Supplementary Material for: Hepatocellular carcinoma with multiple primary malignancy: A Retrospective Study of 106 Cases

Abstract
Background: Multiple primary malignancies (MPM) are a rare scenario, particularly in patients with hepatocellular carcinoma (HCC). Research addressing MPM patients with HCC is limited. Therefore, we conducted a retrospective study to explore the clinical features and outcomes of MPM patients involving HCC.
Methods: We retrospectively analyzed records of patients diagnosed with HCC from January 2013 to October 2023 in the First Affiliated Hospital of Xiamen University. HCC patients with extrahepatic tumors were identified. Their clinical characteristics and survival data were were further analyzed.
Results:Among the 1556 patients with HCC, 106 (6.8%) were identified with EHPM, of which 29 were synchronous and 77 were metachronous. A total of 96 patients had double primary cancers, and 10 patients had triple primary cancers. The most common EHPMs were lung cancer (15%), followed by colorectal tumors and stomach cancer. Compared with the synchronous group, the curative treatment rate of HCC and EHPM in the metachronous group is higher. During follow-up period, 29 patients died, of which 20 (69%) died from HCC-related causes. The median overall survival (OS) time was 88 months, with 1-, 3-, 5-, and 10-year cumulative survival rates of 92.4%, 88%, 82.5%, and 69.6%, respectively. The 1-, 3-, and 5-year HCC-specific OS (HOS) rates were 81.8%, 75.8%, and 71.9%, respectively. Univariate analysis revealed that Child-Pugh class (B-C), HCC tumor size >5cm, non-radical treatment for HCC or EHPM, HCC recurrence, BCLC staging (C-D), and synchronous appearance were significantly associated with shorter OS and HOS. Factors such as Childs class, tumor size, treatment modality, and synchronous presentation were identified as independent predictors of OS through Cox analysis. Childs class, tumor size, non-radical treatment, BCLC staging, and HCC recurrence were found to be independent factors affecting HOS.
Conclusions: The occurrence of extrahepatic primary tumors is not rare, underscoring the importance for oncologists being alert to the development of secondary tumor development in HCC patients. However, the co-occurrence of other primary tumors alongside HCC does not appear to worsen patient prognosis. Notably, curative resection, where feasible, emerges as a vital factor in extending patient survival.