Velvety plaques of acanthosis nigricans
When to watch for underlying malignancies
by John Kraft, MD and Charles Lynde, MD
Vol.16, No.09, September 2008

Acanthosis nigricans (AN) is a relatively common condition characterized by brown velvety or verrucous plaques around the neck and skin folds. The term "acanthosis" refers to clinically thickened skin. The main causes of AN include obesity, insulin-resistant states, endocrinopathies and malig-nancy. In fact, the condition is classified according to these underlying causes. It's more frequent in darker-skinned people.

Classification
Type I acanthosis nigricans is associated with malignancy. It may precede, accompany or follow the onset of malignant disease. This type of AN mainly occurs after puberty or in adults. The onset is abrupt, and findings are more pronounced and extensive than in the other types. There can be multiple skin tags, seborrheic keratoses and tripe palms. Review of systems may reveal recent weight loss.

Malignancies associated with AN include adenocarcinoma of the gastrointestinal tract as well as lung and breast cancer. Less commonly, the condition is linked with genitourinary or endocrine malignancies, or with melanomas. Gastric tumours are the most frequent, though, accounting for about 60% of cases. Be especially suspicious for this type of AN if lesions appear in male, non-obese patients over age 40 years. Tripe palms may be the only presenting feature, especially when associated with lung cancer.

Type II or familial AN is inherited in an autosomal dominant fashion. It's very rare and presents at birth or during childhood. The condition is aggravated during puberty and isn't associated with any malignancy.

Type III is associated with obesity, insulin-resistant states, and/or endocrinopathies (Table 1). It's by far the most common variant. Onset tends to be gradual and isn't as extensive as in the malignancy-associated type. Other variants of AN include unilateral, acral, drug-associated (Table 2), and mixed.

Pathogenesis
The pathogenesis of AN isn't entirely known. The characteristic brown colour and velvety surface of the lesions are caused by hyperkeratosis rather than increased melanin production. Underlying fac-tors stimulate epidermal keratinocyte and dermal fibroblast proliferation. In benign forms of AN, the underlying cause is insulin or an insulin-like growth factor. In malignant AN, it's a substance secreted either directly by the tumour or in response to it. Transforming growth factor-alpha (TGF-alpha) has been implicated, as it's structurally similar to epidermal growth factor. Hereditary forms may be due to an irregular dominant gene.

Clinical findings
Lesion colour can vary from grey to brown to black. Sometimes lesions may be more erythematous and pruritic early after onset, mimicking a psoriasiform dermatitis. Their distribution is symmetric and they're found predominantly in skin folds. Most commonly involved areas include the neck and axillae, but any fold can be affected. Lesions may also manifest on the face, in inframammary folds, in the groin and inner aspects of the thighs, in the antecubital and popliteal fossae, on the dorsal joints of the hands, and around the umbilicus and anus. Extensor surfaces are less often afflicted. In extensive cases, you may also find mucosal involvement (conjunctiva, lips), which can include non-pigmented pedunculated lesions or pigmented macules. Achrocordons - skin tags - sometimes accompany le-sions in the axillae and groin.

Palmar surfaces may show some degree of skin thickening but when exaggerated, this kind of mani-festation reflects underlying malignancy. Tripe palms (acanthosis palmaris) refer to thickened velvety palms, which are associated with cancer in 95% of cases. Skin findings in malignancy-associated AN can appear before any symptoms of an underlying tumour. More than half of these patients have mucosal or mucocutaneous junction disease. If the perioral area and palate are involved, individuals may complain of discomfort, especially when eating.

Differential diagnosis
The most important diagnoses to consider in the differential include intertriginous granular parakeratosis, confluent and reticulated papillomatosis (Gougerot-Carteaud syndrome), and Dowling-Degos disease.

Investigations
AN is predominantly a clinical diagnosis (Table 3). Investigations can be done as needed to look for associated conditions such as an underlying insulin-resistant state. Check fasting blood glucose and insulin levels, and do an oral glucose tolerance test. In some cases of insulin resistance-associated AN, glucose studies are normal but insulin levels are markedly elevated. History and physical should guide investigations to rule out an endocrinopathy or associated malignancy. Consider a complete blood count, age-appropriate cancer screening, chest x-ray, abdominal and pelvic ultrasound, etc.

Treatment
Patients often seek treatment because of discomfort and/or cosmetic reasons. Treating an underlying condition or discontinuing a causative medication is often curative. Reappearance of AN after cancer therapy may correlate with recurrence of malignancy. If the condition is associated with obesity, weight loss is important. Underlying endocrinopathies should also be fully investigated and treated. Insulin sensitizers (e.g. metformin) are helpful if there's known insulin resistance.

Symptomatic and/or cosmetic treatment options are available. Evidence for the effectiveness of different agents is primarily anecdotal, however, and the efficacy often depends on control of any under-lying cause of AN. Topicals are directed at reducing hyperkeratosis and irritation. Patients can try agents containing urea, salicylic acid or ammonium lactate. Topical retinoids (e.g. topical tretinoin) may be applied nightly to affected areas. To treat possible irritation, consider using a low potency topical steroid in the morning. Calcipotriol, a topical psoriasis treatment, also helps to regulate kerati-nocyte proliferation. It's used once daily and may lead to some improvement after several months.

For more extensive cases, you can try systemic retinoids (e.g. acitretin, isotretinoin). Dosages range from 0.5 to 3 mg/kg daily for 4-6 months as tolerated. Improvement may be seen as quickly as 2 months into therapy, but lesions can recur with discontinuation. The benefits of this treatment must be weighed carefully against the multitude of side effects and teratogenicity associated with systemic retinoids.

If none of these approaches are helpful - or contraindicated - and the patient desires treatment, there are surgical alternatives such as dermabrasion and laser therapy. Laser options include the long-pulsed alexandrite laser as well as CO2 laser ablation of lesions. At least 3 sessions are needed at in-tervals of 4-6 weeks.

 

Charles Lynde, MD, FRCP(C) is an assistant professor of Dermatology at the University of Toronto.

John Kraft, MD, is in his third year of the Dermatology Residency Program at the University of Toronto.

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