Dermatology Online Journal

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

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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.

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Introduction

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

Acanthosis nigricans (AN) is a dermatosis characterized by velvety, papillomatous, brownish-black, 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

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)

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].

Related Syndromes

Acanthosis nigricans is linked to a variety of syndromes (Table 1). Most are associated with insulin resistance or fibroblast growth factor receptor (FGFR) mutations. Acanthosis nigricans may also appear as an adverse effect of several medications that promote hyperinsulinemia, such as glucocorticoids [1], niacin [40, 41, 42], insulin [43], oral contraceptives [44], and protease inhibitors [45, 46, 47].

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

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

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)

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 [51, 52].

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 [6, 57].

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.

Hyperinsulinemia does not mediate all forms of acanthosis nigricans. As mentioned previously, certain AN syndromes are due to FGFR defects (Table 1). Some malignancies may be associated with insulin receptor antibodies, as in one reported case of metastatic pheochromocytoma; however, no insulin resistance is described for most cases of paraneoplastic AN [64]. Malignancy-associated AN might be explained by elevated levels of growth factors such as transforming growth factor (TGF-α), which exerts effects on epidermal tissue via the epidermal growth factor receptor (EGFR) [65]. One patient experienced a decrease in urinary TGF-α and improvement of AN after resection of a melanoma [65].

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

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

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/m² 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.

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-Trélat [1]. Acanthosis nigricans that appears after initiation of one of the causative medications should prompt discontinuation, when possible, or consideration of an alternative agent.

Improvement of the skin lesions is often the patient's primary concern. No randomized, controlled trials exist for any treatment of AN. Multiple case reports suggest that acanthosis nigricans improves with treatment of its underlying condition (Table 2).

A randomized, open-label trial that compared the insulin sensitizers metformin and rosiglitazone in 30 overweight Mexican patients for 12 weeks demonstrated only minimal improvement in AN lesions with either agent [87]. Whether the duration of therapy was sufficient to see a clinical change is uncertain. A smaller, 6-month trial of metformin in obese patients resulted in improvement of AN in 3 of 5 patients [88].

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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