Acanthosis nigricans

INTRODUCTION — Acanthosis nigricans is a common condition characterized by velvety, hyperpigmented plaques on the skin. Intertriginous sites, such as the neck and axillae, are common sites for involvement. Less frequently, acanthosis nigricans appears in other skin sites or on mucosal surfaces.

Clinical recognition of acanthosis nigricans is important because the disorder can occur in association with a variety of systemic abnormalities, many of which are characterized by insulin resistance. Obesity and diabetes mellitus are among the most frequently associated disorders. Rarely, acanthosis nigricans develops as a sign of internal malignancy.

The epidemiology, diagnosis, and treatment of acanthosis nigricans will be reviewed here. Specific disorders that may present with acanthosis nigricans are reviewed in greater detail separately.

EPIDEMIOLOGY — Acanthosis nigricans can affect both males and females, as well as infants, children, and adults. Although prevalence rates of this disorder have varied among studies, it is evident that a significant proportion of individuals who are obese or diabetic exhibit this finding and that the prevalence of this disorder may differ among ethnic groups [1-12].

In a multiethnic cross-sectional study of 1730 patients aged 7 to 65 years seen in primary care settings in a variety of sites within the United States in 2007, 19 percent had acanthosis nigricans [13]. Increasing obesity rates are a factor in the prevalence of acanthosis nigricans, notably in pediatric populations [14]. (See 'Obesity, endocrine, and metabolic disorders' below.)

ETIOLOGY — Acanthosis nigricans may be acquired or inherited. Most, if not all, patients with acanthosis nigricans have one of the following categories of disorders:

●Obesity

●Endocrine and metabolic disorders, particularly disorders associated with insulin resistance

●Genetic syndromes with acanthosis nigricans

●Familial acanthosis nigricans

●Malignancy

●Drug reactions

Obesity, endocrine, and metabolic disorders — Obesity and diabetes mellitus are the most common medical disorders linked with acanthosis nigricans [1-3,5,8,15,16].

Insulin resistance likely accounts for the development of acanthosis nigricans in individuals with these conditions (see 'Pathogenesis' below). In one study of 236 children with acanthosis nigricans and 51 overweight children without the disorder, significant associations of acanthosis nigricans with insulin resistance and abnormal glucose homeostasis were detected [17] (see "Insulin resistance: Definition and clinical spectrum"):

●Obesity – The link between acanthosis nigricans and weight was demonstrated in a study of 1133 young patients from multiple communities in the United States in which the prevalence of acanthosis nigricans increased with rising body mass index (BMI) [11]. Among subjects aged 7 to 19 years who were of normal weight, overweight, or obese, acanthosis nigricans was detected in 3, 11, and 51 percent, respectively. An increase in acanthosis nigricans with rising weight was also evident among slightly older subjects (ages 20 to 39 years); 3, 12, and 37 percent of subjects in the respective weight groups within this population were affected. Concordantly, a smaller practice-based study found a high rate of acanthosis nigricans in children who were obese [10]. Among children aged 7 to 17 years with a BMI that met or exceeded the 98^th percentile, 62 percent had the skin condition. (See "Measurement of growth in children", section on 'Body mass index'.)

●Diabetes – Type 2 diabetes mellitus is also strongly associated with acanthosis nigricans [2,6,11,13,15]. In the study of 1133 patients mentioned above, type 2 diabetes was present in 15 percent of patients with acanthosis nigricans, compared with 4 percent of patients without the skin condition [11]. After controlling for age, BMI, and number of diabetes risk factors, patients with acanthosis nigricans were twice as likely to have type 2 diabetes as unaffected individuals.

In addition, a practice-based study with 1730 patients supported the association between type 2 diabetes and acanthosis nigricans [13]. Type 2 diabetes was present in 35 versus 18 percent of patients with or without acanthosis nigricans, respectively. Significantly higher serum levels of insulin were also detected in the patients with acanthosis nigricans.

The prevalence of acanthosis nigricans in a population of patients with newly diagnosed type 2 diabetes was evaluated in a study of 216 adults in Texas in 1998 and 1999. In the study, acanthosis nigricans was detected in 36 percent [6]. The likelihood of having acanthosis nigricans increased with the degree of obesity, with over 50 percent of individuals with a BMI ≥30 mg/m² demonstrating the disorder. (See 'Epidemiology' above and "Obesity in adults: Prevalence, screening, and evaluation", section on 'Body mass index'.)

