Acanthosis nigricans

Also called keratosis nigricans. The term pseudoacanthosis nigricans is used for obesity-related benign cases.

Acanthosis nigricans (AN) is a skin disorder marked by areas of velvety, hyperpigmented thickening of the epidermis, especially in body folds (intertriginous zones). It is often a cutaneous sign of an underlying condition rather than a primary skin disease. Common associations include insulin resistance (e.g. obesity, diabetes) and, infrequently, internal malignancy (paraneoplastic AN).

The prevalence of AN has increased globally in parallel with the obesity and diabetes epidemic. It is most often seen in individuals with obesity or metabolic syndrome. Reported prevalence ranges widely (e.g. <1% in some Caucasian populations up to >10–20% in populations with high obesity rates). AN can occur at any age, including in children with obesity. It affects males and females equally. Ethnic differences are observed: AN is more common in people of African, Hispanic, or Native American ancestry compared to those of European ancestry, likely due to varying rates of insulin resistance. Most cases are benign and associated with metabolic risk factors. Malignant AN is rare; it typically occurs in middle-aged to older adults and may precede the diagnosis of an internal cancer. Importantly, AN is recognized as a clinical marker of insulin resistance and is associated with a higher risk of type 2 diabetes and metabolic syndrome.

AN is classified primarily by its cause. The major categories are: benign AN and malignant AN. Benign forms include: obesity-associated AN (also termed pseudoacanthosis nigricans), by far the most common type, linked to insulin resistance; syndromic AN (occurring as part of hereditary or endocrine syndromes such as the HAIR-AN syndrome in PCOS or other rare genetic syndromes); familial AN (a rare inherited form present from childhood); drug-induced AN (caused by medications like high-dose niacin, insulin, corticosteroids, etc.); and localized variants like acral AN (on hands/feet) or unilateral AN. In contrast, malignant AN (also called paraneoplastic AN) refers to AN caused by an underlying malignancy (most often an adenocarcinoma, especially of the stomach). Clinically, benign and malignant AN look similar, so classification hinges on identifying the underlying condition.

AN results from stimulation of epidermal growth by various factors. In obesity-associated AN, chronic hyperinsulinemia is key: excess insulin binds to growth factor receptors on keratinocytes (like IGF-1 receptors), triggering proliferation and thickening of the skin. Other metabolic hormones (e.g. elevated leptin levels in obesity) may contribute. Genetic predispositions (such as FGFR3 gene mutations in familial cases) can cause similar overgrowth of skin cells. In malignant AN, a tumor (often an internal adenocarcinoma) secretes growth factors (e.g. TGF-α) that stimulate the epidermis and dermal papillae to proliferate, producing sudden and extensive AN. Overall, the common pathway is increased signaling for keratinocyte growth and hyperkeratosis. There is usually no significant inflammation—just exaggerated skin cell growth. When the underlying driver is removed or treated (weight loss, normalization of insulin levels, or cancer therapy), AN lesions often improve or resolve, confirming the pathogenic link to systemic factors.

AN appears as dark brown to gray-brown patches of skin with a velvety, rough texture. The affected areas have thickened skin and accentuated skin lines. Lesions typically occur symmetrically in flexural regions (skin folds). Common sites include the back of the neck, axillae, groin, and under the breasts. Involved skin may feel velvety or slightly verrucous. AN usually develops gradually and is asymptomatic, though mild itching or odor in skin folds can occur. Benign AN associated with insulin resistance often first shows on the neck or axillae, especially in youth with obesity. Patients may notice the skin looks 'dirty' or darker. Malignant AN tends to present with more rapid onset and widespread distribution; it often involves unusual sites like the mouth (oral mucosa) and palms (tripe palms) and may itch intensely. Frequently, small skin tags are found within areas of AN (especially in obesity-associated cases). The presence of extensive or atypically located AN in an otherwise healthy adult should raise concern for an underlying malignancy.

The diagnosis of AN is made clinically by recognizing the characteristic skin findings. A skin biopsy is usually not necessary but will confirm the typical histology if done. Once AN is identified, evaluation focuses on the underlying cause. All patients with new AN should be assessed for insulin resistance or diabetes (through medical history, physical exam, and tests like fasting glucose or HbA1c) and for other features of metabolic syndrome. In children and adolescents with AN and obesity, current guidelines recommend screening for type 2 diabetes. If the patient is not obese or has a very sudden or extensive onset of AN, a search for an occult malignancy is warranted. This might include age-appropriate cancer screenings (such as endoscopy for GI malignancy, imaging, etc.) based on risk factors and symptoms. Medication history is also reviewed to identify any drug that could induce AN. There are no formal diagnostic criteria scales required for AN in practice; the key steps are clinical recognition and then appropriate systemic work-up. The Burke score (grading severity of AN) exists for research purposes, but diagnosis is straightforward by inspection in most cases.

AN typically involves intertriginous zones and areas of friction. The most frequently affected locations are the posterior neck, the axillae, and the groin (including inner thighs). Other common sites are under the breasts, the umbilical area, and sometimes the elbows, knees, and knuckles. In acral variants, the backs of the hands or feet and knuckles show the changes. In benign AN, lesions are usually confined to these areas. The oral mucosa or lips can rarely be affected in benign cases, but mucous membrane involvement is more characteristic of malignant AN. Tripe palms (thickened, rugose palms with a velvety texture) and plantar hyperkeratosis may accompany malignant AN. Thus, AN is mostly seen in skin folds and occasionally on extensor joints; any involvement of atypical sites (like mouth, eyes, palms) should prompt consideration of a paraneoplastic cause. Lesions are generally symmetric when due to systemic causes.

