Vascular invasion and high histologic grade predict poor outcome after surgical resection or liver transplantation for hepatocellular carcinoma (HCC). Despite the known association between tumor size and vascular invasion, a proportion of patients with large tumors can be treated surgically with excellent outcomes. Clarification of the association between tumor size, histologic grade, and vascular invasion has implications for patient selection for resection and transplantation. The objective of this study was to examine the relationship between HCC tumor size and microscopic (occult) vascular invasion and histologic grade in a multicenter international database of 1,073 patients who underwent resection of HCC. The incidence of microscopic vascular invasion increased with tumor size (< or =3 cm, 25%; 3.1-5 cm, 40%; 5.1-6.5 cm, 55%; >6.5 cm, 63%) (P < 0.005). Both size and number of tumors were important factors predicting vascular invasion. Among all patients with tumors 5.1 to 6.5 cm, microscopic vascular invasion was present in 55% compared with 31% for all patients with tumors 5 cm or smaller (P < 0.001). Among patients with solitary tumors only, microscopic vascular invasion was significantly more common in tumors measuring 5.1 to 6.5 cm (41%) compared with 27% of tumors 5 cm or smaller (P < 0.003). Tumor size also predicted histologic grade: 36% of tumors 5 cm or smaller were high grade, compared with 54% of lesions 5.1 to 6.5 cm (P = 0.01). High histologic grade, an alpha-fetoprotein level of at least 1000 ng/mL, and multiple tumor nodules each predicted occult vascular invasion in tumors larger than 5 cm. The high incidence of occult vascular invasion and advanced histologic grade in HCC tumors larger than 5 cm, as well as biologic predictors of poor prognosis, should be considered before criteria for transplantation are expanded to include these patients.
