Acanthosis nigricans: A practical approach to evaluation and management

Steven P Higgins MD1, Michael Freemark MD2, Neil S Prose MD3

Dermatology Online Journal 14 (9): 2
1. Division of Dermatology, Department of Internal Medicine, Duke University Medical Center,
Durham, North Carolina. steven.higgins@alumni.duke.edu
2. Division of Endocrinology and Diabetes, Department of Pediatrics, DUMC, Durham, North
Carolina
3. Departments of Medicine (Dermatology) and Pediatrics, DUMC, Durham, North Carolina

Abstract
Acanthosis nigricans is a dermatosis characterized by thickened, hyperpigmented plaques,
typically of the intertriginous surfaces and neck. Common in some populations, its prevalence
depends on race. Clinicians should recognize acanthosis nigricans; it heralds disorders ranging
from endocrinologic disturbances to malignancy. In this review, we discuss the pathogenesis of
acanthosis nigricans and its clinical implications and management.
Introduction

Figure 1a

Figure 1b

Figure 1. (a) Right neck and (b) left axilla in a 10year-old Asian male with acanthosis nigricans

Acanthosis nigricans (AN) is a dermatosis characterized by velvety, papillomatous, brownishblack, hyperkeratotic plaques, typically of the intertriginous surfaces and neck (Fig. 1)
[1, 2, 3, 4, 5]. Although AN is associated with malignancy, the recognition of its more common
connection to obesity and insulin resistance allows for diagnosis of related disorders including
type 2 diabetes, the metabolic syndrome, and polycystic ovary syndrome [6, 7, 8, 9]. Early
recognition of these conditions is essential for prevention of disease progression.

Clinical Features
Clinically, the neck is the most commonly affected area in children [6]. Ninety-nine percent of
children with AN have neck involvement, compared to 73 percent with axillary involvement [6].
Acanthosis nigricans may also affect eyelids, lips, vulva, mucosal surfaces, dorsal hands, and
flexural areas in the groin, knees and elbows [1]. While usually asymptomatic, AN is
occasionally pruritic [1, 2].

Histopathology

Histopathology (Fig. 2) reveals a thickened stratum corneum with

minimal involvement of the dermis except for thickened and
elongated dermal projections [2]. Despite the term "acanthosis,"
the actual amount of acanthosis, or thickening of the stratum
spinosum, is variable and typically mild [2, 3]. The dark color of
AN is likely due to hyperkeratosis rather than to a mild increase in
melanin pigmentation [10]. A subtle infiltrate composed of
lymphocytes, plasma cells, or neutrophils may be present, as well
as horn pseudocyst formation [1]. Tissue staining with colloidal
iron often shows infiltration of the papillary dermis with
glycosaminoglycans such as hyaluronic acid, particularly in
patients with gonadal disease such as polycystic ovarian
syndrome (PCOS) [7].

Figure 2
Figure 2. Histology of
acanthosis nigricans,
demonstrating
papillomatosis and
hyperkeratosis.
(Hematoxylin and eosin,
original magnification
x40). Reproduced with
permission from Lee HW
et al [5]. (with permission
of the author)

Prevalence
Acanthosis nigricans is common, although the exact prevalence depends on the racial makeup of
the population studied. While obesity increases the risk for development of AN, the differences
in prevalence of AN between racial groups cannot be explained solely by differing rates of
obesity [48]. For example, African Americans are 25 times as likely to have AN as patients of
European descent [6]. In a 1988 Texas school system population of 1412 adolescents, the general

prevalence of AN was 7.1 percent, but was only 0.45 percent among Caucasian students [48]. An
additional study of over 100,000 children in Texas performed 11 years later revealed a
prevalence of AN in 14.4 percent [49]. Also, a random sample of 2205 Cherokee Nation
members found 34.2 percent had AN [50]. In general, AN seems to be most common in Native
Americans, followed by African Americans, Hispanics, and Caucasians[6].

