Why can liver cancer occur with normal alpha-fetoprotein (AFP) levels?

Why Alpha-Fetoprotein (AFP) is Normal in Many Liver Cancer Cases

Alpha-fetoprotein (AFP) is normal in up to 46% of hepatocellular carcinoma (HCC) cases because AFP production varies significantly based on tumor biology, with many HCC tumors lacking the molecular mechanisms needed for AFP expression. 1

Understanding AFP in Hepatocellular Carcinoma

AFP is an oncofetal glycoprotein that has historically been used as a tumor marker for HCC. However, its diagnostic utility is limited by several important factors:

Limited Sensitivity

• According to the National Comprehensive Cancer Network (NCCN) guidelines, normal serum AFP levels (<20 ng/mL) are found in 46% of patients with HCC 1
• Only 18% of HCC patients have AFP values >400 ng/mL, which is the level typically considered diagnostic 1
• In a series of 1,158 patients with HCC, most did not have significantly elevated AFP levels 1

Biological Factors Affecting AFP Expression

Several biological mechanisms explain why AFP remains normal in many HCC cases:

1. Tumor Differentiation:

   • Well-differentiated HCCs are less likely to produce AFP
   • AFP production doesn't correlate consistently with tumor differentiation 2

2. Molecular Heterogeneity:

   • Different HCC cell lines show variable AFP expression patterns 3
   • Proteomic studies have identified distinct protein signatures associated with AFP-producing versus non-producing HCC cell lines 3

3. Differential Expression:

   • Some tumors may produce AFP but not secrete it efficiently into the bloodstream
   • Tissue AFP can be negative even when serum AFP is elevated in some cases 2

Clinical Implications

The limited sensitivity of AFP has important clinical implications:

• Diagnostic Approach: Since AFP is normal in many HCC cases, imaging findings of classic enhancement are considered more definitive for diagnosis than AFP alone 1
• Surveillance Strategy: Ultrasound combined with AFP is recommended for surveillance, as neither test alone is sufficient 1
• Alternative Markers: When AFP is normal, other markers like gamma-carboxyprothrombin may be considered 1

When to Consider HCC Despite Normal AFP

HCC should still be considered in the following scenarios despite normal AFP:

• Patients with cirrhosis and a suspicious liver mass on imaging
• Growing nodules in a cirrhotic liver
• Typical vascular enhancement patterns on multiphasic CT or MRI

Diagnostic Algorithm When AFP is Normal

1. For nodules <1 cm in a cirrhotic liver:

   • Follow with ultrasound every 4 months for the first year
   • Continue surveillance every 6 months thereafter 1

2. For nodules >1 cm:

   • Proceed with multiphasic CT or MRI regardless of AFP level
   • Look for typical vascular pattern (arterial enhancement with portal/venous washout) 1
   • If first imaging is inconclusive, perform an alternative imaging technique
   • Consider biopsy for nodules with atypical vascular patterns 1

Pitfalls to Avoid

1. Don't exclude HCC based on normal AFP alone

   • A negative AFP result does not exclude the diagnosis of HCC 2

2. Don't rely solely on absolute AFP cutoff values

   • The diagnostic accuracy of absolute AFP cutoffs varies by institution and patient population 1

3. Consider AFP trends rather than single values

   • A progressively rising AFP (>7 ng/mL/month) may be more sensitive than a single elevated value 4

4. Be aware of false positives

   • AFP can be elevated in non-HCC conditions including chronic hepatitis, cirrhosis, pregnancy, and other cancers 5
   • Some colon cancer metastases to the liver can produce AFP 6

By understanding the limitations of AFP in HCC diagnosis, clinicians can implement more effective surveillance and diagnostic strategies that don't rely exclusively on this marker.