Serum Procalcitonin: A Novel Tumor Biomarker for Diagnosis and Follow-Up in Fibrolamellar Hepatocellular Carcinoma
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Introduction
Fibrolamellar carcinoma (FLC) is a rare primary liver cancer that predominantly affects young patients with normal known serum tumor biomarkers (alpha-fetoprotein (AFP) and CA19-9). An observation of a markedly elevated procalcitonin (PCT) in one patient prompted us to investigate the potential role of PCT as a biomarker in a larger cohort of FLC.
Methods
We measured serum PCT levels in 34 samples from 18 patients with metastatic FLC and in 64 patients with hepatocellular carcinoma (HCC), 24 with cholangiocarcinoma (CCA), and 20 with cirrhosis. Using RNA sequencing, we analyzed CALCA expression, the gene encoding 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 and PCT immunohistochemistry was conducted on 13 FLC and 34 other primary or secondary liver cancers.
Results
In 8 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 independently validated in a U.S. cohort of 10 FLC patients compared to HCC and CCA (P=0.0002). Across these cohorts, elevated serum PCT was observed in 83% of FLC cases versus 3% of HCC and CCA cases (P<0.0001). In four patients with longitudinal measurements, changes in 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 but not in other liver cancers.
Conclusion
Procalcitonin is a sensitive and specific biomarker for FLC at both the serum and tumor levels among primary liver cancers, with potential utility in diagnosis and monitoring of treatment response.
Evidence before this study
We searched PubMed from 01th January 2000 to 03th October 2025 using the terms “fibrolamellar carcinoma”, “fibrolamellar hepatocellular carcinoma” “biomarker”, “serum”, in articles written in English Language. This analysis identified numerous studies describing the clinical, molecular, and histopathological features of fibrolamellar carcinoma (FLC), but none of them have identified a serum biomarker robustly validated for clinical use. FLC is a rare primary liver cancer typically arising in adolescents and young adults with normal liver, and current serum biomarkers used for hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma (such as alpha-fetoprotein and CA19-9) are systematically normal in FLC. Prior molecular studies have focused mainly on the DNAJB1–PRKACA fusion gene, which is pathognomonic for FLC, but no reliable circulating biomarker has been established for FLC diagnosis or disease monitoring.
Added value of this study
Our study identifies procalcitonin as a sensitive and specific biomarker for FLC, both at the serum and tumor levels. Across two independent cohorts, elevated serum PCT distinguished FLC from other primary liver cancers and from cirrhosis with high accuracy. Serum PCT level correlated with radiologic tumor response or progression, suggesting utility for disease monitoring. Transcriptomic analyses demonstrated that the CALCA gene, encoding PCT, is overexpressed in FLC compared with other liver tumors, and spatial transcriptomics localized CALCA expression specifically to tumor cells bearing the DNAJB1–PRKACA fusion gene. Immunohistochemistry confirmed PCT protein expression in most FLC tumors but not in other primary hepatic cancer. These findings establish a novel and readily measurable serum biomarker for FLC.
Implications of all the available evidence
Taken together, current evidence indicates that serum PCT is a robust diagnostic biomarker for FLC, distinguishing it from other primary liver cancers and chronic liver diseases. Routine measurement of serum PCT could facilitate earlier recognition of FLC and also provide a non-invasive tool to track treatment response. Future research should validate these findings prospectively, explore the biological mechanisms underlying CALCA overexpression in FLC, and assess whether PCT-guided monitoring can predict prognosis, improve patient outcomes or clinical trial design in this rare malignancy