Pathogenesis

Elevated insulin concentrations result in direct and indirect

activation of IGF-1 receptors on keratinocytes and fibroblasts,
leading to proliferation. Other mediators may also contribute,
including other tyrosine kinase receptors such as EGFR and
FGFR. (IGF = insulin-like growth factor, BP = binding protein,
IGF-1R = insulin-like growth factor 1 receptor, EGFR =
epidermal growth factor receptor, FGFR = fibroblast growth
factor receptor)

Figure 3
Figure 3. Proposed
mechanisms for the
pathogenesis of
acanthosis nigricans

Acanthosis nigricans is most commonly associated with disorders

associated with insulin resistance, including obesity, type 2
diabetes, and the polycystic ovary syndrome [8]. In these cases,
hyperinsulinemia is thought to play a pivotal role (Fig. 3). At low concentrations, insulin
regulates carbohydrate, lipid, and protein metabolism and can weakly promote growth by
binding to "classic" insulin receptors [9, 51]. At high concentrations, however, insulin can exert
more potent growth-promoting effects through binding to insulin-like growth factor 1 receptors
(IGF-1Rs), which are similar in size and subunit structure to insulin receptors, but bind IGF-1
with 100- to 1000-fold greater affinity than insulin
A number of observations suggest that insulin-dependent activation of IGF-1Rs can promote
cellular proliferation and facilitate the development of AN. First, IGF receptors are found in
cultured fibroblasts and keratinocytes [53]. Second, insulin can cross the dermoepidermal
junction, and at high concentrations can stimulate growth and replication of fibroblasts [2, 53].
Finally, the severity of AN in obesity correlates positively with the fasting insulin concentration
[48, 54]. Thus, insulin may promote AN through direct activation of the IGF-1 signaling
pathway.

The true pathogenesis of AN, however, is likely to be more complex. Obese patients rarely, if
ever, achieve levels of insulin high enough (10 nM) to activate IGF-1Rs [55, 56]. The
predilection of AN for areas such as the neck and axillae suggests that perspiration and/or
friction also may be necessary cofactors

Hyperinsulinemia may also facilitate the development of AN indirectly by increasing the levels
of free IGF-1 in the circulation. The activity of IGF-1 is regulated by IGF binding proteins
(IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues, and regulate the levels of
the metabolically active "free" IGF-1 [58, 59]. Insulin-like growth factor 1 binding protein and
IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma

concentrations of free IGF-1 [59]. An increase in bioactive IGF-1 promotes cell growth and
differentiation [60].
Insulin-like growth factor 1 is expressed within the stratum granulosum and by dermal
fibroblasts, but not by epidermal basal keratinocytes [61]. In theory, an insulin-induced systemic
reduction of IGFBP-1 and IGFBP-2 could increase local levels of free IGF-1, thereby facilitating
the development of hyperkeratosis and papillomatosis.
Curiously, therapy with IGF-1 has resulted in improvement of extreme insulin resistance
syndromes, including improvement of AN in 5 of 7 patients [62]. Insulin-like growth factor 1
may reduce serum insulin concentrations and downregulate expression of IGF-1R [58, 63]. Since
insulin binds with lower affinity to the IGF-1 receptor than IGF-1 itself, it is possible that insulin
may be less proficient than IGF-1 at downregulating IGF-1Rs
Insulin-like growth factor 1 receptor, FGFR, and EGFR are all tyrosine kinase receptors and
acanthosis nigricans seems to be a final common manifestation of a variety of processes [4]. The
post-receptor intracellular pathways likely converge, although they have not been fully
elucidated [4]. Other perplexing aspects of AN include its predilection for certain races and
anatomic sites, as well as the fact that only some people with predisposing states develop the
condition.
Implications
Understanding the connection between acanthosis nigricans and insulin resistance is critical for
clinicians. Patients with AN are at risk for all of the components of the metabolic syndrome:
obesity, hypertension, elevated triglycerides, low high-density lipoprotein, and glucose
intolerance [66, 67]. The metabolic syndrome, present in 34 percent of American adults, yields a
risk of heart disease equivalent to smoking and in adults increases the risk of the development of
diabetes 3.5-fold within 5 years [68, 69].

Like obesity, PCOS is associated with insulin resistance, hyperinsulinemia, and AN. Between 5
and 33 percent of patients with PCOS have AN [70, 71]. This syndrome includes increased
synthesis of ovarian and adrenal androgens and inhibition of hepatic synthesis of sex hormone-

binding globulin [72]. Insulin resistance is also hypothesized to have a role in the development of
acne, skin tags, male vertex balding, myopia, and epithelial cell cancers[72]

Evaluation and Management

Patients may have multiple underlying diseases. The first step in

evaluation should be identification of the underlying condition.
We recommend obtaining certain basic studies (Fig. 4),
particularly in all overweight adults and children without a known
history of insulin resistance. Overweight in adults is defined as a
body mass index (BMI, weight in kilograms divided by height in
meters squared) of 25 kg/m or greater [73, 74]. In children and
adolescents, overweight is defined as at least the 85th percentile
of the sex-specific BMI-for-age growth chart; the child is
considered obese when the BMI z score exceeds the 95th
percentile for age and gender. Studies should include blood
pressure (BP), fasting lipoprotein profile, fasting glucose,
hemoglobin A1C, fasting insulin, and alanine aminotransferase
(ALT). Any abnormalities should prompt communication with the
primary provider or referral to an endocrinologist.

