Cross Analysis of Genomic-Pathologic Features on Multiple Primary Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a prevalent malignancy cancer worldwide with a poor prognosis. Hepatic resection is indicated as a potentially curative option for HCC patients in the early stage. However, due to multiple nodules, it leads to clinical challenges for surgical management. Approximately 41%-75% of HCC cases are multifocal at initial diagnosis, which may arise from multicentric occurrence (MO-HCC) or intrahepatic metastasis (IM-HCC) pattern with significantly different clinical outcomes. Effectively differentiating the two mechanisms is crucial to prioritize the allocation of surgery for multifocal HCC. In this study, we collected a multifocal hepatocellular carcinoma cohort of 17 patients with a total of 34 samples. We performed whole-exome sequencing and staining of pathological HE sections for each lesion. Reconstruction of the clonal evolutionary pattern using genome mutations showed that the intrahepatic metastogenesis pattern had a poorer survival performance than independent origins, with variants in the TP53, ARID1A, and higher CNV variants occurring more significantly in the metastatic pattern. Cross-modality analysis with pathology showed that molecular classification results were consistent with pathology results in 70.6% of patients, and we found that pathology results could further complement the classification for undefined patterns of occurrence. Based on these results, we propose a model to differentiate the pattern of multifocal hepatocellular carcinoma based on the pathological results and genome mutations information, which can provide guidelines for diagnosing and treating multifocal hepatocellular carcinoma.