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Aims: To investigate the smooth muscle nature of the stromal cells in the capsule of hepatocellular carcinomas., Methods: Immunohistochemical analysis using monoclonal antibody to high molecular weight caldesmon (HCD), a highly specific marker for smooth muscle cells, was performed in 33 encapsulated hepatocellular carcinomas and adjacent hepatic tissues., Results: HCD positive stromal cells were detected in the capsule of 21 of the 33 hepatocellular carcinomas examined., Conclusions: The capsule of hepatocellular carcinomas contains smooth muscle cells.

Platelet-derived endothelial cell growth factor (PD-ECGF), identical to thymidine phosphorylase, has been reported as an angiogenic factor in human malignancies. However, the role of PD-ECGF in human hepatocellular carcinoma (HCC) is still unconfirmed. Herein, we studied the expression of PD-ECGF in 27 human HCC cases by immunohistochemistry, to clarify the relationship to tumor angiogenesis. The immunoreaction of PD-ECGF in HCC cells was scored in both the staining percentage and intensity. CD34, an endothelial cell marker, was used to evaluate the intratumoral microvessel density (IMVD). PD-ECGF expression was noted in carcinoma cells in 14 (51.9%) of 27 HCCs. In these cases, the carcinoma cells showed heterogeneous staining in both the nucleus and cytoplasm. Tumor-associated stroma cells and infiltrating lymphocytes were also stained. Kupffer cells in non-tumor areas were strongly positive. Statistically, the expression of PD-ECGF increased in HCC specimens with high Edmondson grades (III-IV) or portal vein tumor thrombosis (PVTT) (P<0.05). Additionally, the IMVD of PD-ECGF-positive HCC specimens (136.071+/-31.008, mean +/- SD) was higher than that of the PD-ECGF-negative HCC specimens (61.077+/-15.795) (P<0.05). These findings may suggest that PD-ECGF is one of the angiogenic factors in human HCCs. Furthermore, with the increasing expression of PD-ECGF, HCC cells show poor differentiation and invasive behavior.

We report a case of spontaneous hepatocellular adenoma with marked cystic degeneration in the non-cirrhotic liver. A 36 year-old Japanese woman with neither history of liver diseases nor use of oral contraceptives and steroids, complained of a 6 kg weight loss over 6 months. Barium meal study revealed an extramural compression along the fornix of the stomach. Abdominal ultrasonography (UC) and computed tomography (CT) demonstrated a mass in the left lateral segment of the liver that measured 11.6x9.5 cm with cystic lesions. Laboratory data on admission showed no significant findings. Celiac angiography revealed a hyper-vascular mass. Surgical exploration revealed a soft mass arising and protruding from the left lateral segment of the liver. Partial resection of the left lateral segment was performed. Histologically, the tumor was surrounded by a thin fibrous pseudocapsule. The neoplastic cells resembling normal hepatocytes around the tumor were large, pale and arranged in thick, irregular cords. Neither mitotic figures nor foci of dysplasia were present. The central portions of the tumor showed marked cystic degeneration. The tumor was histologically diagnosed as hepatocellular adenoma (HCA). HCA with cystic degeneration has been rarely reported.

The distribution of blood vessels in human hepatocellular carcinoma was studied with the anti-a-smooth muscle actin monoclonal antibody by light and electron microscopy, and with morphometric analysis. a-Smooth muscle actin-positive arterioles were never observed in lobules or pseudolobules of non-cancerous areas, but were frequently seen within hepatocellular carcinomas. Morphometric analysis revealed that most of these arterioles measured between 10 and 25 microns in diameter. The morphology of intratumoural arterioles differed considerably from that of conventional arteries in the portal tracts of the non-cancerous area. The presence of abundant intratumoural arterioles can explain the angiographic hypervascularity of hepatocellular carcinoma and provides a pathological basis for its susceptibility to hypoxia and for arterial embolization as a therapeutic strategy.

The serum level of alpha-L-fucosidase activity has been suggested as a useful marker in the diagnosis of hepatocellular carcinoma, although the precise mechanism behind the elevation of this parameter has not been determined. We found that the serum alpha-L-fucosidase activity level was significantly higher in 67 patients with hepatocellular carcinoma (695.1 +/- 245.5 nmol/ml/hr) than in 47 patients with cirrhosis (389.1 +/- 188.2 nmol/ml/hr; p < 0.001) and in 54 controls (202.0 +/- 104.6 nmol/ml/hr; p < 0.001). However, alpha-L-fucosidase activity was not correlated with tumor size (r = 0.134), whereas the alpha-fetoprotein level was correlated with tumor size (r = 0.580, p < 0.001). When 515.8 nmol/ml/hr was taken as the cutoff value (mean value in the controls plus 3 standard deviations), alpha-L-fucosidase activity was above the cutoff value in 12 of the 17 patients with a hepatocellular carcinoma less than 2 cm in diameter, in 28 of the 37 patients with a hepatocellular carcinoma less than 3 cm in diameter and in 52 of the 67 patients with hepatocellular carcinoma. In contrast, only 10 of the 47 patients with cirrhosis had levels above the cutoff value. These findings suggest that an increase in serum alpha-L-fucosidase activity in patients with cirrhosis may be a marker for detecting a hepatocellular carcinoma, especially a small tumor, because alpha-fetoprotein and des-gamma-carboxy-prothrombin are less promising as tumor markers.

The purpose of this study is to clarify the morphological characteristics and functional significance of the perisinusoidal stromal cells in hepatocellular carcinoma. The liver specimens surgically resected from 24 patients with hepatocellular carcinoma were studied by electron microscopy and immunohistochemistry using monoclonal antibodies against alpha-smooth muscle actin, vimentin and desmin. In the tissue space between endothelial cells and trabeculae of cancer cells, the stromal cells were frequently found. They were strongly positive for alpha-smooth muscle actin, weakly and less frequently positive for vimentin but negative for desmin. They varied in shape, size and distribution, stretching cytoplasmic processes and occasionally surrounding the trabeculae of cancer cells. They contained considerable amounts of microfilaments that were positive for alpha-smooth muscle actin and condensed in cell periphery. Along the cell membrane, the short dense areas and pinocytotic vesicles were seen. The external lamina incompletely invested the stromal cells. They were always surrounded by amorphous material. In the granulation tissue and fibrotic areas around necrotic cancer tissue, they were increased in size and number. On the other hand, immunohistochemically and ultrastructurally, they closely resembled the Ito cells in the piecemeal necrosis that showed myofibroblastic transformation. These results suggest that the perisinusoidal stromal cells in nonnecrotic cancer tissue produce the extracellular matrix in the tissue space and maintain the cancerous trabecular structure. After necrosis of cancer tissue, they may become activated and actively participate in the fibrosis.

An unusual case of solid hepatic hamartoma, which could not be correctly categorized under the WHO classification, is reported. The well defined, solid nodular lesion, arising in the anterior edge of the left hepatic lobe, was found in a 15-month-old female infant. The lesion was composed of irregularly shaped yellow islands of parenchyma and white-gray nodules of fibrous stroma of various sizes, which were intermingled revealing a mosaic pattern. Prominent bile ductal proliferation was observed histologically in the fibrous stroma, associated in parts with dense or loose periductal bundles and vascular proliferation. The stromal proliferation seemed to result in erosion of the islands of differentiated parenchymal cells with no regeneration. Alpha-fetoprotein was demonstrated immunohistologically in the parenchymal cells of the lesion. From these findings, the essential component of this solid hamartoma was thought to be markedly proliferating bile ducts associated with periductal fibrosis, resulting in a fibroadenomatous pattern.