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Development of Hepatic Angiosarcoma in Man Induced by Vinyl Chloride, Thorotrast, and Arsenic Comparison With Cases of Unknown Etiology Hana Popper, MD, PhD, Louis B. Thomas, MD, Norman C. Telles, MD, Henry Falk, MD, and Irving J. Selikoff, MD 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 Ibeir evolution. The uniform volution suggests an'environmental factor also in the cases of unknown etiology, which may be established by epidemiologic studies. A precursor stage is characterized by areas of combined hyperplasia of hepatocytes and a variety of sinusoidal and perisinusoidal cells associated with excess of retlculin 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 hepatocarcinogenic but usually not fully expressed potential. Hie 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 92i349-376, 1978) 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.1 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- From 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. Bethesda, Maryland; the Office of Medical Affairs, Bureau of Radiological Heilth, FDA, Rockville, Maryland; the Chronic Diseases Division, Bureau of Epidemiology, Center for Disease Control, USPKS, Atlanta, Georgia; and the Environmental Sciences Laboratory, Mount Sinai School erf Medicine of the City University of New York, New York, New York. 2- *' Supported in part by National Institute of Occupational Safety and Health (NIOSH) Contract 910-75-0044. Accepted for publication March 30, 1978, Address reprint requests to Louis B. Thomas, MD, Chief. Laboratory of Pathology, National Crnccr Institute, NIH, Building 10, Room 2A27. Bethesda, MD 20014. 0002-9440/78/0810-0349S01.00 349 t AP00019558 350 POPPER ET At American Journal Of Pathology velopment of the same tumor. By contrast, In domestic and experimental animals hepatic angiosarcoma is more common. In humans exposed to vinyl chloride, M arsenicals,7 and Thorotrast,* a peculiar hepatic fibrosis often associated with portal hypertension has been observed; transition of this antecedent lesion to angiosarcoma has been postulated. It therefore appeared important to study available cases of angiosarcoma associated with exposure to vinyl chloride, Thorotrast, or inorganic arsenicals and cases without known etiologic factors in an attempt to a) ascertain differ ences in pattern and evolution associated with various etiologic factors; b) describe a focal hyperplastic precursor lesion; c) trace the evolution of the precursor lesion and of the angiosarcoma; d) stress the connection of sinusoidal cell hyperplasia with the proliferation of the hepatocytes, since hepatocellular carcinoma has also been documented to result from ex posure to Thorotrast * and inorganic arsenicals4 and has been found in rodents exposed to vinyl chloride 10 while in humans this association with vinyl chloride exposure is only suggested by anecdotal observations;11 e) study the relation of a mixed mesenchymal cell reaction to intralobular fibrosis; and f) provide diagnostic criteria for both the precursor stage and angiosarcoma useful in epidemiologic surveys. There were relatively few reports of hepatic angiosarcoma of unknown etiology18 W before the vinyl chloride experience raised interest in the tumor. They fire now supplemented by several others,1**** but even large* scale surveys l,-* emphasized the rarity of the hepatic tumor. This tumor has been reported in all age groups, including children, and has no established sex predilection. These lesions have to be differentiated from benign but actively proliferating vascular tumors such as capillary heman gioendothelioma,81 particularly its infantile variety,** as well as from malignant mesenchymal tumors with conspicuous participation of capil laries such as malignant mesenchymoma,** hemangiopericytoma,** and Kaposi's sarcoma, all of which have been found occasionally in the liver. Highly vascularized hepatocellular carcinomas sometimes also present diagnostic problems. l2A The proper designation of the tumor under discussion has been argued in cases of unknown etiology and in those associated with arsenic and Thorotrast exposure; terms such as "hemangloendothelial sarcoma,"1* "Kupffer cell sarcoma,"*4 "malignant hemangipendothelioma," and "he* mangiosarcoma" have been used. In recent years, however, it has become the custom to use "angiosarcoma" as the most descriptive term although the recent nomenclature proposal for hepatic lesioni 71 lists most of these terms with equal emphasis For simplicity, the ter `angiosarcoma" is used here. Rtv ers AP00019559 Vol. 92, No. 2 August 1978 HUMAN HEPATIC ANGIOSARCOMA 351 Revltw of Available Data The first association of hepatic angiosarcoma with vinyl chloride was reported in the work force of one of the oldest polymerization plants in the United States1 and additional cases have subsequently been reported and well-described histologically.*4'*1 Since then' more instances have been reported in the United States as well as in Canada,* England,"*1 Germany,1**"'" and France.14"" The fibrotic antecedent lesion, initially recognized in Bonn, Germany,* was well documented by laparoscopic and scintigraphic observations,, ,W1 and subsequently reported in this coun try and in England ** in workers exposed to gaseous vinyl chloride. The German investigators were stimulated by the recognition of splenomegaly in workers with acro-osteolysis following exposure to high concentrations of vinyl chloride.4*'44 Characteristic changes in the spleen associated with the antecedent fibrotic lesion were described as resembling the changes initially associated with the Band syndrome.4 These observations con firmed previous reports of nonspecific hepatic lesions in vinyl chloride workers.41,44 Rare instances of cirrhosis were also reported.47 Idiopathic portal hypertension following the long-term exposure to inorganic arsenitals in Fowler's solution used in the treatment of psoriasis has been reported,7'4*"80 a treatment which also has been rarely followed by hepatic angiosarcoma.*1'** The largest series of angiosarcomas following exposure to arsenicals in pesticides, which also cause hepatocellular carci noma and cirrhosis, although less frequently, comes from vineyard work ers in the Rhineland.Hepatic angiosarcomas and carcinomas and, apparently, the fibrotic antecedent lesion following Thorotrast exposure have been well-described in Portugal.**'** The number of angiosarcomas following Thorotrast exposure has increased in recent years,*7"*1 and the lesion has been produced experimentally in rabbits." Finally, inorganic copper has also been incriminated." The initial recognition that vinyl chloride has a carcinogenic potential In rodents44 stimulated the extensive investigations of Maltoni,* and changes in the livers of workers exposed to vinyl chloride have been compared with those in rodents." Angiosarcoma is more frequent in animals, both domestic and experimental, than in humans. It occurs spontaneously in dogs44 and in some strains of inbred mice,47 and it has been observed in rodents and primates exposed to carcinogens, particu larly those which also produce hepatocellular carcinoma"'71 and after infection of hamsters by polyomavirus.7* Materials and Methods This study is based on review of material which became available primarily for consult*- :2 I *L' i aUi |:u*l i APOOOf9560 352 POPPER ET AL American Joumt Pelhotogy lion at the Laboratory of Pathology of the National Cancer Institute and at the Mount Sinai School of Medicine. Most of the material was submitted as a result of an extensive epidemiologic investigation of angiosarcoma in the United States from 1954 to 1974 by the Center for Disease Control, Atlanta, Georgia. Additional material came from the Emi. . rcnmenUl Sciences Laboratory of the Mount Sinai School of Medicine. Some material of vinylchloride-related cases was provided for study directly by pathologists in Louisville, Kentucky; other material came From many pathologists from this country and Europe. Eight of the Thorotrast cases were obtained from the Armed Forces Institute of Path> ology." In addition, cases were pulled from the files at the National Cancer Institute and at Mount Sinai Hospital. In alt instances, histologic slides were studied, and. In some, blocks or wet tissue were also available. Where possible, additional special stains were performed such as Mallory's trichrome, ehromatron aniline blue, silver for reticulum (mainly collagen Type III}" without toning to leave hard collagen (Type I) yellow-brown (otherwise stained by conventional connective tissue stains of the aniline blue variety), PAS reaction after removal of glycogen by diastase to identify increased phagocytosis, iron reaction, and Shikata stain to demonstrate elastic tissue and the s component of hepatitis B antigen. The material studied as well as sea and age distribution ore listed In Table 1. In the vinyl-chloride-assoclated material is a series of cases In which multiple biopsies or biopsies and subsequent autopsies could be studied. The fibrotic precursor lesion was identified in biopsies and occasionally In autopsy specimens in areas sufficiently removed from the angiosarcoma to reasonably exclude mechanical or other effects. These were male patients, ana the estimated exposure to vinyl chloride varied from 12 years to 28 years; the average exposure was 19.6 years. The latent period between first exposure and diagnosisof angiosarcoma ranged from 12 to 38 years; the average latent period was 22.3 years. The arsenic-associated lesions were the result of exposure to Fowler's solution for many years for psoriasis or asthma; in the 4 cases for which detailed information is available, the duration of exposure ranged from 10 to 17 years, with a mean of 14 years. Thorotrast had been gtven for radiologic visualization of. primarily, brain lesions many yean ago. When Thorotrast administration could be verified, records indicated that it had been given 16 to 40 years before the patient sought medical care for a hepatic disease." The patient material designated "unknown" represents the histologically completed part of a survey of cases of hepatic angiosarcoma of unknown etiology retrospectively reviewed after death certificate, autopsy, or surgical biopsy recorded the above diagnosis. Among 117 cases, 4 were children. In this survey the cases not conforming to this diagnosis were eliminated, and in the confirmed cases a search for etiologlc factors was Initiated but is not complete." Among the factors under consideration are previous liver disease, other chemicals, and various sources of exposure to known etiologic agents such as arsenic. Results Features Distinguishing Etiotogic Fedors The same pattern and evolution were encountered in all the cases studied. Independent of the etiology, with hardly any exceptions. The most prominent feature of the Thorotrast-associated lesions was deposi tion of large amounts of Thorotrast In dense connective tissue in the capsule and in the portal tracts but often also within the parenchyma. Proliferation of bile ductules was absent or only rarely seen In the Thoro* trast-associated cases, in contrast to the vinyl chloride and arsenical as well as cryptogenic cases, in which marked bile duct proliferation was com mon. Hematopoietic foci were found in cases of each etiology. Therefore, Pr AP00019561 V0l.2,N0.2 August 1978 HUMAN HEPATIC ANGIOSARCOMA 353 In the following presentation of the observations, little reference will be made to etiology. The same holds true with few exceptions for the legends of the illustrations. Precursor Stag* This stage was characterized by hepatocytic proliferation associated to varying degrees with sinusoidal lining cell proliferation and with focal sinusoidal dilatation. The hepatocytic hyperplasia was observed in two forms which varied In size and degree of demarcation, uniformity of hepatocellular hyperplasia, and extent of associated sinusoidal lining cell activation and fibrosis. in the first form, multiple, poorly circumscribed foci of hepatocytes exhibited variations from the surrounding parenchyma. The cells varied in size and formed two-cell-thick plates with their