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Acanthosis Nigricans

  • Author: Jason H Miller, MD; Chief Editor: William D James, MD  more...
 
Updated: Dec 03, 2015
 

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 acanthosis nigricans was in 1889 in Germany as described by Unna and Pollitzer. By 1909, acanthosis nigricans 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 acanthosis nigricans and insulin resistance was first described. In 2000, the American Diabetes Association established acanthosis nigricans as a formal risk factor for the development of diabetes in children.[1]

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Pathophysiology

Acanthosis nigricans most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation.

In the benign form of acanthosis nigricans, the factor is probably insulin or an insulinlike growth factor (IGF) that incites the epidermal cell propagation. Other proposed mediators include other tyrosine kinase receptors (epidermal growth factor receptor [EGFR] or fibroblast growth factor receptor [FGFR]).

At high concentrations, insulin may exert potent proliferative effects via high-affinity binding to IGF-1 receptors. In addition, free IGF-1 levels may be elevated in obese patients with hyperinsulinemia, leading to accelerated cell growth and differentiation.[2]

Familial and syndromic forms of acanthosis nigricans have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin-resistance syndromes and fibroblast growth factor defects.

Insulin-resistance syndromes include those with mutations in the insulin receptors (ie, leprechaunism, Rabson-Mendenhall syndrome), peroxisome proliferator-activated receptor gamma (ie, type 1 diabetes with acanthosis nigricans and hypertension), 1-acylglycerol-3-phosphate O-acyl transferase-2 or seipin (Berardinelli-Seip syndrome), lamin A/C (Dunnigan syndrome), and Alstrom syndrome gene. Fibroblast growth factor defects include activating mutations in FGFR2 (Beare-Stevenson syndrome), FGFR3 (Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, severe achondroplasia with developmental delay, and acanthosis nigricans [SADDAN]). Familial cases of acanthosis nigricans with no other syndromic findings have also been linked to FGFR mutations.[3, 4]

Perspiration or friction may also play a contributory role, as suggested by the predilection of acanthosis nigricans for body folds.

In malignant acanthosis nigricans, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)–alpha is structurally similar to epidermal growth factor and is a likely candidate. TGF-alpha and epidermal growth factor have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within acanthosis nigricans lesions. Reports of urine and serum TGF-alpha levels normalizing after surgical tumor removal exist, with subsequent regression of skin lesions.[5]

Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely due to activation of IGF receptors.[6, 7] Newer agents such as palifermin (recombinant keratinocyte growth factor used to decrease mucositis with chemotherapy and stem cell transplantation) have reportedly produced transient but dramatic acanthosis nigricans–like lesions, presumably due to activation of the FGFR.[8]

Of interest, ectopic acanthosis nigricans has been described in a syndromic patient who required skin grafting from the groin for syndactyly repair, with delayed acanthosis nigricans formation at the graft sites.[9]

Table. Acanthosis Nigricans Associations (Open Table in a new window)

Syndromes Associated With Acanthosis Nigricans Malignant Diseases Associated With Acanthosis Nigricans
Acromegaly Bile duct cancer
Alstrom telangiectasia Bladder cancer
Barter syndrome Breast cancer
Beare-Stevenson syndrome Colon cancer
Benign encephalopathy Endometrial cancer
Bloom syndrome Esophageal cancer
Capozucca syndrome Gallbladder cancer
Chondrodystrophy with dwarfism Hodgkin disease
Costello syndrome Kidney cancer
Crouzon syndrome[10] Liver cancer
Dermatomyositis Lung cancer
Familial pineal body hypertrophy Mycosis fungoides[11]
Gigantism Non-Hodgkin lymphoma
Hashimoto thyroiditis Ovarian cancer
Hirschowitz syndrome Pancreatic cancer
Lawrence-Moon-Bardet syndrome Pheochromocytoma
Lawrence-Seip syndrome Prostate cancer
Lipoatrophic diabetes mellitus Rectal cancer
Lupoid hepatitis Testicular cancer
Lupus erythematosus Thyroid cancer
Phenylketonuria Wilms tumor
Pituitary hypogonadism  
Pseudoacromegaly  
Prader-Willi syndrome  
Pyramidal tract degeneration  
Rud syndrome  
Scleroderma  
Stein-Leventhal syndrome  
Type A syndrome (HAIR-AN syndrome)  
Werner syndrome  
Wilson syndrome  

 

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Epidemiology

Frequency

United States

The exact incidence of acanthosis nigricans is unknown. In an unselected population of 1412 children, the changes of acanthosis nigricans were present in 7.1%. Obesity is closely associated with acanthosis nigricans, and more than half the adults who weigh greater than 200% of their ideal body weight have lesions consistent with acanthosis nigricans.

