Continuing Education Activity

Acanthosis nigricans is a cutaneous manifestation of an underlying condition. It usually develops in in skin folds, such as the back of the neck, axilla, and groin, where it presents as velvety hyper-pigmented patches with poorly defined borders. Acanthosis nigricans is most commonly associated with diabetes and insulin resistance, but rarely it can be a sign of internal malignancy. It can also occur with hormone disorders or with the use of certain medications like systemic glucocorticoids and oral contraceptives. This activity reviews the workup and treatment of acanthosis nigricans and highlights the role of the interprofessional team in evaluating and treating patients with acanthosis nigricans.

Objectives:

• Identify some of the more common and some of the less common etiologies of acanthosis nigricans.
• Describe the management of acanthosis nigricans, and list any further evaluation that should be considered.
• Explain the pathophysiologic basis for acanthosis nigricans.
• Articulate the role of interprofessional team members in evaluating and treating patients with acanthosis nigricans.

Introduction

Acanthosis nigricans is a velvety, darkening of the skin that usually occurs in intertriginous areas.  This hyperpigmentation has poorly defined borders, usually occurs in skin fold areas, such as the back of the neck, axilla, and groin, and may include thickening of the skin. Acanthosis nigricans is most commonly associated with diabetes and insulin resistance, but rarely it can be a sign of internal malignancy. It can also occur with hormone disorders, and with the use of certain medications like systemic glucocorticoids and oral contraceptives.[1][2][3]

Etiology

There are multiple factors involved in the development of acanthosis nigricans.[4] 

• Increased circulating insulin that activates keratinocyte insulin-like growth factor (ILGF) receptors, particularly IGF-1. At high concentrations, insulin may displace IGF-1 from IGF binding protein. 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 epidermal growth factor receptor.

Familial Acanthosis nigricans: may arise as a result of an autosomal dominant trait, presenting at birth or during childhood. It occurs due to mutations in fibroblast growth factor receptor 3 (FGFR3).[5]

Obesity-associated Acanthosis nigricans: Obesity is one of the most common conditions associated with Acanthosis nigricans. Lesions are usually common in adulthood but can occur at any age. It was once labeled as “pseudoacanthosis nigricans". It may be associated with insulin resistance. Treating obesity with diet, weight reduction or medications can result in revolvement of Acanthosis nigricans.[6][7]

Medications associated Acanthosis nigricans: Multiple medications have been linked to Acanthosis nigricans. These include the use of nicotinic acid, systemic glucocorticoids, diethylstilbestrol, combined oral contraceptive pill, growth hormone therapy, estrogen, protease inhibitors, niacin, injected insulin. Once the offending medication is stopped, acanthosis nigricans usually resolves.[8][9][10] 

Acanthosis nigricans 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. Type A syndromes present with hyperandrogenemia, insulin resistance, and Acanthosis nigricans. Type B syndrome usually occurs in females who have uncontrolled diabetes, ovarian hyperandrogenism or autoimmune disease like SLE, Sjogren's syndrome, scleroderma. Polycystic ovarian syndrome (PCOS) is associated with Acanthosis nigricans. Insulin resistance and hyperandrogenism are seen in patients with PCOS.[11]

Acral acanthotic anomaly: Refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet. It is common in individuals who have dark skin.[12]

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 (sign of Leser-Trelat), or tripe palms.[13][14]

Auto-immune Acanthosis nigricans: Is associated with autoimmune disorders like SLE, Sjogren's syndrome, scleroderma or Hashimoto's thyroiditis.[15]

Unilateral Acanthosis nigricans: Also called as nevoid Acanthosis nigricans. It is very rare and is inherited in an autosomal dominant fashion. Lesions occur unilaterally. Lesions present at infancy, childhood or adulthood.[16]

Epidemiology

Acanthosis nigricans typically occurs in individuals younger than the age of  40 years and is associated with obesity, hypothyroidism, acromegaly, polycystic ovary disease, insulin-resistant diabetes, Cushing, and Addison diseases. Acanthosis nigricans is also associated with rare diseases such as pinealoma, Cushing's disease, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, leprechaunism, lipoatrophic diabetes, pineal hyperplasia syndrome, and Alstrom syndrome.[17][18]

In the United States population, Acanthosis nigricans is more common in Native Americans, African Americans, and Hispanics when compared to Whites or Asian origin individuals.[19][20]

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.[21]

In patients with benign acanthosis nigricans, evidence suggests that insulin or an insulin-like growth factor is enhancing the 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. Excessive friction or sweating 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.

