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- %' Angiosarcoma of the Penis with Hepatic Angiomas in a Patient with Low Vinyl Chloride Exposure LAT1FA 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 jworked in a polyvinyl chloride factory as an accountant Jox-len ygars. The relationship of this lo'w~viny! 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 bejwimary in the A lesion. About 32 cases have been reported up liyef and he was Treated with'a' combination of cyclo until the who worked present.Its on the premises of foaccctourrireesncheainndalinpgatientpf2o6hl,olosw1p9eh7ad8m, aidtwehw, eenAekdhlryeiaminwtyaecsrivnaa,ldsmanaitsdteadmn etoothuottphtraeetxieaUntent .ivuenHrtseilityMwaaoysf 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 were multiple nodules Clinical History: PL. (NCCH#96929} at the base of the penis. Laboratory data showed the following: hematocrit 31%, white blood cell count 2250, The patient was a 61-year-old man who was initially seen platelet count 67,000, total serum protein 6.2 g/ml (albumin in the private clinics of the University of Miami Hospitals 1.6 g, globulins 4.6 g); total bilirubin 4.2, blood urea and Clinics in December 1977. At that time he presented nitrogen 10, calcium 7.4, phosphorus 3.5, uric acid 2.5, with generalized weakness and gross hematuria. The only positive finding on physical examination was a hard lxl cm nodule on the shaft of the penis said not to have 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 mEq/liter. been present previously. Laboratory data showed no ab Urinalysis showed 2-9 white cells/HPF. Bone and brain normality except for an elevated alkaline phosphatase. A scans with Technetium 99 m MPD did not show any areas of cystogram showed a lesion in the lateral wall of the urinary bladder and a liver scan showed a filling defect in increased radionuclide concentration to suggest metastatic disease. Liver scan following the intravenous injection the right lobe. The patient underwent a cytoscopy and of technetium sulfur colloid showed a normal-sized liver biopsy of the bladder, which showed an angiosarcoma infiltrating muscularis. Past medical history was negative except for the removal of a bluish nodule from the cheek with a questionable area of decreased uptake in the porta hepatis. The spleen was enlarged to twice the normal size. five months earlier (August 1977). The material was 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/100 ml. The 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-Mnaymreh, MD. Depart ment of Pathology, University of Miami School of Medicine, 1611 N.W. 12th Avenue. Miami, FL33I36. Accepted for publication March 25. 1980. Autopsy Findings Cross: 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. OO0S-S43X/81/0315/I3I8 S0.B5 C American Cancer Society 1318 URL 15688 i No. 6 Angiosarcoma of Penis Ghandur-Mnaymneh and Gonzalez 1319 The Jungs were heavy, weighing 1020 (right) and 950 (left) g. On cut section, both exhibited multiple 2-3cm reddish ill-defined foci of induration and 0.5-1 cm simitar 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 about 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. i). 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. Fig. 1. Cut surface of the right lobe of the liver with the bamargiomata. Both lesions exhibit e spongy or honey-combed surface. The larger one has a central more solid grayish area. The intervening tissue appears fibrolic. 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 Ihe penis showing the markedly enlarged right corp4 cavemosum, the foci ofinvolvement with dark and white discoloration of the left corpus, and ihc compression of the urethra by the surrounding grayish tumor. S'o. 6 Angiosarcoma of Penis Ghtmdur-Mnaymnch 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 fiat endothelial cells with inconspicuous nuclei. Anaplastic cells with vesicular nuclei and prominent nu cleoli are present within two sinusoids mixed with red blood cells (H A E, x625>. URL 15690 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 perisinusoidat fibrosis. There was no endothelial cell atypicality. Most of the central arteries were, almost naked 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 withtn 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 glial response. Review of the cheek '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 septae have completely disrupted the lobular architecture. The fatty change in the hepatocyles and pseudoduetular proliferation is not apparent at this magnification (H & E. x J50). V 132? Cancer March 15 1981 Vol. 47 Discussion With the history of vinyl chloride exposure, the presence of & filling defect in the liver and the histologic diagnosis of angiosarcoma in cheek and bladder biopsies, it stands to reason that the primary tumor was assumed to be in the liver. The gross and microscopic autopsy JindingsJeave_nQ doubt that, the primary tumor was-in the corpus cavemosum -penis: the lining endothelial cells of the residual cavernous spaces showed premalignant changes and an in situ angiosarcoma progressing into an invasive sarcoma in and around that structure. The tumor in the bladder biopsy represents a direct extension and that in the cheek a metastasis. The primary tumor, evident locally as a nodule on the penis, was not noted by the patient untQ after it had produced metastases and was associated with priapism and dysuria. The tumor had infiltrated locally extensively and. metastasized mainly to the lungs. In the liver, metastatic angio sarcoma was found only within the hemangiomas with sparing of the remaining cirrhotic liver. The brain lesion was grossly thought to be metastatic. Although microscopic sections showed only a hematoma with no tumor cells, it is believed to represent a metastatic focus with hemorrhage. Could the angiosarcoma of the penis be related to vinyl chloride? Was the exposure of sufficient magni tude to have been significant etiologically? To elucidate these points one has to review briefly some of the pertinent data related to VC car cinogenesis. The