The malignant form of acanthosis nigricans is far less common, and, in one study, only 2 of 12,000 patients with cancer had signs of acanthosis nigricans. The most frequent associations were with adenocarcinomas of the gastrointestinal tract (70-90%), particularly gastric cancer (55-61% of malignant acanthosis nigricans cases). Approximately 61.3% of cases are diagnosed simultaneously with the cancer manifestation, while 17.6% of malignant acanthosis nigricans cases predate the diagnosis of malignancy.[5]

International

Epidemiologic studies performed in Iran, United Arab Emirates, and Japan all show statistically significant increases in insulin resistance among obese patients with acanthosis nigricans compared with matched obese controls without acanthosis nigricans, suggesting that acanthosis nigricans is a useful marker for insulin resistance among obese patients regardless of geographic setting.[12]

Race

Acanthosis nigricans is much more common in people with darker skin pigmentation. The prevalence in whites is less than 1%. In Latinos, the prevalence in one study was 5.5%, and, in African Americans, the prevalence is higher, at 13.3%. The incidence is also increased in the Native American population, with one study showing 34.2% of Cherokee patients age 5-40 years with acanthosis nigricans, increasing to 73% of those Cherokee patients with diabetes.[13, 14]

The prevalence in overweight children aged 7-17 years increases to 23% in Latino patients and 19.4% in African American patients. Children of any race with a body mass index greater than the 98th percentile have a 62% prevalence of acanthosis nigricans.[15, 16, 17]

In contrast to the benign form, malignant acanthosis nigricans has no racial predilection.

Sex

The incidence of acanthosis nigricans is equal for men and women. Acanthosis nigricans has no known sex predilection.[1]

Age

Lesions of benign acanthosis nigricans may be present at any age, including at birth, although it is found more commonly in the adult population. Malignant acanthosis nigricans occurs more frequently in elderly persons; however, cases have been reported in children with Wilms tumor, gastric adenocarcinoma, and osteogenic sarcoma.[1]

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Contributor Information and Disclosures
Author

Jason H Miller, MD Private Practice, Hametz and Picascia Dermatology Associates, Freehold, New Jersey

Jason H Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Ronald P Rapini, MD Professor and Chair, Department of Dermatology, The University of Texas MD Anderson Cancer Center; Distinguished Chernosky Professor and Chair of Dermatology, Professor of Pathology, University of Texas McGovern Medical School at Houston

Ronald P Rapini, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Society for Investigative Dermatology, Texas Medical Association

Disclosure: Received royalty from Elsevier publishers for independent contractor; May receive consulting fee from FDA panel for consulting in future, since I am on one of their committees, but at this time so far have received zero from FDA.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center

Ponciano D Cruz, Jr, MD is a member of the following medical societies: Texas Medical Association

Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Jonathan Baron, MD, and Norman Levine, MD, to the development and writing of this article.

References
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Brown velvety plaques with skin tags in the axilla of a patient with acanthosis nigricans.
Acanthosis nigricans.
Acanthosis nigricans, obesity related.
Acanthosis nigricans of the axilla with one skin tag.
Acanthosis nigricans biopsy. The epidermis is papillomatous (undulates) and pigmented ("nigricans"). Acanthosis (thickening of the spinous layer) is often not really present, so acanthosis nigricans is often a misnomer in many cases.
Table. Acanthosis Nigricans Associations
Syndromes Associated With Acanthosis Nigricans Malignant Diseases Associated With Acanthosis Nigricans
Acromegaly Bile duct cancer
Alstrom telangiectasia Bladder cancer
Barter syndrome Breast cancer
Beare-Stevenson syndrome Colon cancer
Benign encephalopathy Endometrial cancer
Bloom syndrome Esophageal cancer
Capozucca syndrome Gallbladder cancer
Chondrodystrophy with dwarfism Hodgkin disease
Costello syndrome Kidney cancer
Crouzon syndrome[10] Liver cancer
Dermatomyositis Lung cancer
Familial pineal body hypertrophy Mycosis fungoides[11]
Gigantism Non-Hodgkin lymphoma
Hashimoto thyroiditis Ovarian cancer
Hirschowitz syndrome Pancreatic cancer
Lawrence-Moon-Bardet syndrome Pheochromocytoma
Lawrence-Seip syndrome Prostate cancer
Lipoatrophic diabetes mellitus Rectal cancer
Lupoid hepatitis Testicular cancer
Lupus erythematosus Thyroid cancer
Phenylketonuria Wilms tumor
Pituitary hypogonadism  
Pseudoacromegaly  
Prader-Willi syndrome  
Pyramidal tract degeneration  
Rud syndrome  
Scleroderma  
Stein-Leventhal syndrome  
Type A syndrome (HAIR-AN syndrome)  
Werner syndrome  
Wilson syndrome  
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