●Polycystic ovarian syndrome – Polycystic ovarian syndrome (PCOS) is associated with insulin resistance and hyperinsulinemia, and studies suggest that 5 to 37 percent of women with PCOS have acanthosis nigricans [18-20].

Among women with PCOS, acanthosis nigricans may be a marker of increased risk for endocrine and metabolic abnormalities. A retrospective study of 401 women with suspected PCOS found that among women who met diagnostic criteria for PCOS, the presence of acanthosis nigricans was associated with higher rates of elevated free testosterone levels, insulin resistance, dyslipidemia, and increased body mass index [20]. In addition, a study of 339 women with PCOS and normal BMI found acanthosis nigricans significantly associated with insulin resistance and reduced high-density lipoprotein cholesterol [21].

●Other disorders – In a 2007 cohort of middle-aged Sri Lankan adults, acanthosis nigricans was present in 296 of 1025 subjects with metabolic syndrome (29 percent) and only 217 of 1924 subjects without the syndrome (11 percent) [2]. In addition, hypertension and dyslipidemia, components of the metabolic syndrome, have been linked to acanthosis nigricans in children [16,17,22-24].

Examples of other metabolic or endocrine disorders associated with acanthosis nigricans include acromegaly and Cushing's syndrome [25]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

Genetic syndromes — Multiple genetic disorders have been associated with acanthosis nigricans, many of which are characterized by insulin resistance that results either from defects in the insulin receptor or the production of antibodies against the insulin receptor. Acanthosis nigricans is a clinical feature that can aid in the recognition of these genetic diseases [26]. Some, but not all, patients with acanthosis nigricans with onset in infancy or early childhood, develop the condition as a feature of a genetic disorder [26,27].

Examples of genetic syndromes characterized by insulin resistance that can present with acanthosis nigricans include Down syndrome, leprechaunism, Rabson-Mendenhall syndrome, congenital generalized lipodystrophy (Berardinelli-Seip syndrome), familial partial lipodystrophy, and Alstrom syndrome [28,29]. Cutis gyrata syndrome, Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, Costello syndrome, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) are additional genetic syndromes that are not characterized by insulin resistance but may also present with acanthosis nigricans [28,30]. (See "Insulin resistance: Definition and clinical spectrum" and "Lipodystrophic syndromes", section on 'Congenital generalized lipodystrophy' and "Lipodystrophic syndromes", section on 'Familial partial lipodystrophy' and "Craniosynostosis syndromes", section on 'Crouzon syndrome' and "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Thanatophoric dysplasia'.)

Familial — Documentation of familial, noninsulin resistance-related, nonsyndromic forms of acanthosis nigricans are limited to reports of a few families and involve mutations in FGFR3 (fibroblast growth factor receptor 3) [27,31]. The inheritance pattern is usually autosomal dominant, and the clinical findings are typically first detected in infancy. A Pakistani family with isolated familial acanthosis nigricans with an autosomal recessive inheritance pattern has been reported [32].

Malignancy — Rarely, acanthosis nigricans occurs as a paraneoplastic disorder [33-35]. Abdominal adenocarcinomas, particularly gastric adenocarcinomas, represent the majority of acanthosis nigricans-associated tumors [35-39]. Mucosal and cutaneous papillomatosis can be a unique presenting sign of malignant acanthosis nigricans [40]. Patients may concurrently develop the sign of Leser-Trélat or tripe palms, which are additional cutaneous disorders that can occur in association with internal malignancy. (See "Cutaneous manifestations of internal malignancy", section on 'Acanthosis nigricans' and "Cutaneous manifestations of internal malignancy", section on 'Tripe palm' and "Cutaneous manifestations of internal malignancy", section on 'Sign of Leser-Trélat'.)

Malignancy-associated acanthosis nigricans is extremely rare in children. Several cases in which children developed acanthosis nigricans in conjunction with gastric adenocarcinoma, Wilms' tumor, or osteogenic sarcoma have been documented [14].

