Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee. The authors review the clinical appearance of typical locations of onset of acanthosis nigricans (AN) to help you develop a heightened awareness of AN, and its association with the development of both diabetes and/or metabolic syndrome. They also discuss the importance of preventative screening. At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax page 57 to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.Amy McMichael, M.D.CME EditorAmy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC. Principal Faculty: Laci LaFleur, M.D, Betsy Wernli, MSIV, Pamela S. Allen, M.D., and Robert A. Wild, M.D., Ph.D., M.P.H.Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 51 to 56 and successfully answering the questions found on page 56. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to www.skinandaging.com.Estimated Time to Complete Activity: 2 hoursDate of Original Release: November 2006Expiration Date: November 2007Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.Disclosure Policy: All those with control over the content of continuing education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the audience any real or apparent conflict(s) of interest related to the content of his or her presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.Faculty Disclosures: Drs. LaFleur and Wild, and Ms. Wernli have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article. Dr. Allen has disclosed that she is a member of the Speakers’ Bureau for Novartis Pharmaceuticals.Learning Objectives: 1.Recognize the clinical appearance of acanthosis nigricans and the locations where it can be found. 2. Develop a heightened awareness of acanthosis nigricans, and its association with the development of both diabetes and/or metabolic syndrome. 3. Understand the need for preventive screening.Target Audience: Dermatologists, Plastic Surgeons, InternistsCommercial Support: NoneSponsor: NACCME Acanthosis Nigricans Acanthosis Nigricans is an epidermal process characterized by thick, light-to-dark brown/black velvety plaques most commonly found on the flexural skin of the axillae, neck, and knuckles. It can also occur on acral or mucosal areas, and is associated with many benign and malignant syndromes and diseases. Endocrinopathies, such as insulin resistance and diabetes mellitus, are the most common diagnosable associations with AN. Other relationships have been shown with malignancy, though even more cases of AN are idiopathic, with no diagnosable associations besides obesity. As the prevalence of obesity in adults and children today continues to rise, AN becomes an even more important finding to alert physicians of possible pathology and halt disease processes at earlier stages, thus decreasing morbidity and mortality.1 The clinical recognition of AN is vital to provide quality patient care. Increased awareness of AN and new screening measures should be instituted in order to properly care for today’s changing society.EpidemiologyThe patient population with AN is diverse, although certain commonalities exist. The average age of patients with AN varies, depending on the subtype and underlying health comorbidities. The hereditary subtype is found in young children, whereas the malignancy subtype is usually an older subgroup. Predilection for a certain sex has not been well documented, and in children and adolescents, AN tends to affect males and females equally.2 However, when considering that hyperandrogen insulin resistance acanthosis nigricans (HAIR-AN) subtype affects females, it must be recognized that obese females with high androgen levels are at an increased risk as compared to males. AN tends to have a higher prevalence among blacks than whites. Stuart et al set out to determine the prevalence of AN in sixth- to eighth-grade children in Texas. AN was found in 7.1% of children, with a definite correlation with certain races. The three ethnic groups in the sample were non-Hispanic whites, Hispanics, and African-Americans, with an AN prevalence of 5%, 5.5% and 13.3%, respectively. Another study of 481 obese women showed that of the 80.7% cases of AN, 66.9% of this group had white skin, whereas 86.1% and 90.6% of the patients had a mulatto and black skin type, respectively.3 Native Americans also have been shown to have an increased risk, which correlates with their increased risk of diabetes.4Appearance and PathophysiologyAN manifests as a thickened, velvety, hyperpigmented plaque, common in the intertriginous areas of the neck, axillae and knuckles. (See Photos 1 and 2.) Acanthosis describes the clinical, not histologic appearance. The darkened