Epithelial to Mesenchymal Transition Expression Profiles as Predictive Biomarkers of Recurrence Following Resection of HCC: Implications for Current Clinical Use and Future Stratification for Systemic Therapy

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for more than 500,000 deaths annually. Hepatic resection, liver transplantation, or tumor ablation are the only curative options for HCC. Despite surgical resection being the preferred treatment modality for small, solitary lesions in patients with preserved liver function, postoperative recurrence remains high, and is a major determinant of overall outcome. The overall rate of HCC recurrence is more than 50 % in most published reports with the vast majority of recurrences occurring in the remnant liver. Intrahepatic recurrences are time dependent and thought to occur secondary to either metastasis from the initial resected lesion (within 2 years of resection) or de novo tumors arising from a field defect of the underlying liver parenchyma (beyond 2 years following resection). The importance of distinguishing between the two mechanisms is important for future adjuvant systemic therapy trials but can be difficult to discern outside of routine clinicopathological tumor features. Early tumor recurrences are generally seen in tumors with poor pathological features, including poorly differentiated tumors, vascular invasion, and/or multifocality. Epithelial mesenchymal transition (EMT) is an important event in tumor metastases whereby epithelial cell layers lose polarity and cell–cell contacts, thus allowing detachment and increasing cell motility. A hallmark of EMT is the loss of the cell adhesion molecule E-cadherin and the induction of the transcription factors: Twist, Snail 1, Snail 2, ZEB 1, and ZEB 2. In the current study, Yamada et al. report on the use of factors associated with EMT as a predictive biomarker for recurrence following resection of HCC. The authors identified a mesenchymal group by the loss of E-cadherin as being associated with a significantly worse disease-free survival (DFS) but no change in overall survival compared with a group defined as epithelial with preserved E-cadherin. This finding is similar to previously published studies demonstrating the presence of E-cadherin as a prognostic biomarker of DFS. However, the absence of other clinicopathological factors in the mesenchymal group, including vascular invasion, histological differentiation, and infiltrative tumor growth, previously demonstrated to be associated with early recurrence is surprising and may be a reflection of the relative late nature of tumor recurrence in both the epithelial and mesenchymal groups. Although there is a significant difference in DFS between the mesenchymal and epithelial groups at 5 years, the split of the Kaplan–Meier curves seems to be more pronounced 2 years following resection, indicating a high likelihood of the formation of de novo tumors and not intrahepatic metastasis as postulated by the authors. Unfortunately, the only way to discern between intrahepatic metastasis and de novo tumors is to test clonality of the tumors, a process that is cumbersome and not clinically applicable. The high recurrence rate following surgical resection of HCC has led to the attempt of identifying biomarkers that Society of Surgical Oncology 2014