Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review

SIMPLE SUMMARY: Neuroendocrine carcinomas (NECs) are generally highly proliferative and clinically aggressive neuroendocrine neoplasms, but recent literature data suggested that NECs could be further subdivided into two prognostic distinct categories based on the Ki67 labeling index (LI) cut-off of 55%. However, no clear indication on the clinical management and the specific treatment protocol of NECs with a low Ki67 LI are available. We performed a systematic review of the literature to explore the clinicopathological features and the treatment response according to Ki67 LI cut-off in NECs, which is a “hot topic” in neuroendocrinology. Using evidence from 8 studies, for a total of 268 NEC affected patients, the systematic review showed that NECs with a low Ki67 LI had a better prognosis than the subgroup with higher Ki67 LI but worse than G3 neuroendocrine tumors suggesting that NECs are a heterogeneous disease for the pathology findings, the clinical behavior and the treatment response. ABSTRACT: Background: Highly proliferative (G3) neuroendocrine neoplasms are divided into well differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), based on the morphological appearance. This systematic review aims to evaluate the clinicopathological features and the treatment response of the NEC subgroup with a Ki67 labeling index (LI) < 55%. Methods: A literature search was performed using MEDLINE, Cochrane Library, and Scopus between December 2019 and April 2020, last update in October 2020. We included studies reporting data on the clinicopathological characteristics, survival, and/or therapy efficacy of patients with NECs, in which the Ki67 LI was specified. Results: 8 papers were included, on a total of 268 NEC affected patients. NECs with a Ki67 LI < 55% have been reported in patients of both sexes, mainly of sixth decade, pancreatic origin, and large-cell morphology. The prevalent treatment choice was chemotherapy, followed by surgery and, in only one study, peptide receptor radionuclide therapy. The subgroup of patients with NEC with a Ki67 LI < 55% showed longer overall survival and progression free survival and higher response rates than the subgroup of patients with a tumor with higher Ki67 LI (≥55%). Conclusions: NECs are heterogeneous tumors. The subgroup with a Ki67 LI < 55% has a better prognosis and should be treated and monitored differently from NECs with a Ki67 LI ≥ 55%.