Acanthosis nigricans

What is acanthosis nigricans?

Acanthosis nigricans is a skin condition characterised by a velvety papillomatous overgrowth of the epidermis. Darkening and thickening (epidermal hyperplasia) of the skin occurs mainly in the flexural areas, particularly the axillae, groin, inframammary region, and neck.

Acanthosis nigricans (AN) is usually a sign of an underlying metabolic or hormonal condition or disease, such as obesity or diabetes (most commonly type 2 diabetes but also reported in type 1 diabetes, particularly when associated with obesity). It may also be associated with certain drugs, such as systemic glucocorticoids or oral contraceptives. Its presence as a sign of internal malignancy (malignant AN) is very rare.

Acanthosis nigricans on the neck 

Axillary acanthosis nigricans 

Acanthosis nigricans 

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Who gets acanthosis nigricans?

• Acanthosis nigricans affects < 1% of Caucasians. In the United States, the estimated prevalence is 13.3% among African Americans, 5.5% among Latinos, and 34.2% among Native Americans.
• It affects both males and females of all ages, with people < 40 years of age typically being more affected.
• Acanthosis nigricans was found in 18.2% of children and 19.5% of adults in a cross-sectional study (n=1730) in the United States. Those diagnosed with AN were twice as likely to have type 2 diabetes compared to those without (35.4% vs. 17.6%).
• Rarely, AN may present as a paraneoplastic syndrome in the setting of internal malignancy. Such malignant AN tends to develop abruptly and to occur in patients who are middle-aged and not obese.

What causes acanthosis nigricans?

The exact cause of AN is still unclear. However, it is predominantly linked to states of insulin resistance (IR) wherein obesity, diabetes, and/or other metabolic disorders (eg, metabolic syndrome, polycystic ovary syndrome, and generalised lipodystrophy) co-exist. Insulin in high concentrations has been shown to cross the dermal-epidermal junction, and in high concentrations to have growth-stimulating effects through its binding to type 1 insulin-like growth factor receptor (IGFR) on keratinocytes. It is this activation of IGFR that stimulates the proliferation of keratinocytes and leads to AN.

Other less common presentations of AN include:

• Drug-related AN, which has been associated with nicotinic acid lotion, fusidic acid ointment, subcutaneous insulin, oral contraceptives, oral corticosteroids, hormones (such as diethylstilbestrol and testosterone), triazinate, and aripiprazole
• Familial AN, a rare autosomal dominant condition that presents at birth or in childhood and progresses until puberty after which it either stabilizes or regresses. It is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene
• Autoimmune AN, which has been associated with systemic lupus erythematosus, Sjögren syndrome, scleroderma, and Hashimoto thyroiditis
• Acral acanthotic anomaly, a presentation that typically occurs in darker skin phenotypes and is limited to the elbows, knees, and dorsal aspects of the hands and feet
• Unilateral AN (also called naevoid acanthosis nigricans), a rare autosomal dominant genodermatosis with lesions occurring unilaterally along Blaschko lines; it can present at any age.

A recently described presentation of AN-like lesions among darker-skinned individuals, involving the forehead, cheeks, including the malar areas, and fingers was also found to be strongly associated with obesity and metabolic disorders.

Malignant AN is a rare paraneoplastic syndrome likely due to the release of stimulatory growth factors by tumour cells and is typically associated with gastrointestinal malignancies, especially gastric adenocarcinoma (60%); other associated cancers include hepatobiliary carcinoma, squamous cell carcinoma, malignant melanoma, and Wilms tumour. The oral cavity is involved in 25–50% of cases.

Tripe palms are a variant of malignant AN with a 90% association with internal malignancy.

What are the clinical features of acanthosis nigricans?

Acanthosis nigricans is characterised by symmetric, thickened, brown, velvety patches and plaques that appear most commonly in the intertriginous areas (ie, the axillae, groin, and back and sides of the neck). In women, the nipples and areolae of the breasts, the vulva, and the perineum may also be involved. The lesions of AN may become macerated and malodorous, and skin tags are an additional frequent finding.

Lesions affecting the mucosal surfaces of the oral cavity, nose, larynx, and oesophagus tend to be more common and more extensive in malignant acanthosis nigricans as does the finding of pruritus. Pruritus may be present and is very common in malignant acanthosis nigricans.

How do clinical features vary in differing types of skin?