nuclei adjacent to the sinusoidal border. Binucleated and even multinudeated hepatocytes were seen (Figure 1). The bile canaliculi were sometimes dilated but devoid of hile plugs. Lipofuscin pigment was often increased. The sinusoidal lining cells in these fod were increased in number and varied in morphologic appearance. They included normal endothelial cells, plump cells with spindle-shaped nuclei and with diffuse PAS-positive diastase-resistant reaction of the cytoplasm, a few macrophages, and many lipocytes, identi fied by small fat droplets. The silver-impregnated reticulum framework was barely increased. The second form was observed when transformation to angiosarcoma was present or subsequently established. A uniform, conspicuous hyper plasia and hypertrophy of hepatocytes in contiguous, almost nodular areas, was associated with an even more conspicuous increase in various sinusoidal cells (Figure 2). The sinusoidal cell proliferation included nor mal and enlarged endothelial cells, macrophages with PAS-positive dias tase-resistant granules, lymphocytes, and occasionally plasma cells or segmented leukocytes (Figure 3). This sinusoidal cell reaction differed from that seen in hepatitis in that it was not associated with degeneration and necrosis of hepatocytes. The reticulum framework was increased in silver stains and showed an excess of both longitudinal and cross fibers. The irregular areas with increased reticulin were recognized under lowpower magnification (Figure 4). The areas of hepatocytic and sinusoidal cell hyperplasia and hypertrophy distorted the lobular architecture. The areas usually involved only part of the lobule but occasionally extended into a neighboring one. They were usually closer to the portal tract than to the central zone and were not round but garland-shaped. The surround ing parenchyma, also curved, was either normal or compressed (Figure 5). The hepatocytes in the compressed areas often revealed degeneration. 354 POPPER ET AL American Journal of Pathology and PAS-positive macrophages accumulated while the reticulin framework was condensed. Sometimes these compressed zones were hyperemic or hemorrhagic. After Thorotrast exposure, Thorotrast granules were found in the macrophages of the compressed areas; they were absent or infrequent in the hyperplastic areas. Bile plugs were noted on the border between the hyperplastic and the compressed areas. The mixed hyperplastic areas differed from nodules In multiple nodular hyperplasia of humans and from the hyperplastic areas and neoplastic nodules of rodents by a) proliferation of various sinusoidal cells, b) increase of the reticulin framework, and c) garland-shaped outline. Focal sinusoidal dilation observed frequently in the precursor stage involved in part portions of the mixed hyperplastic areas and in part the surrounding parenchyma, without relation to lobular topography. The cells lining the irregularly dilated sinusoids were increased in number (Figure 6) and the surrounding reticulin framework was thickened. Nonspecific alterations in the surrounding parenchyma included occa sional focal steatosis and clumping of hepatocytic cytoplasm. The portal tracts showed varying degrees of fibrosis which sometimes disrupted the limiting membrane and extended into the periportal parenchyma. Portal fibrosis was occasionally associated with proliferation of bile ductules and, in a few instances, with accumulation of iymphoid cells around bile ducts (Figure 7). This pericholangitis was usually accompanied by diffuse cana licular cholestasis. Where it was possible to study the capsule, it showed focal capsular and subcapsular fibrosis in vinyl-chloride-associated cases. In the Thorotrast cases, these fibrotic areas contained Thorotrast deposits. Inflammatory cells were not noted in the areas of capsular fibrosis. Transition to Angiosarcoma Five processes participated to varying degrees in the transition to angiosarcoma: 1) proliferation with increasing anaplasia of intralobular endothelial cells; 2) initial hyperplasia of hepatocytes followed by atrophy and disappearance; 3) increasing fibrosis in perisinusoidal spaces; 4) pro gression of sinusoidal dilatation to peliosis; and 5) sarcomatous transfor mation of lining cells of sinusoids and of portal capillaries. The combina tion of the processes resulted in three pathways to angiosarcoma: 1. Intralobular growth with fibroplasia. The number of sinusoidal cells in the hyperplastic areas increased further so that they were in places arranged in more than one layer, although flat endothelial cells lined part of the sinusoidal spaces. The conspicuous hepatocytic hyperplasia might result in hepatocytir trabeculae lined by increased sinusoidal cells (Figure - ' | APOOO19563 Vo). 92. No. 9 AufiUtt 1976 HUMAN HEPATIC ANGIOSARCOMA 955 8). The Disse space was widened and filled with many reticulum fibers In layers of variable thickness since cross fibers were also irregularly in* creased. It contained fibroblasts and many lipocytes. Some sinusoidal lining cells had a bulky cytoplasm and hyperchromatic nuclei; similar cells were found also in the Disse spaces and indented adjacent hepatocytic plates. The sinusoids were either narrowed or somewhat dilated in places and contained an increased number of inflammatory cells. Even tually, spindle-shaped lining cells predominated, while lymphocytes, macrophages, and other inflammatory cells disappeared. Atypical cells formed multiple uniform layers lining the sinusoids and, because of increasing atypia and anaplasia, were considered to be angiosarcoma cells. Further progression was reflected in several features which occurred coincidentally with the previously described changes: a) Hard connective tissue (Type I collagen) associated with elastic fibers increased con spicuously around angiosarcoma cells within and around vascular spaces and compressed adjacent hepatic plates which atrophied and resembled bile ductules (Figure 9) and finally also disappeared. Fibrotic areas often became hyalinized and replaced many lobules, b) The angiosarcoma cells filled and extended the sinusoidal spaces to interfere with micro circulation, and the hepatic parenchyma showed anoxic necrosis (Figure 10). c) The angiosarcoma cells formed large clusters and, occasionally, solid nodules (Figure 11) composed mostly of spindle-shaped and some times of polyhedral cells. 2. Intralobular growth with sinusoidal dilatation. This pattern was an accentuation of the sinusoidal dilatation which was noted mainly in the mixed hyperplastic areas. It was characterized by further proliferation of sinusoidal and perisinusoidal cells. With increasing dilatation, adjacent hepatic plates were disrupted so that small cystic spaces formed by confluence of dilated sinusoids. These irregular spaces were separated by plates of hyperplastic hepatocytes (Figure 12) and the surrounding frame work was remarkably thickened (Figure 13). Often, hematopoietic cells accumulated in the dilated sinusoids. Into larger spaces, blindly ending spurs of hepatocytes extended, covered by atypical sinusoidal or angiosar coma cells. Eventually, the diffuse irregular loosening of the parenchymal architecture by some uniform and some irregular sinusoidal dilatation produced a plexiform, trabecular arrangement of the hepatocytes, with great variations in the quantitative relation between hepatocytes and sinusoidal cells. Initially the hepatocytes appeared hyperplastic and ar ranged in two and more cell layers around bile canaliculi which often contained bulky bile thrombi (Figure 14). When the hyperplastic hepa tocytes predominated, the picture resembled the trabecular type of he- 356 POPPER ET AL American Journal of Pathology patocellular carcinoma although the hepatocytes were not anaplastic. The considerably widened Disse spaces around the trabeculae contained a variety of mesenchymal cells, including segmented leukocytes, macro- . phages, lipocytes, and lymphocytes, as we!! as spindle-shaped angiosar coma cells (Figure 15) and a significantly increased, irregularly arranged reticulum framework. The angiosarcoma cells, often in two layers, did not contain PAS-positive glycogen-resistant granules indicative of phago cytosis, nor iron granules or Thorotrast, even when the latter was found in other locations. The destruction of the lobuiar architecture by the de scribed loosening need not involve the portal and the central canals. They remained as beam-like trabecular structures containing vessels and bile . * ducts and traversed the enlarging blood spaces. They were covered by layers of angiosarcoma cells, which also infiltrated these beams which underwent hyalinizing fibrosis (Figure 16). Bile ductules were similarly initially preserved and appeared also as trabeculae. The blood spaces eventually became grossly visible blood cysts in which fibrin clots formed. Another variant of the trabecular form of angiosarcoma was gradual fibrosis in the hepatocytic cords while inflammatory cells disappeared (Figure 17). Hard, Type I collagen, intermixed with elastic fibers, formed in the reticulin matrix and predominated in later stages. A third variant was relatively thin fibrotic stalks lined by spindle-shaped angiosarcoma cells, presenting a papillary arrangement (Figure 18). In all three variants, angiosarcoma cells also formed solid clusters and, eventually, nodules. 3. Portal growth. Mainly spindle-shaped angiosarcoma cells lined capil laries or lymphatics of the portal tracts or appeared single or in small nests in their connective tissue (Figure 19). This was associated, even in small lesions, with involvement of the periportal parenchyma. Only in few instances was angiosarcoma restricted to the portal tracts. Thus, portal Involvement appeared to be caused by spread of intralobular angiosar coma. This growth pattern was accompanied by proliferation of bile ductules surrounded by inflammatory cells intermixed with angiosarcoma cells. Considerable fibroplasia, mainly of reticulin character, but, sub sequently, also hyalinized collagen, produced masses of fibrous tissue, with varying amounts of either ductules or angiosarcoma cells together with occasional solid nests of predominantly spindle-shaped angiosarcoma cells. Portal angiosarcoma was accompanied in a few instances by connective tissue septums containing proliferated bile ductules, some venules and arterioles, and angiosarcoma cells intermixed to various degrees with ' >mmatory cells. These septums formed bridges connecting portal APOOOt9565 Vo*. 92, No. 2 August 1978 HUMAN HEPATIC ANGIOSARCOMA 357 tracts with each other or with central canals. They subdivided the lobules to create the picture of a cirrhosis (Figure 20). In the thus formed parenchymal nodules the bepatocytic plates were rearranged, usually in layers two and more cells thick, but, in contrast to common cirrhosis, they had an increase in reticulin and in sinusoidal cells surrounding the hepa* tocvtes. Variations in An|tosarcoma Pattern Clusters and nodules were composed of angiosarcoma cells of two types. One type was spindle-shaped and had large nuclei and distinct cytoplasmic extensions (Figure 11). The nuclei were often hyperchromatic and sometimes multiple, but nucleoli were small Few vascular spaces w ere lined by angiosarcoma cells but, occasionally, by flat endothelial cells. The other type of cell was large and had abundant cytoplasm. These polyhedral cells were often multinuclear and showed greater tendency for anaplasia than the spindle-shaped cells (Figure 21). The polyhedral cell nodules had few vascular spaces, while necrosis and hemorrhage were common. Transitions between and admixtures of both types of cells were frequent. The polyhedral cells were not intermixed with inflammatory cells except following necrosis. Sometimes they formed multiple layers lining blood-filled cystic cavities (Figure 22). Roth types of nodules, which also were grossly visible, compressed the surrounding parenchyma and had often a connective tissue pseudocapsule. They were frequently associated with invasion of veins by tumor cells, mainly of branches of the portal vein. Extensive necrosis was com mon with or without vein invasion. With silver stains, some areas of necrosis showed persisting hepatic trabeculae and portal tracts, while others failed to reveal remnants of hepatic structure. Specific developmental patterns were distinguished to trace the evolu tion of the multicentric angiosarcomas to sinusoidal, trabecular, papillary, portal, and nodular end stages.