Faculty Bibliography

We have previously suggested that dysplastic nodules (also referred to as 'adenomatous hyperplasia' or 'macroregenerative nodules'), likely precursors of hepatocellular carcinoma (HCC), develop as an infiltrating clonal expansion, in advance of or parallel to cirrhosis. As part of this hypothesis, to explain aspects of their gross and microscopic appearance, we suggested that dysplastic nodules are resistant to the scarring process affecting the rest of the liver. We sought to test this hypothesis by examining the distribution of activated hepatic stellate cells (HSCs), the hallmark of hepatic scarring, in cirrhotic nodules, dysplastic nodules and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low grade dysplastic nodules, 27 high grade dysplastic nodules, and 20 HCCs with monoclonal antibodies against alpha-smooth muscle actin to identify activated HSCs. Distribution and number of HSCs were graded semiquantitatively (0 to 4+). In our results, HSCs were significantly less widespread in dysplastic nodules than in cirrhotic nodules or in HCCs (both: p < 0.00001). HSCs were also more prominent in the periphery of dysplastic nodules than in the center, though still fewer in number than in cirrhotic nodules. In conclusion, the low number of activated HSCs in dysplastic nodules, compared to both cirrhotic nodules and HCC, supports our hypothesis concerning dysplastic nodule development: that they arise as clonal expansions of neoplastic hepatocytes in advance of, or parallel to, the development of cirrhosis

OBJECTIVE: Chronic hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), but the mechanism of malignant transformation is unknown. To analyze the association of HCV with HCC, we developed a microdissection technique for the detection by polymerase chain reaction of positive (genomic)- and negative (replicative)-strand HCV RNA in histologically confirmed HCC and the surrounding cirrhotic and macroregenerative nodules. MATERIALS AND METHOD: Five HCCs and one macroregenerative nodule and the surrounding cirrhotic liver tissues of all cases were selected for this study. The method entails extraction of RNA from selected areas of formalin-fixed, hematoxylin-stained histologic sections, followed by strand-specific reverse-transcription double polymerase chain reaction and Southern blotting. RESULTS: Positive- and negative-strand HCV RNA sequences were detected in five of six tumors and the surrounding cirrhotic livers. CONCLUSIONS: These results verify the method of polymerase chain reaction detection of HCV RNA from histologically defined, selected lesions. In addition, the findings suggest that HCV RNA persists and replicates in hepatocytes during malignant transformation

Large-cell change of hepatocytes (LCC), also called liver cell dysplasia of large-cell type, is a set of cytologic changes comprising nuclear and cytoplasmic enlargement, nuclear pleomorphism, and multinucleation. This entity is encountered frequently on histologic or cytologic examination of specimens obtained from livers with a variety of chronic diseases and originally was thought to have a premalignant nature. Accumulating evidence, however, now suggests that LCC is merely a reactive change. Having often observed LCC in liver specimens with chronic biliary tract disease, that is, in livers where cholestasis preceded hepatocyte injury, we surmised that LCC may be a result of prolonged cholestasis. To determine whether there was any association between LCC and cholestasis, we examined microscopically a series of 400 nodules from 40 consecutive adult cirrhotic livers, resected on transplantation, and graded LCC and cholestasis semiquantitatively. LCC was present diffusely in cirrhotic nodules of 25 specimens (62.5%). Nine additional specimens (22.5%) had focal mild LCC. Usually, LCC and cholestasis occurred together, in the same cirrhotic nodules and in the same areas of nodules. There was a statistically significant association between the presence and grade of LCC and those of cholestasis (p < 0.0001; chi-square test). Within etiological categories of cirrhosis (chronic hepatitis; n = 28; alcoholic liver disease; n = 6; biliary disease: n = 6), the significance was maintained. We conclude that, in cirrhosis of different etiologies, LCC may represent a reactive change that results from prolonged cytoplasmic cholestasis

