Treatment.

Currently, there are no evidence-based guidelines for the treatment of NL. A complete review of all treatments is found in reference .

Clinical Presentation.

Granuloma annulare is charac­terized by a ring of small, firm, skin-colored or red papules. The localized form, most common in young adult females, is most frequently found on the lateral or dorsal surfaces of the hands and feet ( Fig. 26.2 ). The disease begins with an asymptomatic, skin-colored papule that undergoes central involution. Over months, a ring of papules slowly increases in diameter to 0.5 to 5 cm. The duration of the disease is highly variable. Many lesions undergo spontaneous involution without scarring, whereas others last for years. The familial occurrence of GA is uncommon but has been noted in siblings, twins, and successive generations.

Granuloma annulare. A, A classic lesion with papules on the border. B, Classic presentation showing evolution and atrophy in the center. C, Mid lower back lesion consists only of papules. D, Symmetrical disease on the calves. Papules and small irregular rings are present. E, Classic lesions most commonly involve sites about the foot and ankles. F, Several rings have coalesced on the forearm.

Disseminated GA occurs in adults and appears with numerous skin-colored or erythematous papules, some of which form annular rings. The papules may be accentuated in sun-exposed areas. The course is variable; many lesions persist for years.

Generalized perforating GA is characterized by 1- to 4-mm umbilicated papules on the extremities and is most commonly seen in children and young adults. Biopsy shows transepithelial elimination of degenerating collagen fibers. GA occurred during anti–tumor necrosis factor (anti-TNF) therapy (4.5% of 119 patients) (infliximab, adalimumab, etanercept) for rheumatoid arthritis. Patients who develop GA usually heal, remain remarkably healthy, and do not ordinarily develop other odd diseases.

Subcutaneous GA occurs in children. Painless subcutaneous nodules in the lower anterior tibial region or foot and in the scalp, typically in the occiput, are the most common presenting features. The mean age at presentation is 3.9 years. Diagnosis requires an excisional biopsy. Lesions may resolve spontaneously and recur after excision. No record of progression to systemic illness is reported.

Diagnosis.

The clinical presentation is characteristic, and biopsy may not be required. Histologic examination shows collagen degeneration, a feature similar to that seen in NL.

Treatment.

Localized lesions are asymptomatic and are best left untreated. Those patients troubled by appearance may be treated with intralesional injections of triamcinolone acetonide (2.5 to 5 mg/mL). The solution should be injected only into the elevated border. Topical steroids have little effect. Localized lesions have responded to imiquimod cream. Disseminated GA has been reported to respond to dapsone, isotretinoin, acitretin, hydroxychloroquine, niacinamide (1.5 g/day), fumaric acid esters, hydroxyurea, narrowband ultraviolet B therapy, and psoralen and PUVA therapy. Four patients with disseminated GA were treated with a cycle of cyclosporine therapy for 6 weeks. Cyclosporine was started at a dose of 4 mg/kg/day for 4 weeks, and subsequently reduced by 0.5 mg/kg/day every 2 weeks. The lesions resolved within 3 weeks and there were no relapses. Adalimumab and infliximab may be utilized for severe refractory patients.

Clinical Characteristics.

In all cases the disease presents with symmetric, brown thickening of the skin. In time the skin may become quite thickened as the lesion develops a leathery, warty, or papillomatous surface ( Fig. 26.3 and Table 26.2 ). The lesions range in severity from slight discoloration of a small area to extensive involvement of wide areas. The most common site of involvement is the axilla ( Fig. 26.4 ), but the changes may be observed in the flexural areas of the posterior neck ( Fig. 26.5 ) and groin, along the belt line, over the dorsal surfaces of the fingers, in the mouth, and around the areolae of the breasts ( Fig. 26.6 ) and umbilicus. During the disease process, there is papillary hypertrophy, hyperkeratosis, and an increased number of melanocytes in the epidermis.

Acanthosis nigricans. The skin is brown and thickened and has a papillomatous surface.

Acanthosis nigricans. The axilla is the most common site of involvement. The skin is thickened and hyperpigmented.

Acanthosis nigricans of the neck. The patient was obese.

Acanthosis nigricans. The areola may be affected.

Benign Acanthosis Nigricans.

The majority of cases are idiopathic and are associated with obesity; this process is referred to as pseudo–acanthosis nigricans . Most patients with AN have either clinical or subclinical insulin resistance (IR). There is a high prevalence of AN in obese adults. There is a positive correlation between the development of AN and the severity of the obesity. AN is a common finding in overweight youth. Nearly 40% of Native American teenagers, 13% of black people, 6% of Hispanic people, and less than 1% of white, non-Hispanic children between the ages of 10 and 19 have AN. AN identifies a subgroup within an ethnic group that has the highest insulin concentration, the most severe IR, and the highest risk for the development of type 2 diabetes.

