Materiały źródłowe

• #1 Acanthosis Nigricans – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431057/

  Acanthosis nigricans is a cutaneous manifestation of an underlying condition. It usually develops in skin folds, such as the back of the neck, axilla, and groin, where it presents as velvety hyper-pigmented patches with poorly defined borders. 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 or with the use of certain medications like systemic glucocorticoids and oral contraceptives. […] 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.

• #2 A STUDY OF PATHOGENESIS OF ACANTHOSIS NIGRICANS AND ITS CLINICAL IMPLICATIONS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3276896/

  Acanthosis nigricans (AN) is a dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck. […] In this review, we discuss the pathogenesis of AN and its clinical implications and management. […] The definitive cause of AN has not yet been ascertained, although several possibilities have been suggested. Eight types of AN have been described. Obesity-associated AN, once labeled pseudo-AN, is the most common type of AN. […] Insulin resistance is often present in these patients; however, it is not universal. Syndromic AN is the name given to AN that is associated with a syndrome. […] Understanding the connection between AN and insulin resistance is critical for clinicians. […] AN is most commonly associated with disorders associated with insulin resistance, including obesity, type 2 diabetes, and the PCOS. […] In these cases, hyperinsulinemia is thought to play a pivotal role. […] The goal of therapy is to correct the underlying disease process.

• #3 Acanthosis Nigricans: A practical approach to evaluation and management

  https://escholarship.org/uc/item/7mf6g290

  Acanthosis nigricans is a dermatosis characterized by thickened, hyperpigmented plaques, typically of the intertriginous surfaces and neck. […] In this review, we discuss the pathogenesis of acanthosis nigricans and its clinical implications and management. […] Elevated insulin concentrations result in direct and indirect activation of IGF-1 receptors on keratinocytes and fibroblasts, leading to proliferation. Other mediators may also contribute, including other tyrosine kinase receptors such as EGFR and FGFR. […] Acanthosis nigricans is most commonly associated with disorders associated with insulin resistance, including obesity, type 2 diabetes, and the polycystic ovary syndrome. […] At high concentrations, however, insulin can exert more potent growth-promoting effects through binding to insulin-like growth factor 1 receptors (IGF-1Rs), which are similar in size and subunit structure to insulin receptors, but bind IGF-1 with 100- to 1000-fold greater affinity than insulin.

• #4 Acanthosis nigricans – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/acanthosis-nigricans/

  Several mechanisms to explain the pathogenesis of AN have been proposed, all of which consider enhanced cellular proliferation. […] Hyperinsulinemia present in benign AN results in a decreased number of functional insulin receptors which, via tyrosine kinase activity, regulate glucose uptake, cell growth, DNA synthesis, and protein/fat metabolism. Insulin may also bind to insulin-like growth factor (IGF) receptors resulting in enhanced cellular growth. These receptors are expressed by both keratinocytes and fibroblasts. The decreased number of functional insulin receptors results in increased binding to IGF receptors thus contributing toward the cutaneous lesions of AN. […] Malignant AN may result from direct expression of cellular proliferation-enhancing peptides by tumor cells, which include: transforming growth factor-alpha and epidermal growth factor. Fibroblast growth factor receptor 3 (FGFR3) has also been associated with formation of AN, including malignant AN. Acanthosis nigricans associated with hereditary diseases and FGFR3 germline mutations may be due to the resultant proliferative effect on keratinocytes. Tumor growth factor-alpha, ERK (a mitogen-activated protein kinase) and activation of insulin-like growth factor receptor have been suggested as contributing factors toward AN development.

• #5

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Acanthosis nigricans (AN) is characterized by dark, coarse and thickened skin with a velvety texture, being symmetrically distributed on the neck, the axillae, antecubital and popliteal fossae, and groin folds, histopathologically characterized by papillomatosis and hyperkeratosis of the skin. […] A high prevalence of AN has been observed recently. […] Insulin has been demonstrated to cross dermoepidermal junction (DEJ) to reach keratinocytes. At low concentrations, insulin regulates carbohydrate, lipid and protein metabolism and can weakly promote growth by binding to classic insulin receptors. At higher concentrations, however, insulin can exert more potent growth-promoting effects through binding to insulin-like growth factor 1 receptors (IGF-1Rs) that are similar in size and subunit structure to insulin receptors, but bind IGF-1 with 100- to 1000-fold greater affinity than insulin. The binding stimulates proliferation of keratinocytes and fibroblasts, leading to AN.

• #6 Acanthosis Nigricans: A practical approach to evaluation and management

  https://escholarship.org/uc/item/7mf6g290

  A number of observations suggest that insulin-dependent activation of IGF-1Rs can promote cellular proliferation and facilitate the development of AN. […] The true pathogenesis of AN, however, is likely to be more complex. […] Hyperinsulinemia may also facilitate the development of AN indirectly by increasing the levels of free IGF-1 in the circulation. […] Insulin-like growth factor 1 is expressed within the stratum granulosum and by dermal fibroblasts, but not by epidermal basal keratinocytes. […] Hyperinsulinemia does not mediate all forms of acanthosis nigricans. […] Malignancy-associated AN might be explained by elevated levels of growth factors such as transforming growth factor (TGF-), which exerts effects on epidermal tissue via the epidermal growth factor receptor (EGFR). […] Insulin-like growth factor 1 receptor, FGFR, and EGFR are all tyrosine kinase receptors and acanthosis nigricans seems to be a final common manifestation of a variety of processes.

