in Envronmnental edicine

* ANKARA UNIVERSITY, MEDICAL SCHOOL, ANDYW ANKARA NUMUNE HOSPITAL

Arsenic-Related Bowen's Disease, Palmar Keratosis, and Skin CancerMeltem Q6/,1 Cavit p 2 Atilla Soran,2 Bekir S. Sayli and Selma Ozturk41Department of Public Health, Ankara University Medical School, Ankara, Turkey; 2Department of General Surgery, Ankara NumuneHospital, Ankara, Turkey; 3Department of Genetics, Ankara University Medical School, Ankara, Turkey; 4Department of Family Medicine,Ankara Numune Hospital, Ankara, Turkey

Chronic arsenical intoxication can still be found in environmental and industrial settings.Symptoms of chronic arenic intoxication indude general pigmentation or focal raindrop' pig-mentation of the slin and the ap ce ofheeratois of the palms of the hands and soles ofthe feet. In addition to arenic-relted skin disea including keratosi, Bowen's dies, basal-cell-carcinoma, and squamous-cell carcinoma, there is also an incese risk of some internalmalignancies. Arsenic-related diseases are common in areas of the world where the ddnking waterhas a high arsenic content. In this paper, we describe a 35-year-old male patient who had arsenic-related keratosis, squamouscl arcoma in the palmararea of.his left hand, and Bowen's dis-ease on his left thigh. The patient worked in a borax mine for 15 years, so he was exod toarsenic in drinking water, airborne arsenic in his workplace, and had direct contact. The patientwas treated for 11 months for asic-related keratosis until an azilay lymph node metastasisoccurred; the lesion was excised and diagnosed to bem nt Bowen's disease wa detectedwhen the patient was being treated for cancer. No other malignancy was found. The patient isst receiving regula follow-up care. Key awon&arseic, Bowen's disease, katosis, skin cancer.Environ Heacb Pmpect 107:687-689 (1999). [Online 6 July 1999]bhXp:/fJ cpnet dniXebs.nik doseI199 7p687-6 o*baacot/d£E;t7nml

Case PresentationA 35-year-old male patient with a hyperkera-totic lesion on the palm of his left hand wasadmitted to the SSK Ktitahya Hospital 5years ago. The patient had a history offatigue, weakness, and weight loss, but nocomplaints related to the gastrointestinaltract or other systems.

The lesion, located in the palmar area ofhis left hand, was diagnosed to be arsenic-related keratosis (Figure 1), and treatmentwith topical medications was initiated.

The patient had been working as a col-manit and arsenic mine cleaner and separa-tor in the Emet-Hisarcik borax mine for 15years, where he received intense borax andarsenic exposure. This borax mine is locatedin the western part of Turkey and is ownedby the government. There is a high arseniccontent in the product of the mine-cole-manit. Workers are required to wear gloves,but this patient did not wear gloves and didnot use a mask to prevent arsenic exposurebecause of his inadequate knowledge.

The patient was shifted to another posi-tion at work to prevent further direct expo-sure to arsenic. However, because he lived inthe same region, his exposure to arsenic con-tinued. There was still a high level of arsenicboth in the workplace and in home tap water.

One year after the initial diagnosis, leftaxillary lymphadenopathy was found, and abiopsy of the left axillary lymph node wasperformed in The Ankara University fbn-iSina Hospital. Histopathologic examinationrevealed metastasis of a squamous-cell carci-noma (SCC) to the lymph node. The palmarlesion was biopsied again, with the primaryfocus on axillary malignant disease, but nomalignancy was found. A left axillary lym-phadenectomy was performed afterward,and all lymph nodes were free of malignan-cy. A combination of chemotherapy withcysplatin and 5-fluorouracil (5-FU) andradiotherapy (total dose of 6,000 cGy) wasthen administered to the patient. At the 6-month follow-up, the patient was diagnosedwith a new hyperkeratotic lesion on his leftthigh, which had been present for 5 months(Figure 2). The patient was then seen by theEpidemiology Study Group of AnkaraUniversity, School of Medicine, who were inthe area to perform epidemiologic screening.The patient was evaluated regarding acuteand chronic arsenic intoxication.

