From organelles to therapy: rethinking combined hepatocellular-cholangiocarcinoma

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary malignant hepatic neoplasm, defined by the concurrent presence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) components, which vary in proportion and degree of differentiation. Characterized by insidious onset, high invasiveness, and marked heterogeneity, cHCC-CCA often eludes early diagnosis, leading to a generally dismal prognosis. Its survival outcomes typically fall between those of HCC and intrahepatic cholangiocarcinoma (iCCA). Epidemiological data derived from surgical resection specimens and percutaneous biopsy samples indicate that cHCC-CCA accounts for approximately 0.4%-14.2% of all primary liver cancers. Due to its rarity, standardized treatment protocols are currently lacking. Surgical resection and liver transplantation are considered the primary potential curative approaches. However, only a minority of patients meet surgical criteria at diagnosis, and postoperative recurrence rates are substantially high. For non-surgical candidates, local or systemic therapies are generally administered based on treatment regimens for HCC or iCCA. Additionally, the pronounced genetic and molecular heterogeneity of cHCC-CCA significantly compromises the efficacy of current therapeutic strategies. Its unique biological behaviors, histological features, and immunophenotypic profiles present multifaceted challenges to diagnosis, treatment, and research endeavors. This review aims to comprehensively synthesize the classification systems and pathological characteristics of cHCC-CCA, with a particular focus on the underlying organelle dysfunction. By integrating advances in clinical diagnosis and management, we seek to enhance disease awareness and provide a new reference for clinical practice.