• #7

  https://link.springer.com/article/10.1007/s44337-024-00017-7

  However, in metabolically unhealthy individuals, elevated insulin levels can disrupt the balance and directly stimulate IGF1R on keratinocytes and dermal fibroblasts, strongly activating the Ras/MAP/ERK and PI3K/Akt kinase cascades and promoting cell proliferation, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] Another mechanism of AN involves the activation of fibroblast growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR). […] Leptin also plays a role in insulin resistance as it interacts with insulin receptor substrate 1 (IRS1) and IRS2, promoting insulin sensitivity and reducing insulin levels. […] The increased proliferation induced by leptin, along with the proliferation stimulated by IGFR, likely contributes to the development of AN.

• #8 Acanthosis Nigricans: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1102488-overview

  AN most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. […] In the benign form of AN, 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 (eg, epidermal growth factor [EGF] receptor [EGFR] or fibroblast growth factor [FGF] 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. […] Familial and syndromic forms of AN have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin resistance syndromes and FGF defects.

• #9

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Hyperinsulinemia not only causes AN by exerting a direct toxic effect, but indirectly by increasing free IGF-1 levels in circulation. The activity of IGF-1 is regulated by insulin-like growth binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues and regulate levels of metabolically active free IGF-1. IGFBP-1 and IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma concentrations of free IGF-1, which promotes cell growth and differentiation. […] Observations that insulin-dependent activation of IGF-1Rs can facilitate AN development are (1) IGF receptors are found in cultured fibroblasts and keratinocytes. (2) Insulin can cross DEJ and at high concentrations can stimulate growth and replication of fibroblasts. (3) Severity of AN in obesity correlates positively with fasting insulin concentration. Thus, insulin may promote AN through direct activation of the IGF-1 signaling pathway.

• #10 SciELO Brazil – Association of acanthosis nigricans and skin tags with insulin resistance Association of acanthosis nigricans and skin tags with insulin resistance

  https://www.scielo.br/j/abd/a/msmp5rWGpqkSyn59ZGgyYds/

  Insulin resistance is a metabolic disorder in which target cells fail to respond to normal levels of circulating insulin. Insulin resistance has been associated with presence of acanthosis nigricans and acrochordons. […] The mechanism through which insulin resistance causes acanthosis is complex. The significant presence of IR produces compensatory hyperinsulinemia. Increased serum insulin levels interact with insulin-like growth factor receptors (IGF-1) triggering proliferation of keratinocytes and fibroblasts. AN is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. […] The epidermal growth factor (EGF) is an important mediator of keratinocyte growth in vitro, and both the EGF receptor (EGF-R) and EGF are found in excessive amounts in the hyperproliferative epidermis. EGF needs to interact with insulin-like growth factor/somatomedin (IGF-1) or with high doses of insulin for keratinocyte proliferation.

• #11

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Hyperinsulinemia not only causes AN by exerting a direct toxic effect, but indirectly by increasing free IGF-1 levels in circulation. The activity of IGF-1 is regulated by insulin-like growth binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues and regulate levels of metabolically active free IGF-1. IGFBP-1 and IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma concentrations of free IGF-1, which promotes cell growth and differentiation. […] Observations that insulin-dependent activation of IGF-1Rs can facilitate AN development are (1) IGF receptors are found in cultured fibroblasts and keratinocytes. (2) Insulin can cross DEJ and at high concentrations can stimulate growth and replication of fibroblasts. (3) Severity of AN in obesity correlates positively with fasting insulin concentration. Thus, insulin may promote AN through direct activation of the IGF-1 signaling pathway.

• #12 Acanthosis nigricans – Wikipedia

  https://en.wikipedia.org/wiki/Acanthosis_nigricans

  Acanthosis nigricans is caused by increased activation of growth factor receptor proteins, usually due to endocrine dysfunction. This is most commonly insulin-mediated activation of IGF receptors on keratinocytes, as a result of hyperinsulinaemia or insulin resistance, as seen in diabetes mellitus. […] Factors involved in the development of acanthosis nigricans include: Increased circulating insulin. This activates keratinocyte IGF receptors, particularly IGF-1. At high concentrations, insulin may also displace IGF-1 from insulin-like growth factor-binding protein (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 (TGF), which appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the epidermal growth factor receptor (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.

• #13 Acanthosis Nigricans: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1102488-overview

  AN most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. […] In the benign form of AN, 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 (eg, epidermal growth factor [EGF] receptor [EGFR] or fibroblast growth factor [FGF] 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. […] Familial and syndromic forms of AN have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin resistance syndromes and FGF defects.

