Hepatocellular Carcinoma: Progress in Detection, Pathogenesis, and Treatment

Abstract

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, accounting for approximately 90% of primary liver cancers. Despite significant progress in understanding its molecular pathogenesis and advancements in diagnostic and therapeutic modalities, HCC continues to pose a major clinical challenge due to its aggressive nature and frequent late-stage diagnosis. This review provides a detailed analysis of the latest research on HCC, focusing on key developments in molecular pathogenesis, novel biomarkers for early detection, and cutting-edge treatment strategies. We examine the complex interplay between chronic liver inflammation, cirrhosis, and hepatocarcinogenesis, highlighting critical signaling pathways involved in tumor progression. Furthermore, we discuss the evolving role of liquid biopsy, advanced imaging techniques, and artificial intelligence in improving early diagnosis. The therapeutic landscape of HCC has undergone a paradigm shift with the emergence of immune checkpoint inhibitors, tyrosine kinase inhibitors, and combination therapies that are reshaping clinical outcomes. By synthesizing current evidence and future directions, this review aims to provide clinicians and researchers with a comprehensive update on the management of HCC in the era of precision medicine.

Introduction

Hepatocellular carcinoma represents a major global health burden, ranking as the fourth leading cause of cancer-related mortality worldwide. The incidence of HCC exhibits significant geographical variation, with the highest prevalence observed in regions where chronic hepatitis B virus (HBV) infection is endemic, such as sub-Saharan Africa and East Asia. In Western countries, the rising incidence of HCC has been closely linked to the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatohepatitis (MASH), paralleling the global obesity epidemic. The prognosis of HCC remains dismal, with a 5-year survival rate of less than 20%, primarily due to late diagnosis and the limited efficacy of existing therapies in advanced stages.

The pathogenesis of HCC is a multistep process that typically arises in the setting of chronic liver injury, inflammation, and cirrhosis. Persistent hepatic damage leads to cycles of hepatocyte necrosis, regeneration, and fibrosis, creating a pro-carcinogenic microenvironment characterized by genomic instability, epigenetic alterations, and dysregulated signaling pathways. Recent advances in next-generation sequencing have unraveled the molecular heterogeneity of HCC, revealing distinct mutational signatures and molecular subclasses with implications for prognosis and treatment response.

This review provides a comprehensive overview of the latest developments in HCC research, with particular emphasis on three key areas: (1) novel insights into the molecular mechanisms driving hepatocarcinogenesis, (2) innovative strategies for early detection and surveillance, and (3) the rapidly evolving therapeutic landscape encompassing systemic therapies, locoregional treatments, and emerging immunotherapies. By integrating contemporary research findings with clinical perspectives, we aim to bridge the gap between benchside discoveries and bedside applications in HCC management.

Molecular Pathogenesis of Hepatocellular Carcinoma

Genetic and Epigenetic Alterations

The genomic landscape of HCC is characterized by a high degree of heterogeneity, with frequent mutations affecting oncogenes and tumor suppressor genes. Whole-exome sequencing studies have identified recurrent alterations in the TERT promoter (60-70% of cases), TP53 (25-30%), CTNNB1 (20-35%), and AXIN1 (10-15%), highlighting the critical roles of telomere maintenance, cell cycle regulation, and Wnt/β-catenin signaling in hepatocarcinogenesis. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA dysregulation, contribute significantly to HCC development by silencing tumor suppressor genes and activating oncogenic pathways.

Key Signaling Pathways in HCC Progression

Several interconnected signaling cascades drive the initiation and progression of HCC. The PI3K/AKT/mTOR pathway is frequently hyperactivated in HCC, promoting cell survival, proliferation, and metabolic reprogramming. The Ras/RAF/MEK/ERK cascade mediates growth factor signaling and is often dysregulated in HCC through upstream receptor tyrosine kinase activation. The Wnt/β-catenin pathway plays a dual role in HCC, with CTNNB1 mutations leading to constitutive pathway activation in approximately 30% of cases. Emerging evidence implicates the Hippo-YAP/TAZ pathway as a central regulator of liver size control and tumorigenesis, with YAP overexpression observed in over 50% of HCCs.

Tumor Microenvironment and Immune Evasion

The HCC tumor microenvironment is a complex ecosystem comprising cancer-associated fibroblasts, immune cells, endothelial cells, and extracellular matrix components. Chronic inflammation creates an immunosuppressive milieu characterized by increased regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and exhausted CD8+ T cells. HCC cells exploit multiple mechanisms to evade immune surveillance, including upregulation of immune checkpoint molecules (PD-L1, CTLA-4), secretion of immunosuppressive cytokines (TGF-β, IL-10), and induction of T cell exhaustion. These insights have paved the way for immunotherapeutic strategies aimed at reversing immune tolerance in HCC.

