The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap

Abstract

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.KEY POINTSNeuroendocrine neoplasms are a diverse in terms of sites of origin, functional status, and degrees of aggressiveness.Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype, accumulating evidence suggests that in most organs, well-differentiated neuroendocrine tumors (WD-NETs)s (grade 1 and grade 2) and poorly differentiated neuroendocrine carcinomas PD-NECs (grade 3) are two very different families of neoplasms.WD-NETs arise in the lungs and throughout the gastrointestinal tract and pancreas; WD-NETs of the prostate gland are uncommon.Surgical resection is the mainstay of therapy for WD-NETs; treatment of unresectable disease depends on the site of origin.PD-NECs of all sites often demonstrate P53 mutations and loss of Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy.PD-NECs of the prostate should be suspected in patients who develop rapid progression in the setting of a disproportionately low prostate specific antigen; TMPRSS2-ERG gene rearrangement (present in 50% of patients) distinguishes PD-NECs of the prostate from small cell carcinomas of other primary sites.