Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study.

BACKGROUND/AIMS: In humans, the role of liver cell dysplasia as a preneoplastic lesion is still debated. A prospective, long-term, multicenter study was performed to establish whether liver cell dysplasia in cirrhosis is associated with an increased risk for hepatocellular carcinoma (HCC). METHODS: A cohort of 307 consecutive patients in whom liver cirrhosis was diagnosed by histology was investigated for development of HCC at 6-month intervals by ultrasonography and determination of alpha-fetoprotein levels. RESULTS: At enrollment, liver cell dysplasia was found in 75 patients (24%) and in 53% (P < 0.01) of those positive for hepatitis B surface antigen (HBsAg). After a mean follow-up of 46 months, HCC was detected in 45 cases, and it was significantly more frequent in patients with liver cell dysplasia (P < 0.01) and HBsAg-serum positivity (P < 0.01). Multivariate analysis showed that liver cell dysplasia was the most important risk factor correlated with HCC development. HBsAg positivity and age over 60 years were also independent risk factors for HCC. CONCLUSIONS: These results indicate that liver cell dysplasia is a major risk factor for HCC, and it should be looked for carefully by pathologists in liver biopsy specimens to identify patients requiring more intensive observation.

The evaluation of fine-needle procedures for the diagnosis of focal liver lesions in cirrhosis.

To evaluate the diagnostic accuracy of fine-needle aspiration, fine-needle biopsy and extranodular fine needle biopsy in identifying focal lesions in cirrhosis, 100 consecutive ultrasound detected nodules were studied. Seventy-three were hepatocellular carcinomas (31 were well-differentiated hepatocellular carcinomas), 23 were benign lesions (one angioma and 22 large regenerative nodules) and two were metastases. The lesions were divided according to maximum diameter as follows: < 20 mm in 36, > 20 < 30 mm in 27, and > 30 mm in 33. In four cases there were multiple nodules of different sizes. Fine needle aspiration, intranodular fine needle biopsy and extranodular fine needle biopsy were obtained in each lesion. The sensitivity, specificity and diagnostic accuracy of each procedure were evaluated separately by three independent pathologists. Seven fine needle aspirations and three intranodular fine needle biopsies were considered inadequate. The highest diagnostic accuracy (96%) was obtained by the combined analysis of fine needle aspiration plus intranodular and extranodular fine needle biopsy, and this superiority was confirmed in each group of lesions. Fine needle aspiration showed a lower accuracy (48%) than intranodular fine needle biopsy (67%). When fine needle aspiration and intranodular fine needle biopsy were evaluated together, an accuracy of 91% was found. Intralesional fine needle biopsy plus extranodular fine needle biopsy analysis gave an accuracy of 78% and, particularly relevant, a specificity of 95%. These results indicate that, in patients with cirrhosis with nodular lesions < 30 mm, fine needle biopsy is superior to fine needle aspiration and that the combined evaluation of fine needle aspiration plus intranodular and extranodular fine needle biopsy is the most accurate approach.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver-cell dysplasia and hepatocellular carcinoma.

Liver-cell dysplasia is a well known histological entity with preneoplastic significance in experimental hepatic carcinogenesis. However, while the association of liver-cell dysplasia with hepatitis B virus can be considered as established, it is still controversial whether this lesion represents a premalignant condition in cirrhotic patients. Efforts have been made to render its morphological assessment more reliable, but no firm conclusions can be drawn from the available clinical studies, which are mainly retrospective or based on autopsy series. Preliminary results from a prospective study argue that liver-cell dysplasia is associated with an increased risk to hepatocellular carcinoma. The emergence of liver-cell dysplasia as a preneoplastic lesion in cirrhotic patients will have some impact in the future on their management, including selection for closer monitoring in early detection of hepatocellular carcinoma and for liver transplantation.

Granulomatous and nongranulomatous lymphadenitis in sarcoidosis. An immunophenotypic study of seven cases.

