INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
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• Follow-up
• Miscellaneous
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Background

Although Addison may have seen a case of acanthosis nigricans (AN) before 1885 and misdiagnosed it as Addison disease, the first documented case of AN was in 1889. By 1909, this dermatosis had been described in approximately 50 patients and was suspected to be associated with internal malignancy. In 1976, Kahn et al published their landmark study in which the association between AN and insulin resistance was first described.

Pathophysiology

AN most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. In the benign form of AN, the factor is probably insulin or an insulinlike growth factor that incites the epidermal cell propagation. In malignant AN, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor-alpha is structurally similar to epidermal growth factor and is a likely candidate. Exogenous medications also have been implicated as etiologic factors.

Frequency

United States

The exact incidence of AN is unknown. In an unselected population of 1412 children, the changes of AN were present in 7.1%. Obesity is closely associated with AN, and more than one half of the adults who weigh greater than 200% of their ideal body weight have lesions consistent with AN. The malignant form of AN is far less common, and, in one study, only 2 of 12,000 patients with cancer had signs of AN.

Mortality/Morbidity

AN is divided into 2 broad categories, benign and malignant.

• Patients with the benign form of AN 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 AN. The severity of the insulin resistance is highly variable and ranges from an incidental finding on routine blood studies to overt diabetes mellitus. 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. Insulin resistance is the most common association of AN in the younger age population.
• Malignant AN is associated with significant complications because the underlying malignancy is often an aggressive tumor. Average survival time of patients with signs of malignant AN is 2 years, although cases in which patients have survived for up to 12 years have been reported. In older patients with new onset AN, most have an associated internal malignancy.

Race

AN is much more common in people with darker skin pigmentation. The prevalence in whites is less than 1%. In Hispanics, the prevalence is 5.5%, and, in African Americans, the prevalence is the highest at 13.3%. The incidence is also increased in the Native American population. In contrast to the benign form, there is no racial propensity with malignant AN.

Sex

The incidence of AN is equal for men and women.

Age

Lesions of benign AN may be present at any age, including at birth, although it is found more commonly in the adult population. Malignant AN occurs more frequently in elderly persons; however, cases have been reported in children with Wilms tumor.

CLINICAL

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History

• Patients usually present with an asymptomatic area of darkening and thickening of the skin.
• Pruritus occasionally may be present.
• Lesions begin as hyperpigmented macules and patches and progress to palpable plaques.
• In approximately one third of cases of malignant AN, patients present with skin changes before any signs of cancer. In another one third of cases, the lesions of AN arise simultaneously with the neoplasm. In the remaining one third of cases, the skin findings manifest sometime after the diagnosis of cancer.

Physical

• AN is characterized by symmetrical, hyperpigmented, velvety plaques that may occur in almost any location but most commonly appear on the intertriginous areas of the axilla (see Image 1), groin, and posterior neck. The posterior neck is the most commonly affected site in children. The vulva is the most commonly affected site in females who are hyperandrogenic and obese.
• Acrochordons (skin tags) are often found in and around the affected areas.
• Occasionally, lesions of AN may be present on the mucous membranes of the oral cavity, nasal and laryngeal mucosa, and esophagus. The areola of the nipple also may be affected.
• Eye involvement, including papillomatous lesions on the eyelids and conjunctiva, may occur.
• Nail changes, such as leukonychia and hyperkeratosis, have been reported.
• The lesions of malignant AN are clinically indistinguishable from the benign forms.

Causes

The definitive cause for AN has not yet been ascertained, although several possibilities have been suggested. Eight types of AN have been described.

• Obesity-associated AN, once labeled pseudo-AN, is the most common type of AN.
• • Lesions may appear at any age but are more common in adulthood.
  • The dermatosis is weight dependent, and lesions may completely regress with weight reduction.
  • Insulin resistance is often present in these patients; however, it is not universal.
• Syndromic AN is the name given to AN that is associated with a syndrome. In addition to the widely recognized association of AN with insulin resistance, AN has been associated with numerous syndromes (see Image 2). The type A syndrome and type B syndrome are special examples.
• • The type A syndrome also is termed the hyperandrogenemia, insulin resistance, and AN syndrome (HAIR-AN syndrome). This syndrome is often familial, affecting primarily young women (especially black women). It is associated with polycystic ovaries or signs of virilization (eg, hirsutism, clitoral hypertrophy). High plasma testosterone levels are common. The lesions of AN may arise during infancy and progress rapidly during puberty.
  • The type B syndrome generally occurs in women who have uncontrolled diabetes mellitus, ovarian hyperandrogenism, or an autoimmune disease such as systemic lupus erythematosus, scleroderma, Sjögren syndrome, or Hashimoto thyroiditis. Circulating antibodies to the insulin receptor may be present. In these patients, the lesions of AN are of varying severity.
• Acral AN (acral acanthotic anomaly) occurs in patients who are in otherwise good health.
• • Acral AN is most common in dark-skinned individuals, especially those of African American descent.
  • The hyperkeratotic velvety lesions are most prominent over the dorsal aspects of the hands and feet.
• Unilateral AN, sometimes referred to as nevoid AN, is believed to be inherited as an autosomal dominant trait.
• • Lesions are unilateral in distribution and may become evident during infancy, childhood, or adulthood.
  • Lesions tend to enlarge gradually before stabilizing or regressing.
• Familial AN is a rare genodermatosis that seems to be transmitted in an autosomal dominant fashion with variable phenotypic penetrance.
• • The lesions typically begin during early childhood but may manifest at any age.
  • The condition often progresses until puberty, at which time it stabilizes or regresses.
• Drug-induced AN, although uncommon, may be induced by several medications, including nicotinic acid, insulin, pituitary extract, systemic corticosteroids, and diethylstilbestrol.
• • Rarely, triazinate, oral contraceptives, fusidic acid, and methyltestosterone also have been associated with AN.
  • The lesions of AN may regress following the discontinuation of the offending medication.
• Malignant AN, which is associated with internal malignancy, is the most worrisome of the variants of AN because the underlying neoplasm is often an aggressive cancer.
• • AN has been reported with many kinds of cancer (see Image 3), but, by far, the most common underlying malignancy is an adenocarcinoma of gastrointestinal origin, usually a gastric adenocarcinoma. In an early study of 191 patients with malignant AN, 92% had an underlying abdominal cancer, of which 69% were gastric. Another study reported 94 cases of malignant AN, of which 61% were secondary to a gastric neoplasm.
  • In 25-50% of cases of malignant AN, the oral cavity is involved. The tongue and the lips most commonly are 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. Oral lesions of AN seldom are pigmented.
  • Malignant AN is clinically indistinguishable from the benign forms; however, one must be more suspicious if the lesions arise rapidly, are more extensive, are symptomatic, or are in atypical locations.
  • Regression of AN has been seen with treatment of the underlying malignancy, and reappearance may suggest recurrence or metastasis of the primary tumor.
• Mixed-type AN refers to those situations in which a patient with one of the above types of AN develops new lesions of a different etiology. An example of this would be an overweight patient with obesity-associated AN who subsequently develops malignant AN.

