Document ba3rjz7RGG4K630jeRnVvv7Q1

DOW CHEMICAL U.S.A MIDLAND, MICHIGAN 43640 29 April 1981 Memo to: From V't-. Vinyl Chloride Research Coordinators T. R. Torkelson ANGIOSARCOMA OF THE PENIS (Article attached) Ted Benya sent me on a chase for this article. Any relationship of vinyl chloride to this mans cancer appears to be rather remote, but the implications are tremendous. cc: M. Currier W. Fishbeck P. Gay R. Kociba R. Kolesar J. Lanham/S. Steinberg J. Reuvers H. Scharnweber B. Schwetz ,, H. Shelton L. Skory/R. Oubre J. Venable H. Wallis .. in ^ AN OPERATING UNIT OF THE DOW CHEMICAL COMPANY SCC 1-1024 Angiosarcoma of the Penis with Hepatic Angiomas in a Patient with Low Vinyl. Chloride Exposure LATIFA GHANDUR-MNAYMNEH. MD, AND MARIO S. GONZALEZ, MD A case of angiosarcoma of the penis associated with two hepatic angiomata in a 61-year-old man . Is presented. The patient had worked In a polyvinyl chloride factory as an accoontant for ten years.. The relationship of. this low vinyl chloride exposure to the development of the vascular - , lesions Is discussed with a review of the experimental and epidemiologic data on this subject- -. Cancer 47:1318-1324,1981, .. * ngiosarcoma of the penis is an extremely rare The patient's tumor was considered to be primary in the A lesion- About- 32 cases have been reported up liver and he was treated with a combination of cyclo- . until the present. Its occurrence in a patientphosphamide, Adriamycia, and methotrexate. He was -' * who.-worked on the premises of factories handling followed at weekly intervals as an outpatient until. May 26, 1978, when he was admitted to -the University of vinyl chloride (VC) and the presence of two hepatic Miami Hospital, -National Children's Cardiac Hospital, * angiomas is a unique and most unusual association. because of weakness, painful penis, and intermittent priapism. On physical examination the liver was palpable Case Report at -12 cm below the right costal margin in the anterior' axillary and midclavicular lines. There werc.multiple nodules Clinical History; P.L. (NCCH#96929) The patient was a.61-year-old roan who was initially seen in the private clinics of the University of Miami Hospitals and Climes in December 1977. At that time he presented with generalized weakness and gross hematuria. The only positive finding on physical examination was a hard 1 x 1 cm nodule on the shaft of the penis said not to have been present previously. Laboratory data showed no ab normality except for an elevated alkaline -phosphatase. A cystograni showed a-lesion in the lateral wall of the . urinary bladd&r and a liver scan showed a filling defect in , the right lobe. The patient underwent a cytoscopy and at the base of the penis. Laboratory data showed the* ' following: hematocrit. 31%, white blood ceil-'couat 2250, ' platelet count 67,000, total scrum protein 622 g/ml (albumin. 1.6 g, globulins 4.6 g); total bilirubin 4.2, blood urea nitrogen 10, calcium 7.4, phosphorus 3.5, uric acid 2,5,. creatinine 1.9, cholesterol 288 mg/100 ml; alkaline phos phatase 324 U; serum' glutamic oxalacetic transaminase 166 U; serum sodium 140, and potassium 3.6 oiEq/liter.Urinalysis showed 2-9 white cells/HPF! Bone and brain scans .with Technetium 99 m MPD did not.show any areas of. increased radionuclide concentration to. suggest metastatic disease. Liver, scan following the intravenous injection of technetium sulfur colloid showed a normal-sized Ever biopsy of the bladder, which showfcd an angiosarcoma infiltrating rouscularis. Past medical history was negative except for the removal of a bluish nodule from the cheek five months earlier (August 1977). The material was with a questionable area of decreased uptake in the porta hepaus. The spleen was enlarged to twice the normal size. In the hospital, the patient's condition deteriorated and reviewed and showed similar tumor infiltrating the dermis. With the diagnosis of an angiosarcoma and the presence of a filling defect in the liver, the possibility of a primary liver angiosarcoma was entertained and the patient's occupational history was investigated. The patient worked in data - processing and was employed in factories for the manufacture of plastic products for ten years: between 1955 and 1958 he worked in a Plastic Tapes Factory in New York and he complained of severe pain at the base of the penis; he required sedation. There was increasing urinary ob struction necessitating instrumentation for the delivery of urine: elevation of the blood urea nitrogen was 47 mg/100ml. tThe