* Combinations, however, of several pat terns were usually seen in different parts of the same liver. For instance, fibrosing areas around hepatocytes, presumably derived from intralobular lesions, merged with others around proliferated ductules originating in portal tracts. Two cases of unknown etiology had a combination of both angiosarcoma and hepatocellular carcinoma. In one of them, nodules of these two types of malignant growth were separated by a fibrous pseudocupsule (Figure 23). Additional Futures Foci of hematopoietic cells, mainly nucleated red cells but also mega- 398 POPPER ET AL Anwrtcin Jtiii^ CfP^legy .* t karyocytes, were frequent in all forms of angiosarcoma (Figure 24). The hematopoietic cells were also in the perisinusoidal space but more Fre quently in the spaces lined by the angiosarcoma cells. The portal tracts showed variable amounts of lymphocytic infiltration. Bile ducts and due* tules showed not only proliferation of their epithelial cells, associated with hyperchromasia and formation of several layers, but also excess mucus formation, irregular dilatation, and out-pouching of epithelium into the surrounding, often hyalinized, connective tissue. Extrahepatic metastases (although multicentric origin is not excluded) of either spindle*shaped or polyhedral cell character were reported in 695 of the cases (Table 1). There was a lower percentage of metastases in those of known etiology, notably Thorotrast, than in those of unknown etiology, but the differences are probably not significant. The autopsy records of the entire series list Involvement of other organs as follows: lung and pleura (35%), spleen (28%), lymph nodes (25%), bone (23%), adrenal glands (14%), diaphragm (9%), heart (8%), and brain (8%). Many other organs were involved rarely. Spleen involvement was recorded far more frequently (36%) in the group of unknown etiology than in the vinyl chloride (13%) or Thorotrast group (11%). Diignoss Diagnostic criteria are particularly important in the evaluation of biopsy specimens. The following features proved useful in the survey of the material. The trabecular pattern with sinusoidal dilatation was most diagnostic when plates of hyperplastic hepatocytes were covered by single or multiple layers of angiosarcoma cells and hepatocytic spurs extended into blood-filled spaces. A second diagnostic feature was anaplasia of sinusoidal lining cells with or without an associated inflammatory reao* tion, especially when accompanied by sinusoidal dilatation and peri sinusoidal fibrosis. The diagnosis of angiosarcoma was more difficult when only a few anaplastic cells were observed in the sinusoids since lymphoma, myeloma, or single metastatic carcinoma cells had to be excluded. The association with inflammation is characteristic for angiosarcoma. A third feature, more readily overlooked especially in small biopsy specimens, is angiosarcoma cells mixed with inflammatory cells and proliferated bile ductules in portal spaces. Solid tumor nodules offered the greatest differ ential diagnostic problem; particularly, polyhedral cells are difficult to distinguish from hepatocellular carcinoma and other types of sarcoma. Connective tissue stains, including silver stains, assist in the distinction from hepatocellular carcinoma. Frequent misdiagnoses were encountered in the material available for study because lymphoma, heman- Vet.92.tAugust 1 AP000i9567 . ;. '! ; ; . . 1*'** WNMr:-|Wi?l>Vl^'>ir >- I"----**%** jwmi.*y-i^'<F.lW!' 'ipi.'^t- r.ying-yr-r- Table 1--Reviewed Hepatic Angiosarcoma Material Age 1 Sex at death (yrs) Race Etiology No. M F Average Range W B Vinyl chloride Thorotraat Fowler's solution Unknown 19 26 5 19 -- 52 36-67 19 19 7 54 32-73 25 4 1 49 41-56 5 4mo 1 Children Females Males Total 4 26 66 167t 1 85 128 33 13 2_8 57 61 39 -- - 18-62 16-69 -- 4 23 81 157 3 3 7 information about metaataaes not avallabia (or 1 vinyl chloride and 2 mala cases, t Include* 2 orientals and 1 whose race was unknown. Specimens Biopsy snd Biopsy Autopsy autopsy No. of cases with metastases 13 17 11 9 19 2 2 52 10/16* 6/19 3/5 4 44 13 IS 3 22 70 7 63 133 29 3/4 16/18 50/66* 90/130 ftsar* . . -wvJi-wV&i* wit..- j *awwaiiw|' m\j .nw.'. ;7 1 *i .. ................*< I jp.jjn,, --iJ*fi.T.r l 5 ,* '* V7^Vrt*' `"`'WW *u- MMWB m+wm- , -*,4 .iJHMOU.. . wSRwbsbsbS APOOO19568 300 POPPER ET AL INTRALOlULAft ASWTH FIIROPUUIA AmeroictaPnJheouiomgavi * -4 I? xcoautT FILiOn TexT-nevns 1--Proposed schema of evolution of hepatic angiosarcoma (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 Kelpful. Discussion ' Morphologic study of a large number ofcases 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 vinyl- - chloride-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'*'*0 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 precursor stage. This Information should be helpful in the dine ^ ndustrial hazards. The enforcement of strict hygienic regulatin .ced the levels of vinyl chloride in polymerization plants c es where polyvinyl chloride is pr Vd AU$ es* H< tio thi tai m mi frt1 UK sil ik on In in' ti\ I* ai r.i in ll' P< m b< SI di tl si la ra d. ii fr b gsc' e a> n b AP00019569 vol. 92. No, 2 August 1976 HUMAN HEPATIC ANGIOSARCOMA Ml essed.*1,7* Presumably no additional instances of initiation will occur. However, in view of the long period of promotion of tumors, addi tional cases of angiosarcoma, unfortunately, have to be expected in the future. The differential diagnostic criteria may have practical impor tance if other environmental and industrial hazards produce the same morphologic sequences. The diagnostic significance of the characteristic precursor stage of mixed hyperplasia and hypertrophy of hepatocytes and sinusoidal cells, frequently associated with sinusoidal dilatation, may be helpful in screen ing. although its specificity requires further study. It is best recognized in silver stains even with low-power examination. The second purpose of this paper is an attempt to better understand the development of hepatic angiosarcoma (Text-figure 1). Characteristically it entails, at least in early stages, a proliferation and hyperplasia of both hepatocytes and sinusoidal cells. The metabolic factors accounting for this interplay remain to be established. The appearance points to a prolifera tive. potentially carcinogenic stimulus for the hepatocytes. This is supportod by occasional primary hepatocellular carcinomas seen after arsenic and Thorotrast and, in rare cases, after vinyl chloride exposure. In young rats with less-developed microsomal biotransformation, including lesser metabolite degrading activity," vinyl chloride exposure leads more fre quently to hepatocellular carcinoma than in adult rats.10 This observation points to the possibility that variations in enzymatic biotransformation nuy determine the type of tumor that develops. In experimental animals, Ikith angiosarcoma and hepatocellular carcinoma have been produced, sometimes simultaneously.71 In human hepatocellular carcinoma, varying degrees of sinusoidal celt activity are noted, also expressed in variations of the reticulum framework around the trabecular form of this tumor. This suggests variable stimulation of sinusoidal cells even in frank hepatocellu lar carcinoma. Cases of both tumors in humans have been seen very rarely. Thus, the interaction between carcinogenic effects on sinusoi dal cells and hepatocytes Is a promising area for further study. Peculiarly, in Thorotrast-induced epithelial tumors, bile duct carcinoma may be more frequent than hepatocellular carcinoma.7* The described alterations of the hilc ducts in the angiosarcomas studied in this series suggest a carcino genic stimulus on bile duct cells, but the possibility that this is only a secondary reaction to the presence of a tumor in the liver cannot be excluded. Reports of intensive investigations of the metabolism of vinyl chloride are available.41'**'** It is transformed by hepatic microsomal action to mutagenic**" and potentially oncogenic*7 metabolites which covalently hind to DMA**'** and are injurious to hepatocytes in animals exposed to r 362 POPPER ET AL American Journal Of Pttholpgy very large doses of vinyl chloride.*0 These metabolites are then rendered inactive by enzymatic or nonenzymatic action or by binding to gluta thione.11 In the precursor stage, significant degenerative alterations of the hepa- tocytes, such as steatosis, focal necrosis, and llpofuscin deposits which are not age-dependent, have only been recognized histologically after short intervals between exposure and biopsy; these features subsequently re- gress.*1 This explains why conventional liver function tests are of little diagnostic value in this stage. Only with progression of the process to tumor formation appear measurable alterations of hepatic function. An giographic ** and scintigraphic*1 demonstration of the lesion has greater diagnostic value and the lesions are also reflected in hemodynamic altera tions.*4 A predominant early alteration is the sinusoidal cell proliferation associ ated with sinusoidal dilatation and fibrosis. While in such stages these cells are intermixed with various inflammatory cells, a transformation to angiosarcoma cells is associated with a disappearance of the other mesenchymal cells in all growth patterns. Hypothetically, the inflamma tion may have a suppressing effect from which the angiosarcoma cells seem to escape. Azoxymethane-lnduced angiosarcoma growth is stimu lated by antilymphocytic serum which has no effect on the hepatocellular carcinoma produced by this agent.** An immune complex disorder has been claimed as the basis of the vinyl chloride injury.** This could explain the inflammatory reaction in both parenchyma and portal tracts. Transition to angiosarcoma cells from the sinusoidal lining cells could be traced. They appeared to be derived from endothelial cells, not only because they were devoid of any phagocytic activity but also because they were clearly distinguished from phagocytic macrophages. Their origin from endothelial cells was also confirmed by electron microscopic study.** However, better confirmation by use of histologic markers of endothelial cells, for Instance, Weibel-Palade bodies,** or of catalase and per oxidases " is desirable. The angiosarcoma cells exhibited various forms of arrangement to include a) lining or tectorial, b) enveloping hepatocytes or ~ I bile ductules, c) vasoforming, or d) solid. They were either spindle-shaped with relatively little cytoplasm or polyhedral. The latter sometimes resem bled epithelial cells and thus created differential diagnostic problems. The solid or nodular forms developed from almost any growth pattern, includ ing the intralobular, the portal, and the trabecular. Angiosarcoma may develop in the lobular parenchyma and in the portal tracts. The primary growth in the parenchyma appears to be far more frequent, with the invasion of the portal tracts being secondary. In the fibi in AR00019571 Yd. 92. No. 2 August 1978 HUMAN HEPATIC ANGIOSARCOMA 962 fibrotic stages particularly, both growth patterns are combined, reflected in the presence of both hepatocytes and ductules. The sinusoidal dilatation found in the majority of instances is not explained by passive congestion because of its irregular location in the lobule. Similar forms of sinusoidal dilatation without angiosarcoma have Inm reported in women taking oral contraceptive drugs100 and in men and women receiving large doses of anabolic steroids.101 In the latter Cai*s. the peliosis may be sufficiently advanced to produce hepatic failure. In these instances, it has been explained by Injury to the sinusoidal lining11* and this was also demonstrated In vinyl-chloride-intoxicated mice.