Acanthosis nigricans is a velvety, darkening of the skin that usually occurs in intertriginous areas. This hyperpigmentation has poorly defined borders, usually occurs in skin fold areas, such as the back of the neck, axilla, and groin, and may include thickening of the skin. Acanthosis nigricans is most commonly associated with diabetes and insulin resistance, but rarely it can be a sign of internal malignancy. It can also occur with hormone disorders and with the use of certain medications like systemic glucocorticoids and oral contraceptives.
Earn CME credit as you help guide your clinical decisions.
There are multiple factors involved in the development of acanthosis nigricans.
- Increased circulating insulin activates keratinocyte insulin-like growth factor (ILGF) receptors, particularly IGF-1. At high concentrations, insulin may displace IGF-1 from IGF binding protein. Increased circulating IGF may lead to keratinocyte and dermal fibroblast proliferation.
- Hereditary variants are associated with fibroblast growth factor defects.
- Increased transforming growth factor (TGF) appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the epidermal growth factor receptor.
Familial acanthosis nigricans: may arise as a result of an autosomal dominant trait, presenting at birth or during childhood. It occurs due to mutations in fibroblast growth factor receptor 3 (FGFR3).
Obesity-associated acanthosis nigricans: Obesity is one of the most common conditions associated with Acanthosis nigricans. Lesions are usually common in adulthood but can occur at any age. It was once labeled as “pseudoacanthosis nigricans." It may be associated with insulin resistance. Treating obesity with diet, weight reduction, or medications can result in the revolvement of acanthosis nigricans.
Medications associated with acanthosis nigricans: Multiple medications have been linked to Acanthosis nigricans. These include the use of nicotinic acid, systemic glucocorticoids, diethylstilbestrol, combined oral contraceptive pill, growth hormone therapy, estrogen, protease inhibitors, niacin, and injected insulin. Once the offending medication is stopped, acanthosis nigricans usually resolves.
Acanthosis nigricans associated with endocrine dysfunction: It is more insidious in onset, less widespread, and patients are often obese. Insulin-resistance syndromes may be divided into type A (HAIR-AN) and type B syndromes. Type A syndromes present with hyperandrogenemia, insulin resistance, and Acanthosis nigricans. Type B syndrome usually occurs in females who have uncontrolled diabetes, ovarian hyperandrogenism, or autoimmune diseases like SLE, Sjogren syndrome, or scleroderma. Polycystic ovarian syndrome (PCOS) is associated with acanthosis nigricans. Insulin resistance and hyperandrogenism are seen in patients with PCOS.
Acral acanthotic anomaly: Refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet. It is common in individuals who have dark skin.
Malignant acanthosis nigricans syndrome: Is associated with gastrointestinal adenocarcinomas and genitourinary cancers such as prostate, breast, and ovary. Lung cancer and lymphoma rarely are associated with acanthosis nigricans. Malignant acanthosis nigricans may precede, accompany, or follow the onset of internal cancer. Malignancy-associated acanthosis nigricans usually has a rapid onset and is accompanied by skin tags, multiple seborrheic keratoses (the sign of Leser-Trelat), or tripe palms.
Auto-immune acanthosis nigricans: Is associated with autoimmune disorders like SLE, Sjogren's syndrome, scleroderma, or Hashimoto's thyroiditis.
Unilateral acanthosis nigricans: Also called nevoid acanthosis nigricans. It is very rare and is inherited in an autosomal dominant fashion. Lesions occur unilaterally. Lesions present in infancy, childhood, or adulthood.
Acanthosis nigricans typically occurs in individuals younger than the age of 40 years and is associated with obesity, hypothyroidism, acromegaly, polycystic ovary disease, insulin-resistant diabetes, and Cushing and Addison diseases. Acanthosis nigricans is also associated with rare diseases such as pinealoma, Cushing disease, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, leprechaunism, lipoatrophic diabetes, pineal hyperplasia syndrome, and Alstrom syndrome.