The patient had weakness and fatigue,and had lost 5 kg of body weight over theprevious 2 years, but he had no gastro-intestinal complaints (nausea, vomiting, ordiarrhea). Computed tomography and

ultrasonography of the abdomen were nor-mal. No pathological findings were revealedby neurological examination or electromyog-raphy of the patient. Additionally, no abnor-malities were found in urinary examinationor cystoscopy. The results of the laboratorytests are presented in Table 1.

Multiple biopsies were made from thelesions on the palm and the thigh. The pal-mar lesion was determined to be arsenic-related keratosis, whereas the lesion on thethigh was found to be pagetoid Bowen's dis-ease. We performed a systemic search forinternal malignancy using physical, hemato-logical, biochemical, and radiological tests.

We excised all lesions, including a mar-gin of 2 cm of normal skin. The woundswere closed with full-thickness skin grafts.Findings of the histopathologic examinationof the palmar lesion included large andhyperchromatic nucleated epithelial cellswith atypical mitosis and evident nucleoli,tumor cells with globes, and spindle nucle-oli. The basal membrane was intact, in gen-eral, but a focal invasion was noted. Thepalmar lesion was determined to be a well-differentiated (spindle-cell) SCC, whereas thelesions on the thigh were accepted to beBowen's disease with high grade dysplasia.There were no complications in the postoper-ative period, and the patient was discharged.He was monitored in the first month after thesurgery and no abnormality was found.

DiscussionArsenic is a metal used extensively in themaking of glass, alloys, coloring agents, insec-ticides, and fungicides. Currently, arsenic isemployed in metallurgy, agriculture, animalhusbandry, and forestry; it is widely distrib-uted in nature, being mainly transported bywater in the environment. The industrial

Address correspondence to M. 4:61, DikmenCaddesi No:188/14, Dikmen, Ankara, Turkey.Telephone: 90 312 4824407. Fax: 90 3124192120. E-mail: cavitcol@anh.gov.trReceived 17 December 1998; accepted 10 May

1999.

Environmental Health Perspectives * Volume 107, Number 8, August 1999

m

687

Grand Rounds in Environmental Medicine * Col et al.

applications of arsenic account for the major-ity of use of inorganic and organic arseniccompounds. In an occupational setting, therespiratory tract provides the most commonportal of entry for arsenic. Skin and gastroin-testinal pathways are also possible (1).

Our patient was exposed to arsenicexposure by ingestion (drinking water, andfoods) and by direct contact with colemanit.The drinking water in the area where thepatient lived and worked contained 405,ug/L arsenic, with a range of 45-1,210pg/L. Colemanit (2CaO * 3B203 * 5H2O),the mineral that the patient continuouslyhandled for 15 years, contained 50.9%B20, 21.9% H2O, 27.2% CaO, and 1,000ppm (1 g/kg) arsenic. Fifteen years of higharsenic exposure at work may have causedarsenic-related skin cancer.

The current standard of the U.S.Environmental Protection Agency (U.S.EPA) for inorganic arsenic in drinkingwater is 50 ppb (micrograms per liter);the Occupational Safety and HealthAdministration (OSHA) established a maxi-mum permissible exposure limit (PEL) forworkplace airborne arsenic: 10 pg/m3 (1).Current U.S. EPA risk analyses predict thatbeyond the concentration of 50 ppb arsenicin drinking water, lifetime skin cancer riskwould increase by 3 or 4 per 1,000 (2).

Arsenic poisoning is usually the result ofaccidental or homicidal ingestion of insecti-cides or rodenticides containing copper ace-toarsenate, calcium arsenate, or lead arsenate.Arsenic trioxide, the most dangerous form ofarsenic, is still used in chemistry laboratoriesand a few industries. This is a soluble powderwith an acute lethal dose in humans of60-120 mg (3). Arsenic reacts with thesulfhydryl groups in certain tissue proteinsand thus interferes with a number of enzymesystems essential to cellular metabolism.