*1 The observations here are in keeping with this assumption of a Mnusoidocidal effect. In contrast to this, primary peliosis, the progression of which to large bloody cysts is associated with persistence of hvalinized i-onucctive tissue beams, best seen in silver stains, is a secondary peliosis occurring within angiosarcoma nodules undergoing extensive central necro'N and hemorrhage. In these instances no septums remain in the silver stains. Necrosis with hemorrhage is the predominant gross manifestation <f those tumors. The relation of the sinusoidal cel! hyperplasia to fibroplasia represents an interesting problem. The excess of perisinusoidal and sinusoidal cells of M'viral types, accompanied at least initially by hepatocytic hyperplasia, j*. regularly associated with excess reticulum fibers. This reticulin incTca5e was also found in the presence of sinusoidal dilatation and was a u-cful diagnostic criterion. The morphologic appearance suggests a fibro blastic activity of some of the perisinusoidal cells.101 Increased and en larged Ito cells104 or lipocytes,1" small fat droplets containing periumisoidal cells, were observed In light and in electron microscopic itudies,,1*0T,t"*l0T particularly in the flbrotic precursor stage. They are considered precursors of fibroblasts.1"1100 Their transformation to fibro blasts is associated with formation of collagen Type III, mainly reticu lum.1" Also, the splenic enlargement after vinyl chloride exposure results partially from proliferation of fibroblastic cells.110 Subsequent stages of the hepatic lesion are associated to a varying degree with desmoplasia, either in tlso form of a creeping fibrosis around hepatocytes, often in pseudo- ductular arrangement or around bile ductules, or as massive hvalinized fihrosis. Then hard, collagen Type I, a different gene product than colla gen Type III, develops within the reticulum and eventually replaces it. This implies a significant desmoplastic potential of the tumor, although tlir role of the fibroblasts in the later stages has not been established. A peculiar form is the septal fibrosis which leads to an almost cirrhotic picture. 364 POPPER ET A.L AmrfecnJauRM ofPmo^ |h The characteristic abundance of hematopoietic cells, including mega. .iZ karyocytes, in the developing angiosarcoma, both intrasinusoidal and perislnusoidal, may reflect a local formation of these cells in the activated rv mesenchymelM or bone marrow irritation. The great variability in appearance of the tumor is accounted for by the variable growth potential of hepatocytes and sinusoidal cells and by the irregular tendency for fibrosis and sinusoidal dilatation. However, in virtually all cases a multicentric angiosarcoma of yariable type results. . "iijp*- References ^ L Creech JL Jr, Johnson MN: Angiosarcoma of liver in the manufacture ofpolyvinyl chloride. J Occup Med 16:150-151, 1974 2. Maltoni C, Lefemine G: Carcinogenicity bioassays of vinyl chloride 1. Research plan and early results. Environ Res 7:387-406, 1974 3. MacMahon HE, Murphy AS, Bates MI: Endothelial-cell sarcoma of liver follow ing thorotrast injections. Am J Pathol 23:589-611, 1947 4. Roth F: Arsen-Leber-Tumoren (Haemingtaendotbeliom). Zschr Krebtforsch 4 61:468-503, 1957 ..* * 5. Marsteller HJ. Lelbach WK, MOiler R, J&he 5, Lange CE, Rohner HG, Veltman G; Ctaonisch-toxisehe LeberschSden bei Arbeitem in der PVC-Produktion. Ditch Med Wochenschr 98:2311-2314, 1973 6. Thomas LB, Popper H, Berk PD, Selikoff I, Falk H: Vinyl-chloride-lnduced liver disease: From idiopathic portal hypertension (Band's syndrome) to angiosarcomas. * 4 1 N Engl J Med 292:17-22, 1975 Morris JS, Schmid M, Newman S, Scheuer PJ, Sherlock S: Arsenic and non- cirrhotic porta! hypertension. Gastroenterology 66:86-94, 1974 8. da Silva Horta J: Late effects of thorotrast on the liver and spleen, and their efferent lymph nodes. Ann NY Acad Sci 145:676-699, 1967 9. Smoron GL, Battifora HA: Thorotrast-induced hepatoma. Cancer 30:1252-1259, !* 1972 m Maltoni C: Predictive value of carcinogenesis bioassays. Ann NY Acad Sci 271:431-447, 1976 li. Coke) JM, Liebezeit E, Eder M; Hemtnglosarcoma and hepatocellular carcinoma of the liver following vinyl chloride exposure: A report of two cases. Virchows Arch [Pathol AnatJ 372:195-203, 1976 is. Adam YG, Huvos AG, Ka)du SI: 175:375-383. 1972 Malignant vascular tumors of liver. Ann Sutg m 13. Pollard SM, Millward-Sadler GH: Malignant haemangioendothelioma involving the liver. J Clin Pathol 7:214-221, 1974 14. MacSween RNM, Vetters JM, Ross 5K, Ferguson J, Johnstone JM, Sandison AT: Haemangio-endothelial sarcoma of the liver. J Pathol 109:39-44. 1973 15. Sugahan K, Shirakura T, Kawano N, Kino I: Primary malignant hernsn- gloendothelioma of the liver: Report of a successful case of resection and review of the Japanese literature. Am J Gastroenterol 62:240-244, 1974 16. Fukuhara M, Tsujii T, Merita T, Ishikawa H; An autopsy case of primary cardiac faemangiosarcoma and analysis of cases in the literature. Jpn J Med 15:235-241, 1976 17. Fiechtner JJ, Reyes CN Jr rcoma of the liver In a rur-- jlation: Four cases diagnosed in a 29-; 4. JAMA 236:1704-170 18. Chowdhury AR, Black ` i, CheyWY: Hem* jliomatosis of the liver: A 12-year f- iroenterology 72:15? ^ VAeug-uMs.t 19- I i 20. F 21. \ 22. 1 i t 43 1 i 24 l 4 25 i i 27. v 2s \ \ 29. 1 1 1U | 31 ` 32. 1 < 33.. ; i 34. ' 35. ' 36. I 37. 1 38. I c 39. \ 40. * V `-'at AP00019573 VOL92.N&2 August 1978 HUMAN HEPATIC ANGIOSARCOMA 365 {9 Baxter PJ. Anthony PP, MacSween RNM, Scheuer PJ: Angiosarcoma of the liver in Great Britain, 1963-73. Br Med J 2:919-921, 1977 20. Brady J, Uberatore F, Harper P, Creeowald P, Burnett W, Davies JNP, Bishop M, piiJan A, Vienna N: Angiosarcoma of the liver: An epidemiologic survev. J Natl Cancer Inst 59:1383-1385, 1977 I Kurrem F: Systemic angioendothellomatosis with metastaSes. J Clin Pathol 29:347-353,1978 Edmondson HA: Tumors of the liver and intrahepatic bile ducts. Atlas of Tumor Pathology, Section 7, Fascicle 25. Armed Forces Institute of Pathology. Washing* Inn, DC, 1958 3 Enringer FM, Smith BH: Hemangiopericytoma. An analysis of 106 cases. Hum Pathol 7:61-82. 1976 2i Baker H de C, Paget GE, Davson J; Haemangio-endothelioma (KupfFer-cell jar* coma) of the liver. ] Pathol 72:173-182, 1956 23 l.eevy CM, Popper H. Sherlock S (editors): Diseases of the Liver and Biliary Tract; Standardization of Nomenclature, Diagnostic Criteria, and Diagnostic Methudolngy. Fogarty International Center Proceedings No. 22, DHEW Publication No. iMH) 76-725, 1976 26 Falk H. Creech JL. Heath CWJr, Johnson MN, Key MM: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63, 1974 2" MdkkL,CreecbJL,WhelanJG,JohnsonMN: Liver damage and angiosarcoma in v invl chloride workers. A systematic detection program. JAMA 230:64-68, 1974 2v Muk KG; Mesenchymal tumors of the liver. Hepatocellular Carcinoma. Edited by K Okuda, RL Peters. New York, John Wiley & Sons, 1976, pp 286-295 23 Delorme F, M4kk L: Angiosarcomes du foie chez des ouvriers ayant en contact prolong^ avec le chlorure de vinyle; Description morphologique des lesions. Union Med Can 104:1836-1344, 1975 10 Let* FI, Ham- DS: Angiosarcoma of the liver in a vinyl-chloride worker. Lancet 1:1316-1318,' 1974 >1 Smith PM, Williams DMJ. Evans DMD: Hepatic angiosarcoma in a vinvl chloride worker. Bull NY Acad Med 52:447-452, 1976 12 l.iitige C-E, Jflhe S, Veltman G: Ueber das Auftreten von Angiosarkomen der Leber bei zwei Arbeitem der PVC-herstellenden Industrie. Dtsch Med Wochenschr 99:1598-1599, 1974 11 Zimmermenn H, Eck H: Zunjiathologischen Anatomie der Vinylchlorid-Krank- hvit. Virchows Arch [Pathol Anat] 368:51-59, 1975 U WallnBfer H, Zinnagl N: Haemangiosarkomatose nach PoI)vrinylchlorid-evposi tion. Med Klin 72:410-413, 1977 13 Muller R, Bechtelscheimer H, Gedigk P, Manteller HJ, Lelbach WK; Das mor- phologische Bild der Lebenchaedigung nach chronischer Vinylchlorid-Exposition. Lrber Magen Darm 5:204-208. 1975 * Ravier E, Diter JM. Fialat J: Un cas d angiosarcoma hepatique chez un ouvrier evposi au chlorure de vinyle monomdre. Arch Mai Prof 36:171-177, 1975 7*. R6tv J, Sauvage T, Habraid A: Le 3 cas franpais d'angiosarcome hepatique chez un ouvrier du chlorure de vinyle. Arch Mai Prof 37:551-556,1976 38 Bonneton G, Champetier J, Sotto JJ, Guidtcelli H, Letoublon C, Pahn M: Un cas de rupture spontanea d'angiasarcome hepatique chez un travaiileur expose au chlorure de vinyle. Chirurgie 101:936-942, 1975 38 Bicrsack HJ, Lange CE, Ebinger H, Manteller HJ, Lelbach WK, Veltman G. Winkler C: Sequenzszintlgraphische Untersuchungen von Leber und Milz be! Patienten mit Vinylchlorid-Krankhelt Dtsch Med Wochenschr 100:615-617,1975 to Manteller HJ, Lelbach WK, Mailer R, Gedigk P, Lange CE: Klinische und laparoskopische Aspekte der Leberechaeden bei Chexniearbeiteni in der Vinvlchlorid-Polymerisatlon. Leber Magen Darm 5:196-202, 1975 366 POPPER ET AL American Journal a Pathology 61. GuUcker HW, Lelbach WK (editors): Leberschfiden durch Vlnylchiorld-Krtnkhelt. Baden-Baden, Veilag Gerhard Witutrock. 1977 42. Smith PM, Crossley IR, Williams DMJ: Portal hyperteniion in vinyl-chloride production workers. Lancet 2:602-604, 1976 43. Wilson RH, McCormick WE, Tatum CF, Creech JL: Occupational acroosteolysb' Report of 31 cases. JAMA 201:577,1967 44. Lange CE, jQhe S, Stein G, Veltman C: Die sogenannte Vlnytchlorid-ICrankheit: Elne berufsbedlngte Systemsklerose? Int Arch Occup Environ Health 32:1-32, 1974 45. Sudu I, Drejman 1, Valaskai M: Etude des maladies dues au chlorure de vinyle. Med Lav 58:261-271,1937 46. Pushin GA: O porashenii petscheni i sheltschnylch putel u rabotschlch zanjatyich w proizwodstwe nekatoriyich widow plastmass. Sov Med 28:132, 1965 47. Smith PM, Williams DMJ: Vinyl chloride and cirrhosis. Digestion 10:321-322, 1974 48. Huet P-M, Guillaume E, C6t4 J, L6gar A, Lavoie P, Viallet A: Noncirrhotic presinusoldat portal hypertension associated with chronic arsenical intoxication. Gastroenterology 68:1270*1277, 1975 49. Knolle J, FSrster E, Roessner A, Themann H, HOhn P, Meyer zum BOsehenfelde K-H: Die nieht-zirrhotische portale Fibrose (hepatoportale Sklerose) nach ` chronischer Arsenvergifbng: Klinische und pathologisch-anatomliche Befunde. Dtsch Med Wochenschr 99:903-608, 1974 50. Datta DV: Arsenic and non-ctrrhotic portal hypertension. Lancet 1:433. 1976 51. Regebon W, Kim U, Ospina J, Holland JF: Hemangloendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522, 1968 52. Lander JJ, Stanley RJ, Sumner HW, Boswell DC, Aach RD; Angiosarcoma of the liver associated with Fowler's solution (potassium arsenite). Gastroenterology 68:1582-1586, 1975 53. Denk R, Holzmann H, Lange HJ, Greve D: Ueber Aisenspaetschaden bei obdu- rierten Moselwinzem. Med Welt 20:557-567, 1969 54. Luechtrath H: Cirrhosis of the liver in chronic arsenical poisoning of vintners. Ger Med Mon 2:127-128, 1972 55. da Silva Horta J: Late lesions in man caused by colloidal thorium dioxide (thorotraal): A new case of sarcoma of the liver twenty-two years after the injection. Arch Pathol 62:403-418, 1956 56. da Silva Horta J, Cayolla da Motta L: Follow-up study of thorium dioxide patients in Portugal. Ann NY Acad Sci 145:830442, 1967 57. Dahlgren S: Thorotrast tumours: A review of the literature and report of two cases. Acta Pathol Microbiol Scand 53:147-161, 1961 58. Visfeldt J, Poulsen H: On the histopathology of liver and liver tumours in tho rium-dioxide patients. Acta Pathol Microbiol Scand [A] 80:97-108, 1972 59. Tesluk H, Nordin WA; Hemangioendothelioma of liver following thorium di oxide administration. Arch Pathol 60:493-501, 1955 60. Nettleship A, Fink WJ: Neoplasms of the liver following injection of thorotrast. Am J Clin Pathol 35:422-426, 1961 61. Tetles NC, Thomas LB, Popper H. Ishalc K, Falk H: Evolution of thorotrastinduced hepatic angiosarcomas. Environ Res (In press) 62. Swarm RL, Miller E, Michelitch HJ: Malignant vascular tumors in rabbits in jected intravenously with colloidal thorium dioxide. Pathol Microbiol (Basel) 25:27- 44, 1962 63. Pimentel JC, Menezes P: liver disease in vineyard sprayers. Gastroenterology 72:275-283, 1977 64. Viola PL, Bigotti A, O.puto A: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Can- 4 31:516-522,1971 s I : i j ' AP00019575 Vol. 92.NOJ August 1878 HUMAN HEPATIC ANGIOSARCOMA 367 63 Popper H, Maltoni C, Selikoff I], Squire RA, Thomas LB: Comparison of neo plastic hepatic lesions in man aind experimental animals. Cold Spring Harbor Conferences on Cell Proliferation, Vol 4: Origins of Human Cancer, Cold Spring Harbor Laboratory, 1977, pp 1359-1582 *6 U'aJIer T, Rubarih S: Hacmangloendothelloma is domestic animals. Acta Vet Scand 6.234-261. 