Advances in Early Detection and Diagnosis

Current Surveillance Strategies

The established surveillance protocol for high-risk patients (cirrhosis of any etiology or chronic HBV carriers) includes abdominal ultrasound with or without serum alpha-fetoprotein (AFP) measurement every six months. However, the sensitivity of ultrasound for early HCC detection is suboptimal (approximately 60-70%), particularly in obese patients and those with nodular cirrhotic livers. The diagnostic performance of AFP is limited by its modest sensitivity (40-60%) and specificity (80-90%), prompting the search for more accurate biomarkers.

Emerging Biomarkers and Liquid Biopsy

Recent years have witnessed significant progress in the development of novel biomarkers for HCC detection. The GALAD score, incorporating gender, age, AFP, AFP-L3%, and des-γ-carboxyprothrombin (DCP), demonstrates superior diagnostic accuracy compared to AFP alone. Liquid biopsy approaches, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosome-based assays, show promise for the early detection and monitoring of treatment response. Methylation signatures in cell-free DNA and specific miRNA profiles (e.g., miR-122, miR-21) are being investigated as potential biomarkers for HCC surveillance.

Advanced Imaging Techniques

Multiphasic contrast-enhanced CT and MRI remain the mainstay for HCC diagnosis, with the Liver Imaging Reporting and Data System (LI-RADS) providing standardized interpretation criteria. Emerging functional imaging modalities, including diffusion-weighted imaging (DWI), hepatobiliary contrast-enhanced MRI, and perfusion CT, improve the characterization of indeterminate liver nodules. Artificial intelligence applications in radiology, particularly deep learning algorithms for automated lesion detection and classification, are showing remarkable potential to enhance diagnostic accuracy and reduce interpretation variability.

Evolution of Treatment Paradigms

Surgical and Locoregional Therapies

Liver resection and transplantation represent potentially curative options for early-stage HCC. The Milan criteria (single tumor ≤5 cm or up to three tumors ≤3 cm) continue to guide transplant selection, though expanded criteria are being evaluated. For unresectable HCC, radiofrequency ablation (RFA) and microwave ablation achieve comparable outcomes to surgery for tumors <3 cm. Transarterial chemoembolization (TACE) remains the standard for intermediate-stage HCC, while radioembolization with yttrium-90 microspheres offers an alternative for selected patients.

Systemic Therapy: From Sorafenib to Combination Regimens

The systemic treatment landscape for HCC has evolved dramatically since the approval of sorafenib in 2007. First-line options now include atezolizumab plus bevacizumab (showing superior overall survival versus sorafenib), durvalumab plus tremelimumab, and lenvatinib (non-inferior to sorafenib). Second-line therapies such as regorafenib, cabozantinib, and ramucirumab (for AFP-high patients) provide additional options after progression on first-line treatment. The development of resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge, with ongoing research focusing on combination strategies and novel targets.

Immunotherapy and Emerging Approaches

Immune checkpoint inhibitors have transformed HCC treatment, with single-agent PD-1 inhibitors (nivolumab, pembrolizumab) demonstrating durable responses in a subset of patients. The success of the IMbrave150 trial established atezolizumab (anti-PD-L1) plus bevacizumab (anti-VEGF) as a new first-line standard, highlighting the synergy between immunotherapy and angiogenesis inhibition. Ongoing clinical trials are evaluating novel combinations with CTLA-4 inhibitors, T cell engagers, and cancer vaccines. Cell-based therapies, including CAR-T cells targeting GPC3, and oncolytic viruses represent promising investigational approaches.

Future Perspectives and Conclusion

The field of HCC research is advancing at an unprecedented pace, with molecular characterization enabling more precise risk stratification and treatment selection. The integration of multi-omics data (genomics, transcriptomics, proteomics) holds promise for identifying novel therapeutic vulnerabilities and developing personalized treatment algorithms. Challenges remain in improving early detection rates, overcoming therapeutic resistance, and expanding access to advanced therapies in resource-limited settings.

Future directions include the development of circulating biomarker panels for population-based screening, refinement of immunotherapy combinations to enhance response rates, and exploration of metabolic therapies targeting the unique nutrient requirements of HCC cells. As our understanding of HCC biology deepens, the translation of these insights into clinical practice will be critical to improving outcomes for patients worldwide.

Read more such content on @ Hidoc Dr | Medical Learning App for Doctors