What is the approach to diagnosing and treating liver masses suspected to be hepatocellular carcinoma (HCC)?

Approach to Liver Masses and Hepatocellular Carcinoma

Surveillance for High-Risk Patients

High-risk patients (cirrhotic HBV carriers, non-cirrhotic patients with high HBV DNA, HCV-related or alcoholic cirrhosis) should undergo abdominal ultrasound every 6 months with concurrent serum AFP measurement to maximize early detection rates. 1, 2

• The American Association for the Study of Liver Diseases recommends six-monthly ultrasound as the primary screening modality, with sensitivity of 72% and specificity of 94% 2
• Adding AFP to ultrasound increases early-stage HCC detection from 45% to 63% 2, 3
• A large Chinese randomized trial of 18,816 patients demonstrated that screening with AFP and ultrasonography every 6 months resulted in a 37% reduction in HCC mortality 2
• Critical caveat: Ultrasound is highly operator-dependent and requires an experienced operator skilled in assessing chronic liver disease 2

Diagnostic Algorithm Based on Lesion Size

Nodules <1 cm

• Follow with ultrasound at 3-6 month intervals 1
• Do not proceed to advanced imaging or biopsy at this stage 1

Nodules 1-2 cm in Cirrhotic Liver

• Investigate with at least two dynamic imaging studies (triphasic CT, contrast-enhanced ultrasound, or MRI with contrast) 1
• If two techniques show typical HCC appearance (arterial hypervascularity with portal venous washout), interpret as HCC without biopsy 1
• If imaging is atypical, perform biopsy or surgical extirpation at physician discretion 1

Nodules >2 cm

• A single dynamic imaging study (CT or MRI) showing typical HCC features is diagnostic and does not require biopsy 1, 4
• Any nodule with AFP >400 ng/ml or rising AFP on sequential determinations should be considered proven HCC regardless of imaging characteristics 1
• Patients with potentially resectable liver mass and AFP >400 ng/ml should proceed directly to surgery without preoperative biopsy 1

Optimal Imaging Modalities

MRI has superior sensitivity and specificity compared to triphasic CT in patients with nodular cirrhotic livers, though overall sensitivity is similar in non-cirrhotic livers. 1

• Triphasic CT with arterial phase imaging increases tumor nodule detection but has low sensitivity in nodular cirrhotic livers 1
• MRI provides better characterization of lesions in cirrhotic patients 1, 5, 6, 7
• Contrast-enhanced ultrasound can serve as an alternative dynamic imaging technique 1, 7

Role of Alpha-Fetoprotein (AFP)

AFP ≥200 ng/mL provides high specificity (97-98%) and positive predictive value (97.5%) for HCC diagnosis in patients with a liver mass, but sensitivity is only 22-49%. 3

• AFP is elevated in only 50-75% of HCC cases 1
• Up to 35-40% of HCC cases have normal AFP levels, even with large tumors 2, 3
• AFP should never be used alone for HCC diagnosis or screening due to inadequate sensitivity 2, 3
• AFP can be falsely elevated in active hepatitis, regenerating cirrhotic nodules, pregnancy, cholangiocarcinoma, colon cancer metastases, lymphoma, and germ cell tumors 3

Staging Evaluation

Staging should include chest imaging (X-ray or CT) and abdominal CT or MRI to assess tumor burden, vascular invasion, and extrahepatic spread. 1

• For transplant candidates, add chest CT and bone scintigraphy 1
• Use BCLC (Barcelona Clinic Liver Cancer) or CLIP (Cancer of the Liver Italian Program) staging systems rather than TNM alone, as these incorporate liver function 1, 4
• Assess hepatic functional reserve using Child-Pugh classification 1, 4
• Child-Pugh grade C patients should receive only supportive care 1
• Child-Pugh grade A and favorable grade B patients should be evaluated for specific treatment options 1

Treatment Approach by Stage

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

Surgical resection (partial hepatectomy) is the standard treatment for patients without cirrhosis. 1, 4

• For patients with cirrhosis, choose between surgical resection or liver transplantation based on hepatic functional reserve 1, 4
• Liver transplantation should follow Milan criteria, with 5-year survival >75% in appropriate candidates 1
• Only about 5% of HCC patients are suitable for transplantation 1

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

Consider total hepatectomy with liver transplantation first for unresectable disease. 1

Alternative locoregional therapies include:

• Transarterial chemoembolization (TACE) for multifocal HCC with adequate hepatic reserve and no vascular invasion 1, 4
• Percutaneous ethanol injection for fewer than 3-4 tumor nodules, maximum 5 cm in size 1
• Radiofrequency ablation for tumors <5 cm and/or fewer than four in number 1

Advanced Disease with Vascular Invasion or Extrahepatic Spread

Atezolizumab plus bevacizumab is the preferred first-line immune checkpoint inhibitor-based regimen for advanced HCC. 4

• Sorafenib remains an alternative first-line option, extending survival by 2.8 months in phase III trials (median survival 10.7 vs 7.9 months, HR 0.69, p=0.00058) 8
• Sorafenib dosing: 400 mg orally twice daily without food (at least 1 hour before or 2 hours after meals) 8
• Systemic chemotherapy with anthracyclines, cisplatin, and 5-FU has only 10% response rate with no survival benefit 1

Post-Treatment Surveillance

After curative resection, perform AFP and liver imaging every 3-6 months for 2 years, as curative therapy can still be offered at relapse. 4

• Use modified RECIST criteria for response assessment on dynamic CT or MRI 4
• Any deterioration in liver function in a patient with known cirrhosis should raise suspicion for HCC recurrence 1

Critical Clinical Pitfalls

• Do not biopsy potentially resectable lesions with AFP >400 ng/ml - proceed directly to surgery to avoid tumor seeding 1
• Do not rely on AFP alone - 35-40% of HCCs have normal AFP even with large tumors 2, 3
• Do not use CT for screening - CT is a confirmatory diagnostic test, not a surveillance tool 2
• Do not offer curative treatment to Child-Pugh C patients - they have limited treatment options and should receive supportive care only 1
• Tumors are multifocal in 75% of cases at diagnosis, requiring comprehensive staging 1