Hepatocellular carcinomas expressing 'stemness'-related markers: clinicopathological characteristics

Hepatocellular carcinoma (HCC) is heterogeneous in histopathology, pathogenesis and biological behavior. There is accumulating evidence that the expression of 'stemness'-related markers such as K19, EpCAM and CD133 in HCC is associated with an aggressive biological behavior and poor clinical outcome compared to conventional HCCs that do not express stemness-related markers. Compared to conventional HCCs, these tumors more frequently demonstrate infiltrative growth patterns, vascular invasion and more intratumoral fibrous stroma, and there is a spectrum of morphological and immunophenotypic features between HCCs with stemness-related marker expression, scirrhous HCCs and combined hepatocellular-cholangiocarcinoma with stem cell features. Clinically, HCCs with stemness-related marker expression are associated with increased serum α-fetoprotein levels and a poor prognosis, and are also beginning to be noticed radiologically. These tumors have also been recognized as a specific subtype in recent molecular classifications, and increasing interest in the molecular pathogenesis of HCCs with stemness-related marker expression will shed light on the development of targeted therapy for these tumors. Therefore, it is important that pathologists identify HCCs expressing stemness-related markers such as K19 during routine pathological evaluation of surgically resected or biopsied HCC tissue, as it will help to identify a high-risk subgroup of HCCs characterized by increased chemoresistance, earlier recurrence after surgical and/or locoregional treatment, increased invasiveness/metastasis and poor overall survival. We will discuss the clinicopathological characteristics of a HCC subtype expressing stemness-related markers and its future perspectives.