Faculty Bibliography

We examined the expression of mutant p53 gene products in primary malignant epithelial tumors of the liver. Fourteen of 68 hepatocellular carcinomas, one of seven hepatoblastomas and one of nine intrahepatic cholangiocarcinomas showed nuclear staining for p53 proteins. None of the surrounding non-tumorous tissues expressed nuclear staining. The detection of p53 proteins in tumor cells was significantly higher in hepatocellular carcinomas of Oriental patients (31.6%) compared to non-Orientals (6.7%, p < 0.015). No significant differences were seen in p53 antigen expression between hepatitis B and non-hepatitis B associated hepatocellular carcinomas in Oriental patients. These results suggest a role for other environmental factors, such as aflatoxin, in the etiology of p53 mutation in hepatocellular carcinoma in Oriental patients

We report an incidental small hepatocellular carcinoma in a patient with chronic hepatitis C infection without cirrhosis. The existence of portal triads and the Meyenburg complexes within the lesion and atypical subnodules suggests that the carcinoma has arisen in the context of a macroregenerative nodule rather than the whole nodule being an early, spreading carcinoma. A growing body of evidence supports macroregenerative nodules as being precursor lesions in the development of hepatocellular carcinoma. Although they are generally thought of as being large cirrhotic nodules, this case suggests that they may be lesions that develop in the context of chronic liver disease, parallel to, but independently of, cirrhosis. Moreover, the development of carcinoma within the nodule suggests that macroregenerative nodules may play a role in carcinogenesis in noncirrhotic livers

Twenty-eight macroregenerative nodules from 14 cirrhotic patients who underwent orthotopic liver transplantation were evaluated for DNA ploidy by means of image analysis of Feulgen-stained tissue sections. The lesions were classified as type 1 (16 cases) or type 2 (12 cases) on the basis of the absence or presence of cellular or architectural atypia in the nodules. The surrounding cirrhotic nodules were evaluated for liver cell dysplasia. Aneuploid peaks were significantly more frequent in type 2 macroregenerative nodules (58.3%) than in the cirrhotic regenerative nodules (7.1%) (p < 0.007). In addition, aneuploid peaks occurred with increased frequency in type 2 nodules (58.3%) than in type 1 macroregenerative nodules (6.2%) (p < 0.02). Only two aneuploid peaks (14.2%) were found in dysplastic cirrhotic livers. The nuclear area of aneuploid hepatocytes (71.6 microns 2 +/- 10.1%, mean +/- S.D.) differed significantly from that of diploid liver cells (45.4 microns 2 +/- 6.5%) (p < 0.0001). Tetraploid peaks occurred in three type 2 lesions (25%); they were also found in one type 1 macroregenerative nodule (6.2%), one cirrhotic liver without dysplasia (7.1%) and three cirrhotic livers with dysplasia (21.4%). These findings support the notion that macroregenerative type 2 nodules are directly implicated in hepatocarcinogenesis and that their presence should be sought as an indicator of malignant potential in cirrhotic livers

Intrahepatic cholangiocarcinoma associated with fibropolycystic disease of the liver and biliary cystadenocarcinoma are rare tumors that are considered distinct entities. We present a case of a malignant tumor with features of hepatic cystadenocarcinoma arising in a background of fibropolycystic disease

The nuclear lamina is a meshwork of intermediate filaments adjacent to the inner nuclear membrane that in mammalian cells is predominantly composed of three proteins: lamin A, lamin B, and lamin C. Because lamin A and C (A-type lamins) expression has been shown to be lacking in several types of undifferentiated or rapidly proliferating cells, we investigated lamin expression in the human liver in conditions with hepatocellular regeneration (cirrhosis of various etiologies and macroregenerative nodules) and in hepatocellular carcinomas of various grades of differentiation. Immunohistochemical stains for A-type lamins and lamin B were performed on frozen tissue sections with the avidin-biotin complex method. Normal and regenerating hepatocytes, biliary epithelial cells (ductal and ductular cells), and hepatocellular carcinoma cells invariably expressed both A-type lamins and lamin B. These findings indicate that in hepatocellular regeneration and malignant transformation the production of both A-type lamins and lamin B is preserved

Cytomegalovirus (CMV) hepatitis is a common and serious complication of orthotopic liver transplantation. Immunohistochemical studies are the most sensitive methods of diagnosis. We compared immunoperoxidase staining with monoclonal antibodies to CMV immediate early and early antigens with routine hematoxylin-eosin stain. Eleven of 140 liver allograft recipients at our institution had CMV hepatitis identified by hematoxylin-eosin stain on biopsy specimens. We stained serial sections of all previous biopsy specimens and one post-ganciclovir biopsy specimen (when available) from each of these patients. One or both monoclonal antibodies confirmed the original hematoxylin-eosin stain diagnoses. Cytomegalovirus was detected in earlier, hematoxylin-eosin stain-negative biopsy specimens in seven of 11 patients. Detection of immediate early antigen often preceded that of early antigen. Earlier biopsy specimens demonstrated less positive staining, which become more extensive closer in time to the hematoxylin-eosin stain-positive biopsy specimens. Sinusoidal cells became positive earlier than hepatocytes. In one patient occult CMV antigens persisted in biopsy specimens following ganciclovir treatment. We conclude that (1) immunohistochemical staining for CMV antigens can result in earlier detection of viral infection, which may lead to earlier, more effective treatment; (2) CMV infection and antigen expression is focal, requiring extensive examination for diagnosis; (3) extent of occult infection may indicate the extent of active infection in the organ as a whole; (4) most CMV hepatitis begins with infection of sinusoidal lining cells as a result of hematogenous spread from within the allograft or from systemic viremia; and (5) posttreatment biopsy specimens may be more sensitive than resolution of serum liver enzyme abnormalities in evaluating the success of ganciclovir therapy

Macroregenerative nodules, also called nodules of adenomatous hyperplasia, have been well documented in Japan. Extensive studies support the hypothesis that in the Japanese population these lesions represent a possible pathway for hepatocarcinogenesis. However, reporting of these lesions in non-Japanese populations has so far been rare. We examined 44 sequential cirrhotic hepatectomy specimens from adult patients who underwent orthotopic liver transplantation at our institution. All livers were serially sectioned every 0.5 cm. Macroregenerative nodules were defined as regenerative nodules at least 1 cm in diameter. Forty-eight macroregenerative nodules were found in 11 livers (25% of livers). The antecedent diseases in these livers included hepatitis C (3), alcoholism (2), primary biliary cirrhosis (2) (one with iron overload), cryptogenic cirrhosis (2), hepatitis B (1) and alpha 1-antitrypsin deficiency (1). The macroregenerative nodules often differed from the surrounding nodular parenchyma in color, texture or the degree to which they bulged beyond the cut liver surface. Three livers contained grossly apparent hepatocellular carcinomas. Microscopically, macroregenerative nodules could be classified as those with (type 2) and without (type 1) dysplasia. Four livers had type 1 lesions, two had type 2 lesions and five had lesions of both types. We found 36 type 1 lesions in all and 12 type 2 lesions, 3 containing foci of microscopic carcinoma. All hepatocellular carcinomas arose in livers containing macroregenerative nodules (either type). Liver cell dysplasia, large-cell or small-cell, was observed in cirrhotic nodules of 27 livers. Microscopic or macroscopic hepatocellular carcinoma occurred in three livers with large-cell but not small-cell dysplasia and in one liver without dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)