Acanthosis nigricans

Introduction

Acanthosis nigricans (AN) is characterized by dark, coarse and thickened skin with a velvety texture, being symmetrically distributed on the neck, the axillae, antecubital and popliteal fossae, and groin folds, histopathologically characterized by papillomatosis and hyperkeratosis of the skin.

 

Two main forms exist: benign and malignant forms.In the benign form of acanthosis nigricans, the factor is probably insulin or insulin like growth factor (IGF). Other proposed mediators include other tyrosine kinase receptors (epidermal growth factor receptor [EGFR] or fibroblast growth factor receptor [FGFR]).

 

At high concentrations, insulin may exert potent proliferative effects via high-affinity binding to IGF-1 receptors. In addition, free IGF-1 levels may be elevated in obese patients with hyperinsulinemia. 

In malignant acanthosis nigricans, the stimulating factor is hypothesized to be a substance secreted by the tumor. Transforming growth factor (TGF)–alpha is structurally similar to epidermal growth factor and is a likely candidate. Reports of urine and serum TGF-alpha levels normalizing after surgical tumor removal exist, with subsequent regression of skin lesions. 

 

 

Epidemiology

 

AN can occur at any age. The benign form is most common in adults but also common in obese children. The malignant form, which is rare, usually arises in older age groups >40 years.

 

Predisposing factors

 

AN is associated with a number of benign and malignant conditions with a common pathway of keratinocyte and fibroblast proliferation by circulating factors. Perspiration or frictions are mechanical contributing factors, as suggested by the predilection of acanthosis nigricans for body folds.

 

 

Clinical features

Acanthosis nigricans is characterized by dark, coarse, thickened skin with a velvety texture. The earliest change is grey-brown/black pigmentation that is palpably thickened and covered by small papillomatous elevations, giving it a velvety texture. As thickening increases, skin lines are further accentuated and the surface becomes mammilated and rugose, with the development of larger warty excrescences.  Acrochordons (skin tags) are often found in and around the affected areas. AN is usually asymptomatic, but occasionally, it can be pruritic. The lesions are symmetrically distributed on the back and sides of neck, axillae, groin, and antecubital and popliteal areas.  Neck is the most common site affected (99%) in children when compared with axillae (73%). Face, extensor surface of elbows and knees, dorsa of joints of hands, umbilicus, external genitalia, inner aspects of thighs and anus are also involved. With extensive involvement, lesions can be found over the areolae, and eye, including papillomatous lesions on the eyelids and conjunctiva. Involvement of mucous membranes is uncommon, but oral mucous membrane may show delicate velvety furrows.  Generalized involvement can be a rare manifestation of certain types of AN, being common in adults with underlying malignancy. When on the face, it should be considered in the differential diagnosis of facial hyperpigmentation. On the face, AN presents as poorly demarcated hyperpigmentation with a predilection for the malar region inferior to the zygoma and the nasolabial folds, and has even been described on the supraalar creases. Recognizing this entity is becoming steadily more important as the rates of obesity and non-insulin-dependent diabetes increases. Tripe palms presents as rugose hyperkeratosis and prominent dermatoglyphics of palms, likened to bovine gut lining. It is paraneoplastic in occurrence associated with malignancy in 90%, gastric cancer being the most frequent. 

 

 

Clinical variants

 

Nine types of acanthosis nigricans have been described.

 

Obesity-associated acanthosis nigricans

 

Obesity-associated acanthosis nigricans, once labeled pseudo–acanthosis nigricans, is the most common type of acanthosis nigricans. Lesions may appear at any age but are more common in adulthood. More than half the adults who weigh >200% of their ideal body weight have AN. The dermatosis is weight dependent, and lesions may completely regress with weight reduction. Insulin resistance is often present in these patients.

 

Syndromic acanthosis nigricans

 

Syndromic acanthosis nigricans is the name given to acanthosis nigricans that is associated with a syndrome. The type A syndrome and type B syndrome are special examples.

 

The type A syndrome also is termed the hyperandrogenemia, insulin resistance, and acanthosis nigricans syndrome (HAIR-AN syndrome). This syndrome is often familial, affecting primarily young women. It is associated with polycystic ovaries or signs of virilization (eg, hirsutism, clitoral hypertrophy). High plasma testosterone levels are common.

 

Type B insulin resistance syndrome is characterized by the association of AN with diabetes and hyperandrogenism, or with an autoimmune disease (including systemic lupus erythematosus, systemic sclerosis, Hashimoto thyroiditis and Sjögren syndrome). Circulating antibodies to the insulin receptor may be present.

 

Acral acanthosis nigricans

 

Acral acanthosis nigricans occurs in patients who are in otherwise good health and in dark-skinned individuals and manifests as velvety thickening and hyperpigmentation of the skin on the dorsa of the hands and feet, especially the knuckles.