The pathogenesis of acanthosis nigricans is likely related to growth factor levels and insulin-mediated activation of insulin-like growth factor (IGF) on keratinocytes and increased growth factor levels. The pathophysiological process behind acanthosis nigricans appears to be related to the proliferation of fibroblasts and the enhanced stimulation of epidermal keratinocytes.
In patients with benign acanthosis nigricans, evidence suggests that insulin or an insulin-like growth factor is enhancing the propagation of epidermal cells. Other mediators that have been identified include fibroblast growth factor and tyrosine kinase receptors (epidermal growth factor receptor). High concentrations of insulin are thought to cause proliferative effects by binding to IGF-1 receptors. It is important to note that free IGF-1 levels also are high in people with metabolic syndrome, leading to faster cell differentiation and cell growth.
Recently, both syndromic and familial forms of acanthosis nigricans have been observed. Familial and syndromic forms of acanthosis nigricans have been identified. Many other syndromes share similar features, such as hyperinsulinemia, craniosynostosis, and obesity. These are subdivided into insulin-resistant syndromes and fibroblast growth factor defects.
Other insulin-resistant syndromes include Rabson Mendenhall syndrome, leprechaunism, Berardinelli-Seip syndrome, Dunningan syndrome, and Alstrom syndrome. Excessive friction or sweating may also be playing a contributory role.
In patients with malignant acanthosis nigricans, the most probable stimulating factor is secreted by the cancer cells. Two possibilities are transforming growth factor and epidermal growth factor because both have high levels in people with gastric adenocarcinoma. Other reports indicate normalization of urine transforming growth factor after surgical removal of a tumor, followed by regression of the skin lesions.
Usage of medications like insulin has also been implicated, most likely due to the activation of IGF receptors. A few case reports on ectopic acanthosis nigricans in syndromic patients report patient acquisition of the disorder after skin grafting from an affected site.
The histological exam will reveal papillomatosis, hyperkeratosis with minimal hyperpigmentation. The dermal papillae usually have an upward projection with thinning of the epidermis. There is usually no dermal inflammatory infiltrate.
History and Physical
Patients usually present with an asymptomatic area of darkening and thickening of the skin, pruritus, and lesions that are velvety, hyperpigmented macules and patches and progress to palpable plaques. In approximately one-third of cases, malignant acanthosis nigricans presents with skin changes before any signs of cancer. In another one-third of cases, lesions arise simultaneously with the neoplasm. In the remaining one-third of cases, the skin findings manifest sometime after the diagnosis of cancer.
In nearly one-third of patients with malignant acanthosis nigricans, the skin changes usually occur before any clinical signs of the malignancy. In another one-third of patients, the skin lesions develop at the same time as the presentation of cancer. In the remaining patients, the skin features occur after cancer has developed. Malignant acanthosis nigricans can appear suddenly and often is associated with intense pruritus.
The lesions of acanthosis nigricans typically occur in areas of skin folds like the groin, axilla, or posterior neck. In children, the most common site of acanthosis nigricans is the posterior neck. Rarely, acanthosis nigricans may occur on the mucous membranes of the nose, oral cavity, esophagus, or larynx. Women also may develop lesions on the nipple. Rare cases of acanthosis nigricans have been reported in the conjunctiva.
In some patients, there also may be associated with skin tags in the same area. Nail changes like hyperkeratosis and leukonychia may be present. Clinically, it is not possible to differentiate the lesions of benign versus malignant acanthosis nigricans.
Acanthosis nigricans is diagnosed clinically and confirmed with a skin biopsy. Blood tests, endoscopy, or X-rays may be required to eliminate diabetes or cancer. On biopsy, hyperkeratosis, leukocyte infiltration, epidermal folding, and melanocyte proliferation may be seen. The workup focuses on ruling out malignancy. Since the vast majority of cases are associated with insulin resistance and/or obesity, screening for diabetes and measuring glycosylated hemoglobin is recommended.
