Acanthosis nigricans is a medical sign characterised by brown-to-black, poorly defined, velvety

hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

of the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

. It is usually found in body folds, such as the posterior and lateral folds of the neck, the

armpits The axilla (also, armpit, underarm or oxter) is the area on the human body directly under the shoulder joint. It includes the axillary space, an anatomical space within the shoulder girdle between the arm and the thoracic cage, bounded superio ...

groin In human anatomy, the groin (the adjective is ''inguinal'', as in inguinal canal) is the junctional area (also known as the inguinal region) between the abdomen and the thigh on either side of the pubic bone. This is also known as the medial comp ...

navel The navel (clinically known as the umbilicus, commonly known as the belly button or tummy button) is a protruding, flat, or hollowed area on the abdomen at the attachment site of the umbilical cord. All placental mammals have a navel, although ...

, forehead and other areas. It is associated with endocrine dysfunction, especially insulin resistance and hyperinsulinaemia, as seen in

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

. This activates the insulin-like growth factor receptors, which leads to proliferation of

keratinocytes Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

and other cells in the skin. Activation of other growth factor receptors such as

fibroblast growth factor receptors A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

can also be responsible.

Signs and symptoms

Acanthosis nigricans may present with thickened, velvety, relatively darker areas of skin on the neck,

armpit The axilla (also, armpit, underarm or oxter) is the area on the human body directly under the shoulder joint. It includes the axillary space, an anatomical space within the shoulder girdle between the arm and the thoracic cage, bounded superior ...

and in skin folds.

Causes

It typically occurs in individuals younger than age 40, is associated with insulin resistance,

Type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...

, obesity or endocrinopathies, such as hypothyroidism, acromegaly,

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...

Cushing's disease Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (spe ...

, and may be genetically inherited.

Type I – familial

Familial acanthosis may arise as a result of an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

trait, presenting at birth or developing during childhood. File:Familial acanthosis nigricans.jpg File:Familial acanthosis nigricans2.jpg File:Familial acanthosis nigricans3.jpg File:Familial acanthosis nigricans4.jpg File:Familial acanthosis nigricans5.jpg

Type II – endocrine

Endocrine syndromes associated with acanthosis nigricans can develop in many conditions, particularly: * starts with insulin resistance, such as

and

metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...

* excess circulating

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

s, particularly

, acromegaly,

Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adre ...

and hypothyroidism * Rare diseases, including

pinealoma A pinealoma is a tumor of the pineal gland, a part of the brain that produces melatonin. If a pinealoma destroys the cells of the pineal gland in a child, it can cause precocious puberty. Signs and symptoms The pineal gland produces the hormone me ...

leprechaunism Donohue syndrome (also known as leprechaunism) is an extremely rare and severe genetic disorder. ''Leprechaunism'' derives its name from the hallmark elvish features (small stature, bulging eyes, thick lips, and upturned nostrils) exhibited by the ...

lipoatrophic diabetes Lipoatrophic diabetes is a type of diabetes mellitus presenting with severe lipodystrophy Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical cond ...

, pineal hyperplasia syndrome, pituitary basophilism, ovarian hyperthecosis, stromal luteoma, ovarian dermoid cysts, Prader-Willi syndrome, and

Alström syndrome Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystr ...

. Acanthosis nigricans associated with endocrine dysfunction is more insidious in its onset, is less widespread, and the patients are often concurrently obese. File:Fibrome.jpg, A. nigricans, right armpit; notice the

skin tag A skin tag, or acrochordon (pl. acrochorda), is a small benign tumor that forms primarily in areas where the skin forms creases (or rubs together), such as the neck, armpit and groin. They may also occur on the face, usually on the eyelids. ...

s, an indicator for levated blood sugar and hyperinsulinaemia File:Acanthosis nigricans, axillär, ©WIKIDERM.jpg, A. nigricans, axillary

Type III – obesity and pseudoacanthosis nigricans

In young persons, acanthosis nigricans is a visible marker which strongly suggests insulin resistance. Higher than normal insulin levels in the blood stream cause the growth of darkened skin over certain areas of the body. No skin treatment will get rid of AN. Acanthosis nigricans may lighten up and possibly go away by treating the root cause, insulin resistance, but it can take months or years to do so. Insulin resistance syndromes may be divided into type A (HAIR-AN) and type B syndromes. The majority of cases of acanthosis nigricans are associated with obesity and otherwise idiopathic. This is likely because of insulin resistance and more likely to occur in darker-skinned persons. This can also be referred to as pseudoacanthosis nigricans. In some cases, AN attributable to obesity and insulin resistance will occur on ones face. Most typically it will be present as a horizontal band on the forehead, but may also appear as perioral hyperpigmentation, periorbital hyperpigmentation, or generalized facial skin darkening.

