Arsenical keratosis is a precancerous dermatosis seen in patients with chronic arsenic toxicity (CAT). It is characterized by corn-like, yellowish, hyperkeratotic papules and plaques, primarily affecting the palms and soles. Often it starts as small areas of hyperkeratosis, which increase in number and size to involve the entire palms and soles. Rarely, it can spread to the dorsa of the hands and feet, other parts of the body, and may progress to squamous cell carcinoma.
Arsenical keratosis with skin hyperpigmentation is the earliest and most common presenting complaint in CAT. Therefore, it plays a crucial role in guiding clinicians towards the early diagnosis and treatment of CAT. Apart from benign conditions like skin hyperpigmentation and Mees' lines in nails, arsenical keratosis can sometimes coexist with single or multiple lesions of Bowen's disease, basal cell carcinoma, and squamous cell carcinoma. Identification and elimination of the source of arsenic exposure are of utmost importance, as these patients are at high risk of developing multisystem disorders and visceral malignancies.
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. The time taken for skin lesions to appear depends on the physical and chemical form of arsenic, the route, dose, duration, frequency of exposure, and can vary from anywhere between 4 years to 40 years. Inorganic arsenic is a ubiquitous element that has been identified as a class I human carcinogen by the International Agency for Research on Cancer. Some of the well-recognized and documented sources of arsenic exposure are as follows:
A greater incidence and prevalence of arsenic keratosis is reported from countries with documented environmental arsenic contamination, most commonly in groundwater. This includes Bangladesh, India, Taiwan, Mexico, Chile, Argentina, Japan, and China, to name a few. Though arsenical keratosis can occur at any age, the incidence was found to be higher in the older age group. Many studies done in arsenic-endemic areas have found that with similar exposure to arsenic, men have an increased prevalence of arsenical keratosis compared to women. The widely accepted explanation for this is the gender difference in the biomethylation of arsenic.
Though the exact pathomechanism underlying the premalignant and malignant manifestations of chronic arsenic exposure is unknown, there are several hypotheses that have been proposed and researched in several parts of the world. Arsenic metabolism in the body has a key role in most of these theories. Some such tested theories are as follows:
The development of premalignant and malignant lesions is further facilitated by an individual's genetic susceptibility. This includes polymorphism in the DNA repair pathway genes (e.g., ERCC2, XRCC3), tumor suppressor gene (TP53), glutathione S-transferase superfamily enzymes, IL10, TNF alpha, and NLRP2. Studies have demonstrated an exaggerated expression of pro-inflammatory cytokines in chronic arsenic toxicity. Recent studies have revealed the role of arsenic-induced epigenetic alterations i.e., changes in gene expression in the development of premalignant dermatoses and malignancy. Thus, a complex interaction of toxicodynamics of arsenic with an individual's genetics leads to aberrations in cellular proliferation and differentiation, resulting in unregulated cell growth seen in arsenical keratosis and other tumors.
Prominent compact hyperkeratosis, parakeratosis, and acanthosis are the constant features found on histopathological examination of arsenical keratosis. Papillomatosis and vacuolated keratinocytes may be present. Keratinocyte atypia may or may not be seen, and its severity can vary from mild atypia to features of squamous cell carcinoma in situ, which is indistinguishable from Bowen's disease. None of these histopathological features are specific for arsenical keratosis. Although biopsy does not confirm the diagnosis of arsenical keratosis, it is useful in detecting malignant transformation.
A similar histopathological picture can be seen in actinic keratosis, Bowen's disease, and verruca vulgaris.
Arsenic, a metalloid, naturally occurring in sediments and minerals, is a colorless, odorless, and tasteless chemical carcinogen. The inorganic forms of arsenic, especially arsenite (trivalent state) was found to be more toxic to humans than the organic form present in seafood like fish and crustaceans. Hence, the chances of toxicity due to seafood consumption are negligible.
Arsenic enters the bloodstream predominantly through gastrointestinal absorption. Entry through the respiratory route and transcutaneous absorption is also known to occur. A small portion of the absorbed arsenic gets excreted unchanged in the urine. The major portion undergoes hepatic biomethylation to monomethylarsonic acid and dimethyl arsenic acid and gets excreted in the urine. Thus there is rapid elimination of arsenic from the bloodstream. But with chronic exposure to arsenic, it accumulates preferentially in liver, kidney, lung, gastrointestinal tract, skin, and muscle. This can be explained by the high affinity of arsenic for sulfhydryl group-containing proteins and enzymes present in these organs.
Most of the accumulated arsenic gets excreted over time; however, keratin-rich tissue like nails, hair, and skin are an exception to this.