1667 67 Deringer MK: Response of strain HR/De mice to painting with urethan. J Natl Cancer Inst 26:1107-1121, 1662 (fit Stewart HL: Hemanglosarconu (malignant hemangioendothelioma). Cancer. Ed ited by FF Becker. New York, Plenum Publishing Co., 1975, vol 4, pp 303-374 69 Herrold KM: Histogenesis of malignant Uver turnon induced by dlmethylnitrosamine: An experimental study in Syrian hamsters. J Natl Cancer Inst 39.1099-1111, 1967 TO Andervont HB: Induction of hemangio-endotheltomas and sarcomas in mice with o-aminoazotoluene. J Natl Cancer Inst 10.-927-941, 1650 71 Niirisau-a T, Wong C-Q, Weisburger JH: Axoxymethane-lnduced liver beman* tfinsarcomas in inbred strain-2 guinea pigs. } Natl Cancer Inst 56:653-654, 1976 72 Stanton MF: Transplantability, morphology, and behavior of polyoma virus-in duced hepatic hemangiomas of hamsters. J Natl Cancer Inst 35:201-213, 1865 73 Falk H, Telies NC, lshslc KG, Thomas LB, Popper H: Epidemiology of thorotrast induced hepatic angiosarcoma in the United States. Environ Res (In press) 74 Miller EJ, Matukas VJ: Biosynthesis of collagen: The biochemist's view. Fed Proc TM197-1204, 1974 (73 l-alk H, Thomas LB, Popper H, Ish&k KG: Investigation of hepatic angiosarcoma in the U.S. (In preparation) 76 Nicholson WJ: Cancer following occupational exposure to asbestos and vinyl c hloride. Cancer 39:1792-1801, 1977 77 Stnming TA, Bresnick E: Hepatic epoxide hydrase in neonatal and partially hrpatectomized rats. Cancer Res 34:2811^2813, 1974 78 Adamson RH; Long-term administration of carcinogenic agents to primates. Medical Primatology. Edited by J Moor-Jankowski. Basel, S. Karger AC, 1972, pp 216-255 79 Suckow EE, Henegar GC, Baserga R; Tumors of the liver following administra tion of thorotrast. Am J Pathol 38.-663-677, 1961 50 Burkin A, Brest! H, Croisy A, Jacquignon P, Malaveille C. Montesano R, Bartsch Hr Llver-microsome-mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Blochem Biophys Res Commun 67:596-603, 1975 51 Watanabe PG, Hefner RE Jr, Cehring PJ: Vinyl chloride-induced depression of hepatic non-protein, sulfhydryl content and effects on bromosulphaleln (BSP) clearance in rats. Toxicology 6:1-8,1976 S3. Watanabe PC, McGowan GR, Cehring PJ: Fate of [uC]vinyi chloride after single oral administration in rats. Toxicol Appl Pharmacol 36:339-352, 1976 S3 Bolt HM. Laib RJ, Kappus H, Buchter A: Pharmocokinctics of vlny) chloride In the rat. Toxicology 7:179-188, 1977 St. Creim H. Bonse G, Radwan Z, Reichert D, Henschter D: Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic nirane formation. Blochem Pharmacol 24:2013-2017,1975 SS McCann J, Simmon V, Streitwieser D, Ames BN; Mutagenicity of chloroacetaldrhyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc Natl Acad Sd USA 72:3190-3193, 1975 ^ Loprieno N, Barale R, BaroncelU S, Bartsch H, Bronzetti G, Cammellini A, Corsi C, Frezza D, Nleri R, Leporinl C, Roselilni D, Rossi AM: Induction of gene muta- 366 POPPER 6T AW AittificuiJotuM ' tlons and gene conversion* by vinyl chloride metabolites In yeast. Cancer ft-- 37:251-257, 1977 ^ 87. Green T, Hathway DE: The biological fate in rats of vinyl chloride in relation fc ` its oncogenicity. Chem Bio! Interact 11:545-562, 1975 ^' 88. Kappus H, Bolt HM, Bnchter A, Bolt W: Rat liver microsomes catalyse enalew 1 binding of MC-vinyl chloride to macromoIeCules. Nature 257:134--135, 1975 89. Osterman-Colkar S, Hultmark D, SegerbJck D, Calleman CJ, GOthe R, Ehrenberg >. L, Wachtmeister CA: Alkylation of DNA and proteins in mice exposed to vtm( chloride. Biochem Biophys Rea Commun 76:259-266, 1977 90. Reynolds E5, Treinen Moslen MT, Szabo S, Jaeger RJ, Murphy SD: toxicity of vinyl chloride and 1,1-dichloroetbylene: Role of mixed function -`Mm systesi. Am J Pathol 81:219-236, 1975 91. Schattenbera P-J, Totovic V, Gedigk P, Mariteller HJ: Die Ultrastruktur drr Leber schSdigung bel der chroniscnen Vlnylchlortd-Intoxlkalioit. Virchows Arch - (Pathol Anat] 373:233-247, 1977 92. Whelan JG, Creech JL, Tamburro CH: Angiographic and radionuclide character* istics of hepatic angiosarcoma found in vinyl chloride workers. Radiology 116:549- 557,1976 93. Biersack HJ, San Luis T Jr, Lange CE, Thelen M, Veltman G, Winkler G Scintigraphy of liver and spleen in vinyl chloride workers. Acta Hepatoeai- troenterol (Stuttg) 24:357-301, 1977 . - . \ 94. Blendii LM, Smith PM, Lawrie BW, Stephens MR, Evans WD: Haemodynamic studies In vinyl chloride monomer workers with portal hypertension. Gut 18:100- 401, 1977 95. Kroes R, Berkvens JM, Weisburger JH: Immunosuppression in primary liver and colon tumor induction with N-hydroxy-N-2-fluorenylacetamide and azoxyjnethane. Cancer Res 35:2651-2656, 1975 96. Ward AM, Udnoon S, Watkins J, Walker AE, Darke CS: Immunological mecha nisms in the pathogenesis of vinyl chloride disease. Br Med J 1:936-938,2976 97. Schaffner F, Popper H, SelikoS IJ: Initial features of vinyl chloride (VC) bepalie in/ury. Gastroenterology 71:A35,1976 98. Weibel ER, Palade GE: New cytoplasmic components in arterial endothrlfe. J Cell Biol 23:101-112, 1964 - ~ 99. 100. 101. 102. 103. 104. 106. 106. Fahlrai HD, Gray BA, Henog VK: Cytochemical localization of catalase tad u peroxidase in sinusoidal cells or rat liver. Lab Invest 34:192-201, 1976 Winkler K, Poulsen H: Liver disease with periportal sinusoidal dilatation. A ' possible complication to contraceptive steroids. Scand J Gastroenterol 10:699-70*. - 4 1975 -^S. Bagheri SA, BoyerJL: Peliosis hepatls associated with androgenic-anabolic steroid * - therapy. Ann Intern Med 81:610-616, 1974 -'--w. Nadell J, Kosek J: Peliosis hepatls. Twelve cases associated with oral androgen therapy. Arch Pathol Lab Med 101:405-410, 1977 '"T^v Popper H, Thomas LB, Schaffner F, Maltoni C, Selikoff IJ; Interaction between ;rg-. sinusoidal cells and hepatocytes in human and experimental angiosarcoma induced f."" by environmental factors. Kupffer Cells and Other Sinusoidal Ceils. Edited by E ^ . Wlsse, DL Snook. Amsterdam, Elsevier North-Holland Biomedical Press, 1977, pp 173-181 Ito T: Recent advances In the study on the fine structure of the hepatic sinusoidal wall; A review. Cunma Rep Med Scl 6:110-163, 1073 Bronfenmajer S, Schaffner F, Popper H: Fat-storing cells (lipocytes) in human . liver. Arch Pathot Lab Med 82:447-453. 1966 Triche T, Nanba K, Ishak K, WolkoffA, Berk PD: Hepatic ultrastruetural change* . ,^.- In vinyl-chloride (VC) workers. Clin Res 23:259A, 1975 5 .'ll1'* .* 10' 10 to Ac AP00019577 APOOO19578 Osfcr 53 ET AL [IlluttraUonafollow ] AP00019579 AP00019580 Figure 5--Mixe increased sin', the hepatsc cells of wh:,* plates. Au" loss of he (NAE. xior canallculi < anapla$>a i elastic area in left lower comer eh. ills. The surrounding parenchyma ro bent. Autopsy (A75-75). (HAH xi& sased. Note hepatocytic nuclei r.*81). (H&E. XI00) Figure 7--" the limiting plate. Note accumo 1 8--Hepatoeyles in two-celt or - bw), Sinusoidal and perijinu1 multiple layers (curved nr.-c -x-ev hepatocytes in two-cell-thick pia** .nick plates and appears compreassA -Irregular dilatation of sinusords. *' rder as Indication of two-ee!' f ut extending Into periportal p* tes In right tower aspect- Ai sometimes containing bite n a variety of cells, sc it). (Hae. xi00) *r AP00019581 APddo19582 ...H U M r t'iw v *(; ?- nvw>. r- AP00019583 00 m & ZOQQ ***IS V V *n aor| 'S Mjq si *d 'U JO iopa *! tt PIs l|dB3 J uo >prui .not|c uosw ns npnoj ! u StIOl) dUlMd ItpVjttMn ma3]l X *!! p! * rX|aKua0t|3d U) wojt -* tll DB0U SU9S , /<S23 L lb r.v y , '.V.hool oi -Aniicin* UflJverity of Pittsburgh 3*w Bhh/amut H. Romms amd Job* S. Lvsmr Vi 1L Vhn, X, to JCMtaMr, T.x BrytMaa Alhlrffci Alffc* m! B*U MyiWiJU, (!**) Am. Om. Ik. (Apr.) IBM. DtrUM M QrfuW EVimMi r, m, }S M*. Kari, S4 KmWm?, Vmakl BrjUrtM ikiMta. HL InlatW* J Chwt. --Hm T a Maw AA*M4, ErytWaMifta, J. Am. Oas. Sh. *1: mt-itto (lUr) M 1M. Uaaa, Dam; I>U, HIM, axl OrM A. .; FtankM A'tha /*** ihMh I. nl SiMiim Mnl ft*M tt, J. FWI. * Tkaraj, M: M- (M) UU. ^ IM. Iim, a a Tlgt, 3. , aat OWIsili. Braaa: Mianaaiil^le VadUkaMas *4 ik. aiMH tenUM, J. Am. Ptaw. A. Mi M4-1M (Apt.) IBM. tot KeM a. mi Iawa, J. V.; A PkacwMiiapItal Mai/ if a* Rxtnat { SrrMrW Oil*. oaM (<uw), /. riii--.a a Thap. m: m-m (jm> 1*44. m. M a a; q--w.a, d. k, * zu*im, j. a: tw twtk> m HtuM kmw b? BalawjWaMIa HjfcaMlirlSa, rtrrikMa. 9m**. *4: STT-SM (Jala) 1h. J*- *^i.aa. mi Wi.iMila, It T.I Tba AcOm af Bata anU..^ nyAratMatHa, .pajatlalik Qaart Us IU-1M (Jm.) 1MJ. IM. WIIHimi. J. ttnaDaH Bata toylkaWaa IlyrfaaehbrMa fa HllTMil n*rarr OHa Mata K. J. 97: NMt4 (dpt) )MI. ^ Pw th* farfeaTMlkt of tawt>i<iia)agtoa who arc eowbatplMhM apfrfMtfaB for eerUAeatfaa by tto Altaicaa Board of AuaUlwri titer, let, or tk* an tratoing phyritk-- faa the specialty, tbs feUowfag hare bow employed for Part I (written) m- fintfinw m the paat ta PkytMtgpt 1. DcocrfbO fatoatotlw therapy tM it todfaeted in the piwai af pulmonary adewa. 3. Dim* the important prink to bo to--M of to mwetfw *Rb cyaaoata to tba aneetbethwd patient (Cover all mKay methode of ametfaettoh* patient*) 3. What are tot approximate ainaal rafaet for oxygen and for carton dieaodo, nprceagf in eltoar aiHimeters. or ten* aha, or pereantaga, to: (a) Inspired air (e) Arterial blood (a) Venom blood (b) Pnlwwaty (d) Tiaoe* na dnali 4. Whet phyMeghal fanrtltnt at too Over art of portlonlar totmot to too anesthetist and wby f 5. (a) Ammiac that they an trailalia, nader wtot eiroma* tanoaa dartof tatbiato onM pan Rtgawod tor totnranom ma af wboia oitaated Mood, ptom, aaln* tioaa of gtnoooa, phpMetfa tattoo aolatM, or aohrtwna a! Maria, gelatin, paetto ar hlngton (afar aar] t \ . (b) Under what airmiiifiiiin wonld yen on itaPpitoMr --tatancM via toear labatonm and with whkh adb Maneaa and to *bat daert . rvnwinilng toa artieie, AtimpHin, PfatotoMlim and BUwl natian of Ethyl Btbar"> wba unto it, rrtava and whan woo it pahtitoed, aod what important mnlrtonticm to ImowMpi of toe cliniMl we of other did It aaelainl i*. 1MT UttzCCHFIlVVii?iD APR 2 7 1981 " ^ABR ANESTHESIA XXVII. NABCOSIS WITH VINYL CHLORIDE V Bpt--' H. Oo*m Ph.IX, C. Jnujwr Caca, PjlD^ an lomx C. Kuto, Ja, Pn.D, with (he technical wwwUiwf of Uni Jamb BaomwaIA, B.A. Jtdtrmn, Xd. toMlrci Nr foMbatlco DetmV It ttM js oar etudieR <m vmrioue volatile organic compotwd* avaltoMe as imtoletion aneothetke, oar attention wan directed to vinyl chloride. Vinyl hloride ia an mdmtrial chemical used hi the ayntbeeie of many organic irmpoanda. The mbetance is a gu which boila at --18 C. It ia aolable in the etherUl solvents sad its vapora an oomhoatiblo. Tmyl chloride was suggested aa an anesthetic by Patty, et al. (1) and tried on human subjects by Schanmann (2) Patty'S experiments r*a gmaea pigs revealed that the action cf vinyl chloride was aimOar to that of ethyl chloride and lese harmful than either chloroform or car ton tetrachloride. According to Bchaamana the narcotie limiting eon* nutrition for man ia 7 to 10 per cent; 12 per oent a dangerous. In our 'Indies, planned to give a first approximation of the anesthetic ayn* ilrmne ef vinyl chloride, we suggest that this compound not he used as an anesthetic in man. dtemotMeropevtie Contideratmu: There ia a dictum m phamacol* tgy (3) that potency and ansatarmrion parallel each other among analovorn organic eompoonda. Thin holds fer ethane and its more potent naAlogM, ethylene. It is also true for ethyl ether and its mors potent analogue, divinyi atbeyi 3Therefore, one might expect that vinyl chlo ride would bihirinore potent anesthetic than its analogue, ethyl chloride. Thi rslatj.eae|iipnh<WfeWQ iflptars not to obtain between these two dilorinatefl hydniMarber^t'.'YCiWet^V chloride, 3.8 to 45 volumes per 1141^'^ required for antithesis with 20 tog. per cent in the blood. *rhatann (2) wed 7 to 10 volumes per cent of vinyl chloride to pro duce anesthesia and fonnd 17 to 20 ng. per cent m the Hood. Oar obxtrilioaR in dogs conform well to the indication af these data, aamely, that (here is tittle difference ia potency