Figure 4
Figure 4. Recommended
evaluation for patients
with acanthosis
nigricans, with potential
etiologies.

The prevalence of obesity in the US has grown at an alarming rate [73, 74]. While detection of
AN is unnecessary for obesity screening, counseling patients about AN provides an excellent
opportunity to initiate treatment for obesity or overweight. Nonpharmacologic lifestyle
modifications with diet and exercise can be initiated. Pharmacologic therapy may be required for
patients with hypertension, hypercholesterolemia, hypertriglyceridemia, low levels of high
density lipoprotein (HDL), or elevated fasting glucose [75, 76, 77].
Warning flags that should trigger a careful evaluation for malignancy in patients presenting with
acanthosis nigricans include unintentional weight loss and rapid onset of extensive AN [1].
Mucosal involvement is more common in patients who have AN in association with a
malignancy, as are tripe palms, florid cutaneous papillomatosis, and the sign of Leser-Trlat [1].
Acanthosis nigricans that appears after initiation of one of the causative medications should
prompt discontinuation, when possible, or consideration of an alternative agent.

Retinoids have been successfully used to treat AN. Topical 0.1 percent tretinoin caused
improvement of AN in two case reports. One 18-year-old woman with AN experienced clearing
of her neck in 10 days, with improvement in color and hyperkeratosis of her axillae within 2
weeks [89]. Another patient had clearing of AN of the left axilla after tretinoin 0.1 percent gel
was applied twice daily for 2 weeks. The right axilla, used as a control, did not show any
improvement [90]. In another case report, the combination of 0.05 percent tretinoin cream and 12
percent ammonium lactate cream led to resolution of AN [91].

Oral retinoids, such as isotretinoin and acitretin, also can be effective [92, 93, 94]. Improvement
required large doses and extended courses, and relapse was described. One obese woman
improved with isotretinoin 3 mg/kg/day, but relapsed when this was stopped [92]. An 18-year-old
man with generalized idiopathic AN experienced complete recovery after 45 days with acitretin
0.8 mg/kg (50 mg) divided into 2 daily doses. After starting maintenance therapy of 25 mg daily
for 2 months, lesions recurred that subsequently resolved with topical retinoic acid 0.1 percent
[93]. An obese man taking isotretinoin 80 mg/day noted 90 percent improvement of his palms
and 50 percent improvement of his axillae within 2 months. After gradually tapering this dose
over more than a year and receiving over 30g, he experienced an exacerbation of his skin lesions
that improved with metformin 1000 mg twice daily [94]. Use of systemic retinoids for AN may
be inappropriate given their side effect profile and potential for toxicity.
Other therapies found beneficial in case reports include calcipotriol, fish oil, and laser. One obese
man had AN in the flexural areas that improved after 3 months of calcipotriol 0.005 percent
cream twice daily [95]. Another obese woman improved with calcipotriol ointment twice daily,
also for 3 months [96]. Fish oil containing omega-3 fatty acids effectively reduced
hyperpigmentation and normalized skin texture in one woman with acquired generalized
lipodystrophy and AN [10]. This occurred after 6 months of taking 10 to 20g per day of fish oil.
Long-pulsed (5 msec) alexandrite laser treatment led to resolution of AN in one woman [97].
Greater than 95 percent clearance of the left axilla was observed after 7 treatments, spaced 4 to 8
weeks apart (fluence was 16 to 23 J/cm2, with spot sizes of 10 or 12.5 mm). The right axilla,
initially used as a control, showed no improvement until it was treated.
Multiple anecdotal reports suggest that acanthosis nigricans is reversible. Given their ease of use
and safety profile, topical retinoids are a reasonable first-line treatment. However, whether
another therapy is superior remains unclear. Randomized, controlled trials of lifestyle
intervention and other therapies are needed.

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