DIFFERENTIALS

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Other Problems to be Considered

Becker nevus
Confluent and reticulated papillomatosis of Gougerot and Carteaud syndrome
Dowling-Degos disease
Hypertrophic seborrheic keratosis
Ichthyosis hystrix
Linear epidermal nevus
Parapsoriasis en plaque
Pemphigus vegetans

WORKUP

Section 5 of 11  

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Lab Studies

• For patients with adult onset of AN, perform a basic workup for underlying malignancy.
• 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.

Histologic Findings

Histologic examination reveals hyperkeratosis, papillomatosis, and slight irregular acanthosis with minimal or no hyperpigmentation. The dermal papillae project upward as fingerlike projections, with occasional thinning of the adjacent epidermis. Pseudohorn cysts may be present. Clinical dyschromia is secondary to the hyperkeratosis and not to increased melanocytes or increased melanin deposition.

TREATMENT

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Medical Care

• The goal of therapy is to correct the underlying disease process. Treatment of the lesions of AN is for cosmetic reasons only. Correction of hyperinsulinemia often reduces the burden of hyperkeratotic lesions. Likewise, weight reduction in obesity-associated AN may result in resolution of the dermatosis.
• No treatment of choice exists for AN. Topical medications that have been effective in some cases include keratolytics (eg, topical tretinoin). Oral agents that have shown some benefit include etretinate, isotretinoin, metformin, and dietary fish oils. Cyproheptadine has been used in cases of malignant AN because it may inhibit the release of tumor products. Dermabrasion and long-pulsed alexandrite laser therapy may also be used to reduce the bulk of the lesion.

MEDICATION

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The goal of pharmacotherapy is to improve cosmetic appearance.

Drug Category: Topical retinoids

These agents promote shedding of hyperkeratotic skin. They are modifiers of keratinocyte adhesion, differentiation, and proliferation.

FOLLOW-UP

Section 8 of 11  

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Complications

• Complications vary depending on the etiology of AN.
• Appearance of AN during childhood usually is associated with a benign condition, and there are no important sequelae.
• Adult onset AN is more worrisome, and an underlying malignancy must be ruled out. However, most cases of adult onset AN are benign and often are associated with insulin resistance.

Prognosis

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

Patient Education

• Patients should be instructed that AN is not a skin disease per se, but rather a sign of an underlying problem. If a patient does have AN on the basis of insulin resistance, which is the most common reason, the treatment of the metabolic abnormality may lead to improvement of the appearance of the skin. Dietary changes and weight loss may cause the AN to regress almost completely.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• The only significant medical/legal pitfall in the management of AN is the failure to promptly diagnose an internal malignancy associated with AN. One should be aware of this possibility in middle-aged or older patients with a recent onset of AN that was extensive, symptomatic, or located in unusual sites.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Brown velvety plaques with skin tags in the axilla of a patient with acanthosis nigricans.
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Media file 2:  Syndromes associated with acanthosis nigricans.
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Media file 3:  Malignant diseases associated with acanthosis nigricans.
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REFERENCES

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• '.
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• Stuart CA, Smith MM, Gilkison CR, et al. Acanthosis Nigricans among Native Americans: an indicator of high diabetes risk. Am J Public Health. Nov 1994;84(11):1839-42. [Medline].
• Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans. British Journal of Dermatology. 2002;147:1096-1101. [Medline].
• Walling HW, Messingham M, Myers LM, et al. Improvement of acanthosis nigricans on isotretinoin and metformin. Journal of Drugs in Dermatology. 2003;2:677-681. [Medline].
• Yeh JS, Munn SE, Plunkett TA, et al. Coexistence of acanthosis nigricans and the sign of Leser-Trelat in a patient with gastric adenocarcinoma: a case report and literature review. J Am Acad Dermatol. Feb 2000;42(2 Pt 2):357-62. [Medline].

Article Last Updated: Oct 5, 2006