Diagnostic value of serum Heat Shock Protein 90 in alpha fetoprotein negative hepatocellular carcinoma

Background: A substantial proportion of hepatocellular car-cinoma (HCC) cases are alpha-fetoprotein–negative (ANHC), limiting early detection. Heat shock protein 90 (HSP90) is overexpressed in HCC and may serve as a complementary biomarker. This study evaluated the diagnostic value of serum HSP90 in hepatitis C–related ANHC. Patients and methods: 96 enrolled patients were divided into 3 groups: group I included HCV-related cirrhotic patients (32 patients), group II included alpha-fetoprotein positive HCC cases (APHC) defined as HCV-related naïve HCC cases with high serum AFP level (≥ 20 ng/ml) (32 patients), and group III included ANHC defined as HCV-related naïve HCC cases with serum AFP level (< 20 ng/ml) (32 patients). Non-invasive diagnosis of HCC was based on the Liver imaging Reporting and Data System (LIRADS) CT/MR v2018 criteria. The Child-Turcotte-Pugh (CTP) class, MELD score were determined for each patient. Barcelona Clinic Liver Cancer (BCLC) staging was done for HCC cases. Both Alpha-fetoprotein (AFP) and HSP 90 serum levels were measured for all enrolled patients. Results: Serum HSP90 levels were significantly higher in ANHC than in APHC and cirrhotic groups. HSP90 cutoff of 5.57 ng/mL identified ANHC with 78.1% sensitivity, 51.6% specificity, and AUC 0.823. AFP alone at a cutoff of 5.65 ng/ mL showed limited performance (AUC 0.55). Combining HSP90 (5.57 ng/mL) with AFP (5.65 ng/mL) markedly imp-roved detection of ANHC, achieving 93.8% sensitivity, 75% specificity, AUC 0.95, and overall accuracy 80.2%. Serum HSP90 showed no significant correlation with CTP class, MELD score, or BCLC stage in ANHC cases. Conclusion: Serum HSP90 is a promising diagnostic biomarker for AFP-negative HCC, with significant improvement when combined with AFP. This combined approach substantially enhances diagnostic accuracy and may help overcome the limitations of AFP-based detection in ANHC.