Neuroendocrine neoplasms

One particularly important change in the 5th edition is in the classification of neuroendocrine neoplasms (NENs), which occur in multiple sites throughout the body. In this volume, NENs are covered within each organ‐specific chapter, including the chapter on tumours of the pancreas, where detailed sections describing each functioning and non‐functioning subtype are provided. Previously, these neoplasms were covered only in the volume on tumours of endocrine organs.2 The general principles guiding the classification of all NENs are presented in a separate introduction to this topic (Table (Table2).2). To consolidate our increased understanding of the genetics of these neoplasms, a group of experts met for a consensus conference at the International Agency for Research on Cancer (IARC) in November 2017 and subsequently published a paper in which they proposed distinguishing between well‐differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) in all sites where these neoplasms arise.3 NEN are divided into NET and NECs, based on their molecular differences. Mutations in MEN1, DAXX and ATRX are entity‐defining for well‐differentiated NETs, whereas NECs usually have TP53 or RB1 mutations. In some cases, these mutations can be of diagnostic benefit. Genomic data have also led to a change in the classification of mixed NENs, which are now grouped into the conceptual category of ‘mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs)’. Mixed adenoneuroendocrine carcinomas (MANECs), which show genomic alterations similar to those of adenocarcinomas or NECs rather than NETs, probably reflect clonal evolution within the tumours, which is a rapidly growing area of interest. The study of these mixed carcinomas may also lead to an improved understanding of other facets of clonality in tumours of the digestive system and other parts of the body.

Table 2

Classification and grading criteria for neuroendocrine neoplasms (NENs) of the GI tract and hepatopancreatobiliary organs

Terminology Differentiation Grade Mitotic rate* (mitoses/2 mm2) Ki‐67 index*
NET, G1 Well differentiated Low <2 <3%
NET, G2 Intermediate 2–20 3–20%
NET, G3 High >20 >20%
NEC, small‐cell type (SCNEC) Poorly differentiated High >20 >20%
NEC, large‐cell type (LCNEC) >20 >20%
MiNEN Well or poorly differentiated Variable Variable Variable

LCNEC, Large‐cell neuroendocrine carcinoma; MiNEN, Mixed neuroendocrine–non‐neuroendocrine neoplasm; NEC, Neuroendocrine carcinoma; NET, Neuroendocrine tumour; SCNEC, Small‐cell neuroendocrine carcinoma.

*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 two proliferation indexes places the neoplasm in the higher‐grade category.
Poorly differentiated NECs 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, but this conceptual category allows for the possibility that one or both components may be well differentiated; when feasible, each component should therefore be graded separately.

Another important change concerns the recognition that well‐differentiated NETs may be high grade (G3 in the WHO grading system, defined as having a mitotic rate >20 per 2 mm2 or Ki67 >20%), but these neoplasms remain well‐differentiated genetically and distinct from poorly differentiated NECs. G3 NETs were first recognised and are most common in the pancreas, but they can occur throughout the GI tract. Thus, the current WHO classification includes three grades (G1, G2 and G3) for NETs. NECs are no longer graded, as they are recognised to be uniformly high grade by definition, but continue to be separated into small‐and large‐cell types.