CASE #1: Acanthosis nigricans

Acanthosis nigricans (AN) results from epidermal keratinocyte stimulation and dermal fibroblast proliferation secondary to increases in insulin, insulin-like growth factor, and other aspects that occur against a background of insulin resistance, obesity, cancer, diabetes, and other diseases. The disorder occurs commonly in the general population, and most cases are linked to obesity and insulin resistance.

In one large population study, AN was present in 7% of school-age children.1 The percentage increased to 66% of children who weighed more than 200% of their ideal body weight. Despite similar obesity rates, an unequal distribution of the disease was found based on ethnicity. The prevalence was highest in blacks (13%) and Hispanics (5%) and lower in whites (0.5%). AN affects both genders equally.

AN manifests with mildly to moderately rugose, velvety, dark-brown plaques. The plaques occur most commonly at flexural areas, specifically the axillae, neck, inframammary and inguinal creases. Other areas can be involved, but this is uncommon. Papillomatosis (multiple fingerlike growths) commonly occurs on cutaneous and mucosal surfaces. Skin tags can be found in and around areas of AN.

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The onset of AN is slow and subtle, often taking years to develop. While most cases are attributable to insulin resistance (prediabetes) or diabetes, AN can also herald the development of an underlying cancer. AN associated with malignancy usually presents in a more striking and sudden fashion. While AN in malignancy can affect the standard flexural areas, malignancy-associated AN manifests in such unusual sites as the mucous membranes, the palms and soles and even the eyelid.

Eyelid involvement in AN is rare and can be associated with malignancy. Some believe that eyelid AN such a reliable predictor of malignancy that its appearance requires a thorough systemic evaluation,2 but that may be an overstatement.

Because of changes in epidemiology and the overall decrease of stomach cancer, AN is no longer a reliable paraneoplastic indicator. In 1900, stomach cancer —which is linked to AN — was the most common type of cancer in the United States and is now rare. Representing approximately 55% of cases of AN, gastric adenocarcinoma is the most common malignancy now associated with the disorder. Other malignancies associated with AN include malignant lymphoma, squamous cell carcinoma of the cervix, bronchial carcinoma, and bronchogenic squamous cell carcinoma.2-6

Most cases of AN are not related to malignancy. AN in the general population indicates a state of hyperinsulinemia. Any suspicion of AN should elicit an inquiry about a family history of diabetes. A recent study reported a prevalence of 17% of AN in African individuals with type 2 diabetes.7 Investigators also have found that children with AN are almost four times more likely to have hyperinsulinemia than are children without the disorder.8

The differential diagnosis for AN includes the reticulated papillomatosis of Gougerot-Carteaud syndrome, tinea versicolor, erythrasma and related infections, Dowling-Degos disease and its variants and intertrigo.

The distinctive physical exam findings and medical history usually allow a diagnosis of AN to be made clinically. The first sign noticed by patients is hyperpigmentation, with the affected skin having a darker or “dirty” appearance. Thickening of the epidermis and deepening of the skin folds (rugation) follows.9

When making an AN diagnosis, ask about family history of diabetes, obesity and insulin resistance. It is also helpful to ask about personal history of weight changes, as obesity-related AN may follow weight gain, and AN of malignancy can correlate with weight loss.

Hormonal agents, birth control pills, growth hormones, human chorionic gonadotropin, antiretrovirals, and nicotinic acid have been reported to cause AN.8,10 Cases of AN have also been linked to increased androgen production, and some are idiopathic. Palifermin (Kepivance) — a modified version of recombinant keratinocyte growth factor (KGF) designed to decrease the incidence of mucositis associated with stem-cell transplantation — caused striking but transient AN, perhaps due to KGF and fibroblast growth factor.11

If the presentation is atypical and there is uncertainty about the diagnosis of AN, a biopsy may be indicated. Histology reveals hypertrophy and hyperplasia of the epidermis and papillary dermis accompanied by hyperkeratosis and acanthosis. Typically, there is an increase in extracellular matrix, resulting in papillary extension into the dermis.8 There is no inflammatory infiltrate of any significance into the dermis.10

Sometimes, AN may be associated with horn pseudocyst formation resembling the changes seen in a seborrheic keratosis.12 Although histologic examination occasionally demonstrates increased melanin in the basal epithelium, hyperkeratosis and papillomatosis account primarily for the darkened appearance of the skin lesion.4,10 Examination under an electron microscopic shows an increase in tonofilaments.13 Other studies have shown an unusually high expression of keratin 18 and 19 proteins.14

Most medical treatments for AN are ineffective. Treatment is targeted at the underlying cause for the disorder. For malignancy-associated AN, treatment of the primary cancer will resolve the disorder. AN can then be used as a marker for disease recurrence.4 Since AN is most often caused by insulin resistance, glucose control should be the primary focus of treatment. Achievement of euglycemia in diabetic patients is accompanied by marked regression of AN.15 Weight loss can abate AN in many cases.16 In addition, oral metformin has been shown to significantly improve obesity-associated AN.17-19

If the patient desires further treatment, topical application of 0.1% tretinoin (Vesanoid) cream can be tried to lighten the lesion;8 combining tretinoin with 12% ammonium lactate cream has also been successful.16-20 Another study proved the effectiveness of topical calcipotriol.21 If topical therapy fails, oral isotretinoin or acitretin may be tried.16, 22 Extremely thick lesions can have a bad odor, and treatment with antibacterial soaps may help in these cases.23

One year after the initial examination, the patient’s glucose and hemoglobin A1c were normal, according to her internist. The eye plaques and skin tags were unchanged.