 

Unilateral acanthosis nigricans (Nevoid acanthosis nigricans)

It is a rare form of AN, inherited as an autosomal dominant trait. Clinically, it appears as a unilateral pigmented plaque, along a line of Blaschko, and resembles an epidermal naevus and may become evident during infancy, childhood, or adulthood. Unilateral nevoid AN is not related to endocrinopathy. 

Familial acanthosis nigricans

It is a rare autosomal dominant genodermatosis beginning during early childhood. The condition often progresses until puberty after which it stabilizes or regresses.

 

Generalized acanthosis nigricans

 

Generalized acanthosis nigricans is very rare, and seen only in children without underlying systemic disease or malignancy. There is generalized hyperpigmenation and velvety thickening of the skin.

 

Drug-induced acanthosis nigricans

 

This may appear as an adverse effect of several medications that promote hyperinsulinemia, including pituitary extract, systemic corticosteroids, testosterone and exogenous estrogens, including oral contraceptives. Nicotinic acid is most widely recognized association.   The lesions of acanthosis nigricans may regress following discontinuation of the offending medication. Erickson et al. first described AN as a rare local cutaneous side-effect of insulin injection likely due to activation of IGF receptors. Prescription of the correct insulin and use of proper technique will prevent AN development. 

Malignant acanthosis nigricans

 

Malignant acanthosis nigricans, which is associated with internal malignancy, is the most worrisome of the variants of acanthosis nigricans because the underlying neoplasm is often an aggressive cancer.

 

Acanthosis nigricans has been reported with many kinds of cancer, but, by far, the most common underlying malignancy is a gastric adenocarcinoma.

 

In 25-50% of cases of malignant acanthosis nigricans, the oral cavity is involved. The tongue and the lips are most commonly affected, with elongation of the filiform papillae on the dorsal and lateral surfaces of the tongue and multiple papillary lesions appearing on the commissures of the lips.

 

Tripe palms may show altered dermatoglyphics due to alteration of epidermal rete ridges

 

Malignant acanthosis nigricans is clinically indistinguishable from the benign forms.

 

Papillomatous lesions on the eyelids and conjunctiva may occur. Leukonychia and nail hyperkeratosis has been reported. In one-third of cases skin changes occur before signs of cancer, in another one-third AN and neoplasm arise simultaneously and in remaining one third, skin findings manifest after diagnosis of cancer.  Warning signs that call for evaluation for malignancy in AN patients include age >40 years, not having any previous endocrine disorder or any genetically determined disease, unintentional weight loss, rapid onset of extensive AN, higher rate of pruritus, atypical sites, tripe palms, florid cutaneous papillomatosis, in which there is a rapid development of numerous warty papules on the trunk and the extremities that are clinically indistinguishable from viral warts and sign of Leser-Trélat.  

Regression of acanthosis nigricans has been seen with treatment of the underlying malignancy, and reappearance may suggest recurrence or metastasis of the primary tumor.

Malignant acanthosis nigricans might be explained by elevated levels of transforming growth factor (TGF-α), exerting effects on epidermal tissue through epidermal growth factor (EGF) receptor. TGF-α produced by cancer cells is structurally similar to EGF-α, interacts with the same receptor on the cell surface, probably binding with it in different sites. The receptor for EGF is found on actively proliferating cells of the basal layer where it is involved in growth and differentiation of normal keratinocytes. When these growth factors are produced by the primary tumor and circulate in large quantities, they may cause epidermal cell proliferation, leading to AN.

 

 

Mixed-type acanthosis nigricans

 

Mixed-type acanthosis nigricans refers to those situations in which a patient with one of the above types of acanthosis nigricans develops new lesions of a different etiology. An example of this would be an overweight patient with obesity-associated acanthosis nigricans who subsequently develops malignant acanthosis nigricans.

 

Pathogenesis

Insulin has been demonstrated to cross dermoepidermal junction (DEJ) to reach keratinocytes. At low concentrations, insulin regulates carbohydrate, lipid and protein metabolism and can weakly promote growth by binding to "classic" insulin receptors. At higher concentrations, however, insulin can exert more potent growth-promoting effects through binding to insulin-like growth factor 1 receptors (IGF-1Rs) that are similar in size and subunit structure to insulin receptors, but bind IGF-1 with 100- to 1000-fold greater affinity than insulin. The binding stimulates proliferation of keratinocytes and fibroblasts, leading to AN.

Hyperinsulinemia not only causes AN by exerting a direct toxic effect, but indirectly by increasing free IGF-1 levels in circulation. The activity of IGF-1 is regulated by insulin-like growth binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues and regulate levels of metabolically active "free" IGF-1. IGFBP-1 and IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma concentrations of free IGF-1, which promotes cell growth and differentiation [Flow Chart].

