Acanthosis Nigricans

Background

Acanthosis nigricans (AN) is characterized by an asymptomatic area of darkening and thickening of the skin, occasionally with pruritus; lesions begin as hyperpigmented macules and patches and progress to symmetric, hyperpigmented, and velvety plaques with ill-defined borders, typically involving intertriginous areas.^[1]

Although Addison may have seen a case of acanthosis nigricans (AN) before 1885 and misdiagnosed it as Addison disease, the first documented case of AN was in 1889 in Germany, as described by Unna and Pollitzer. By 1909, AN had been described in approximately 50 patients and was suspected to be associated with internal malignancy. In 1976, Kahn et al published their landmark study in which the association between AN and insulin resistance was first described. In 2000, the American Diabetes Association established AN as a formal risk factor for the development of diabetes in children.^[2]

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Pathophysiology

AN most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation.

In the benign form of AN, the factor is probably insulin or an insulinlike growth factor (IGF) that incites the epidermal cell propagation; other proposed mediators include other tyrosine kinase receptors (eg, epidermal growth factor [EGF] receptor [EGFR] or fibroblast growth factor [FGF] receptor [FGFR]).^[3]

At high concentrations, insulin may exert potent proliferative effects via high-affinity binding to IGF-1 receptors. In addition, free IGF-1 levels may be elevated in obese patients with hyperinsulinemia, leading to accelerated cell growth and differentiation.^[4]

Familial and syndromic forms of AN have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin resistance syndromes and FGF defects.

Insulin resistance syndromes include those with mutations in the insulin receptors (ie, leprechaunism, Rabson-Mendenhall syndrome), peroxisome proliferator-activated receptor gamma (ie, type 1 diabetes with AN and hypertension), 1-acylglycerol-3-phosphate O-acyl transferase-2 or seipin (Berardinelli-Seip syndrome), lamin A/C (Dunnigan syndrome), and Alstrom syndrome gene.

FGF defects include activating mutations in FGFR2 (Beare-Stevenson syndrome), FGFR3 (Crouzon syndrome with AN, thanatophoric dysplasia, severe achondroplasia with developmental delay, and AN [SADDAN]). Familial cases of AN with no other syndromic findings have also been linked to FGFR mutations.^{[5, 6]}

Perspiration or friction may also play a contributory role, as suggested by the predilection of AN for body folds.

In malignant AN, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)-α is structurally similar to EGF and is a likely candidate. TGF-α and EGF have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within AN lesions. Normalization of urine and serum TGF-α levels after surgical tumor removal has been reported, with subsequent regression of skin lesions.^[7]

Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely through activation of IGF receptors.^{[8, 9]} Agents such as palifermin (recombinant keratinocyte growth factor used to decrease mucositis with chemotherapy and stem cell transplantation) have reportedly produced transient but dramatic AN-like lesions, presumably due to activation of the FGFR.^[10]

Ectopic AN has been described in a syndromic patient who required skin grafting from the groin for syndactyly repair, with delayed AN formation at the graft sites.^[11]

Conditions associated with AN include those listed in Table 1 below.

Table 1. Acanthosis Nigricans Associations

View Table

See Table

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Etiology

The definitive cause of AN remains to be established, though several possibilities have been suggested. Nine types of AN have been described.

Obesity-associated acanthosis nigricans

Obesity-associated AN, once labeled pseudo–acanthosis nigricans, is the most common type. Lesions may appear at any age but are more common in adulthood. The dermatosis is weight-dependent, and lesions may completely regress with weight reduction. Insulin resistance is often present in these patients but is not universal.

Obesity-associated AN may be a marker for higher insulin needs in obese women with gestational diabetes.^[14] AN has been shown to be a reliable early marker for metabolic syndrome in pediatric patients.^{[15, 16]}

Syndromic acanthosis nigricans

In addition to the widely recognized association of AN with insulin resistance, AN has been associated with numerous syndromes (see Pathophysiology, Table 1). The type A syndrome and type B syndromes are special examples.

The type A syndrome is also is termed the HAIR-AN (hyperandrogenemia, insulin resistance, and AN) syndrome. It is often familial, affecting primarily young women (especially Black women). It is associated with polycystic ovaries or signs of virilization (eg, hirsutism, clitoral hypertrophy). High plasma testosterone levels are common. The lesions of AN may arise during infancy and progress rapidly during puberty.

The type B syndrome generally occurs in women who have uncontrolled diabetes mellitus, ovarian hyperandrogenism, or an autoimmune disease such as systemic lupus erythematosus (SLE), scleroderma, Sjögren syndrome, or Hashimoto thyroiditis. Circulating antibodies to the insulin receptor may be present. In these patients, the lesions of AN are of varying severity.