• The skin may appear darker and more leathery in darker skin phototypes
• People with skin phototypes IV, V, and VI have a higher frequency of acanthosis nigricans on the neck compared to those with skin phototypes I, II, and III, and facial acanthosis nigricans is almost exclusive to those with darker skin types
• There is a very high prevalence of insulin resistance in those with light skin who have acanthosis nigricans. However, in darker skinned individuals, acanthosis nigricans may present without concurrent insulin resistance. Thus, skin phototype influences the likelihood of acanthosis nigricans being a predictor of insulin resistance.

What are the complications of acanthosis nigricans?

• Cosmetic disfigurement
• Psychological distress
• Acanthosis nigricans is an independent risk factor for the presence of diabetes
• Complications associated with underlying disease (eg, obesity-associated complications)

How is acanthosis nigricans diagnosed?

• Diagnosis is made clinically, including taking a thorough review of systems, history of current and past medical conditions, family history, and medications
• If there is diagnostic uncertainty, a biopsy may be performed to obtain tissue for histopathologic analysis
• Abrupt onset in an individual without the typical risk factors for AN should alert the physician to the possibility of an underlying malignancy, prompting an appropriate history, physical examination, and pursuit of imaging/laboratory investigations as indicated

What is the differential diagnosis for acanthosis nigricans?

• Confluent and reticulated papillomatosis, which occurs more commonly in females with a mean age of 18–21 years. Reticulation is heterogeneous (as opposed to homogeneous in acanthosis nigricans). Pigmentation is not associated with peripheral reticulation in acanthosis nigricans.
• Erythrasma, which is characterised by well-demarcated red patches often with maceration and possible scaling and is found mainly in intertriginous regions. A Wood lamp exam reveals a characteristic ‘coral-red’ fluorescence pattern in erythrasma which is absent in acanthosis nigricans.
• Intertrigo, which is characterised by erythematous patches or plaques, is often macerated or fissured, may show satellite pustules if complicated with candidiasis, and/or may have accompanying pruritus or tenderness. Morphology and a history of associated symptoms are helpful distinguishing features.
• Postinflammatory hyperpigmentation (PIH), which is distinguishable from AN due to its frequent localisation to areas of inflammation and the ability to often elicit a history of skin trauma or irritation from the patient.
• Tinea versicolor, especially when hyperpigmented and presenting on the neck, may also be confused with acanthosis nigricans. Obtaining a bedside scraping of scales and seeing the characteristic “spaghetti and meatballs” yeast form pattern of tinea versicolor can be an extremely helpful distinguishing finding.

What is the treatment for acanthosis nigricans?

The mainstay for treatment is to manage the underlying disease. Patient education is also an important component.

General measures

• Non-pharmacologic treatment includes lifestyle modifications, such as establishing healthy eating habits and increasing exercise with the aim of improving insulin resistance/glucose metabolism.
• Pharmacologic treatment includes metformin and rosiglitazone, which are used to reduce insulin levels and moderately improve AN.
• Malignant acanthosis nigricans should be addressed with careful workup and management of any underlying malignancy. Cyproheptadine has been shown to aid in the regression of malignancy-associated AN by inhibiting the release of paraneoplastic, tumour-produced factors that contribute to AN.
• Resolution of drug-induced AN requires identification and withdrawal of the suspected drug(s).
• Syndromic AN may be improved with treatment of the underlying syndrome, such as with the use of oral contraceptives in the setting of polycystic ovarian syndrome.

Specific measures

Treatment of acanthosis nigricans can also be undertaken for cosmetic reasons. Towards this end, some pharmacologic modalities include:

• Keratolytic agents: salicylic acid, glycolic acid, trichloroacetic acid
• Topical retinoids: adapalene gel, tretinoin cream
• Calcipotriol
• Omega-3 fatty acids (eg, fish oil)
• Podophyllin.

Procedural modalities include:

• Psoralen plus UVA (PUVA)
• Dermabrasion
• Long-pulsed alexandrite laser

What is the outcome for acanthosis nigricans?

Outcomes depend on the cause. Acanthosis nigricans may be a vital marker of underlying conditions which themselves carry significant risk to overall morbidity and mortality, such as obesity, metabolic syndrome, diabetes, and even serious internal malignancies.

Outcomes naturally depend on the underlying cause of the AN. If the underlying etiology can be addressed, such as through weight loss interventions, then the acanthosis nigricans is expected to improve or fully resolve. Obesity, metabolic syndrome, and diabetes have deleterious effects on overall morbidity and mortality. Hereditary acanthosis nigricans may stabilise or even regress spontaneously in some cases. Malignant acanthosis nigricans, however, is associated with a poor prognosis, with an average survival time of two years from diagnosis of the AN due to mortality from advanced underlying malignancy.

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