Table 1.
Characteristics, classification, and grading criteria for NEN.1,2,6-15 Adapted from Nagtegaal et al.6
| NET, G1 | NET, G2 | NET, G3a | NEC, SCNEC | NEC, LCNEC | MiNEN | |
|---|---|---|---|---|---|---|
| Grade | Low | Intermediate | High | Highb | Highb | Variablec |
| Mitotic rate,d mitoses/2 mm2 |
<2 | 2-20 | >20 | >20 | >20 | Variablec |
| Ki-67 index,e % | <3 | 3-20 | >20 | >20 | >20 | Variablec |
| Differentiation | Well differentiated | Well differentiated | Well differentiated | Poorly differentiated | Poorly differentiated | Well or poorly differentiatedc |
| Additional characteristics | Produce secretory granules with high levels of neuroendocrine markers, and are characterized by well-developed “organoid” arrangements or neuroendocrine shape with nesting, trabecular, or gyriform/serpentine growth pattern | Characterized by a sheetlike proliferation pattern, with cells that have irregular nuclei, high mitotic features, fewer cytoplasmic secretory granules, and low levels of neuroendocrine markers | Mixed neuroendocrine and non-neuroendocrine histology | |||
| Commonly associated mutations |
MEN1, DAXX, PTEN, and ATRX, and mTOR family member signaling pathway mutations are observed in pancreatic NETs; NOTCH1 is absent or poorly expressed Some sporadic pancreatic NETs have been shown to harbor germline mutations in the DNA repair genes MUTYH, CHEK2, and BRCA2 |
TP53 or RB1 mutations May also have KRAS and SMAD4 mutations BRAF mutations in colorectal NEC |
NOTCH1 and Hes1 expression is reduced or absent in the neuroendocrine cells, but both expressed in the adenomatous component The most frequent alterations occurred in TP53, RB1, PTEN, APC, PIK3CA, KRAS, BRAF, and MYC |
|||
Only includes gastrointestinal and pancreatic NETs.
Poorly differentiated NEC are not formally graded, but are considered high-grade by definition.
In most MiNENs, both the neuroendocrine and non-neuroendocrine components are poorly differentiated, and the neuroendocrine component has proliferation indices in the same range as other NECs; this MiNEN category allows for one or both components to be well differentiated; when feasible, each component should therefore be graded separately.
Mitotic rates are to be expressed as the number of mitoses/2 mm2 as determined by counting in 50 fields of 0.2 mm2 (i.e., in a total area of 10 mm2).
The Ki-67 proliferation index value is determined by counting at least 500 cells in the regions of highest labelling (hot-spots), which are identified at scanning magnification; the final grade is based on whichever of the 2 proliferation indexes places the neoplasm in the higher-grade category.
Abbreviations: DLL3, delta-like ligand 3; LCNEC, large-cell neuroendocrine carcinoma; MiNEN, mixed neuroendocrine–non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; SCNEC, small-cell neuroendocrine carcinoma.