Pathologic changes in fatal inorganic arsenicalpoisoning are fatty degeneration of the liver,hyperemia and intestinal hemorrhages, andrenal tubuler necrosis. The peripheral nervesoften show fragmentation and resorption ofmyelin, with disintegration of axis cylinders.Gastrointestinal symptoms develop after acuteingestion, followed by a mixed motor andsensory neuropathy after 2-3 weeks. Tendonreflexes are absent or diminished, and atrophyof affected muscles develops rapidly. Thepatients who present with arsenic poisoningdo not have neurological complaints or find-ings. The symptoms of acute poisoning byoral exposure are vomiting, diarrhea, weak-ness, prostration, and weight loss (4). Patientswho recover from acute poisoning and thosewith chronic intoxication usually develop skinand mucosal changes, peripheral neurologicalsymptoms, and typical pigmentations in thenails. The cutaneous manifestations appearwithin 1-4 weeks and consist of a diffuse, dry,scaly desquamation, occasionally with hyper-pigmentation, over the trunk and extremities.Hyperkeratoses of the soles of the feet andedema of the face and extremities may alsooccur. The mucous membranes also showevidence of irritation, for example, conjunc-tivitis, photophobia, pharyngitis, or irritatingcough. About 5 weeks afterexposure to arsenic, a trans-verse white stria, 1-2 mm inwidth, appears above thelunula of each fingernail(Mees lines). Our patient I'had a hyperkeratotic lesionin the palmar area of hisleft hand.

Symptoms of headache,drowsiness, confusion, andconvulsions are seen in both -acute and chronic intoxica-tion. The extremities show a

decrease in sensitivity to touch, pain, andtemperature sensation, with a symmetrical"stocking-glove" distribution; distal weak-ness of grip; and wrist drop.

Our patient suffered from weakness,fatigue, and loss of weight, but he had nogastrointestinal complaints. Computedtomography and ultrasonography of theabdomen were normal.

The laboratory findings of acute arsenicpoisoning usually consist of moderate ane-mia and a leukopenia of 2,000-5,000 whiteblood cells with mild eosinophilia. There isslight proteinuria, and liver function testsshow mild abnormalities. Our patient didnot have leukopenia, eosinophilia. or pro-teinuria, and his liver function tests werenormal. In urinary examination and cys-toscopy, no abnormalities were found. Noneof the clinical or laboratory manifestations ofarsenic poisoning are specific, and the diag-nosis depends on analysis of the hair andurine for arsenic. A normal person has anaverage concentration of 0.05 mg arsenic per100 mg hair, with a range of 0.025-0.088mg. Concentrations of arsenic > 0.1 mg/100mg hair indicate arsenic poisoning.

Because we do not have the facilities toanalyze the samples in our laboratories, we

Figure 1. Arsenic related skin cancer on the palmar area of the left hand. Figure 2. Bowen's disease on the left thigh.

Volume 07, Number 8, August 999 * Environmental Health Perspectives688

Grand Rounds in Environmental Medicine * Arsenic-related Bowen's disease

were unable to determine the arsenic levelsin serum, tissue, and urine.

It is difficult to establish the minimallevel of arsenic in urine indicating intoxica-tion. Normal persons have been found toexcrete between 0.01 and 0.06 mg arsenic/Lof urine. Collection of urine for arsenicanalysis should be performed after abstain-ing from eating seafood, which containsarsenobentaine (which is relatively harm-less). Although there is considerable overlap,most patients with evidence of arsenicintoxication excrete > 0.1 mg/L; soon afteracute exposure, many show concentrations> 1 mg/L (4).

The relationship of arsenic ingestion topalmar and plantar keratoses and to skin can-cer has been documented in studies involvingwide-scale exposure to known sources ofarsenic (5-8). The strongest epidemiologicevidence on the effects of arsenic on the skinwas reported in a Taiwanese study performedin an area with high arsenic concentrations inwell water (5,6). Jaafar et al. (i) reported threecases of skin cancer caused by arsenic poison-ing in patients who had lived near tin minesin Malaysia. In Slovakia, skin cancers werereported to be common in areas polluted witharsenic (8). Arsenic-related Bowen's diseasehas predominantly been found in agriculturalworkers who use arsenical powders in cropdusting and wine growing (). Malignant andpremalignant skin lesions have been reportedamong paraquat manufacturing workers(10,11). Studies have demonstrated a signifi-cant dose-response relationship with theduration of exposure (11,12).

