
Non-ulcerated nodule, centred in the dermis
|
LCNEC, classic + G2 ADC with intestinal differentiation
|
LCNEC: synaptophysin, chromogranin A, (TTF1−) ADK: CK20, SATB2
|
High-grade
|
Not clinically relevant
|
Not clinically relevant
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers
|
Same as for conventional carcinoma
|
Poor (OS time: 9 months)
|
|
|
Cervix and vagina
{15381906; 16730307; 21965825; 22534245; 23722515; 27532149; 28603541; 33241100}
|
Large invasive mass
|
ADC: histological features of conventional cervical ADC
SCC: histological features of conventional cervical HPV-related or unrelated SCC
AdSC: histological features of conventional cervical AdSC
Carcinosarcoma: histological features of conventional cervical carcinosarcoma
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional SCNEC
|
ADC: CK7, p16
SCC: CK5/6, p63, p40, p16 (if HPV-related)
AdSC: pertinent mixed pattern
Carcinosarcoma: mesenchymal markers in sarcomatous cells; cytokeratins in carcinomatous cells
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 (+/−)
Mesonephric adenocarcinoma: CD10, GATA3
Adenoid-cystic carcinoma: KIT (CD117), myoepithelial markers
|
High-grade
|
Mixed cytology on Pap smear
|
May be high-risk HPV–related
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers
|
Same as for conventional carcinoma
|
Not specifically defined, seems poor and aligned to that of NECs
|
|
|
Endometrium
{26945341; 7883422; 3020961; 32773531; 31576694}
|
Large invasive masses
|
EC: histological features of conventional EC
HGSC: histological features of conventional HGSC
Carcinosarcoma: histological features of conventional endometrial carcinosarcoma
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
|
EC: ER, PR, PAX8
HGSC: WT1, p53, PAX8
Carcinosarcoma: mesenchymal markers in sarcomatous cells; cytokeratins in carcinomatous cells
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 (+/−)
|
High-grade
|
Not clinically relevant
|
Not clinically relevant
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers
|
Same as for conventional carcinoma
|
Prognosis reported to be slightly better than that of stage-matched pure NECs
|
|
|
Ovary
{17460463; 19047907; 33194158; 1384368}
|
Large solid-cystic masses with necrosis and haemorrhage; may be bilateral
|
EC: histological features of conventional EC
HGSC: histological features of conventional HGSC
MC: histological features of conventional ovarian MC
UC: histological features of poorly differentiated carcinoma with no morphologically recognizable differentiation
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
|
EC: ER, PR, PAX8
HGSC: WT1, p53, PAX8
MC: PAX8−/+, ER−, PR−, SATB2−/+, CDX2−/+, napsin A
UC: variable immunophenotype
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 (+/−)
|
High-grade
|
Not clinically relevant
|
Not clinically relevant
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers
|
Same as for conventional carcinoma
|
Not specifically defined, seems poor and aligned to that of NECs
|
|
Urinary and male genital tracts
|
|
|
Kidney
{27169712}
|
Large solid masses with necrosis and haemorrhage
|
UrC: histological features of conventional UrC
SCC: histological features of SCC
CCRCC: histological features of conventional CCRCC
PRCC: histological features of conventional PRCC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
NET: histological features of conventional NET
|
UrC: GATA3, p63, CK7, CK20 focally +, CDX2 focally +
SCC: p63, CK5/6
CCRCC: CD10, vimentin
PRCC: CK7
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 (+/−)
NET: synaptophysin, chromogranin A
|
High-grade (with NEC component)
Intermediate-grade (with NET component)
|
Not clinically relevant
|
Not clinically relevant
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
|
Same as for conventional carcinoma
|
Not specifically defined, seems poor and aligned to that of NECs
|
|
|
Urinary tract
{33454836; 29763719; 29535424}
|
Large exophytic and ulcerated masses
|
UrC: histological features of conventional UrC and its subtypes
ADC: histological features of conventional CCRCC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
|
UrC: GATA3, p63, CK7, CK20 focally +, CDX2 focally +
ADC: CDX2, ADC
SCNEC and LCNEC: synaptophysin, chromogranin A, TTF1 (+/−), p16
|
High-grade
|
Mixed cytology on urinary samples
|
Not clinically relevant
|
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers
|
Same as for conventional carcinoma
|
Significantly stage-related; aligned to that of NECs
|
|
|
Prostate
{30965328; 24705311; 26885643}
|
Large, invasive, frequently locally advanced masses
|
Acinar ADC: histological features of acinar ADC
SCNEC: histological features of conventional SCNEC
LCNEC: histological features of conventional LCNEC
|
Acinar ADC: PSA, AR, ERG, AMACR
SCNEC and LCNEC: synaptophysin, chromogranin A, INSM1, AR−, PSA−, ERG may be +
|
High-grade
|
Not clinically relevant
|
Not clinically relevant
|
No previously diagnosed prostatic ADC treated with androgen deprivation therapy
Two morphologically identifiable malignant components, NE and non-NE
Immunohistochemistry: pertinent non-NE markers for the non-NE component and ≥ 2 NE markers for the NE component
|
Same as for conventional carcinoma
|
Patients with prostatic MiNEN may respond to adjuvant therapy and have a better outcome than those with pure de novo or post–adjuvant therapy LCNEC of the prostate
|
|
Skin
|
|
|
Skin
{24729037; 9027628; 9808429; 19609205; 26022453; 26099430; 26433246; 25720654; 31759946; 33533503}
|
Flesh-coloured or violaceous nodule or plaque
|
SCC: histological features of conventional SCC
BCC: histological features of BCC
MCC: small to intermediate and large cells with nuclei showing a fine granular salt-and-pepper chromatin pattern without nucleoli
|
SCC: CK5/6, p63, p40
BCC: CK5/6, p63, BerEP4, BCL2
MCC: synaptophysin, chromogranin A, CK20, p63 (+/−)
|
High-grade
|
Not clinically relevant
|
Not clinically relevant
|
Mixed tumour morphology
Immunohistochemistry: pertinent non-NE markers for the non-NE component (p40, p63, CK5/6, BerEP4) and ≥ 2 NE markers, CK20, and p63 (+/−) for the MCC component
|
Same as for MCC
|
|