Over-expression and lack of retinoblastoma protein are associated with tumor progression and metastasis in hepatocellular carcinoma

Abstract

To determine the role of retinoblastoma (Rb) gene alteration in hepatocarcinogenesis, we examined Rb protein expression immuno-histochemically in a series of surgically resected specimens including non-cancerous liver tissues with cirrhosis or chronic hepatitis, large regenerative nodules, pre-cancerous adenomatous hyperplasias as well as primary and metastatic lesions of hepatocellular carcinoma (HCC). All of the non-cancerous liver tissues, large regenerative nodules and adenomatous hyperplasias showed normal Rb protein expression. Altered Rb protein expression was observed in 31 (lack of Rb protein in 16 and over-expression in 15) of the 81 primary HCCs (38%) and was significantly associated with tumor differentiation grade: altered Rb protein expression occurred in 1 of 23 (4%), 16 of 43 (37%) and 14 of 15 (93%) well-, moderately and poorly differentiated tumors (moderately vs. well-differentiated p < 0.01; poorly vs. moderately differentiated p < 0.001). Incidences of both Rb protein absence and over-expression were higher for moderately differentiated than for well-differentiated tumors and even higher for poorly differentiated tumors. Rb protein absence and over-expression were observed in 9 (39%) and 10 (44%) of the 23 metastatic lesions of HCC, respectively, and the incidence of altered Rb protein expression (absence or over-expression) was significantly higher than in primary lesions (83% vs. 38%, p < 0.001). Our observations suggest that elevated and absent Rb protein are closely associated with tumor progression and developing metastatic disease rather than tumor initiation in cases of HCC. Int. J. Cancer (Pred. Oncol.) 84:604-608, 1999.