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.

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: Transforming growth factor‐beta (TGF‐β) is a pluripotent regulatory molecule, found in at least five different isoforms. It is produced in many different organs. In the liver, TGF‐β is expressed in non‐parenchymal cells, but not in hepatocytes. This growth factor is known to induce fibrosis in the course of a variety of pathologic processes. Recently, TGF‐β has also been identified in hepatocellular carcinoma (HCC) cells, and the suggestion has been made that this growth factor may play a role in hepatocarcinogenesis. In this study, we report the findings of immunohistochemical stains for TGF‐β, performed on paraffin sections of 14 human HCCs of the usual type and 11 examples of the fibrolamellar variant (FLC). TGF‐β was detected in tumor cells of 3 HCCs (21%) and 9 FLCs (82%). Compared with the HCCs, the FLCs displayed a more diffuse and intense staining pattern for TGF‐β. Our findings suggest that lamellar fibrosis, which is a histologic hallmark of FLC, may be due to the action of TGF‐β produced by tumor cells.