Arsenical Keratosis

Etiology

Arsenical keratosis is a cutaneous manifestation of arsenicosis, defined by the World Health Organization (WHO) as a chronic health condition resulting from the ingestion of arsenic above the safe limit for a minimum duration of 6 months.[5][6] The time taken for skin lesions to appear depends on the physical and chemical form of arsenic, the route, dose, duration, and frequency of exposure, and can vary from anywhere between 4 years to 40 years.[7][8] Inorganic arsenic is a ubiquitous element classified as a group 1 human carcinogen by the International Agency for Research on Cancer.[6][9] Some of the well-recognized and documented sources of arsenic exposure are as follows:

• Contaminated groundwater: Exposure occurs from drinking, cooking, and irrigating crops using contaminated well water.[10][11]

• Food crops: Crops grown in contaminated soil or irrigated using contaminated water can be a source of arsenic.[10][11] Whole-grain rice is known to have higher arsenic levels compared to polished rice.                                                                                                             
• Medications: Fowler's solution (1% potassium arsenite) was used in the 20th century to treat various dermatoses and asthma.[7] In the early 1900s, until the advent of penicillin, arsenic-containing drugs, salvarsan and neosalvarsan, were used to treat syphilis.[12] Currently, arsenic trioxide is the only medicinal form of arsenic approved by the FDA for treating relapsed or refractory acute promyelocytic leukemia.[13][14] Arsenic is also found in Chinese herbal medicines and ayurvedic medicines.[15]

• Occupational exposures: Arsenic is used in the manufacture of alloys and the processing of pigments, textiles, glass, paper, hide (tanning process), wood preservatives, and ammunition. Workers involved in the smelting and mining of metals have greater exposure to arsenic compared to those engaged in manufacturing insecticides, pesticides, herbicides, pharmaceuticals, and poultry feeds. The population living close to these industries or mining activities is also at risk.[7]

• Tobacco: Tobacco plants can naturally absorb arsenic from contaminated soil and insecticides. Cigarettes manufactured in the 1950s had high arsenic content, which has been gradually reduced to acceptable levels over the years. However, regulating the arsenic content in handmade cigarettes such as bidis has not yet been possible.[16]

Epidemiology

Arsenical keratosis is more commonly reported in countries with documented environmental arsenic contamination, particularly in groundwater. Affected countries include Bangladesh, India, Taiwan, Mexico, Chile, Argentina, Japan, and China.[10][11] Many studies conducted in arsenic-endemic areas have found that with similar exposure to arsenic, men have an increased prevalence of arsenical keratosis compared to women.[17] The widely accepted explanation for this is the gender difference in the biomethylation of arsenic.[6][8] Although arsenical keratosis can occur at any age, the incidence was higher in the older age group.[10] 

Pathophysiology

Although the exact pathomechanism underlying the premalignant and malignant manifestations of chronic arsenic exposure is unknown, several hypotheses have been proposed. Arsenic metabolism in the body has a crucial role in most of these theories, which include the following:[10][18]

• Genetic polymorphism of enzymes involved in the metabolic pathway; arsenite methyltransferase (AS3MT) is the primary mediator in the biomethylation of arsenic.[19]

• Global DNA hypomethylation is due to the depletion of S-adenosylmethionine in cells during arsenic biomethylation, leading to aberrant gene expression and carcinogenesis.[20]

• Reactive oxygen species generated during the metabolism of arsenic cause oxidative DNA damage, resulting in chromosomal abnormalities and sister chromatic exchange.[21]

An individual's genetic susceptibility further facilitates the development of premalignant and malignant lesions. Key genetic factors include polymorphism in the DNA repair pathway genes, such as ERCC2 and XRCC3; tumor suppressor genes, such as TP53; glutathione S-transferase superfamily enzymes; IL10; TNF alpha; and NLRP2. Studies have shown an exaggerated expression of pro-inflammatory cytokines in chronic arsenic toxicity. Recent studies have revealed the role of arsenic-induced epigenetic alterations, which affect gene expression and contribute to the development of premalignant dermatoses and malignancies.[18] Thus, a complex interaction of arsenic toxicodynamics with an individual's genetics leads to aberrations in cellular proliferation and differentiation, resulting in unregulated cell growth observed in arsenical keratosis and other tumors.

Histopathology

Prominent features in the histopathological examination of arsenical keratosis include compact hyperkeratosis, parakeratosis, and acanthosis. Papillomatosis and vacuolated keratinocytes may be present. Keratinocyte atypia may or may not be observed, and its severity can vary from mild atypia to features of SCC in situ,[22][23] which is indistinguishable from Bowen's disease.[1] None of these histopathological features are specific to arsenical keratosis.