Patients with AN often report a gradual darkening and thickening of certain skin areas. In a typical scenario, an overweight or obese patient notices the back of their neck or armpits becoming discolored over months or years. It is often asymptomatic, so they might not seek care until it becomes cosmetically concerning or is pointed out by a health professional. Sometimes patients or parents believe the area is 'dirty' and attempt washing without success. Key historical points include weight gain or signs of metabolic issues (like thirst or frequent urination if diabetes is developing) and any relevant family history of diabetes or PCOS. If AN appears in an older, non-obese adult and progresses rapidly, the history might reveal systemic symptoms (e.g. weight loss, abdominal pain) suggesting an internal malignancy, although sometimes no cancer symptoms are obvious. For drug-induced AN, the patient’s history may show the onset of skin changes followed the start of a new medication (for example, high-dose niacin or hormones). Stopping that drug often leads to improvement, which can also be noted historically. Overall, the history typically aligns with the underlying cause: slow onset in metabolic AN, rapid onset in paraneoplastic AN, and temporal correlation if drug-related.

A skin biopsy of AN shows papillomatosis (undulating epidermal hyperplasia) and marked hyperkeratosis (thick stratum corneum). The spinous layer (acanthosis) may be mildly thickened. The pigmentation seen clinically is due to increased melanin in basal keratinocytes, but the number of melanocytes is normal (it's not a melanocytic proliferation). Notably, there is minimal to no inflammation in the dermis. The dermal papillae are often enlarged and project upward, creating a pattern of peaks and valleys corresponding to the surface papillomatosis. These histologic features are not specific to the cause—benign and malignant AN look the same under the microscope. Therefore, biopsy can confirm the diagnosis of AN but cannot distinguish if it is associated with malignancy or benign conditions. The main histologic hallmarks (hyperkeratosis, papillomatosis, and slight acanthosis with basal layer hyperpigmentation) align with the clinical thickening and velvety texture of the lesions.

AN itself is a benign skin change, so serious complications from the lesions alone are uncommon. The plaques do not ulcerate or become cancerous. Potential minor issues include irritation or intertrigo (bacterial or fungal infection) in heavily affected flexures due to friction and sweat. Also, patients may be self-conscious about the cosmetic appearance. The primary concern with AN is what it signifies: it often indicates underlying metabolic dysfunction or malignancy. Thus, the 'complications' are essentially those of the associated condition. For example, untreated insulin resistance indicated by AN can lead to type 2 diabetes and its complications over time. In malignant AN, the associated cancer can be life-threatening. Therefore, while the skin lesions might only cause discomfort or cosmetic concern, AN should prompt interventions to prevent the complications of the underlying disorder (like cardiovascular disease from diabetes). Psychosocial effects (embarrassment or low self-esteem due to the skin’s appearance) can also be considered a complication impacting quality of life.

The skin changes in AN can be chronic but are reversible to varying degrees if the underlying cause is addressed. In benign AN associated with obesity and insulin resistance, substantial weight loss and metabolic control can lead to partial or complete resolution of the lesions over months to years. If the metabolic issue remains, AN tends to persist (or even progress), but it remains a benign finding. Hereditary AN often stabilizes after adolescence and may improve spontaneously. Drug-induced AN usually fades away within months after the offending drug is stopped. Crucially, the prognosis of malignant AN depends on the course of the underlying cancer. Malignant AN often indicates an advanced malignancy; the average survival is around 2 years, reflecting the poor prognosis of the cancer. If the tumor is successfully treated, the AN lesions may regress significantly or disappear. Conversely, if the cancer progresses, the skin findings may worsen. Overall, for benign AN, the prognosis in terms of life expectancy is excellent (since the skin itself is harmless), but it serves as a marker for conditions that need management to ensure a healthy prognosis (like preventing diabetes). For malignant AN, the prognosis is generally guarded due to the associated neoplasm.

Preventing AN largely means preventing or controlling the underlying risk factors. The most effective measure is maintaining a healthy weight and normal insulin sensitivity through a balanced diet and regular exercise, thereby reducing the chance of developing obesity-related AN. In those at risk (e.g., with familial history of diabetes), early lifestyle interventions can prevent insulin resistance and its skin manifestations. Routine screening and management of prediabetes or metabolic syndrome (including treating conditions like PCOS or hypothyroidism) can prevent AN or catch it early. For instance, pediatric guidelines advocate screening overweight youths for signs like AN and intervening promptly. Avoiding or substituting medications that cause AN when possible is another preventive approach (for example, using alternative lipid-lowering therapies instead of high-dose niacin if AN becomes an issue). There is no guaranteed way to prevent paraneoplastic AN except general cancer prevention strategies and vigilance: early detection of malignancies through regular health check-ups might avert the development of extensive paraneoplastic syndromes. In summary, maintaining metabolic health is the key to preventing most cases of AN. When AN does appear, early recognition allows for prompt treatment of the underlying condition, which can prevent further progression of the skin changes and improve overall outcomes.

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