A Practical Approach to the Diagnosis of Liver Metastases from Cancer of Unknown Primary: Application of Immunohistochemistry and an Update

Cancers of unknown primary (CUP) are tumors whose site of origin remains undetectable despite thorough clinical, radiologic, and histopathologic evaluations. They make up about 2% to 3% of all epithelial tumors and generally have a poor prognosis. Immunohistochemical (IHC) markers complement epidemiological and histomorphologic approaches to determine tumor type, subtype, and primary site, influencing patient prognosis, outcome, and treatment. This retrospective observational study examined patients who underwent liver biopsies for hepatic metastasis between January 2022 and January 2024. Data on age, gender, liver segment localization, tumor number and size, histomorphology, and IHC work-up were analyzed. The average age of metastatic patients was 62±12 years, with 85.5% aged 50 or older. Males slightly outnumbered females (51.1% vs. 49.9%). On average, there were 1.8 metastatic foci per case. The most common metastasizing tumors included colorectal (30.5%), pancreaticobiliary (29%), breast (8.4%), lung (6.9%), and lymphomas (4.6%). Histomorphologically, 66.4% were adenocarcinomas, followed by poorly differentiated tumors (9.2%) and neuroendocrine neoplasms (8.4%). At the time of biopsy, 33.6% had initial CUP (i-CUP), 22.9% had their primary site detected by IHC, and 10.7% had true CUP (t-CUP). On average, 9.4 IHC markers were used per case, rising to 13.8 in t-CUP cases. Significant correlations were found between histomorphologic patterns, primary site detection, and IHC marker usage ( P =0.01 and 0.02). IHC continues to enhance the diagnosis and treatment of metastatic liver tumors with its use of tumor-specific or organ-specific antibodies, including newly developed transcription factors, aiding pathologists in personalized medicine.