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British Journal of Industrial Medicine 1990;4? ^ l ft- J I. ~J J- vw Cutaneous haemangioendothelioma: a possible link with chronic exposure o vinyl chloride r k- Michaela F P Davies, M Curtis, J M T H >wat \jr^" Abstract A patient who worked with polyvinyl chldride developed a malignant haemangioendot lelioma of a toe. This rare tumour is more t ommonly found in the liver where it has >een reported to arise in association with expo sure to the vinyl chloride monomer. Malignant haemangioendothelioma, or angiosar coma, is a rare tumour of vascular endothelium. It may arise m any tissue but has been reported nost commonly in muscle, bone, breast, and livr Cutaneous forms, first described by Wilson-Jo ies,! may arise in the scalp and face of elderly pauen Both previous trauma and radiotherapy have been implicated in their aetiology.:,s The histoloj;ical features are identical with those of the postmas tec tomy angiosarcoma (Stewart-Treves syndrome) hat may occur in a chronically oedematous arm ; fter mastectomy and radiotherapy.'" Our patent developed a cutaneous haemangioendothelioma a fter working for many years with polyvinyl chlo ide (PVC); the monomeric form of which, VCM, has been incriminated in the development of simjib tumours found in the liver." ' Case report A 55 year old man presented with a three mohth history of an ulcerating lesion affecting the nail bee; of his third left toe. This had not responded to sun ale dressings and antifungal agents. He had worked the plastics industry for many years first as a we! b and then for 28 years as a moulder of polyvi lyl chloride. His medical history was unremarkal lc, although two years previously he had developed a rash, thought to be psoriasis, which had spontt neously resolved. He had been a heavy drinker in the past and still consumed 20-30 pints of beer a weel .. Examination of his toe showed the nail bed to be split by a raised moist lesion (fig 1). There was 10 inguinal lvmphadenopathy and no hepatomegaly. Radiographic examination of the toe was unremark able and, with the exception of a mild rise in the hepatic enzymes, both haematological and bio chemical results were normal, as was ultrasonic examination of the liver. The lesion was biopsied under local anaesthesia. Histological examination showed a malignant haemangioendothelioma with plump cells in a loose connective tissue stroma. In some places they were in clumps; in others they formed capillary sized channels with open lumina. There was pronounced cellular pleomorphism and many bizarre mitotic figures. Reticulin fibres were seen frequently around the cells (figs 2 and 3) and many of the cells were stained positively with factor VIII related antigen with stiver enhancement and with a special lectin stain ,UEA-1), a feature typical of tumours arising from vascular endothelium."" Amputation was carried out through the metacarpo phalangeal iomt. Twelve months later there was no evidence of local or distant recurrence. Discussion Malignant haemangioendothelioma or angiosar coma, although uncommon, may arise after exposure to certain chemical agents--for example, arsenic and thorium dioxide.10 More recently a link has been well established between haemangioendothelioma of the liver and the production of polyvinyl chloride (PVC), Department of Surgery, North Manchester GenekaJ Hospital, Manchester MS 6RB Michaela F P Davies, J M T Howat Department of Pathology, North Manchester Hos pital. Manchester M8 6RB M Curtis Figure 1 Tumour at presentation. . o'-j lb" SPI-01320 (Jutaneous naemangioendotheuoma. d possible imn :vitn cnr,nic exposure to fnv/ chlorxdt 6? that molecules from both VCM and. perhaps mote important, its metabolites, appear m the skin of ra s within hours of inhalation of `C-labetled VCM,1' " and epidermoid carcinomas have been described n the facial areas of rats experimentally exposed to vinyl chloride. 