sification systems reflect the observation that NETs
consist of a spectrum of disease ranging from indolent, well-differentiated, low-grade tumors to aggressive, poorly differentiated, high-grade tumors.
In general, tumors with a high histologic grade, a
mitotic count > 20 per 10 high-powered fields (HPF),
or a Ki-67 proliferation index of >20% represent aggressive neuroendocrine carcinomas that have a
different natural history and response to treatment
compared to low-grade, well-differentiated tumors.
Well-differentiated NETs can be broadly sub-
classified as either carcinoid or pancreatic NETs.
Carcinoid tumors may arise from multiple different
organ systems and traditionally have been classi-
fied according to site of embryonic origin, namely
foregut (gastric, bronchial), midgut (small intestine,
appendix, proximal large bowel), and hindgut (dis-
tal colon, rectum, genitourinary). While carcinoid
and pancreatic NETs may have similar histologic
characteristics, these 2 tumor subtypes have dif-
ferent biology and respond differently to therapy,
with most therapeutic agents demonstrating higher
response rates in pancreatic NET patients as com-
pared with carcinoid NET patients.
GENETIC BASIS OF NEUROENDOCRINE
There are no established environmental risk
factors for carcinoid tumors, nor has a clear underlying genetic cause for carcinoid tumors been
defined. Most carcinoid tumors occur as nonfamilial (sporadic) tumors. However, several genetic
syndromes, including multiple endocrine neoplasia
type 1 (MEN1), von Hippel-Lindau syndrome, neu-rofibromatosis type 1 (NF- 1), and tuberous sclerosis, have been associated with gastrointestinal
NETs. Although the majority of NETs are sporadic,
the molecular genetics of these tumor susceptibility syndromes provide insight into the genetic
mechanisms of this disease.
MEN1 is an autosomal dominant syndrome char-
acterized by the development of parathyroid and
pituitary adenomas and enteropancreatic NETs.
Table 1. Nomenclature and Classification for Neuroendocrine Tumors
Differentiation Grade Mitotic Count* Ki-67 Index† Traditional ENETS 2,3 WHO4
Well differentiated Low grade (G1) < 2 per 10 HPF ≤2% Carcinoid, islet cell, pancre-
atic (neuro)endocrine tumor
2–20 per 10 HPF 3%–20% Carcinoid, atypical carci-
noid,‡ islet cell, pancreatic
Poorly differentiated High grade (G3) > 20 per 10 HPF >20% Small cell carcinoma Neuroendocrine carcinoma,
Large cell neuroendocrine
grade 3, large cell
ENETS = European Neuroendocrine Tumor Society; WHO = World Health Organization.
*Counted in 10 high-power fields (HPF). High-power field = 2 mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic
density. Cut-offs per AJCC Cancer Staging Manual, 7th ed. 5
†MIB1 antibody; percentage of 2000 tumor cells in areas of highest nuclear labeling. Cut-offs per AJCC Cancer Staging Manual, 7th ed. 5
‡Term "atypical carcinoid" only applies to intermediate-grade NET of the lung.