patient also complained of double vision and cerebellar symptoms. Gradually he lapsed into coma and died on June 14, 1978, 22 months after initial mani between 1963 and 1970 he worked for a company that festations. manufactured plastic goods in Miami, Florida. Pathologic findings From the Department of Pathology. University of Miami School of Medicine, Miami. Florida. * Address for reprints: L. Ghandur-M.naymneh, MD. Depart ment of Pathology, University of Miami School of Medicine, 1611 N.W. 12th Avenue. Miami. FL33I36. Accepted for publication March 25, I960. Autopsy Findings Gross: The skin was jaundiced with a 3-cm wellhealed scar over the right cheek. There was no fluid in the body cavities. The heart was unremarkable. 0008-J43X/8I/0335/13J8 $0.65 American Cancer Society 1318 see 1-1025 Ko. 6 Angiosarcoma of Penis * Ghondur-Mnaymneh and Gonzalez 1319 The lungs were heavy, weighing 1020 .(right) and 950 (left) g. On cut section, both exhibited^multiple 2-3cm reddish ill-defined foci of induration arid 0.5-1 cm similar but greyish foci. The liver weighed 1160 g. Its cut surface was bile-stained and finely nodular with nodules less than 0.5 cm in diameter. In the right lobe, there were two subcapsular reddish purple areas, roughly quadrangular in shape, with ill-defined borders, one aboilt 4 cm and the other 2 cm in diameter. Their cut sections were fleshy-red and honey-combed; the larger had a central 1 cm in diameter area of greyish discoloration (Fig. 1). The spleen was enlarged to 230 g. The gastrointestinal tract was intact with no esophagel varices appreciated. The kidneys weighed 150 and 160 g and showed slight dilatation of the pelvicalyces. In the pelvic cavity, there was extensive . replacement of the prostate, seminal vesicles, and periurethral tissues by greyish and reddish fleshy tissue extending into the lateral pelvic walls. The same tissue infiltrated the bladder neck and the posterior wall producing thickening with mucosal ulcerations. There were three diverticula in the posterior wall of the bladder varying between 2 and 5 cm in diameter. The neck of the bladder was surrounded by tumor that extended to and deformed the base-of.^the penis.. The proximal penis was markedly deformed with an increase in the diameter to about 6 cm, which was due to an enlargement of the right corpus cavemosum penis (Fig. 2). Both corpora cavernosa were replaced by the same fleshy red tissue, the right more than the left. This also involved the corpus spongiosum with narrowing of the penile urethra. The brain showed a 2 x 2 x 3.6 cm cir cumscribed hemorrhagic lesion in the right occip ital lobe. FlC. I. Cut surface of the right lobe of the liver with the hamargiomata. Both lesions exhibit a spongy or hooey-combed surface. The larger one has a central more solid grayish area. The intervening tissue appears fibrou'e. The remaining hepatic paren chyma is finely nodular. neoplastic cells had large vesicular nuclei, with very prominent nucleoli and irregular chromatin clumping. Around the corpora cavernosa, tumor nests, were seen*'within vascular structures and in perineural lymphatics. Sections from around the bladder neck and the seminal vesicles showed a poorly differentiated anaplastic sarcoma diffusely infiltrating the tissue; however, there were always attempts at vessel forma tion by the tumor cells (Fig. 4). Sections from the red lesions in the liver showed a cavernous hemangioma (Fig. 5). In several sections, the endothelial spaces were filled with clusters oftumor Microscopic Examination Sections of the corpora cavernosa showed a gamut of changes: in some areas, the vascular spaces were lined by normal-appearing endothelial cells with small nuclei and attenuated cytoplasm. In other areas, the lining cells were large and atypical with prominent vesicular nuclei sometimes containing large nucleoli. Further on, the lining cells were definitely anaplastic with clustering and intravascular tufting (Fig. 3): In all the above areas, the fibromuscular trabecula main tained the normal architecture of the corpus cavernosum. In other fields, there was replacement of the normal architecture by large masses of tumor cells with their own fibrous stroma. The tumor cells were either spindly, forming fascicles and sometimes lining small lumens, or round forming large sheets of loose cells separated by fibrous trabecula. In both areas, the Fig. 2. Cross-section of the base of the penis showing the markedly enlarged right corpus cavemosum, ihc foci ofinvolvcmcnt with dark nnJ while