Serum procalcitonin: A novel tumor biomarker for diagnosis and disease monitoring in fibrolamellar hepatocellular carcinoma.

[BACKGROUND & AIMS] Fibrolamellar carcinoma (FLC) is a rare primary liver cancer that predominantly affects young patients with normal known serum tumor biomarkers. An observation of elevated procalcitonin (PCT) in one patient prompted us to investigate PCT as a biomarker in a larger FLC cohort.

[METHODS] We measured serum PCT levels in 34 samples from 18 patients with FLC and in 64 patients with hepatocellular carcinoma (HCC), 24 with cholangiocarcinoma (CCA), and 20 with cirrhosis. Using RNA sequencing, we analyzed expression of CALCA, which encodes PCT, in 27 FLC tumors, 331 HCC tumors, 39 CCA tumors, 71 hepatoblastomas, 34 hepatocellular adenomas, and 55 non-tumor liver samples. Spatial transcriptomics was performed on three FLC tumors, and PCT immunohistochemistry was performed on 13 FLC tumors and 34 other primary or secondary liver cancers.

[RESULTS] In eight patients with FLC from the European cohort, median serum PCT was significantly elevated (55.2 μg/L) compared to patients with HCC (0.14 μg/L), CCA (0.16 μg/L), and cirrhosis (0.11 μg/L; p = 0.0005). These findings were validated in a US cohort of 10 patients with FLC compared to HCC and CCA (p = 0.0002). Across these cohorts, elevated serum PCT was observed in 83% of FLC cases vs. 3% of HCC and CCA cases (p <0.0001). In four patients, changes in serum PCT levels correlated with radiologic response according to RECIST 1.1. RNA sequencing demonstrated significant overexpression of CALCA in FLC compared to other primary liver tumors (p <0.0001), and spatial transcriptomics localized CALCA expression specifically to tumor cells. Immunohistochemistry confirmed PCT overexpression in 77% of FLC tumors but not in other liver cancers.

[CONCLUSION] Procalcitonin is a sensitive and specific serum biomarker for FLC among primary liver cancers, with potential utility for diagnosis and monitoring of treatment response.

[IMPACT AND IMPLICATIONS] This study is justified by the lack of reliable serum biomarkers for fibrolamellar carcinoma (FLC) and demonstrates that procalcitonin is specifically overexpressed by FLC tumor cells and detectable in the blood of the patients with FLC. These findings are important for clinicians and researchers, as they identify a readily available biomarker that may facilitate diagnosis, improve disease monitoring, and support clinical trial design in a rare cancer that predominantly affects young patients. In clinical practice, serum PCT measurement could be incorporated as a non-invasive adjunct to imaging for the diagnosis and longitudinal assessment of FLC, although prospective studies in larger and more diverse cohorts are needed to refine diagnostic cut-offs and confirm specificity.