Official reprint from UpToDate

www.uptodate.com 2014 UpToDate

Author
Inbal Braunstein, MD
Section Editor
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor
Abena O Ofori, MD
Acanthosis nigricans
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2014. | This topic last updated: Mar 26, 2014.
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 obese and diabetic individuals exhibit this finding, and that the prevalence of this disorder may differ
among ethnic groups [1-12]. In the United States, acanthosis nigricans appears to be more common in people
of Native American, African-American, and Hispanic origin than in white or Asian individuals [1,5-10,13,14].
Examples of studies that have evaluated the prevalence of acanthosis nigricans in the United States include the
following:
Increasing obesity rates are an additional factor in the prevalence of acanthosis nigricans, notably in pediatric
populations [16]; however, differing rates of obesity cannot solely account for different prevalence of acanthosis
nigricans between racial groups [8]. (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:

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 [15].

A study of 618 children (ages 7 to 17 years) in an urban community in Illinois performed between 2001 and
2002 found that Caucasian youth were less likely than African-American or Hispanic youth to have
acanthosis nigricans on the neck [10]. In the study, 4, 19, and 23 percent of children had acanthosis
nigricans, respectively.

Among 2200 Native Americans in the Cherokee Nation (ages 5 to 40 years) evaluated between 1995 and
1999, 34 percent had acanthosis nigricans on the neck [14].

Obesity
Endocrine and metabolic disorders, particularly disorders associated with insulin resistance
Genetic syndromes with acanthosis nigricans
Familial acanthosis nigricans
Malignancy
Obesity, endocrine, and metabolic disorders Obesity and diabetes mellitus are the most common
medical disorders linked with acanthosis nigricans [1-3,5,8,17,18].
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 [19]. (See "Insulin resistance: Definition and clinical spectrum".)
Genetic syndromes Multiple genetic disorders have been associated with acanthosis nigricans, many of
Drug reactions
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
obese children; among children aged 7 to 17 years with a BMI that met or exceeded the 98 percentile,
62 percent had the skin condition [10]. (See "Measurement of growth in children", section on 'Body mass
index (BMI)'.)

th
Diabetes Type 2 diabetes mellitus is also strongly associated with acanthosis nigricans [2,6,11,15,17].
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 [15]. 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/m demonstrating the disorder. Ethnic
differences were also evident; 50 of 95 African-American subjects (53 percent), 28 of 78 Latin-American
subjects (36 percent), 1 of 39 non-Hispanic white subjects (3 percent), and none of four Asian subjects
were affected [6]. (See 'Epidemiology' above and "Screening for and clinical evaluation of obesity in
adults", section on 'Measurement of BMI'.)

2
Polycystic ovarian syndrome Polycystic ovarian syndrome (PCOS) is associated with insulin
resistance and hyperinsulinemia, and studies suggest 5 to 33 percent of women with PCOS have
acanthosis nigricans [20,21]. Acanthosis nigricans can be seen in women with PCOS with normal BMI
and is significantly associated with insulin resistance and reduced high-density lipoprotein cholesterol
[22].

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 [18,19,23-25].
Examples of other metabolic or endocrine disorders associated with acanthosis nigricans include
acromegaly and Cushings syndrome [26]. (See "The metabolic syndrome (insulin resistance syndrome or
syndrome X)".)

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 [27]. 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 [27,28].
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 [29,30]. 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
[29,31]. (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 "Prenatal diagnosis of
the lethal skeletal dysplasias", section on 'Thanatophoric dysplasia'.)
Familial Documentation of familial, non-insulin 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) [28]. 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]. Patients may concurrently develop the sign of Leser-Trlat 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-Trelat'.)
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 [16].
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 [40], oral
contraceptives [41], niacin [42], protease inhibitors [43], palifermin (a recombinant human keratinocyte growth
factor used to manage severe chemotherapy-induced mucositis) [44,45], testosterone [46], and aripiprazole
[47].
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 receptors (FGFR), and epidermal growth factor receptor (EGFR), have been proposed as potential
contributing factors [29].
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 [29]. 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 [29]. Activating mutations in FGFR3 have been
linked to several inherited syndromes that present with acanthosis nigricans, including Crouzon syndrome,
severe achondroplasia with developmental delay, SADDAN, and thanatophoric dwarfism [28]. In addition,
FGFR3 mutations were identified in a family with familial acanthosis nigricans [28], and at least two patients
with malignancy-associated skin lesions [48].
Transforming growth factor (TGF)-, a cytokine that may exert proliferative effects via activation of EGFR, may
also contribute to the development of malignancy-associated acanthosis nigricans [49,50]. In support of this
theory is a report of a patient in whom reduction of elevated serum TGF- levels and amelioration of acanthosis
nigricans followed the removal of a malignancy [50].
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,
grey-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 non-intertriginous 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 [51-54].
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 of sub-Saharan African origin, has also been
described (picture 4) [16,33,55]. The term acral acanthotic anomaly has been used to refer to these lesions
[56].
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 [38,57,58].
Features that suggest the possibility of an underlying malignancy in a patient with acanthosis nigricans include
the following:
Malignancy-associated acanthosis nigricans may be accompanied by localized or generalized pruritus [33]. In
addition, other paraneoplastic dermatoses may occur with malignancy-associated acanthosis nigricans, such
Rapid onset of skin lesions
Additional paraneoplastic findings (eg, rapid growth or inflammation of seborrheic keratoses [the sign of
Leser-Trlat] or the presence of tripe palms)