• #14

  https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0666

  Fibroblast growth factor receptor 3 (FGFR3) belongs to the transmembrane tyrosine kinase receptors (1). Constitutive activating FGFR3 germline mutations cause genetic syndromes with acanthosis nigricans (AN) (25). […] In order to elucidate the pathogenesis of MAN, we examined FGFR3 protein expression in these two cases, compared with 20 samples of normal skin, by immunohistochemical analysis. […] We speculated that activation of FGFR3 might have some relevance to the formation of MAN, and investigated FGFR3 expression in two cases of MAN and 20 samples of normal epidermis by immunohistochemical analysis. […] These results indicate activation of FGFR3 to have some relevance to the development of MAN, probably due to the proliferative effect on epidermal keratinocytes. […] The activation of FGFR3 might also contribute to ras/MAPK signalling in the lesions, because EGFR and FGFR3 are both transmembrane tyrosine kinase receptors (TKRs) and located upstream of the ras/MAPK pathway (15).

• #15 Acanthosis nigricans – UtahDERM Diagnoses

  https://utahderm.med.utah.edu/diagnoses/acanthosis-nigricans/

  Acanthosis nigricans is associated with a variety of medical conditions, including adenocarcinomas of the GI tract, but is more frequently associated with metabolic syndrome and insulin resistance. […] The pathogenesis of the condition is possibly related to tyrosine kinase growth factor receptor signaling. Multiple different receptors have been theorized, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and insulin-like growth factor receptor-1 (IGFR1). […] Increased serum concentrations of serum insulin due to insulin resistance may bind to IGFR1 leading to the characteristic findings of acanthosis nigricans. […] Other reports have implicated FGFR3 in the pathophysiology of acanthosis nigricans, primarily due to the known association of mutations that lead to the activation of FGFR3 such as Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN) and a higher than expected incidence of acanthosis nigricans. […] Regardless of the exact signaling cascade that produces the classic characteristic features, histopathologically acanthosis nigricans is often associated with epidermal hyperkeratosis, dermal proliferation with possible infiltrates of lymphocytes and plasma cells, and papillomatosis.

• #16

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Unknown autoantibodies other than insulin-receptor antibody have been implicated; this could explain the effectiveness of cyclosporine in treating AN with autoimmune manifestations. […] Insulin and IGF-1 levels are affected by hepatitis C infection and both of them may be implicated in etiogenesis of acrochordons and AN through their proliferative and differentiating properties. […] Acanthosis nigricans maligna (ANM) might be explained by elevated levels of transforming growth factor (TGF-), exerting effects on epidermal tissue through epidermal growth factor (EGF) receptor. IGF-1, fibroblast growth factor, and melanocyte stimulating hormone that regulates melanocyte pigmentation and stimulates growth of keratinocytes, can play a role in the pathogenesis of hyperplasia and hyperpigmentation.

• #17 A STUDY OF PATHOGENESIS OF ACANTHOSIS NIGRICANS AND ITS CLINICAL IMPLICATIONS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3276896/

  Acanthosis nigricans (AN) is a dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck. […] In this review, we discuss the pathogenesis of AN and its clinical implications and management. […] The definitive cause of AN has not yet been ascertained, although several possibilities have been suggested. Eight types of AN have been described. Obesity-associated AN, once labeled pseudo-AN, is the most common type of AN. […] Insulin resistance is often present in these patients; however, it is not universal. Syndromic AN is the name given to AN that is associated with a syndrome. […] Understanding the connection between AN and insulin resistance is critical for clinicians. […] AN is most commonly associated with disorders associated with insulin resistance, including obesity, type 2 diabetes, and the PCOS. […] In these cases, hyperinsulinemia is thought to play a pivotal role. […] The goal of therapy is to correct the underlying disease process.

• #18 Acanthosis nigricans: A dermatologic marker of metabolic disease – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/acanthosis-nigricans-a-dermatologic-marker-of-metabolic-disease/

  Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. […] It is suggested that most, if not all patients with AN have either clinical or subclinical Insulin Resistance (IR). […] The glucose disposal rates were significantly lower in AN (obese or nonobese) as compared to controls, confirming that AN is associated with a significant IR. […] AN therefore today is considered as an epiphenomenon of the IR state. […] Dunaif et al also showed that the severity of the histopathologically diagnosed AN correlated positively only with magnitude of peripheral insulin resistance (i.e. decreased insulin – mediated glucose disposal) rather than basal or glucose challenge – induced hyperinsulinemia. […] AS is evident from our study, AN is a marker for insulin resistance. […] Acanthosis occurs in patients with hyperinsulinemia owing to stimulation of the insulin like growth factor – I and epidermal growth factor, which cause proliferation of the epidermal cells.

• #19 Acanthosis Nigricans: Causes, Diagnosis, and Treatment

  https://dermnetnz.org/topics/acanthosis-nigricans

  Malignant AN is a rare paraneoplastic syndrome likely due to the release of stimulatory growth factors by tumour cells and is typically associated with gastrointestinal malignancies, especially gastric adenocarcinoma (60%); other associated cancers include hepatobiliary carcinoma, squamous cell carcinoma, malignant melanoma, and Wilms tumour. […] Acanthosis nigricans is an independent risk factor for the presence of diabetes. […] Outcomes depend on the cause. Acanthosis nigricans may be a vital marker of underlying conditions which themselves carry significant risk to overall morbidity and mortality, such as obesity, metabolic syndrome, diabetes, and even serious internal malignancies.

