Hepatocellular carcinomas in native livers from patients treated with orthotopic liver transplantation: Biologic and therapeutic implications

The gross and histopathologic characteristics of 212 non-fibrolamellar hepa tocellular carcinomas (HCCs) discovered in native livers removed at the tim e of liver transplantation were correlated with features of invasive growth and tumor-free survival. The results show that most HCCs begin as small we ll-differentiated tumors that have an increased proliferation rate and indu ce neovascularization, compared with the surrounding liver. But at this sta ge, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear wit hin the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular i nvasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mito sis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P < .006), apoptosis/mitosis ratio (P < .03), and number of tum ors (P < .04) were independent predictors of tumor-free survival and none o f 24 patients with tumors having an apoptosis/mitosis ratio greater than 7. 2 had recurrence. A minority of HCCs (< 15%) quickly develop aggressive fea tures (moderate or poor differentiation, low apoptosis/mitosis ratio, and v ascular invasion) while still small, similar to flat carcinomas of the blad der and colon. In conclusion, hepatic carcinogenesis in humans is a multist ep and multifocal process. As in experimental animal studies, aggressive bi ologic behavior (vascular invasion and recurrence) correlates significantly with profound alterations in the apoptosis/mitosis ratio and with architec tural and cytologic alterations that suggest a progressive accumulation of multiple genetic abnormalities.