between the saturated and the nmaturated analogues, and actually ethyl chloride appears to be the Wore potent * Ito Dm PgSMt--U ef nuamlip wf TiftMafy, MaS sf Jletohs mti Dm ***'7, H lUrylmi, BaKhMR. I Tk npcMt *f cue mwHpili m tofrayri ysitlalir *T (*>* n*M the OW ^IM wM Huitolalu Ciiukj ( ClerrieM, Ohto. * S ( * AP00019587 * R, H. (Win, r. 3. Pam Ann 3. (). Khaxtx, Jm. XM. 1 Obserrotion AnettMtsiat f Doga: Two dof were anesthetized with vinyl chloride * being mixtures of the gs* and oxygen. For indoctioa the concentration of the gaa momentarily me allowed to ran to 90 vol ume* per cent and then ndwcd to 7 *olunM per eent Indoetioa vu rapid. There was continuous "crowing" even under deep anctthnia. There waa mseh salivation. Abdominal relaxation was good, bat the lege ahowed rigidity and ineoordinated leg nwrentnU throughout the anesthesia. The recovery period was prompt hat accompanied by riolent excitation. In a third dog anesthesia vu produced aaiag 25 roiimca per eent momentarily, and a similar syndrome earned. Blood Pressure m Dog* -. Tovr doge were prepared for blood pressate tracing* by cananbting the femoral artery. The operation war performed under monocaine hydrochloride local aneatheaia. After a normal Mood pressure tracing bad been obtained, the animals were aneetbctiied with vinyl chloride-oxygen mixtam, Doing 19 volumes per eent of the former. In all 4 cases the magnitude of the blood pressure remained within normal limits daring anestheem. There was definite evidence of eardiae irregularity, however, such aa intermittent tachy cardia, extraventricular systoles and vagal bents, line irregalaritiee disappeared npm changing tbs anesthetic to ethyl ether. These cardiac disturbance* confirmed onr etethoseopie observation* on the unoperated dogs. ^ Electroemrdiognpkie Studies hi Dogs; Six dogs were anesthetized with vinyl chloride-oxygen mixfares, using 10 volumes per cent of the former, Etootrocardiographie records, lead II, were made at light snrgical aneetbeeia, surgical anesthesia and threatened respiratory col lapse. All of the animals manifested marked changes in cardiac rhythm in snrgical anesthesia. Marked tachycardia followed by bradycardia was typical. Ia 2 of the 8 animals the B-pik was inverted daring surgical anesthesia and in 1, evidence of incipient ventricular fibrilla tion obtained. Inversion of the B-eptfce with bradycardia is shown ia the record from,dog 6* lead XI, chart 1. Abnormalities in tike QR8 complex wet* fownd ia all 6 doge varying from ninne arrhythmia and transitory ubine left axis deviation to very serious conditions me)tiding aarienknenttisalar Mock, ventrientar *Tfc* HqlriMa Mai hKw WM N Wi|Wl> ht atopertel; imWfl Iff.X Rato f MnbM CImMi lac, tteRtow^ Md. R vac WcMMccS vtth S3 net *< i nsaj nw iSaict etc ceaqaaal waa farWal a, fcMcm: "Ttayt cHirtli f atAi% Vr *%* fwUj MMaSSy Mg ty S|*l MrMMaUfSw. U na. ef ciariic*, aa* a (ia aaUM; vcc anfU) IUWH to wam MtUenOftoe*. Tto atfaund *ayt eHwHi w toi< wH tape-- laialna tUwMc, ylMphwto act*, out Mai ever fOaiat fataaatw IjJiaHt. The pariScS rtori a*WWa vac (ml to at* tto Mb*** pcritcMtom: AccCyfevct Kai Vy aait IW Artel*! AaMbi Noam, TrtaMwtBvtot! Ttoc," rtto tod. D. Koischwitz und Mitirb.: Das vinykhloridinduzierte Leberangiosarkom /S& S-) Fortschr. Rfintgenjtr, 13 mit haufiger Abbitdung einer intratumoralen Cholelithiasis. Niche nur die bcstehcnde Lebcrinvaaion per contimutatem, londern auch die zum Zritpunkt der computertomographischen Diagnose bereits vorlicgende hamatogene und lymphogene Metasusierung des biliiren Karzinoms erklart, jedoch unverandert das therapeufische Dilemma und die ungiinstige Prognose dieser Tumoren. Lilerxtur (1) Aifidi, R. J-: Computerized tomo graphy of the gallbladder and biliary tract. Sera. Roentgenol. 11 (1976) 143 (2) Buck, J., S. Botnjakovic, F. Hindi, R. Schulze; Eio Beltragder R&crgenGtnzkdrper-Comptaer-TomcigMphie cur Diagnose und Differentisldiignose det Ikrerus. Radiologe 19 (1979) 333-360 (3) Ferris, R. A..LP. Kinchner,J. H. Mero, D. H. Chuns: Increased atte nuation value in a hydropic gallblad der. J. Comput. Assist Tomogr. 3 {1979)343-546 (4) Goldberg, H.R. A. Filly, M. Korobkin, A. A. Moss, H. Y. Kresscl, P. W. Callen: Capabilityof CT body scanning end ultrasonography to de monstrate the status of the biliary duc tal tyscem in patients with jaundice. Radiology 129 < t978) 731-737 (5) Hiernl, M., Die An- gjogrsphie Id biliaran hteoplaaien. Fortschr. Romgenstr. 124(1976) 314-319 (fi) HavHIIa,T. R., N. E. Reich. J. R_ Haags, F, E. Seidelmann, A. M. Cooperman, R. J. Al/idii Computed tomo graphy of the gallbladder. Amer.J. Roentgenol. 130 (1978) 1039-1047 (7) Heuck, F., J. Buck: Dcr (nfoems- rionswett der Rontgen-Computer.To* mographic fur die Beurteilung von GailenwegenundGsIleoblase. Radiolog* 20 (1930) 6-15 (8) Levitt, R. G-, 5. S. Sagd, R. I. Stanley, R. G. Jost: Accuracy or com puted tomopaphy of die liver and bi liary tract. Radiology 124 (1977) 123-128 (9) Moss, A. A, H. T. Goldberg: Com puted tomography, ultrasound and xray: an integrated approach. Masson Publishing, Mew York 1979 (10) Shanser, J. D., M. Korobkin, H. I. Goldberg, B. M. RoMfing; Computed tomographic diagttoiie oTobstructive jaundice in the absence of intrahcpatic ductal dilatation. Amer. J. Roent genol. 131(1978) 389-392 (11) Solomon, A., L Kreei, D. Pinto: Contrast computed tomography in the dlagnosisofacutecholecysHds. J. Comput. Assist. Tomogr. 3 (1979) J85-J88 (12) Thomas, J. L, M. E. Bernardino: Segmental biHary obstnicdon: its de tection and significance. J. Comput. Assist. Tomogr. 4(1980) 155-158 Prof. Dr. med. Michael Hacrtel [nstituc fur Diagnosrische Radiologie Universitat Bern, InscUpital CH-3010 Bern Rece,C^ Fonschr. Rdntgenstr. 134. 3 {1991) 283-290 Das vinykhloridinduzierte Leberangiosarkom und hepatozellulare Karzinom Von D. Koischwitz, W. K. Lelbach, K. Lackner und D. Hermanutz 3 Abbildungen Radiologlsche Kllnfk (Direkior: Prof. Dr. P. Thura) und Medizinische Kllnilc (Direkior: Prof. Dr, M. J. DengJer) der Univertitat Bonn Es wird iiber drei Patienten cines PVC-herstellcnden Betriebes berichtet, die an Angiosarkomen der Leber, in einem Fall kombiniert mit einem multilokularen primaren hepatozellularen Karzi nom, erkrankten. Epidemiologie, Klinik und Diagnostik unter besonderer Beriicksichtigung der angiographischen, sonographischen und computertomographischen Befunde werden diskutiert. Dabei erweisen sich die nicht-invasiven Uncersuchungsverfahren Computertomographie und Sonographie als Mittel der Wahl, wenn nach einer VCM-Langzeitexposition ein Angiosarkom der Leber angenommen wird. MAY 5 ,9SI ' BARR Vinyl chloride-induced angiosarcoma and hepato-cellular cardnoma of the liver Three patients with industrial exposure to PVC are described, who developed angio-sarcomas of the liver; in one patient this was combined with a multi-locular primary hepato-cellular carcinoma. The epidemiology, clinical features and diagnosis are discussed, with particular reference to angiography, sonography and computerized tomography. The nor-invasive methods, such as computerized tomography and sonography, are the techniques of choice if an angio sarcoma is suspected after long exposure to PVC. Die Toxizitlr des Vinylchlorid* ist erst in jungster Zeic (1970-1974) erkannt worden, obwohl scit iiber 40 Jahren Polyvinylchiorid (PVC), einer der am haufigsten verwendeten Kunststoffe, durch Polymerisation des gasfbrmigen Monomers (VCM) groGtechnisch hergescellt wird. Erste Berichte aus Rut land iiber Leberschadcn, als ,,chronische epithelialc Hepatitis" beieichnet (Tribukh et al. 1949), sowie weiterc Hinweise auf die Toxizitar des Vinylchlorids aus Rumaru'en (Sudu et al. 1963) fanden anfangs wenig Beachtung. Ein groGcrcs (nteresse sctzte erst ein, als seit 1966 aus verschiedenen Landem iiber ein vorwiegend bei Autoklavenreinigern beobachtetes Krankheitsbild berichtet wurde, das auf eine VCM-Langzeitexposition zuriickgefuhrt wird und sich zunachst mit der Trias von Akroosteolysen, Raynaud-Syndrom und sklerodermieartigen Hautveranderungen prasentierte (CbateLun und Motillon 1967, Qordier et al. 1966, Marin et al. 1967, Wilton et al. 1967). Tierexperimentelle Unrersuchungen mit geniigend langer Laufzeit, die der Erforschung der Veranderungen an den Akren dienen sollten, deckten erstmaU die onkogene Potenz des VCM auf (Viola 1970, Maltoni und Lefemine 1975, Keplinger t al. 1976). Seither folgten zahlreiche Mitteiiungen, die sich teils anhand tierexperimenteller Unrersuchungen, toils anhand klinischer Beobachtungen mit dem Auftreten VCM-induzierter Tumoren befaSten {Crotch und Johnson 1974, Lange et al. 1974, Makk et al. 1974, Gtdigk et al. 1975). Insbesondere 0340-1618/81 0332-0283 8 03.00 < 1981 Georg Thiem Variag, Stuttgart - New York AP000I9588 284 Fonschr. RSntgensrr. 134,3 D. Koischwitz und Mitarb. I Abb. 1 a ZOliakographie, arterleile Durchstrfimungsphase. Abb. 1 Angiosaikom dar Leber bei VC-Krankheit. Abb. 1 b SpatvenCse Durchstrflmungsphase. leberverkteinemng mit geschilngeltem Vertaul dot intrafiepaliscswi Artarton. Bereits in derarteriellen Phase begirtnsnde(A) und in der venOsen Phase lang persislierende, fleckige Kontrastierung eines Angiosarkoma im rachten Leberiappen. wurde beim Menschen liber das Auhreten von Angiosarkomen der Leber, sehr selten auch von hepatozellularen Karzinomen berichtet (Creech und Johnson 1974, Lloyd 1974, Delorme 1978, Gokel et al. 1976, Topper et al. 1978), wohingegen aufgrund riercxperimenteller Untersuchungen von Viola (1970, 1974) auch mit dem Auftrecen von Ceschwiilsten der Nicrcn, des Gehims, des Skeletts, der Haur, des lymphatischen und hamatopoetischen Systems gerechnet werden muS, Seit der ersten Mineilung uber 4 Patienten mit VCM-induziertem Angiosarkom der Leber in den USA (Creech und Johnson 1974) hat das National Institute for Occupational Safery and Health (NIOSH) bis Hcrbst 1978 weltweit Daten uber insgesamt 76 Patienten mit VCM-induziertem Angiosarkom der Leber zusammengetragen, davon 68 bei Arbeirem aus der unmittelbaren PVC-Produkdon (Spirtas und Kaminski 1977, 1978). In der Bundcsrepublik Deutschland sind bis Ende 1978 16 Patienten mit VCM-induziertem Angiosarkom der Leber beobachtet worden (Reinl ct ai. 1978). Sicbcn dieser Patienten srammen aus einer Gruppe von Arbeitem eines PVC-herstellenden Betriebes, die sich seit 1970 in klinischer Betreuung der Bonner Umversitats-Klinikcn befinden. Uber klinische und histologische Befunde bei zwei Patienten dieser Gruppe wurde bereits friiher berichtet (Lange et al. 1974, Gedigket al. 1974). Bei drei weitercn Patienten diesct Gruppe konnte bereits zu Lebzeiten durch radiologische Untersuchungen der Tumor* nachweis in der Leber gefuhrt werden. Deshalb soil hier insbcsondere iiber die angiographischen, computerromographischen und sonographischen Beiunde der VCM-induzierten Tumoren der Leber berichtet werden. Kasuistik I. Patient, E. U., 57 Jahre ArbeitianamnesellX Tahre VCM-ExpruificmKtinik: Im Januar 1975 erstmals Untereuchung in der Medizinischen Universitatsklinik Bonn. Leichte Hepatomegalie. Normale MtlzgroGe. Deudiche Thrombozytopenie. Piabete* mellims seit 1967. Laborbtfundt: Deutliche Aktiviratserhohung der alkalischen Phospha tase. 45-Minuten-8romsulfaleinterention 20,6%. Leberszintigramm: Speicherdefekte im lateralen Teil des rechren Lebertappens. Laparoskopit: Braunliche, flachhockerige bis klcinknorige, zirrhosc* artige Leberoberflache mit ausgedehnter flachenhafter, weifilicher Kapselfibrose. Zeichen der ponalen Hypertension. Keine umschriebenen tumorverdiichtigen Areale. Histoiogiscb (linker Leberiappen) ceils scptale, reils pottnekrorische Zirrhosc mil maSigcr Parenchymside* rose. Perisinusoidale Fibrose. Kettenformige Proliferation sinusoidaler (Jferzellen. Verlauf: Im Juli 1975 erstmaliger Nachweis geringer Osophagusvari* ten. In den folgenden Monaten Entwicldung einer Splenomegalie und Zunahme der ponalen Hypertension, (m December 1975 rasebe Eruwicklung von Ikterus und Aszites. Zoliakographie: (5. 12. t975) (Abb. I a und b): Kleine Leber. GncMangeVtet Vttlau! der inmWepatiscben Arterien. Kdne auffattigen TucnorgefaSe. In der parenchymatosen Durchstrfimungsphase fleckige Kontrastierung des polyzyklisch bcgrenzten Tumors im latera* len Teil des rechcen Leberlappens. Weiterer Verlauf: Exitus letalis infolge Leberinsuffizienz nach Varizen* blurung am 15.12.1975. Autoptiscb ntuitizentrisch wachsendei Ham* angiosarkom ira rechten Leberiappen*. 