The usual presenting complaints are horny lesions over the extremities, particularly involving the palms and soles, which may be associated with pain and/or fissuring. The lesions are insidious in onset and gradually increase in number and size. On physical examination, multiple yellowish to pigmented hyperkeratotic papules and plaques that start over the pressure points over soles and palms are seen. As the disease progresses, the lesions increase in number, size, and thickness and can coalesce to form large verrucous plaques. There can be diffuse involvement of palms and soles and can spread to the dorsa 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:
Arsenical keratosis is often accompanied by pigmentary disturbances, which can be generalized/ diffuse hyperpigmentation or localized patchy hyperpigmentation predominantly involving the skin folds. Two striking patterns of pigmentation are seen in CAT; symmetrically distributed hyperpigmented macules over trunk and extremities described as 'raindrop' pattern, and guttate hypopigmentation on a background of hyperpigmentation described as 'raindrop on a dusty road' pattern. Oral mucosal pigmentation has also been described. Aldrich-Mees lines are single or multiple transverse white bands traversing the full width of the nail and involve the fingernails and toenails of patients. Additionally, these patients may develop single or multiple lesions of Bowen's disease, squamous cell carcinoma, and basal cell carcinoma over normal skin of both exposed and covered sites.
CAT 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 non-specific gastrointestinal symptoms like anorexia, dyspepsia, and diarrhea. They may also complain of headache, weakness, fatigue, redness of eyes (conjunctival congestion), and swelling of legs (non-pitting pedal edema). Diabetes and hypertension are prevalent in these patients.
Thus, while evaluating a patient from an arsenic-endemic area, presenting with acquired palmoplantar keratoderma, arsenical keratosis should be suspected, and the clinician must look for other skin manifestations and systemic symptoms of CAT. This should be followed by appropriate laboratory investigations to confirm the diagnosis. Arsenical keratosis usually manifests after years of arsenic exposure; therefore, a thorough history which includes past, personal, medical, drug, and occupational details are required to identify the source of arsenic exposure. The history of similar skin or systemic complaints in other members of the family, neighborhood, and workplace points to an environmental toxin like arsenic being the cause.
Investigations should be directed towards establishing CAT in the patient and identifying the source of arsenic exposure.
Estimation of arsenic concentration in drinking water is usually the first step in the evaluation of CAT. However, in clinical scenarios where drinking water data is unreliable, like in the case of a migratory population, the patient's biological sample analysis is crucial in establishing the diagnosis.
After establishing arsenic toxicity in the patient, and positively identifying the source of arsenic exposure, prevention of further exposure forms the mainstay of treatment. Mild to moderate disease have shown improvement in many such instances. Smoking and nutritional deficiencies are predisposing factors for this premalignant condition; therefore, patients should be advised to stop smoking and consume a well-balanced high protein diet. Supplementation of antioxidants like vitamins A, C, E is also believed to prevent cancer.
Treatment of arsenical keratosis is not mandatory, and the objective is to administer a supportive and symptomatic treatment that relieves 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, the severity of the disease, comorbidities, and tolerance for pain. Treatment options that have been tried over the years are as follows:
Acitretin with topical keratolytic agents can be used to treat patients with extensive lesions. It can play the role of chemoprevention in CAT associated cancers. Patients should be instructed to apply imiquimod cream once daily for 6 weeks or 3-5 times per week for 8 weeks. Biannual clinic visits, annual chest radiographs, and selective tests based on symptoms are of utmost importance for early detection of cutaneous and visceral malignancies.
Arsenical keratosis is a precancerous condition and can progress to squamous cell carcinoma (SCC). Though rare, the SCC that arises in arsenical keratosis are locally aggressive and demonstrate a greater metastatic potential compared to SCC arising in actinic keratosis. Studies have found the patients with arsenical keratosis to be at a higher risk of subsequently developing bladder and lung cancer.
Arsenical keratosis is an early cutaneous marker of CAT, which is a multisystem disorder with complications that can develop years after arsenic exposure. Hence, in addition to steps towards prevention of further exposure to arsenic, emphasis should be laid on the importance of regular follow-up to recognize and treat the cutaneous and extracutaneous manifestations of CAT at an early stage.
Smoking and nutritional deficiencies increase the chances of developing arsenical keratosis, and measures should be taken to mitigate the same. Patients should be taught to identify the features of malignant transformation of arsenical keratosis and seek medical care early on.
Patients with arsenical keratosis often present to their primary care clinician. These patients need to be referred for further evaluation to a dermatologist as several skin diseases can be clinically similar, and a dermatologist will be able to diagnose them based on the concomitant signs and risk factors. As it is an early manifestation of CAT, a missed diagnosis can have adverse long term outcomes. Once diagnosed and initiated on treatment, the patient can be referred to their primary care clinician for further management of arsenical keratosis. A dermatopathologist has an important role in management when a malignant transformation is suspected; if the histology reveals malignancy, surgical excision is done by a plastic surgeon.
Regular follow-up visits to identify systemic complaints and timely referral can lead to early diagnosis and treatment of associated systemic diseases, including malignancies. Hence, holistic management by an interprofessional team consisting of a dermatologist, primary care clinician, dermatopathologist, and plastic surgeon improves the outcomes of this multisystem disorder of public health relevance.
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