Five cases of prescalenic granulomatous lymphadenitis (GL) and 2 cases of prescalenic nongranulomatous lymphadenitis (NGL) in 7 patients with sarcoidosis were studied with a large panel of monoclonal antibodies (anti-CD 1, CD 3, CD 4, CD 8, CD 14, CD 22, CD 25, HLA-DR, HLA-DQ, HNK-1, R 4/23). Immunopathologic analysis was performed by studying three different compartments of GL--granuloma, intergranulomatous area and sinuses--and of NGL--cortex, paracortex and sinuses. Intra- and intergranulomatous T lymphocytes were mainly of the CD 4 type in 4 out of 5 cases; in all the cases less than 25% of T lymphocytes stained also for CD 25. Epithelioid cells were HLA-DR+, HLA-DQ+, CD 14+ and, frequently, CD 1+ and CD 25+, the latter positivity being mainly restricted to the marginally located epithelioid cells. Sinuses were filled with T- and B- cells; sinusal histiocytes were HLA-DR+, HLA-DQ+, CD 14+ and, frequently, CD 1+ and CD 25+. In the cortex and paracortex of NGL, T-cell subsets paralleled the distribution and ratio observed in the intergranulomatous area of GL; furthermore the immunophenotype of NGL sinusal histiocytes roughly overlapped that observed in the same district of GL with a strong CD 1 and CD 25 positivity. These results, besides confirming the global imbalance of the CD 4/8 ratio in all the areas of GL, seem to demonstrate that the prevalence of CD 4+ or CD 8+ T-cells probably reflects different functional phases of the granulomatous process.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal DNA content in liver-cell dysplasia: a flow cytometric study.

To clarify the true nature of liver-cell dysplasia (LCD), a flow cytometric study has been performed. The DNA content of hepatocytes from 26 cases of cirrhosis with diffuse areas of LCD was investigated and compared to that of hepatocytes from 21 control patients with non-neoplastic and neoplastic liver conditions. Flow cytometric analysis was performed on propidium-stained nuclei from archival paraffin-embedded material. Analysis was directed to assessment of diploid as well as non-diploid peaks by calculation of DNA index (DI), using normal hepatocytes present in each sample as individual and specific references. Since only samples containing at least 10,000 nuclei were considered suitable for analysis, 4 of the 26 LCD cases were discarded. Eight of 22 LCD cases had an abnormal DNA content compared with 0/11 non-neoplastic cases (p less than 0.05) and 8/10 hepatocellular carcinomas (p less than 0.05). Non-neoplastic control cases displayed uniformly diploid stemlines whereas hepatocellular carcinomas had in 8/10 cases bimodal or trimodal populations. Thus, LCD is a heterogeneous lesion in terms of ploidy, and the abnormal DNA content observed in some cases supports its pre-neoplastic nature.

A morphometric study of liver cell dysplasia.

Thirty-seven cases of cirrhosis with large liver cell dysplasia (LLCD) were evaluated by morphometric analysis and the results compared with those in 11 cases of hepatitis B surface antigen (HBsAg)-positive cirrhosis, 12 cases of cirrhosis with nodules of active regeneration, 15 cases of hepatocellular carcinomas, and 15 cases of inactive cirrhosis. The nuclear-cytoplasmic, nucleolar-cytoplasmic, and nucleolar-nuclear ratios of LLCD were significantly higher than those observed in all other nonneoplastic groups. Whereas the nuclear-cytoplasmic and nucleolar-cytoplasmic ratios of hepatocellular carcinoma cells were significantly higher than those measured in dysplastic cells, the latter had a nucleolar-nuclear ratio similar to that of neoplastic cells. These results show that, in contrast to previously accepted criteria, the nuclear-cytoplasmic ratio of LLCD is increased and that some morphometric features of LLCD are consistent with its supposed premalignant nature. The usefulness of a morphometric analysis in evaluating any group of abnormal-appearing hepatocytes is stressed.

Immunophenotypic analysis of the transformation zone of human cervix.