Acral acanthosis nigricans

Acral AN (acral acanthotic anomaly) occurs in patients who are in otherwise good health. Acral AN is most common in dark-skinned individuals, especially those of African American or sub-Saharan African descent. The hyperkeratotic velvety lesions are most prominent over the dorsal aspects of the hands and feet, with knuckle hyperpigmentation often most prominent.

Unilateral acanthosis nigricans

Unilateral AN, sometimes referred to as nevoid AN, is believed to be inherited as an autosomal dominant trait. Lesions are unilateral in distribution and may become evident during infancy, childhood, or adulthood. Lesions tend to enlarge gradually before stabilizing or regressing. Unilateral AN lesions may represent a unilateral epidermal nevus.

Generalized acanthosis nigricans

Generalized AN is rare and has been reported in pediatric patients without underlying systemic disease or malignancy.^[17]

Familial acanthosis nigricans

Familial AN is a rare genodermatosis that seems to be transmitted in an autosomal dominant fashion with variable phenotypic penetrance. The lesions typically begin during early childhood but may manifest at any age. Familial AN often progresses until puberty, at which time it stabilizes or regresses.

Drug-induced acanthosis nigricans

Drug-induced AN, though uncommon, may be induced by several medications, including nicotinic acid, insulin, pituitary extract, systemic corticosteroids, and diethylstilbestrol. Nicotinic acid is most widely recognized association, with AN developing on abdomen and flexor surfaces and resolving within 4-10 weeks after discontinuance.^[2] Rarely, triazinate, oral contraceptives, fusidic acid, and methyltestosterone have also been associated with AN. FGFR ligands such as palifermin may cause drug-induced AN.^[10]

The lesions of AN may regress once the offending medication has been discontinued.

Malignant acanthosis nigricans

Malignant AN, which is associated with internal malignancy, is the most worrisome of the AN variants because the underlying neoplasm is often an aggressive cancer (see Pathophysiology, Table 1).

AN has been reported with many kinds of cancer, but by far the most common underlying malignancy is an adenocarcinoma of gastrointestinal (GI) origin, usually a gastric adenocarcinoma. In an early study of 191 patients with malignant AN, 92% had an underlying abdominal cancer, of which 69% were gastric. Another study reported 94 cases of malignant AN, of which 61% were secondary to a gastric neoplasm.

Malignant AN in pediatric patients has been described with gastric adenocarcinoma, Wilms tumor, and osteogenic sarcoma.^[2]

In 25-50% of cases of malignant AN, the oral cavity is involved. The tongue and the lips most commonly are affected, with elongation of the filiform papillae on the dorsal and lateral surfaces of the tongue and multiple papillary lesions appearing on the commissures of the lips. Oral lesions of AN seldom are pigmented.

Tripe palms (acanthosis palmaris) may show altered dermatoglyphics due to alteration of epidermal rete ridges.

Malignant AN is clinically indistinguishable from the benign forms; however, one must be more suspicious if the lesions arise rapidly, are more extensive, are symptomatic, or are in atypical locations.

Regression of AN has been seen with treatment of the underlying malignancy, and reappearance may suggest recurrence or metastasis of the primary tumor.

Mixed-type acanthosis nigricans

In mixed-type AN, a patient with one of the above types of AN develops new lesions of a different etiology. An example of this would be an overweight patient with obesity-associated AN who subsequently develops malignant AN.

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Epidemiology

US and international statistics

The exact incidence of AN in the United States has not been defined; the prevalence has been estimated to be as high as 19.4%.^[18] In an unselected population of 1412 children, the changes of AN were present in 7.1%. Obesity is closely associated with AN, and more than half of adults whose weight exceeds 200% of their ideal body weight (IBW) have lesions consistent with AN. The malignant form of AN is far less common, and in one study, only two of 12,000 patients with cancer had signs of AN. The most frequent associations have been with adenocarcinomas of the GI tract (70-90%), particularly gastric cancer (55-61% of malignant AN cases).

