Loss of DPC4/SMAD4 expression in primary gastrointestinal neuroendocrine tumors is associated with cancer-related death after resection

Background. Gastrointestinal neuroendocrine tumors have frequent loss of DPC4/SMAD4 expression, a known tumor suppressor. The impact of SMAD4 loss on gastrointestinal neuroendocrine tumors aggressiveness or cancer-related patient outcomes is not defined. We examined the expression of SMAD4 in resected gastrointestinal neuroendocrine tumors and its impact on oncologic outcomes. Methods. Patients who underwent complete curative operative resection of gastrointestinal neuroendocrine tumors were identified retrospectively (n = 38). Immunohistochemical staining for SMAD4 expression was scored by a blinded pathologist and correlated with clinicopathologic features and oncologic outcomes. Results. Twenty-nine percent of the gastrointestinal neuroendocrine tumors were SMAD4-negative and 71 % SMAD4-positive. Median overall survival was 155 months (95 % confidence interval, 102-208 months). Loss of SMAD4 was associated with both decreased median disease-free survival (28 months; 95% confidence interval, 16-40) months compared with 223 months (95% confidence interval, 3-443 months) for SMAD4-positive patients (P =.03) and decreased median disease-specific survival (SMAD4: 137 [95 % confidence interval 81-194] months versus SMAD4-positive: 204 [95% confidence interval, 143-264] months; P =.04). This translated into a decrease in median overall survival (SMAD4-negative: 125 (95% confidence interval, 51-214) months versus SMAD4-positive: 185 (95 % confidence interval 138-232) months; P =.02). Conclusion. Consistent with the known biology of the DPC4/SMAD4 gene, an absence of its protein expression in primary gastrointestinal neuroendocrine tumors was negatively associated with outcomes after curative operative resection.