Are Neuroendocrine Tumors Going Mainstream?
Authors: Matthew H. Kulke
Journal: Journal of Clinical Oncology (2012)

Neuroendocrine tumors were thrust to the forefront of the oncology world last year with the much-heralded approval of two drugs, everolimus and sunitinib, for the treatment of advanced pancreatic neuroendocrine tumors. The large, prospective randomized trials leading to these approvals were a clear break from the recent past, when clinical practice was based, in large part, on small institutional series and anecdotal experience. Less well publicized have been parallel advances in the development of methods to increase understanding of the clinical behavior of this diverse group of malignancies. The American Joint Committee on Cancer (AJCC) and similar organizations recently adopted formal pathologic staging and histologic classification schemes for neuroendocrine tumors. In the article that accompanies this editorial, Strosberg et al report on a large series of more than 600 small bowel carcinoid tumors and evaluate how well these new systems work. Remarkably, formal TNM staging systems were first adopted for neuroendocrine tumors only in the last decade. The first of these systems was developed by the European Neuroendocrine Tumor Society (ENETS) during a consensus conference held in 2006. The AJCC formally adopted a TNM staging system for neuroendocrine tumors in 2010. Although broadly similar to the system used by ENETS, the AJCC system differs in some respects with its classification of pancreatic neuroendocrine tumors and appendiceal carcinoids. Several investigators have now performed validation studies of these staging systems in large institutional series. Although both the ENETS and the AJCC systems have been broadly validated for pancreatic neuroendocrine tumors, recent studies have also suggested that that the systems are not completely interchangeable. A European study of more than 1,000 patients with pancreatic neuroendocrine tumors, for example, found that the ENETS system provides more definitive and detailed prognostic information than AJCC system in this setting. Differences between the AJCC and ENETS staging systems for small bowel carcinoid are minimal, and both European investigators as well as the current North American–based study by Strosberg et al have now confirmed their general prognostic validity. However, as with pancreatic neuroendocrine tumors, several observations suggest that future revisions may be warranted. For example, there seem to be minimal differences in outcome in node-negative (stage I and II) resected small bowel carcinoid tumors, which suggests that tumor size and depth of invasion have little independent impact on outcome. Strosberg et al additionally point out that lymph node status alone seems to have less of an impact on prognosis than whether lymph nodes and associated mesenteric disease have been resected. These findings are consistent with clinical experience. It is often the associated mesenteric disease rather than the primary tumor itself that is the main contributor to patient morbidity. The optimal histologic classification of neuroendocrine tumors remains controversial. The importance of histologic grade in determining outcomes for neuroendocrine tumors is broadly accepted and has been recognized by WHO for years. Conversely, defining the boundaries between histologic categories has proved challenging. A current classification scheme, first recommended by ENETS and subsequently adopted by the AJCC, uses a mitotic count cutoff of less than two per 10 high-powered fields (hpf) and a Ki-67 proliferative index of no more than 2% to define the boundary between the most indolent low-grade tumors and the somewhat more aggressive intermediategrade group. Strosberg et al suggest that, at least for small bowel carcinoid tumors, a mitotic count cutoff value of less than five per 10 hpf more reliably distinguishes between truly indolent low-grade tumors and their intermediate-grade counterparts. Recent data from studies in pancreatic neuroendocrine tumors similarly suggest that the Ki-67 proliferative rate index cutoff distinguishing lowand intermediate-grade tumors could potentially be raised from 2% to 5%. Parallel questions surround the histologic definition of highgrade tumors. According to current classification systems, tumors with a mitotic rate of more than 10 mitoses per 10 hpf or a Ki-67 proliferative index of more than 20% are classified as high grade. The distinction between low-, intermediate-, and high-grade tumors is of more than academic interest, given that it has potentially significant clinical implications. In general, high-grade tumors are treated with platinum-based chemotherapy regimens. In contrast, patients with more slowly growing lowor intermediate-grade tumors are more likely to benefit from treatment with somatostatin analogs or targeted therapies. A recent retrospective study of 252 patients with highgrade tumors suggests that the Ki-67 cutoff value of 20% may be too low to effectively distinguish between these groups. In this study, platinum-based therapy was beneficial primarily in the group of patients with a proliferative index of more than 55%, and seemed to offer little benefit to the group of patients with lower Ki-67 indices. Additional studies that correlate tumor histology not only with prognosis but also with treatment outcomes are likely to be helpful in further refining histologic classifications. Although not a primary focus of the article, the findings by Strosberg et al highlight a persistent and vexing question regarding survival durations for patients with neuroendocrine tumors. There is surprisingly limited data regarding median disease-free and overall JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 4 FEBRUARY 1 2013