skin is not associated with a change or increase in melanocytes, but is due to hyperkeratosis of the basal layer.5 The pathogenesis underlying insulin’s effect involves insulin-like growth factor receptors found on fibroblasts and keratinocytes. As the levels of insulin in the body increase, it binds to these receptors, inducing DNA synthesis, new cell growth and hyperplasia. This results in the thickened, velvety skin seen in AN.6,7Clinical SubtypesAlthough up to eight types of AN have been described, Curth et al describes four main types with different etiologies and clinical presentations: 1. malignancy associated 2. hereditary 3. endocrinopathy associated 4. drug induced.8 Some cases are idiopathic, with no known cause. Brown et al showed that in 90 AN cases, 20 patients had endocrine disease, 17 had a malignancy, six had inherited causation, two had nicotinic-acid-induced AN, and the rest of the cases were idiopathic. The most prevalent form is idiopathic, but the most common form associated with a diagnosable condition is Type III, or endocrinopathy AN.9The first two subtypes are not seen as often clinically as Type III. Type I is associated with internal malignancy, most often adenocarcinoma, and will be described in more detail later. Type II AN, or familial AN, is seen at birth or in early childhood. The clinical features tend to worsen during puberty. It has an autosomal dominant inheritance pattern and is not associated with any increase in cancer risk.5Type III AN is associated with endocrinopathies. Obesity is highly related, as is insulin resistance and diabetes mellitus. Flier et al stated that patients who present with AN should be worked up for diabetes mellitus, as most have either clinical or subclinical insulin resistance.10 Also, Mukhtar et al showed that hyperinsulinemia and obesity are both independently positively correlated with AN. In a study of 675 middle school students from New Mexico, 18.9% were found to have AN. The estimated hyperinsulinemia prevalence in this population was 8.9%, and 47% of the students with AN were obese and had increased insulin levels.11 The HAIR-AN type typically presents in a young girl with signs of increased androgen levels, clinically manifested by insulin resistance and pubic hair development before the age of 8 years old.12 Dunaif et al studied a group of hyperandrogenic women to determine whether the etiology of AN in these patients was due to the effects of androgens or insulin. They concluded that insulin played the major role in AN development, similar to its role in diabetic and insulin resistant patients.13Physicians should evaluate thyroid function in AN patients. Hypothy-roidism and thyrotoxicosis have been found in AN patients and are easily treatable. Resolution can lead to improvement of AN.14 Other disease processes that are associated with Type III AN are seen in Table 1. While most cases of AN with a diagnosable underlying condition are related to Type III, most cases are idiopathic.9 In these cases, many patients are obese, but no endocrinopathic etiology can be determined.15Type IV AN, or medication-induced AN, is a less commonly reported cause of the disease. Pharmaceuticals associated are nicotinic acid, diethylstilbestrol, niacinamide, oral contraceptive pills, glucocorticoids, and triazinate.5 AN can also be associated with autoimmune diseases such as systemic lupus erythematous and scleroderma, often preceding the development of the disease. Long-term follow-up for all AN patients is recommended.16HistopathologyOn histologic inspection, marked acanthosis of the epidermal layer is not seen. Instead, hyperkeratosis, papillomatosis and slight irregular acanthosis with minimal or no hyperpigmentation are present.5 (See Photo 3.) AN associated with hyperandrogenism is slightly different histologically. The papillary dermis contains glycosaminoglycans from hyaluronic acid, not found in other subtypes of AN.17 Metabolic SyndromeAN is highly associated with the spectrum spanning from insulin resistance to frank diabetes mellitus (DM). Undiagnosed DM type II is common in the United States. Stuart et al reported that the prevalence of non-insulin dependent diabetes and obesity has increased in the United States over the last 20 years, making diabetes prevention a major concern for healthcare agencies.18 As many as 50% of people with diabetes, or about 8 million people, are undiagnosed, according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus by Gavin III, et al.19 This report emphasized that patients with undiagnosed type II diabetes are at a significant increased risk for stroke, cardiovascular disease and peripheral