2. Patient, W. F., 54 Jahre Arbeitsammmse: 10 Jahre als Autoklavenreiniger und weitere 9 Jahre (bis 1974) als Vorarbeiter am selben Arbcitspiarz VCM-exponien titig. Klimk: Seit 1972 Diabetes mellims bekannt. Hepatomegalie, alt ,,Fettleber" gedeutet. M3Jge Splenomegalie. Seit 1974 progredienre Thrombozytopenie. Im Februai 1975 entmalige Untersuchung in dec Medizinischen Universitatsklinik Bonn. Allgemeines Krankheitsgefuhl. Teerstiihle. Braunliche Hautpigmentation. Laborbefunde: Lediglich grenzwemge Ethohung von GesamtbiUrubin, SGOT, SGPT, Gamma-GT und BSP-Rerendon. Laparoskopit: Gernischrformige, mikro- und makronodulSre Zirrhose mit zahlreichen flachen, postnekrotischen Narben. Kapselfibrose. * Die pathologj$cK*morphologischen Befunde verdanken wir Prof. Dr. P. Gedigk, Direktor des Parhologischen Institutes der UniversirSt Bonn, der gesondert berichten wird. AP00019589 Oat vinylchloridinduiierte Leberangiosarkom und hepatoxellulare Karzinom Fortschr. RSntgenstr. 154, 3 285 Briunllche Verfltrbung des Leberparenchyms. Zeichen der portalen Hypertension. Histolagiscfr. icili septaie, reils posmekrottsdie Zir* rhose. Bedeutende Siderore. Fokale Verfettung. Kein Nachweii von SinucseUatypien, keine Sinuselctasie. Kein Malignocnnachweis. Explorative Laparotomies Keilbiopsien aus bciden Leberiappen. Ebenfallt kein Malignomnachweil. Histologie identisch mh Punkrionsbiop- siebefund. Rbntgenbefundt Osophagogramm (22. 2. 1975): Varizen im unteren Otophagus. Selective Hepatikographie und initrekte Splenopcrtograpbie (24. 2. 1973) (Abb. 2a): Stark vaskularisieiter Tumor mit uhlreichen arteriovenosen Shunts, der den gesamten rechten Leberiappen einnimmt. Linker Leberiappen unauffallig. Retrograde DurchstrSmurg der V. portae und der V. mesenteric superior bei regelrechrer Dutch* stromung der V. lienalii ala Zeichen eines intraheparischen Blocks mir hepatofugalem Kodateralkreiiiauf. Sonograpkle der Leber (GerSt mlr bistabiler Speidierrohre) (31. 3.1975): Keine Lebervergr&12erung.Scharfkantige Margo inferior hepatis. Zentrai im rechten Leberiappen 8 cm im Durchmesser roessender Tumor, der bei stufenweiser Schallinrensitatsverstarkung ein zunehmende* irregulares Reflexbild zeigr. Sonographie der Leber (20.10.1977) (Abb. 2b und c): LebervergrdSe- rung unter Bevorzugung des linken Leberlappens. Verplumpung des Lobus caudatus. Abrundung der Margo inferior hepatis. Diffuse Leberparenchymverinderung bei Verstiirkung des Leberstmkrurecho. musters. Verstiirkung der Schallabsorption. Multiple, verstarkt reflek* tierende Tumoren innerhatb des rechten und linken Leberlappens. Diffuse PankreasvergrdSerung mit Verstiirkung des Strukturreflcxmu* sters. Selektive Htpatikograpbie und indirekte Splertopcrtographit (5. 11. 1977) (Abb. 2d und e): Bogige Verlagerung des rechten intra* hepatischen Hauptasres der A. hepatica propria durch einen 8 cm im Durchmesser messendrn, hypervaskularisicrtcn Tumor zcntral im rechten Leberiappen. Multiple weitere, 1 bis 3 cm im Durchmesser messende Tumoren rait ausgepriigter Kentrastminelanreieherung und langer -speicherung. Keine Darstellung der friiher nachgewiesenen retrograden Pfortaderdurchstromung. Computertomographie (7. 11. 1977) (Abb. 2f und g): Im rechten und linken Leberiappen multiple, 2 bis 4 cm im Durchmesser messende, idIweise konfluierende, hypodense Areale mit einer Dichte von nativ 40 bis 45 Haunsfieldeinheiten, die nach i.v. Kontrastmirtclapplikation (100 mi Tetebrix 300} teilwdsc hypodens bleiben, teilweise, bei einer Dichte des Leberparenchyms von 65 bis 70 Hounsfieldeinheiten, isodens werden. In der Differentialdiagnose wird ein multilokularer Tumor oder aber multiple Leberregeneratknoten erwogen. Weiterer Verlauf: Computerrotnographische undsonographische Kon* trolluntersuchungen zeigen tine weitere Zunahme der LcbcrgroGe, eine Progredienz der Leberrumoren sowie einen zunchmenden Asziies. Am 23. 3. 1978 rontgenologisther Nachweis drier Osteolyse im Margo lateralis scapulae rechts. Palliative Scrahlenbehandlung der rechten Schulterregion und deutliche Bessemng der Schmeraen. Die Osreolyse bestiitigt letztiich die Diagnose eines metastasierenden Malignoms, das aufgrund der sonographischen, computcrtomographiichen und angiographischen Befunde in der Leber diagnostiziett worden war. Unter weiteret GroBenzunahme der Leber, insbesondere deutlichcr Vergro* Gerung des linken Leberlappens, Zunahme des Asxltes und Entwicklung eines auf der Abdomenoberflache siebtbaren Koliateralkreislau- fes, progrediente Verschlechterung des Allgemeinzustandet des Pattern ten. Anhaltende Blurstuhle mit erheblichem Hb.Abfall. Die Ursache der Blutungcn kann endoskopisch nicht eruiere werden (Himobilie). Exitus letalis am 7. 8. 1978. Die Autopsie bestiitigt das rontgenolo* gisch und klinisch diagnosrizierte metastasierende Lebermalignom; es fend sich ein multizenrrisch wachsendes Angiosarkom, kombiniert mit etnem multizentriseh wachsenden primarer hepatozellularen Karzinom der Leber. 3. Patient, B. K., 54 Jahre Arbeitsanamitese: 18 Jahre VCM-exponiert (bis 1973) in derPVC- Polymerisation. "l-` erstmals Teerstiihle; die Ursache wird in einem blutenden Ulcus duodeni angenommen. Emeut Melaena 1970 und 1972. Des* Abb. 2a Selective Hepatikographie (24.2.1975). Stark vaskuiari* sierter solitirer Tumor im rechten Leberiappen mit Irregul&rem GefSflbild. Zahlreiche AV*Shunts mil verstftrktam Kontrastmittsldurcfisatz durch den Tumor und retrograder Pfortaderdurchstrdmung. halb 1972 Magenresektion nach Billroth II. Intraoperativ Feststeilung eines Aszites sowie einer vergroSerten, ,,zirrho$eartigen" Leber. Histologiich Iediglich geringe portale Fibrose. Postoperativ erstmals Ikterus. im Februar 1973 erstmalige Untersuchung in der Medixinitchen Uni* versicitsklinik Bonn. Dabei Druckgefuhl im rechten Oberbaucb. KaU teempfLndlicbkeir an Handen und FuSen. Raynaud-Syndrom. Splenomegalie. Leichte Leukopenie und Thrombopenie. Laborbefunde: Grenzwerrige Hyperbilirubinimie. Geringe Aktivitats* erhShung der alkalischen Phosphatase. Alle iibrigen Laborwerte im Normbereicb. Gastroskopie urtd Laparoskopie: Nadiweis von Osopbagut- und Magenfundusvarizen. Fein- bis grobknotige Leberzirrhose. Zeichen der portalen Hypertension. Histologisch Iediglich geringe septaie und portale Fibrose. Verlauf. Trot* Beendigung der VCM-Exposition Progredienz der Oso* phagus- und Magenfundusvarizen. Im MSrz 1975 massive Varizenblutung. Konservarive Therapie. Eine angeratene splenorenale Shuntoperation wird abgelehnt- Im September 1976 erneute Varirenblutung. Endoskopische Osophaguswandsklerosierung und Wiedetholung der Skierosiening im Mare 1977. Progredienz der Splenomegalie. Im August 1979 rezidivierende Epistaxis. Schmerzen im rechten Oberbauch und Epigastrium. Derbcr, der Leber angehorender Tumor tastbar. Starke Kopfschmerzen rechts parietal. Optische Halludnationen. Verdaeht auf Himmetastasen. Rcntgenbefunde Computertomographie des Gebims(12. 1.1980): Multiple Himmeta stasen mit perifokalem Odem in bciden Himhemisphiren. Sonographic des Oberbauches (1. 2. 1980) (Abb. 3a und b): Ausgedehnter, 12 x 15 cm im Durchmesser messender reflexarmer Tumor zentrai intrahepatisch zwischen linkem und rechtem Leberiappen gelc* gen, der aus mulriplen, mndlichen Strukturen konglomeratkhnlich zusammengesetzt isL Keine LebervergrSSerung. MKfiige Splenomega lie. Portale Hypertension mit Erwciterungder Pfortader auf 1,5 em im Durchmesser. Computertomographie des Abdomens (6. 2. 1980) (Abb. 3 c und d): Grofier, solitlrer, intrahepatischer Tumor von 15 cm Durchmesser, zentrai in der Leber gelegen, sowohl den rechten wie den linken Leberiappen betreffend, der sirit nativ hypodens mir Dichtewerten urn 40 Hounsfieldeinheiren dsntellt und nach i.v. Kontrastmittelapplikarion (100 ml Telebrix300) dem Lebergewebe mit 55 bis 60 Hauns fieldeinheiten isodeni erscheint. MSGige Splenomegalie. Lymphkno- AP00019590 286 Forachr. Rdntgenscr. 134,3 D. Kotschwicz und Micaib- Abb. 8b TransverBalsonogramm der Leber. LebervergrCUerung. Multiple, stark rellektierendeintrahepatlsche Tumoren. WS - Wirbetsiule, Ao TM Aorta, rfJ * rechte Niere. Abb. 2 Kombinatlon von multilokulSrem Angiosarkom der Leber und multilokulSrem primiren hepatozellulSren Karzlnom der Leber be! VC-Krankhelt. Abb. 2c Lortgitudlnalsonogramm des linken Leberfappens' Bevorzugte VerQrOQerurtg des linken Lebertappens und des Lobus caudatus, Abrundung der Leberkante. Multiple Intrehepatische Tumoren, D - Dlaphragma, P - Pankreas, Ao - Aorta. Abb. 2d Selektive Hepatikographie, arterielle Phase (5.11.1977). Bog'ige Verfagerung des rechten intrahepalischen Hauptastas der A. hepatica propria. GroBer hypervaskularisiartar Tumor inr rechten Leberlappen. Weitere stark kontrastanreichernde Tumoran im linken Leberiappen. Abb. 2 Selektive Hepatikographie, venose Phase (5.11.1977). VerzbgerterAbtluB des Kontraslmlttels aus den peritumoralen Lebervenen im rechten Leberlappen. Lange Kontreatmlttelspelcherung in multlplen Tumoren, insbesondere inks. tenvergr&Sening paraaorral im Hiatus diaphragmatis und im hintemn untercn Mediastinum. Veriauf: Schnelle Verschlechterung des Gesaratzustandes des Parien* ten. Desoriendenheit. Bewufitlosigkeit. Exitus letalii am 22. 2.1989. Die Autopsie besrarigt die angenommene Diagnose eines metastasierenden Lebermalignoms (Angiosarkom der Leber) mit Him-. Lungenund Lymphknotenmetaarasen*. Diskussion Das primare Angiosarkom der Leber wird im Schrifttum unter einer Vielzahl von Synonyma aufgefiihrt, so als angioblastisches Sarkom, angioplastisches Retikulosarkom, Endocheliom, Endothelioblastom, Hamangioblastom, Hamangioendothe- liom, hamangiocndotheiiales Sarkom, Kupffer-Zcll-Sarkom, malignes Hamargiom, metastasierendes Hamangiom, reciku- loendotheliales Sarkom, primares Sarkom der Leber (Zimmermatin und Eck 1975, Popper und Thomas 1975, Lelbaeh und Marsteller 1981). Die zahlreichen Synonyma erschwecen es, die Zahl der bisher mitgeteilren Beobaehtungen exakt zahlenmafiig anzugeben. Zweifellos handelc es sich urn ein auSerordentlich seltenes Malignom, das semen Ausgang vocv den sinusoidalen Uferzeilen, GefaBendochelien mesenchymalen Ursprungs, nimmt. In groBen Autopsiestatistiken land sidi ein Angiosarkom der Leber auf 20000 bis 100000 Autopsien, und 165 aus dem Schrifttum zusammengefaEte Angiosarkome der Leber stellten lediglich 1,8% aller innerhalb dieser Gruppe AP000I9591 Dat vinyWiloridindurierte Leberangiosarkom und hepatowlluliirc Karzinom Fortsehr. Ronigeiutr, 134,3 287 nachgewiescnen primaren Lebermalignome dar (Alrettga 197J). Das erwartete spontane Auftreten von Angiosarkomen der Leber in den USA wird mit 0,014 auf 100000 Einwohneroder 25 bis 30 Erkrankungen pro Jahr fur die gesamten USA erreefanet (Heath et al. 1975). Deshalb kam der Beobachtung von 4 Patienten mic Angiosarkomen der Leber unrer 270 Arbeitem einer PVC-herstellenden Fabrik in Kentucky, USA, zwischen 1967 und 1973 cminente Bedeumng zu, da sie eine neue, schwere Berufserkrankung aufdeckte (Creech er al. 1974, Creech und Johnson 1974). Die Entstehung von Angiosarko men der Leber beim Menschen war bis zu diesem Zeitpunkt nur im Zusammenhang mit zwei anderen Substanzen beobachtet worden, einem Thoriumdioxidpriiparat (Thorotrast), das als Kontrastmittel verwendet worden war (Da Silva Horta 1967), sowie dera im Weinbau als Insektizid verwenderen Arsentrioxid (Roth 1957). Heath er al. (1975} zeigren fur die VCM-exponierten Arbeiter der PVC-Polyraerisadonsindustrie ein 400fach hoheres Risiko auf an einem Angiosarkom der Leber zu stcrben, als es der Spcntanentwicklung cntsprechcn wiirde. Obwohl tierexperimentelle Untersuchungen (Viola et al. 1971, Maltoni und Lefermne 1975, Popper t1 al. 1978) belegen, daS neben Angiosarkomen auch hepatozellulare Karzinome bei VCM-Exposition auftreten, wurden bisher nur 3 Patienten mit solitaren hcpttozellularen Karzinomen (Gokeittal. 