Journal of Pakistan Association of Dermatologists 2012; 22 (4):366-369. Case Report Arsenical keratoses and non-Hodgkin’s lymphoma: arsenic-induced or coincidental conditions? Kiymet Handan Kelekci*, İlgül Bilgin*, Murat Ermete ** *Ministry of Health, İzmir Atatürk Education and Research Hospital, Dermatology Clinic, İzmir, Turkey **Ministry of Health, İzmir Atatürk Education and Research Hospital, Pathology Clinic, İzmir, Turkey Abstract Arsenic, a naturally occurring metal, is best known as a poison and can generate both acute and chronic toxicity. Exposure can occur through air, water, soil, and food. Chronic arsenic toxicity is usually asymptomatic and the first sign may be cutaneous findings. Arsenic keratosis is a precancerous lesion related to chronic arsenism. Non-Hodgkin’s lymphoma (NHL) is a T or B cell malignancy usually originating from lymph nodes and fewer in every other organ.We report a concomitant occurrence of arsenic keratosis and NHL in a Caucasian man.To our knowledge, this is the first such reported case. Key words Arsenic, arsenical keratoses, non-Hodgkin’s lymphoma. Introduction raindrop.2 Neurologic effects, pregnancy and delivery problems of pregnant women, Inorganic arsenic, a human carcinogen, is hypertension, diabetes mellitus, respiratory ubiquitous in the environment.1 The symptoms disorders, cardiovascular problems, cirrhosis, of chronic arsenic poisoning may appear due to lung cancer, cutaneous cancers, urinary system arsenic exposure from environmental, cancers, hepatic angiosarcoma, leukemia, and occupational and nutrition habits. Chronic lymphoma may occur.1,3,5 arsenic toxicity is usually asymptomatic and the first sign may be cutaneous findings. Non-Hodgkin’s lymphoma (NHL) is a T or B Arsenic keratosis is a precancerous lesion cell malignancy usually originating from related to chronic arsenism. 1,2 It is lymph nodes and fewer in every other organ. characterized by 2-10 mm keratotic palpable NHL is more prevalent in cases of immune papules settled on the palmar and plantar suppressive conditions such as viral infections region, lateral and dorsalis of fingers.1-4 The (HTLV-1, EBV, HHV8, HCV, and AIDS) and other cutaneous findings of chronic arsenism drug usage (TNF-alfa inhibitors, are hyperpigmentation on nipples, axilla, groin chemotherapy) and in dye and metal industry and compression sites of the body and diffuse workers and occupations that involve alopecia. The hypopigmentation on a pesticides.5-8 We report a concomitant hyperpigmentation region is shaped like a occurrence of arsenic keratosis and NHL in a Caucasian man. To our knowledge, this is the Address for correspondence first reported case of NHL such an occurrence Kiymet Handan Kelekci Korutürk Mah. in arsenic keratosis. Kasırga Sok. Özyıldırım sitesi No:21/1 D:3 Balçova / İzmir Phone:090 232 244 4444 E-mail:[email protected] 366 Journal of Pakistan Association of Dermatologists 2012; 22 (4):366-369. Case report A 61-year-old patient was admitted to the outpatient clinic complaining of dry skin on his face, hands and legs for three months. He had worked in the metal industry for 40 years and had retired five years ago. He was a pack a day smoker for 31 years. Stage II bulky CD30+ anaplastic large cell NHL had been diagnosed with biopsy of left axillary mass five months ago. Figure 1 2-6 mm wide white keratotic papules and xerotic appearance on both hands and forearm. Dermatologic examination revealed white keratotic papules 2-6mm in diameter on dorsalis of both feet and legs and hand and arms; guttate hypopigmentation on hyperpigmentation area of back; 5x5 in diameter mass in axilla with peripheral erythema; and xerotic view of face and extremities ( Figure 1 and 2). Routine biochemistry and urinalysis were normal. Radiologic examination was normal. The patient did not consent to measure arsenic levels in his hair and nails. Anti- Figure 2 Multiple nodules, 5x5 cm, (stage IIB cytomegalovirus IgG, Epstein-Barr virus bulky CD 30(+) anaplastic large cell NHL) and nonblanchable erythema. (EBV) VCA IgG and EBV EBNA IgG were positive. A skin biopsy taken from the dorsal side of the hand revealed hyperkeratosis, mild papillomatosis, mild atypical epidermal cells throughout basement membrane, normal papillary of dermis, all compatible with arsenic keratosis ( Figure 3). The cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) protocol was administered by the hematology department. Arsenical keratoses of arms, dorsal sides of hands and feet were treated by topical Figure 3 Hyperkeratosis, mild papillomatosis, epidermis with mild atypia throughout basement retinoic acid. layer and normal dermis (H&E). Discussion Epidemiologic studies point that arsenic toxicity is a major health problem in some Arsenic, a