Epidemiologic studies performed in Iran, United Arab Emirates, and Japan have shown statistically significant increases in insulin resistance among obese patients with AN as compared with matched obese controls without AN, suggesting that AN is a useful marker for insulin resistance among obese patients regardless of geographic setting.^[19]

Age-, sex-, and race-related demographics

Lesions of benign AN may be present at any age, including at birth, though the condition is more common in adults. Malignant AN occurs more frequently in elderly persons; however, cases have been reported in children with Wilms tumor, gastric adenocarcinoma, and osteogenic sarcoma.^[2]

AN can affect both males and females; no sex predilection has been definitively established.^[2]

AN is much more common in people with darker skin pigmentation. The prevalence in Whites has been reported as below 1%; that in African Americans has been reported to be as high as 13.3%. In one study, the prevalence in Latinos was 5.5%. The incidence has also been found to be increased in the Native American population, with one study reporting acanthosis nigricans in 34.2% of Cherokee patients aged 5-40 years and 73% of Cherokee patients with diabetes.^{[20, 21]}

There remains a need for further data on race- and ethnicity-related factors in AN. A systematic review of 21 clinical trials (N = 575) on AN found that 10 of the 21 did not include any data on Fitzgerald skin type (FST).^[22] In the 11 that did include such data, patients were predominantly FST III (20.6%), FST IV (50.0%), or FST V (28.2%); only a few (1.2%) were FST II, and none were FST I or VI. These findings suggested the importance of including all skin types in future research.

The prevalence in overweight children aged 7-17 years has been reported as 23% in Latino patients and 19.4% in African American patients. Children of any race with a body mass index (BMI) above the 98th percentile have a 62% prevalence of AN.^{[23, 24, 25]}

In contrast to the benign form, malignant AN has no racial predilection.

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Prognosis

Patients with benign AN experience very few, if any, complications of their skin lesions. However, many of these patients have an underlying insulin-resistant state that is the cause of their acanthosis nigricans. The severity of the insulin resistance is highly variable and ranges from an incidental finding after routine blood studies to overt diabetes mellitus. The severity of skin findings may parallel the degree of insulin resistance, and a partial resolution may occur with treatment of the insulin-resistant state.

Insulin resistance is the most common association of AN in the younger population. The finding that children with AN have higher levels of basal and glucose-stimulated insulin than obese children without AN suggests an association of AN with hyperinsulinemia that is independent of BMI.^{[26, 27]}

Patients with malignant AN have a poorer prognosis because the underlying malignancy is often an aggressive tumor. The average survival time for patients with signs of malignant AN is 2 years, though cases in which patients have survived for as long as 12 years have been reported. Most older patients with new-onset AN have an associated internal malignancy.

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Patient Education

Patients should be informed that AN is not a skin disease per se but, rather, a sign of an underlying problem. If a patient does have AN related to insulin resistance, which is the most common association, treatment of the metabolic abnormality may lead to improvement of the appearance of the skin. Dietary changes and weight loss may cause AN to regress almost completely.

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History

Patients with acanthosis nigricans (AN) usually present with an asymptomatic area of darkening and thickening of the skin. Pruritus occasionally may be present. Lesions begin as hyperpigmented macules and patches and progress to palpable plaques.

In approximately one third of cases of malignant AN, patients present with skin changes before any signs of cancer are apparent. In another one third, the lesions of AN arise simultaneously with the neoplasm. In the remaining one third, the skin findings manifest sometime after the diagnosis of cancer. Malignant AN has been reported to appear abruptly and exuberantly and may be associated with a higher rate of pruritus.^[2]

Onset may be related to medication or supplement usage.

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Physical Examination

AN is characterized by symmetricl, hyperpigmented, velvety plaques that may occur in almost any location but most commonly appear on the intertriginous areas of the axilla, groin, and posterior neck. The posterior neck is the most commonly affected site in children. Acrochordons (skin tags) are often found in and around the affected areas. (See the images below.)

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Brown velvety plaques with skin tags in axilla of patient with acanthosis nigricans.

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Acanthosis nigricans.

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Acanthosis nigricans (obesity-related).

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Acanthosis nigricans of axilla with one skin tag.

Occasionally, lesions of AN may be present on the mucous membranes of the oral cavity, nasal and laryngeal mucosa, and esophagus. The areola of the nipple also may be affected. Eye involvement, including papillomatous lesions on the eyelids and conjunctiva, may occur. Nail changes, such as leukonychia and hyperkeratosis, have been reported.

The lesions of malignant AN are clinically indistinguishable from those of benign AN.

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Complications

Complications of AN vary, depending on the cause. The appearance of AN during childhood usually is associated with a benign condition, and no important sequelae are described. Adult-onset AN is more worrisome, and an underlying malignancy must be ruled out; however, most cases of adult-onset AN are benign and often are associated with insulin resistance.

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Laboratory Studies

In middle-aged and older patients with extensive skin or severe skin and mucosal findings, a workup for internal malignancy is indicated.