Medications — Infrequently, acanthosis nigricans develops as a side effect of drug exposure. This most commonly occurs in the setting of medications that promote hyperinsulinemia. Medications that have been associated with acanthosis nigricans include systemic glucocorticoids [33], injected insulin [41], oral contraceptives [42], niacin [43], protease inhibitors [44], palifermin (a recombinant human keratinocyte growth factor used to manage severe chemotherapy-induced mucositis) [45,46], testosterone [47], and aripiprazole [48].

PATHOGENESIS — The pathways that lead to acanthosis nigricans are not well understood. Abnormalities involving three types of tyrosine kinase receptors, insulin-like growth factor receptor-1 (IGFR1), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR), have been proposed as potential contributing factors [28].

The association of acanthosis nigricans with multiple disorders characterized by insulin resistance suggests that hyperinsulinemia plays a key role in the development of acanthosis nigricans. Elevated levels of insulin may stimulate keratinocyte and dermal fibroblast proliferation via interaction with IGFR1, resulting in the plaque-like lesions that typify the disorder [28]. Acanthosis nigricans related to genetic syndromes of insulin resistance, obesity, diabetes mellitus, or other disorders associated with insulin resistance may be attributable to this theory (see 'Etiology' above). These theories are supported by the finding of inherited form of acanthosis nigricans due to a homozygous mutation in the insulin receptor gene [32].

Other mechanisms may also be involved in acanthosis nigricans, particularly in cases in which insulin resistance is absent. As an example, mutations in certain FGFRs may contribute to acanthosis nigricans through the promotion of keratinocyte proliferation and survival [28]. Activating mutations in FGFR3 have been linked to several inherited syndromes that present with acanthosis nigricans, including Crouzon syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), thanatophoric dwarfism, and hypochondroplasia [27,49]. In addition, FGFR3 mutations were identified in a family with familial acanthosis nigricans [27,31], and at least two patients with malignancy-associated skin lesions [50].

Transforming growth factor (TGF)-alpha, a cytokine that may exert proliferative effects via activation of EGFR, may also contribute to the development of malignancy-associated acanthosis nigricans [51,52]. In support of this theory is a report of a patient in whom reduction of elevated serum TGF-alpha levels and amelioration of acanthosis nigricans followed the removal of a malignancy [52].

The mechanisms by which other forms of acanthosis nigricans occur remain elusive. The predominant distribution of acanthosis nigricans in skin folds suggests a contributory role for friction or irritation in the disorder, but this has not been scientifically proven.

CLINICAL MANIFESTATIONS — Acanthosis nigricans typically presents with thickened, velvety to verrucous, gray-brown, hyperpigmented plaques on the skin. The back of the neck, sides of the neck, and axillae are the most common sites of involvement (picture 1A-E). Other intertriginous areas, such as the anogenital region and the inframammary, abdominal, antecubital, and inguinal skin folds, are less frequently affected (picture 2). Additionally, severe cases may demonstrate lesions on the areola, perineum, umbilicus, lips, buccal or other mucosa, and other nonintertriginous areas (picture 3A-C) [33].

In mild or early acanthosis nigricans, affected skin has a dirty appearance and a rough or dry texture with minimal plaque-like elevation. As the lesions progress, the skin becomes thicker and demonstrates accentuation of dermatoglyphics (skin lines) and papillomatous projections. Acrochordons (skin tags) may be present within or around affected areas (picture 1E). Unlike cutaneous lesions, mucosal acanthosis nigricans usually does not demonstrate hyperpigmentation.

Acanthosis nigricans typically develops in a symmetrical distribution. Unilateral cases of acanthosis nigricans may instead represent a variant of epidermal nevus [53-56].

An acral form of acanthosis nigricans, characterized by hyperpigmented plaques on the knuckles of the hands, elbows, knees, or feet and most commonly seen in individuals from sub-Saharan Africa, has also been described (picture 4) [14,33,57]. The term acral acanthotic anomaly has been used to refer to these lesions [58].

Acanthosis nigricans is usually asymptomatic. However, lesions in skin folds that become macerated and inflamed may become uncomfortable or malodorous. In particular, this may occur in the setting of secondary bacterial colonization or yeast infection.

Malignancy-associated acanthosis nigricans — The paraneoplastic form of acanthosis nigricans is most frequently diagnosed in older individuals and patients often are not obese. The lesions can arise before or after the detection of malignancy. In some cases, the diagnosis of acanthosis nigricans predates recognition of the malignancy by years [38,59,60].