1976, Fox und Collier 1977) und 3 weitere Patienten mit einer Kombination von Angiosarkom und hepatozellularem Karzinom angetroffen (Byrett und Holtnberg 1975, Delorme 1978, Tamburro et a!. 1978), denen wir einen weiteren Patienten (W. F.) hinzuftigen konnen. Es ist bisher nicht geklart, warum die Hepatozyten im Gegensatz zu den sinusoidalen Uferzellen von der kanzerogenen Wirkung des VCM in gcringerem Mafie betroffen scheinen. Die klinischc Sympromatik des Angiosarkoms der Leber ist uncharakteristisch. Zunehmende Verschlechterung dei Allgemeinbefindens, Gewichtsveriust, einhergehend mit uncharakterisdschen Oberbauchbeschwerden Oder geringen Schcnerzen, sind gewohnlich die ersten jedoeh vieldeutigen Symptome. Gelegentlich kann ein geringer Ikterus bestehen. Die laborchemischen Parameter der Leber sind nicht Oder nur gering, meistens jedoeh uncharakteristisch verandert (Williams et al. 1975, Lelbach und Marsteller 1981). Audi hatsich dieBesrimmung des Alpha-Fetoproteins nicht als hilfreich fur die Dia gnosesrellung erwiesen. Im fortgeschrittenen Stadium fallen LebervergroBerung und Blutung aus dem Intestinakrakt auf (Thomas und Popper 1975, Roche et al. 1978, Konetzke ct al. 1978}, zu denen im weiteren Verlauf Aszites, Odeme und Marasmus hinzukommen, wie es auch bei alien von uns beobachteten Patienten der Fall war. Wahrend die Leber von den meisten Autoren als stark vergroUert bezeichnec wird (Thomas und Popper 1975), fand sich nur bei einem der von uns beobachreten Patienten eine relariv grofie Leber mit 3200 Gramm, wahrend sie bei den beiden resrlichen Patienten rail 1350 und 1150 Gramm eher verkleinert war. Mittels Laparoskopie und Leberbiopsie gelingt es zwar mit hoher Treffsicherheit, die diffusen, VCM-induzienen Leberveranderungen zu erkennen, wie subkapsulare und portale Fibros?, sinusoidale Dilatation und atypische proliferierende sinusoidale Uferzellen, wobei letzteres als Tumorvorstufe zu weiten ist (Marstelleret al. 1973, Creech et al. 1974, Falk et al. 1974, Thomas und Popper 1975). Die umschriebenen tumorosen Lasionen konnen jedoeh verborgen bleiben (Smith et al. 1976), wie es auch bei einem der hier vorgesteilten Patienten Abb. 2f Computertomogramm dar Leber, Nativuntersuchung. Mul tiple hypodensa intrahepatiech* Tumoran, im reehten Leberlappen bis zu 8 cm im Durchmesser messend (A) und von geiingerer GrCGs auch im linken Leberlappen (A), mit Dlchlswerten von 40bis 45 HE. N rechte Nlere, Mi Milz. Abb. 2g Computertomogramm der Leber, Kontrastuntereuchung nach i.v. Applikatton von 100 mlTalebrix 300. Verschiedana Tumotareale werden isodens, andereTumoranteile im reehten (A) wie Im linken (A) Leberlappen bleiben )doch hypodens bei multilokul&rem Angiosarkom und hepatozellularem Karzinom. N -- rechte Niere, Mi - Milz. der Fall war, der unter angiographisch und sonographisch erhobenem Tumorverdacht laparotomiert wurden und trotz multipier defer Keilbiopsien eine Tumordiagnose miSlang. Falls das Angiosarkom die Leberoberflache erreicht, stellt es sich als grobknotige, hypervaskularisierte Oder zystisch erscheinende Veranderung dar, ihnlich einer grobknotigen Leberzirrhose oder einer Metastasenieber. Eine transkutane Nadelbiopsie bei Verdacht auf ein Angiosarkom der Leber ist AP00019592 288 Fomchr. Rontgerotr. 134, 3 D. Koiachwia und Mitarb. Abb. 3 Longiiudlnalsonogramm dutch den rechten leberlappen. Konglomeratartig aus multiplen, wenig reftektierenden Arealen aufgabautas Angiosarkom der Leber (A). weilgehend den rechten Leber lappen ausfiillend. D -- Diaphragma, HO Hiatus diaphragmatis, Vp * Vena portae. Abb. 3b Longltudinalschnittdurch die Leberpforte, OasAngiosar kom involviert auch den linken Leberlappen (A). Verplumpung der Margo inferior hepatis. Portale Hypertension. D -- Diaphragma. Vp -- Vena portae. Abb. 3e Cemputertomogramm darLeber, Nativunterauchung. GroSersoiMrerhypiodenser Tumor von 12 cm Durchmesser, zentralin der Leber gelegen. sowohi in den rechten wie in deniinken Leberlappen reichend. Dichte nativ 40 HE. Aazltes (A), Ma * Magen, N rechte Mere, Mi - Milz. Abb. 3 Angiosarkom dar Leber bei VC-Krankhelt Abb. 3d Computertomogramm der Leber, Kontrastuntersuchung nach i.v. Applikation von 100 miTelebrix 300. DasTumorgewebe wird dem Lebetgewebe nahezu voBslftndig tsodens (55 bis 60 HE). Ledlflllcli eln zentraler Rest bieibt hypodens (A). i \ abcr wcgcn der zu befiirchrenden, nichr kontrollierbaren Nachblutung konrraindiziert. Deshalb haben sich die radiologischen Nachwcisverfahrcn wie Szinrigraphie, Leberangiographic und insbesondere Sonogra phic und Computertomographie dcs oberen Abdomens als die diagnostischen Verfahren der Wahl erwiescn, wcnn ein Angiosarkorn der Leber angenommen wird. Die Lcberszintigraphie zeigt zwar isolierte odcr multiple Aktivitatsdefekte, die durch die intrahepatischen Tumoren verursacht sind, und glcichzeirig konnen auch atypische Aktivitatsanreicherungen in der Mite erkannt werden (Biersack et al. 197S), aber peripher gelegene und multiple Aussparungen der Aktivitatsanreicherung sind schwer zu eifassen, und ihre Interpretation stbEt auf Schwierigkeiten (Whelan et al. 1976). Bei der Hepatikograptiie sind Verlagerung der A. hepatica propria und ihrer Aste dutch den Tumor, Hypervaskularisarion dcs Tumors mit irregularem CcfaGbild und insbesondere mit Kontrastmictelanreicherungen im gesamcen Tumor oder nur in der Tumorperipherie, die in APOOOI9593 Dai vinykhtoridiitduzicm Leberangiosarkom und hepatoiellulare Karzinom Fotrcehr. 134, 3 289 der venosen Phai nocb large, bis uber 30 Sekunden persistierr, als typische Befunde d Angiosarkoms beschrieben worden (Abb. lb, 2d und c) (Whelan et al. 1976). Neben vetschiedenen Gradcn eincr Peliosis hepatis wurde einmal Uber einen portalen Reflux mit heparofugalem Kollateralkreislauf bcim Angiosarkom der Leber beriehtct (Whelan et al. 1976), wie er auch bei einem von uns angiographisch untersuchten Patienten beobachtet werden konnte (Abb. 2 a). Die retrograde Pfortaderperfusion srellr beim Angiosarkore der Leber anscheinend ein btsher noch selten beobachteres Phanomen dar, das beim primiiren hepatozellularen Karzinom hiiufiger beschrieben wurde: Okuda et al. (1973, 1977) berichten iiber eine retrograde Fullung des Pforraderhauptstammes iiber den Leberhilus hinaus bei 25,4% von 114 Patienten mit primarem hepatozellularen Karzinom, was als Folge intratumoraler arterioportaler Shunts interpretiert wird. Da bei dem von uns beobachteten Patienten mit retrograder Pfortaderperfusion eine Kombination von Angiosarkom und hepatozellularem Karzinom vorlag, ist die Zuordnung dieses Phanomens zur sarkomacosen oder karzinomatosen Tumorkomponente hier niebt sicher. Auch ist die Reversibilirat der retrograden Pfortaderperfusion bei der zweiten, 2V* Jahre spiiter erfolgten angiographischen Untcrsuchung nicht geklart. Trotz hoher Treffsicherheit beim Tumomaehweis kann in Einzelfallen die Erstellung der korrekten Diagnose eines Angiosarkoms der Leber auch bei wiederholten Angiographien milingen (Roche ct al. 1978). Sonographie und'Computertomo* graphie bicten sich aber neuerdings als nicht-invasive, den Parienten nicht belastcnde Verfahren mit hoher Aussagekraft an (Bosnjakovic et al. 1980), insbesondere bei wiederholten Untersuchungcn von VCM-exponierten Patienten zur Befundkontrolle oder zur Begutachtung (Taylor a al. 1976). Da viele dieser Patienten bereits zahlreiche, haufig auch belastende und invasive Untersuchungcn durchlaufcn haben, werden Computertomographie und Sonographie bevorzugt toleriert. Die Sonographie erbrachte bei beiden von uns untersuchten Patien* ten den Nachwei* solitarcr oder multilokularer, entweder reflexarmer oder ventirkt reflcktierender, konglomeratartiger intrahepatischer Turaoren. Daneben konnten eindeurig Leberund MilzgroGe, diffuse Leberparenchymverandecungen sowie die Weite der V. portae beurteiit werden. Computertomographisch zeigten die Tumoren bet beiden untersuchten Patienten nativ hypodense Strukturen mit Dichtewerten von 40 bis 45 HE, wahrend tie nach Kontrastmittelinjektion dem Lebcrparenchym isodens erschienen. Bei einem Patienten (W. F.) jedoch verhielten sich einzelne Tumoranteile nach Kontrastmittelinjektion isodens, andere Tumoranteile blieben hypodens, was entweder Tumornekrosen oder den beiden histologisch unterschiediichen Tumorarten zuzuordnen ist. Beide Verfahren konnen mit annahernd gleich hoher Sensitivitat bereits den praklinischen Nachweis intrahepatischer Turao ren erbringen (Snout et ai, 1979, Scherer et al. 1979, Stadleret al. 1980, Janson et al. 1980). Gleichzeilig ist die Bcurteilung diffuser Leberveranderungen, Beschaffenheit und Grofie anderer Oberbauchorgane sowie die Weite des ponalen Gcfafisystems moglich {Williams et al. 1976, Taylor et al. 1976). Im Zusammenhang mit der Anamnese einer chronischen VCMExposition ist die Spezifitat beim Tumocnachweis hoch. Deshalb erscheint es gerechtfcrtigt, die sonographische und computenomographischc Untcrsuchung der Leber in der Reihe der Kontroll- und Oberwachungsuntersuchungen bei der Beurteilung der VCM-bedingten Tumorentstehung bevorzugt einzusetzen. Fur die technische Mitarbeit danken wir Fr. M. Smeets. Literstur (1) Alrenga, D. P.i Primary utiJoiAr- comaof the liver. Review aniek. bu. Surg. 60(1975) 198 (2) Bicrsack, H. J., H. 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Koischwitz Radiologische Klinik der Universitat Bonn Ronrgenabieilung Medizinische Klinik 5300 Bonn-Venusberg Fortschr. Rontgenstr. 134, 3 (1981) 299-292 Internal endoprosthesis as treatment of obstructive jaundice in pancreatitis By F. Burcharth and J. Holst Pedersen 3 Figures Departments of Surgical Gastroenterology (Director; Ptof. H- Baden) and Radiology (Director; Proi. O. Pedersen), Heriev Hospital, University of Copenhagen, Denmark In five patients with pancreatitis, obstructive jaundice was relieved by internal drainage of the biliary tract with an endoprosthesis inserted by percutaneous transhepatic technique. The average duration of treatment was 3.5 months. The endoprosthesis were removed by means of a duodenoscope, and jaundice did not recur. Interne Endoprothcst zur Befaandlung do Stauungriktcnis bi Pankreatiris Bci 5 Padenrcn mir Pinkreatitis kontttc dec dabei aufgctretene Stauungeiktems mieeela intemer Drainage der Gallengange durch eine Endoprothesc behoben werden, die perkutan-transheparischeingesetzr wurde. Die durchschnitrliche Behsndlungsdauer betrug 3,5 Monate. Die Endoprothese wurde nach Behandlungseode mirtels Duodenoskop entfemr, ohne da Rezidivierung de* Ikterus eimrat. Obstructive jaundice occurs in approximately 20% of patients with acute or chronic pancreatitis (1, 5, 3). In the absence of gallstones, hepatocellular disease or pancreatic cancer it is generally attributed to pancreatic oedema or fibrous, pancrea tic cyst* or abscesses (1, 7, 8). The obstruction may lead to cholangitis, depletion of bile sales and electrolytes, and if long standing, to biliary cirrhosis (1, 6, 9) making decompression of the biliary system imperative. We report the results of internal biliary drainage by an endo prosthesis in patients without associated biliary tract disease. Patients and methods During a 3-year period 135 parients were admitted to the department with pancreatitis. Five of these had obstructive jaundice without associated biliary disease (4%) and were treated with endoprosthesis. They were all males with an age range from 34 to 68 years (Table 1), and had jaundice with marked elevations of plasma bilirubin and alkaline phosphatase. The pancreatitis was in two patients classified as chronic, in two at acute relapsing and m one as acute. Etiology was in all cases alcohol. Ultrasonic scanning showed diffuse enlargement of the pancreas and in one patient also a small pseudocyst in the head of pancreas (patient 2). In one care cancer was ruled our by autopsy, and in the others the dinical course made carcinoma extremely unlike. Percutaneous transhepatic cholangiography revealed smooth stenoses in the intrapancreatic part of the distal common bile duet and dilation of the biliary tree (Table 1) (Fig. 1). Because jaundice persisted for more than 3 weeks, and pseudocysts were absent or too small to justify surgery, internal drainage was performed. The endoprostheses were inserted under local anaesthesia according to a technique previously described (2, 3,) (Fig. 2 and 3). The endoprostheses were removed later by means of a duodenoscope (3). 0340-1618/81 0332-0290 $03.00 1981 Georg Thieme Varlag, Stuttgart New York AP00019595