Pathology and Diseases

HCC Review Completed: A Comprehensive Analysis

Explore a detailed analysis of hepatocellular carcinoma, covering key pathways, risk factors, diagnostic methods, treatment options, and prognostic insights.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and a leading cause of cancer-related deaths worldwide. Its incidence continues to rise due to chronic viral hepatitis, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-related liver disease. Early detection remains difficult, and treatment varies based on tumor stage and liver function.

Understanding HCC requires examining its molecular drivers, risk factors, diagnostic advancements, and evolving therapeutic strategies.

Oncogenic Pathways

HCC arises from genetic alterations and dysregulated signaling networks that drive malignant transformation. The Wnt/β-catenin axis plays a key role, with CTNNB1 mutations leading to aberrant Wnt activation, fueling uncontrolled cell proliferation and resistance to apoptosis. Approximately 20–40% of HCC cases harbor CTNNB1 mutations, often in the absence of cirrhosis, suggesting a distinct molecular subtype.

TERT promoter mutations occur early in hepatocarcinogenesis, sustaining telomere maintenance and promoting cellular immortality. These alterations frequently co-occur with TP53 mutations, which impair DNA repair and apoptosis. TP53 mutations, present in 30–50% of HCC cases, are often linked to aflatoxin exposure, particularly in regions with high dietary contamination. The loss of p53 function contributes to genomic instability and therapeutic resistance.

The PI3K/AKT/mTOR pathway is another major driver, with dysregulation observed in nearly half of HCC cases. Mutations in PIK3CA, PTEN loss, and AKT overactivation enhance cell survival, metabolic reprogramming, and angiogenesis. While mTOR inhibitors have been explored as treatments, efficacy remains limited due to compensatory survival pathways. The Ras/Raf/MEK/ERK cascade, often activated through KRAS mutations or overexpression of growth factor receptors like EGFR and MET, fosters tumor proliferation and invasion.

Epigenetic modifications also shape HCC progression. Hypermethylation of tumor suppressor genes like CDKN2A and RASSF1A leads to their silencing, while global hypomethylation promotes chromosomal instability. Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), modulate gene expression and tumor behavior. For example, miR-122, a liver-specific microRNA, is frequently downregulated in HCC, contributing to tumor growth and metastasis.

Common Risk Factors

Chronic liver injury and inflammation drive HCC development. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain leading causes. HBV has a direct oncogenic effect through viral DNA integration, triggering genetic instability and tumorigenic pathways. Even without cirrhosis, HBV-related HCC can occur, highlighting the importance of antiviral therapy. HCV, in contrast, promotes carcinogenesis through chronic inflammation and fibrosis, with sustained viral replication causing oxidative stress and DNA damage. Direct-acting antivirals (DAAs) have significantly reduced HCV-related liver complications, though cirrhotic patients remain at risk for HCC post-clearance.

MASLD is a growing concern, particularly in regions with rising obesity and type 2 diabetes rates. MASLD-related HCC can develop in non-cirrhotic livers, complicating early detection. Insulin resistance drives hepatic lipid accumulation and inflammation, accelerating fibrogenesis. Altered adipokine signaling also contributes, with elevated leptin levels promoting tumor proliferation and reduced adiponectin levels impairing protective pathways. MASLD-associated HCC exhibits distinct molecular signatures, including Hippo-YAP pathway dysregulation.

Chronic alcohol consumption is another major risk factor, with ethanol metabolism generating acetaldehyde, a carcinogen that induces DNA damage. Alcohol exacerbates oxidative stress and disrupts gut-liver axis homeostasis, increasing inflammation. It also synergizes with other risk factors like viral hepatitis and MASLD, accelerating fibrosis and HCC risk. Even moderate alcohol intake has been linked to increased risk, challenging assumptions about safe consumption levels.

Environmental exposures further influence HCC risk. Aflatoxin B1, a mycotoxin from Aspergillus species in improperly stored grains and nuts, induces mutagenic TP53 lesions, impairing DNA repair and promoting unchecked proliferation. Industrial pollutants like vinyl chloride and arsenic may also contribute through epigenetic alterations and mitochondrial dysfunction. Addressing these environmental risks is critical for targeted public health interventions.