The vast majority of cases of acanthosis nigricans (AN) are due to obesity, insulin resistance, or both. Screening for diabetes may be done with a glycosylated hemoglobin level or a glucose tolerance test. A good screening test for insulin resistance is a plasma insulin level, which will be high in those with insulin resistance. This is the most sensitive test for detecting a metabolic abnormality of this kind because many younger patients do not yet have overt diabetes mellitus and an abnormal glycosylated hemoglobin level but do have a high plasma insulin level.

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Procedures

Skin biopsy may be useful if a clinical diagnosis is not easily made.

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Histologic Findings

Histologic examination reveals hyperkeratosis, papillomatosis, and minimal or no acanthosis or hyperpigmentation. The dermal papillae project upward as fingerlike projections, with occasional thinning of the adjacent epidermis. Pseudohorn cysts may be present. Clinical dyschromia is secondary to the hyperkeratosis and not to increased melanocytes or increased melanin deposition. Dermal inflammatory infiltrate is minimal or nonexistent. Mucosal AN reveals epithelial hyperkeratosis and papillomatosis along with parakeratosis.^[2] (See the image below.)

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Acanthosis nigricans biopsy. Epidermis is papillomatous and pigmented. Acanthosis (thickening of the spinous layer) is often not really present; thus,....

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Medical Care

No treatment of choice has been established for acanthosis nigricans (AN).^[28] The goal of therapy is to correct the underlying disease process. Treatment of the lesions of AN is for cosmetic reasons only. Correction of hyperinsulinemia often reduces the burden of hyperkeratotic lesions. Likewise, weight reduction in obesity-associated AN may result in resolution of the dermatosis.

Cessation of the inciting agent in drug-induced AN often results in resolution. Acipimox may be used in place of nicotinic acid to induce AN regression while improving the lipid profile.^[29] Dietary fish oil may be beneficial in patients with lipodystrophic diabetes and generalized AN, even if niacin is continued.

Topical medications that have been effective in some cases of AN include keratolytics (eg, topical tretinoin 0.05% or 0.025%,^[30] ammonium lactate 12% cream, or a combination of the two) and triple-combination depigmenting cream (tretinoin 0.05%, hydroquinone 4%, fluocinolone acetonide 0.01%) nightly with daily sunscreen.^{[31, 32]}  Calcipotriol, podophyllin, urea, adapalene, and salicylic acid also have been reported, with varying results.^{[2, 33, 34]}

Oral agents that have shown some benefit include etretinate, isotretinoin,^[35] metformin,^[36] and dietary fish oils. Octreotide yielded sustained improvement in one patient with insulin resistance 6 months after completion of the course.^[37]

Patients with HAIR-AN (hyperandrogenemia, insulin resistance, and AN) syndrome may be treated with oral contraceptives and metformin.^[2]

Cyproheptadine has been used in cases of malignant AN on the grounds that it may inhibit the release of tumor products.^[38]

Psoralen plus UVA (PUVA) has been reported as beneficial for symptomatic relief in cases of paraneoplastic AN.^[7]

Dermabrasion and laser therapy may also be used to reduce the bulk of the lesion, with occasional long-term remissions.^{[39, 40]}  Chemical peeling (eg, with glycolic acid or trichloroacetic acid) may be effective.^[41]

A 2024 systematic review (19 trials) of topical, laser, and oral therapies for AN yielded a strong recommendation for topical tretinoin and endorsed appropriate use of adapalene gel, urea cream, and fractional carbon dioxide laser therapy.^[18]

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Surgical Care

Surgical removal of tumors is the mainstay of treatment for malignant AN, if possible, because clearance following primary malignancy excision has been described.^[42]

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Diet

Weight loss and glycemic control are essential for those with obesity-related AN or hyperinsulinemic states.

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Consultations

Depending on the underlying etiology of AN, multidisciplinary evaluation may include the following:

• Primary care physician (pediatrician, internist, or family practitioner)
• Endocrinologist
• Oncologist
• Geneticist
• Dermatologist

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Tretinoin topical (Altreno, Atralin, Avita)

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Adapalene (Differin)

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Ammonium lactate (AmLactin, Lac Hydrin, Proxymetacaine)

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Urea topical (Ureacin 10, Aquacare, Carmol 10)

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Isotretinoin (Absorica, Absorica LD, Amnesteem)

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Fluocinolone/tretinoin/hydroquinone (Tri-Luma)

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Fluocinolone/tretinoin/hydroquinone (Tri-Luma)

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Calcipotriene (Calcitrene Ointment, Dovonex, Sorilux)

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Metformin (Glucophage (DSC), Glucophage XR (DSC), Glumetza)

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