Loss of SMAD4 and effect on overall survival in resected gastrointestinal neuroendocrine tumors.

Abstract

250 Background: Studies by comparative genomic hybridization have demonstrated that the 18q chromosomal region is frequently lost in gastrointestinal neuroendocrine tumors (GI-NET). However, the impact of DPC/SMAD4 loss, which is located 18q21, in the pathogenesis of GI-NET remains controversial. In this study, we sought to determine the protein expression of SMAD4 in GI-NET and the impact on oncologic outcomes. Methods: To investigate the role of SMAD4 in GI-NET, a tissue microarray consisting of 33 GI-NET was constructed and analyzed by immunohistochemistry for SMAD4 expression. SMAD4 expression was classified as negative, SMAD4-low (≤10% cells +) or SMAD4-high (>10% cells+). Staining results were correlated clinicopathologic features and overall survival. Results: Of the 33 tumors examined, 93% were low- or intermediate-grade and 7% high-grade. 35% of GI-NET were negative for SMAD4, 45% were SMAD4-low and 15% SMAD4-high. Expression of Chromogranin was observed in 91% of all tumors, synaptophysin in 94%, CDX2 in 64%, and CK19 in 55%. We were unable to identify any association between loss of SMAD4 and stage or tumor grade. There was an inverse correlation between loss of SMAD4 and CK19 expression, whereby 75% of SMAD4-neg tumors expressed CK19 and only 32% of SMAD4+ expressed CK19 (p=0.01). At a median follow-up of 123 months, median overall survival was 203 months. Survival differences related to SMAD4 status resulted in clinically meaningful, although statistically non-significant, differences in overall survival (SMAD4-low: 132 months vs. SMAD4-high: 203 months, p=0.058). Conclusions: Differences in SMAD4 expression result in clinically important differences in overall survival, although this cohort may be underpowered to detect a statistically-significant difference. Future studies with larger patient populations may be critical to evaluate the importance of SMAD4 in the pathogenesis of GI-NET.