Expression of PTEN and mTOR in pancreatic neuroendocrine tumors

Abstract

The purposes of this study were to clarify the expression patterns of phosphorylated mammalian target of rapamycin (p-mTOR), mTOR, and phosphatase and tensin homolog (PTEN) in primary pancreatic neuroendocrine tumors (pNETs) and their significance in predicting clinical behaviors and postoperative outcomes. The expressions of p-mTOR, mTOR, and PTEN were assessed in 20 normal pancreatic islets and in 90 resectable pNETs using immunohistochemistry. The associations of the biomarker expressions with clinicopathologic variables and survival duration were analyzed. The percentages of G1, G2, and G3 tumors were 54.4, 43.3, and 2.2 %, respectively. A strongly positive staining was observed for both mTOR and PTEN in normal pancreatic islets, whereas negative staining was observed for p-mTOR. In primary pNETs, the mTOR and p-mTOR positive rates were 70.8 % (63/89) and 44.4 % (40/90), respectively. p-mTOR expressions strongly correlate with mTOR expressions. No significant correlation between p-mTOR and clinicopathological features was found. The high expression rate of PTEN was 56.7 % (51/90), whereas the low expression rate was 43.4 % (39/90). PTEN loss (low expression) was significantly more frequent in patients with advanced WHO grades (p = 0.004) and in patients with higher Ki-67 index (p = 0.002). In our immunohistochemical classification system, the Ki-67 index was significantly higher in the PTEN low expression/p-mTOR-positive subgroup (2.7 ± 2.5) than in the PTEN high expression/p-mTOR-negative subgroup (1.0 ± 1.7, p = 0.006). Patients in the PTEN low expression/p-mTOR-positive subgroup presented a significantly lower 5-year overall survival (OS) than those in the PTEN high expression/p-mTOR-negative subgroup (p = 0.049; 5-year OS = 79 vs. 100 %, HR = 7.0). ENETS TNM staging and major vascular invasion were independently associated factors for predicting the overall survival rate of patients (p = 0.019 and 0.011, respectively). In conclusion, positive p-mTOR expression and PTEN loss may have a synergic effect on tumorigenesis and proliferation; targeted therapy based on mTOR/PTEN signal pathway and its associated molecular mechanism may play a role in the treatment of pancreatic neuroendocrine tumors.