Type IV – drug-related

Acanthosis nigricans has been linked to the use of nicotinic acid,

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

use,

combined oral contraceptive pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: proges ...

s, and

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

therapy.

Type V – malignancy

Malignant acanthosis nigricans refers to acanthosis nigricans occurring as a paraneoplastic syndrome associated with a cancer. Malignant acanthosis nigricans is most commonly associated with gastrointestinal adenocarcinomas, as well as

genitourinary The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathw ...

cancers such as those of the prostate, breast, and ovary. Other cancers, such as those of the lung, stomach, and lymphoma, are occasionally associated with acanthosis nigricans. This form of acanthosis nigricans is more likely to involve mucous membranes (25–50% of cases) Malignant acanthosis nigricans that may either precede (18%), accompany (60%), or follow (22%) the onset of an internal cancer. Malignancy-associated acanthosis nigricans is usually rapid in onset and may be accompanied by

skin tags A skin tag, or acrochordon (pl. acrochorda), is a small benign tumor that forms primarily in areas where the skin forms creases (or rubs together), such as the neck, armpit and groin. They may also occur on the face, usually on the eyelids. Tho ...

, multiple seborrheic keratoses, or

tripe palms Tripe palms, is a cutaneous condition characterized by ridged velvety lesions on the palms resembling the lining of a cow's stomach (tripe). It is a paraneoplastic syndrome in gastric cancer. See also * Acrokeratosis paraneoplastica of Bazex * ...

Acral acanthotic anomaly

Acral acanthotic anomaly refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet, in the absence of any other findings, in otherwise healthy individuals. While the etiology remains unknown, its presence does not suggest a likelihood of malignancy.

Pathophysiology

Acanthosis nigricans is caused by increased activation of

growth factor receptor A growth factor receptor is a receptor that binds to a growth factor. Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins. Growth factors, which are ligands that bind to ...

proteins, usually due to endocrine dysfunction. This is most commonly

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

-mediated activation of IGF receptors on

, as a result of hyperinsulinaemia or insulin resistance, as seen in

. Factors involved in the development of acanthosis nigricans include: * Increased circulating insulin. This activates keratinocyte IGF receptors, particularly

IGF-1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans is ...

. At high concentrations, insulin may also displace IGF-1 from

insulin-like growth factor-binding protein The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1). Function Approximately 98% of IGF-1 is always bound to one of six binding proteins (IGF-BP). IGFBP-3, the most abund ...

(IGFBP). Increased circulating IGF may lead to keratinocyte and dermal fibroblast proliferation. * In hereditary forms of acanthosis nigricans, fibroblast growth factor receptor (FGFR) defects * Increased

transforming growth factor Transforming growth factor (, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ. The name "Transforming Growth Factor" is somewhat arbitrary, since the two classes of TGFs are not structurally or genetically ...

(TGF), which appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the

(EGFR). In conjunction with increased end levels of IGF, it is likely that perspiration and friction may be necessary predeterminants for lesions, since the level of insulin is usually not enough to activate IGF receptors across the body.

Diagnosis

Acanthosis nigricans is typically diagnosed clinically. A skin biopsy may be needed in unusual cases. If no clear cause is obvious, it may be necessary to search for one. Blood tests, an

endoscopy An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...

, or

X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

s may be required to eliminate the possibility of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

as the cause. On biopsy, hyperkeratosis, epidermal folding, leukocyte infiltration, and melanocyte proliferation may be seen.

Differential diagnosis

Acanthosis nigricans should be distinguished from the casal collar appearing in

pellagra Pellagra is a disease caused by a lack of the vitamin niacin (vitamin B3). Symptoms include inflamed skin, diarrhea, dementia, and sores in the mouth. Areas of the skin exposed to either sunlight or friction are typically affected first. Over t ...

Classification

Acanthosis nigricans is conventionally divided into benign and malignant forms, although may be divided into syndromes according to cause:James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . * Benign This may include obesity-related, hereditary, and endocrine forms of acanthosis nigricans. * Malignant. This may include forms that are associated with tumour products and insulin-like activity, or

tumour necrosis factor The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular pro ...

. An alternate classification system still used to describe acanthosis nigricans was proposed in 1994. It delineates acanthosis nigricans syndromes according to their associated syndromes, including benign and malignant forms, forms associated with obesity and drugs, acral acanthosis nigricans, unilateral acanthosis nigricans, and mixed and syndromic forms.

Treatment

People with acanthosis nigricans should be screened for diabetes and, although rare, cancer. Controlling

blood glucose Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...

levels through exercise and diet often improves symptoms. Topical fade creams (normally used for eliminating age spots) can lighten skin cosmetically in less severe cases.

Selenium sulfide Selenium sulfide can refer to either of the following: * Selenium disulfide, SeS2 * Selenium hexasulfide, Se2S6 {{Short pages monitor