Although biopsy does not confirm the diagnosis of arsenical keratosis, it is useful in detecting malignant transformation.[5] A similar histopathological picture can be observed in actinic keratosis, Bowen's disease, and verruca vulgaris; therefore, exposure history is essential in diagnosing arsenical keratosis.[8]

Toxicokinetics

Arsenic is a metalloid element with atomic number 33 and naturally occurs in elemental, inorganic, organic, or gaseous forms. This element is most commonly silver-gray but can also be black or yellow. Arsenic is odorless and tasteless and is a known carcinogen.[7][9] The inorganic forms of arsenic, especially arsenite (As³⁺), are more toxic to humans compared to the organic form found in seafood, such as fish and crustaceans.[1][24] Therefore, the risk of toxicity due to seafood consumption is negligible.[25] 

Arsenic enters the bloodstream predominantly through gastrointestinal absorption, although inhalation and dermal absorption are also known to occur. A small portion of the absorbed arsenic is excreted unchanged in the urine. The major portion undergoes hepatic biomethylation to form monomethylarsonic acid and dimethyl arsenic acid, which are then excreted in the urine.[8] This process leads to the rapid elimination of arsenic from the bloodstream. However, with chronic exposure, arsenic accumulates in the liver, kidneys, lungs, gastrointestinal tract, skin, and muscles due to its high affinity for sulfhydryl group-containing proteins and enzymes in these organs.[8] Most of the accumulated arsenic gets excreted over time; however, keratin-rich tissues such as nails, hair, and skin are exceptions.[25]

History and Physical

The typical presenting complaints of arsenical keratosis include horny lesions on the extremities, particularly affecting the palms and soles, which may be associated with pain and fissuring. The lesions are insidious in onset and gradually increase in size and number.

On physical examination, multiple yellowish to pigmented hyperkeratotic papules and plaques that start over the pressure points on soles and palms are observed. As the disease progresses, the lesions increase in size, number, and thickness and can coalesce to form large verrucous plaques.[2][6] There can be diffuse involvement of palms and soles, which can spread to the dorsal surfaces of hands, feet, and the rest of the body. Based on the thickness and size of the lesions, arsenical keratosis can be graded as follows: [2][6]

• Mild: Slight thickening of skin or papules of size <2 mm on a background skin with grit-like texture, best appreciated by palpation.                                       
• Moderate: Multiple raised, warty, keratotic, corn-like papules 2 to 5 mm in size.                                                          
• Severe: Keratotic papules of size >5 mm or confluent keratotic plaques, with or without fissures.

Arsenical keratosis is often accompanied by pigmentary disturbances, manifesting as either generalized or diffuse hyperpigmentation or localized patchy hyperpigmentation, primarily involving the skin folds.[5] Two striking patterns of pigmentation are observed in chronic arsenic toxicity—symmetrically distributed hyperpigmented macules over the trunk and extremities described as a raindrop pattern, and guttate hypopigmentation on a background of hyperpigmentation described as a raindrop on a dusty road pattern. Oral mucosal pigmentation has also been described.[5] 

Aldrich-Mees lines are single or multiple transverse white bands traversing the entire width of the nail and involve the fingernails and toenails of patients.[1] In addition, individuals with arsenical keratosis may develop single or multiple lesions of Bowen's disease, SCC, and basal cell carcinoma over normal skin of exposed and unexposed sites.[7]

Chronic arsenic toxicity is a multisystem disorder, and patients with arsenical keratosis can have symptoms of chronic liver disease, chronic lung disease, distal sensorimotor neuropathy, peripheral vascular disease, ischemic heart disease, chronic kidney disease, and nonspecific gastrointestinal symptoms, such as anorexia, dyspepsia, and diarrhea. In addition, patients may report headache, weakness, fatigue, redness of eyes (conjunctival congestion), and swelling of legs (non-pitting pedal edema). Diabetes and hypertension are prevalent in these patients.[2][17]

When evaluating a patient from an arsenic-endemic area presenting with acquired palmoplantar keratoderma, arsenical keratosis should be suspected. The clinician should assess for other skin manifestations and systemic symptoms associated with chronic arsenic toxicity and follow with appropriate laboratory investigations to confirm the diagnosis.[5]

Arsenical keratosis typically manifests after years of arsenic exposure; therefore, a detailed history, which includes past, personal, medical, drug, and occupational details, is required to identify the source of arsenic exposure.[7] A history of similar skin or systemic complaints in other family members, the neighborhood, and the workplace suggests environmental exposure to arsenic.

Evaluation

For patients presenting with skin lesions suggestive of arsenical keratosis, it is crucial to determine where and how they are being exposed to arsenic. Various methods for testing arsenic exposure include urine, hair, nail, and blood tests. Most arsenic testing does not differentiate between inorganic and organic arsenic; therefore, recent seafood ingestion can falsely elevate arsenic levels in samples tested. Speciation of arsenic can be performed to determine the contribution of organic arsenic better.[26]

• Estimation of arsenic concentration in urine: This evaluation indicates recent exposure to arsenic and should ideally be performed with a 24-hour urine collection. An easier alternative is to test a spot or the first-morning urine sample. Both methods are comparable as the arsenic excreted remains stable throughout the day. Seafood containing the non-toxic organic form of arsenic should be avoided for at least 4 days before testing, as it can make the results unreliable. A concentration >50 μg/L proves recent exposure to arsenic.[5][6]                                                                                                                                               
• Estimation of arsenic concentration in hairs and nails: After washing hair with arsenic-free shampoo and ensuring the patient has not used any coloring agent, 30 hairs of 6 cm length from females and 60 hairs with the base from males are collected and tested. Nail clippings from all fingernails and toenails are also obtained. A concentration of arsenic >1 mg/kg of dry hair and >1.5 mg/kg of the nail indicates arsenic exposure in the preceding 9 months.[5][6]