Insulin and IGF-1 levels are both may be implicated in etiogenesis of acrochordons and AN through their proliferative and differentiating properties.

 

Insulin resistance and AN

Insulin resistance is a metabolic disorder in which target cells fail to respond to normal levels of circulating insulin, resulting in compensatory hyperinsulinemia. IR has been associated with AN and acrochordons which may represent an easily identifiable sign of IR and noninsulin-dependent diabetes. AN is so closely associated with IR that it has been called a clinical surrogate for laboratory determined hyperinsulinemia. Katie S in their study observed that posterolateral neck texture had the highest sensitivity (96%) for IR compared with neck/axillary texture and pigment and proposed the term insulin neck (visibly increased texture on posterolateral neck appearing as visible lines and/or furrows and ridges) for this finding. They suggested that all patients with elevated BMI should be examined for insulin neck and if neck texture is normal, IR is less likely to be present.  IR occurs in 20-25% of the individuals. Obese patients and patients with polycystic ovary syndrome have Type A IR.

 

 

Acanthosis nigricans and cardiovascular disease

 

Insulin resistance is thought to be a primary etiological factor in the development of cardiac dysfunction, higher prevalence being reported in non ischemic heart failure population. It predates the development of cardiovascular disease and independently defines a worse prognosis. Reduction in endothelial function may be a link between IR and decline in cardiovascular performance.

 

 

Acanthosis nigricans and adipokines

Acanthosis nigricans patients have hyperinsulinemia and may be at greater risk of atherosclerotic cardiovascular disease.  The commonest underlying cause of IR is excess abdominal adipose tissue which releases increased amounts of free fatty acids which directly affect insulin signaling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in liver. Other factors presumed to play a role in IR are tumor necrosis factor α, adiponectin, leptin, interlukin-6 and other adipokines. When β-cells fail to secrete excess insulin needed, diabetes mellitus Type 2 and coronary heart disease occur as a complication of IR. 

 

Metabolic syndrome, insulin resistance and adipokines

Obesity is commonly associated with type 2 diabetes, coronary artery disease, and hypertension, coexistence of which is termed the metabolic syndrome. IR lies at the heart of the metabolic syndrome. Elevated serum triglycerides commonly associated with IR represent a valuable clinical marker of metabolic syndrome.

White adipose tissue is a major site of energy storage and it has been increasingly recognized as an important endocrine organ that secretes a number of biologically active "adipokines" (leptin, adiponectin, resistin), some of which (especially resistin and adiponectin) have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism.

Chronic state of IR is associated with secondary changes in levels of "adipokines" (decreased serum adiponectin, increased serum resistin and decreased adiponectin gene expression). Decrease in adiponectin levels by genetic and environmental factors contributes to the development of the metabolic syndrome. Adiponectin is important because of its antidiabetic and antiatherogenic effects; hence it is expected to be a novel therapeutic tool for the metabolic syndrome. The thiazolidinedione (TZD) class of antidiabetic drugs, having pleiotropic effects on cardiovascular diseases and lipid metabolism exert their effects partly through increasing levels of adiponectin. Adiponectin expression and levels in circulation are upregulated by rosiglitazone. 

Laboratory Studies

 

In middle-aged and older patients with extensive skin or severe skin and mucosal findings, a workup for internal malignancy is indicated.

 

The vast majority of cases are due to obesity and/or insulin resistance. Screen for diabetes with a glycosylated hemoglobin level or glucose tolerance test.

 

 

Screen for insulin resistance

 

A good screening test for insulin resistance is a plasma insulin level, which will be high in those with insulin resistance. This is the most sensitive test to detect a metabolic abnormality of this kind because many younger patients do not yet have overt diabetes mellitus and an abnormal glycosylated hemoglobin level, but they do have a high plasma insulin level.

 

Glucose/insulin ratio has been used in studies as an index of IR. It is a highly sensitive and specific measurement of insulin sensitivity. In adults, a ratio of <4.5 is abnormal, whereas in prepubertal children <7 is abnormal. 

 

 

Histologic Findings

 

Histologic examination reveals hyperkeratosis, papillomatosis, with minimal or no acanthosis. The dermal papillae project upward as fingerlike projections. Clinical hyperpigmentation is secondary to the hyperkeratosis and not to increased melanocytes or increased melanin deposition. Dermal inflammatory infiltrate is minimal or nonexistent. Mucosal acanthosis nigricans reveals epithelial hyperkeratosis and papillomatosis along with parakeratosis.

 

 

Prognosis

 

The prognosis for patients with malignant acanthosis nigricans is often poor. The associated malignancy frequently is advanced, and the average survival of these patients is approximately 2 years.