Extensive involvement
Lesions in atypical sites (eg, mucous membranes, palms, or soles)
Unexplained weight loss
Older adult
as velvety to rugose thickening of the palmar skin (tripe palms) (picture 5) and the eruptive onset of multiple
seborrheic keratoses (sign of Leser-Trlat) [59]. (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-Trelat'.)
HISTOPATHOLOGY Hyperkeratosis and epidermal papillomatosis are the major pathological 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
[60].
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 [61].
The histological 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 [62]. 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, Cushings
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, Cushings 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

The possibility of an occult malignancy should always be considered in older, non-obese adults 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.
Other diagnostic considerations include pregnancy-associated hyperkeratosis of the nipple [63], Hailey-Hailey
disease (picture 10A-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 Addisons disease.
TREATMENT Since acanthosis nigricans is a benign, often asymptomatic disorder, cosmetic concerns are
typically the primary indications 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 [64].
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 obese patients [65,66].
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
spectrum'.)
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.

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 8). 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 9). Lesions typically appear in early adulthood. Some patients also exhibit
comedones and pitted facial scars.

We support and encourage weight loss efforts in patients with obesity-related acanthosis nigricans. (See
"Overview of therapy for obesity in adults" and "Management of childhood obesity in the primary care setting".)
Insulin resistance Agents that improve insulin sensitivity, such as metformin and rosiglitazone, may
have some benefit for acanthosis nigricans related to insulin resistance [64,67-72]. A small, unblinded, non-
placebo-controlled, 12-week randomized trial that compared metformin to rosiglitazone in overweight and obese
patients with acanthosis nigricans found no significant change in lesion severity, and only modest improvement
in skin texture [68]. In a separate 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 [69]. 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 [16]. (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 [16,37-39,73-76].
Other interventions Other therapies that have been associated with improvement of acanthosis
nigricans in isolated patients include octreotide in an obese adolescent [77], and fish oil supplementation in a
patient with a lipodystrophic form of diabetes [78].
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.
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, and laser therapy [16,85]. Improvement in axillary acanthosis nigricans in a patient treated with
long-pulsed alexandrite laser therapy has been reported [85]. Greater than 95 percent clearance of the lesions
was observed after five to seven treatments.
Topical retinoids Retinoids have keratinolytic effects on the skin, and topical tretinoin 0.1% gel applied
to localized areas of acanthosis nigricans for up to two weeks has been linked to improvement in
acanthosis nigricans in a few patients [79,80].
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 [81]. 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 [82].

Topical vitamin D analogs Topical vitamin D analogs are capable of reducing keratinocyte proliferation,
and have been associated with lesion improvement in several patients [67,83,84]. As an example,
calcipotriol (calcipotriene) 0.005% cream applied twice daily for three months led to improvement in
acanthosis nigricans in flexural areas in an obese man with bladder cancer [83]. 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 [84].

Treatment with systemic retinoids such as isotretinoin and acitretin has been associated with moderate to
marked improvement in several patients with extensive acanthosis nigricans [67,70,86,87]. However, systemic
retinoids have a wide range of potential adverse effects, and relapse appears to be common upon tapering or
discontinuation of therapy [67,70]. 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 [88,89]. A reduction in pruritus was noted in a lung cancer
patient with treated psoralen plus ultraviolet A (PUVA) phototherapy [88], 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 [89]. One case of improvement with liraglutide a glucagon-like peptide 1 (GLP-1) analog has
been reported [90].
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 [91].
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
Acanthosis nigricans is a common, benign disorder that typically presents with velvety, hyperpigmented
plaques on the skin. Mucosal involvement is an occasional feature. Individuals of any age may be affected.
(See 'Clinical manifestations' above and 'Epidemiology' above.)

