Enhancer of zest homolog 2 (EZH2) expression in well and moderately differentiated pancreatic neuroendocrine tumor (pNET)

Background: Enhancer of zest homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 with histone H3 methyltransferase function. EZH2 has been shown to be over-expressed in several malignant neoplasms and to be associated with aggressive behavior. Few data are currently available for NETs. EZH2 represents a potential therapeutic target and EZH2 inhibitor drugs are in development. In this study, we evaluated EZH2 expression in well differentiated G1 (Ki67 <2%) or moderately differentiated G2 (2% < Ki-67 < 20%) pNET, to investigate any correlations with histological and clinical parameters. Methods: Immunohistochemical analyzes for nuclear EZH2 expression were performed using a commercially available detection kit on removed primary tumor tissue. We assessed the percentage of positive tumor cells. we considered negative score if expression was positive in less than 10% cells. We used the Chi Square test to compare the expression of EZH2 in the different groups. Histopathological data and clinical data pNET were also collected. Results: Thirty patients with pNET have been assessed (9 G1 and 21 G2 pNET). Eleven patients had metachronous metastases at median time of 49 (15-114) months, 8 patients had synchronous metastases and 11 patients had primary tumor radically removed without recurrence of disease. EZH2 was overexpressed in both G1 and G2 pNET: we found no significant difference of EZH2 expression between G1 and G2 pNET. In metastatic patients, negative score (<10%) was documented in 87.5% of metachronous metastatic patients and in 18.2% of synchronous metastatic patients (p <0.005) In radically resected patient negative score was present in 36% of patient. Conclusions: EZH2 is expressed in pNET. Data show a statistically significant difference in the expression of EZH2 between groups with metachronous metastases (more indolent clinical course), and the group with synchronous metastases (more aggressive clinical course), with lower expression in the first group. This data could be interesting in terms of therapeutic strategy. Further analisis are currently in progress in a larger group of NET patients. Investigation of EZH2 inhibitor drugs in pNET appear feasible