discoloration of the left corpus, and the compression of the urethra by the surrounding grayish tumor. sec 1-1026 - Jx'O, Angiosarcoma of Penis * Ghandur-Mnaynmch and Gonzalez 1321 Fig. 5. Microscopic ap pearance of one of the hemangiomata in the liver. Multiple sections of the entire surface area showed all sinusoids to be lined by flat endothelial cells with inconspicuous nuclei. Ana plastic cells with vesicular nuclei and prominent nu cleoli are present within two sinusoids mixed with red blood cells '(H & E. X625). dilatation was noted in the cirrhotic part. One section with overlying capsule did not show subcapsular scarring. Sections from the spleen showed slight prominence of the sinusoidal endothelial lining with perisinusoidal fibrosis. There was no endothelial cell atypicality. Most of the central arteries were, almost nakftd with marked depletion of lymphoid tissue. Sections of the lungs showed foci of broncho pneumonia and multiple metastases. Neoplastic cells similar to those described above were present within alveoli, in vascular lumens, and infiltrating perivascular tissues. The hemorrhagic lesion in the occipital lobe of the brain showed a recent hematoma with no tumor cells, macrophages, or glia! response. Review of .the check 'and the bladder biopsies showed an angiosarcoma similar in all respects to that present in the other organs. Fig. 6. Microscopic appearance of liver. The fibrous sepiae have completely disrupted the lobular architecture. The fatty change in the hepaioeytes and pseudoductular proliferation s not apparent at this magnification (H & - E. x 150). SCC 1-1027 1320 Cancer'March 15 1981. voL<7` Fig. 3. Microscopic sec* ..tioa of the corpus caver* -nosum penis. The cndothe. Ual Unins celts are hyper* chromatic and show tufting and papillary projections (H&.E. X62S). cells growing mainly as round cells with ill-definedborders and prominent nucleoli. In such areas, the lining endothelium was benign in appearance and conspicuously different from the contained tumor cells. Sections from the remaining part of the liver showed a micronodular cirrhosis consisting of porta] fibrosis with bridging of fibrous tissue from one portal area to another. In many fields, the septa extended from portal area to central vein with obliteration .of lobular architecture'(Fig. 6). Some portal areas showed a moderate degree of pseudoductular proliferation. A conspicuous number of hepatocytes showed multivesicular fat accumulations scattered throughout the lobule with no zonal preference. There was a moderate degree of intracytoplasmic and canalicular bile stasis. The Kupffer cells were not prominent and no sinusoidal Fig. 4. Invasive angiosarcoma as seen In pelvic cavity and metastatic foci. The tumor ceils are either spindle- or polyhedral with hyperchromatic or vesicular neclei. They form nests and fascicles with cleft formations (H & E, x IJO). see 1-1028 1322 Cancer March 15 1981 Vol.47 . Discussion from VC. This part of the plastics industry is referred to as PVC production or polymerization and it is the With the history of vinyl chloride exposure, the section with the highest concentration of VC.* It is presence of a filling defect in the -liver and the to be distinguished from PVC processing wherein histologic diagnosis of'angiosarcoma in cheek and the already manufactured. PVC plastic, in powder form, bladder biopsies, it stands to reason that the primary- is mixed with stabilizers, colors, and other materials tumor was assumed to be in the liver. The gross and and processed into the different shapes (sheets microscopic autopsy findings leave no doubt that the tubings cables, etc.) and consistency (rigid or flexible) primary tumor was in the corpus cavernosum penis: in which it will be used.14,17 Vinyl chloride is the the lining endothelial cells of the residual cavernous toxic gas with the carcinogenic effect whereas PVC is spaces showed premalignant changes and an in situ the inert plastic end product. Because .most of the ' angiosarcoma progressing into an invasive sarcoma in hepatic angiosarcomas related to VC exposure were and around that structure. The tumor .in the bladder observed in workers involved with PVC production, biopsy represents a direct extension and that in the i.e., in the stage of polymerization of the toxic VC cheek a metastasis. The primary tumor, evident gas into the inert PVC.resin,- the impression was that locally as a nodule on the penis, was not noted by PVC processing entails no toxic or carcinogenic risks, the patient until