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KLIMSTRA ET AL
The Spectrum of Neuroendocrine Tumors: Histologic
Classification, Unique Features and Areas of Overlap
David S. Klimstra, MD, Himisha Beltran, MD, Rogerio Lilenbaum, MD, and Emily Bergsland, MD
OVERVIEW
Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will
introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification,
biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite
sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated
neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of
neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely
resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They
arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical
resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade
3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated
with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple
endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs
arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and
therapeutic strategies and is an area of active investigation.
Neuroendocrine neoplasms are a diverse group of neoplasms.
Although these share certain pathologic features
regardless of where they arise, they have largely been
studied and classifıed in an organ-specifıc manner (which has
led to a variety of different terminological variations) and
their grading and staging remain site specifıc. Nonetheless,
conceptual commonalities cross organ boundaries. This review
will introduce some of the common features of neuroendocrine
neoplasms and will also explore the differences
in pathology, classifıcation, biology, and clinical management
between tumors of different anatomic sites, specifıcally
the lungs, pancreas, and prostate.
PATHOLOGIC CONCEPTS IN NEUROENDOCRINE
TUMORS
The concept of neuroendocrine differentiation in tumors can
be defıned as the secretion into the bloodstream of bioactive
substances, usually peptide hormones or bioamines, by the
neoplastic cells. The histologic similarity of the cells composing
many neuroendocrine neoplasms and non-neoplastic
neuroendocrine cells suggests that the tumors may arise from
these mature counterparts. Although this concept is likely
overly simplistic even in the case of WD-NETs, which bear
the closest resemblance to their normal cell counterparts.
Pathologically, neuroendocrine differentiation has come to
be defıned as architectural and cytological patterns reminiscent
of non-neoplastic neuroendocrine cells (such as a nesting
or trabecular growth pattern and coarsely stippled
nuclear chromatin) and the production of characteristic neurosecretory
proteins that can be detected by immunohistochemistry.
These include most importantly chromogranin A
and synaptophysin, although some authorities accept the expression
of CD56 (neural cell adhesion molecule or even
neuron specifıc enolase (NSE) as adequate evidence of neuroendocrine
differentiation. 1-3 However, NSE has been
widely questioned as a neuroendocrine marker, based on the
lack of specifıcity. Thus, in practice, WD-NETs are usually
readily recognizable as having neuroendocrine differentiation
based on their routine histologic features, and proof can
be obtained with universally available immunohistochemical
stains. The historic terms for WD-NETs was a carcinoid tumor
or, in the pancreas, an islet cell tumor, although recent
practice in the gastroenteropancreatic system has been to replace
these terms with NET to avoid the connotation that a
carcinoid tumor is a benign neoplasm. 1-3
From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY; Yale Cancer Center, New Haven, CT; UCSF Helen Diller Family Comprehensive Cancer
Center, San Francisco, CA.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Emily Bergsland, MD, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., Room A727, San Francisco, CA 94143; email: emily.bergsland@ucsf.edu.
© 2015 by American Society of Clinical Oncology.
92 2015 ASCO EDUCATIONAL BOOK | asco.org/edbook