Sebastiao N Martins-Filho1,2, Venancio A F Alves1,3, Alda Wakamatsu3, Miho Maeda4, Amanda J Craig4, Aline K Assato3, Carlos Villacorta-Martin4, Delia D'Avola5, Ismail Labgaa4,6, Flair J Carrilho7, Swan N Thung8, Augusto Villanueva4,9. 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, Lausanne, 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.
Abstract
AIMS: Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation 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 difficult. METHODS AND RESULTS: We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological 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 subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; 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 significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. CONCLUSIONS: This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.
AIMS: Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation 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 difficult. METHODS AND RESULTS: We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological 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 subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; 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 significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. CONCLUSIONS: This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.