The interaction between excessive amounts of circulating insulin with insulin-like growth factor receptors on keratinocytes may lead to the development of AN.

In rare instances AN may occur as an autosomal-dominant trait with no obesity, associated endocrinopathies, or congenital abnormalities; it may appear at birth or during childhood and is accentuated at puberty.

Drug-Induced Acanthosis Nigricans.

Drug-induced AN has occurred with the use of nicotinic acid, systemic corticosteroids, estrogen, insulin, niacin, oral contraceptive pills, pituitary extract, triazinate, methyltestosterone, fusidic acid, protease inhibitors, diethylstilbestrol, melanocyte-stimulating hormone preparation.

Endocrine Syndromes With Acanthosis Nigricans.

In a large and heterogeneous group of conditions, insulin action at the cellular level is markedly reduced (see Table 26.1 ). AN appears to represent a cutaneous marker of tissue IR, irrespective of its cause (antibodies to the insulin receptor or congenital or acquired defects of receptor or postreceptor function). These patients may not require insulin therapy, and many do not have diabetes. For patients without diabetes, IR is established by the documentation of high levels of circulating insulin or by the observation of an impaired response to exogenous insulin. Prolonged hypersecretion of insulin may lead to pancreatic exhaustion, glucose intolerance, and type 2 diabetes.

Two syndromes of IR and AN are of special interest. Type A syndrome, also called the HAIR-AN syndrome, is characterized by hyperandrogenemia (HA), extreme IR, and AN occurring in the absence of obesity or lipoatrophy. It is distinguished from type B IR by a lack of antibodies to the insulin receptor or other evidence of autoimmune disease. It is familial and affects mainly black women, who have the onset of AN in infancy or childhood.

Treatment.

Lesions are usually asymptomatic and do not require treatment. Reducing thicker lesions in areas of maceration may decrease odor and promote comfort. A 12% ammonium lactate cream, applied as needed, may soften lesions. Retinoic acid (Retin-A cream or gel) applied each day, or less often if irritation occurs, is effective. Calcipotriene (calcipotriol) is thought to decrease keratinocyte proliferation and may be applied twice daily for several months.

Malignant Acanthosis Nigricans.

The cases of greatest concern are those originating in nonobese adult patients. These cases may result from secretion of tumor products with insulin-like activity or transforming growth factor alpha, which stimulates keratinocytes to proliferate. These patients must be evaluated for internal malignancy. The stomach is the most common site for the tumor, but cancer in several other areas has been reported. Malignant AN has a different clinical appearance. Lesions develop rapidly and tend to be more severe and extensive. Hyperpigmentation is prominent and is not limited to the hyperkeratotic areas. Mucous membrane involvement and thickening of the palms and soles occur more frequently. Itching is common. The presence of AN in conjunction with tripe palms and the sign of Leser–Trélat is highly suggestive of an internal malignancy. In approximately one third of patients, the skin lesions precede the clinical manifestations of cancer, and in several cases they have disappeared with successful removal of the tumor. A recurrence of AN may mark the recurrence or metastasis of the previously treated cancer. In patients with malignant acanthosis, chemotherapy may relieve many of the distressing cutaneous symptoms.

Pathophysiology.

The liver secretes lipoproteins, which are particles composed of various combinations of cholesterol and triglycerides. These particles are made water soluble to facilitate transport to peripheral tissues by polar phospholipids and 12 different specific proteins termed apolipoproteins. The apolipoproteins also serve as cofactors for plasma enzymes and interact with cell surface receptors. Lipoproteins are divided into five major classes: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). LDL and HDL have each been divided into two subfractions.

Classification: Primary Versus Secondary Hyperlipoproteinemia.

Dyslipoproteinemias are categorized as primary or secondary. Primary conditions ( Table 26.4 ) are genetically determined and were grouped by Fredrickson into five or six types on the basis of specific lipoprotein elevations. This classification recognizes elevations of chylomicrons (type I), VLDL or pre-beta lipoproteins (type IV), “broad beta” disease (or type III hyperlipoproteinemia), beta lipoproteins (LDL) (type II), and elevations of both chylomicrons and VLDL (type V). In addition, the combined elevations in pre-beta (VLDL) and beta (LDL) lipoproteins were recognized as type IIb hyperlipoproteinemia. This older classification still provides a useful conceptual framework. It does not, however, include HDL cholesterol nor does it differentiate severe monogenic lipoprotein disorders from the more common polygenic disorders. The World Health Organization has classified lipoprotein disorders on the basis of arbitrary cut-points, but the traditional classification will be used in this text.

