What serological tests are useful in diagnosing Hepatocellular Carcinoma (HCC)?

Serological Tests for Diagnosing Hepatocellular Carcinoma

Alpha-fetoprotein (AFP) remains the primary serological test for HCC diagnosis, but should only be used as an adjunctive tool in combination with imaging—never as a standalone diagnostic test—with an AFP >200 ng/mL having very high positive predictive value when a liver mass is present in cirrhotic patients. 1

Primary Serological Marker: Alpha-Fetoprotein (AFP)

Diagnostic Performance and Limitations

• AFP has inadequate sensitivity (39-65%) and variable specificity (76-97%) depending on cutoff values used, making it insufficient as a standalone diagnostic test 1, 2
• At the commonly recommended cutoff of 20 ng/mL, AFP sensitivity is only 60%, meaning it would miss 40% of HCC cases 1
• When AFP cutoff is raised to 200 ng/mL, sensitivity drops dramatically to only 22%, though specificity approaches 100% 1
• Up to 40-60% of HCC patients have normal AFP levels, with particularly poor sensitivity in early-stage disease where only 10-20% show abnormal AFP 2, 3

Clinical Application of AFP

For diagnostic purposes (not screening), AFP >200-400 ng/mL in a cirrhotic patient with a liver mass has very high positive predictive value for HCC and can establish diagnosis without biopsy 1, 3

• Multiple international guidelines (EASL, BSG, Korean, BASL, SGA, ESMO) recommend AFP only as an adjunctive diagnostic tool, not for standalone diagnosis 1
• A rising AFP over time, even below diagnostic thresholds, is highly suspicious for HCC and warrants intensified surveillance 3
• False positives occur in active hepatitis, regenerating cirrhotic nodules, pregnancy, and other malignancies (cholangiocarcinoma, colon cancer metastases) 3

Additional Serological Markers

Des-gamma-carboxy Prothrombin (DCP/PIVKA-II)

DCP can be used as a complementary marker to AFP but lacks sufficient evidence for routine use in most countries 1

• DCP is currently approved only in Japan, South Korea, and Indonesia 1
• Combining DCP with AFP increases diagnostic sensitivity but is not widely available or validated for routine clinical use 1
• DCP may be a marker for portal vein invasion, suggesting it detects later-stage rather than early disease 1

AFP-L3 (Lens Culinaris Agglutinin-Reactive AFP)

• The combination of AFP and AFP-L3 can improve HCC detection sensitivity, but this testing is available only in select countries 1
• AFP-L3 has not been adequately investigated for routine clinical recommendation 1

Other Markers Not Recommended

Alpha-fucosidase, glypican-3, and proteomic profiling have insufficient evidence and cannot be recommended for clinical use 1

Practical Clinical Algorithm

When to Use Serological Tests

1. For patients with detected liver nodules on imaging:

   • If AFP >200 ng/mL with characteristic imaging features (arterial enhancement, portal venous washout), diagnosis can be made without biopsy 1, 3
   • If AFP <200 ng/mL, proceed to definitive imaging (dynamic CT/MRI) or biopsy 1

2. AFP should NOT be used alone for screening or surveillance due to poor sensitivity and high false-positive rates 1, 2

3. When combining AFP with ultrasound for surveillance, AFP adds only 6-8% additional detection but increases false positives by 80% and costs by 50% 3

Critical Pitfalls to Avoid

• Never rely on AFP alone to rule out HCC—up to 35% of HCC cases have normal AFP even with large tumors 3
• Do not use AFP as a screening test in isolation—imaging (ultrasound, CT, MRI) has superior performance characteristics 1
• Two-thirds of HCCs <4 cm have AFP <200 ng/mL, so normal AFP does not exclude early-stage disease 3
• Avoid biopsy if curative surgery is planned when diagnosis can be established by AFP >200 ng/mL plus characteristic imaging 1