Features that suggest the possibility of an underlying malignancy in a patient with acanthosis nigricans include the following:

●Rapid onset of skin lesions

●Additional paraneoplastic findings (eg, rapid growth or inflammation of seborrheic keratoses [the sign of Leser-Trélat] or the presence of tripe palms)

●Extensive involvement

●Lesions in atypical sites (eg, mucous membranes, palms, or soles)

●Unexplained weight loss

●Older adult

Malignancy-associated acanthosis nigricans may be accompanied by localized or generalized pruritus and cutaneous and mucosal papillomatosis [33,40]. In addition, other paraneoplastic dermatoses may occur with malignancy-associated acanthosis nigricans, such as velvety to rugose thickening of the palmar skin (tripe palms) (picture 5) and the eruptive onset of multiple seborrheic keratoses (sign of Leser-Trélat) [61]. (See "Cutaneous manifestations of internal malignancy", section on 'Acanthosis nigricans' and "Cutaneous manifestations of internal malignancy", section on 'Tripe palm' and "Cutaneous manifestations of internal malignancy", section on 'Sign of Leser-Trélat'.)

HISTOPATHOLOGY — Hyperkeratosis and epidermal papillomatosis are the major pathologic features, and acanthosis is relatively mild. The hyperkeratosis is primarily responsible for the clinical finding of cutaneous hyperpigmentation; however, increased melanin in the basal layer of the epidermis also is sometimes detected [62].

The dermis may demonstrate a mild infiltrate with lymphocytes, plasma cells and, occasionally, a few neutrophils. However, inflammation is not a prominent feature. Biopsies of mucosal lesions exhibit mild parakeratosis with epidermal hyperplasia and papillomatosis [63].

The histologic features of acanthosis nigricans are consistent among the various forms of the condition. For example, microscopy cannot be used to distinguish paraneoplastic acanthosis nigricans from other types of acanthosis nigricans.

DIAGNOSIS AND PATIENT EVALUATION — The clinical examination is usually sufficient to establish a diagnosis of acanthosis nigricans. In the rare cases in which the diagnosis is uncertain, a skin biopsy can be performed to confirm the clinical impression. (See 'Histopathology' above.)

Due to the association of acanthosis nigricans with other abnormalities, the assessment for signs or symptoms of other disorders is an important component of the evaluation of affected patients [64]. In general, we proceed with the following work-up in children and adults with acanthosis nigricans:

●Patient history:

•Age of onset – Onset in infancy or early childhood suggests the possibility of a syndromic or familial disorder, and malignancy-associated acanthosis nigricans is more common in adults than in children.

•History or symptoms suggestive of an underlying endocrinopathy – This information may help to identify the presence of type 2 diabetes, polycystic ovarian syndrome, acromegaly, Cushing's syndrome, or other endocrine disorders.

•Family history of acanthosis nigricans – In the absence of other underlying causes, may suggest familial acanthosis nigricans.

•Possible exposure to drugs that may induce acanthosis nigricans (see 'Medications' above).

●Physical examination:

•Height and weight – Used to establish the presence or absence of obesity, a common cause of acanthosis nigricans.

•Growth rate in children – Abnormal growth may suggest the presence of an endocrinopathy or genetic syndrome.

•Physical signs suggestive of an underlying endocrinopathy – May help to identify the presence of type 2 diabetes, polycystic ovarian syndrome, acromegaly, Cushing's syndrome, or other endocrine disorders.

•Blood pressure assessment – Assesses for hypertension, which may occur at increased frequency in patients with acanthosis nigricans.

●Laboratory studies – Patients with acanthosis nigricans should be evaluated for the possibility of diabetes mellitus (see "Screening for type 2 diabetes mellitus", section on 'Screening tests'). Additional laboratory studies and other investigational tests are ordered based upon the findings on history and physical examination and suspicion for specific disorders. For example, women with features that suggest polycystic ovarian syndrome should be evaluated for this condition. (See "Diagnosis of polycystic ovary syndrome in adults" and "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents" and "Insulin resistance: Definition and clinical spectrum", section on 'Clinical features'.)