Inorganic arsenic is a carcinogenic agentfor the respiratory system, skin, liver, andbladder. In epidemiologic studies in differentcountries, a positive association betweenarsenic and the prevalence of skin cancer hasbeen reported (7,8,13).

Table 1. Laboratory findings.

Test ResultHemoglobin 14.2 g/dLHematocrit 40.8%Erythrocyte sedimentation rate 40 mm/hrWhite blood cell count 4.5 x 103Platelet count 218 x 103Glucose 111 mg/dLBlood urea nitrogen 20 mg/dLCreatinine 1.4 mg/dLUric acid 10 mg/dLCalcium 10.3 mg/dLInorganic phosphorus 5 mg/dLAlbumin 4 g/dLTotal bilirubin 0.7 mg/dLAspartate amino transferase 29 U/LAlanine amino transferase 39 U/LLactic dehydrogenase 180 U/LAlkaline phosphatase 245 U/LCarsino embriogenic antigene 2.7 ng/mLCA 15-3 23.6 U/mL

Inorganic arsenic compounds in drink-ing water, exposure in the workplace, anddrug therapy with inorganic arsenicals havebeen causally related to the development ofskin cancer. Smelter employees and otherworkers exposed to arsenic trioxide havebeen shown to have a gready increased riskof lung cancer (3). Increased mortality frombronchial carcinoma has been found inchemical workers in the production of inor-ganic arsenicals. Exposure in the past hasbeen heavy and has been predominantly toarsenic trioxide; in smelter workers, exposurepatterns are mixed, and other suspected car-cinogens are frequently present. Data fromother than occupational sources support thecarcinogenic role of arsenic for lung cancer,bladder cancer, and liver angiosarcoma (14).

The site of lesions was also typical forarsenic-related skin cancer. Arsenic exposureis a well-known cause of skin cancer, but forthis case, we believe that chronic and directcontact of arsenic with the skin at the site oflesion should be overlooked.

Malignant transformation of arsenic-related keratosis is quite rare. In this case,either a malignant transformation ofarsenic-related keratosis or synchronous ini-tiation of both diseases may be possible.Bowen's disease is an intraepidermal SCC ofthe skin or mucous membrane that pursuesa slow and relatively benign course (hori-zontal or intraepidermal growth) over aperiod of years, but may progress to invasiveSCC (vertical growth). Arsenic, ultravioletlight (UV), radiation, psoralen, and pso-ralen plus UV light of A wavelength(PUVA) may have a role in the etiology ofBowen's disease (15-17). In Bowen's dis-ease, lesions may be found in areas of theskin and mucous membranes including thenailbeds, palms, and soles. Individual lesionsof Bowen's disease tend to persist for manyyears without progression to invasive carci-noma. If untreated, 5-15% will presentinvasion and/or metastasis. Statistical stud-ies do not support a relationship betweenBowen's disease and internal cancers (18).The relationships among arsenic exposure,punctuate keratoses, and internal malignan-cies are less documented, although highlysuggestive (19). Subsequent reports did notsupport that palmar and plantar keratosescould be markers of systemic cancer(20,21). In our patient, no primary focusfor internal malignancy was detected.

In conclusion, the presented case is animportant example of arsenic-related skin dis-ease. One should always be concerned aboutmalignancy in such cases. Although it is yetunproven, direct contact with arsenic may behazardous and should be avoided. Presenceof arsenic in the environment (water, food,etc.) should be closely monitored. For this

purpose, an epidemiologic study to deter-mine the effects of arsenic and borax onpublic and environmental health has beeninitiated by the Public Health Departmentof Ankara University Medical School inTurkey; Turkey is the greatest borax producerin the world after the United States.

REFERENCES AND NoTEs

1. Dickerson OB. Antimony, arsenic and their compounds.In: Occupational Medicine (Zenz C, ed). 3rd ed. St. Louis,MO:Mosby-Yearbook, Inc., 1996;466-473.

