Acanthosis Nigricans

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 (Open Table in a new window)

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.

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.

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.

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.