Acanthosis Nigricans

Background

Although Addison may have seen a case of acanthosis nigricans (AN) before 1885 and misdiagnosed it as Addison disease, the first documented case of acanthosis nigricans was in 1889 in Germany as described by Unna and Pollitzer. By 1909, acanthosis nigricans 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 acanthosis nigricans and insulin resistance was first described. In 2000, the American Diabetes Association established acanthosis nigricans as a formal risk factor for the development of diabetes in children.^[1]

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Pathophysiology

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

In the benign form of acanthosis nigricans, 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 (epidermal growth factor receptor [EGFR] or fibroblast growth factor receptor [FGFR]).

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.^[2]

Familial and syndromic forms of acanthosis nigricans have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin-resistance syndromes and fibroblast growth factor 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 acanthosis nigricans and hypertension), 1-acylglycerol-3-phosphate O-acyl transferase-2 or seipin (Berardinelli-Seip syndrome), lamin A/C (Dunnigan syndrome), and Alstrom syndrome gene. Fibroblast growth factor defects include activating mutations in FGFR2 (Beare-Stevenson syndrome), FGFR3 (Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, severe achondroplasia with developmental delay, and acanthosis nigricans [SADDAN]). Familial cases of acanthosis nigricans with no other syndromic findings have also been linked to FGFR mutations.^{[3, 4]}

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

In malignant acanthosis nigricans, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)–alpha is structurally similar to epidermal growth factor and is a likely candidate. TGF-alpha and epidermal growth factor have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within acanthosis nigricans lesions. Reports of urine and serum TGF-alpha levels normalizing after surgical tumor removal exist, with subsequent regression of skin lesions.^[5]

Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely due to activation of IGF receptors.^{[6, 7]} Agents such as palifermin (recombinant keratinocyte growth factor used to decrease mucositis with chemotherapy and stem cell transplantation) have reportedly produced transient but dramatic acanthosis nigricans–like lesions, presumably due to activation of the FGFR.^[8]

Of interest, ectopic acanthosis nigricans has been described in a syndromic patient who required skin grafting from the groin for syndactyly repair, with delayed acanthosis nigricans formation at the graft sites.^[9]

Table. Acanthosis Nigricans Associations

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See Table

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Etiology

The definitive cause for acanthosis nigricans has not yet been ascertained, although several possibilities have been suggested. Nine types of acanthosis nigricans have been described.

Obesity-associated acanthosis nigricans

Obesity-associated acanthosis nigricans, once labeled pseudo–acanthosis nigricans, is the most common type of acanthosis nigricans. 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; however, it is not universal.

Obesity-associated acanthosis nigricans may be a marker for higher insulin needs in obese women with gestational diabetes.^[12] Acanthosis nigricans has been shown to be a reliable early marker for metabolic syndrome in pediatric patients.^{[13, 14]}

Syndromic acanthosis nigricans

Syndromic acanthosis nigricans is the name given to acanthosis nigricans that is associated with a syndrome. In addition to the widely recognized association of acanthosis nigricans with insulin resistance, acanthosis nigricans has been associated with numerous syndromes (see the Table in Pathophysiology). The type A syndrome and type B syndrome are special examples.

The type A syndrome also is termed the hyperandrogenemia, insulin resistance, and acanthosis nigricans syndrome (HAIR-AN syndrome). This syndrome 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 acanthosis nigricans 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, scleroderma, Sjögren syndrome, or Hashimoto thyroiditis. Circulating antibodies to the insulin receptor may be present. In these patients, the lesions of acanthosis nigricans are of varying severity.

Acral acanthosis nigricans

Acral acanthosis nigricans (acral acanthotic anomaly) occurs in patients who are in otherwise good health. Acral acanthosis nigricans 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 acanthosis nigricans, sometimes referred to as nevoid acanthosis nigricans, 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 acanthosis nigricans lesions may represent a unilateral epidermal nevus.

Generalized acanthosis nigricans

Generalized acanthosis nigricans is rare and has been reported in pediatric patients without underlying systemic disease or malignancy.^[15]

Familial acanthosis nigricans

Familial acanthosis nigricans 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 acanthosis nigricans often progresses until puberty, at which time it stabilizes or regresses.

Drug-induced acanthosis nigricans

Drug-induced acanthosis nigricans, although 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 acanthosis nigricans, developing on abdomen and flexor surfaces and resolving within 4-10 weeks of discontinuation.^[1] Rarely, triazinate, oral contraceptives, fusidic acid, and methyltestosterone have also been associated with acanthosis nigricans. Fibroblast growth factor receptor ligands such as palifermin may cause drug-induced acanthosis nigricans.^[8]

The lesions of acanthosis nigricans may regress following discontinuation of the offending medication.

