Poorly differentiated neuroendocrine carcinoma (NEC G3): Prognostic factors and potential novel targets.

Abstract

e15071 Background: Poorly differentiated neuroendocrine carcinomas (NEC G3) represent a subgroup of neuroendocrine neoplasms with aggressive clinical behavior and poor prognosis, but showing quite variable clinical courses. In metastatic disease objective response to first-line therapy with cisplatin/ etoposide ranges between 40-67%, however median duration of response is short (4 to 9 months). There is no established second-line therapy. Methods: Clinical data of 42 patients with gastro-entero-pancreatic NEC G3 were analyzed in retrospect. In 26 cases tissue was analyzed for cell size, expression of p-mTOR and downstream effectors (p-eIF4E and p-4EBP1), somatostatin receptor (SSTR)-subtypes and growth factor receptors (EGFR and IGF-1R). Histopathological findings were analyzed using Kaplan-Meier curve, log rank test and Cox regression. Results: Patients with large cell NEC showed a more favorable survival than patients with small cell NEC. Median overall survival (mOS) was 31 versus 11 months (P=0.034). Expression of p-mTOR and p-eIF4E was seen in 64% and 24% of cases. High expression levels of p-mTOR (mOS 9 vs 25 months, P=0.026) and expression of p-eIF4E (mOS 9 vs 25 months, P=0.015) was significantly associated with shorter survival. In multivariate Cox regression p-mTOR and p-eIF4E proved to be independent prognostic factors for survival taking cell size and TNM staging into account. EGFR (cytoplasmatic and nuclear) and IGF-1R expression was found in 73.1%, 65.4% and 69.2% of the cases respectively, without significant association to survival. Expression of SSTR subtypes, Ki67 value and response to first line chemotherapy was not of prognostic value analyzed by log rank test. Conclusions: The clinical impact of cell size discrimination requires further evaluation in NEC G3. The mTOR pathway seems to play a role in tumor growth in some NEC and may represent a novel therapeutic target.