The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population

Abstract

Background & aims: The percentage of Lens culinaris agglutinin-reactive (alpha)-fetoprotein (AFP-L3%) is proposed as a diagnostic and prognostic marker for hepatocellular carcinoma (HCC). We evaluated the utility of AFP-L3% for diagnosis of HCC in a US referral population.

Methods: This retrospective study included 272 patients: 166 with HCC and 106 with benign liver disease (chronic liver disease, 77; benign liver mass, 29). The AFP-L3% was measured using a clinical auto-analyzer.

Results: The AFP-L3% is not reported for a total alpha-fetoprotein (AFP) less than 10 ng/mL, and all patients with an AFP greater than 200 ng/mL had HCC; thus the AFP-L3% was noninformative for these patients. In patients with a total AFP of 10-200 ng/mL, an AFP-L3% greater than 10% had a sensitivity of 71% and a specificity of 63% for diagnosis of HCC. An AFP-L3% greater than 35% had a reduced sensitivity of 33%, but an increased specificity of 100%. The high specificity of the AFP-L3% cut-off of 35% allowed the confident diagnosis of an additional 10% of HCCs not diagnosed using an AFP cut-off of 200 ng/mL. After adjustment for AFP level, no association was observed between AFP-L3% and tumor size, stage, vascular invasion, grade, or survival.

Conclusions: Patients with indeterminate total AFP values of 10-200 ng/mL present a diagnostic dilemma. We found that an AFP-L3% greater than 35% has 100% specificity for HCC in these patients. AFP-L3%, used in combination with AFP, may be a clinically useful adjunct marker for the diagnosis of HCC.

Figure 1

Figure 1A. Receiver operating characteristic (ROC) curves comparing total AFP with AFP-L3% for diagnosis of HCC in individuals with total AFP greater than 10 ng/ml. Figure 1B. ROC curves comparing total AFP with AFP-L3% for diagnosis of HCC in individuals with total AFP between 10 and 200 ng/ml.

Figure 1

Figure 1A. Receiver operating characteristic (ROC) curves comparing total AFP with AFP-L3% for diagnosis of HCC in individuals with total AFP greater than 10 ng/ml. Figure 1B. ROC curves comparing total AFP with AFP-L3% for diagnosis of HCC in individuals with total AFP between 10 and 200 ng/ml.

Figure 2. Scatter plot of AFP-L3 by AFP category

For individuals with a total AFP in the indeterminate range of 10-200 ng/ml, an AFP-L3% of greater than 35% was 100% specific, with no false positives. The curved line represents an absolute AFP-L3 cut-off value of 11 ng/ml, which was also 100% specific. NR: AFP-L3 values are non-specific and not reported when total AFP is in the range 0.8 - 10 ng/ml and AFP-L3 is >0.5%.

Figure 3. Distribution of AFP-L3 level by tumor characteristics

Histograms showing the relationship between AFP-L3% and tumor characteristics: 3A, tumor size; 3B, tumor stage; 3C, vascular invasion; and 3D, histologic grade. The means were calculated without taking into consideration AFP-L3 values which were not detected (ND), not reported (NR), not measurable because the total AFP was undetected (U), or not measurable because the total AFP was >300,000 ng/ml (H). There is little effect of L3% for tumor size, tumor grade, and vascular involvement. There is a possible trend for TNM, but the numbers are small.

Figure 3. Distribution of AFP-L3 level by tumor characteristics

Histograms showing the relationship between AFP-L3% and tumor characteristics: 3A, tumor size; 3B, tumor stage; 3C, vascular invasion; and 3D, histologic grade. The means were calculated without taking into consideration AFP-L3 values which were not detected (ND), not reported (NR), not measurable because the total AFP was undetected (U), or not measurable because the total AFP was >300,000 ng/ml (H). There is little effect of L3% for tumor size, tumor grade, and vascular involvement. There is a possible trend for TNM, but the numbers are small.

Figure 3. Distribution of AFP-L3 level by tumor characteristics

Histograms showing the relationship between AFP-L3% and tumor characteristics: 3A, tumor size; 3B, tumor stage; 3C, vascular invasion; and 3D, histologic grade. The means were calculated without taking into consideration AFP-L3 values which were not detected (ND), not reported (NR), not measurable because the total AFP was undetected (U), or not measurable because the total AFP was >300,000 ng/ml (H). There is little effect of L3% for tumor size, tumor grade, and vascular involvement. There is a possible trend for TNM, but the numbers are small.

Figure 3. Distribution of AFP-L3 level by tumor characteristics

Histograms showing the relationship between AFP-L3% and tumor characteristics: 3A, tumor size; 3B, tumor stage; 3C, vascular invasion; and 3D, histologic grade. The means were calculated without taking into consideration AFP-L3 values which were not detected (ND), not reported (NR), not measurable because the total AFP was undetected (U), or not measurable because the total AFP was >300,000 ng/ml (H). There is little effect of L3% for tumor size, tumor grade, and vascular involvement. There is a possible trend for TNM, but the numbers are small.

Figure 4. Survival in hepatocellular carcinoma patients by AFP-L3% level and total AFP level

4A: AFP-L3% level >10% predicts survival of patients with HCC (p=0.0012). 4B: Total AFP >200 ng/ml is a better predictor of survival of HCC patients (p<0.0001). Once total AFP is taken into account, there is no additional prognostic value of the AFP-L3% in this cohort.

Figure 4. Survival in hepatocellular carcinoma patients by AFP-L3% level and total AFP level

4A: AFP-L3% level >10% predicts survival of patients with HCC (p=0.0012). 4B: Total AFP >200 ng/ml is a better predictor of survival of HCC patients (p<0.0001). Once total AFP is taken into account, there is no additional prognostic value of the AFP-L3% in this cohort.