naturally occurring metal, is best regions of the world characterized by high known as a poison and can generate both acute arsenic content (>50µg/L) such as Argentina, and chronic toxicity. Exposure can occur Taiwan and Bangladesh.1,2 through air, water, soil, and food. 367 Journal of Pakistan Association of Dermatologists 2012; 22 (4):366-369. Arsenic tends to concentrate in ectodermal prevalence of malignancy such as lung, renal, tissues, including the skin, hair, and nails, even hepatic cancer and NHL increased in Ihado, by at low-level exposures. Thus, the skin is a drinking water that contained high levels of primary target organ for chronic arsenic arsenic (2-10µg/L), but when taken into toxicity. The skin is very sensitive to arsenic account confounding factors such as smoking, and skin lesions are, therefore, the most gender, body mass index (BMI) in the common and earliest non-malignant population studied, there was no significant manifestation of chronic arsenism. 5 relationship between malignancy and arsenic. Hypomelanotic guttate macules on diffuse In our country, the arsenic content of well hyperpigmentation and arsenical keratosis may water is higher, especially in rural areas. be formed. These hypomelanotic guttate Marshall pointed out in a retrospective study macules on diffuse hyperpigmentation that mortality from lung and bladder cancers resemble ''raindrops on a dusty road''.3 Our increased in some regions of Chile where case had typical cutaneous presentation of drinking water contained high levels of chronic arsenic toxicity. Manifestations of arsenic.12 Lee et al .10 reported a case where chronic arsenicosis may appear after latent Bowen disease and small cell lung cancer were period between six months and 50 years or diagnosed as a cause of treatment with herbal more.3,4,10 Bowen disease and squamous cell medicine, which contained high levels of carcinoma may develop under arsenical arsenic. In another study, it was reported that keratosis.1,2,5 Diagnosis of arsenic intoxication the prevalence of lung, liver and bladder is often difficult because clinical presentation cancers doubled in Bangladesh, where there is varies depending on route of exposure, high content of arsenic in fresh water.13 In our chemical form, dose, and time elapsed since case, there were both pigmentary changes and exposure. It can be difficult to elicit a clear keratoses associated with arsenic on skin and history of exposure either to contaminated food NHL. However, cancers may be triggered by or well water, or through occupational various causative factors. Examination of the exposure. Furthermore, because arsenic affects arsenic content of drinking water may be of multiple systems, poisoning can present with a limited value.10 wide variety of signs and symptoms.10 Fritschi et al .8 performed a study to determine Arsenic may cause impaired nucleotide repair the relationship between NHL and with DNA mutations. Cells rich in keratin such occupational risk factors because of the as epidermal keratinocyte are subject to arsenic increased prevalence of NHL in Australia toxicity. Arsenic may cause keratinocyte during the last decade. They found that proliferation and differentiation by raised exposure to hydrocarbons with aromatic growth factors. However, it is not completely chlorine except benzene, aliphatic solvent and understood how arsenic compounds might firewood powder may cause NHL. Skoy et al .9 cause carcinogenic process.4,5,10 found that NHL was more common in workers of metal industry and welders in Denmark. The World Health Organization (WHO) has According to WHO, pigmentation or keratosis, stated precisely that the upper allowable limit both cutaneous lesions are necessary to of arsenic in drinking water is %0.01µg/L. diagnose arsenism. 14 In another study, it was Therefore, chronic exposure more than found that arsenic toxicity might increase the allowable upper limits may cause benign skin risk of visceral malignancy among metal changes, cutaneous malignancy and visceral workers.7 Cases of occupational origin are malignancy. 2 Han et al .11 revealed that the most commonly caused by metal arsenic 368 Journal of Pakistan Association of Dermatologists 2012; 22 (4):366-369. trioxide used as insecticide, copper cancers. J Cutan Pathol 2007; 34 :203-6. acetoarsenite, lead arsenate, and calcium 3. Smith M. Environmental and sports- related skin disease. In: Bolognia JL, arsenate used as insecticides or copper arsenite Rapini RP, eds. Dermatology . used as a pigment in wallpapers and paints Philadelphia: Mosby; 2007. P. 1396-99. manufacturing. Other possible sources are 4. Chen J C-S. Arsenical keratosis. Medscape dermatology, e-medicine 24 mart, 2008. cigarette smoke, city smoke and pesticides. In 5. Centeno