Document MMB1NMOo532Oebxdwar1MbrYM
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 or 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 accountant 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.
Conctr 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. who worked on the
premises
Its of
foaccctourrrieesncheainndalinpgatientpf2o6hl,oloswp19eh7ad8m, aidtwehw, eenAekdhlryeiaminwtyaecsrivnaa,ldsmanaitsdteadmn etoothuottpthraeetxieaUntent .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: 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 Clinics 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 cystogram showed a lesion in the lateral wall of the urinary bladder 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 cell'count 2250, platelet count 67,000, total scrum protein 6.2 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; scrum glutamic oxalacetic transaminase 166 U; serum sodium 140, and potassium 3.6 mEq/litcr. 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 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 five months earlier (August 1977). The material was 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
with a questionable area of decreased uptake in the porta hepatis. The spleen was enlarged to twice the normal size.
In the hospital, the patient's condition deteriorated 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
he worked in a Plastic Tapes Factory in New York 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-Mnaymneh, MD, Depart ment of Pathology. University of Miami School of Medicine, 1611 N.W, 12th Avenue, Miami, FL 33136.
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.
000R-343X/81/0315/1318 S0.85 American Cancer Society
1318
SL 041400
No. 6 '
Angiosarcoma of Penis Ghmidur-Mnaymuch mid 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,
*625).
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 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 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 glial response.
Review of the cheek and the bladder biopsies showed an angiosarcoma similar in all respects to that present in the other organs. f'
Fig. 6. Microscopic appearance of liver. The fibrous septae have completely disrupted
the lobular architecture. The fatty change in the
hepatocytes and pseudoductular proliferation is not apparent at this magnification |H & E, x J50).
SL 041401
1322
Cancer March 15 1981
Vol. 47
Discussion
With the history of vinyl chloride exposure, the presence of a 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 findings leave no doubt that the primary tumor was in the corpus cavernosum 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 until 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 197130 and later confirmed on a larger scale by Maltoni 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 Johnson* 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 powdcrform, 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.1*'11 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 t xic VC gas into the inert PVC resin, the impressi n 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 t 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 t 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.*4 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 non polymerization factory.11 Schweitzer*4 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.*0 Data by Creech and Makk* 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: (l) PVC production, representing the highest exposure; (2) other areas of production; (3) main tenance personnel for PVC production; (4) all other maintenance employees; (5) all other employees, in cluding administration, plant protection, secretarial
SL 041402
So. 6
Angiosarcoma of Penis Ghandur-Xfnaynmeh 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 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 el al.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.13'18 In a hypothetical discussion of the relationship of carcinogen to frequency of induction of cancer, Peto11 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.Radlike et al.11 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 Thomas31 and othe^s,,1S233,, 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,33 were absent in the liver but similar changes were observed in the corpus cavcrnosum,
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 DIB, 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 al. Angiosarcoma of the liven 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 Sci 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, Bechtelsheimer H. Morphology of liver damage among polyvinyl chloride production workers. A report on 51 cases. Ann NY Acad Sci 1975; 246:278-285.
10. Hefner RE Jr, Watanabe PG, Gehring PG. Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sci 1975; 246:135-149. (Discussion by Oster. p. 149)
11. Jaeger 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. Kcplinger ML, Goode JW, Gordan DE, Calandra JC. Interim results of exposure of rats, 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, Lcfcmine G. Carcinogenicity bioassay of vinyl chloride: Current results. Ann NY Acad Sci 1975: 246:195-218.
17. Marstcller HJ, Lelbach WK, Muller R, Gcdigk P. Unusual splenomcgalic liver disease as evidenced by peritoneoscopy and
SL