Malignant acanthosis nigricans

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

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

Malignant acanthosis nigricans in pediatric patients has been described with gastric adenocarcinoma, Wilms tumor, and osteogenic sarcoma.^[1]

In 25-50% of cases of malignant acanthosis nigricans, 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 acanthosis nigricans seldom are pigmented.

Tripe palms may show altered dermatoglyphics due to alteration of epidermal rete ridges

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

Mixed-type acanthosis nigricans

Mixed-type acanthosis nigricans refers to those situations in which a patient with one of the above types of acanthosis nigricans develops new lesions of a different etiology. An example of this would be an overweight patient with obesity-associated acanthosis nigricans who subsequently develops malignant acanthosis nigricans.

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Epidemiology

Frequency

United States

The exact incidence of acanthosis nigricans is unknown. In an unselected population of 1412 children, the changes of acanthosis nigricans were present in 7.1%. Obesity is closely associated with acanthosis nigricans, and more than half the adults who weigh greater than 200% of their ideal body weight have lesions consistent with acanthosis nigricans.

The malignant form of acanthosis nigricans is far less common, and, in one study, only 2 of 12,000 patients with cancer had signs of acanthosis nigricans. The most frequent associations were with adenocarcinomas of the gastrointestinal tract (70-90%), particularly gastric cancer (55-61% of malignant acanthosis nigricans cases).

International

Epidemiologic studies performed in Iran, United Arab Emirates, and Japan all show statistically significant increases in insulin resistance among obese patients with acanthosis nigricans compared with matched obese controls without acanthosis nigricans, suggesting that acanthosis nigricans is a useful marker for insulin resistance among obese patients regardless of geographic setting.^[16]

Race

Acanthosis nigricans is much more common in people with darker skin pigmentation. The prevalence in whites is less than 1%. In Latinos, the prevalence in one study was 5.5%, and, in African Americans, the prevalence is higher, at 13.3%. The incidence is also increased in the Native American population, with one study showing 34.2% of Cherokee patients age 5-40 years with acanthosis nigricans, increasing to 73% of those Cherokee patients with diabetes.^{[17, 18]}

The prevalence in overweight children aged 7-17 years increases to 23% in Latino patients and 19.4% in African American patients. Children of any race with a body mass index greater than the 98th percentile have a 62% prevalence of acanthosis nigricans.^{[19, 20, 21]}

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

Sex

The incidence of acanthosis nigricans is equal for men and women. Acanthosis nigricans has no known sex predilection.^[1]

Age

Lesions of benign acanthosis nigricans may be present at any age, including at birth, although it is found more commonly in the adult population. Malignant acanthosis nigricans occurs more frequently in elderly persons; however, cases have been reported in children with Wilms tumor, gastric adenocarcinoma, and osteogenic sarcoma.^[1]

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Prognosis

The prognosis for patients with malignant acanthosis nigricans is often poor. The associated malignancy frequently is advanced, and the average survival of these patients is approximately 2 years.

Patients with the benign form of acanthosis nigricans 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 acanthosis nigricans in the younger population. New studies indicate that children with acanthosis nigricans have higher levels of basal and glucose-stimulated insulin compared with obese children without acanthosis nigricans, suggesting an association of acanthosis nigricans with hyperinsulinemia independent of body mass index.^{[22, 23]}

Malignant acanthosis nigricans is associated with significant complications because the underlying malignancy is often an aggressive tumor. Average survival time of patients with signs of malignant acanthosis nigricans is 2 years, although cases in which patients have survived for up to 12 years have been reported. In older patients with new-onset acanthosis nigricans, most have an associated internal malignancy.

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Patient Education

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

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History

Patients 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 acanthosis nigricans, patients present with skin changes before any signs of cancer. In another one third of cases, the lesions of acanthosis nigricans arise simultaneously with the neoplasm. In the remaining one third of cases, the skin findings manifest sometime after the diagnosis of cancer. Malignant acanthosis nigricans has been reported to appear abruptly and exuberantly and may be associated with a higher rate of pruritus.^[1]

Onset may be related to medication or supplement usage.

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Physical Examination

Acanthosis nigricans is characterized by symmetrical, 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. Occasionally, lesions of acanthosis nigricans 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 acanthosis nigricans are clinically indistinguishable from benign acanthosis nigricans.

Note the images below.

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Brown velvety plaques with skin tags in the axilla of a 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 the axilla with one skin tag.

