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Introduction: Serum alpha-Fetoprotein (AFP) is widely utilized in screening patients at risk for hepatocellular carcinoma (HCC). AFP levels also provide prognostic information, as several reports have associated high AFP levels (>1000ng/ml) with poor survival. Although clearly associated with transformation to HCC and with poor outcomes, the etiologic process leading to AFP elevation remains debatable. Some experts interpret high AFP as an indication of de-differentiation and vascular invasion. We investigate here the predictive value of AFP to survival and poor histologic features following liver resection in a single-institution series.Methods: A retrospective analysis was performed on 238 patients with HCC maintained in a prospective database. All patients had underlying chronic hepatitis B, and underwent liver resection as definitive therapy for HCC. Kaplan-Meier, chi square, univariate, and multivariate regression analysis were performed using SPSS software (SPSS, Chicago, IL).Results: Seventy six patients (32%) were diagnosed with tumors that did not produce AFP (AFP-, <9ng/ml). Of the 143 patients (60%) whose tumors did produce AFP (AFP+), 80 (56%) were diagnosed with moderate serum AFP elevation (AFPmod, 10-999ng/ml), and 63 (44%) had high AFP (AFPhigh, >1000ng/ml). AFP- patients had better survival following resection compared to AFP+ patients (72% vs. 61% 5-yr, p=.013). When analyzed inclusive of all 238 patients, AFPhigh was associated to tumor size >5cm (p=.021, OR 2.1), poor differentiation (p=.006), and vascular invasion (p=.028, OR 4.8) by univariate analysis. In multivariate analysis only tumor size >5cm retained significance (p=.027, OR 2.2). When AFP- patients were excluded, a clear trend towards better survival was seen in AFPmod patients compared to AFPhigh (73% vs. 51%, p=.11). In univariate analysis inclusive only of AFP+ patients, tumor size >5cm was associated with high AFP levels (p=.036, OR 2.1), but poor differentiation and vascular invasion were not.Conclusion: HCCs that do not produce serum AFP are associated with better survival following liver resection, and tumors associated with high levels of AFP (>1000ng/ml) have worse survival outcomes overall. High serum AFP levels are associated with tumor size, but not with poorly-differentiated histology or vascular invasion on regression analysis, and the predictive value of high AFP for these features is poor (Table 1). The association of high serum AFP to poor survival and large tumor size is presumably due to delay in diagnosis, rather than more aggressive tumor biology.
Table 1. Predictive value of high serum AFP (>1000ng/ml) to histologic features indicative of aggressive tumor biology.

	Vascular Invasion	Poorly-Differentiated Histology
Sensitivity	42%	49%
Specificity	71%	65%
Positive Predictive Value	87%	47%
Negative Predictive Value	21%	67%