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This is the seventh reported case of soft tissue sarcoma attributed to thorotrast extravasated during the course of an injection for arteriography. An extraskeletal osteosarcoma occurring the cervical region of a 51-year-old man 30 years after a cerebral arteriogram is presented. The other reported cases include a fibrosarcoma, two neurofibrosarcomas, two spindle cell sarcomas, and an extraskeletal chondrosarcoma. The latency period has varied from 5 to 30 years. The thorotrast granules are readily identified in macrophages near or adjacent to the tumor, and the demonstration of alpha tracks on autoradiographs is diagnostic.

Two cases of osteosarcoma are described arising in patients who had undergone angiography with Thorotrast during childhood. In both patients, there was radiographic and pathologic evidence of radioactive thorium dioxide deposition in bone as well as throughout the reticuloendothelial system. Thorotrast deposits were demonstrated in the immediate vicinity of the primary tumors by both histology and autoradiography. Previous cases of osteosarcoma associated with Thorotrast administration from the literature are cited, and possible causal relationahips are discussed between thorium retention in bone and neoplastic transformation by chronic radiation.

Three cases of carcinoma of the maxillary sinus 10, 18, and 21 years after the instillation of thorium dioxide (Thorotrast) into the maxillary sinus are reported. Histologically, one was an adenocarcinoma, one was a squamous cell carcinoma, and one was a mucoepidermoid carcinoma. A cause and effect relationship between the substance used and the production of the cancer appears highly probable. These cases add to the existing accumulated evidence that Thorotrast or otherrelated radioactive substances should not be used as a diagnostic medium since their persistence in the form of colloidal particles in the tissues over long periods represents a definite hazard for a possible carcinogenic effect. (auth)

A case of a surgically resected solitary juvenile hemangioendothelioma of the liver is reported. Thirty-two cases with multiple tumors and 4 cases with solitary tumors have been previously described. Only 2 cases with multiple tumors survived. Four of the 5 patients with solitary lesions survived: in these 4 cases, the tumor was surgically resectable. These tumors have occurred in man after injection of Thorotrast, a 20% colloidal solution of thorium dioxide, and in animals after injection of Thorotrast or urethan. In infants, a pathogenesis of this tumor may be a reaction of the hepatic vasculature during fetal development or in early infancy. Solitary lesions can be resected and cured. Multiple lesions may regress spontaneously but have not been amenable to therapy.

New additions since 1968 to the literature on radiation carcinogenesis in man support the earlier conclusion of an approximately linear increase in cancer incidence in a broad intermediate dose range for most sites of cancer. Questions are raised regarding the nature of the dose-response relation at very low and at very high dose exposures. Analyses of some data on exposure to radiation from internal deposits of radioactive material suggest that the dose-response curve at low and intermediate ranges in concave up, implying a smaller effect per unit exposure at very low doses than at intermediate ranges. Data on exposure to the very high but anatomically limited doses of radiation used in cancer therapy give conflicting results, suggesting in one report a continuation of the linear relation into the high-dose range. Other reports suggest a lesser effect per unit dose at high doses than at intermediate doses. Extensive laboratory studies of exposure of experimental animals indicate that over broad dose ranges, exceptions to simple linear relations are the rule, and that factors of dose rate and fractionation also affect the dose-response relation.

Two cases of osteosarcoma are described arising in patients who had undergone angiography with Thorotrast during childhood. In both patients, there was radiographic and pathologic evidence of radioactive thorium dioxide deposition in bone as well as throughout the reticuloendothelial system. Thorotrast deposits were demonstrated in the immediate vicinity of the primary tumors by both histology and autoradiography. Previous cases of osteosarcoma associated with Thorotrast administration from the literature are cited, and possible causal relationships are discussed between thorium retention in bone and neoplastic transformation by chronic radiation.

Twenty-three years after an injection of Thorotrast, profound depression of humoral and cellular immunity associated with extensive marrow plasmocytosis developed in a man aged 75 years. Twelve months of chemotherapy with L-phenylalanine mustard, resulted in hematologic remission. Radioautograph of his marrow showed signs of alpha-radiation; whole body counting revealed a significant thorium burden. One year after chemotherapy was stopped, and two years after initial presentation, aleukemic acute granulocytic leukemia led to his death. The role of thorium in the etiology of possibly two successive hematopoietic neoplasms is discussed.

An hepatic angiosarcoma that developed 36 years after thorotrast administration is described with radiological and autoradiographic findings. An unusual feature of this case is the remarkably long latent period.