Secondary hyperlipoproteinemias occur as a result of another disease process that can induce symptoms ( Box 26.1 ), lipoprotein changes, and xanthomas that mimic the primary syndromes. Diagnosis should be made as follows:

• 1.
  

  Determine the type of xanthoma.

  
  
• 2.
  

  Measure fasting blood levels of cholesterol, triglycerides, and HDL, VLDL, and LDL.

  
  
• 3.
  

  Rule out secondary diseases (see Box 26.1 ). The diagnosis of primary hyperlipoproteinemia is one of exclusion.

  
  
  
  
  • a.
    

    Thyroid, liver, renal function tests

    
    
  • b.
    

    Glucose tolerance tests

    
    
  • c.
    

    Complete blood count (CBC); serum and urine immunoelectrophoresis

    
    
  • d.
    

    Chest X-ray film, bone marrow aspiration

    
    
  • e.
    

    Antinuclear antibodies (ANAs) testing

  
  

Xanthelasma and Plane Xanthomas.

Plane xanthomas occur in several areas of the body and are flat or slightly elevated ( Figs. 26.7 and 26.8 ). Xanthelasma is the most common form (see Fig. 26.7 ). Xanthelasma can be associated with familial hypercholesterolemia, phenotype IIa or IIb, but 50% of the patients have normal cholesterol levels. Longevity studies have shown that xanthelasma, with or without hypercholesterolemia, is a risk factor for death from atherosclerotic disease. Further study of these patients with normal levels of cholesterol and triglycerides often reveals elevated LDL and VLDL levels and decreased HDL level. This profile is found for patients who have a high risk of atherosclerotic cardiovascular disease. Premature carotid atherosclerosis is observed in some patients with normolipidemic and hyperlipidemic xanthelasma. Patients with xanthelasma should be considered to have an increased risk of cardiovascular disease independent to the level of plasma lipids. It may be that all patients with xanthelasma have an increased risk for atherosclerosis.

Xanthelasma. Lesions are usually located on the medial side of the lids.

Plane xanthomas (macular) of the palms are characteristic of type III dysbetalipoproteinemia.

Trichloroacetic acid (TCA) is commonly used for cosmetic treatment. Papulonodular lesions required an average of two applications with 100% TCA, three with 70% TCA, and four with 50% TCA. Flat plaques responded to an average of one, two, and three sittings with 100%, 70%, and 50% TCA, respectively. Macular lesions responded to only one application of all strengths of TCA applied. Hypopigmentation is the most common side effect, followed by hyperpigmentation. Scarring is a minor problem.

Eruptive Xanthomas.

These are yellow, 1- to 4-mm papules with a red halo around the base. They appear suddenly in crops on extensor surfaces of the arms, legs, and buttocks and over pressure points ( Fig. 26.9 ). Lesions clear rapidly when serum lipid levels are lowered.

Eruptive xanthomas are found on the buttocks, shoulders, and the extensor surfaces of the extremities. The red-yellow papules erupt abruptly and may resolve in a few weeks. Pruritus is common. They are a sign of hypertriglyceridemia and appear in secondary hyperlipidemias (e.g., diabetes).

Tuberous Xanthomas.

These are slowly evolving yellow papules, nodules, or tumors that occur on the knees, elbows, and extensor surfaces of the body and the palms ( Fig. 26.10 ).

Tuberous xanthomas are painless, red-yellow nodules that develop in pressure areas.

Tendinous Xanthomas.

These smooth, deeply situated nodules are attached to tendons, ligaments, and fascia. They are most often found on the Achilles tendons and the dorsal aspects of the fingers.

Regression of Xanthomas.

Certain xanthomas disappear with treatment. The eruptive and palmar xanthomas can regress rapidly. The eruptive type of tuberous xanthomas can disappear. Tendinous xanthomatous lesions tend to persist.

Café-au-Lait Macules.

Café-au-lait macules are light-colored to brown macules (see Chapter 19 ). The criteria for establishing the diagnosis with reference to the number and size of CALMs are listed in Box 26.2 . The macules are present in virtually every patient with NF, usually at birth, but they may not appear for months. Their size and number increase with age ( Fig. 26.11A ). Intertriginous freckling, a pathognomonic sign, may occur in the axillae, inframammary region, and groin ( Fig. 26.11B ). Café-au-lait macules alone are not absolutely diagnostic of NF1, regardless of their size and number.

Von Recklinghausen neurofibromatosis. A, Café-au-lait macules vary in size and have a smooth border. B, Axillary freckling (Crowe sign) is a pathognomonic sign.

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