What is the pathophysiology of acanthosis nigricans (AN)?

Updated: Oct 14, 2020
  • Author: Jason H Miller, MD; Chief Editor: William D James, MD  more...
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Answer

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] 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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