Immunohistochemistry based molecular subtyping of pancreatic neuroendocrine tumor correlates with clinicopathological outcome: A single institute retrospective study

Abstract Purpose Pancreatic neuroendocrine tumors (PanNETs) account for ~3-4% of all pancreatic tumors worldwide. The WHO grading and TNM staging in PanNET do not accurately predict the clinical behaviour and prognosis. Methods In this single institute retrospective study, cases of PanNETs were selected. Immunohistochemistry (IHC) for ATRX, DAXX, Menin, ARX and PDX-1 markers were performed on formalin-fixed tissue. FITC-labelled telomere-specific fluorescent in-situ hybridization (FISH) was performed to assess altered telomere lengthening (ALT). The tumors were divided into molecular subgroups based on immunohistochemical expression and the subgroups were correlated with clinical, pathological features and follow-up duration using appropriate statistical methods. Results Total 78 cases including 75 PanNET (45 Grade 1, 20 Grade 2 and 10 Grade 3) and 3 pancreatic neuroendocrine carcinoma were identified. ATRX and DAXX mutations were identified in 20.9% and 29.9% of PanNET cases respectively. ATRX mutation was significantly associated with nodal metastasis (p=0.007), higher TNM stage (p=0.004), higher WHO grade (p=0.014), lymphovascular invasion (p <0.001), recurrence (p= 0.025). DAXX mutation was significantly associated with a larger tumor size (p=0.007), higher TNM stage (p=0.011), higher WHO grade (p=0.002), lymphovascular invasion (p=0.001), perineural invasion (p=0.046). Univariate survival analysis revealed significantly lower overall follow-up in ATRX mutant (p<0.001), DAXX mutant (p=0.007) subtypes. ALT positivity correlated with higher TNM stage, lymphovascular invasion and ATRX/DAXX mutation. Multivariate cox-regression analysis showed ATRX mutation as independent predictor of poorer overall survival (HR=10.1, CI=1.3-76.7, p=0.025). Conclusion ATRX/DAXX mutant PanNETs have aggressive clinical, histological behaviour and are predictors of poor outcome.