1 : There seems no doubt that some elements of the skin are susceptible to the oncogen: c effects of VCM although, with the exception of live r malignancies, no increase in the incidence of deaths from cancers has been observed in man in associatio i with exposure to VCM.1" To date, cases of haemangioendotheiioma hav; been identified exclusively in workers engaged in th; process of polymerising VCM to PVC but not 1 1 those exposed only to the finished polymer or processing it into plastic products. Although hig i levels are required, exposure need not be contin uous.-' " Those who clean the pressure vessels use 1 to polvmerise vinyl chloride at high temperatures seem particularly at risk but hepatic tumours ma also occur in production workers and others engage I in the industry." During the manufacture of PVC some of the VCM remains absorbed on the finished polymer at a concentration of 0 005",. or higher.1"'' Release of small amounts of monomer may sub sequently occur during handling and processin ; finished articles from raw PVC. The significance of this small exposure is uncertain. "11 Our patient had direct contact with PVC over many years and in moulding or welding PVC at high temperatures i: seems likely that small quantities of the monome may be released, although for practical purposes it i , considered to be infinitesimally small and to b: undetectable (B Bennett, personal communication;. The possibility that the lesion on the toe was : cutaneous metastasis from a primary hepatic tumou is excluded by the normal ultrasound of the liver anc the continuing good health of the patient. Thi biochemical evidence of mild hepatic dvsfunctior probably reflects excessive alcohol consumptior rather than exposure to VCM." That the tumour ir the present case was a subungual amelanotic malig nant melanoma is excluded by the positive stainms by specific histochemical markers for tumours o vascular endothelium. It is of interest, however, tha Heldass et ai raised the possibility that a causa relation might exist between exposure to VCM anc the development of cutaneous malignant melan oma.This association has not been confirmed by more recent studies.1" The relation of PVC manufacture to hepatic angiosarcoma was only firmly established in 197-1 and the tumour is known to have a long latency (2030 years:. More cases may be expected to arise over the next three decades despite changes in legislation to ensure that workers are exposed to lower levels of VCM."1" If the cutaneous angiosarcoma in the present case has occurred as a result of exposure to VCM then similar lesions may be encountered in the future. VC'e are most grateful for the advice and guidance given by Dr Brian Bennett of 1CI Chemicals and Polymers Ltd during the preparation of this manuscript. 1 Silva LG. Capttao-Mor MM. Angioendothclioma mahgno . ,-Lru .Vft'i I'.'ri 1981.3 51-0 2 Mehregan AH. L'sndek HE Malignant angioendothelioma. Arch Demaiot 1976.112.1565-" 3 Wiison-jones E. Malignant angioendotneuoma of the skin. Br J Dermatol 1964.76.21-3 4 Holden AC. Spittle MF. Wilson* Jones E. .Angiosarcomas of the lace and scalp; prognosis and treatment, cancer 1987.591 046--5 i 5 Hon Y Malignant naemangioendothelioma of the skin. J Dermal ot Pure Uncol 1981." I 3d--0 6 Girard C. Johnson WC. Granam JH Cutaneous angiosarcoma Cancer 1970.26:868-8 3 7 Stewart FW, Treves N Lvmphangiosarcoma in postmastectomv limps. Cancer l48;l'0+-6l 3 Forman D. Bennett B. Stafford J. Doll R. Exposure to vinvl chloride and angiosarcoma ot the liver; a report of the register of cases. Br J Ind Med 1985.42.750-3. 