• #20 Acanthosis nigricans in the pediatric population: a narrative review of the current approach to management in primary care – Pollock – Pediatric Medicine

  https://pm.amegroups.org/article/view/6555/html

  Although most studies report that AN is a clinical indicator of underlying insulin resistance, some researchers believe that AN is not an independent marker and as such all children with a BMI standard deviation score above or equal to 3 should be screened for hyperinsulinemia. […] The presence and severity of AN can be used as a clinical predictor of metabolic disorders and underlying nutritional status in normal, overweight, and obese children and adolescents.

• #21 Acanthosis Nigricans: Causes, Diagnosis, and Treatment

  https://dermnetnz.org/topics/acanthosis-nigricans

  Acanthosis nigricans is a skin condition characterised by a velvety papillomatous overgrowth of the epidermis. Darkening and thickening (epidermal hyperplasia) of the skin occurs mainly in the flexural areas, particularly the axillae, groin, inframammary region, and neck. […] Acanthosis nigricans (AN) is usually a sign of an underlying metabolic or hormonal condition or disease, such as obesity or diabetes (most commonly type 2 diabetes but also reported in type 1 diabetes, particularly when associated with obesity). […] The exact cause of AN is still unclear. However, it is predominantly linked to states of insulin resistance (IR) wherein obesity, diabetes, and/or other metabolic disorders (eg, metabolic syndrome, polycystic ovary syndrome, and generalised lipodystrophy) co-exist. Insulin in high concentrations has been shown to cross the dermal-epidermal junction, and in high concentrations to have growth-stimulating effects through its binding to type 1 insulin-like growth factor receptor (IGFR) on keratinocytes. It is this activation of IGFR that stimulates the proliferation of keratinocytes and leads to AN.

• #22 Acanthosis Nigricans: Pointer of Endocrine Entities

  https://www.mdpi.com/2075-4418/12/10/2519

  Acanthosis nigricans (AN) has been reported in relation to insulin resistance (IR). […] Many pathogenic contributors are described in relation to signature IR, at the skin level. Insulin-like growth factor (IGF), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) have been recognized as promoters of epidermal keratinocyte and dermal fibroblast proliferation. These are associated with a general pro-inflammatory status that may be a contributor to AN development as well as IR-activated pathways of glucose and lipid metabolism anomalies. […] AN has been reported in association with IR and other disorders, such as obesity, DM, MS, PCOS, some autoimmune diseases, malignancies (most frequently, gastrointestinal neoplasms and neuroendocrine neoplasia), endocrine tumors, such as acromegaly and Cushing’s syndrome, iatrogenic circumstances or so called drug-induced AN (for instance, local AN due to insulin injections, topic corticotherapy, etc.), and atypical presentations on the nasal crease due to local factors. […] The pivotal role of this dermatosis could massively improve endocrine and metabolic assessments.

• #23 Acanthosis Nigricans | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688503/all/Acanthosis_Nigricans

  High levels of insulin stimulate epidermal keratocytes and dermal fibroblasts via insulin-like growth factor receptors (IGF-1). The keratocyte proliferation leads to skin changes like papillomatosis and hyperkeratosis. […] Malignant AN is characterized by sudden onset, rapid progression, and more extensive lesions. […] 90-95% are associated with abdominal cavity adenocarcinomas.

• #24 Acanthosis Nigricans: Causes, Diagnosis, and Treatment

  https://dermnetnz.org/topics/acanthosis-nigricans

  Malignant AN is a rare paraneoplastic syndrome likely due to the release of stimulatory growth factors by tumour cells and is typically associated with gastrointestinal malignancies, especially gastric adenocarcinoma (60%); other associated cancers include hepatobiliary carcinoma, squamous cell carcinoma, malignant melanoma, and Wilms tumour. […] Acanthosis nigricans is an independent risk factor for the presence of diabetes. […] Outcomes depend on the cause. Acanthosis nigricans may be a vital marker of underlying conditions which themselves carry significant risk to overall morbidity and mortality, such as obesity, metabolic syndrome, diabetes, and even serious internal malignancies.

• #25 Malignant Acanthosis Nigricans, Florid Cutaneous and Mucosal Papillomatosis and Tripe Palms in a man with gastric adenocarcinoma | Actas Dermo-Sifiliográficas

  https://actasdermo.org/en-acantosis-nigricans-maligna-papilomatosis-cutaneo-mucosa-articulo-S1578219015001055

  We describe the case of a 67-year-old man with a clinical history of smoking, hypertension, and hyperhomocysteinemia. […] More than 50 types of cutaneous paraneoplastic manifestations have been described, including malignant acanthosis nigricans (MAN), florid cutaneous and mucosal papillomatosis, and acquired pachydermatoglyphia. […] MAN is characterized by the presence of brownish, symmetric, nonpruritic plaques in the skin folds and on the back of the neck that can infiltrate and present as hyperkeratotic plaques. In contrast to the benign form of acanthosis nigricans, the paraneoplastic form is characterized by abrupt onset, rapid progression, and involvement of a large skin surface area. There is a strong correlation between MAN and intra-abdominal tumors, particularly tumors of gastric origin.

