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eISSN: 2084-9893
ISSN: 0033-2526
Dermatology Review/Przegląd Dermatologiczny
Bieżący numer Archiwum Artykuły zaakceptowane O czasopiśmie Zeszyty specjalne Rada naukowa Bazy indeksacyjne Prenumerata Kontakt Zasady publikacji prac Standardy etyczne i procedury
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1/2011
vol. 98
 
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Acanthosis nigricans – a common significant disorder usually unassociated with malignancy

Robert A. Schwartz
,
Edmund J. Janniger

Przegl Dermatol 2011, 98, 1–6
Data publikacji online: 2011/03/04
Plik artykułu:
- Acanthosis nigricans.pdf  [2.07 MB]
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Introduction

Acanthosis nigricans (AN) was originally noted as an important cutaneous finding signifying an internal malignancy. Pollitzer and Unna [1] first characterized it in 1890 in a patient who most likely had a gastrointestinal cancer. Most early accounts of acanthosis nigricans illuminated the rare fulminant form with malignancy [1-4], rather than the common types are unassociated with it [5, 6]. Acanthosis nigricans has been classified into eight types [4]. They are benign (non-syndromic, insulin resistance-associated AN), obesity-related, syndromic, malignant (paraneoplastic), unilateral, acral, drug-induced, and mixed AN, a combination of two or more of the above.

The most salient cause of AN is obesity and compensatory hyperinsulinemia [4-6]. While AN may be a significant indicator of insulin sensitivity independent of body mass index, body mass index percentile may be more sensitive than acanthosis nigricans, at least in screening Native American children for diabetes risk [7]. In addition, AN was shown to be a significant predictor of metabolic syndrome in polycystic ovary syndrome, occurring in 65.6% of South Asian women with this syndrome [8]. Children in Chicago 8 to 14 years of age with AN were found to have severe insulin resistance, with more than 1 in 4 already having abnormal glucose homeostasis [9]. Thus, AN identified a high-risk population, for whom appropriate interventions may be pivotal.

Pathogenesis

Acanthosis nigricans occurs most commonly in association with hyperinsulinemia, a result of insulin receptor gene defects causing insulin resistance, and less frequently due to mutations in fibroblast growth factor receptors (FGFR). The latter is most evident with AN and lipodystrophic disorders [6]. Type A insulin resistance syndrome results from primary insulin receptor defects, many mutations of which have been described. Type B results from antibodies to the receptor. The mechanism of AN due to insulin resistance is by activation of the insulin-like growth factor 1 receptor due to high levels of circulating insulin. A family was described associating AN with a mutation of the FGFR3 gene located at 4p16.3 [10]. Thus, these genetic syndromes may be divided into insulin resistance syndromes and fibroblast growth factor (FGF) defects [6].

Acanthosis nigricans presumably results from growth factor stimulation of keratinocytes and dermal fibroblasts. Tyrosine kinase growth factor receptor signaling may be pivotal in the pathogenesis of AN [6]. AN appears to result from activation of three distinct sets of cellular receptors, epidermal growth factor receptor, insulin-like growth factor receptors and FGF receptors, all part of the tyrosine kinase receptor superfamily.

Clinical manifestations

The diagnosis of AN is usually clinically evident [3-5, 11]. It typically has symmetric, hyperpigmented, hypertophic, verruccous and at times papillomatous patches or plaques that confer a velvety texture to the skin and are usually brownish-black in color. The most commonly affected areas include the axillae, posterior neck fold, flexor surfaces of the upper and lower extremities, umbilicus, groin, inframammary folds, face, and perioral and perianal surfaces. In obese individuals, involvement of the maxillary and periorbital skin surfaces may be noted, but this is more common in patients with generalized or malignancy-associated AN. AN becomes first evident with hyperpigmentation first evident in the axillae or posterior neck fold. Involvement of the mucosal surfaces of the conjunctivae, lips, oral cavity and vulva may occur, often with a papillomatous appearance more prominent than hyperpigmentation.

Benign acanthosis nigricans

Benign acanthosis nigricans is non-syndromic, insulin resistance-associated AN. It is usually congenital or develops during childhood or adolescence [4, 11-16]. It may be inherited as an autosomal dominant trait with variable penetrance. Early AN can be unilateral, with extension of clinical involvement associated with puberty sometimes to become generalized. AN has been delineated in one family, all of whom tested had a mutation of the FGFR3 gene [10]. It was inherited in an autosomal dominant manner with no obvious associated skeletal or neurological abnormalities save for short stature. A few other families with isolated nonsyndromic, noninsulin resistance–associated familial AN have been described, inherited autosomal dominantly with variable penetrance. This familial form of AN tends to appear in infancy, matures and stabilizes at puberty, and is not associated with obesity or diabetes mellitus.

Obesity-associated acanthosis nigricans

This is the most common cause of AN in children and adults worldwide [4, 19-23]. The cutaneous manifestations are usually evident after puberty, but may occur at any age (Fig. 1, 2). Progressive hyperinsulinemia leads to a rapid progression of acanthotic changes during the pubertal years, and slows thereafter [17, 18]. Full regression of the skin lesions may occur with weight loss. A lineage between intrahepatic fat deposition and insulin resistance in adolescence has been described and may be significant [19].

Syndromic acanthosis nigricans

There are numerous syndromic disorders that feature AN as a key phenotype or an associated sign [4, 23-28]. The type A insulin resistance syndrome is also known as HAIR-AN syndrome, a constellation of hyperandrogenism, insulin resistance and AN. This commonly affects young black females, who demonstrate more severe lesions in early childhood [28]. Associated polycystic ovaries and signs of virilization may also be noted.