after it had produced metastases and inasmuch as this step involves handling of inert PVC was associated with priapism and dysuria. The tumor and does not utilize VC gas. According to Marsteller ' had infiltrated locally extensively and. metastasized et al.,11' PVC processing is listed as harmless (er mainly to the lungs. In the liver, metastatic angio roneously) in many occupational bulletins and standard sarcoma was found only within the hemangiomas'with textbooks. However, during processing, the PVC is sparing of the remaining cirrhotic liver. The brain heated to temperatures of 100-300 C to give it the lesion was grossly thought to be metastatic. Although hardness and the shape required for the particular, microscopic sections showed only a hematoma with no need. This results in the liberation of VC, trapped tumor cells, it is believed to represent a metastatic within the PVC during its polymerization, with escape focus with hemorrhage. of fumes, gases, and smoke into, the surroundiiig Could the angiosarcoma of the penis be related to atmosphere.14,tT Prior to 1974 the trapped VC mono vinyl chloride? Was the exposure of sufficient magni mer in the PVC averaged about 50(3--1000 ppm, tude to have been significant etiologically? To sometimes reaching 7000 ppm.35 The presence of the elucidate these points one has to review briefly characteristic sweet odor of VC in such areas indicates some of the pertinent data related to VC car a high atmospheric concentration. This characteristic . cinogenesis. odor is also noted in closed storage areas of PVC' The carcinogenic effects of VC were first recognized * sheets.10 Measurements made by Jaeger in factories in in experimental animals in 197130 and later confirmed the Boston area detected 1/2--1 ppm of VC in a non- on a larger scale by Maltoiu and Lefemine.16 These polymerization factory.11 Schweitzer34 noted a con authors noted that animals exposed to VC gas de centration of 1 --2 ppm in air outside the B.F. Goodrich veloped a variety of tumors, including sebaceous gland Plant in Louisville, Kentucky. carcinomas, hepatic and extrahepatic angiosarcomas, angiomas, fibromas, neuroblastomas, lung adenomas, and hepatic and mammary carcinomas. The extrahepatic angiosarcomas developed in kidney,* sub Workers in PVC processing show abnormalities of liver function tests, blood counts, platelet numbers, and in size of the spleen.14 Furthermore^ of five cases of death from cancer in a group of 257. workers, two cutaneous tissue. Ups, lung, uterus, and intra-abdominally diffusely. The angiomas, occurred in the were not involved in PVC production,. but were maintenance employees.30 Data by Creech and Makk5 liver, cecum, heart, subcutaneous tissue, and in the peritoneum. indicate that minimal exposures are associated with significant biochemical changes- These authors divided In. 1974, Creech and Johnson4 described the first the workers in a PVC production plant into five case of angiosarcoma of the liver in a worker exposed categories representing decreasing areas of exposure to occupational vinyl chloride. Review of the death certificates and the institution of screening tests on all workers at the same plant revealed six additional to VC: (1) PVC production, representing the highest exposure; (2) other areas of production; (3) main tenance personnel for PVC.production; (4) all other cases.33 All seven instances occurred in employees of unit 62 where polyvinyl chloride (PVC)' is produced maintenance employees; (5) all other employees, in cluding administration, plant protection, secretarial see 1-1029 NO- 6 Angiosarcoma, of Penis Ghattdur-Mnaymneh and Gonzalez 1323 services and the like, representing the population least exposed to VC. Their studies revealed that each of the five categories showed almost the same:percentage of individuals having abnormal SMA-12 profiles, with elevation of alkaline phosphatase, total bilirubin, and serumglutamic oxalacetic transaminase. This indicated that workers far removed from the VC-PV C production area exhibit biochemical manifestations of altered liver function. However, no pre-employment tests are available for comparison. Although hepatic angio sarcomas related to VC-PVC production have occurred in workers' in the immediate production area, recent observations, show that remote exposures may also be significant. In an epidemiologic study of 26 cases of angiosarcoma of the liver in New York State, Brady el at.3 found 19 patients in whom no direct exposure to VC-PVC, arsenic, or thorium dioxide