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Complications

Complications vary depending on the etiology of acanthosis nigricans (AN). Appearance of acanthosis nigricans during childhood usually is associated with a benign condition, and no important sequelae are described.

Adult-onset acanthosis nigricans is more worrisome, and an underlying malignancy must be ruled out. However, most cases of adult-onset acanthosis nigricans 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 are due to obesity and/or insulin resistance. Screen for diabetes with a glycosylated hemoglobin level or glucose tolerance test.

Screen for insulin resistance; 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 to detect a metabolic abnormality of this kind because many younger patients do not yet have overt diabetes mellitus and an abnormal glycosylated hemoglobin level, but they do have a high plasma insulin level.

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Procedures

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

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Histologic Findings

Histologic examination reveals hyperkeratosis, papillomatosis, with 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 acanthosis nigricans reveals epithelial hyperkeratosis and papillomatosis along with parakeratosis.^[1]

Note the image below.

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Acanthosis nigricans biopsy. The epidermis is papillomatous (undulates) and pigmented ("nigricans"). Acanthosis (thickening of the spinous layer) is o....

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Medical Care

No treatment of choice exists for acanthosis nigricans (AN).^[24] The goal of therapy is to correct the underlying disease process. Treatment of the lesions of acanthosis nigricans is for cosmetic reasons only. Correction of hyperinsulinemia often reduces the burden of hyperkeratotic lesions. Likewise, weight reduction in obesity-associated acanthosis nigricans may result in resolution of the dermatosis.

Cessation of the inciting agent in drug-induced acanthosis nigricans often results in resolution. Acipimox may be used in place of nicotinic acid to induce acanthosis nigricans regression while improving the lipid profile.^[25] Dietary fish oil reportedly is beneficial in patients with lipodystrophic diabetes and generalized acanthosis nigricans, even if niacin is continued.^[26]

Topical medications that have been effective in some cases of acanthosis nigricans include keratolytics (eg, topical tretinoin 0.05%, ammonium lactate 12% cream, or a combination of the 2) and triple-combination depigmenting cream (tretinoin 0.05%, hydroquinone 4%, fluocinolone acetonide 0.01%) nightly with daily sunscreen.^[27] Calcipotriol, podophyllin, urea, adapalene, and salicylic acid also have been reported, with variable results.^{[1, 28, 29]}

Oral agents that have shown some benefit include etretinate,^[30] isotretinoin,^{[31, 32]} metformin,^[33] and dietary fish oils.^[34] Octreotide showed sustained improvement in one patient with insulin resistance 6 months after completing the course.^[35]

Hyperandrogenemia, insulin resistance, and acanthosis nigricans syndrome (HAIR-AN syndrome) patients may be treated with oral contraceptives and metformin.^[1]

Dermabrasion and long-pulsed alexandrite laser therapy may also be used to reduce the bulk of the lesion, with occasional long-term remissions.^[36]

Surgical removal of tumors is the mainstay of treatment for malignant acanthosis nigricans, if possible, because clearance following primary malignancy excision has been reported.^[37]

Cyproheptadine has been used in cases of malignant acanthosis nigricans because 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 acanthosis nigricans.^[5]

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Surgical Care

Dermabrasion and long-pulsed alexandrite laser therapy may also be used to reduce the bulk of the lesion, with occasional long-term remissions.^[39]

Surgical removal of tumors is the mainstay of treatment for malignant acanthosis nigricans, if possible, because clearance following primary malignancy excision has been described.^[37]

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Consultations

Based on underlying etiology, multidisciplinary evaluation may include the following:

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

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Diet

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

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Medication Summary

The goal of pharmacotherapy in acanthosis nigricans is to improve cosmetic appearance.

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Tretinoin topical (Avita, Retin-A)

• Dosing, Interactions, etc.

Clinical Context:  Topical tretinoin promotes detachment of cornified cells and enhances shedding of corneocytes. It inhibits microcomedo formation and eliminates lesions that are present. Tretinoin makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is available as 0.025%, 0.05%, and 0.1% creams and as 0.01% and 0.025% gels.

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Class Summary

These agents promote shedding of hyperkeratotic skin. They are modifiers of keratinocyte adhesion, differentiation, and proliferation.

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Ammonium lactate

• Dosing, Interactions, etc.

Clinical Context:  Ammonium lactate is an alpha-hydroxy acid; it is a normal constituent of tissues and blood. Ammonium lactate is believed to act as a humectant when applied to the skin. This may influence hydration of the stratum corneum. In addition, when applied to the skin, it may act to decrease corneocyte cohesion. The mechanism(s) by which this is accomplished is not yet known.

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