• #26 Malignant acanthosis nigricans: a case report | BMC Ophthalmology | Full Text

  https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-020-01708-2

  Acanthosis nigricans is rare. […] There are two forms of acanthosis nigricans, benign and malignant, with the underlying disease mechanisms differing between the two types. […] Malignant acanthosis nigricans, on the other hand, is considered to represent a paraneoplastic syndrome co-occurring with cancers and is associated with internal malignancies, particularly gastric adenocarcinomas (5561%). […] Mucous membrane involvement is rare in acanthosis nigricans and is suggestive of the malignant form. […] The presence of acanthosis nigricans on the eyelid margins with a velvety overgrowth is highly suggestive of an internal malignancy. […] In fact, the filiform papillomas on the eyelid margins were found to be associated with underlying malignant acanthosis nigricans in this patient, and the radiological investigations and hematological tumor marker tests showed evidence of advanced cancer.

• #27 Acanthosis nigricans – Wikipedia

  https://en.wikipedia.org/wiki/Acanthosis_nigricans

  Acanthosis nigricans is caused by increased activation of growth factor receptor proteins, usually due to endocrine dysfunction. This is most commonly insulin-mediated activation of IGF receptors on keratinocytes, as a result of hyperinsulinaemia or insulin resistance, as seen in diabetes mellitus. […] Factors involved in the development of acanthosis nigricans include: Increased circulating insulin. This activates keratinocyte IGF receptors, particularly IGF-1. At high concentrations, insulin may also displace IGF-1 from insulin-like growth factor-binding protein (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 (TGF), which appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the epidermal growth factor receptor (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.

• #28

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Unknown autoantibodies other than insulin-receptor antibody have been implicated; this could explain the effectiveness of cyclosporine in treating AN with autoimmune manifestations. […] Insulin and IGF-1 levels are affected by hepatitis C infection and both of them may be implicated in etiogenesis of acrochordons and AN through their proliferative and differentiating properties. […] Acanthosis nigricans maligna (ANM) might be explained by elevated levels of transforming growth factor (TGF-), exerting effects on epidermal tissue through epidermal growth factor (EGF) receptor. IGF-1, fibroblast growth factor, and melanocyte stimulating hormone that regulates melanocyte pigmentation and stimulates growth of keratinocytes, can play a role in the pathogenesis of hyperplasia and hyperpigmentation.

• #29

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  TGF- produced by cancer cells is structurally similar to EGF-, interacts with the same receptor on the cell surface, probably binding with it in different sites. The receptor for EGF is found on normal epidermal cells, particularly on actively proliferating cells of the basal layer where it is involved in growth and differentiation of normal keratinocytes. TGF- and its receptor participate in tumor progression through auto and paracrine secretion leading to autostimulation. When these growth factors are produced by the primary tumor and circulate in large quantities, they may cause epidermal cell proliferation, leading to AN.

• #30 Acanthosis nigricans: To be or not to be afraid (Review)

  https://www.spandidos-publications.com/10.3892/ol.2018.9736

  Hyperinsulinemia acts in multiple ways to induce AN: direct effect and an indirect one. […] The appearance of paraneoplastic AN is considered to be the effect of signaling molecules secreted by the tumor. […] The most incriminated in AN progression is transforming growth factor- (TGF-). […] The evolution of paraneoplastic AN is tightly connected to the evolution of cancer, regressing after the surgical ablation of the tumor or in some cytostatic treatments; it could even be a valuable parameter for monitoring of therapy, since it reactivates in case of tumor relapse or development of metastases.

• #31 Paraneoplastic Acanthosis Nigricans, Leser-Trélat and Tripe Palms Associated With Gastro-Esophageal Junction Adenocarcinoma: A Case Report | Hagen | Journal of Medical Cases

  https://www.journalmc.org/index.php/jmc/article/view/217/192

  The optimal treatment of paraneoplastic AN differs between individual cases. Some cases are resistant to any form of therapy, even if the patient is successfully treated for the associated malignancy. Fortunately, in some cases, no separate treatment is needed for AN, as it fully regresses when the associated tumor is effectively treated.

• #32 Acanthosis Nigricans | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688503/all/Acanthosis_Nigricans

  Acanthosis nigricans (AN) is a benign dermatosis characterized by velvety, hyperpigmented, hyperkeratotic plaques, which are usually symmetric. […] Typically a sign of hyperinsulinemia and insulin resistance but can be a marker of malignancy. […] Etiologies include obesity, insulin resistance, genetic syndromes, familial AN, malignant AN, and drug reactions. […] Obesity induced (pseudo-AN) and insulin resistance are the most common etiologies of AN. […] Higher prevalence of AN in individuals with more risk factors for diabetes and those with type 2 diabetes. […] Other endocrinopathies associated with AN include polycystic ovarian syndrome (PCOS), acromegaly, and Cushing syndrome; thyroid diseases; hirsutism; and Addison disease. […] Genetic disorders characterized by insulin resistance can also present with AN.

• #33 Acanthosis Nigricans – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431057/

  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.

• #34 Acanthosis Nigricans: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1102488-overview

  AN most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. […] In the benign form of AN, 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 (eg, epidermal growth factor [EGF] receptor [EGFR] or fibroblast growth factor [FGF] 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. […] Familial and syndromic forms of AN have been identified. Many syndromes share common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulin resistance syndromes and FGF defects.