The possibility of an occult malignancy should always be considered in adults who are older, nonobese, and with new-onset acanthosis nigricans without another identifiable cause and/or clinical features suggestive of malignancy-associated acanthosis nigricans (see 'Malignancy-associated acanthosis nigricans' above). However, there is little consensus on the appropriate cancer evaluation in such patients. At minimum, patients should be evaluated with a thorough review of symptoms, a complete physical examination, and age-appropriate cancer screening. Because many of the associated tumors involve the gastrointestinal tract, referral to gastroenterology is indicated.

DIFFERENTIAL DIAGNOSIS — Multiple other cutaneous disorders share features with acanthosis nigricans. The possibility of such disorders should be considered in patients with lesions that are not classic for acanthosis nigricans:

●Confluent and reticulated papillomatosis of Gougerot and Carteaud – This is an uncommon disorder that typically affects young adults. Reticulated, hyperpigmented, and slightly scaly plaques occur on the neck, chest (especially inframammary chest), and upper back (picture 6A-B).

●Granular parakeratosis – Granular parakeratosis is a disorder characterized by the appearance of hyperkeratotic brown-red papules that coalesce to form plaques (picture 7). Although the axilla is the most common site for involvement, the disorder may also occur in other intertriginous sites. Pruritus is typically present.

●Lichen planus pigmentosus – Lichen planus pigmentosus is an uncommon variant of lichen planus that predominantly affects individuals with skin phototypes III and IV (table 1). The inverse form of lichen planus pigmentosus presents with hyperpigmented macules and patches in intertriginous areas (picture 8). Some patients will also display typical lesions of lichen planus on other sites. (See "Acquired hyperpigmentation disorders", section on 'Lichen planus pigmentosus'.)

●Linear epidermal nevus – Epidermal nevi are benign hamartomatous growths that are usually present at birth or become evident during the first year of life. The skin lesions are well-defined and often linear hyperpigmented, papillomatous plaques (picture 9). Epidermal nevi may become more prominent over time.

●Reticulated pigmented anomaly of the flexures (Dowling-Degos disease) – This is a rare, autosomal dominant disorder that presents with reticulated hyperpigmentation that has a predilection for flexural areas (picture 10). Lesions typically appear in early adulthood. Some patients also exhibit comedones and pitted facial scars.

●Nevoid acanthosis nigricans (NAN) or rounded and velvety epidermal nevus (RAVEN) – NAN/RAVEN is a rare disorder that has a similar appearance to acanthosis nigricans; however, it is typically unilateral or localized and appears in childhood with an initial period of activity followed by stability without resolution. There are no systemic associations. It can be inherited as an autosomal dominant trait, and mutations in fibroblast growth factor receptor 3 (FGFR3) have been identified [65-67].

Other diagnostic considerations include pregnancy-associated hyperkeratosis of the nipple [68], Hailey-Hailey disease (picture 11A-C) (which is distinguished by the presence of inflammatory and erosive intertriginous plaques), pellagra (which can present with hyperpigmented plaques on the neck and other sun-exposed areas), and cutaneous hyperpigmentation related to Addison's disease.

TREATMENT — Although acanthosis nigricans is a benign, often asymptomatic disorder, the appearance of acanthosis nigricans is a concern for some patients, prompting a desire for treatment. Treatment of the underlying cause, when feasible, is the preferred method of management, and obesity-related, drug-induced, and malignancy-associated acanthosis nigricans appear to frequently respond well to this intervention. In contrast, the likelihood for clinically significant improvement in acanthosis nigricans following the treatment of insulin resistant states is less certain [69].

For patients in whom reversal of the underlying cause of acanthosis nigricans is impossible, in whom the degree of improvement is unsatisfactory, or who desire accelerated improvement in the cosmetic appearance of lesions, topical therapies that normalize epidermal proliferation, such as topical retinoids and topical vitamin D analogs, may be of benefit. Systemic retinoids have also been utilized for this indication but are not indicated for the treatment of most patients.

Patient with acanthosis nigricans sometimes attempt to improve the appearance of lesions through excessive scrubbing of the affected skin during bathing. Such behavior should be discouraged, since it may result in lichenification (thickening of the skin) and worsening hyperpigmentation.

