Acanthosis Nigricans

Article Author:
Mark Brady
Article Editor:
Steve Bhimji
Updated:
10/17/2018 7:36:03 AM
PubMed Link:
Acanthosis Nigricans

Introduction

Acanthosis nigricans is a poorly defined, dark-brownish hyperpigmentation with thickening of the skin that usually is found in areas of the body with skin folds such as the neck, forehead, groin, armpits, and navel. Acanthosis nigricans can be a benign skin disorder or associated with a malignancy. The benign condition may be associated with endocrine-related or hormone-related obesity. The malignant form is associated with tumor products, tumor necrosis factors, and insulin-like activity.

Etiology

There are multiple factors involved in acanthosis nigricans development. 

  • Increased circulating insulin that activates keratinocyte ILGF receptors, particularly IGF-1. At high concentrations, insulin may displace IGF-1 from IGFBP. Increased circulating IGF may lead to keratinocyte and dermal fibroblast proliferation.
  • Hereditary variants are associated with fibroblast growth factor defects
  • Increased transforming growth factor (TGF) appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the estimated glomerular filtration rate.

Acanthosis type 1 or familial acanthosis may arise as a result of an autosomal dominant trait, presenting at birth or during childhood. Acanthosis nigricans type 3 is associated with endocrine dysfunction; it is more insidious in onset, less widespread, and patients are often obese. Insulin-resistance syndromes may be divided into type A (HAIR-AN) and type B syndromes. Acanthosis nigricans type 4 has been linked to the use of nicotinic acid, glucocorticoids, stilbestrol, combined oral contraceptive pill, and growth hormone therapy. Acral acanthotic anomaly refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet. Malignant acanthosis nigricans syndrome is associated with gastrointestinal adenocarcinomas and genitourinary cancers such as prostate, breast, and ovary. Lung cancer and lymphoma rarely are associated with acanthosis nigricans. Malignant acanthosis nigricans may precede, accompany, or follow the onset of internal cancer. Malignancy-associated acanthosis nigricans usually has a rapid onset and is accompanied by skin tags, multiple seborrheic keratoses, or tripe palms.

Epidemiology

Acanthosis nigricans typically occurs in individuals younger than age 40 and is associated with obesity, hypothyroidism, acromegaly, polycystic ovary disease, insulin-resistant diabetes, Cushing, and Addison diseases. Acanthosis nigricans also is associated with rare diseases such as pinealoma, Cushing pituitary basophilism, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, leprechaunism, lipoatrophic diabetes, pineal hyperplasia syndrome, and Alstrom syndrome.

Pathophysiology

The pathogenesis of acanthosis nigricans is likely related to growth factor levels and insulin-mediated activation of Insulin-like growth factor (IGF) on keratinocytes and increased growth factor levels. The pathophysiological process behind acanthosis nigricans appears to be related to the proliferation of fibroblasts and the enhanced stimulation of epidermal keratinocytes.

In patients with benign acanthosis nigricans, there is evidence suggesting that insulin or an IGF is enhancing propagation of epidermal cells. Other mediators that have been identified include fibroblast growth factor, tyrosine kinase receptors (epidermal growth factor receptor). High concentrations of insulin are thought to cause proliferative effects by binding to IGF-1 receptors. It is important to note that free IGF-1 levels also are high in people with metabolic syndrome, leading to faster cell differentiation and cell growth.

Recently, both syndromic and familial forms of acanthosis nigricans have been observed. Familial and syndromic forms of acanthosis nigricans have been identified. Many other syndromes share similar features, such as hyperinsulinemia, craniosynostosis, and obesity. These are subdivided into insulin-resistant syndromes and fibroblast growth factor defects.

Other insulin resistant syndromes include Rabson Mendenhall syndrome, leprechaunism, Berardinelli-Seip syndrome, Dunningan syndrome, and Alstrom syndrome. One common cause of acanthosis nigricans is excessive friction or sweating which may also be playing a contributory role.

In patients with malignant acanthosis nigricans, the most probable stimulating factor is secreted by the cancer cells. Two possibilities are transforming growth factor or epidermal growth factor because both have high levels in people with gastric adenocarcinoma. Other reports indicate normalization of urine transforming growth factor after surgical removal of a tumor, followed by regression of the skin lesions.

Use of medications like insulin also has been implicated most likely due to the activation of IGF receptors. A few case reports on ectopic acanthosis nigricans in syndromic patients report patient acquisition of the disorder after skin grafting from an affected site.

History and Physical

Patients usually present with an asymptomatic area of darkening and thickening of the skin, pruritus, and lesions that are hyperpigmented macules and patches and progress to palpable plaques. In approximately one-third of cases, malignant acanthosis nigricans presents with skin changes before any signs of cancer. In another one-third of cases, lesions arise simultaneously with the neoplasm. In the remaining one-third of cases, the skin findings manifest some time after the diagnosis of cancer.

In nearly one-third of patients with malignant acanthosis nigricans, the skin changes usually occur before any clinical signs of the malignancy. In another one-third of patients, the skin lesions develop at the same time as the presentation of cancer. In the remaining patients, the skin features occur after a cancer has developed. Malignant acanthosis nigricans can appear suddenly and often is associated with intense pruritis.

The lesions of acanthosis nigricans typically occur in areas of skin folds like the groin, axilla, or posterior neck. In children, the most common site of acanthosis nigricans is the posterior neck. Rarely, acanthosis nigricans may occur on the mucous membranes of the nose, oral cavity, esophagus, or larynx. Women also may develop lesions on the nipple. Rare cases of acanthosis nigricans have been reported in the conjunctiva.

In some patients, there also may be associated skin tags in the same area. Nail changes like hyperkeratosis and leukonychia may be present. Clinically, it is not possible to differentiate the lesions of benign versus malignant acanthosis nigricans.

Evaluation

Acanthosis nigricans is diagnosed clinically and confirmed with a skin biopsy. Blood tests, endoscopy, or x-rays may be required to eliminate diabetes or cancer. On biopsy, hyperkeratosis, leukocyte infiltration, epidermal folding, and melanocyte proliferation may be seen. The workup focus on ruling out a malignancy. Since the vast majority of cases are associated with insulin resistance and/or obesity, screening for diabetes and measuring hemoglobin glycosylation is recommended.

Treatment / Management

Acanthosis nigricans is not treatable. It may fade over time by treating the cause, insulin resistance. Controlling blood glucose levels through exercise and diet often improves symptoms. Topical fade creams can lighten skin in less severe cases. Acanthosis nigricans malignant may resolve if the causative tumor is removed successfully.

The goal of treatment is to treat the underlying disease. In the majority of patients, the treatment is done only for aesthetic reasons. In some patients, weight loss and correction of insulin resistance lowers the burden of hyperkeratotic lesions.

All inciting agents and medications should be discontinued. One should make attempts to lower the lipid profile. Reports suggest that dietary fish and niacin may help.

Dermatologists sometimes prescribe keratolytics, such as topical retinoids and podophyllin. The success of these treatments is variable. Other agents that have been tried include metformin and etretinate. In one report octreotide also showed marked improvement in a patient with insulin resistance.

Cosmetic treatments that have been tried include laser, dermabrasion, and chemical peels. Surgical removal is the main treatment for malignant lesions. 



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