could be documented. Of these 19 patients, five lived nearer to VC processing or polymerization plants than did their matched controls, supporting an indirect mode of exposure. Thus,' the hazards of VC are not limited to individuals with high exposures, but include those with low exposures as well; such low exposures would be incidental to working in PVC factories as nonproduction personnel or to living in the vicinity of such plants. Experimentally, animals exposed to low VC concentrations develop the same tumors as those exposed to*high concentration but less frequently.,3-16 In a hypothetical discussion of the relationship of carcinogen to frequency of Induction of cancer, Peto21 showed that lowering the dose decreases the number of induced cases but does not eliminate the risk altogether. Nicholson19 states that two cases of angiosarcoma of the liver have occurred in non production workers, one in a. processing employee and the other in an accountant working in a PVC processing plant. Experimentally there are other synergystic factors. that affect the metabolic pathway of VC and the frequency of VC tumor induction.Radltke el al.u have shown that the latent period for the de velopment of angiosarcoma in rats fed 5% ethanol and exposed to 600 ppm VC was 38 weeks compared with 58 weeks in rats not fed ethanol. In the patient under discussion, the portal fibroblastic changes described to be typical for VC effect by Popper and Thomas8* and others*'15'*2-* were not ob served. This could have been masked by the already existing cirrhotic changes. The endothelial changes of the hepatic sinusoidal cells, also considered typical for VC,28 were absent in the liver but similar changes were observed in the corpus cavernosum, suggesting that these could be the result of VC effect. The lymphoid hyperplasia in the spleen described in VC-exposed individuals22 was conspicuously absent in this patient and not unexpectedly: the patient was receiving chemotherapy until his demise and hence' lymphoid depletion is expected. Although hepatic and extrahepatic angiomas and hepatic and extrahepatic angiosarcomas have been induced experimentally by VC exposure, there is no indication at this time that the extremely common cavernous hemangioma of the liver in man is related to vinyl chloride exposure. Likewise, extrahepatic angiosarcomas related to VC exposure have not been reported in man. The role of VC in the lumorigenesis of the present case cannot be unequivocally proven, nor can it be easily dismissed. REFERENCES 1. Ashley DJB. Edwards EC. Sarcoma of the penis. Br J Surg 1957;45:170-179. . 2. Barnett CP, Low JR. Hemangioendothelioma of the corpus cavemosum penis: case report. J Urol .1960; 83:160--162. 3. .Brady J, Liberatore F, Harper P et a!. Angiosarcoma of the liver; An epidemiologic survey. J Nail Cancer Inst 1977; 59; 1383-1385. 4. Creech JL Jr. Johnson MN. Angiosarcoma of the liver tn the manufacture of polyvinyl chloride. J Oecup Med 1974; 16: 150-151. 5. Creech JL Jr, Makk L. -Liver disease among polyvinyl chloride production workers. Ann .'NY- Acad Set -1975; 246: 88-94. 6. Dehner LP. Smith BH. Soft tissue tumors of the penis. Cancer 1970;25:1431-1447. 7. Deutsch M, Leen RLS, Mercardo R Jr. Hemangioendothe lioma of the penis with late appearing metastasis: Report of a case with review of the literature. J Surg Oncol 1973; 5:27--34. 8. Garcia AE, Monserrai JU, Gonzalez-Martin G. Hemangiosarcoma del pene. Rev Argent Urol 1968; 37:7-9. 9. Gedik P, Muller R, Bechtelshcimer H. Morphology of liver damage among- polyvinyl chloride production workers. A report on 51 eases. Ann NY Acad Set 1975; 246:278--28S. 10. Hefner RE Jr, WatanabePG, GehringPG. Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Amt NY Acad Set 1975; 246:135-149. (Discussion by Oster. p. J49) 11. Jaeger RJ. Vinyl chloride monomer: Comments on its hepatotoxieity and interaction with. l-Dichlorethylene. Ann NY AcadSci 1975;246:150-151. 12. Johnson CA. Clinical management ofworkers exposed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 1975; 246: 313-319. (Discussion by Dr. J. Jaeger, p. 317). 13. Kcpllnger ML, Goode JYV, Gordan DE, Calandra JC. Interim results of exposure of rals, hamsters and mice to vinyl chloride. Ann NY Acad Sci 1975: 246:219-224. 14. Lange CE, Juhe GS. Veltman G. Further results in polyvinyl chloride production workers. Ann NY Acad Sci 1975; 246:18--21. 15. Makk L, Delmore F, Creech JL Jr et al. Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 1976;37:149-163. 