Histopathological examination of the keratotic skin lesions should be performed to look for signs of malignant transformation. Still, because the histopathology is nonspecific to arsenic, it cannot be used to confirm arsenic toxicity.[5]

Investigations should be directed toward establishing chronic arsenic toxicity in the patient and identifying the source of arsenic exposure, including the following:

• Estimation of arsenic concentration in drinking water or well water: An acid-washed plastic container is used to collect at least 50 mL of water to be tested. WHO has set a provisional guideline value of 10 μg/L for the maximum permissible concentration of arsenic in drinking water.[10] However, countries such as India and Bangladesh follow the old guidelines and have a higher cut-off value of 50 μg/L.[5]                                                                                                                                                                           
• Determination of arsenic concentration in suspected sources, such as medications or pesticides, is carried out using atomic absorption spectrometry, calorimetric method, and spectrophotometry.[5]                                                                                                                                                                                                                  
• Histopathological examination of the keratotic skin lesions is performed to assess for malignant transformation, but it limited utility in confirming the diagnosis of arsenical keratosis.[5]

Estimating arsenic concentration in drinking water is typically the first step in evaluating chronic arsenic toxicity. However, in clinical scenarios where drinking water data are unreliable, such as in a migratory population, analyzing the patient's biological samples is crucial in establishing the diagnosis.

Treatment / Management

After establishing arsenic toxicity in the patient and positively identifying the source of arsenic exposure, preventing further exposure forms the mainstay of treatment. Mild-to-moderate diseases have shown improvement in many such instances.[2] Smoking and nutritional deficiencies are predisposing factors for this premalignant condition; therefore, patients should be advised to quit smoking and consume a well-balanced, high-protein diet.[10] Antioxidant supplementation, such as vitamins A, C, and E, is also believed to potentially help in cancer prevention.[10]

Treatment of arsenical keratosis is not mandatory; instead, the goal is to provide supportive and symptomatic care to alleviate the patient's discomfort. There are no universally accepted standard guidelines for the treatment of arsenical keratosis. Treatment should be tailored to the patient's needs, disease severity, comorbidities, and pain tolerance. Various treatment options that have been explored over the years include: [1][6]

• Cryotherapy
• Curettage and electrodessication
• Carbon dioxide laser ablation
• Topical keratolytic agents, such as salicylic acid (5% to 10%) and urea (10% to 20%)
• Imiquimod 5% cream
• Topical 5-fluorouracil
• Oral retinoids
• Surgical excision

Acitretin with topical keratolytic agents can be used to treat patients with extensive lesions and may offer chemoprevention for cancers associated with chronic arsenic toxicity.[1][13] Patients should be instructed to apply imiquimod cream once daily for 6 weeks or 3 to 5 times per week for 8 weeks. Biannual clinic visits, annual chest radiographs, and selective tests based on symptoms are of utmost importance for the early detection of cutaneous and visceral malignancies.[16](B3)

Differential Diagnosis

When assessing a patient with suspected arsenical keratosis, it is essential to consider a range of differential diagnoses to ensure accurate diagnosis and appropriate management. These conditions may present with similar clinical features, such as hyperkeratotic lesions on the palms and soles, and include both benign and malignant disorders. The differential diagnoses to consider when assessing a patient for arsenical keratosis include the following:

• Verruca vulgaris
• Corns/calluses
• Dermatophyte infection
• Lichen planus
• Hyperkeratotic eczema
• Palmoplantar psoriasis
• Porokeratosis punctata palmaris et plantaris
• Clavi syphilitici
• Inherited palmoplantar keratoderma
• Spiny keratoderma

Prognosis

Arsenical keratosis is a precancerous condition and can progress to SCC. Although rare, SCC that arises in arsenical keratosis is locally aggressive and demonstrates a greater metastatic potential compared to SCC arising in actinic keratosis.[1][6] Studies have found that patients with arsenical keratosis are at a higher risk of subsequently developing bladder and lung cancer, likely secondary to chronic arsenic toxicity.[12]

Complications

Understanding the potential complications of arsenical keratosis is crucial for effective patient management and long-term care. If left untreated, this condition can lead to severe health issues beyond the skin, including systemic diseases and malignancies. Considerations of complications are as follows:

• In extreme cases of arsenical keratosis, diffuse involvement of palms and soles with painful fissuring can occur,[6] which can be debilitating for the patient and impact daily activities and quality of life.                                                                         

• Arsenical keratosis is one of the several skin conditions that can be associated with a cutaneous horn.

• Malignant transformation, typically SCC, should be suspected when there is a sudden increase in size, induration, fissuring, bleeding, inflammation, perilesional erythema, and ulceration.[1][6]                                                                                                                                                                                                                                                          
• Several organ systems can be affected in chronic arsenic toxicity, some leading to irreversible changes, chronic disease, and also predisposing to visceral malignancies.[1]