Treatment / Management
Acanthosis nigricans is not treatable. It may fade over time by treating the cause, insulin resistance. Controlling blood glucose levels through exercise and diet often improves symptoms. Topical fade creams can lighten skin in less severe cases. Acanthosis nigricans malignant may resolve if the causative tumor is removed successfully.
The goal of treatment is to treat the underlying disease. In the majority of patients, the treatment is done only for aesthetic reasons. In some patients, weight loss and correction of insulin resistance lower the burden of hyperkeratotic lesions. Acanthosis nigricans associated with insulin resistance can be treated with drugs such as metformin and rosiglitazone, which are insulin-sensitizing agents.
All inciting agents and medications should be discontinued. One should make attempts to lower the lipid profile. Reports suggest that dietary fish and niacin may help.
Dermatologists sometimes prescribe keratolytics, such as topical retinoids (e.g. topical tretinoin 0.1% or a combination of tretinoin 0.05% and 12% ammonium lactate) and podophyllin. Topical vitamin D analogs (e.g. calcipotriol (calcipotriene) 0.005%) act by decreasing keratinocyte proliferation and cause an improvement of the acanthosis nigricans lesions. The success of these treatments is variable. Other agents that have been tried include metformin and etretinate. In one report, octreotide also showed marked improvement in a patient with insulin resistance.
Melatonin can also improve cutaneous symptoms in obese patients with Acanthosis nigricans by improving the inflammatory status and insulin sensitivity.
- Linear epidermal nevus
- Granular parakeratosis
- Cutaneous hyperpigmentation related to Addison disease
Patients with the benign form of acanthosis nigricans have few or no skin complications, good prognosis, and potential for resolution with treatment. Complications can stem from underlying diseases like diabetes and insulin resistance. Prognosis in patients with the malignant form of acanthosis nigricans is poor as the malignancy is advanced usually at the time of diagnosis in these patients.
Complications depend on the cause of acanthosis nigricans. Most cases of acanthosis nigricans are due to insulin resistance, but however serious complications like malignancy can also be associated with this condition.
A dermatology referral may be warranted if the diagnosis is uncertain. Referral to an endocrinologist may be needed in patients with diabetes and other metabolic disorders.
Deterrence and Patient Education
Patients need to be educated that hyperpigmentation of the skin may not solely be a skin condition and should be evaluated further, especially if it occurs in middle-aged to elderly patients. Patients need to follow up with their primary care physicians regarding any abnormal pigmentation in their skin. Hyperpigmentation of the skin due to acanthosis nigricans can be treated and sometimes resolves with adequate treatment of the skin condition or treatment of the underlying condition. Patients need to be educated on identifying the risk factors and signs and symptoms of a malignant condition associated with acanthosis nigricans. Depression and low self-esteem can occur in patients with acanthosis nigricans and diagnosis and psychological treatment should be started early in these patients.