Treatment of underlying disorders

Obesity — Weight loss has been linked to improvements in acanthosis nigricans in patients who are obese, including children [70-72]. We support and encourage weight loss efforts in patients with obesity-related acanthosis nigricans. (See "Obesity in adults: Overview of management" and "Prevention and management of childhood obesity in the primary care setting".)

Insulin resistance — Agents that improve insulin sensitivity, such as metformin, rosiglitazone, and other agents, may have some benefit for acanthosis nigricans related to insulin resistance [69,73-80]. A small, unblinded, non-placebo-controlled, 12-week, randomized trial that compared metformin with rosiglitazone in patients who were overweight and obese and had acanthosis nigricans found no significant change in lesion severity and only modest improvement in skin texture [74]. A 12-week, randomized trial that compared the effects of metformin with a product containing alpha-lipoic acid (an antioxidant associated with improvement in glucose metabolism), biotin, calcium, pantothenate, and zinc sulfate in 33 patients with acanthosis nigricans on the neck found similar, statistically significant reductions in acanthosis nigricans severity in the two groups [80]. In an uncontrolled study, subjective improvement in acanthosis nigricans was noted in three out of five adolescents and adults with insulin resistance or diabetes who were treated with metformin for six months [75]. Additional studies are necessary to explore the efficacy and safety of such agents in the treatment of acanthosis nigricans.

Drugs — Medications associated with the onset of acanthosis nigricans should be discontinued if medically feasible. Discontinuation of the inciting drug often results in the resolution of the skin lesions [14]. (See 'Medications' above.)

Malignancy — Treatment of the underlying malignancy is the preferred therapeutic intervention for patients with malignancy-associated acanthosis nigricans. Improvement or resolution of acanthosis nigricans has been reported in multiple patients following successful treatment of the associated malignancy [14,37-39,81-84].

Other interventions — Other therapies that have been associated with improvement of acanthosis nigricans in isolated patients include octreotide in an adolescent who was obese [85] and fish oil supplementation in a patient with a lipodystrophic form of diabetes [86].

Skin-directed therapy — Data on the efficacy of therapies aimed at directly improving the skin lesions of acanthosis nigricans are limited to case reports and documentation of clinical experience. Although improvement has been reported with several topical and systemic agents, the optimal approach to treatment, the likelihood for treatment success, and the long-term efficacy of these interventions remains unknown.

Topical agents, such as topical retinoids, vitamin D analogs, and keratolytics are the primary agents used in the treatment of localized lesions. Topical therapy is impractical for the management of patients with widespread involvement, and treatment options for this population are limited:

●Topical retinoids – Retinoids have keratinolytic effects on the skin, and topical retinoid therapy has been linked to improvement in acanthosis nigricans in a small, split-neck, randomized trial that compared tretinoin 0.025% cream with adapalene 0.1% gel for the treatment of pediatric acanthosis nigricans as well as case reports [87-89]. The randomized trial found similar efficacy of tretinoin and adapalene.

Combination therapy with tretinoin and other agents may also be effective. Once-daily application of tretinoin 0.05% cream and twice-daily application of 12% ammonium lactate cream or lotion for a few months was associated with improvement in acanthosis nigricans on the front of the neck in a series of five patients [90]. Of note, improvement was not detected on the sides of the neck, which were treated with either agent as monotherapy. In addition, a triple combination cream containing tretinoin 0.05%, hydroquinone 4%, and fluocinolone acetonide 0.01% applied daily for one month was effective in a patient with limited neck and face lesions [91].

●Topical vitamin D analogs – Topical vitamin D analogs are capable of reducing keratinocyte proliferation and have been associated with lesion improvement in several patients [73,92,93]. As an example, calcipotriol (calcipotriene) 0.005% cream applied twice daily for three months led to improvement in acanthosis nigricans in flexural areas in a male who was obese and had bladder cancer [92]. Moreover, twice-daily use of calcipotriol ointment for four weeks by a man with hypogonadism-associated acanthosis nigricans was associated with complete remission of the lesions [93].

Skin irritation is a potential adverse effect of topical retinoids and topical vitamin D analogs.