PURPOSE: To evaluate detection and characterization of hepatocellular nodules in fresh whole explanted cirrhotic livers at thin-section magnetic resonance (MR) imaging. MATERIALS AND METHODS: T1-weighted spin-echo and T2-weighted fast spin-echo MR imaging (5-mm-thick sections) were performed in a head coil at 1.5 T in the whole cirrhotic livers of 28 consecutive patients within 4 hours of explantation. MR imaging findings were correlated with findings at pathologic examination, and new international terminology was used to classify the hepatocellular nodules. RESULTS: At pathologic examination, 42 suspect (other than regenerative) nodules were identified in 11 patients. MR imaging depicted 41 of 42 (98%) of these nodules (five of five hepatocellular carcinomas [HCCs :diameter, > or = 2 cm:], 10 of 10 small HCCs [diameter, < 2 cm], two of two dysplastic nodules with subfoci of HCC, three of three high-grade dysplastic nodules, and 21 of 22 low-grade dysplastic nodules. Lesions demonstrated the following combinations of signal intensity characteristics on thin-section T1- and T2-weighted images, respectively: HCC, hyperintense, hypointense (n = 3); hyperintense, hyperintense (n = 1); hypointense, isointense (n = 1). Small HCC, hyperintense, hypointense (n = 7); hypointense, hyperintense (n = 2); hyperintense, hyperintense (n = 1). Both dysplastic nodules with subfoci of HCC, hyperintense, hypointense. All seven nonsiderotic low-grade dysplastic nodules, hyperintense, hypointense. All 14 siderotic low-grade dysplastic nodules, hypointense, hypointense. All three high-grade dysplastic nodules, hyperintense, hypointense. CONCLUSION: The variable signal intensity characteristics of HCCs made reliable diagnosis impossible, but the thinsection unenhanced in vitro MR images were sensitive for detection of HCCs and dysplastic nodules in cirrhotic livers

We studied 12 histologically malignant salivary tumors that showed complete encapsulation or only limited microscopic invasion. Most cases were histologically characterized by atypical and mitotically active luminal cells forming dilated, angular, variably sized glands in the subcapsular region, varying proportions of nonluminal tumor cells, and a background of central fibrosed hyalinized stroma. The appearance is that of a low-grade carcinoma. Focal higher grade carcinoma was superimposed on this histologic data in three cases. Neither recurrences nor metastases were seen in 11 of 12 patients after surgical resection with a follow-up of 1.2 to 13 yrs (mean, 4.2 years). Ploidy studies were performed on the paraffin-embedded tissue in 11 cases and yielded results for 7 cases. Aneuploid cell populations were found in five tumors; two had normal diploid populations; and the ploidy results are not predictive of tumor behavior. This type of salivary gland tumor fits diagnostically within the category of noninvasive and minimally invasive carcinoma ex pleomorphic adenoma (also referred to as in situ and low-grade malignant mixed tumors), a class that requires additional awareness and precise recognition as it signifies a good prognosis after surgical resection

Macroregenerative nodules are commonly thought to be hyperplastic lesions, deriving both their large size and premalignant potential from an increased proliferative rate. We have previously suggested an alternate model of macroregenerative nodule development in which neither size nor premalignant potential of macroregenerative nodules would depend on increased proliferation. We tested this hypothesis by examining the proliferative activity in macroregenerative and surrounding cirrhotic nodules. Methods: Eighteen macroregenerative nodules, including five type I and 13 type II, were immunostained for proliferating cell nuclear antigen (PCNA). Type II macroregenerative nodules included ten with diffuse large (7) or small (3) liver cell dysplasia only and eight containing nodule-in-nodule lesions. Five nodule-in-nodule lesions met the histologic criteria for hepatocellular carcinoma. PCNA labeling indices (PCNA-LIs; percentage positive hepatocyte nuclei/500 randomly counted cells) were determined in macroregenerative nodules and the four largest adjacent cirrhotic nodules. Nodule-in-nodule lesions were assessed separately from the background macroregenerative nodule. Results: 4/5 type I and 12/13 type II macroregenerative nodules (exclusive of NIN lesions) had PCNA-LIs lower than the mean of surrounding cirrhotic nodules. All nodule-in-nodule lesions, whether atypical or overtly malignant, had PCNA-LIs greater than any surrounding nodules. In conclusion, macroregenerative nodules have PCNA-LIs indistinguishable from, and often lower than, surrounding cirrhotic nodules. Increased proliferative activity only occurs with the development of atypia and transition to hepatocellular carcinoma. Conclusion: Macroregenerative nodules derive neither their size nor their premalignant potential from on-going rapid proliferation, a finding consistent with our alternate hypothesis of macroregenerative nodule development