Document Yrv9YNZ95bej8MJdYVGppJV

Development of Hepatic Angiosarcoma in Man Induced by Vinyl Chloride, Thorotrast, and Arsenic Comparison With Cases of Unknown Etiohgy Hans Popper, MD, PhO, Louis B. Thomas, MD, Norman C. Telles, MO, Henry Falk, MD, and Irving J. Selikoff, MO Examples of human angiosarcoma following exposure to vinyl chloride, Thorotrast, or arsenic (medicinal and industrial) and cases, including children, of unknown etiology were studied to establish diagnostic criteria and to study their es'olution. The uniform evolution suggests an environmental factor also in the cases of unknown etiology, which may be established by epidemiologic studies. A precursor stage is characterised by areas of combined hyperplasia of hepatocytes and a variety of sinusoidal and perisinusoida! cells associated with excess of reticulin and with sinusoidal dilatation. The diagnostically useful picture in silver impregnations indicates reticulum formation by the perisinusoidal cells, presumably the lipocytes. The hepatocytic proliferation suggests a hepatocarcinogcnic but usually nbt fully expressed potential. The mixed hyperplasia of the various sinusoidal cells proceeds to an overgrowth of angiosarcoma cells, presumably derived from endothelial cells. In early stages they are usually in contact with hepatocytes (intralobular growth). A trabecular arrangement results from loosening of the lobular plate arrangement by dilatation of sinusoids, leading to primary peliosis. With disappearance of the hepatocytes, various growth patterns develop, terminating in nodular, solid angiosarcoma composed of either spindle-shaped or polyhedral cells which undergo necrosis or hemorrhage (secondary peliosis). The interaction between hepatocytes and sinusoidal cells requires elucidation. (Am J Pathol 92:349-376, 1976) The recognition of the association between exposure to gase ous vinyl chloride during its polymerization to the common plastic poly vinyl chloride and the appearance of hepatic angiosarcoma1 has increased the interest in this tumor. This concern was accentuated by its production in rodents exposed experimentally to vinyl chloride before the human lesion was recognized.2 Until then, hepatic angiosarcoma had been con sidered rare in man, although it has been known that exposure to thorium dioxide (Thorotrast)* and inorganic arsenicals4 may be followed by de- Fmm the Stratton Laboratory for Liver Disease, Mount Sinai School of Medicine of the City University of New York. New York, New York; the Laboratory of Pathology, National Cancer Institute, NIH, Bclhesda, Maryland; the Office of Medical Affairs, Bureau of Radiological Health, FDA. Rockville, Man-land; the Chronic Diseases Division, Bureau of Epidemiology. Center for Disease Control, USPHS, Atlanta, Georgia; and the Environmental Sciences Laboratory, Mount Sinai Sch<Hi! of Medicine of die City University of New York, New York. New York. Supported in part hv National Institute of Occupational Safetv and Health (NIOSH) Contract 210-75-0044. Accepted for publication March 30. 1978. Address reprint requests to Louis B. Thomas, MD, Chief, Laboratory f Pathology, National Camcr Institute, NIH. Building 10, Room 2A27, Bclhesda, MD 20014. 0002-9440/7S/0810-0349$01.00 349 i/<? fprn* ' 7r 7*f-3?c 360 POPPER ET AL INTftALOaULAA AS WITH HlflOnASIA American Journal of Pathology Text-kicvbe l--Proposed schema of evolution of hepatic angiosurcoma (AS). giopericytoma, mixed mesenchymoma, hemorrhagic hepatocellular carci noma, or various types of metastatic tumor were diagnosed as angiosar coma. The mixed hyperplastic areas are not readily diagnosed In needle biopsy specimens. Silver stains are then most helpful. Discussion Morphologic study of a large number of cases of angiosarcoma and their developmental stages revealed few, if any, differences between the cases induced by agents such as vinyl chloride, arsenic, Thorotrast and those in which no etiologic agent has been established. Intensive study of a far larger number of cases did not confirm our early impression that vinylchloride-related angiosarcoma differs morphologically from cryptogenic cases.* This suggests that in cryptogenic cases, environmental factors are responsible, the nature of which is being sought by intensive epidemio logic studies.'* The available surveys ,#,,c indicate a recognized environ mental etiology in only a small percentage of cases of hepatic angiosar coma. The observations provided information of potential assistance in the diagnosis of the lesion, including the precursor stage. This inhvmation should he helpful in the diagnosis of industrial hazards. The enforcement of strict hygienic regulations has reduced the levels of vinyl chloride in the polymerization plants or other places where polyvinyl chloride is pmc-