 

Patients with the benign form of acanthosis nigricans experience very few, if any, complications of their skin lesions. However, many of these patients have an underlying insulin-resistant state that is the cause of their acanthosis nigricans. The severity of skin findings may parallel the degree of insulin resistance, and a partial resolution may occur with treatment of the insulin-resistant state.

 

Treatment of AN

Management of AN is the management of the underlying condition. In familial AN or AN not associated with an underlying condition, treatment is aimed at improving the cosmetic appearance of the condition.

 

Weight loss and exercise have shown to increase insulin sensitivity and reduce insulin levels causing improvement in obesity associated AN.  Correction of hyperinsulinemia reduces hyperkeratotic lesions.

 

Cessation of the inciting agent in drug-induced acanthosis nigricans often results in resolution. Dietary fish oil reportedly is beneficial in patients with lipodystrophic diabetes and generalized acanthosis nigricans. 

 

Topical treatment

Retinoids

Topical retinoid is considered first-line treatment, especially for unilateral nevoid AN.  It corrects hyperkeratosis and causes near complete reversion to normal state. Intermittent tretinoin application is needed to maintain improved status. 

Combination of ammonium lactate and tretinoin

Retinoids affect cell growth, differentiation, and morphogenesis and alter cell cohesiveness. Lactic acid is an alpha-hydroxy acid that works as a peeling agent and also via release of desmogleins, indicating disintegration of desmosomes. Though the exact mechanism of action of the two agents is unknown, synergistic interaction is thought to play a role. 

Peels

Trichloroacetic acid (TCA) is a superficial chemical exfoliating agent causing destruction of the epidermis with subsequent repair and rejuvenation. TCA (15%) is caustic and causes coagulation of skin proteins leading to frosting. Precipitation of proteins leads to necrosis and destruction of epidermis, followed by inflammation and activation of wound repair mechanisms. This leads to re-epithelialization with replacement of smoother skin. The advantages of TCA are that it is a stable product, hence systemic absorption and peel depth correlate with the intensity of frost and endpoint is easy to judge. TCA is safe, easily available, cheap, and easy to prepare. TCA 15% is a safe and effective therapeutic modality for AN in comparison to other topical treatments. 

Calcipotriol

Calcipotriol is another beneficial treatment in AN.  It inhibits keratinocyte proliferation and promotes differentiation by increasing intracellular calcium levels and cyclic GMP levels in keratinocytes. Gregoriou et al. concluded that it is safe, well-tolerated, alternative treatment for AN when an etiological treatment is not possible or necessary. Bohm et al. reported a case of mixed-type AN responding favorably to calcipotriol. 

Miscellaneous treatment

Urea, salicylic acid and triple-combination depigmenting cream (tretinoin 0.05%, hydroquinone 4%, fluocinolone acetonide 0.01%) with sunscreens are other options. 

Oral treatment

 

Oral retinoids

Oral retinoids (isotretinoin, acitretin) can be effective; improvement requires large doses and extended courses, and relapses are described. The mechanism of action is probably normalization of epithelial growth and differentiation.  Acitretin has been rarely reported for AN treatment and has showed good success in cases with syndromic and benign AN. Oral isotretinoin has been used successfully treat to extensive AN. 

Metformin and rosiglitazone

Metformin and rosiglitazone are useful in AN characterized by IR. Paula et al. observed reduction in fasting insulin levels with rosiglitazone when compared to metformin and modest improvement of skin texture with both. Duration of treatment may be related to improvement as metformin improves AN and IR if given for 6 months or more.  Metformin reduces glucose production by increasing peripheral insulin responsiveness, reduces hyperinsulinemia, body weight and fat mass and improves insulin sensitivity. The combined use of metformin and TZDs which increase sensitivity to insulin in peripheral muscles, also give good results.

 

 

 

Cosmetic treatment

Because darkening of affected areas is common in AN, Alan Rosenbach considered the possibility that long-pulsed alexandrite laser, which was designed to target melanin in hair could improve this condition. They hypothesized that thermal heating of epidermis and dermis results in tissue remodeling and pigment reduction. They reported 95% clearance of AN of axillae after seven sessions and concluded that long-pulsed alexandrite laser can effectively and safely treat acanthosis nigricans of the axillae. 

 

Treatment of malignant AN

 

Surgical removal of tumors is the mainstay of treatment for malignant acanthosis nigricans, if possible, because clearance following primary malignancy excision has been described. 

 

Conclusion

 

Though mainly a disease of cosmetic concern, AN can be pointer to underlying metabolic syndrome or malignancy. A thorough investigation and treatment is therefore mandatory to prevent long term consequences.

 

 

Therapeutic ladder

First line

·        Topical retinoids – may reduce the hyperkeratosis

Second line

·        Topical α‐hydroxyacids and keratolytics such as salicylic acid may improve appearance by reducing hyperkeratosis

Third line

·        In extensive cases oral isotretinoin has been used with some success