title: Large cell change (liver cell dysplasia) and hepatocellular carcinoma in cirrhosis: matched case-control study, pathological analysis, and pathogenetic hypothesis.
abstract: Large cell change (LCC), characterized by cellular enlargement, nuclear 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 prognostic value of LCC as a marker of subsequent hepatocellular carcinoma (HCC) through a case-control study that compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant recipients with HCC to specimens from a control group of recipients without HCC, matched for 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 specimens. 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 histogenetic association between the two lesions. LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a greater degree of apoptosis than normal hepatocytes (labeling indices of 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 polyploidization. Such derangements, possibly caused by chronic inflammation-induced DNA damage, could yield a population of enlarged liver cells with nuclear atypia and pleomorphism, frequent binuclearity, and minimal proliferation. According to this hypothesis, LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC but would not represent a direct malignant precursor.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, PA, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Lee
authors.forename: A C
authors.initials: AC
authors.lastname: Tsamandas
authors.forename: A J
authors.initials: AJ
authors.lastname: Demetris
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000209:etiology / Q000473:pathology*; D016022:Case-Control Studies; D002455:Cell Division; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology*; D008113:Liver Neoplasms / Q000737:chemistry / Q000209:etiology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis
chemical_list: D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen