Acanthosis Nigricans

 

EPIDEMIOLOGY

Acanthosis nigricans is probably the most readily recognized skin manifestation of diabetes. Acanthosis nigricans is common in the general population, and most cases are linked to obesity and insulin resistance. In some cases, increased androgen production is also identified. Drug-related and idiopathic acanthosis nigricans or familial acanthosis nigricans have been reported. In general, though, acanthosis nigricans should be considered a prognostic indicator for developing type 2 diabetes. In a large, population-based study from Galveston, Texas, acanthosis nigricans was present in 7 percent of school-age children. This percentage increased to 66 percent of children who weighed 200 percent of their ideal body weight. In this study, fasting insulin levels correlated with the presence and severity of skin findings. The rate of acanthosis nigricans varies among different ethnic groups. In the Galveston study, despite similar obesity rates, the prevalence was lower in whites (0.5 percent) and Hispanics (5 percent) than in African American children (13 percent). This finding suggests a possible genetic predisposition or increased sensitivity of the skin to hyperinsulinemia among certain populations. Although historical data have emphasized the relationship between acanthosis nigricans and malignancy, a true association is rare. Only when the onset is particularly rapid, the clinical findings are florid, or in the non-obese or non-diabetic adult with acanthosis nigricans is an evaluation for malignancy beyond routine age appropriate screening warranted . In one author's experience with seeing more than 12,000 patients with cancer, only two developed acanthosis nigricans.

ETIOLOGY AND PATHOGENESIS

Advances are taking place in understanding the pathogenesis of acanthosis nigricans. Insulin clearly plays a central role in the presentation of acanthosis nigricans. In a subset of women with hyperandrogenism and insulin resistance with acanthosis nigricans, loss of function mutations in the insulin receptor or anti-insulin receptor antibodies can be found (type A and type B syndrome).²¹ It is postulated that excess growth factor stimulation in the skin causes the aberrant proliferation of keratinocytes and fibroblasts that results in the phenotype of acanthosis nigricans.¹⁶ In states of insulin resistance and hyperinsulinemia, acanthosis nigricans may result from excess insulin binding to IGF-1 receptors on keratinocytes and fibroblasts. IGF-1 receptors are expressed on basal keratinocytes and are upregulated in proliferative conditions. Studies show that high concentrations of insulin stimulate fibroblast proliferation through IGF-1 receptors in vitro. Other members of the tyrosine kinase receptor family, including the epidermal growth factor receptor and the fibroblast growth factor receptor, have been implicated in acanthosis nigricans. Several genetic syndromes [Crouzon and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans)] with mutations in fibroblast growth factor receptor 3 result in acanthosis nigricans in the absence of hyperinsulinemia or obesity. Implicating this growth factor receptor in the pathogenesis of acanthosis nigricans.²² In several reports of acanthosis nigricans associated with malignancy, evidence suggests that transforming growth factor-β released from the tumor cells may stimulate keratinocyte proliferation via the epidermal growth factor receptors.Support for the role of different growth factors in the pathogenesis of acanthosis nigricans continues to accrue.

In addition to the direct effects of hyperinsulinemia on keratinocytes, insulin also appears to augment androgen levels in women. High insulin levels stimulate the production of ovarian androgens and ovarian hypertrophy with cystic changes.²¹ Although associated with elevated androgen levels, the acanthosis nigricans in women with polycystic ovarian syndrome (PCOS) does not respond reliably to antiandrogen therapy, implicating the relative importance of hyperinsulinemia over hyperandrogenism in acanthosis nigricans. Several drugs have also been reported to cause acanthosis nigricans, including systemic glucocorticoids, nicotinic acid, and estrogens such as diethylstilbestrol.

CLINICAL FINDINGS: CUTANEOUS LESIONS

Clinically, acanthosis nigricans presents as brown to gray-black papillomatous cutaneous thickening in the flexural areas, including the posterolateral neck, axillae, groin, and abdominal folds. The distribution is usually symmetric. The affected skin has a dirty, velvety texture. In some cases, oral, esophageal, pharyngeal, laryngeal, conjunctival, and anogenital mucosal surfaces may be involved. In general, however, the back of the neck is the most consistently and severely affected area. The development of superimposed acrochordons in involved areas is well described . In particularly florid cases, involvement on the back of the hands over the knuckles and even on the palms can be seen. When the palms are involved, the rugated appearance of

the palmar surface has been called tripe palms and is usually associated with acanthosis nigricans seen in the setting of malignancy . In the majority of cases, the most important factor in diagnosing acanthosis nigricans is recognizing the usually associated hyperinsulinemia, which is a known risk factor for type 2 diabetes.

The histopathology of clinical lesions demonstrates papillomatosis and hyperkeratosis but minimal acanthosis. Hyperpigmentation of the basal layer has been variably demonstrated and the brown color of the lesions is attributed to the hyperkeratosis by most.

TREATMENT

Treatment of acanthosis nigricans is generally ineffective. Topical treatment with calcipotriol,salicylic acid, urea, systemic and topical retinoids have all been used with anecdotal success. When identifiable, treatment of the underlying cause may be beneficial. Improvement or resolution does occur with weight loss in some obese patients. Medications that improve insulin sensitivity, such as metformin, have a theoretic benefit. Removal of an offending medication generally results in clearance of the skin. In patients with acanthosis nigricans in association with malignancy, there is usually improvement following treatment of the underlying malignancy. The skin finding may present before or after the diagnosis of malignancy is made. When it is associated with malignancy, a tumor of intra-abdominal origin, usually gastric, is seen in the majority of cases. It has been repeatedly described that patients' skin improves with chemotherapy and remits with recurrences.