The immunocompetent cell population of the cervical transformation zone of 18 uteri removed for noncervical disease, has been investigated with monoclonal antibodies. The panel included Leu 2a, 3a, 4, 14, and IL II receptor for lymphocytes and T cell subsets, Leu 7 for NK cells, Leu M5, Leu 10, HLA-DR, DRC 1 for dendritic cells, and Leu 6 for Langerhans' cells (LC). In ectocervical epithelium HLA-DR, Leu 6 and Leu 10 antibodies identified subpopulations of dendritic cells which differed in number and in topographic distribution. Furthermore, a strong HLA-DR epithelial positivity was constantly observed in endocervical columnar cells as well as in keratinocytes of squamous metaplasia. Leu 2a+ cells (T suppressor/cytotoxic) prevailed in the stromal and epithelial compartments of ecto/endocervix; in 6 cases, however, Leu 3a+ cells (T helper/inducer) represented the main T cell subset in the ectocervical stroma. B lymphocytes were occasionally noticed in the subepithelial stroma while NK and DRC-1 cells were never observed. Finally, only few lymphocytes displayed a positivity for IL II receptor. This study suggests that several phenotypes of intraepithelial dendritic cells are present in the transformation zone and that endocervical columnar cells and keratinocytes of squamous metaplasia express HLA-DR products; the latter finding may be related to the presence of intraepithelial and stromal T lymphocytes.

Cytology of yolk-sac tumor of the ovary in ascitic fluid. Report of a case.

The cytologic, serologic, immunocytochemical and histologic findings of a yolk-sac tumor of the ovary in which the diagnosis was suggested by the cytologic examination of ascitic fluid specimens are reported. The case emphasizes the importance of evaluating, in addition to smears, the cytologic findings of a cell block specimen (which is generally prepared from an effusion) to obtain more diagnostic clues. A preliminary cytomorphologic diagnosis of this highly malignant tumor is valuable as a guide in planning further immunocytochemical and serologic studies.

Liver cell dysplasia in cirrhosis. A serologic and immunohistochemical study.

Liver cell dysplasia (LCD) was investigated for hepatitis B virus (HBV) markers, alpha-fetoprotein (AFP) and ferritin by serologic and immunohistochemical methods in 101 patients with cirrhosis. LCD was found in 30 cases (29.7%), with the highest incidence in cases of posthepatitic cirrhosis (67%). In the group of dysplastic cirrhosis (DC) 46.6% of the patients had active HBV infection (hepatitis B surface antigen [HBsAg] serum positivity) compared with 7% of the patients with nondysplastic cirrhosis (NDC) (P less than 0.01). The mean serum AFP concentration was significantly raised in the DC group compared with that in the NDC group (P less than 0.05). In seven patients with LCD at the initial biopsy, the histologic followup showed the persistence of LCD in all cases, and the development of hepatocellular carcinoma (HCC) in three cases. In serologic HBsAg-positive cases, dysplastic cells, at variance with the surrounding liver parenchyma, were almost always negative for tissue HBsAg, and always negative for tissue hepatitis B core antigens (HBcAg). AFP was never detected in either normal or dysplastic cells. Ferritin was found in all cases, but dysplastic foci displayed a lesser amount of this protein. These serologic and immunohistochemical data strongly suggest a preneoplastic significance of LCD. The importance of monitoring cirrhotic patients with LCD and particularly those with HBV infection and/or increased AFP levels with more aggressive follow-up is also stressed.

Liver cell dysplasia and hepatocellular carcinoma: a histological and immunohistochemical study.

Liver cell dysplasia (LCD) was found in 28 (60%) of 47 patients with hepatocellular carcinoma (HCC); 22 (79%) of them had associated liver cirrhosis. LCD was more frequently observed in posthepatitic cirrhosis (82%) than in the other forms. Carcinoembryonic antigen (CEA), alpha-1-antitrypsin (AAT) and alpha-fetoprotein (AFP), as demonstrated by the peroxidase-antiperoxidase method, were similarly expressed both in normal and in dysplastic cells. Hepatitis B surface antigen was found in eight cases (17%), six of which were associated with LCD. HBsAg was rarely found in dysplastic cells and frequently displayed a peculiar perinuclear pattern. The possible preneoplastic role of LCD is stressed.

Extra and intracranial meningiomas.

Two cases of extracranial meningiomas respectively in the left frontal region in a 64-year-old woman and in the right frontal sinus in a 13-year-old boy are reported. Both cases were associated with an intracranial meningioma later detected after primary histologic diagnosis of the extracranial surgical specimen. The possibility of an extracranial meningioma, especially when an angioblastic, fibroblastic or meningothelial pattern is prominent, must always be considered together with the existence of an intracranial equivalent, as our 2 cases clearly demonstrate.