Other local therapies that have been suggested for the treatment of acanthosis nigricans include topical urea, salicylic acid, trichloroacetic acid, glycolic acid peels, and laser therapy [14,94-96]. A randomized trial (n = 38) in which patients with acanthosis nigricans were randomly assigned to treatment with either tretinoin 0.025% cream once daily or urea 10% cream twice daily found improvement in skin hyperpigmentation with both therapies [97]. However, topical tretinoin demonstrated greater efficacy. In addition, fractional 1550 nm erbium laser was more effective for improving skin roughness than tretinoin 0.05% cream in a split-neck, randomized trial with 18 patients with acanthosis nigricans [98]. Improvement in axillary acanthosis nigricans in a patient treated with long-pulsed alexandrite laser therapy has been reported [94]. Greater than 95 percent clearance of the lesions was observed after five to seven treatments.

Treatment with systemic retinoids such as isotretinoin and acitretin has been associated with moderate to marked improvement in several patients with extensive acanthosis nigricans [73,76,99,100]. However, systemic retinoids have a wide range of potential adverse effects, and relapse appears to be common upon tapering or discontinuation of therapy [73,76]. Treatment with these agents is not indicated in most patients.

Case reports have documented beneficial effects of pharmacologic interventions in small numbers of patients with malignancy-associated acanthosis nigricans [101,102]. A reduction in pruritus was noted in a lung cancer patient with treated psoralen plus ultraviolet A (PUVA) phototherapy [101], and marked improvement in signs and symptoms of the disorder was reported in a patient with both gastric and prostate cancer who was treated with cyproheptadine [102]. One case of improvement with liraglutide a glucagon-like peptide 1 (GLP-1) analog has been reported [103].

PROGNOSIS — Acanthosis nigricans is a chronic disorder that persists in the absence of removal of the underlying cause or successful skin-directed therapy. In isolation, the long-term persistence of acanthosis nigricans usually has no physical adverse consequences.

However, patients with acanthosis nigricans associated with obesity or medical disorders are subject to disease-specific sequelae. The prognosis for malignancy-associated acanthosis nigricans often is poor since malignancy is frequently diagnosed at an advanced stage [104].

INDICATIONS FOR REFERRAL — Referral to a dermatologist is indicated if the diagnosis of skin lesions is uncertain. Evaluation by a clinician with expertise in the management of endocrine or metabolic disorders is indicated if such disorders are detected.

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Acanthosis nigricans is a common, benign disorder that typically presents with velvety, hyperpigmented plaques on the skin (picture 1A-E). Mucosal involvement is an occasional feature. Individuals of any age may be affected. (See 'Clinical manifestations' above and 'Epidemiology' above.)

●Etiology – A wide variety of endocrine, metabolic, genetic, and malignant disorders may contribute to the development of acanthosis nigricans. An evaluation for the underlying cause should always be performed:

•Obesity is the most common cause of this disorder. Acanthosis nigricans may also be induced by drugs. (See 'Etiology' above and 'Diagnosis and patient evaluation' above.)

•Malignancy is a rare cause of acanthosis nigricans. In particular, the possibility of an occult malignancy should be considered in adults with extensive or atypical presentations of acanthosis nigricans or new onset acanthosis nigricans of unknown cause. (See 'Malignancy-associated acanthosis nigricans' above and 'Diagnosis and patient evaluation' above and "Cutaneous manifestations of internal malignancy", section on 'Acanthosis nigricans'.)

●Pathogenesis – Insulin resistance likely plays a key role in many cases of acanthosis nigricans, including cases linked to obesity, diabetes, and some genetic syndromes. (See 'Pathogenesis' above.)

●Treatment – Data are limited on the treatments for acanthosis nigricans:

•If an underlying cause is present, treatment or removal of the inciting cause should be attempted. Obesity-related, drug-induced, and malignancy-associated acanthosis nigricans often respond to this form of therapy. The role of agents that improve insulin sensitivity in patients with acanthosis nigricans related to insulin resistance remains uncertain. (See 'Treatment of underlying disorders' above.)

•For patients who desire accelerated improvement of acanthosis nigricans or in whom treatment of the underlying disorder is not possible or satisfactory, we suggest a trial of topical tretinoin or a topical vitamin D analog, such as calcipotriol (calcipotriene) (Grade 2C). Systemic retinoids may lead to clinical improvement in patients with extensive or severe disease, but relapse is common after treatment discontinuation. (See 'Skin-directed therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kathryn Schwarzenberger, MD, and Inbal Sander, MD, who contributed to earlier versions of this topic review.