16. Maltoni C. Lefcmine G. Carcinogenicity bioassay of vinyl chloride: Current results. Ann NY Acad Sci 1975: 246:195-218. 17. Mamcller HJ, Lelbach WK, Muller R, Gcdigk P. Unusual splcnomegalic liver disease as evidenced -by peritoneoscopy and see 1-1030 British Journal of Industrial Medicine 1982;39:306-307 ^f-Yc/pv'c,-TX^* Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma of the liver . D B JONES AND P M SMITH From the Department ofGastroenterology, Uandough Hospital, Penarth, S Glamorgan, UK abstract Two vinyl chloride monomer (VCM) workers, who developed non-cirrhotic portal fibrosis and portal hypertension, died from angiosarcoma of the liver five and ten years later respectively, despite withdrawal from occupational exposure. We suggest that non-cirrhotic por tal fibrosis caused by exposure to VCM is potentially premalignant and that those workers who already have the condition should be carefully monitored. Since the original communication by Creech and results showed a normal serum bilirubin with a Johnson1 there have been several further case raised alkaline phosphatase (201 IU/1) and reports of vinyl chloride monomer (VCM) induced -/-glutamyl transpeptidase (83 lUfl). Radioisotope angiosarcoma of the liver. A commoner hepatic liver scan showed a small liver with no filling defects lesion is non-drrhotic portal fibrosis1 leading to por and needle liver biopsy showed a well-pronounced tal hypertension. It has been suggested that this micronodular drrhosis with no evidence to tumour. lesion may be a precursor to angiosarcoma He responded to protein restriction and lactulose formation,1** but there has been only one report of a and was discharged. Within a week of discharge he patient with documented hepatic fibrosis developing was readmitted with an endoscopically confirmed angiosarcoma at a later date.4 Wc describe two bleeding duodenal ulcer. After this, he lapsed into further cases. hepatic coma and died. Necropsy showed multiple malignant tumours in the liver (wt 1130 g), one of Case reports which was haemorrhagic. Histologically, a great variety of liver cell lesions were present, some resem CASK I bling angiosarcomas, some hepatocardnomas, and A 60-year old white man initially presented in 1969 some adenomas. There were also atypical sinusoidal to the dermatology department with a skin eruption. cells and fibrosis in the non-tumorous parts of the Examination at that time showed anaemia, thrombo liver. cytopenia, hepatosplenomegaly, and occult faecal blood loss. He had an occupational history of expos CASE 2 ure to VCM at high concentration for seven years A 49-year-old man with a 12-year history of expos while working as a poiydcaner and a blowdown ure to vinyl chloride monomer while working as a recovery operator. After two haematemeses, barium spray drier bagger, premix operator, and paste studies and splenic venography confirmed portal charging operator was, during a factory survey of hypertension and oesophageal varices, and he process workers in 1974, found to have thrombo underwent an end-to-side portocaval shunt. At cytopenia. This was later shown to be due to laparotomy the liver looked nodular, but operative hypersplenism and presinusoidal portal hyperten liver biopsy showed non-drrhotic portal fibrosis sion. He was otherwise well and drank five pints of only. Over the next four years the patient developed beer a night. Liver function test results were normal chronic portosystemic encephalopathy and maturity apart from a raised y-glutai..yl transpeptidase level onset diabetes mcllitus that was treated with oral of 82 IU/1. Varices were shown by barium studies hypoglycaemic agents. In May 1980 he presented and endoscopy, and liver biopsy showed fatty with worsening mental deterioration, hepatic foetor, change and slight non-drrhotic portal fibrosis. Two asterixis, and an enlarging liver. Liver function test years later the patient developed insulin dependent diabetes meliitus, but otherwise remained well until Received 5 October I981 Accepted 2(1 November 1981 October 1979 when he presented with a large haematemesis. Endoscopy' confirmed oesophageal 306 . see 1-1031 Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma ofthe liver 307 varices to be the source of haemorrhage, and these were treated by injection sclerotherapy. The serum alkaline phosphatase and y-glutamyl transpeplidase levels rose over the next three months to"334 IU/l and 106 IU/1 respectively. Radioisotope liver scan showed multiple filling defects consistent with tumour deposits. Ascites and ankle