• #35 Acanthosis nigricans – Wikipedia

  https://en.wikipedia.org/wiki/Acanthosis_nigricans

  Acanthosis nigricans is caused by increased activation of growth factor receptor proteins, usually due to endocrine dysfunction. This is most commonly insulin-mediated activation of IGF receptors on keratinocytes, as a result of hyperinsulinaemia or insulin resistance, as seen in diabetes mellitus. […] Factors involved in the development of acanthosis nigricans include: Increased circulating insulin. This activates keratinocyte IGF receptors, particularly IGF-1. At high concentrations, insulin may also displace IGF-1 from insulin-like growth factor-binding protein (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 (TGF), which appears to be the mechanism for malignancy-associated acanthosis nigricans. TGF acts on epidermal tissue via the epidermal growth factor receptor (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.

• #36 Acanthosis Nigricans: Treatment, Pictures, and Causes

  https://www.healthline.com/health/acanthosis-nigricans

  Acanthosis nigricans skin patches occur when epidermal skin cells begin to reproduce rapidly. This atypical skin cell growth is most commonly triggered by high levels of insulin in the blood. […] The most frequent trigger for acanthosis nigricans is an excess of insulin in your bloodstream. […] Excess insulin causes skin cells to reproduce at a rapid rate. For people with skin that has more pigment, these new cells have more melanin. This increase in melanin produces a patch of skin thats darker than the skin surrounding it. […] The presence of acanthosis nigricans is a strong predictor of future diabetes. […] Certain medications can trigger acanthosis nigricans, such as injected supplementary insulin, nicotinic acid, birth control pills, diethylstilbestrol, human growth hormones, systemic glucocorticoids, thyroid medications, some bodybuilding supplements, protease inhibitors, and estrogen.

• #37 Acanthosis Nigricans: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1102488-overview

  In malignant AN, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)- is structurally similar to EGF and is a likely candidate. TGF- and EGF have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within AN lesions. […] Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely through activation of IGF receptors. […] Malignant AN, which is associated with internal malignancy, is the most worrisome of the AN variants because the underlying neoplasm is often an aggressive cancer (see Pathophysiology, Table 1). […] AN has been reported with many kinds of cancer, but by far the most common underlying malignancy is an adenocarcinoma of gastrointestinal (GI) origin, usually a gastric adenocarcinoma. […] Regression of AN has been seen with treatment of the underlying malignancy, and reappearance may suggest recurrence or metastasis of the primary tumor.

• #38 Acanthosis Nigricans: Treatment, Pictures, and Causes

  https://www.healthline.com/health/acanthosis-nigricans

  All of these medications can cause changes in insulin levels. […] In rare cases, acanthosis nigricans can occur due to stomach cancer, adrenal gland disorders, disorders of the pituitary gland, low levels of thyroid hormones, high doses of niacin, some types of stomach cancer, genetics, and some autoimmune disorders like Sjgrens disease or Hashimotos thyroiditis.

• #39

  https://journals.lww.com/idoj/fulltext/2014/05030/an_approach_to_acanthosis_nigricans.1.aspx

  Hyperinsulinemia not only causes AN by exerting a direct toxic effect, but indirectly by increasing free IGF-1 levels in circulation. The activity of IGF-1 is regulated by insulin-like growth binding proteins (IGFBPs), which increase IGF-1 half life, deliver IGFs to target tissues and regulate levels of metabolically active free IGF-1. IGFBP-1 and IGFBP-2 are both decreased in obese subjects with hyperinsulinemia, increasing plasma concentrations of free IGF-1, which promotes cell growth and differentiation. […] Observations that insulin-dependent activation of IGF-1Rs can facilitate AN development are (1) IGF receptors are found in cultured fibroblasts and keratinocytes. (2) Insulin can cross DEJ and at high concentrations can stimulate growth and replication of fibroblasts. (3) Severity of AN in obesity correlates positively with fasting insulin concentration. Thus, insulin may promote AN through direct activation of the IGF-1 signaling pathway.

• #40

  https://link.springer.com/article/10.1007/s44337-024-00017-7

  However, in metabolically unhealthy individuals, elevated insulin levels can disrupt the balance and directly stimulate IGF1R on keratinocytes and dermal fibroblasts, strongly activating the Ras/MAP/ERK and PI3K/Akt kinase cascades and promoting cell proliferation, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] Another mechanism of AN involves the activation of fibroblast growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR). […] Leptin also plays a role in insulin resistance as it interacts with insulin receptor substrate 1 (IRS1) and IRS2, promoting insulin sensitivity and reducing insulin levels. […] The increased proliferation induced by leptin, along with the proliferation stimulated by IGFR, likely contributes to the development of AN.

• #41

  https://link.springer.com/article/10.1007/s44337-024-00017-7

  However, in metabolically unhealthy individuals, elevated insulin levels can disrupt the balance and directly stimulate IGF1R on keratinocytes and dermal fibroblasts, strongly activating the Ras/MAP/ERK and PI3K/Akt kinase cascades and promoting cell proliferation, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] Another mechanism of AN involves the activation of fibroblast growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR). […] Leptin also plays a role in insulin resistance as it interacts with insulin receptor substrate 1 (IRS1) and IRS2, promoting insulin sensitivity and reducing insulin levels. […] The increased proliferation induced by leptin, along with the proliferation stimulated by IGFR, likely contributes to the development of AN.

