LARGE-CELL CHANGE (LIVER-CELL DYSPLASIA) AND HEPATOCELLULAR-CARCINOMAIN CIRRHOSIS - MATCHED CASE-CONTROL STUDY, PATHOLOGICAL ANALYSIS, ANDPATHOGENETIC HYPOTHESIS

Large cell change (ICC), characterized by cellular enlargement, nuclea r pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain uncertain. Therefore, we assessed the prognos tic value of LCC as a marker of subsequent hepatocellular carcinoma (H CC) through a case-control study that compared pretransplant liver bio psy specimens from 37 cirrhotic liver transplant recipients with HCC t o specimens from a control,group of recipients without HCC, matched fo r sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in 16 (43%) of the study and 7 (19%) of the control group biopsy specime ns. By matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a morphological transition or a his togenetic association between the two lesions. LCC hepatocytes display ed a low proliferative rate by Ki-67 or proliferating cell nuclear ant igen immunostaining (labeling indices of 0.27 and 0.73) but showed a g reater degree of apoptosis than normal hepatocytes (labeling indices o f 1.9 and 0.23; P = .03) To reconcile these findings, we propose that LCC derives from derangements in the hepatocyte's normal process of po lyploidization. Such derangements, possibly caused by chronic inflamma tion-induced DNA damage, could yield a population of enlarged liver ce lls with nuclear atypia and pleomorphism, frequent binuclearity, and m inimal proliferation. According to this hypothesis, LCC would be a hab itual feature of cirrhosis and a regular accompaniment of HCC but woul d not represent a direct malignant precursor.