oedema developed, and he died suddenly in January 1980 from an intraperitoneal bleed after a liver biopsy. Necropsy showed that a large haemorrhagic tumour, occupying most of the right lobe of the liver, had ruptured into the peritoneum. Several smaller haemorrhagic tumours were found elsewhere in the liver. An enlarged spleen (wt 760 g) and thrombosed, oesphageal varices were also noted. Histology showed the tumours to be angiosarcomas, with areas of sinusoidal dilatation and portal fibrosis in unaf fected areas of the liver. absence of portal hypertension, and may then be difficult to detect. It does not lead to a disturbance of liver function tests and may even be missed on needle biopsy of the liver.2 Greyscale ultrasonogra phy is a useful diagnostic aid," but it has yet to be used in a large industrial survey, and there are prob ably several unrecognised affected VCM workers. Stringent measures to control levels of exposure should lead to eventual disappearance of noncirrhotic fibrosis. Those patients who already have the condition, however, are still at risk of developing hepatic angiosarcoma in the future. A problem highlighted by the second case is that angiosarcoma is, by definition, a vascular lesion, and there is a risk of uncontrolled haemorrhage after blind liver biopsy. We believe, therefore, that the diagnosis should be sought either by laparoscopic biopsy or by hepatic angiography. Discussion Vinyl chloride monomer is transformed by hepatic microsomal enzymes to toxic metabolites that coval ently bind to DNA.7 After exposure to VCM hepatocytic proliferation, sinusoidal lining cell pro liferation, and focal sinusoidal dilatation occur1 and angiosarcoma may later develop from the sinusoidal lining cells. Enlarged lipocytes may be seen in the space of Disse*; these cells are fibroblast precursors and can lay down collagen.' Hepatic fibrosis results and may be associated with presinusoidal portal hypertension.1 It is commoner than angiosarcoma.2 Although fibrosis was found in tumour-free portions of the liver tissue from VCM workers dying of angiosarcoma,2 transition of hepatic fibrosis to angiosarcoma, although postulated,2 has not been observed. The two patients described here were originally included in a series of seven VCM workers with por tal hypertension.2 They were followed for five and 10 years respectively from the time of diagnosis of portal hypertension to death from angiosarcoma. During this period they were not further exposed to VCM. Their case histories indicate that hepatic fibrous in a VCM worker may be a precursor of future malignant change and life-long follow-up is necessary. We know of only one other similar patient who died seven years after a portacaval shunt from an angiosarcoma.* Non-cirrhotic fibrosis can also occur in the We thank Dr D M D Evans and Professor Peter Scheuer for their help in interpreting the biopsy material. References ' Creech JL. Johnson MN. Angiosarcoma of ihe liver to ihe manu facture of polyvinyl chloride. SOM 1974;16:150-1. 1 Smith PM, Crusslcy IR, Williams DMJ. Portal hypertension in vinyl chloride monomer workers. Lancet 1976;ii:602-4. * Popper H. Maltoni C, Selikoff LI. Vinyl chloride-induced hepatic lesionsin man and rodents. A comparison. Liver 19fci; 1:7-20. * Tamburro CH. The hepatic role in carcinogenesis and its early detection--the vinyl chloride model. Yale J Biot Med 1978;51:67-80. * Popper H, Thomas LB, Telles NC, Falk H, Selikoff U. Develop ment of hepatic angiosarcoma in man induced by vinyl chloride, thorotrast and arsenic. Am J Palhot 1978;92:349-69. * Makk L, Dclmore F, Creech JL,era/. Clinical and morphological patients of hepatic angiosarcoma in vinyl chloride workers. Cancer I y76;37:149-63. 1 Osiermann-Colkar S, Hulunark D, Segcrback D, et el. Alkyla tion of DNA and protein in mice exposed to vinyl chloride. Bioehem Biophys Res Commun 1977;76:259-66. * Schaffner F. Popper H, Selikoff LI. Initial features of vinyl chloride (VC) hepatic injury. Gastroenterology I976;72:A35. * Kent O. Gay S. Inouye T. Bahu R, Minick OT, Popper H. Vita min A containing lipocytes and formation of type ill collagen in liver injury. Proc Nad Acad Sei USA 1976;73:3719-22. * Blcndis LM, Smith PM. Laurie BW, Stephens MR, Evans WD. Portal hypertension in vinyl chloride monomer workers. A hemodynamic study. Gastroenterology 1978;75:206-11. " Williams DMJ, Smith PM. Taylor KJW, Crossley IR. Duck BW. Monitoring liver disorders in vinyl chloride monomer workers using greyscale ultrasonography. Br J tnd Med I976;33:1527.