Acanthosis (Latin for thick) nigricans (Latin for dark) (AN) is a rare skin disorder characterized by poorly defined, darkening (light brown to black) (hyperpigmentation) and velvety thickening (hyperkeratosis) of the skin. AN occurs mainly in the folds of the skin in the armpit (axilla), groin, umbilicus and posterior and lateral folds of the neck with very visible markings and creases.   

The posterior neck is the most commonly affected site in children and the vulva in females who are hyperandrogenic and obese.

Sometimes, the lips, palms, soles of feet, or other areas (the knuckles, between the legs, the elbow, under the breasts, around the belly button, the areola of the nipple) may be affected.  

AN lesions may also appear on the mucous membranes of the oral cavity, nasal and laryngeal mucosa and oesophagus.

Acanthosis nigricans can begin at any age including at birth, although it is found more commonly in the adult population. The skin changes appear slowly, sometimes over months or years as hyperpigmented macules and patches that progress to palpable plaques. Usually asymptomatic, occasionally, the affected areas may itch.

Papillomatosis (multiple finger-like growths) is common on cutaneous and mucosal surfaces. Acrochordons (skin tags) are often found in and around the affected areas. Acanthosis nigricans usually doesn't cause any symptoms other than skin changes but sometimes pruritus (itching) may be present. The incidence of AN is equal for men and women.  

It's much more common and most obvious in people who have darker skin pigmentation. There are two important types of acanthosis: benign and malignant. Although classically described as a sign of internal malignancy, this is very rare. Malignant AN is clinically indistinguishable from the benign forms.

Lesions of benign AN may be present at any age, Malignant AN occurs more frequently in elderly persons; Appearance of AN during childhood usually is associated with a benign condition, and there are no important sequelae. Adult onset AN, especially  of abrupt onset, needs particular attention and an underlying malignancy must be ruled out. However, most cases of adult onset AN are benign and often are associated with insulin resistance.

AN  is not a skin disease per se but a cutaneous sign of various benign and malignant conditions.

AN may be a skin manifestation of insulin resistance, which is a condition characterized by impaired biological responses to insulin (insulin is a hormone produced by the pancreas that regulates blood glucose levels) because the body becomes resistant to its effects. Insulin resistance leads to chronic hyperinsulinemia, which in turn stimulates increased ovarian production of testosterone and also has growth-promoting effects on fibroblasts and keratinocytes to produce the clinical features. Why AN develops, is not yet been clearly defined but 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. 

In malignant AN, the stimulating factor could be a substance secreted either by the tumor or in response to the tumor. It is very important to differentiate acanthosis nigricans related to malignancy from that related to benign conditions because tumours in malignant AN are usually very aggressive and spread quickly.

When acanthosis nigricans develops in older patients, not overweight but with weight loss, without known cancer and it is of recent onset, it is extremely important to perform a thorough medical work-up. If the hidden tumour is idenfied and successfully treated, the AN may resolve.

AN is often associated with type 2 diabetes or obesity. In some cases, it is inherited. Certain medications  - such as human growth hormone, oral contraceptives (“the pill”) and large doses of niacin – can contribute to the condition. Rarely, AN (severe) is associated with certain types of cancer (lymphoma or cancer of the gastrointestinal or genitourinary tracts) Based on the pre-disposing conditions, acanthosis nigricans may be divided in:

• Benign Acanthosis Nigricans

• Pseudoacanthosis Nigricans

• Acanthosis Nigricans With Insulin Resistance (HAIR-AN syndrome) Type A

• Acanthosis Nigricans With Insulin Resistance (HAIR-AN syndrome) Type B

• Drug-induced Acanthosis Nigricans

• Hereditary Benign Acanthosis Nigricans

• Malignant Acanthosis Nigricans

• Mixed-type Acanthosis Nigricans

• Unilateral Acanthosis Nigricans

Pseudoacanthosis Nigricans (now called Obesity associated AN). It is the most common type of AN. Lesions may appear at any age but are more common in adulthood.

• It is weight dependent and lesions may completely regress with weight reduction.

Benign acanthosis nigricans or Acral AN  (acral acanthotic anomaly) occurs in patients who are in otherwise good health.

• most common in dark-skinned individuals, especially those of African American descent.

• thick, hyperkeratotic velvety lesions are most prominent over the dorsal aspects of the hands and feet in patients in otherwise good health.

Acanthosis Nigricans with Insulin Resistance (HAIR-AN syndrome) Type  A HAIR-AN means hyperandrogenemia, insulin resistance, and AN syndrome. Type A affects young women with severe AN and hyperandrogenism. It is often familial and is associated with polycystic ovaries or signs of virilization (eg, hirsutism, clitoral hypertrophy). The lesions of AN may arise during infancy and progress rapidly during puberty. 

Acanthosis Nigricans with Insulin Resistance (HAIR-AN syndrome) Type  B  generally occurs in older women with AN of varying severity, who have circulating autoantibodies to the insulin receptors. These women have uncontrolled diabetes mellitus, ovarian hyperandrogenism, or an autoimmune disease (e.g. systemic lupus erythematosus, scleroderma, Sjögren syndrome, or Hashimoto thyroiditis). 

Drug-induced AN, uncommon, may be induced by several medications, including human growth hormone, oral contraceptives and large doses of niacin, insulin, pituitary extract, systemic corticosteroids, estrogens, somatotropin.

• the lesions of AN may regress following the discontinuation of the offending medication.

Hereditary benign acanthosis nigricans or 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.

• The condition often tend to enlarge gradually until puberty, before stabilising and/or regressing on their own.

Malignant AN, which is associated with internal malignancy, is the most worrisome of the variants of AN because the underlying neoplasm is often an aggressive cancer.

In this case acanthosis nigricans is a paraneoplastic syndrome.  Patients with malignant AN tend to be middle-aged, not obese, losing weight, and lesions are of recent onset, of abruptly development, are more extensive, more florid, symptomatic, more severe or are in atypical locations (often involving oral and conjunctival mucosae, and the palms.

Palmar markings and fingerprints are exaggerated and are known as ‘tripe palms’) . Skin changes may arise  before any signs of cancer (one third of cases), simultaneously with the neoplasm (one third of cases), after the diagnosis of cancer (remaining one third of cases).  

AN 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.

• the oral cavity (tongue and lips) is involved in 25-50% of cases. Multiple papillary lesions appear on the commissures of the lips and the filiform papillae on the dorsal and lateral surfaces of the tongue are elongated and seldom pigmented.

• the treatment of the underlying malignancy induce regression of AN; reappearance may suggest recurrence or metastasis of the primary tumor.

Mixed-type acanthosis nigricans in which patients with one type of the above types of AN also develop new lesions of a different cause.

• e.g. overweight patient with obesity-associated AN who subsequentely develops malignant AN.

Unilateral AN (nevoid AN), is an inherited type.

• Lesions are unilateral in distribution, may become evident during infancy, childhood, or adulthood and tend to enlarge gradually before stabilizing or regressing.

There's no specific treatment for AN. However treating any underlying medical conditions that may be causing skin changes, may induce AN  to fade:

• Correct hyperinsulinaemia through dietary changes and medication

• Lose weight with obesity-associated AN

• Excise or treat underlying tumour

• Stop offending medicines in drug-induced AN

Treatment to just improve the appearance includes Retin-A, 20% urea, alpha hydroxyacids, and lactic or salicylic acid prescriptions. Dermabrasion or laser therapy may help reduce the thickness of certain affected areas.