Patients with the type B insulin resistance syndrome are generally hyperinsulinemic African-American females who manifest acanthosis nigricans in the 4th decade of life [28, 29]. Periocular acanthosis nigricans is a remarkable attribute in the type B syndrome [17]. Hyperandrogenism may be an important component feature in this syndrome, particularly in women of reproductive age. These patients often have other autoimmune diseases, most often systemic lupus erythematosus, but also Sjögren syndrome, progressive systemic sclerosis, Hashimoto’s thyroiditis, and autoimmune thrombocytopenia.

Other syndromic associations are noteworthy [4, 6, 30-32]. These include Lawrence-Seip syndrome of congenital or acquired generalized lipodystrophy, a generalized absence of subcutaneous fat, which may be associated with acanthosis nigricans, owing to extreme insulin resistance and hyperandrogenism, as well as Hirschowitz’s syndrome, polycystic ovarian syndrome, Donohue’s syndrome (leprechaunism), Rabson-Mendenhall syndrome, Alström’s syndro­me, and Lelis syndrome of ectodermal dysplasia with hypotrichosis, hypohidrosis and AN [31, 32].

Acral acanthosis nigricans

Acral AN, also known as acral acanthotic anomaly, affects the elbows, knees, knuckles, and dorsal surfaces of the feet in otherwise healthy individuals with axillae and other intertriginous regions appearing normal [4, 33, 34] (Fig. 3). Knuckle hyperpigmentation may be most prominent. This is common in patients of Subsaharian African lineage who are otherwise usually healthy. It was originally described in 1981 by Schwartz [33]. The name acral AN emphasizes that it is a type of AN, the term acral acanthotic anomic stresses its uniqueness. This relatively common disorder is seen as velvety hyperpigmented plaques in individuals with dark complexions. Although one patient with possible acral AN and dermatofibrosarcoma has been described, acral AN alone is not an indication to evaluate a patient for an internal malignancy. The cause of acral AN remains elusive.

Unilateral acanthosis nigricans

Unilateral AN is an epidermal nevoid condition that may represent a unilateral epidermal nevus or be a precursor to bilateral AN [4, 35-40]. Unilateral AN may also be inherited in an autosomal dominant fashion with variable penetrance [4]. Unilateral AN has a unilateral or localized distribution manifesting during childhood or later, a short period of activity for 4-5 years and remains stable, with no tendency to resolve. It is not associated with systemic, endocrine or syndromic conditions and, unlike classical AN, there does not appear to be documentation of familial involvement in unilateral AN. Since its first description in 1991 by Krishnaram [35], less than 10 others have been documented in the world literature [37, 38]. AN may occur with both unilateral linear and symmetrical nonlinear changes, probably a result of early loss of heterozygosity causing the segmental skin lesions superimposed on less pronounced nonsegmental AN [40].

Epidermal nevi and unilateral AN share clinical and histopathological features [38]. Unilateral AN has a late onset with velvety thickening of the skin and ill-defined margins merging with normal skin. The streaky, curvilinear pattern so commonly seen in epidermal nevi is absent. Although the histopathology of AN is not diagnostic, lack of significant acanthosis excluded EN. Unilateral AN does not have a predilection for intertrigenous areas. Most cases have their origin from the midline with unilateral distribution.

Drug-induced acanthosis nigricans

Acanthosis nigricans can be induced by pharmacologic agents [40-45]. Nicotinic acid, an anti-hyperlipidemic agent that also induces insulin-resistance, is the common one with plaques of AN typically developing on the abdomen and flexor surfaces of the skin and resolving within 4-10 weeks of stopping the medication. Insulin injection sites may develop localized AN [44]. It may also develop following long-term use of oral contraceptives, diethylstilbestrol, heroin, corticosteroids, methyltestosterone, fusidic acid, and hydantoin-like derivatives. Additionally, estrogens, niacin, triazinate, and somatotrophin have been linked. Palifermin, a modified human keratinocyte growth factor, was linked with AN in a cancer patient [45], a speculative association at best.

Histopathology

Acanthosis nigricans is characterized by epidermal hyperkeratosis and minimal to mild acanthosis [4]. There is an associated upward projection of the dermal papillae into a thinned overlying epidermis; keratinaceous debris may fill the regions between the ridges. Hyperpigmentation evident clinically is usually the result of epidermal hyperkeratosis, but it sometimes may be due to an increased number of melanosomes in the stratum corneum [46]. Mucosal acanthosis nigricans also exhibits epidermal hyperkeratosis and papillomatosis along with parakeratosis.

Differential diagnosis

Acanthosis nigricans may initially resemble an inflammatory dermatitis with pruritic and erythematous patches, superficial fungal infections, confluent and reticulated papillomomatosis, and the continuum of acanthosis nigricans, the sign of Leser-Trélat and florid cutaneous papillomatosis (Schwartz-Burgess syndrome) [47, 48]. Ichthyosis hystrix, generalized epidermal nevi, and diffuse lichenification of atopic dermatitis may also occasionally require distinction.

Conclusion

Acanthosis nigricans is often an important cutaneous marker of insulin resistance that is more commonly being diagnosed in obese children and adolescents worldwide. Early intervention with dietary modification and achievement of endocrinologic hormone balance is vital to avert the potentially devastating future complications associated with these conditions, including type 2 diabetes mellitus and cardiovascular disease.

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Otrzymano: 31 XII 2010 r.

Zaakceptowano: 17 I 2011 r.
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