vascular disease. Obesity and being overweight are reaching epidemic proportions in the United States. According to National Health and Nutrition Examination Survey III data, approximately 65% of U.S. adults are overweight and about 30% are obese.20 Obesity is a well-known risk factor for diabetes and heart disease. AN is common in obese patients and in those persons at risk for diabetes who may or may not be obese. According to Gilkison et al, hyperinsulinemia is an indicator of insulin resistance, which leads to the development of DM. This group feels that including AN screening in a disease prevention program could help identify people at risk for DM type II prior to the actual onset of glucose intolerance.21 AN is visibly diagnosed, and screening of a large patient population can be easily done. Studies are needed to develop a universal grading scale that assesses extent and severity of AN. A valid and reliable tool is necessary to determine the predictive value of AN for the incidence of diabetes and/or heart disease.The National Cholesterol Education Program (ATP III) labeled diabetes as a coronary heart disease (CHD) equivalent because it confers a high risk of developing new CHD within 10 years and because of its frequent association with multiple risk factors.22 Obesity and insulin resistance are powerful predictors of CHD risk. Abbasi et al suggest that insulin resistance at any given degree of obesity increases the risk of CHD and type II diabetes.23 Appel et al demonstrated that preceding the development of DM type II or cardiovascular disease there is a well-defined pathway known as metabolic syndrome (MS), which leads to vascular injury or cardiovascular disease.24 MS is diagnosed by the presence of three out of five criteria: abdominal obesity (waist >40 inches in men, >35 inches in women); atherogenic dyslipidemia (elevated triglyceride >150 mg/dl; low HDL cholesterol <40 mg/dl in men or <50 mg/dl in women; and small LDL particles); blood pressure >130/85 mmHg; and/or fasting glucose >100 mg/dL. It is associated with insulin resistance, prothrombic and proinflammatory states.Not everyone who has MS will have DM type II, but those who exhibit both are at the highest risk for cardiovascular disease. Managing MS, as outlined in the ATP III, has a two-fold objective: 1. Reduce underlying causes such as obesity and physical inactivity. 2. Treat associated non-lipid and lipid risk factors. Obesity is a subset of MS and an independent risk factor for the development of AN. Android obesity, also referred to as male-type obesity, is characterized by a central or upper body fat distribution.25 It is highly associated with AN and MS.26 Hud et al graded AN on a scale of 0 to 4 based on severity and location. He felt that AN might be a reliable cutaneous marker of hyperinsulinemia in obese individuals.23 Furthermore, Bolding et al concluded that obese adolescent patients with AN were older and heavier, with higher systolic and diastolic blood pressure as compared to obese adolescent patients without AN. Contrary to Hud et al, this group called into question whether or not AN is a late sequelae of hyperinsulinemia in obese adolescents.27 In one analysis of 50 adolescents with non-insulin dependent diabetes (NIDDM) as compared with a similar group with insulin-dependent diabetes (IDDM), 86% of the NIDDM group had clinical AN, compared to none of the IDDM group, thus reinforcing the hyperinsulinemia theory of AN causation.28Cardiovascular risk factors are very prevalent and are often undiagnosed. In a recent screening survey in the January/February 2006 issue of the Journal of Women’s Health, 90% of women, mean age 47, were found to have at least one modifiable cardiovascular risk factor. One half were found to have criteria for metabolic syndrome. Although waist circumference was measured in this survey, the presence or absence of AN was ignored. Proper quantifying presence of this simple physical finding might well be a better marker of persons at risk than even a waist measurement. Obesity and insulin resistance are established risk factors for diabetes and cardiovascular disease. Additionally, the presence of AN is associated with insulin resistance and obesity. Scales to evaluate severity of AN, however, are few. The most extensively studied scale is reported by Burke et al.29 This scale evaluates several areas of the body for AN by looking at severity and texture. A Likert graded scale of 0 to 4 was used. After developing the scale, Burke et al attempted to associate diabetes risk factors, such as obesity, basal metabolic index (BMI), fasting insulin, glucose, cholesterol, blood pressure, etc., with