A phenotypic map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites

Abstract

Background

Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterization of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages and paired primary‐metastatic comparisons between samples from the same patient are difficul.

Methods

We report the evaluation of 88 patients with HCC who underwent autopsy, including multi‐regional sampling of primary and metastatic sites totaling 230 nodules analyzed. The study included morphologic assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC.

Results

We confirm a strong predilection of HCC for lung dissemination, including sub‐clinical micro‐metastases (unrecognized during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumor nodule, multi‐nodularity, macrovascular invasion, high histological, nuclear and architectural grades, and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significant higher K19 and EpCAM expression than primary liver tumors. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumor, sometimes to a specific hepatic nodule.

Conclusions

This study suggest limited heterogeneity in metastatic sites compared to primary tumor sites.

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