Clinicopathological Characteristics And Prognostic Significance Of Akt/mTOR Pathway In Gastroenteropancreatic Neuroendocrine Neoplasm(GEP-NEN)

Part1The clinicopatholgical features of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN)Purpose To identify the clinicopathological characteristics of GEP-NEN.Patients and Methods We retrospectively reviewed216patients with GEP-NEN who had undergone surgical excision between2000and2010in our hospital.Results Oesophageal NEN and gastrointestinal NEN (GI-NEN) patients were predominantly male and most commonly presented with non-specific symtoms. The median age at diagnosis was ranged from60to70years. However, pancreatic NEN showed no gender predominance with a median age of50years. Pancreatic NEN patients most commonly presented with hormonal hypersecretory symptoms, whereas patients with oesophageal NEN and Gl-NEN generally presented with non-specific symptoms. Under the guidance of WHO (2010) classification, we found that pancreatic NEN was lower malignant than oesophageal NEN and GI-NEN.Conclusion1. The most common localization of the primary tumors was in pancreas, followed by stomach, esophagus and colorectum in this series.2. Pancreatic NEN was often diagosed at an earlier age and was more frequently with hormonal hypersecretory symptoms than NEN in other sites which was often with non-specific symptoms.3. The malignant potential of GEP-NEN differs from primary site.Part2Evaluation of WHO grading system and clinicopathological parameters for potential prognostic factors in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN)Purpose To evaluate the relationship between WHO (2010) grading system, clinicopathological parameters and prognosis in GEP-NEN.Patients and Methods216GEP-NEN encompassing all the histologic types were carefully investigated histologically to identify prognostically informative parameters at univariable and multivariable analysis.Results1. WHO grading system lost its power in predicting the prognosis of esophageal NEN(P>0.05). In a univariable analysis, infiltrating growth pattern (P=0.033), neuroinvasion(P=0.038) and TNM(P=0.036) proved effective in predicting disease-specific death in NEC. For large and small cell NEC, location of tumor as well as neuroinvasion significantly affected prognosis. In a multivariate analysis, both growth pattern and neuroinvasion retained their significance.2. In gastric NEN, the difference in survival among NET G1, NET G2and NEC did not reach a statistical significance (P=0.103). Larger tumor size indicated poor outcome. For NEC, both larger tumor size and stromal fibrous were correlated with poor outcomes.3. In colorectal NEN, no correlation was found between WHO grading system(P=0.223), clinicopathological characteristics and prognosis(P>0.05).4. In pancreatic NEN, WHO grading system correlated significantly with prognosis (P=0.000). In univariate analyses, mitotic fingures, vascular invasion, necrosis and lymph node metastasis were correlated with overall survival and disease-free survival. By multivariate analysis, both for overall survival and disease-free survival, only mitotic figures was an indepent prognostic factor.5. The survival rate was significantly different among the priamry site including esophagus, stomach, colorectum and pancreas(P=0.000). Pancreas harbored the most favorable prognosis while esophagus harbored the wrost.Conclusion1. WHO (2010) grading system emerged as a useful prognostic tool only for panreatic NEN.2. Patients outcome was significantly different according to the primary site. Pancreas harbored the most favorable prognosis, followed by stomach, colorectum and esophagus.3. For esophageal NEN, infiltrating growth pattern and neuroinvasion correlated with poor outcome. Furthermore, patients outcome varied with tumor location both in small cell type and large cell type. Growth pattern and neuroinvasion were independent prognostic factors.4. For gastric NEN, larger tumor size suggested poor outcomes, while stromal fibrosis was a poor predictor in NEC5. Pancreatic NEN patients with high mitotic figures, vascular invasion, necrosis and lymph node metastasis had a dismal prognosis. Mitotic figures was an indepent prognostic factor.Part3Correlationship between m TOR signalling elements and prognosis in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN)Purpose To identify mTOR signal pathway related biomarkers to predict patients outcome and new potential targets for therapy.Patients and Methods We detected the expression of mTOR pathway biomarkers in a cohort of169human GEP-NEN by immunohistochemistry on tissue microarrays to assess potential prognostic factors. Also multivariate analysis of disease-free and overall survival were performed.Results1. In esophageal NEN, loss or low expression of SSR2, Bcl-2, CD99as well as CD117were significantly associated with both longer overall and disease-free survival. Whereas shorter survival was significantly associated with low expression of TSC2, mTOR, PS6, P16, β-catenin and CK19. Multivariate analysis demonstrated that mTOR and CD99were significantly correlated with overall survival. While PS6, SSR2and P16were independent prognostic indicators of disease-free survival.2. In gatric NEN, increased P70S6K,4EBP1and CD99expression were associated with poor disease-free survival and overall survival, while P16and CD44expression were associated with significantly better survival. A multivariate analysis showed that CD99expression was independent prognostic indicators of both overall survival and disease-free survival, while P16only retained its significance in disease-free survival.3. In colorectal NEN, loss expression of Bcl-2and CD56suggested a good prognosis in overall survival.4. The results of univariate analysis for pancreatic NEN revealed that the differences, both in disease-free survival and overall survival, between negative and positive expression of mTOR, cyclinDl, CHG and CD56were statistically significant. A favor survival was correlated with positive expression of these markers. High expression of P70S6K and P16could predict the same better outcomes. PTEN and TSC2expression had better outcomes in both univariate and multivariate analysis.Conclusion1. Independent prognostic indicators for NEN were as follows: For esophageal NEN:high expression of mTOR and low expression of CD99suggested a favor prognosis(OS),while loss expression of SSR2and high exprssion of PS6and P16indicated a longer DFS.For gastric NEN:high expression of CD99predicted a wrose outcome in both OS and DFS, while ioss expression of P16indicated a worse outcome only in OS.For pancreatic NEN:loss expression of PTEN and TSC2predicted a worse prognosis in both OS and DFS.2. Our results strongly supported a role for the mTOR componets and other biomarkers above mentioned in predicting both disease-free survival and overall survival of GEP-NEN. However, the same biomarker may work through different pathway in influenting patients outcomes through different organs.3. mTOR signalling elements, SSR2and CD117expression raised the potential for them to be evaluated as markers of responsing to special agents.