How should hepatocellular carcinoma be evaluated and managed across its stages, including diagnostic workup, liver function assessment, and treatment options?

Hepatocellular Carcinoma: Evaluation and Management

Hepatocellular carcinoma requires a systematic approach integrating liver function assessment with tumor staging to determine optimal treatment, where surgical resection or transplantation offers the only curative options for early-stage disease in patients with preserved hepatic reserve.

Diagnostic Workup

Initial Diagnosis

• Diagnosis can be established without biopsy when AFP >200-400 ng/mL combined with characteristic imaging findings in cirrhotic patients 1, 2.
• Imaging must demonstrate arterial phase hypervascularity with washout in portal venous or delayed phases on multiphasic CT or MRI 1, 2.
• For potentially resectable masses with AFP >400 ng/mL, proceed directly to surgery without preoperative biopsy to avoid tumor seeding 1.
• Biopsy is reserved for indeterminate imaging findings or when diagnosis remains uncertain 1.

Staging Evaluation

• Obtain chest X-ray and abdominal CT to assess for metastatic disease 1.
• Use TNM/AJCC staging criteria for anatomic tumor classification 1.
• Incorporate BCLC (Barcelona Clinic Liver Cancer) or CLIP staging systems that account for both tumor burden and underlying cirrhosis 1, 3.

Risk Factor Assessment

• Test for hepatitis B surface antigen and hepatitis C antibody, as viral hepatitis represents the most important global risk factor 2, 4.
• Evaluate for alcoholic cirrhosis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are increasingly prevalent etiologies 4, 5.

Liver Function Assessment

Child-Pugh Classification

Child-Pugh grade determines treatment eligibility and is the most critical prognostic factor 1, 6.

• Child-Pugh A and favorable B patients: Evaluate for curative or locoregional therapies 1.
• Child-Pugh C patients: Offer supportive care only, as they cannot tolerate hepatic resection 1, 7.

Additional Hepatic Reserve Markers

• Calculate MELD score for transplant candidates; MELD <9 predicts zero perioperative mortality 6.
• Assess albumin, bilirubin, and PT/INR as markers of synthetic and excretory function 7.
• Consider ICG retention test (ICG R15) where available; values <20-25% indicate adequate reserve for limited resection 6.
• Measure liver stiffness by transient elastography; values >12-14 kPa predict increased risk of post-hepatectomy liver failure 6.

Portal Hypertension Evaluation

• Assess for clinically significant portal hypertension (HVPG >10 mmHg), which adversely affects surgical outcomes 6.
• Use surrogate markers: platelet count <100,000/mm³ with splenomegaly suggests portal hypertension 6.
• Moderate portal hypertension is not an absolute contraindication to limited resection in patients with preserved liver function 6.

Treatment Algorithm by Stage

Localized Resectable Disease (T1, T2, T3, selected T4; N0; M0)

For non-cirrhotic patients, surgical resection (partial hepatectomy) is the standard curative treatment 1.

For cirrhotic patients, treatment selection depends on hepatic functional reserve:

• Child-Pugh A with adequate future liver remnant (FLR): Surgical resection or liver transplantation 1, 6.
• Minimum FLR requirements: ≥20% in normal liver, higher percentages required with cirrhosis 6.
• Consider preoperative portal vein embolization if FLR is insufficient to induce hypertrophy 6.

Localized Unresectable Disease (selected T2, T3, T4; N0; M0)

Liver transplantation should be considered first for unresectable tumors in cirrhotic patients meeting Milan criteria 1, 8.

Alternative locoregional therapies for non-transplant candidates 1:

• Radiofrequency ablation or percutaneous ethanol injection: For tumors <5 cm and/or ≤4 nodules in number.
• Transarterial chemoembolization (TACE): For multifocal HCC with adequate hepatic reserve (Child-Pugh A/B).
• These approaches are appropriate for intermediate-stage disease with preserved liver function 5.

Advanced Disease (any T; N1; M1)

Immune checkpoint inhibitor-based systemic therapy is now the preferred first-line treatment for advanced HCC 5.

• Historical systemic chemotherapy (anthracyclines, cisplatin, 5-FU) showed only 10% response rates with no survival benefit 1.
• Sorafenib demonstrated modest survival extension of 2.8 months in phase III trials 1.
• Modern ICI-based combinations have transformed outcomes for advanced disease 4, 5.

Critical Pitfalls and Caveats

Avoid These Common Errors

• Do not perform biopsy on potentially resectable lesions with AFP >400 ng/mL—this delays curative surgery and risks tumor seeding 1.
• Do not attempt hepatic resection in Child-Pugh C patients—perioperative mortality is prohibitive; only transplantation offers potential cure 1, 8.
• Do not overlook portal hypertension assessment—significant portal hypertension (platelet <100K with splenomegaly) increases post-hepatectomy liver failure risk 6.

Future Liver Remnant Considerations

• Inadequate FLR is the primary cause of post-hepatectomy liver failure 6.
• Portal vein embolization performed 4-6 weeks preoperatively can increase FLR volume by 20-40% 6.
• Maintain low central venous pressure during resection and use ultrasonic dissection devices to minimize blood loss 6.

Surveillance After Curative Treatment

• Follow patients with AFP and liver imaging every 3-6 months for 2 years post-resection 1.
• Early detection of recurrence allows for repeat curative intervention in select cases 1.
• Consider antiviral therapy for hepatitis B/C to reduce recurrence risk 1.