Secretory versus non-secretory hepatocellular carcinoma: associations of serum AFP, CEA and CA19-9 levels with clinical presentation, metastatic patterns, and survival

Introduction: Hepatocellular carcinoma (HCC) is a global health challenge, with disproportionately high mortality rates in low- and middle-income countries (LMICs). Tumor markers such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) are used for diagnostic purposes and for monitoring treatment results. The relationship between these markers, individually or in combination, with clinical presentation, metastatic patterns and survival outcomes has not been extensively researched. Methods: In this South African retrospective study, we assess the association of the tumor marker levels on presentation, diagnosis, and prognosis. Data was analyzed using chi-square tests, t-tests, and Kaplan-Meier survival analysis. Results: The study included 501 patients, treated between 2010 and 2024. Elevated AFP levels were associated with chronic hepatitis B virus (HBV) infection, hepatomegaly, and pulmonary metastases, while elevated CA19-9 levels were associated with more advanced liver disease. Survival analysis confirmed shorter survival for patients with elevated AFP and CA19-9 levels compared to normal levels (p < 0.001). Elevated CEA levels were not significantly associated with survival. Patients with no elevated markers (i.e., "triple-negative" for AFP, CEA, and CA19-9) had the longest survival, compared to those with multiple elevated markers (p < 0.001). Conclusion: AFP and CA19-9 elevations were associated with more advanced disease and poorer survival outcomes. We emphasize the importance of integrating tumor marker levels with imaging and histopathology for a multimodal diagnostic approach. Further research is needed to validate these associations to better define the role of biomarkers in HCC management.