Introduction Gastroenteropancreatic neuroendocrine tumours (GEPNETs) are heterogeneous with respect to biologic behaviour and prognosis. Since 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 GEPNETs.
Methods Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. TMA sections were immunostained for Hypoxia inducible factor 1α (Hif-1α), Vascular Endothelial Growth Factor A (VEGF-A), Carbonic Anhydrase IX (CaIX) and Somatostatin receptors (SSTR) 1 to 3 and Ki-67. Biomarker expression was correlated with clinico-pathological 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. Forty-four cases (51%) had distant metastases (liver 72%, lymph nodes 28%). Median tumour size was 3.0 cm (range 0.6–12.5). Vascular invasion and necrosis were present in 20 (23%) and 18 (21%) of the specimens. Median overall survival (OS) was 8.8 years (range 0.1–13.5). Overexpression of CaIX was observed in 10% of the specimens, VEGF-A in 78%, Hif-1α in 59%, SSTR1 in 17%, SSTR2 in 31% and SSTR3 in 1%. Ki-67 index was obtained in all cases and scored as G1 in 84%, G2 in 13% and G3 in 4%. SSTR2 overexpression was predominant in pancreatic NETs (p < 0.01), whilst Hif-1α was predominant in non pancreatic NETs (p = 0.05). Higher Ki-67 labelling was associated with larger tumour size (p < 0.001) and necrosis (p = 0.03). Overexpression of Hif-1α and VEGF-A correlated with the presence of liver metastases (p < 0.001). Patients with Ki-67 count > 1% (p = 0.02), high Hif-1α and low SSTR2 expression (p = 0.03) displayed significantly shorter OS times.
Conclusion We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEPNETs. Tumours with low proliferation index, preserved SSTR2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.
Disclosure of Interest None Declared
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