Acanthosis nigricans

Acanthosis nigricans is a cutaneous finding characterized by brown-to-black, velvety hyperpigmentation of the skin, most often affecting body folds such as the posterior neck, axillae, groin and umbilicus.^[1] It is strongly associated with insulin resistance and hyperinsulinaemia, including in type 2 diabetes and metabolic syndrome. Excess insulin activates insulin and insulin-like growth factor signalling pathways, stimulating proliferation of keratinocytes and fibroblasts and producing the characteristic plaques.^[2]

Acanthosis nigricans
Acanthosis nigricans on the armpit
Specialty	Dermatology

Acanthosis nigricans may also occur in hereditary syndromes, as a reaction to medications or as a paraneoplastic syndrome associated with internal malignancy. In children, it is an important clinical marker of metabolic and cardiometabolic risk.^[3]

Signs and symptoms

Acanthosis nigricans presents as hyperpigmented, velvety plaques with poorly defined borders. Common sites include:

• posterior and lateral neck folds
• axillae
• groin and genitals
• umbilicus
• elbows and knees
• forehead, periorbital and perioral areas

Lesions are usually asymptomatic, though mild pruritus may occur.^[1]

Causes

Acanthosis nigricans arises from several distinct mechanisms. It most commonly reflects insulin resistance and is frequently associated with type 2 diabetes, obesity and endocrine disorders such as hypothyroidism, acromegaly, polycystic ovary syndrome and Cushing's disease.^[4][5] It may also be inherited, medication-related or associated with internal malignancy. Review articles describe acanthosis nigricans primarily as a marker of systemic metabolic dysfunction rather than a primary skin disease.^[6][7][8]

Acral acanthotic anomaly

Acral acanthotic anomaly is a localized variant affecting the elbows, knees, knuckles and dorsal feet. It occurs in otherwise healthy individuals, and its etiology is unknown.^[9][10] It is not associated with internal disease.^[11]

Familial (Type I)

Familial acanthosis nigricans is an autosomal dominant condition presenting at birth or during childhood.^[12][13]

• 
  Familial acanthosis nigricans

Endocrine (Type II)

Endocrine-associated acanthosis nigricans occurs in metabolic or hormonal disorders that alter glucose or androgen levels.^[14]: 978

Common associated conditions include:

• marked insulin resistance (diabetes mellitus, metabolic syndrome)
• androgen excess (acromegaly, Cushing's disease, polycystic ovary syndrome)
• Addison's disease and hypothyroidism
• rare syndromes including Alström syndrome, Prader–Willi syndrome, leprechaunism, pinealoma, lipoatrophic diabetes, pituitary basophilism, pineal hyperplasia, ovarian hyperthecosis, stromal luteoma and ovarian dermoid cysts

This form usually has a gradual onset and often occurs in people who are also obese.^[15]: 676

• 
  Skin tags (acrochordons), which may accompany endocrine-associated AN

Malignancy (Type V)

Malignant acanthosis nigricans is a paraneoplastic syndrome most often associated with gastrointestinal adenocarcinomas, particularly gastric cancer.^[8][16] Less commonly, it occurs with malignancies of the breast, ovary, prostate, thyroid, lung or lymphoid tissues.

It may precede, accompany or follow a cancer diagnosis.^[13]: 506 Mucosal involvement is more common than in benign forms.^[17] Additional findings may include multiple seborrhoeic keratoses, skin tags and tripe palms.^[15]: 676

Obesity and pseudoacanthosis nigricans (Type III)

In young people, acanthosis nigricans is a visible marker of insulin resistance. Elevated insulin stimulates epidermal proliferation.^[18] Insulin resistance syndromes may be classified as type A (HAIR-AN) or type B.^[14]: 978

Most cases are obesity-associated and otherwise idiopathic. This pattern is more common in darker-skinned individuals and is sometimes termed pseudoacanthosis nigricans.^[12]: 86

Facial involvement may appear as a horizontal forehead band or as periorbital or perioral hyperpigmentation.^[19]