Usage of medications like insulin have also 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.

Histopathology

The histological exam will reveal papillomatosis, hyperkeratosis with minimal hyperpigmentation. The dermal papillae usually have an upward projection with thinning of the epidermis. There is usually no dermal inflammatory infiltrate.

History and Physical

Patients usually present with an asymptomatic area of darkening and thickening of the skin, pruritus, and lesions that are velvety, 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 cancer has developed. Malignant acanthosis nigricans can appear suddenly and often is associated with intense pruritus.

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 with 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 focuses on ruling out malignancy. Since the vast majority of cases are associated with insulin resistance and/or obesity, screening for diabetes and measuring glycosylated hemoglobin is recommended. [22][23]

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.[24][25]

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. Acanthosis nigricans associated with insulin resistance can be treated with drugs such as metformin and rosiglitazone which are insulin-sensitizing agents.[26][4]

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 (e.g. topical tretinoin 0.1% or combination of tretinoin 0.05% and 12% ammonium lactate) and podophyllin.[27][28] Topical vitamin D analogs (e.g. calcipotriol (calcipotriene) 0.005%) act by decreasing keratinocyte proliferation and cause improvement of the Acanthosis nigricans lesions.[29] 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.[30]

Melatonin can also improve cutaneous symptoms in obese patients with Acanthosis nigricans by improving the inflammatory status and insulin sensitivity.[31]

Cosmetic treatments that have been tried include using alexandrite laser, dermabrasion, and chemical peels.[32] Surgical removal is the main treatment for malignant lesions.[33] 

Differential Diagnosis

• Seborrhea
• Tinea
• Erythrasma
• Candidiasis
• Pellagra
• Ichthyosis
• Linear epidermal nevus
• Granular parakeratosis
• Cutaneous hyperpigmentation related to Addison's disease

Prognosis

Patients with the benign form of acanthosis nigricans have few or no skin complications, good prognosis, and potential of resolution with treatment. Complications can stem from the underlying disease like diabetes and insulin resistance. Prognosis in patients with the malignant form of acanthosis nigricans is poor as the malignancy is advanced usually at the time of diagnosis in these patients.

Complications

Complications depend on the cause of acanthosis nigricans. Most cases of acanthosis nigricans are due to insulin resistance but however serious complications like malignancy can also be associated with this condition.

Consultations

Dermatology referral may be warranted if the diagnosis is uncertain. Referral to an endocrinologist may be needed in patients with diabetes and other metabolic disorders.

Deterrence and Patient Education

Patients need to be educated that hyperpigmentation of the skin may not solely be a skin condition and should be evaluated further, especially if it occurs in middle-aged to elderly patients. Patients need to follow up with their primary care physicians regarding any abnormal pigmentation in their skin. Hyperpigmentation of the skin due to acanthosis nigricans can be treated and sometimes resolves with adequate treatment of the skin condition or treatment of the underlying condition. Patients need to be educated on identifying the risk factors and signs and symptoms of a malignant condition associated with acanthosis nigricans. Depression and low self-esteem can occur in patients with acanthosis nigricans and diagnosis and psychological treatment should be started early in these patients.[34][35]

Enhancing Healthcare Team Outcomes

Acanthosis nigricans is not a common skin disorder but when it presents, the diagnosis can often be difficult. The condition can be benign or malignant, and hence an interprofessional approach is necessary to make a prompt diagnosis. Healthcare workers in primary care including nurse practitioners should always refer the patient to a dermatologist if unsure about the rash. The overall prognosis for patients with the malignant form of acanthosis nigricans is poor with an average survival of fewer than 24 months. Those with the benign form have an excellent prognosis, provided the condition causing it is treated. The majority of practitioners are likely to see acanthosis nigricans in the younger population with insulin resistance; hence a referral to an endocrinologist is recommended. Finally, patients should be educated that acanthosis nigricans is not a primary skin disorder but usually due to an underlying condition. In many benign cases, just changing diet and losing weight may lead to a cure. [36][37](Level V)