carcinogenic effects of VC were first recognized in experimental animals in 1971s0 and later confirmed on a larger scale by Malloni and Lefemine.1* These authors noted that animals exposed to VC gas de veloped a variety of tumors, including sebaceous gland carcinomas, hepatic and extrahepatic angiosarcomas, angiomas, fibromas, neuroblastomas, lung adenomas, and hepatic and mammary carcinomas. The extrahepatic angiosarcomas developed in kidney, sub cutaneous tissue, lips, lung, uterus, and intra-abdominally diffusely. The angiomas occurred in the liver, cecum, heart, subcutaneous tissue, and in the peritoneum. In 1974, Creech and Johnson4 described the first case of angiosarcoma of the liver in a worker exposed 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 cases.33 All seven instances occurred in employees of unit 62 where polyvinyl chloride (PVC) is produced from VC. This part of the plastics industry is referred to as PVC production or polymerization and it is the section with the highest concentration of VC. It is to be distinguished from PVC processing wherein the already manufactured PVC plastic, in powder form, is mixed with stabilizers, colors, and other materials and processed into the different shapes (sheets, tubings cables, etc.) and consistency (rigid or flexible) in which it will be used.14,17 Vinyl chloride is the toxic gas with the carcinogenic effect whereas PVC is the inert plastic end product. Because most of the hepatic angiosarcomas related to VC exposure were observed in workers involved with PVC production, i.e., in the stage of polymerization of the toxic VC gas into the inert PVC resin, the impression was that PVC processing entails no toxic or carcinogenic risks, inasmuch as this step involves handling of inert PVC and does not utilize VC gas. According to Marsteller et al. ,17 PVC processing is listed as harmless (er roneously) in many occupational bulletins and standard textbooks. However, during processing, the PVC is heated to temperatures of 100-300 C to give it the hardness and the shape required for the particular need. This results in the liberation of VC, trapped within the PVC during its polymerization, with escape of fumes, gases, and smoke into the surrounding atmosphere.14,17 Prior to 1974 the trapped VC mono mer in the PVC averaged about 500-1000 ppm, sometimes reaching 7000 ppm." The presence of the characteristic sweet odor of VC in such areas indicates a high atmospheric concentration. This characteristic odor is also noted in closed storage areas of PVC sheets.10 Measurements made by Jaeger in factories in the Boston area detected 1/2-1 ppm of VC in a nonpolymerization factory.11 Schweitzer" noted a con centration of 1 -2 ppm in air outside the B.F. Goodrich Plant in Louisville, Kentucky. 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 were not involved in PVC production, but were maintenance employees." Data by Creech and Makks indicate that minimal exposures are associated with significant biochemical changes. These authors divided the workers in a PVC production plant into five categories representing decreasing areas of exposure to VC: (I) PVC production, representing the highest exposure; (2) other areas of production; (3) main tenance personnel for PVC production; (4) all other maintenance employees; (5) at! other employees, in cluding administration, plant protection, secretarial URL 15692 < i S. No. 6 Angiosarcoma of Penis Ghandur-Mnaymneh and Gonzalez 1323 URL 15693 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-I2 profiles, with elevation of alkaline phosphatase, total bilirubin, and serum glutamic oxalacetic transaminase. This indicated that workers far removed from the VC-PVC 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 et cl.* 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.13,16 In a hypothetical discussion of the relationship of carcinogen to frequency of induction of cancer, Peto31 showed that lowering the dose decreases the number of induced cases but does not eliminate the risk altogether. Nicholson13 states that two cases of angiosarcoma of the liver have occurred in nonproduction 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.10,n,s#Jt Radlike ct 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 Thomas*3 and othersw,ls,I3,!R 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,*3 were absent in the liver but similar changes were observed in the corpus cavemosum. suggesting that these could be the result of VC effect. The lymphoid hyperplasia in the spleen described in VC-exposed individuals33 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 tumorigenesis 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 I960; 83:160-162. 3. Brady J, Liberatore F, Harper P et al. Angiosarcoma of the liver. An epidemiologic survey. J Natl Cancer Inst 1977; 59: 1383-1385. 4. Creech JL Jr, Johnson MN. Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Occup 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, Monsemi JU, Gonulcz-Manin G. Hemangio* sarcoma del pene. Rev Argent Urol 1968; 37:7-9. 9. Gedik P, Muller R, Bechtelsheimer H. Morphology of hver damage among polyvinyl chloride production workers. A report on 51 cases. Ann NY Acad Sci 1975; 246:278-283. 10. Hefner RE Jr, Watanabe PG.GehringPG. Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sd 1975; 246:135-149. (Discussion by Oster, p. 149) 11. Jaegei RJ. Vinyl chloride monomer: Comments on its hepatotoxicity and interaction with 1-Dichlorethylene. Ann NY Acad Sci 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. Keplinger ML, Goode JW, Gordan DE, Calandra JC. Interim results of exposure of rats, hamsters and mice to vinyl chloride. Ann NY Acad Sd 1975; 246:219-224. J4. Lange CE. Juhe GS, Vehman G. Further results in polyvinyl chloride production workers. Ann NY Acad Sd 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, Lcfemine G. Carcinogenicity bioassay of vinyl chloride: Current results. Ann NY Acad Sci 1975: 246:193-218. 17. Marsteller HJ. Lelbach WK, Muller R, Gedigk P. Unusual splenomcgalic liver disease as evidenced by peritoneoscopy and