Pediatric associations

In children and adolescents, acanthosis nigricans commonly co-occurs with overweight and obesity and functions as a clinical marker of insulin resistance and increased cardiometabolic risk.^[3] Longitudinal studies show higher rates of subsequent metabolic syndrome.^[20] Cross-sectional studies link acanthosis nigricans with low serum 25-hydroxyvitamin D levels.^[21]

Drug-related (Type IV)

Medications associated with acanthosis nigricans include nicotinic acid, glucocorticoids, combined oral contraceptives and growth hormone therapy.^[12]: 86 A systematic review has reported additional agents, including insulin, hormonal therapies, antineoplastic medications and certain biologics.^[22]

Pathophysiology

Acanthosis nigricans results from activation of growth factor receptor pathways, most commonly insulin-mediated stimulation of insulin-like growth factor receptor on keratinocytes and fibroblasts.^[2] Hyperinsulinaemia may also displace IGF-1 from its binding proteins, amplifying epidermal proliferation.

Contributing mechanisms include:

• insulin and IGF-1 driven proliferation of keratinocytes and fibroblasts^[2]
• fibroblast growth factor receptor abnormalities in hereditary forms^[2]
• transforming growth factor-α overexpression in malignancy-associated cases, activating the epidermal growth factor receptor^[12]: 86

Sweat, friction and occlusion may accentuate lesion development in predisposed areas.^[2]

Diagnosis

Acanthosis nigricans is typically diagnosed clinically based on its characteristic velvety hyperpigmentation and distribution.^[14] A skin biopsy is rarely needed but, when performed, shows hyperkeratosis, papillomatosis and mild basal hyperpigmentation.^[12]: 87

Evaluation aims to identify associated conditions. Investigations may include:

• fasting glucose or HbA1c
• thyroid function tests
• androgen measurements, when indicated
• endoscopy or imaging when malignancy is suspected^[12]: 87

Classification

A conventional clinical distinction separates:

• Benign acanthosis nigricans: obesity-related, endocrine-associated, hereditary and drug-induced forms^[14]
• Malignant acanthosis nigricans: associated with internal malignancy, particularly gastrointestinal adenocarcinoma^[16]

A broader classification proposed in 1994 groups acanthosis nigricans into benign, malignant, obesity-associated, drug-induced, acral, unilateral and mixed or syndromic variants.^[23]

Treatment

Management focuses on addressing the underlying condition.

• **Insulin resistance and obesity:** Weight reduction and improved glycaemic control often lead to improvement.^[3]
• **Drug-induced AN:** Lesions may resolve after discontinuation of the causative medication.^[22]
• **Malignancy-associated AN:** Improvement may follow successful treatment of the underlying tumour.^[16]

Topical therapies may provide cosmetic benefit. Options include:

• keratolytics (topical retinoids, salicylic acid)
• topical vitamin D analogues
• low-concentration chemical exfoliants

Selenium sulfide as a short-contact therapy may reduce surface scale and pigmentary contrast.^[24] Evidence for topical treatments remains limited.

Prognosis

The prognosis depends on the underlying cause. Obesity- and insulin resistance–related forms often improve with weight loss and metabolic control. Drug-induced cases typically resolve with withdrawal of the causative agent. Hereditary variants may persist. Malignancy-associated acanthosis nigricans may regress following tumour treatment.^[12]: 87

History

Acanthosis nigricans was first described by Paul Gerson Unna in 1889.^[25]

Epidemiology

Acanthosis nigricans is reported worldwide, with prevalence varying by age, ethnicity and underlying metabolic risk. In clinic- and community-based samples of people with obesity and insulin resistance, reported prevalence ranges from about 7% to over 70%, depending on the population and diagnostic criteria used.^[7][8]

Higher rates are consistently observed among individuals of African, Hispanic/Latino, Native American and some Asian ancestries, reflecting both genetic susceptibility and a higher burden of obesity and metabolic syndrome in many of these populations.^[7][3] In children and adolescents, the prevalence of acanthosis nigricans has risen alongside increasing rates of overweight and obesity and is common in pediatric cohorts with insulin resistance or metabolic syndrome.^[3][20]

Across studies, acanthosis nigricans is more frequent among people with higher body mass index, increased waist circumference and biochemical markers of insulin resistance.^[7][3][21]