Takesaburo Mori

Pathomorphologic characteristics of 102 cases of thorotrast-related hepatocellular carcinoma, cholangiocarcinoma, and hepatic angiosarcoma

The pathomorphologic characteristics of 102 autopsy cases of Thorotrast (Th)‐related hepatic malignancies were described and compared to the features of non‐Th‐related cases. Among the 102 Th‐related hepatic malignancies, 44 (43.1%) were cholangiocarcinoma (CHC), 39 (38.3%) were angiosarcoma (AGS), 16 (15.7%) were hepatocellular carcinoma (HCC), and 3 (2.9%) were double cancer. In the non‐Th‐related cases approximately 90% were HCC, and AGS was very rare. Grossly, the majority (91.7%) of Th‐related CHC was located in the middle‐peripheral portion of the liver. In contrast, 77.8% of the non‐Th‐related cases were located in the hilar portion. Th‐related AGS was classified into four types: diffuse micronodular, multi‐nodular, massive, and mixed multi‐nodular and massive. Histologically, AGS was characterized by two cell types (spindle‐shaped cells and polyhedral cells) and three growth patterns (sinusoidal, carvernous, and solid). In noncancerous areas foci of varying degrees of sinusoidal dilatation with hyperplastic changes of sinusoidal lining cells were observed in all AGS cases and in some of the cases of Th‐related CHC and HCC cases. In many (80%) of the non‐Th‐related HCC, mixed macronodular and micronodular cirrhosis was associated. By contrast, in Th‐related HCC cases cirrhosis was superimposed on varying degrees of hepatic fibrosis related to Th deposition in only four cases (21.1%). Taken together, these findings suggest that Th influences are more carcinogenic to epithelial cells of the bile duct and sinusoidal lining cells than hepatocytes.

Frequency of mutant T lymphocytes defective in the expression of the T-cell antigen receptor gene among radiation-exposed people

The frequency of mutant T lymphocytes defective in T-cell receptor gene (alpha or beta) expression was measured using the 2-color flow cytometric technique. Results for a total of 203 atomic bomb survivors, 78 of whom were proximally exposed (DS86 doses of greater than or equal to 1.5 Gy) and 125 of whom were distally exposed (DS86 dose of less than 0.005 Gy), showed that the mutant frequency was significantly higher in males than in females. No significant dose effects were observed. In contrast, a significant increase of mutant frequency was observed for 6 patients treated with Thorotrast, a contrast medium containing thorium-232 formerly used for radioligands. In addition, thyroid disease patients treated with 131I showed a dose-related increase of mutant frequency. It was suggested that the present T-cell receptor mutation assay has a unique characteristic as a biological dosimeter for measurement of recent exposures to genotoxic agents.

Flow Cytometric Measurements of Somatic Cell Mutations in Thorotrast Patients

Exposure to ionizing radiation has long been well‐recognized as a risk factor for cancer development. Since ionizing radiation can induce mutations, an accurate way of measuring somatic mutation frequencies could be a useful tool for evaluating cancer risks. In the present study, we have examined in vivo somatic mutation frequencies at the erythrocyte glycophorin A (GPA) and T‐cell receptor (TCR) loci in 18 Thorotrast patients who have been continuously irradiated with alpha‐particles emitted from the internal deposition of thorium dioxide and who thus have increased risks of certain malignant tumors. When compared with controls, the results showed a significantly higher frequency of mutants at the lymphocyte TCR loci but not at the erythrocyte GPA loci in the Thorotrast patients. The discrepancy between the results of the two assays is discussed.

Clinicopathological study of hematological disorders after Thorotrast administration in Japan.