the presence or absence of AN in Mexican-Americans.30 They compared diabetes-related risk factors and severity of AN in diabetic and non-diabetic women and demonstrated that the scale correlated with BMI and fasting insulin levels. Unfortunately, the scale had limited reproducibility except for the neck area. No similar study has been performed in other racial groups or in men. In this study, mucosal surfaces including ocular, oral and genital regions were not included. However, Grasinger et al31 reported that AN is commonly found on the vulva in women, an area not assessed in the study by Burke et al.32Prevalence and severity of insulin resistance/MS is known to be different in different racial groups. Location and severity of AN may relate to severity of insulin resistance and/or to MS. Studies are underway to develop an instrument that scores AN based on all locations, severity and ethnicities which will be an optimal tool for grading AN.It is important to establish the relationship between AN and the future risk of developing heart disease/diabetes, which can lead to premature morbidity and mortality.Malignancy AssociatedAN usually occurs without an associated malignancy, however, today’s physician should keep a high clinical suspicion of not only benign causes, but also malignant processes when evaluating an AN patient. Malignancy-associated AN (Type I AN) is usually more rapid in onset and associated with other skin findings, such as multiple acrochordons, lip changes and seborrheic keratoses. Thus, the sudden development of AN in a non-obese patient should raise the suspicion of a paraneoplastic process. AN may development before, during or after the diagnosis of a malignancy.33 It is important to have a high clinical suspicion of AN because up to 18% of cases precede the malignancy, allowing for earlier diagnosis and treatment, and potentially decreasing mortality.5 Malignant AN is activated by a tumor; other types of AN are not.34 It often presents with hyperpigmentation of the flexures, face and oral cavity.35 Oral mucosal involvement is found in 40% of malignant AN, contrary to its usual absence in the benign forms.33 (See Photo 4.) Other reported mucosal sites affected by AN include the vulva and the palpebral conjunctiva.36  Any patient with marked AN associated with oral florid papillomatosis, tripe palms and the sign of Leser-Tre’lat should undergo a thorough search for malignancy.34,37,38 Tripe palms is a velvety thickening of the palms, with exaggeration of normal skin markings.38 An evaluation of 77 patients with tripe palms showed that 95% had a malignancy. Furthermore, 77% also had the typical AN pattern with palmar involvement.39 The sign of Leser-Tre’lat is the presence of multiple seborrheic keratoses and skin tags; it is also highly associated with malignancy.38AN is a paraneoplastic manifestation of adenocarcinoma.40 The most common associated neoplasm is gastric adenocarcinoma, however involvement anywhere in the gastrointestinal or even genitourinary tract has been reported.41 Rigel et al reviewed 277 cases of malignant AN and found that 56% of cases were associated with gastric carcinomas, 17.7% with intra-abdominal carcinomas and 26.8% with malignancies in other sites.42 Nair et al described a patient with AN and tripe palms who was found to have metastatic adenocarcinoma of the liver with an unknown primary from the GI tract.35 Other associations with Type I AN are carcinomas of kidney, thyroid, bile duct and bladder. Lymphoma has also been reported.34 Kebria et al reported the first case of ovarian cancer in association with AN, tripe palms, and signs of Leser-Tre'lat.38 Because undiagnosed neoplasms, which are associated with malignant AN, are aggressive in nature, it is important to conduct an extensive search of malignancy once AN develops. Longshore et al presented a case of a patient with malignant AN diagnosed 2.5 years before a diagnosis of endometroid adenocarcinoma of the parametrium, which was only discovered after a diagnostic laparoscopy followed by exploratory laparotomy was performed.The overall prognosis for Type I AN patients is poor secondary to the underlying malignancy.41 The skin findings usually resolve once the malignancy is in remission, but aggressively returns if it recurs. If metastasis occurs, many patients die within a year after the onset of AN.34 Because chemotherapy may help to resolve AN, a close relationship between dermatologists and oncologists is required.40 Complete regression may never occur.41TreatmentPatients with AN must be approached in a manner appropriate to the underlying cause and subtype. To date, no satisfactory