An osteosarcoma developed near the right lesser trochanter of a 55-year-old woman. The neoplasm fulfilled the generally accepted criteria for a Thorotrast related malignancy. Strengthening this relationship was the occurrence of the tumor in an unusual location and uncommon age group. Thorium was confirmed both in the tumor and in bone marrow histiocytes by its characteristic x-ray spectrum. Including this case only twelve Thorotrast-associated neoplasms of bone have been reported. The mean latency period after Thorotrast administration was 26 years. Regression analysis revealed that latency period and Thorotrast dose are inversely related. All tumors were reported to be sarcomas. Six osteosarcomas, one fibrosarcoma, one chondrosarcoma, and one undifferentiated sarcoma were proven histologically. All patients, for whom follow-up was given, had died of the tumor. The reasons behind the low frequency of reported Thorotrast-associated bone malignancies may be the low concentration of 232Th and radioactive daughters in bone, long latency period or the general lack of knowledge concerning the possible relationship between Thorotrast and bone tumors. Statistical association between Thorotrast injection and bone sarcoma is shown. The criteria for the diagnosis of Thorotrastosis are discussed as well as the long term deleterious effects. The distribution of Thorotrast within the body is discussed as well as the associated radiographic changes.

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, cavernous, 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.

This is the seventh reported case of soft tissue sarcoma attributed to thorotrast extravasated during the course of an injection for arteriography. An extraskeletal osteosarcoma occurring the cervical region of a 51-year-old man 30 years after a cerebral arteriogram is presented. The other reported cases include a fibrosarcoma, two neurofibrosarcomas, two spindle cell sarcomas, and an extraskeletal chondrosarcoma. The latency period has varied from 5 to 30 years. The thorotrast granules are readily identified in macrophages near or adjacent to the tumor, and the demonstration of alpha tracks on autoradiographs is diagnostic.

A 64-year-old man developed hepatic angiosarcoma, and combined hepatocellular and cholangiocarcinoma, 36 years after Thorotrast administration. The patient presented with a large mass in the right upper quadrant. His serum alpha-fetoprotein increased from 800 ng/ml to 51.2 micrograms/ml, and liver biopsy disclosed hepatocellular carcinoma. At autopsy, the liver had two different malignant neoplasms; angiosarcoma and combined hepatocellular and cholangiocarcinoma. Metastases of angiosarcoma to both lungs and of cholangiocarcinoma to periaortic lymph nodes were also seen. Interestingly, some neoplastic cells of angiosarcoma exhibited globular hyaline inclusions, which were Periodic-Acid-Schiff reaction positive and diastase-resistant.

A case report of a patient who developed acute myelogenous leukemia 15 years after injection of Thorotrast and who has been in a sustained long term remission for 14 years is presented with a review of the problems associated with Thorotrast, subsequently shown to be radioactive with long term sequelae.

Reported is a 59-year-old patient, who died of a peritoneal mesothelioma 36 years after contamination with thorotrast of the peritoneal cavity during cholangiography at cholecystectomy. Eleven years before death, the right kidney had to be removed for hydronephrosis due to fibrous stenosis of the pyeloureteral junction, because of thorium dioxide deposits.

The occurrence of a glioblastoma with sarcoma, a gliosarcoma, in the left frontal-temporal area of a 49-year-old woman with a history of Thorotrast exposure, is described. Thorotrast-laden histiocytes and free Thorotrast material were found in both components of the tumor. An overlying, adherent dural cranial lesion was found to contain massive deposits of Thorotrast embedded in a dense fibrotic and sclerotic stroma with focal calcification. These features are typical of "Thorotrastoma." Thorotrast stains greenish-brown with hematoxylin and eosin and appears as refractile granular particles of relatively uniform size either within histiocytes or as free material. The radioactivity of the deposits was confirmed through the use of a scintillation counter, and 232 thorium was definitively identified though the use of scanning electron microscopy with energy-dispersive X-ray analysis. Immunohistochemical studies of the tumor demonstrated glial fibrillary acid protein (GFAP) immunoreactivity in areas of glioma and focal vimentin and actin immunoreactivity in areas of sarcoma. Thorotrast-associated lesions of the central nervous system (CNS) are infrequently reported, and a Thorotrast-associated gliosarcoma has not yet been reported. The use of Thorotrast, its radiobiology, and sequelae are reviewed with particular emphasis on lesions occurring in the CNS.

The case history is presented of a malignant tumor in man attributed to the injection of Thorotrast. 55 references. (C.H.)