Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. The incidence of GEP-NETs has increased markedly over the past 3 decades, probably as a result of trends in imaging and improvements in diagnosis. Advances in molecular biology have translated into an expansion of treatment options for patients with GEP-NETs. Somatostatin analogs, initially developed for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Newer drugs, targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways, have been approved for progressive pancreatic NETs; however, their role in nonpancreatic NETs remains controversial. Alkylating cytotoxic agents, such as streptozocin and temozolomide, play an important role in the treatment of pancreatic NETs, although estimated response rates vary widely and phase III data are lacking. During the next few years, randomized clinical trials are expected to provide more clarity regarding the role of radiolabeled somatostatin analogs. Predictive biomarkers that would allow for individualized selection of treatments are needed.
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies arising in the diffuse neuroendocrine system. They are characterized by a relatively indolent rate of growth and a propensity to secrete a variety of peptide hormones and biogenic amines. Although NETs may develop in almost any organ, they predominate within the pancreas and the gastrointestinal tract, where they are thought to originate from the islets of Langerhans and enterochromaffin cells of the gut, respectively. The term “carcinoid,” although somewhat archaic, is still widely used to describe NETs originating in the GI tract.
Gastroenteropancreatic NETs (GEP-NETs) present as hormonally functioning or nonfunctioning tumors and have distinct clinical features based on their site of origin. Since their seminal classification by Williams and Sandler in 1963, gastrointestinal NETs are often subdivided into foregut (gastric, duodenal), midgut (jejunal, ileal, cecal), and hindgut (distal colic and rectal) tumors. While hindgut and foregut NETs are rarely associated with a hormonal syndrome, metastatic midgut carcinoids often secrete serotonin and other vasoactive substances, giving rise to the typical carcinoid syndrome, characterized primarily by flushing, diarrhea, and right-sided valvular heart disease. Malignant potential and growth rate also vary based on primary site. For example, NETs of the small intestine have a relatively high malignant potential but tend to progress rather indolently and are associated with a favorable life expectancy. Conversely, gastric and rectal NETs are often small superficial tumors of low malignant potential; however, in the metastatic setting they tend to progress relatively rapidly compared with midgut tumors.[3,4] Pancreatic NETs (pNETs) are usually hormonally silent but can secrete a variety of peptide hormones, including insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP).
Impressive progress has been made in the field of biotherapy over the last decade. Recognition of somatostatin receptor (SSTR) downstream signaling as a key regulator of NET secretion and growth has led to an expansion in the role of somatostatin analogs (SSAs) for control of tumor progression. Identification of aberrant tumor angiogenesis and hyperactive mammalian target of rapamycin (mTOR) pathways as drivers of NET progression has provided a framework for the development and clinical testing of new drugs. As a consequence, treatment options for metastatic NETs have expanded and prognosis of patients with advanced disease has improved significantly.[4,6] In this review, we summarize biologic, pathologic, and clinical aspects of GEP-NETs, focusing on recent advances in their treatment.
Although previously regarded as rare, GEP-NETs represent the second most common digestive cancer.[4,7] In the most updated series of 29,664 patients with GEP-NETs reported to the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute, an incidence of 3.65/100,000 individuals per year was reported. The age-adjusted incidence of GEP-NETs has increased steadily over the last 4 decades, with a 3.6-fold increase occurring between 1973 and 2007. The precise reasons for this steep rise in incidence are unclear, but the expanding use of endoscopic and imaging studies is believed to play a role. GEP-NETs are most common in the small intestine (30.8%), followed by the rectum (26.3%), colon (17.6%), pancreas (12.1%), and appendix (5.7%). The Table summarizes the incidences of GEP-NET subtypes. Although no clear risk factors have been identified in non-syndromic patients, there appears to be a 3.6-fold increased risk of disease in individuals with a family history of carcinoid in a first-degree relative.
The pathogenesis of pNETs has become clearer in recent years. Chromosomal instability (CIN) has been implicated in tumor progression in pNETs, and losses of genetic material more often than chromosomal gains have been described. Driver mutations of MEN1, DAXX or ATRX, and mTOR pathway genes have been identified as crucial factors in pNET tumorigenesis. MEN1 is a tumor suppressor gene encoding menin, a protein that interacts with histone H3 methyltransferase to act as a scaffold for epigenetic coordination of transcription and cell proliferation. Likewise, DAXX/ATRX mutations appear to affect incorporations of histone H3.3 complexes into telomeres. Mutations in DAXX/ATRX are strongly associated with induction of the alternative lengthening of telomeres (ALT) pathway and CIN. Mutations in mTOR pathway genes, including PTEN or PIK3CA, are identified in approximately 15% of pNETs.
The genetic landscape of carcinoid tumors is much less well understood. Chromosome 18 deletions have been observed in up to 74% of small intestinal NETs, followed by arm-level gains of chromosomes 4, 5, 14, and 20,[14,15] but strikingly few recurrent somatic gene alterations have been described. Recently, the discovery of mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene encoding p27, has raised the possibility that cell cycle dysregulation may play a role in the pathogenesis of small bowel NETs. Although discrete mutations in mTOR pathway genes are rarely found in carcinoid tumors, overexpression of mTOR and/or its downstream targets is observed in a high frequency of cases and is associated with higher proliferative activity and adverse clinical outcomes.
In recent years, the tumor microenvironment has emerged as a key factor in NET progression (Figure). GEP-NETs overexpress proangiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).[18,19] As result, they are among the most extensively vascularized cancers. A paradoxical decrease in tumor vascularization has been noted recently with progressive de-differentiation in pNETs (the so-called “neuroendocrine paradox”), but its biologic and clinical significance need further exploration. Infiltration of CD3+ T cells is a frequent event in NETs and is associated with better survival in patients with intermediate-grade disease. In midgut NETs, an increase of systemic FOXP3+ T-regulatory cells (Tregs) seems to drive anergy by downregulation of the T-cell proliferative capacity. Tumor-infiltrating mast cells have been reported to orchestrate a complex inflammatory and angiogenic response, and inhibition of their degranulation can cause vascular collapse and tumor regression.
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