• #42 Insulin resistance in acanthosis nigricans – EADV

  https://eadv.org/2023/10/03/insulin-resistance-in-acanthosis-nigricans/

  Acanthosis nigricans has been associated with certain prescription medications and malignancy but is most commonly associated with obesity and insulin resistance. […] Insulin and its receptors are key players in acanthosis nigricans. […] However, in individuals with metabolic imbalances, elevated insulin levels can disrupt the balance and directly stimulate the IGF1 receptor on keratinocytes and dermal fibroblasts, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] However, in cases of obesity, elevated leptin levels can act as a pro-inflammatory cytokine and lead to insulin resistance. […] This resistance, in turn, drives increased insulin levels, further promoting leptin synthesis and release. […] Proliferation induced by leptin, along with the proliferation stimulated by the IGF receptor, may contribute to the development of acanthosis nigricans.

• #43 Insulin resistance in acanthosis nigricans – EADV

  https://eadv.org/2023/10/03/insulin-resistance-in-acanthosis-nigricans/

  Acanthosis nigricans has been associated with certain prescription medications and malignancy but is most commonly associated with obesity and insulin resistance. […] Insulin and its receptors are key players in acanthosis nigricans. […] However, in individuals with metabolic imbalances, elevated insulin levels can disrupt the balance and directly stimulate the IGF1 receptor on keratinocytes and dermal fibroblasts, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] However, in cases of obesity, elevated leptin levels can act as a pro-inflammatory cytokine and lead to insulin resistance. […] This resistance, in turn, drives increased insulin levels, further promoting leptin synthesis and release. […] Proliferation induced by leptin, along with the proliferation stimulated by the IGF receptor, may contribute to the development of acanthosis nigricans.

• #44

  https://link.springer.com/article/10.1007/s44337-024-00017-7

  However, in metabolically unhealthy individuals, elevated insulin levels can disrupt the balance and directly stimulate IGF1R on keratinocytes and dermal fibroblasts, strongly activating the Ras/MAP/ERK and PI3K/Akt kinase cascades and promoting cell proliferation, resulting in acanthosis, hyperkeratosis, and papillomatosis. […] Another mechanism of AN involves the activation of fibroblast growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR). […] Leptin also plays a role in insulin resistance as it interacts with insulin receptor substrate 1 (IRS1) and IRS2, promoting insulin sensitivity and reducing insulin levels. […] The increased proliferation induced by leptin, along with the proliferation stimulated by IGFR, likely contributes to the development of AN.

• #45 A study of pathogenesis of Acanthosis nigricans – ProQuest

  https://www.proquest.com/scholarly-journals/study-pathogenesis-acanthosis-nigricans-clinical/docview/918227965/se-2

  Acanthosis nigricans (AN) is a dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck. […] In this review, we discuss the pathogenesis of AN and its clinical implications and management. […] The commonest histopathological feature of patients with AN was hyperkeratosis, seen in 100% patients, papillomatosis was seen in 90% patients, dermal infiltrate of lymphocytes and plasma cells was seen in 60% patients, horn pseudocysts were seen in 30% patients, and irregular acanthosis was seen in 26.6% patients.

• #46 Oral malignant acanthosis nigricans associated with endometrial adenocarcinoma | International Journal of Oral Science

  https://www.nature.com/articles/ijos20141

  We report a 59-year-old patient with malignant acanthosis nigricans associated with metastasis of endometrial carcinoma. […] The article highlights the importance of biopsy and histopathological diagnosis in presumed benign lesions and the role of doctors in screening for body internal tumors. […] The primary pathological manifestations of benign and malignant acanthosis nigricans are identical, characterized by hyperkeratosis, acanthosis, increased dermal pigmentation and papillomatous hyperplasia of the epidermis. […] The difference between these two types is the cause of the lesion, with the benign related to benign conditions, common in insulin-resistant patients, including type 2 diabetes mellitus, obesity, polycystic ovary syndrome and Donohue syndrome, whereas the malignant are associated with internal carcinoma.

• #47

  https://journals.lww.com/ijd/fulltext/2011/56060/a_study_of_pathogenesis_of_acanthosis_nigricans.14.aspx

  Acanthosis nigricans (AN) is a dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck. […] In this review, we discuss the pathogenesis of AN and its clinical implications and management. […] The definitive cause of AN has not yet been ascertained, although several possibilities have been suggested. Eight types of AN have been described. Obesity-associated AN, once labeled pseudo-AN, is the most common type of AN. […] Insulin resistance is often present in these patients; however, it is not universal. Syndromic AN is the name given to AN that is associated with a syndrome. In addition to the widely recognized association of AN with insulin resistance, AN has been associated with numerous syndromes. […] Understanding the connection between AN and insulin resistance is critical for clinicians. […] AN is most commonly associated with disorders associated with insulin resistance, including obesity, type 2 diabetes, and the PCOS. […] In these cases, hyperinsulinemia is thought to play a pivotal role.