2. Brown KG, Guo HR, Kuo TL, Greene HL Skin cancer andinorganic arsenic: uncertainty-status of risk. Risk Anal17(1):37-42 (1997).

3. Goulding R. Arsenic, poisoning from chemicals. In:Oxford Textbook of Medicine, Vol 1. 2nd ed. Oxford:Oxford University Press, 1988;6,13-16.

4. Poskanzer DC, Bennett IL. Heavy metals. In: Harisson'sPrinciples of Internal Medicine. 7th ed. New York:McGraw-Hill, 1974;667-671.

5. Hsueh YM, Cheng GS, Wu MM, Yu HS, Kuo TL, Chen CJ.Multiple risk factors associated with arsenic-inducedskin cancer effect of chronic liver disease and malnutri-tional status. Br J Cancer 71(1):109-114(1995).

6. Hsueh YM, Chiou HY, Huang YL, Wu WL, Huang CC, YangMH, Lue LC, Chen GS, Chen CJ. Serum beta-carotenelevel, arsenic methylation capability, and incidence ofskin cancer. Cancer Epidemiol Biomarkers Prev6(8):589-596 (1997).

7. Jaafar R, Omar I, Jidon AJ, Wan-Khamizar BW, Siti-Aishah BM, Sharifah-Noor-Akmal SH. Skin cancercaused by chronic arsenical poisoning-a report ofthree cases. Med J Malays 48(1):86-92 (1993).

8. Plesko I, Vlasak V, Kramarova E, Obsitnikova A. The roleof the registry in the study of relation between cancerand environment experiences from Slovakia. Cent Eur JPublic Health 1(1):19-24 (1993).

9. Luchtrath H. The consequences of chronic arsenic poi-soning among Mosalle wine growers. Pathoanatomicalinvestigations of post-mortem examinations performedbetween 1960 and 1977. J Cancer Res Clin Oncol105:173-182 (1983).

10. Bowra GT, Duffield DP, Osborn AJ, Purchase IFH.Premalignant and neoplastic skin lesions associated withoccupational exposure to tarry products during manufac-ture of 4,4'-bipyridyl. Br J Ind Med 39:76-81 (1982).

11. Wang JD, Li WM, Hu FC, Hu KH. Occupational risk andthe development of premalignant skin lesions amongparaquat manufacturers. Br J Ind Med 44:196-200 (1987).

12. Fierz U. Katamnestiche Untersuchungen uber dieNebenwirkung der Therapie mit anorganischen Arsenbei Hautkrankheiten. Dermatologica 131:41-58 (1965).

13. Tan SH, Tham SN, Goh CL. Skin cancers at TertiaryReferral Skin Hospital in Singapore. Int J Dermatol34(11 (:770-776 (1995).

14. Kazantzis G. Occupational Health. In: Oxford Textbook ofMedicine, Vol 1, 2nd ed. Oxford:Oxford University Press,1988;6,158-159.

15. Lever LR, Farr PM. Skin cancers or premalignant lesionsoccur in half of high-dose PUVA patients. Br J Dermatol131(2):215-219 (1994).

16. lindelof B, Sigurgeirsson B. PUVA and cancer: a casecontrol study. BrJ Dermatol 129(1):39-41 (1993).

17. Maier H, Schemper M, Ortel B, Binder M, Tanew A,Honigsmann H. Skin tumors in photochemotherapy forpsoriasis: a single-center follow-up of 496 patients.Dermatology 193:185-191 (1996).

18. Arbesman H, Ransohoff DF. Is Bowen's disease a pre-dictor for the development of internal malignancy?A methodological critique of the literature. JAMA257:516-518 (1987).

19. Dobson RL, Young MR, Pinto JS. Palmar keratoses andcancer. Arch Dermatol 92:553-556 (1965).

20. Rhodes EL Palmar and plantar seed keratoses and inter-nal malignancy. Br J Dermatol 82:361-363 (1970).

21. Stolman LP, Kopf AW, Garfinkle L Are palmar keratoses asign of internal malignancy? Arch Dermatol 101:52-55(1970).

Environmental Health Perspectives * Volume 107, Number 8, August 1999 689