p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.

Residual cardiomyocytes and scintigraphic findings in advanced coronary artery disease: correlation with technetium-99m-tetrofosmin and thallium-201 single photon emission computed tomography.

A 68-year-old man suffering from chronic heart failure due to coronary artery disease (CAD) underwent rest technetium-99m (99mTc)-tetrofosmin and thallium-201 (201Tl) with reinjection studies, but died thereafter. The heart was removed and sectioned into short-axis slices and examined by gross and microscopic pathologic methods. A close correlation between the amount of residual cardiomyocytes and the level of regional tracer activity in the left ventricular wall was obtained for redistribution 201Tl, reinjection 201Tl and rest 99mTc tetrofosmin images. The correlation coefficients were r=0.901 for the 201Tl redistribution images, r=0.913 for the 201Tl reinjection images and r=0.917 for the rest 99mTc-tetrofosmin images. This case report provides further evidence of the validity of SPECT tetrofosmin imaging for the determination of myocardial viability in CAD.

Intrahepatic cholangiocarcinomas associated with nonbiliary cirrhosis. A clinicopathologic study.

To determine the prevalence and clinicopathologic features of cholangiocarcinoma (CC) associated with nonbiliary cirrhosis, we performed a clinicopathologic study. Among the 5,563 autopsies in our laboratories during the past 14 years, 85 (1.5%) were CCs. Four (4.7%) were associated with cirrhosis, due to hepatitis B virus in one case and cryptogenic (probably non-A non-B hepatitis virus) in the remaining three. Clinically, patients with CC and cirrhosis were characterized by male preponderance, lower age, past history of liver injury, and elevated values of zinc sulfate and thymol turbidity tests. Pathologically, all CCs with cirrhosis were basically adenocarcinoma; other histologic features included adenocarcinoma resembling bile ductules without mucin (one case), adenocarcinoma with broad areas of signet ring cell carcinoma (one case), adenocarcinoma with extensive sarcomatoid transformation (one case), and adenocarcinoma associated with hepatoliths (one case). Immunohistochemically, immunophenotypes of carcinoma cells of CC with cirrhosis were not different from those of CC without cirrhosis. Carcinoembryonic antigens, CA19-9, DU-PAN-2, and biliary-type cytokeratins were positive and alpha-fetoprotein was negative, suggesting that our CCs are not hepatocellular neoplasms but true CCs. It must be stressed that there are actual CCs arising in nonbiliary cirrhotic livers.

Hepatocellular carcinoma in primary biliary cirrhosis: an autopsy study.

A survey of Japanese autopsy cases of primary biliary cirrhosis disclosed that hepatocellular carcinoma is apparently becoming a better recognized complication of the advanced stage of primary biliary cirrhosis. Six autopsy cases (five women and one man) of primary biliary cirrhosis associated with hepatocellular carcinoma were obtained from several Japanese institutions and examined. All cases were in an established cirrhotic stage of primary biliary cirrhosis. Hepatocellular carcinoma was incidentally found at autopsy in four cases and, in these, the carcinomas were small in size and number. The other two cases showed advanced hepatocellular carcinoma and one case showed extrahepatic metastasis. Histologically, all cases showed well-differentiated hepatocellular carcinomas. Fatty changes or bile plugs were frequently seen within the tumors. Mallory body clusters and focal deposition of copper-binding protein were consistently found in cirrhotic liver tissues and also in the carcinoma tissues of almost all cases. The presence of atypical adenomatous hyperplasia in the peripheries of some carcinomas suggested that hepatocellular carcinoma in primary biliary cirrhosis may evolve through multiple steps.

Pathology of the liver in "idiopathic portal hypertension" associated with autoimmune disease. The Ministry of Health and Welfare Disorders of Portal Circulation Research Committee.

The histopathology of the liver in idiopathic portal hypertension (IPH) associated with autoimmune disease (15 cases), was examined and compared with that of IPH without autoimmune disease (31 cases). It was found that hepatic histopathology was heterogeneous in the cases with autoimmune disease. That is, the hepatic histopathology in 7 cases was similar to that of classic IPH without autoimmune disease, and the remaining 8 cases disclosed unusual lesions such as focal non-suppurative cholangitis, nodular parenchymal hyperplasia, moderate portal inflammation, and intrahepatic ductopenia. These unusual lesions, which frequently coexisted in the same case, were not typical ones for making other diagnoses such as primary biliary cirrhosis or nodular regenerative hyperplasia of the liver. These findings suggest that unusual histologic lesions in the livers of IPH patients with autoimmune disease may represent an accentuated immunologic reaction inherent in IPH, or that such cases may be an abortive or incomplete form of primary biliary cirrhosis or nodular regenerative hyperplasia of the liver.

Risk lesions in cirrhosis and development of hepatocellular carcinoma: an autopsy study.

