Metachronous esophageal squamous cell carcinoma and hepatocellular carcinoma in the absence of common hereditary syndromes: an unusual case report and literature review

Introduction and Importance Metachronous primary malignancies involving esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma (HCC) are rare. Although shared risk factors such as alcohol and tobacco use are recognized, the development of these cancers in a non-cirrhotic liver and in the absence of common hereditary syndromes poses considerable diagnostic and therapeutic challenges. Case Presentation A 78-year-old male with a history of smoking and alcohol use was initially diagnosed with early-stage (pT1bN0M0) ESCC in 2016 and underwent curative radical esophagectomy. Nine years later, he presented with a large (12 cm) liver mass. Imaging revealed features of HCC with vascular invasion, and biopsy confirmed moderately differentiated hepatocellular carcinoma in a non-cirrhotic liver. Immunohistochemistry showed proficient mismatch repair proteins in both tumors, while p53 expression differed between the two malignancies. The markedly elevated PIVKA-II level (5305.27 mAU/mL) further supported primary hepatocarcinogenesis. Clinical Discussion The nine-year interval strongly supports the diagnosis of metachronous primary malignancies over metastatic disease. This case underscores the role of chronic environmental carcinogen exposure and age-related genomic instability in driving multi-organ carcinogenesis outside the context of cirrhosis or inherited syndromes. The diagnostic approach integrated clinical history, distinct histopathology, and specific biomarkers. For advanced HCC, systemic therapy with lenvatinib was selected based on its established efficacy profile. Conclusion This case highlights the importance of a comprehensive diagnostic workup to differentiate a second primary cancer from metastasis in long-term cancer survivors. It demonstrates that ESCC and HCC can develop sequentially due to sporadic, field carcinogenesis mechanisms. These findings support the consideration of individualized long-term surveillance strategies for high-risk survivors, even in the absence of hereditary syndromes or cirrhosis.