Acanthosis Nigricans 

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]

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] Newer 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.^[7]

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.^[8]

Table. Acanthosis Nigricans Associations (Open Table in a new window)

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). Approximately 61.3% of cases are diagnosed simultaneously with the cancer manifestation, while 17.6% of malignant acanthosis nigricans cases predate the diagnosis of malignancy.^[5]

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.^[9]

Mortality/Morbidity

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.^{[10, 11]}

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.

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.^[12]

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.^{[13, 14]}

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]