Can Hepatocellular Carcinoma (HCC) occur with normal Alpha-Fetoprotein (AFP) levels?

Yes, HCC Absolutely Occurs with Normal AFP Levels

Hepatocellular carcinoma frequently presents with normal AFP levels—up to 35-46% of HCC cases have completely normal AFP (<20 ng/mL), even when tumors are large. 1, 2 This is a critical clinical reality that must guide your diagnostic approach.

Key Evidence on AFP-Negative HCC

AFP is an inadequate standalone marker for HCC diagnosis or exclusion. The data are unequivocal:

• Up to 20% of HCC patients do not produce AFP at all, even with very large tumors 3
• Two-thirds of HCCs less than 4 cm have AFP levels below 200 ng/mL 3
• Only 10-20% of early-stage HCC tumors present with abnormal AFP serum levels 1
• In a large cohort of 1,158 HCC patients, 46% had completely normal AFP levels (<20 ng/mL), and only 18% had AFP >400 ng/mL 1
• 18% of patients in another series had normal AFP (<10 ng/mL) at HCC diagnosis 4

Clinical Implications: Never Rule Out HCC Based on Normal AFP

A normal AFP does NOT exclude HCC—always combine with imaging. 1, 2 This is the most important pitfall to avoid in clinical practice.

Diagnostic Algorithm When HCC is Suspected

1. Primary surveillance approach: Ultrasound every 6 months combined with AFP measurement for high-risk patients (cirrhosis, chronic hepatitis B/C, advanced fibrosis) 2

2. When AFP is normal but HCC is suspected:

   • Proceed immediately to multiphasic CT or MRI looking for arterial hyperenhancement with portal venous or delayed phase washout 1, 2
   • Ultrasound alone is insufficient—definitive cross-sectional imaging is mandatory 1

3. For lesions ≥1 cm with typical imaging features: Diagnosis can be made without biopsy, even if AFP is normal 1, 2

4. If imaging is atypical or non-diagnostic: Proceed to biopsy for definitive diagnosis 1

AFP Performance Characteristics

Understanding AFP's limitations is essential:

• At 20 ng/mL cutoff: Sensitivity only 60%, meaning it misses 40% of HCC cases 2
• At 200 ng/mL cutoff: Sensitivity drops to 22%, though specificity approaches 100% 1, 2
• At 400 ng/mL cutoff: Sensitivity only 32%, but specificity 99% 5

The higher the AFP threshold, the more cases you will miss. 5

When AFP is Elevated: Prognostic Value

While normal AFP doesn't exclude HCC, elevated AFP does provide prognostic information:

• AFP >400 ng/mL predicts: Portal vein thrombosis (OR 4.08), larger tumor size (OR 2.19), and advanced BCLC stage (OR 4.19) 4
• Rising AFP over time, even if not reaching 400 ng/mL, is virtually diagnostic of HCC 3
• AFP >400 ng/mL is an independent predictor of mortality (HR 2.23) in patients receiving therapy 4

Critical Pitfalls to Avoid

1. Never rely on AFP alone for screening or diagnosis due to poor sensitivity 1, 2
2. Never assume normal AFP rules out HCC—more than one-third of cases will be missed 1, 2
3. False positives occur frequently: Active hepatitis, regenerating cirrhotic nodules, pregnancy, cholangiocarcinoma, colon cancer metastases, lymphoma, and germ cell tumors can all elevate AFP 1, 6
4. Two-thirds of small HCCs (<4 cm) have AFP <200 ng/mL, making AFP particularly unreliable for early detection 3

Bottom Line for Clinical Practice

Imaging is mandatory for HCC diagnosis—AFP is only an adjunctive tool. 1, 2 In high-risk patients with normal AFP, maintain the same level of suspicion and proceed with definitive imaging when clinically indicated. The combination of ultrasound surveillance every 6 months with AFP measurement remains the standard approach, but the imaging component is non-negotiable, regardless of AFP level. 2