Acanthosis Nigricans

Acanthosis nigricans is a velvety, darkening of the skin that usually occurs in intertriginous areas.  This hyperpigmentation has poorly defined borders, usually occurs in skin fold areas, such as the back of the neck, axilla, and groin, and may include thickening of the skin. Acanthosis nigricans is most commonly associated with diabetes and insulin resistance, but rarely it can be a sign of internal malignancy. It can also occur with hormone disorders, and with the use of certain medications like systemic glucocorticoids and oral contraceptives.[1][2][3]

There are multiple factors involved in the development of acanthosis nigricans.[4] 

• Increased circulating insulin that activates keratinocyte insulin-like growth factor (ILGF) receptors, particularly IGF-1. At high concentrations, insulin may displace IGF-1 from IGF binding protein. Increased circulating IGF may lead to keratinocyte and dermal fibroblast proliferation.
• Hereditary variants are associated with fibroblast growth factor defects.
• Increased transforming growth factor (TGF) appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the epidermal growth factor receptor.

Familial Acanthosis nigricans: may arise as a result of an autosomal dominant trait, presenting at birth or during childhood. It occurs due to mutations in fibroblast growth factor receptor 3 (FGFR3).[5]

Obesity-associated Acanthosis nigricans: Obesity is one of the most common conditions associated with Acanthosis nigricans. Lesions are usually common in adulthood but can occur at any age. It was once labeled as “pseudoacanthosis nigricans". It may be associated with insulin resistance. Treating obesity with diet, weight reduction or medications can result in revolvement of Acanthosis nigricans.[6][7]

Medications associated Acanthosis nigricans: Multiple medications have been linked to Acanthosis nigricans. These include the use of nicotinic acid, systemic glucocorticoids, diethylstilbestrol, combined oral contraceptive pill, growth hormone therapy, estrogen, protease inhibitors, niacin, injected insulin. Once the offending medication is stopped, acanthosis nigricans usually resolves.[8][9][10] 

Acanthosis nigricans associated with endocrine dysfunction: It is more insidious in onset, less widespread, and patients are often obese. Insulin-resistance syndromes may be divided into type A (HAIR-AN) and type B syndromes. Type A syndromes present with hyperandrogenemia, insulin resistance, and Acanthosis nigricans. Type B syndrome usually occurs in females who have uncontrolled diabetes, ovarian hyperandrogenism or autoimmune disease like SLE, Sjogren's syndrome, scleroderma. Polycystic ovarian syndrome (PCOS) is associated with Acanthosis nigricans. Insulin resistance and hyperandrogenism are seen in patients with PCOS.[11]

Acral acanthotic anomaly: Refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet. It is common in individuals who have dark skin.[12]

Malignant Acanthosis nigricans syndrome: Is associated with gastrointestinal adenocarcinomas and genitourinary cancers such as prostate, breast, and ovary. Lung cancer and lymphoma rarely are associated with acanthosis nigricans. Malignant acanthosis nigricans may precede, accompany, or follow the onset of internal cancer. Malignancy-associated acanthosis nigricans usually has a rapid onset and is accompanied by skin tags, multiple seborrheic keratoses (sign of Leser-Trelat), or tripe palms.[13][14]

Auto-immune Acanthosis nigricans: Is associated with autoimmune disorders like SLE, Sjogren's syndrome, scleroderma or Hashimoto's thyroiditis.[15]

Unilateral Acanthosis nigricans: Also called as nevoid Acanthosis nigricans. It is very rare and is inherited in an autosomal dominant fashion. Lesions occur unilaterally. Lesions present at infancy, childhood or adulthood.[16]

Acanthosis nigricans typically occurs in individuals younger than the age of  40 years and is associated with obesity, hypothyroidism, acromegaly, polycystic ovary disease, insulin-resistant diabetes, Cushing, and Addison diseases. Acanthosis nigricans is also associated with rare diseases such as pinealoma, Cushing's disease, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, leprechaunism, lipoatrophic diabetes, pineal hyperplasia syndrome, and Alstrom syndrome.[17][18]

In the United States population, Acanthosis nigricans is more common in Native Americans, African Americans, and Hispanics when compared to Whites or Asian origin individuals.[19][20]

The pathogenesis of acanthosis nigricans is likely related to growth factor levels and insulin-mediated activation of insulin-like growth factor (IGF) on keratinocytes and increased growth factor levels. The pathophysiological process behind acanthosis nigricans appears to be related to the proliferation of fibroblasts and the enhanced stimulation of epidermal keratinocytes.[21]

In patients with benign acanthosis nigricans, evidence suggests that insulin or an insulin-like growth factor is enhancing the propagation of epidermal cells. Other mediators that have been identified include fibroblast growth factor, tyrosine kinase receptors (epidermal growth factor receptor). High concentrations of insulin are thought to cause proliferative effects by binding to IGF-1 receptors. It is important to note that free IGF-1 levels also are high in people with metabolic syndrome, leading to faster cell differentiation and cell growth.

Recently, both syndromic and familial forms of acanthosis nigricans have been observed. Familial and syndromic forms of acanthosis nigricans have been identified. Many other syndromes share similar features, such as hyperinsulinemia, craniosynostosis, and obesity. These are subdivided into insulin-resistant syndromes and fibroblast growth factor defects.

Other insulin resistant syndromes include Rabson Mendenhall syndrome, leprechaunism, Berardinelli-Seip syndrome, Dunningan syndrome, and Alstrom syndrome. Excessive friction or sweating may also be playing a contributory role.

In patients with malignant acanthosis nigricans, the most probable stimulating factor is secreted by the cancer cells. Two possibilities are transforming growth factor or epidermal growth factor because both have high levels in people with gastric adenocarcinoma. Other reports indicate normalization of urine transforming growth factor after surgical removal of a tumor, followed by regression of the skin lesions.

Usage of medications like insulin have also been implicated, most likely due to the activation of IGF receptors. A few case reports on ectopic acanthosis nigricans in syndromic patients report patient acquisition of the disorder after skin grafting from an affected site.

The histological exam will reveal papillomatosis, hyperkeratosis with minimal hyperpigmentation. The dermal papillae usually have an upward projection with thinning of the epidermis. There is usually no dermal inflammatory infiltrate.