Diagnostic Tools

HCC detection relies on imaging, serologic biomarkers, and histopathology. Because early-stage HCC is often asymptomatic, surveillance in high-risk populations, such as those with cirrhosis or chronic viral hepatitis, is crucial. The American Association for the Study of Liver Diseases (AASLD) recommends biannual screening with ultrasound (US), with or without alpha-fetoprotein (AFP) measurement. However, ultrasound sensitivity declines in obese patients or those with advanced fibrosis, necessitating more advanced imaging when suspicion arises.

Multiphasic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are standard diagnostic tools for lesions over 1 cm. These modalities highlight HCC’s vascular profile—arterial phase hyperenhancement followed by washout in the portal venous or delayed phases. The Liver Imaging Reporting and Data System (LI-RADS) standardizes imaging interpretation, categorizing lesions by malignancy probability. MRI, especially with hepatobiliary contrast agents like gadoxetate disodium, excels in detecting small or atypical tumors.

Serologic biomarkers aid in risk stratification and diagnosis. AFP, while widely used, lacks specificity due to elevation in benign liver diseases. Des-gamma-carboxy prothrombin (DCP) and AFP-L3 fraction offer better discrimination, particularly in distinguishing HCC from non-malignant nodules. The GALAD score, incorporating age, gender, and biomarker levels, improves early detection, particularly where imaging access is limited.

When imaging and biomarkers fail to provide definitive conclusions, liver biopsy remains the gold standard. While invasive, biopsy enables molecular profiling that informs prognosis and treatment. However, concerns about sampling error, procedural risks, and tumor seeding limit its widespread use. Liquid biopsy, analyzing circulating tumor DNA (ctDNA) and extracellular vesicles, is emerging as a noninvasive alternative for early detection and disease monitoring, though it remains experimental.

Therapeutic Modalities

HCC treatment depends on tumor stage, liver function, and patient health. Options range from curative interventions like resection and ablation to systemic therapies for advanced disease.

Resection

Surgical resection is the preferred curative option for patients with localized tumors and preserved liver function. Ideal candidates have a single tumor, no cirrhosis-related portal hypertension, and adequate hepatic reserve, as assessed by Child-Pugh and MELD scores. Five-year survival rates exceed 70% in well-selected patients. However, recurrence is a major challenge, with up to 70% developing new tumors within five years. Postoperative surveillance with imaging and biomarker monitoring is essential.

Ablation

For patients ineligible for surgery, thermal ablation techniques like radiofrequency ablation (RFA) and microwave ablation (MWA) offer minimally invasive alternatives. RFA is most effective for tumors under 3 cm, achieving survival outcomes comparable to resection in select cases. MWA, generating higher intratumoral temperatures, improves efficacy for slightly larger lesions. Tumor location affects success, as subcapsular or perivascular lesions pose technical challenges. Combination strategies, such as transarterial chemoembolization (TACE) followed by ablation, enhance local tumor control.

Pharmacologic Agents

Systemic therapy is essential for advanced or unresectable HCC, with targeted agents and multi-kinase inhibitors forming the backbone of treatment. Sorafenib, a tyrosine kinase inhibitor (TKI) targeting VEGFR, PDGFR, and RAF kinases, was the first to show survival benefits, extending median overall survival from 7.9 to 10.7 months in the SHARP trial. Lenvatinib, another TKI, offers similar efficacy with improved progression-free survival.

Combination therapies, such as atezolizumab plus bevacizumab, have surpassed TKIs in efficacy, with the IMbrave150 trial reporting a median survival of 19.2 months. However, systemic therapy is often limited by adverse effects, including hypertension, hand-foot syndrome, and gastrointestinal toxicity. Personalized treatment selection, guided by molecular profiling and patient tolerance, is increasingly emphasized.

Prognostic Indicators

HCC prognosis depends on tumor characteristics, liver function, and patient-specific factors. Tumor burden—including size, number of lesions, and vascular invasion—heavily influences survival. Large or multifocal tumors, particularly those exceeding Milan or UCSF criteria, have higher recurrence rates and reduced curative options. Vascular invasion, especially in the portal or hepatic veins, signifies an aggressive phenotype with poor progression-free survival.

Underlying liver disease is a key determinant of survival. Cirrhosis severity, assessed by Child-Pugh or MELD scores, dictates treatment feasibility. Patients with Child-Pugh A cirrhosis tolerate aggressive therapies, whereas those with decompensated disease face limited options due to heightened treatment toxicity. Elevated biomarkers like AFP and DCP correlate with increased recurrence risk. The ALBI (Albumin-Bilirubin) grade refines prognosis by providing an objective liver function assessment.

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