SummaryTen leukemia and four aplastic anemia cases were clinicopathologically studied in autopsies from patients who had been administered the contrast medium, Thorotrast, three to five decades previously. The short period from the appearance of hematological symptoms to death, the relatively low percentage of leukemic cells in the peripheral blood, the high frequency of erythroleukemia, i.e., 50% of leukemia patients, and a case of atypical megakaryocyte proliferation were revealed in leukemia patients. Leukemic cell infiltration in the spleen tended to become slight or minimal with the progress of fibrosis. As a result, the degree of spleen swelling was mild or lacking in leukemia patients who had been administered Thorotrast. On the other hand, cases such as hyperplastic or normoplastic bone marrow, an increase in immature granulocytic series or no decrease in the number of megakaryocytes were observed in aplastic anemia of Thorotrast-administered patients. It was thought that fibrosis in the bone marrow as well as in the spleen was induced by Thorotrast deposition. Thus, in hematological disorders of Thorotrast-administered patients, both leukemia and aplastic anemia cases were considered to be mainly of the atypical type, and it was speculated that the damage due to Thorotrast may affect the hemopoietic stem cell level and hemopoietic microenvironment.

ULTRASTRUCTURAL LOCALIZATION OF THOROTRAST (THORIUM DIOXIDE) IN HUMAN LIVER BY ANALYTICAL SCANNING ELECTRON MICROSCOPE

The distribution of thorium dioxide (Thorotrast) in the liver from a Thorotrast‐administered autopsy case was examined stereographically by analytical scanning electron microscopy. Thorium particles were detected in the macrophages of the portal triad and hepatic sinusoid. These macrophages were irregularly shaped and tended to be aggregated. In the sinusoid, accumulation of the macrophages formed a thrombus‐like structure. Furthermore, observed in the sinusoid were free Thorotrast particles that appeared to have been released into the sinusoid as a result of breakdown of the macrophages (Kupffer cells).

Cancer mortality in Thorotrast-exposed patients in Japan: Aichi series

AbstractBackground. To evaluate the late effect of internally deposited alpha emitters in humans, we performed, during the period 1979–1992, a follow-up study of patients who had received intravascular injections of Thorotrast (thorium dioxide) 30–50 years previously. The study was performed independently of and with no overlap of subjects in the previous Japanese study by Mori and coworkers.nMethods. The patients were 198 war-wounded veterans with intrahepatic and splenic Thorotrast deposits that were detected by abdominal X-ray examination during the period 1975–1978.nResults. During our observation period (1979–1992), 143 of 198 patients (1526 person-years) who had had Thorotrast injections died.nConclusion. Compared with 1113 war-wounded veterans with no history of Thorotrast injection, the Thorotrast-exposed patients had a 3.1-fold greater risk of death from all causes (95% confidence interval, 2.6–3.8), a 45.3 times greater risk of liver cancer (95% confidence interval, 24.8–82.5), and a 5.1 times greater risk of liver cirrhosis (95% confidence interval, 1.9–14.1).

LUNG CANCER IN A THOROTRAST ADMINISTERED PATIENT

A 79‐year‐old man developed small cell carcinoma in the lung 43 years after Thorotrast‐injection. The tumor with interstitial fibrosis arose in the periphery of the lung. Thorotrast particles were observed in the liver, spleen, bone marrow, and lymph nodes but not in the lungs. Four other Japanese cases of lung cancer after Thorotrast injection were reviewed. ACTA PATH‐OL. JPN. 35: 1467–1473, 1985.

Effect of PSK, a protein‐bound polysaccharide preparation, on liver tumors of Syrian hamsters induced by Thorotrast injection

The contrast medium Thorotrast, an agent well known to be carcinogenic, was injected into 400 congeneic Syrian hamsters. The resulting incidence of malignant hepatic tumors such as cholangiocarcinoma, hepatocellular carcinoma and hemangiosarcoma, was significantly higher in the male experimental group than in the control group, and the 50% survival period in the male group was shortened by about 100 days (P < 0.01). However administration of the antitumor drug PSK (Polysaccharide Kureha), a protein bound‐polysaccharide extracted from basidiomycete fungi, prevented this carcinogenic effect. The incidence of malignant hepatic tumors in the experimental group was 22.5% compared with 2.8% in the control group (P < 0.01) and 10.5% in the PSK‐treated group (P < 0.01). PSK also increased the 50% survival period by 61 days (P < 0.01).