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.)

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.)

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'.)

Treatment of the clinical manifestations of acanthosis nigricans is not required since the condition does
not induce physical harm. The primary indications for treatment of the skin lesions are cosmetic concerns
of the patient. (See 'Treatment' above and 'Diagnosis and patient evaluation' above.)

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 editors of UpToDate would like to acknowledge Kathryn Schwarzenberger, MD,
who contributed to earlier versions of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 13754 Version 2.0
GRAPHICS
Acanthosis nigricans
A velvety, slightly verrucous plaque is present on the neck.
Graphic 72964 Version 1.0
Acanthosis nigricans
A mildly hyperpigmented, velvety plaque with small papillary projections is
present on the neck.
Graphic 52948 Version 1.0
Acanthosis nigricans
Hyperpigmented velvety plaques are present in the axilla.
Reproduced with permission from: www.visualdx.com. Copyright Logical
Images, Inc.
Graphic 66384 Version 3.0
Acanthosis nigricans
Close view of acanthosis nigricans on the posterior neck.
Hyperpigmented velvety plaques are present.
Reproduced with permission from: www.visualdx.com. Copyright Logical
Images, Inc.
Graphic 81693 Version 3.0
Acanthosis nigricans
A velvety hyperpigmented plaque with associated acrochordae is
present in the axilla.
Graphic 61666 Version 1.0
Acanthosis nigricans
Hyperpigmented, velvety plaques are present in the groin.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 76234 Version 3.0
Acanthosis nigricans
A hyperpigmented, velvety plaque is present on the umbilicus.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 50592 Version 4.0
Acanthosis nigricans
Verrucous changes are present on the lips.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 63422 Version 3.0
Acanthosis nigricans
A hyperpigmented plaque with a verrucous surface is present on the nipple.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 52056 Version 3.0
Acral acanthosis nigricans (acral acanthotic anomaly)
Hyperpigmented thin plaques are present on the dorsal hand. The lesions are
primarily located over the joints.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 70582 Version 3.0
Tripe palm
The palmar ridges show maximal accentuation, thus resembling the
mucosa of the stomach of a ruminant (tripe palm).
Reproduced with permission from: Fitzpatrick, TB, Johnson, RA, Wolff, K,
Suurmond, D. Color Atlas of Clinical Dermatology: Common and Serious
Diseases. McGraw Hill, New York 2001. p.151. Copyright 2001 McGraw Hill
Companies, Inc.
Graphic 61955 Version 3.0
Confluent and reticulated papillomatosis
Reticulated, hyperpigmented patches and thin plaques with fine scale
are present on the upper back.
Reproduced with permission from: www.visualdx.com. Copyright Logical
Images, Inc.
Graphic 67566 Version 3.0
Confluent and reticulated papillomatosis
Reticulated, hyperpigmented patches and thin plaques with mild scale
are present on the chest and inframammary areas.
Reproduced with permission from: www.visualdx.com. Copyright Logical
Images, Inc.
Graphic 76296 Version 3.0
Granular parakeratosis
Hyperkeratotic red-brown papules are present in the axilla.
Graphic 73591 Version 1.0
Epidermal nevus
A hyperpigmented, verrucous, linear plaque is present on the neck.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 64855 Version 3.0
Reticulated pigmented anomaly of the flexures (Dowling-
Degos disease)
A reticulated, hyperpigmented plaque is present perianally.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 77681 Version 3.0
Hailey-Hailey disease
Typical axillary plaque of Hailey-Hailey disease, showing superficial
erosions and crusts.
Graphic 61689 Version 2.0
Vulvar Hailey-Hailey disease
A large erythematous plaque with multiple superficial erosions involving
the vulvar and groin area in a patient with Hailey Hailey disease.
Courtesy of Lynne J Margesson, MD.
Graphic 80862 Version 3.0
Perianal Hailey-Hailey disease
Large erythematous and crusty perianal plaque in a patient with Hailey
Hailey disease.
Graphic 74552 Version 3.0
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