Combined Assessment of EZH2, GPC3 and SUOX could Improve Diagnosis of Regenerative Nodule, Liver Dysplasia and Small HCC in Cirrhotic Patients

Background: Hepatocellular carcinoma (HCC) has become the main cause of death in patients with liver cirrhosis. In Egypt, HCC has been increased with a doubling incidence in the last few years. Diagnosis of the disease at an early asymptomatic stage is the only mean to achieve long-term survival. Aim of Work: To validate the diagnostic accuracy of the panel of biomarkers; enhancer of zeste homologue 2 (EZH2), glypican-3 (GPC3) and sulfite oxidase (SUOX) in series of biopsies from liver nodules of cirrhosis. Methods: Sections from formalin-fixed paraffin-embedded tissues of 125 liver nodules were assessed for EZH2, GPC3 and SUOX expressions by immunohistochemistry. Results: Liver nodules were classified as; 40 cirrhotic large regenerative nodules (CLRN), 35 high-grade dysplastic nodules (HGDN), 20 well differentiated hepatocellular carcinomas with nodules 3 cm or smaller (S-HCCs), and 30 HCCs with nodules larger than 3 cm (L-HCCs). The sensitivity and specificity of EZH2 expression levels for S-HCC and L-HCC detection versus non-malignant liver tissues were 65 % and 90.7 % vs. 83.3 % and 93.3 % respectively (p <0.001). The sensitivity and specificity of GPC3 expression levels for S-HCC and L-HCC detection versus non-malignant liver tissues were (70% and 74.7% vs. 80% and 77.3%) respectively. SUOX expression significantly decreased with progression of hepatocarcinogenesis from CLRN to L-HCC (p <0.001). By contrast, EZH2 and GPC3 were significantly increased with progression of hepatocarcinogenesis. A panel of EZH2, GPC3 and SUOX showed a high sensitivity, speci?city and AUC (93.3%, 94.7%, and 0.96) respectively for L-HCC detection. In the diagnosis of S-HCCs, the sensitivity, speci?city and AUC of a combination of the 3-markers panel were (90%, 78.7%, 0.893%) respectively. Conclusions: The combination of the three biomarkers (EZH2, GPC3 and SUOX) could greatly improve the prospects of the early detection of small HCCs in liver biopsies.