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KLIMSTRA ET AL
matin remodeling genes, such as MEN1, PSIP1, and
ARID1A. 40
Prostatic Neuroendocrine Tumors
In contrast to the lung and pancreas, where WD-NETs are
relatively commonly encountered, the prostate almost never
gives rise to true WD-NETs (carcinoid tumors). Individual
case reports exist, but many such neoplasms may represent
the more common manifestation of neuroendocrine differentiation
in prostatic neoplasia and adenocarcinoma with
neuroendocrine differentiation. A recent consensus group
proposed a formal classifıcation of prostatic neuroendocrine
neoplasia. 41
Conventional prostatic adenocarcinomas can exhibit
neuroendocrine differentiation, but in the absence of a morphologically
evident neuroendocrine component, focal
immunohistochemically detected neuroendocrine differentiation
is not thought to affect prognosis and it is not recommended
to perform immunohistochemistry to search for it. 41
Prostatic adenocarcinoma with Paneth cell-like neuroendocrine
differentiation is defıned as a conventional prostatic
adenocarcinoma containing morphologically evident neuroendocrine
cells, which are typically highly granulated and
resemble intestinal Paneth cells. 42 This phenomenon may be
particularly marked following androgen deprivation therapy.
The neuroendocrine cells lack an androgen receptor
(AR) and have a well differentiated morphology, with bland
nuclei and a low proliferative rate. When Paneth cell-like
neuroendocrine differentiation is extensive, the tumor may
resemble a true prostatic carcinoid tumor, but prostate specifıc
antigen (PSA) expression is typically retained and elements
of conventional adenocarcinoma are also usually
identifıed. This pattern of differentiation is, if anything, a favorable
prognostic sign, and the Gleason grade should be assigned
based only on the pattern in the conventional
adenocarcinoma elements. The rarest of all prostatic neuroendocrine
neoplasms is a true carcinoid tumor, which can
only be diagnosed when prostatic origin can be confırmed (as
opposed to metastasis or direct extension from an adjacent
organ) and Paneth cell-like neuroendocrine differentiation
in a conventional prostatic adenocarcinoma is ruled out. 41
The absence of any adenocarcinoma component and negative
immunostaining for PSA are required for the diagnosis.
The other types of prostate neuroendocrine neoplasms are
PD-NECs, including small cell carcinoma 43,44 and LCNEC,
the latter being very rare. 45 These tumors are often (but not
always) positive for neuroendocrine markers (chromogranin,
NSE, CD56, and/or synaptophysin) by IHC. As in
other prostatic neuroendocrine neoplasms, AR expression is
reduced or absent. Copy number loss of the tumor suppressors
RB1 (85% to 90%) 46 and mutation of TP53 (50% to 60%)
is shared with small cell carcinomas of other sites. 46,47 Notably,
the combination of RB1 and TP53 alterations can drive
small cell prostate cancer formation in mouse models. 48,49 In
addition, PD-NEC of the prostate (NEPC) is associated with
increased stem-like and neuronal signaling pathways (e.g.,
MYCN, ASCL1), 50 as evidenced by decreased expression of
the master repressor of neuronal differentiation, RE1-
silencing transcription factor (REST), 51 increased expression
of cell cycle programs (e.g., AURKA, AURKB, PLK1), 47,50,52
and overexpression of the chromatin modifıer DEK 53 and the
polycomb complex gene, EZH2. 47,54 The role of these molecular
alterations as diagnostic or predictive biomarkers remains
to be determined.
These highly aggressive carcinomas can occur in pure form
or—as in the lung, GI tract, and pancreas—they can be combined
with elements of conventional adenocarcinoma.
Mixed tumors are often heterogeneous with both AR positive
and AR negative cells coexisting. Further demonstrating the
relationship of these PD-NECs with conventional prostatic
adenocarcinoma, some cases retain focal PSA immunoexpression.
The prostate cancer-specifıc TMPRSS2-ERG gene
rearrangement is detectable by fluorescence in situ hybridization
(FISH) in approximately 50% of PD-NECs of the
prostate (similar to the frequency in prostate adenocarcinomas)
and distinguishes PD-NECs of the prostate from small
cell carcinomas in other primary sites. 47,55
Primary Site Determination in Neuroendocrine
Neoplasms
In some clinical scenarios, it may be important to identify the
site of origin of a neuroendocrine tumor presenting with
metastatic disease. A variety of transcription factors can be
helpful, although none are perfectly sensitive or specifıc on
their own. 26 Thyroid transcription factor-1 (TTF1) labels
pulmonary carcinoid tumors and is a good, if not insensitive,
marker for WD-NETs provided a medullary thyroid carcinoma
can be excluded. CDX2 is an intestinal lineage marker
and generally stains only small bowel WD-NETs. Isl1 and
PAX8 are positive in pancreatic WD-NETs and also, interestingly,
label NETs of the rectum. A combination of these
stains can supplement data from imaging studies in an attempt
to identify the primary site. Defıning the site of origin
of a PD-NEC is more problematic, especially in the case of
small cell carcinomas, which commonly express TTF1 as a
primary in the lung, GI tract, pancreas, or prostate. In cases of
small cell carcinoma of an unknown primary where prostate
is suspected, ERG FISH is clinically indicated to support
prostatic origin (though a negative test does not exclude it).
CLINICAL FEATURES AND MANAGEMENT OF
PANCREATIC NEUROENDOCRINE TUMORS
Clinical Features
PanNETs arise in and around the pancreas and comprise approximately
one-third of gastroenteropancreatic NETs (the
remainder being traditional intestinal carcinoid tumors originating
in the stomach and intestinal tract). 56 PanNETs account
for approximately 1% to 2% of pancreatic tumors by
incidence, but 10% by prevalence. 17,57,58 Interestingly, as with
other NETs, the incidence of PanNETs is on the rise. It is
unclear if this reflects improved diagnostic tools, an increased
awareness of the disease, an aging population, or
other factors. 59,60
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