Non-neoplastic morphologic changes in various types of cirrhosis were evaluated in relationship to the presence or absence of hepatocellular carcinoma (HCC), using autopsy livers from Hokuriku (Japan) and Los Angeles (USA). Macronodular cirrhosis was closely related to HCC in B-viral cirrhosis, alcoholic cirrhosis and cirrhosis of uncertain type. Liver cell dysplasia was most frequently seen in cases with and without HCC in B-viral cirrhosis but was significantly more frequent with HCC in cases of alcoholic cirrhosis and cirrhosis of uncertain type. Nodular bulging activity within regenerative nodules was closely related to HCC in alcoholic cirrhosis. A positive relationship between HCC and Mallory bodies was found in non-alcoholic cirrhosis. These data suggest that patients with macronodular cirrhosis, liver cell dysplasia, nodular bulging activity and Mallory bodies may have an increased risk of developing, or having HCC dependent on the etiology of cirrhosis. The geography and race differences had some relationship to the incidence of HCC.

Histological study of intrahepatic cavernous transformation in a patient with primary myelofibrosis and portal venous thrombosis.

Cavernous transformation in the liver was examined histologically by serial section observations, in an autopsy case of portal venous thrombosis and primary myelofibrosis. Cavernous transformation was present from the hepatic hilus to medium-sized portal tracts and was composed of dilated and thin-walled vessels. Serial sections disclosed that these vascular channels were anastomotic and occasionally communicated with occluded portal venous radicles. In places they entered directly into the hepatic parenchyma without accompanying biliary or arterial elements, and also drained into the patent portal venous branches beyond the occluded segment. The study demonstrated that cavernous transformation in the liver develops as hepatopetal collaterals secondary to the portal venous obstruction. Periportal and peribiliary capillary plexus may become cavernous in the presence of portal venous occlusion.

Incidental solitary hepatocellular carcinomas smaller than 1 cm in size found at autopsy: a morphologic study.

The morphologic features and growth pattern of single hepatocellular carcinomas less than or equal to 1 cm in size, found incidentally at autopsy, were studied in nine cases. In all but one case, the hepatic parenchyma showed advanced cirrhosis. In three cases, the hepatocellular carcinomas were localized within a regenerative nodule as a form of "nodule within nodule." The carcinoma was rimmed by nonneoplastic hepatic tissue. A fourth carcinoma consisted of an expansile hepatocellular carcinoma nodule enclosed by a fibrous band of cirrhotic stroma. The remaining five cases consisted of hepatocellular carcinomas which infiltrated the surrounding regenerative nodules or hepatic lobules. These observations suggested that hepatocellular carcinomas arise within regenerative nodules, some of which still retain residual nonneoplastic tissue around the tumor. Others invaded the adjacent liver tissue. The grossly visible fibrous capsule, often seen in more advanced hepatocellular carcinomas, was absent in all cases. All of the hepatocellular carcinomas were well-differentiated. Four cases showed a trabecular pattern with slight sinusoidal dilatation, 3 showed a scirrhous pattern and 2 showed a compact pattern. Their histologic features included marked bile production, Mallory body formation by clusters of tumor cells, resistance to hemosiderin deposition in a markedly siderotic background and loss or decrease of reticulin fibers. These features were hallmarks of small hepatocellular carcinomas. Pathologists should study cirrhotic livers carefully so as not to miss small carcinomas. Clinicians should be aware that even small liver nodules may be hepatocellular carcinomas.

Quantitation and serial section observations of focal venocclusive lesions of hepatic veins in liver cirrhosis.

The pathogenesis and functional significance of the venocclusive (VO) lesions in small hepatic veins occurring in liver cirrhosis, remain controversial. The present study, using quantitative examination and serial sections has disclosed that these lesions are present in 71.7% of 106 autopsy livers with alcoholic, HBsAg-positive, biliary or cryptogenic cirrhosis. The lesions were usually focal: their number in a liver section (10 cm2) was below 15 in 86.7% of the livers having them. The incidence and morphology of the lesions appeared similar in cirrhotic livers with different aetiology. Serial sections disclosed that the affected veins disappeared within the fibrous stroma at one side and were directly connected with the patent larger hepatic veins at other side, indicating that these veins had lost their function as a draining vein of the hepatic parenchyma. In addition, there was frequent recanalization within the VO lesions, and the recanalized vessels frequently communicated with neighboring thin-walled veins in cirrhotic stroma, suggesting an intrahepatic vein to vein anastomosis. In conclusion, VO lesions, when focal, may themselves be responsible to a lesser degree for obstruction of hepatic venous outflow in liver cirrhosis.

Pathological study on livers with noncirrhotic portal hypertension and portal venous thromboembolic occlusion: report of seven autopsy cases.