Enhancing Healthcare Team Outcomes
Acanthosis nigricans is a common skin disorder, but when it presents, the diagnosis can often be difficult. The condition can be benign or malignant, and hence an interprofessional approach is necessary to make a prompt diagnosis. Healthcare workers in primary care, including nurse practitioners, should always refer the patient to a dermatologist if unsure about the rash. The overall prognosis for patients with the malignant form of acanthosis nigricans is poor, with an average survival of fewer than 24 months. Those with the benign form have an excellent prognosis, provided the condition causing it is treated. The majority of practitioners are likely to see acanthosis nigricans in the younger population with insulin resistance; hence a referral to an endocrinologist is recommended. Finally, patients should be educated that acanthosis nigricans is not a primary skin disorder but is usually due to an underlying condition. In many benign cases, just changing diet and losing weight may lead to a cure. [Level 5]
(Click Image to Enlarge)
(Click Image to Enlarge)
(Click Image to Enlarge)
Smid CJ, Modaff P, Alade A, Legare JM, Pauli RM. Acanthosis nigricans in achondroplasia. American journal of medical genetics. Part A. 2018 Dec:176(12):2630-2636. doi: 10.1002/ajmg.a.40506. Epub 2018 Oct 31 [PubMed PMID: 30380187]
Ozlu E, Uzuncakmak TK, Takır M, Akdeniz N, Karadag AS. Comparison of cutaneous manifestations in diabetic and nondiabetic obese patients: A prospective, controlled study. Northern clinics of Istanbul. 2018:5(2):114-119. doi: 10.14744/nci.2017.68553. Epub 2018 May 21 [PubMed PMID: 30374476]
González-Saldivar G, Rodríguez-Gutiérrez R, Treviño-Alvarez AM, Gómez-Flores M, Montes-Villarreal J, Álvarez-Villalobos NA, Elizondo-Plazas A, Salcido-Montenegro A, Ocampo-Candiani J, González-González JG. Acanthosis nigricans in the knuckles: An early, accessible, straightforward, and sensitive clinical tool to predict insulin resistance. Dermato-endocrinology. 2018:10(1):e1471958. doi: 10.1080/19381980.2018.1471958. Epub 2018 May 21 [PubMed PMID: 30279953]
Hermanns-Lê T, Scheen A, Piérard GE. Acanthosis nigricans associated with insulin resistance : pathophysiology and management. American journal of clinical dermatology. 2004:5(3):199-203 [PubMed PMID: 15186199]
Fukuchi K, Tatsuno K, Matsushita K, Kubo A, Ito T, Tokura Y. Familial acanthosis nigricans with p.K650T FGFR3 mutation. The Journal of dermatology. 2018 Feb:45(2):207-210. doi: 10.1111/1346-8138.14107. Epub 2017 Oct 25 [PubMed PMID: 29068064]
Ng HY. Acanthosis nigricans in obese adolescents: prevalence, impact, and management challenges. Adolescent health, medicine and therapeutics. 2017:8():1-10. doi: 10.2147/AHMT.S103396. Epub 2016 Dec 16 [PubMed PMID: 28031729]
Kuroki R, Sadamoto Y, Imamura M, Abe Y, Higuchi K, Kato K, Koga T, Furue M. Acanthosis nigricans with severe obesity, insulin resistance and hypothyroidism: improvement by diet control. Dermatology (Basel, Switzerland). 1999:198(2):164-6 [PubMed PMID: 10325466]
Stals H, Vercammen C, Peeters C, Morren MA. Acanthosis nigricans caused by nicotinic acid: case report and review of the literature. Dermatology (Basel, Switzerland). 1994:189(2):203-6 [PubMed PMID: 8075456]Level 3 (low-level) evidence
Mellor-Pita S, Yebra-Bango M, Alfaro-Martínez J, Suárez E. Acanthosis nigricans: a new manifestation of insulin resistance in patients receiving treatment with protease inhibitors. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2002 Mar 1:34(5):716-7 [PubMed PMID: 11823959]
