Scientific publications

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

Martins-Filho SN (1,2), Alves VAF (1,3), Wakamatsu A (3), Maeda M (4), Craig AJ (4), Assato AK (3), Villacorta-Martin C (4), D'Avola D (5), Labgaa I (4,6), Carrilho FJ (7), Thung SN (8), Villanueva A (4,9).

(1) Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
(2) Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
(3) Laboratorio de Patologia do Fígado LIM 14, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
(4) Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(5) Liver Unit, Clínica Universidad de Navarra, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain.
(6) Department of Visceral Surgery, Lausanne University Hospital CHUV, Switzerland.
(7) Departamento de Gastroenterologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
(8) Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(9) Division of Hematology and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Magazine: Histopathology

Date: Jan 12, 2019



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.


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.


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.


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

CITATION  Histopathology. 2019 Jan 12. doi: 10.1111/his.13809

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