Loss of PTEN and Increased pAKT Expression Distinguishes Aggressive Low-grade Neuroendocrine Tumors

A major problem in neuroendocrine pathology is the identification and separation of aggressive low-grade neuroendocrine tumors (LGNETs) from those with a benign or more indolent behavior. Presently there are no known morphologic or molecular parameters which can predict how localized LGNETs will behave. The phosphatase and tensin homolog (PTEN) gene negatively regulates the PI3K-AKT-mTOR pathway and inhibits neoplastic cell survival and proliferation and has recently been identified as a neuroendocrine tumor differentiation marker. We hypothesized loss of PTEN may also identify LGNETs that demonstrate aggressive behavior. We studied PTEN and pAKT expression in 18 LGNETs using specific monoclonal antibodies. Follow up was obtained for a minimum of five years on all patients. 8/18 cases had strong PTEN expression and showed no evidence of disease on >5 years follow-up. 10 cases demonstrated loss of PTEN expression; 9/10 had positive pAKT expression, and 7/9 had recurrence and/or metastases. Lung and appendiceal LGNETs uniformly had high PTEN expression and a markedly better prognosis than their gastroenteropancreatic (GEP) counterparts. Loss of PTEN correlated significantly with the positive expression of pAKT (P=0.0027) and aggressive behavior of LGNETs (p=0.0002). Loss of PTEN and increased pAKT correlated with the metastatic potential of LGNETs (p=0.0011 and 0.0248 respectively). Loss of PTEN and increased pAKT expression distinguishes aggressive LGNETs from those with more indolent behavior.