Fleming MG, Simon SI. Cutaneous insulin reaction resembling acanthosis nigricans. Archives of dermatology. 1986 Sep:122(9):1054-6 [PubMed PMID: 3527077]
Schmidt TH, Khanijow K, Cedars MI, Huddleston H, Pasch L, Wang ET, Lee J, Zane LT, Shinkai K. Cutaneous Findings and Systemic Associations in Women With Polycystic Ovary Syndrome. JAMA dermatology. 2016 Apr:152(4):391-8. doi: 10.1001/jamadermatol.2015.4498. Epub [PubMed PMID: 26720591]
Anand V, Das A, Kumar P, Kumar R, Hassan S. Acral acanthosis nigricans (acral acanthotic anomaly). Indian dermatology online journal. 2014 Dec:5(Suppl 2):S140-1. doi: 10.4103/2229-5178.146201. Epub [PubMed PMID: 25593810]
Liu XK, Li J. Hyperpigmentation in the skin folds. BMJ (Clinical research ed.). 2018 Jan 18:360():j5729. doi: 10.1136/bmj.j5729. Epub 2018 Jan 18 [PubMed PMID: 29348270]
Yu Q, Li XL, Ji G, Wang Y, Gong Y, Xu H, Shi YL. Malignant acanthosis nigricans: an early diagnostic clue for gastric adenocarcinoma. World journal of surgical oncology. 2017 Nov 25:15(1):208. doi: 10.1186/s12957-017-1274-5. Epub 2017 Nov 25 [PubMed PMID: 29178944]
Kondo Y, Umegaki N, Terao M, Murota H, Kimura T, Katayama I. A case of generalized acanthosis nigricans with positive lupus erythematosus-related autoantibodies and antimicrosomal antibody: autoimmune acanthosis nigricans? Case reports in dermatology. 2012 Jan:4(1):85-91. doi: 10.1159/000337751. Epub 2012 Mar 30 [PubMed PMID: 22649336]Level 3 (low-level) evidence
Das A, Bhattacharya S, Kumar P, Gayen T, Roy K, Das NK, Gharami RC. Unilateral nevoid acanthosis nigricans: Uncommon variant of a common disease. Indian dermatology online journal. 2014 Nov:5(Suppl 1):S40-3. doi: 10.4103/2229-5178.144529. Epub [PubMed PMID: 25506563]
Karadağ AS, You Y, Danarti R, Al-Khuzaei S, Chen W. Acanthosis nigricans and the metabolic syndrome. Clinics in dermatology. 2018 Jan-Feb:36(1):48-53. doi: 10.1016/j.clindermatol.2017.09.008. Epub 2017 Sep 8 [PubMed PMID: 29241752]
Martínez-Rojano H, Pizano-Zárate ML, Sánchez-Jiménez B, Sámano R, López-Portillo A. Acantosis nigricansis associated with risk factors related to cardiovascular disease in Mexican children with obesity. Nutricion hospitalaria. 2016 Sep 20:33(5):570. doi: 10.20960/nh.570. Epub 2016 Sep 20 [PubMed PMID: 27759974]
Kong AS, Williams RL, Rhyne R, Urias-Sandoval V, Cardinali G, Weller NF, Skipper B, Volk R, Daniels E, Parnes B, McPherson L, PRIME Net Clinicians. Acanthosis Nigricans: high prevalence and association with diabetes in a practice-based research network consortium--a PRImary care Multi-Ethnic network (PRIME Net) study. Journal of the American Board of Family Medicine : JABFM. 2010 Jul-Aug:23(4):476-85. doi: 10.3122/jabfm.2010.04.090221. Epub [PubMed PMID: 20616290]
Nguyen TT, Keil MF, Russell DL, Pathomvanich A, Uwaifo GI, Sebring NG, Reynolds JC, Yanovski JA. Relation of acanthosis nigricans to hyperinsulinemia and insulin sensitivity in overweight African American and white children. The Journal of pediatrics. 2001 Apr:138(4):474-80 [PubMed PMID: 11295708]
Lause M, Kamboj A, Fernandez Faith E. Dermatologic manifestations of endocrine disorders. Translational pediatrics. 2017 Oct:6(4):300-312. doi: 10.21037/tp.2017.09.08. Epub [PubMed PMID: 29184811]
Rodríguez-Gutiérrez R, Salcido-Montenegro A, González-González JG. Early Clinical Expressions of Insulin Resistance: The Real Enemy to Look For. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2018 Feb:9(1):435-438. doi: 10.1007/s13300-017-0348-2. Epub 2017 Dec 5 [PubMed PMID: 29209995]
