An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes

Background: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. Methods: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1 alpha (Hif-1 alpha), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinicopathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods. Results: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P = 0.03), advanced stage (P<0.001), high Hif-1 alpha and low SSTR-2 expression (P = 0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1 alpha expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1 alpha-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1 alpha+ GEP-NETs had a median survival of only 4.2 years (P = 0.006). Conclusion: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1 alpha expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.