Seven adult autopsied cases with noncirrhotic portal hypertension and thromboembolic occlusion of the large extra- and intrahepatic portal veins are presented. There were two types of portal venous occlusion: old thromboembolic occlusion (group A, two cases) and fresh thromboembolic occlusion (group B, five cases). In group A the occlusion was complete and the affected veins, which were identified clearly by elastic fiber stains, were characteristically shrunk to cause a long-standing portal hypertension. Extra- and intrahepatic collaterals were prominent. In group B the extra- and, sometimes, intrahepatic larger portal veins with fresh thromboemboli revealed variable degrees of phlebosclerosis, probably resulting from organization of repeated portal venous thromboemboli. These sclerotic changes further extended into the medium-sized and smaller intrahepatic portal veins. The latter and other hepatic morphology resembled those of idiopathic portal hypertension without larger portal venous occlusion (group C). Thus, in group B the widespread involvement of the portal venous system by thromboembolic events, particularly the smaller ones, might be important not only for the development of portal hypertension but also for understanding the hepatic pathology of idiopathic portal hypertension.

[Pathological study of hepatolithiasis with special reference to unusual cases].

Morphological survey was performed in 140 liver specimens of hepatolithiasis which were collected from several pathological and surgical Departments in Japan. Among them there were 19 cases with unusual features suggestive of presumed lithogenic processes. They consisted of association of congenital dilatation of biliary tree (5 cases), association of stenosis or obstruction of biliary tree occurring prior to lithiasis (4 cases), association of anomalous communication between biliary tree (1 case), presence of serous glands simulating to pancreatic exocrine glands in biliary tree (1 case), association of non-biliary hepatic cirrhosis (4 cases), association of chronic ulcerative colitis (1 case), intrahepatic cholesterol stone (2 cases) and association of granulomatous cholangitis (1 case). Chronic proliferative cholangitis which is consistently seen in a common type of hepatolithiasis was found in about a half of these unusual cases and not in the remaining cases. Based on the observations of these unusual cases, the following suggestions were obtained: dilatation, bile stasis or cholangitis may be a lithogenic factor of hepatolithiasis, and chronic proliferative cholangitis associated with a numerous amount of mucinous glands is not always a prerequisite lesion and exerts a promoting and accelerating effect in hepatolithiasis.

Florid duct lesions and extensive bile duct loss of the intrahepatic biliary tree in chronic liver diseases other than primary biliary cirrhosis.

Intrahepatic biliary tree with either florid duct lesions or a moderate to severe degree of the duct loss in four livers with chronic hepatic diseases other than primary biliary cirrhosis were studied with histometric and serial section observations. Florid duct lesions, distributed segmentally in the liver, were found in one case with incomplete septal cirrhosis and one case with idiopathic portal hypertension. The florid duct lesions including marked plasma cell infiltration and occasional periductal granulomas, were not associated with any bile duct loss in the two cases. The duct lesions were reversible in one case during a long clinical course. On the other hand, a moderate to severe bile duct loss with biliary epithelial degeneration and necrosis was associated with no or little periductal inflammatory cell infiltration in one other case with chronic intrahepatic cholestasis, probably drug-induced, and in one case with idiopathic portal hypertension. Although florid duct lesions and bile duct loss were important diagnostic features of primary biliary cirrhosis, one of them was observed to develop independently in severely diseased livers, not consistent with a diagnosis of primary biliary cirrhosis, sclerosing cholangitis or intrahepatic bile duct paucity syndrome.

[Heterotopic ossification in the skeletal muscle metastases of advanced stomach cancer].

The formation of heterotopic bone tissue in carcinomas of the gastrointestinal tract and/or their metastases is extremely rare. In a 74-year-old female with gastric adenocarcinoma, we observed extensive bone formation within metastases in the skeletal muscles. There are only 7 other cases of heterotopic bone formation in gastric cancer reported in the world literature. We suggest that heterotopic ossification in primary cancers and/or their metastases is probably the result of metaplasia of stromal fibroblasts into osteoblasts.

Cytoplasmic blood plasma inclusions in human hepatocytes.

Hepatocellular blood plasma inclusions were demonstrated in conventional formalin-fixed paraffin-embedded liver tissue by the immunoperoxidase technique in 114 out of 197 liver specimens. They were usually round or elliptical in shape, their size varying from a few microns to about 30 microns in diameter. Albumin, fibrinogen, alpha 1-antitrypsin, IgG, IgM, IgA, ceruloplasmin and transferrin were demonstrated in the inclusions, in that order of frequency. A majority were negative with the periodic acid Schiff stain after amylase digestion, but a few were positive. Many of them seemed to correspond to vacuoles in the hepatocytes but some were not seen in HE-stained sections. The inclusions were frequently seen in autopsy liver specimens, but were rare in surgical ones. Most of the inclusions might develop at an agonal stage, probably as a result of hypoxia or circulatory disturbances in the livers.