González-Saldivar G, Rodríguez-Gutiérrez R, Ocampo-Candiani J, González-González JG, Gómez-Flores M. Skin Manifestations of Insulin Resistance: From a Biochemical Stance to a Clinical Diagnosis and Management. Dermatology and therapy. 2017 Mar:7(1):37-51. doi: 10.1007/s13555-016-0160-3. Epub 2016 Dec 5 [PubMed PMID: 27921251]
Charnvises K, Weerakiet S, Tingthanatikul Y, Wansumrith S, Chanprasertyothin S, Rojanasakul A. Acanthosis nigricans: clinical predictor of abnormal glucose tolerance in Asian women with polycystic ovary syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2005 Sep:21(3):161-4 [PubMed PMID: 16335908]Level 2 (mid-level) evidence
Patel NU, Roach C, Alinia H, Huang WW, Feldman SR. Current treatment options for acanthosis nigricans. Clinical, cosmetic and investigational dermatology. 2018:11():407-413. doi: 10.2147/CCID.S137527. Epub 2018 Aug 7 [PubMed PMID: 30122971]
Romo A, Benavides S. Treatment options in insulin resistance obesity-related acanthosis nigricans. The Annals of pharmacotherapy. 2008 Jul:42(7):1090-4. doi: 10.1345/aph.1K446. Epub 2008 May 20 [PubMed PMID: 18492785]
Darmstadt GL, Yokel BK, Horn TD. Treatment of acanthosis nigricans with tretinoin. Archives of dermatology. 1991 Aug:127(8):1139-40 [PubMed PMID: 1863071]
Blobstein SH. Topical therapy with tretinoin and ammonium lactate for acanthosis nigricans associated with obesity. Cutis. 2003 Jan:71(1):33-4 [PubMed PMID: 12553628]
Gregoriou S, Anyfandakis V, Kontoleon P, Christofidou E, Rigopoulos D, Kontochristopoulos G. Acanthosis nigricans associated with primary hypogonadism: successful treatment with topical calcipotriol. The Journal of dermatological treatment. 2008:19(6):373-5. doi: 10.1080/09546630802050506. Epub [PubMed PMID: 18608738]
Phiske MM. An approach to acanthosis nigricans. Indian dermatology online journal. 2014 Jul:5(3):239-49. doi: 10.4103/2229-5178.137765. Epub [PubMed PMID: 25165638]
Sun H, Wang X, Chen J, Gusdon AM, Song K, Li L, Qu S. Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans. International journal of endocrinology. 2018:2018():2304746. doi: 10.1155/2018/2304746. Epub 2018 Mar 12 [PubMed PMID: 29706998]
Rosenbach A, Ram R. Treatment of Acanthosis nigricans of the axillae using a long-pulsed (5-msec) alexandrite laser. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2004 Aug:30(8):1158-60 [PubMed PMID: 15274711]
Ghosh S, Roychowdhury B, Mukhopadhyay S, Chowdhury S. Clearance of acanthosis nigricans associated with insulinoma following surgical resection. QJM : monthly journal of the Association of Physicians. 2008 Nov:101(11):899-900. doi: 10.1093/qjmed/hcn098. Epub 2008 Jul 31 [PubMed PMID: 18669553]
Huang Y, Chen J, Yang J, Song K, Wang X, Cheng X, Qu S. Evaluation of depressive symptoms in obese patients with or without acanthosis nigricans. Hormones (Athens, Greece). 2015 Jul-Sep:14(3):417-24. doi: 10.14310/horm.2002.1575. Epub [PubMed PMID: 26188226]
Pirgon Ö, Sandal G, Gökçen C, Bilgin H, Dündar B. Social anxiety, depression and self-esteem in obese adolescent girls with acanthosis nigricans. Journal of clinical research in pediatric endocrinology. 2015 Mar:7(1):63-8. doi: 10.4274/jcrpe.1515. Epub [PubMed PMID: 25800478]
Kong AS, Williams RL, Smith M, Sussman AL, Skipper B, Hsi AC, Rhyne RL, RIOS Net Clinicians. Acanthosis nigricans and diabetes risk factors: prevalence in young persons seen in southwestern US primary care practices. Annals of family medicine. 2007 May-Jun:5(3):202-8 [PubMed PMID: 17548847]