NcXHF

THE SPECTRUM OF NEUROENDOCRINE TUMORS
TABLE 3. IASLC/WHO Grading System for Pulmonary Neuroendocrine Neoplasms
Neoplasm Morphology Mitoses Necrosis Immunohistochemistry
Typical carcinoid tumor Polygonal cells arranged in nested 2 per 10 HPF Absent Chromogranin, synaptophysin, CD56
or trabecular patterns
(supportive, but not required)
Atypical carcinoid tumor
Large cell neuroendocrine
carcinoma
Small cell carcinoma
Polygonal cells arranged in nested
or trabecular patterns
Large cells, moderate cytoplasm,
round nuclei, frequent nucleoli
Small cells, scant cytoplasm,
fusiform nuclei, no nucleoli
2-10 per 10 HPF Present, usually punctate Chromogranin, synaptophysin, CD56
(supportive, but not required)
10 per HPF Present, usually extensive Chromogranin, synaptophysin, CD56
(at least one required)
10 per HPF Present, usually extensive Chromogranin, synaptophysin, CD56
(supportive, but not required)
Abbreviations: IASLC, International Association for the Study of Lung Cancer; WHO, World Health Organization; HPF, high power microscopic fields.
exome sequencing studies. 18 Well-differentiated PanNETs
differ substantially from pancreatic ductal adenocarcinomas,
which lack frequent alterations in KRAS, TP53, CDKN2A,
and SMAD4. Instead, there are alterations in chromatin remodeling
genes, such as MEN1, DAXX, and ATRX. 27 Additionally,
alterations in members of the mTOR pathway are
seen. Potential therapeutic targets can be proposed for
PanNETs based on these alterations. Both MEN1 and
mTOR pathway alterations may be expected as a result of
the occurrence of PanNETs in patients with MEN1, von
Hippel-Lindau, neurofıbromatosis-1, and tuberous sclerosis
syndromes. PD-NECs of the pancreas have different molecular
alterations from PanNETs, including common TP53
and Rb mutations, as well as less frequent alterations in KRAS
and CDKN2A. 28 These fındings demonstrate the genetic
distinction between the well differentiated and poorly
differentiated families of pancreatic neuroendocrine
neoplasms.
In terms of predicting response to specifıc therapy, there
are few well-established biomarkers. Loss of expression of
MGMT or methylation of its promoter can predict sensitivity
to temozolomide. 29 In theory, inactivation of the mTOR
pathway should also correlate in the response to mTOR inhibitor
therapy, but this is a complex pathway with multiple
positive and negative regulators, and a simple biomarker of
pathway activation status has not been developed. 30,31
Pulmonary Neuroendocrine Tumors
The classifıcation of neuroendocrine neoplasms in the lung
has been established for many years and, in many ways, represents
the standard against which other neuroendocrine tumor
families are judged (Table 3). 14 Well-differentiated
NETs in the lung (and thymus) are still referred to as carcinoid
tumors, with the designation of atypical carcinoid denoting
the intermediate grade tumor. The high grade entities
are the PD-NECs, small cell lung carcinoma (SCLC), and
LCNEC. 32-34 Although a relatively new entry in the WHO
classifıcation, LCNEC received various designations in the
past. In resected specimens, the morphology is typically neuroendocrine
(trabecular pattern, rosettes, etc.), but the cells
are larger than SCLC, with abundant cytoplasm and prominent
nucleoli. Immunohistochemistry (IHC) confırmation
with labeling for chromogranin, synaptophysin, or CD56 is
required (Table 3). Important differential diagnostic considerations
include, large cell carcinoma with nuclear envelope
(NE) morphology (which displays the typical NE morphology,
but lacks IHC labeling for neuroendocrine markers) and
large cell carcinoma with NE differentiation (which lacks NE
morphology, but nonetheless expresses NE markers by IHC).
Both of these entities should be approached clinically as a
non–small cell lung cancer (NSCLC), as opposed to LCNEC,
which is managed similarly to SCLC. Although the general
concept of three grades and a separation between welldifferentiated
and poorly differentiated entities is the same as
it is for the pancreas and GI tract, there are some subtle differences
in the parameters for classifıcation. Unlike in the GI
and pancreatic NETs, the proliferative rate in the thoracic
NETs is determined solely based on the mitotic rate. There
are studies showing a positive correlation with the Ki67 index,
and a formal classifıcation of lung NETs that incorporates
Ki67 has been proposed, but to date, the offıcial WHO
classifıcation remains based only on mitotic rate. 35 However,
the presence of necrosis is included, as either necrosis or an
elevated mitotic rate can defıne a WD-NET as an atypical carcinoid
tumor. Another difference is the threshold of the proliferative
rate that separates intermediate grade (atypical
carcinoid) from high grade (PD-NEC; small cell carcinoma
or LCNEC). In the GI tract and pancreas, more than 20 mitoses
per 10 high-power fıeld (HPF) are needed, whereas in
the lung, 10 mitoses per 10 HPF are suffıcient to categorize a
neoplasm as high grade.
As in other anatomic sites, pulmonary neuroendocrine
neoplasms actually constitute two families that may not be
closely related. 36 Carcinoid tumors, which can be central or
peripheral in the lung, usually arise in nonsmokers and can
occur in the setting of MEN1. They may also be associated
with hyperplasia of pulmonary neuroendocrine cells, and
they are usually not combined with adenocarcinoma or squamous
cell carcinoma. 37 The PD-NECs, in contrast, are closely
linked to tobacco use and commonly (up to 30%) contain
elements of adenocarcinoma or squamous cell carcinoma.
Such tumors are designated as combined neuroendocrine
carcinomas. Finally, individual neoplasms containing both
carcinoid tumor and PD-NEC are almost nonexistent. Molecular
data further support the separation of carcinoids from
PD-NECs. The latter commonly exhibit TP53 and Rb mutations,
38,39 whereas carcinoid tumors lack these changes and
instead (like pancreatic WD-NETs) have alterations in chro-
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 95