9 Sugita M. Masuda Y. Tsucniva K Earlv detection and signs of hepatoangiosarcoma among vinvl chloride workers. Am J Ind Med 1986.10 411-" M) Popper H. Thomas LB. Tcilev NG. Falk H. SeiikofT IJ Develop ment ot hepatic jngiosurcoma in man induced bv vin \ I chloride, ihorotrust anu arsenic: comparison wiin cases ot unknown aetioloev Am j /\jr>u>M978.92:344-7o 11 Creech JL, Johnson MN. Angiosarcoma of the liver m the manufacture ot polvvmvl chloride. J Occup .Wed 1974;3. 150-1 12 Dannaher CL, Tamburro CH. Yam LT. Occupational carcino genesis: the Louisville experience with vinvl chloride associated hepatic angiosarcoma. Am J Med 1981;70:279-87. 13 Harris DK. Adams WGF. Acro-osteolvsis in men engaged m the polymerisation of vinvl chloride. Br Med J 1967;iii:712--4. 14 Wilson RH, McCormick WE, Tatum CE. Creech JL. Occupational acro-osteolysis. JAMA 1967;201:83-7 15 Watanabe PG, McGowan GR. Madrid EO, Gehnng PJ. Faie of l*Ovinyl chloride following inhalauonai exposure m rats. Toxicol Appl Pharmacol 1976;37:49-59. 16 Duprat P. Fabry JP, Gradiski D. Magadur JL. Metabolic approach to industrial poisoning: blood kinetics and distnbu* tion of MC-vinvl chloride monomer VCM,. Acta Pharmacol Toxicol 1977.41. suppl 1:142-5 17 Viola PL. Bigotti A. Caputo A Oncogenic response of rat skin. lungs and bones to vinvl chloride. Cancer Research 1971, 31:516--9 18 Jones RD. Smith DM. Thomas PG. A mortality studv of vinvl chloride monomer workers employed in the United Kingdom in 1940-1974. Pcand J Work Environ Health 1988;14:153-60. 19 Barnes AW Vinvl chloride and the production of PVC. Proceeatngs or the Roval Societv of Medicine 1976;69:277-81. 20 Heldass SS. Langard SL, .Andersen A. Incidence of cancer among vinvl chloride and polvvmvl chloride workers. Br J Ind Med 1984;41:25-30. 21 Baxter PJ. Epidemiological studies of PVC manufacturers and fabricators and pnmarv angiosarcoma of the liver Proceedings of the Roval Societv of Medicine 1976:69:297-9 22 Duck BW Medical surveillence of vinvl chloride workers. Proceedings ot the Roval Sovieti ot Medicine 1976;69:307-9 Accepted 3 April 1989 SPI-01321 ^. . c--f ;.r ?*i*t**> u:o : 9 .cc- <;' a o*..* tic..- 'Oi _ S.** CwOu"m' **A C -A^tS Sn34. * 3CNN1 ** t tdAO .t -tus 3 :A 3 TA^AftJ* law offices Kell E R A X D HeCK.M A N !*0 1 7'- STREET. N v\ sint i-juo SHINOTON. D C 2003* (202) e - s e o o Received JUL 1 4 1986 DR. R. T. GOTTESMAN S'-I** r : s*rr ( . 3 .f ' oooct*. 't-C* *9 9 S 9 TtttCO*iC* i*o' (* CAS_C AODCiS ((.uao * *CS O CC* => A. (202) 956-564 a u j. \ y , Dr. Michael M. O'Mara BFGoodrich Research Cen ner 9921 Brecksville Road Brecksville, Ohio 44141 Re: JECFA Eval Uation of Vinyl Ohio ide and DEHP Dear Mike: As you may be av are, the Food an d Agricultural Organization (FAO) and Wo rid Health Orga nization (WHO) of the United Nations op erates a group k r.own as the Joint FAO/WHO Expert Con mittee on Food A dditives (JECFA), This committee evaluate food additives and, while its decisions have no bindin g legal effect, it is quite influential in the Unite States and aro ur.d the world. JECFA recommendations a re used by other UN groups such as the Codex Committee on Food Additives (CCFA) and the joint FAO/WHO Codex Al irrus . cmm: -- O'"! 3 S 2 hhci_c for decisions on the saf sty of substance s that are added to or contact food. I recently becam s aware of the enclosed toxicological evaluations of Lnyl chloride and bis(2-ethvlhexyl) phthaiate (DEHP). Altho igh these evaluations are about two years old, I understand :hat they represent JECFA's current view. I thought that yo might appreciate having a copy of this material to add to /our data base. I have also included the introduction and in 0!X in the event you are interested in anv other oortions of the Dubl icatior.. SPI-01322