How to diagnose hepatocellular carcinoma (HCC) in a patient with chronic liver disease and a triple phase computed tomography (CT) scan suggestive of HCC but with normal alpha-fetoprotein (AFP) levels?

Diagnosis of HCC with Typical Imaging but Normal AFP

In a patient with chronic liver disease and triple-phase CT showing typical HCC features (arterial hypervascularity with portal venous washout), HCC can be diagnosed without biopsy regardless of AFP level, as normal AFP does not exclude HCC and occurs in up to 35-46% of cases. 1, 2

Diagnostic Algorithm Based on Lesion Size

For Nodules ≥2 cm

• One imaging modality (CT or MRI) showing typical HCC characteristics is sufficient for diagnosis, regardless of AFP level 3
• Typical hallmark features required: arterial phase hypervascularity with washout in portal venous or delayed phases 3
• This approach is supported by the 2009 Korean Liver Cancer Study Group, 2010 AASLD, and 2012 EASL guidelines, which all removed AFP as a mandatory diagnostic criterion 3

For Nodules 1-2 cm

• If typical imaging features are present on dynamic CT or MRI, diagnosis can be made without biopsy 3
• If imaging is atypical or inconclusive, obtain a second contrast-enhanced study with an alternative modality (MRI if CT was first, or vice versa) 3
• If both studies remain non-diagnostic, proceed to biopsy with repeat biopsy if initial results are inconclusive 3

For Nodules <1 cm

• Follow with ultrasound every 3-4 months for the first year, then every 6 months 3
• Perform repeat imaging if growth is detected 3

Why Normal AFP Does Not Exclude HCC

Critical evidence demonstrates that AFP has severe limitations as a diagnostic marker:

• Up to 46% of HCC patients have completely normal AFP levels (<20 ng/mL), even with large tumors 1
• Two-thirds of HCCs smaller than 4 cm have AFP levels below 200 ng/mL 1
• Only 10-20% of early-stage HCC cases present with abnormal AFP levels 1
• At the commonly used 20 ng/mL cutoff, AFP sensitivity is only 60%, missing 40% of HCC cases 2, 4

This is precisely why the 2010 AASLD guideline excluded AFP from diagnostic criteria—its sensitivity for HCC diagnosis was lower than ultrasonography for tumors less than 3 cm 3

Imaging Takes Precedence Over AFP

The evolution of guidelines reflects increasing confidence in imaging accuracy:

• The 2010 AASLD and 2012 EASL guidelines established that nodules ≥1 cm with typical features on one imaging technique can be diagnosed as HCC without biopsy 3
• The 2010 APASL guideline goes further, stating HCC can be diagnosed by dynamic imaging regardless of tumor size and AFP level 3
• Studies demonstrated nearly 100% diagnostic accuracy for tumors ≥2 cm with typical imaging characteristics 3

When to Consider Biopsy

Biopsy is indicated only in specific circumstances:

• Atypical imaging features (iso- or hypovascular in arterial phase, or arterial hypervascularity without portal venous washout) 3
• Uncertainty after two different imaging modalities 3
• Lesions in non-cirrhotic patients where non-invasive criteria cannot be applied 3
• If initial biopsy is inconclusive, repeat biopsy is recommended 3

Common Pitfalls to Avoid

Never delay diagnosis waiting for AFP elevation - This outdated approach will miss nearly half of HCC cases and delay potentially curative treatment 1, 2

Do not order biopsy if imaging is典型 - For lesions ≥1 cm with characteristic features, biopsy adds risk without diagnostic benefit and may cause tumor seeding 3, 1

Ensure imaging quality meets guideline standards - Non-invasive diagnosis requires 4-phase multidetector CT or dynamic contrast-enhanced MRI; suboptimal imaging may require two techniques or biopsy 3

Remember non-invasive criteria apply only to cirrhotic patients - In non-cirrhotic chronic liver disease, lower threshold for biopsy confirmation 3

Additional Diagnostic Considerations

If imaging remains equivocal after standard CT/MRI, consider:

• Contrast-enhanced ultrasound (CEUS) with Kupffer cell-specific agents 3
• SPIO-MRI (superparamagnetic iron oxide MRI) 3
• These modalities exploit the fact that HCC has fewer Kupffer cells than surrounding liver tissue 3

The key principle: In your patient with chronic liver disease and typical triple-phase CT findings, proceed with HCC diagnosis and staging regardless of normal AFP, as imaging accuracy supersedes tumor marker levels for lesions with characteristic features. 3, 1