topical therapy for this cutaneous disorder has been described.43 Type I AN is treated by addressing and resecting the primary malignancy. Topical calcipotriol 0.005% applied twice daily can also decrease the pigmented lesions, aside from management of the malignancy.44 Type II AN can prove more difficult to treat, however studies have shown some success. A 20-year-old woman had widespread AN since the age of 3. A 3-week trial of oral etretinate 1 mg/kg/day for 40 days improved her hyperpigmentation greatly. Within 1 year, the AN had totally cleared.45 Type III AN, on the other hand, is highly amenable to weight loss and glucose control.34,46 Weight reduction is a complex task that includes nutritional counseling, behavioral and motivational interventions with close follow-up.21 Kuroki et al reported a 27-year-old Japanese male who weighed 151 kg, was hypothyroid and insulin resistant along with AN. He was placed on a low-calorie diet and hospitalized to ensure weight loss. After losing 36 kg, the hyperpigmentation from AN significantly decreased, proving that weight control can and should be the primary treatment in such patients.47Other topical and medicinal adjuncts to weight loss are available. Blobstein et al successfully used a combination of 12% ammonium lactate cream and 0.05% tretinoin cream to treat AN associated with obesity.43 Retinoids and colecalciferol (Vitamin D3) topically reduce the hyperkeratotic and papillomatous skin changes.46 Etretinate has been shown to successfully treat AN.45 The long-pulsed alexandrite laser has been shown to effectively and safely treat AN of the axilla.48 Dermabrasion may be helpful in debulking lesions. Cyproheptadine may be effective for malignant AN by inhibiting release of tumor products.49 In AN with diabetes, metformin is the oral agent of choice, as insulin secretagogues and injections may actually exacerbate AN.50,51 Octreotide has proven effective, reducing insulin secretion in patients with AN, severe obesity and hyperinsulinemia.46 For HAIR-AN, treatment is aimed at decreasing insulin resistance and regulating ovulation, while treating and reducing the patient’s acne, AN and hirsutism.52 Chronically lowering the level of hyperinsulinemia will help resolve AN.18,21 Oral colecalciferol has been shown to clear AN.34,46 For other endocrinopathies, simply treating the hormonal disturbance may prove efficacious. Dix et al reported a young girl who presented with hypothyroidism, AN of the neck, axillae, heels and umbilicus together with cervical hypertrichosis. She was treated with L-thyrozine for thyroid replacement. After 3 months, her AN had completely resolved along with the hypertrichosis.53 Givens et al reported a 17-year-old African-American female with hirsutism, amenorrhea and AN. Plasma levels of androstendione and testosterone were increased, as were urine 17-keto-steroids. A bilateral ovarian wedge resection and administration of norethindrone and mestranol suppressed androgen levels and totally resolved her AN.54Type IV AN (drug-induced) can be treated by discontinuing the medication, however, other options are available. Darmstadt et al reported a case in which a 55-year-old man had thick, hyperpigmented skin in the axillae and popliteal fossae induced by nicotinic acid. The drug was continued, however, topical tretinoin 0.1% was applied to affected areas once per week. The AN completely cleared within 6 months.55 An Important DiagnosisIn recent years, focus on AN and its metabolic associations have taken center stage given the rising prevalence of obesity, insulin resistance, diabetes and the metabolic syndrome. Though the etiology behind this skin condition can be somewhat complex, a systematic review of patient health status concerning all body systems should be sought. Remembering that the most common diagnosable cause of AN is endocrinopathic, a thorough work-up for insulin resistance and diabetes should be done, while keeping in mind other co-morbidities such as thyroid and endocrine organ dysfunction.Because Type I AN is related to malignancy and often precedes clinical tumor detection, a careful approach to the AN patient can actually serve to treat and stop cancer at earlier stages, thus saving lives. Once the underlying etiology has been determined, treatment should be tailored to the cause. Weight management can control or induce remission for many Type III patients. Others need hormonal replacement or treatment of an underlying malignancy. Thorough skin examinations should be done for all patients since the detection of AN has proven such a cost-effective preliminary screening method for so many prevalent conditions today.