• #48 SciELO Brazil – Association of acanthosis nigricans and skin tags with insulin resistance Association of acanthosis nigricans and skin tags with insulin resistance

  https://www.scielo.br/j/abd/a/msmp5rWGpqkSyn59ZGgyYds/

  Insulin resistance has been associated with AN and AC, and it is known that early diagnosis and early treatment are of paramount importance to prevent a series of future manifestations. Reduction of insulin action may be accompanied by a group of metabolic disorders such as hypertension, hypertriglyceridemia, reduced HDL/cholesterol levels, carbohydrate intolerance, central obesity, increased plasminogen activator inhibitor-1 concentrations (fibrinolytic disorders), hyperuricemia and atherosclerotic cardiovascular disease. This set of changes is known as insulin resistance syndrome or metabolic syndrome. Therefore, AN becomes an easy signal for tracking insulin resistance and non-insulin-dependent DM, with implications regarding changes in lifestyle and adoption of early treatment.

• #49 Acanthosis nigricans: A dermatologic marker of metabolic disease – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/acanthosis-nigricans-a-dermatologic-marker-of-metabolic-disease/

  Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. […] It is suggested that most, if not all patients with AN have either clinical or subclinical Insulin Resistance (IR). […] The glucose disposal rates were significantly lower in AN (obese or nonobese) as compared to controls, confirming that AN is associated with a significant IR. […] AN therefore today is considered as an epiphenomenon of the IR state. […] Dunaif et al also showed that the severity of the histopathologically diagnosed AN correlated positively only with magnitude of peripheral insulin resistance (i.e. decreased insulin – mediated glucose disposal) rather than basal or glucose challenge – induced hyperinsulinemia. […] AS is evident from our study, AN is a marker for insulin resistance. […] Acanthosis occurs in patients with hyperinsulinemia owing to stimulation of the insulin like growth factor – I and epidermal growth factor, which cause proliferation of the epidermal cells.

• #50 Prevalence of Acanthosis Nigricans in an urban population in Sri Lanka and its utility to detect metabolic syndrome | BMC Research Notes | Full Text

  https://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-4-25

  Insulin resistance (IR) plays a major role in the pathogenesis of metabolic syndrome. Acanthosis nigricans (AN) is an easily detectable skin condition that is strongly associated with IR. […] A number of studies have shown an association between AN and insulin resistance and the recent increase in the prevalence of AN may well reflect increasing trends in obesity and type 2 diabetes worldwide. […] Patients with AN are at risk for all components of the metabolic syndrome, such as, obesity, hypertension, elevated triglycerides, low HDL, and impaired glucose tolerance. […] Despite this, there are few studies investigating the role of AN as a clinical marker to detect people who are at risk of having metabolic syndrome. […] Although AN was common in our study population, its low sensitivity does not make it a suitable screening test to detect metabolic syndrome. However, the high specificity and NPV make AN a very useful sign to predict its presence.

• #51 Malignant acanthosis nigricans: a case report | BMC Ophthalmology | Full Text

  https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-020-01708-2

  Acanthosis nigricans with eye involvement was first noted in 1904 by Birch-Hirschfeld. […] The dermatologic manifestations of malignant acanthosis nigricans have been noted to improve or even resolve after surgical resection of the causative tumor; however, they may worsen again as metastases develop. […] The mucosa and the skin are the organs of the body that can be most quickly and easily assessed. Acanthosis nigricans is a well-established marker of malignant tumors in the internal organs.

• #52 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1045440

  The observation that following chemotherapy, there was an apparent disappearance of papillomatosis suggests a chemotherapeutic effect on the factor determining epidermal growth leading to acanthosis nigricans as seen in our patient. […] Collectively, these observations led us to conclude that acral-type acanthosis nigricans may also be accompanied with internal malignant diseases and that its presence may therefore necessitate a thorough search for underlying primary malignancies.

• #53 Acanthosis Nigricans: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1102488-overview

  In malignant AN, the stimulating factor is hypothesized to be a substance secreted either by the tumor or in response to the tumor. Transforming growth factor (TGF)- is structurally similar to EGF and is a likely candidate. TGF- and EGF have both been found in gastric adenocarcinoma cells, and EGFR expression has been identified in skin cells within AN lesions. […] Exogenous medications also have been implicated as etiologic factors, including insulin injections (especially at the injection site), likely through activation of IGF receptors. […] Malignant AN, which is associated with internal malignancy, is the most worrisome of the AN variants because the underlying neoplasm is often an aggressive cancer (see Pathophysiology, Table 1). […] AN has been reported with many kinds of cancer, but by far the most common underlying malignancy is an adenocarcinoma of gastrointestinal (GI) origin, usually a gastric adenocarcinoma. […] Regression of AN has been seen with treatment of the underlying malignancy, and reappearance may suggest recurrence or metastasis of the primary tumor.

• #54 Acanthosis nigricans: To be or not to be afraid (Review)

  https://www.spandidos-publications.com/10.3892/ol.2018.9736

  Hyperinsulinemia acts in multiple ways to induce AN: direct effect and an indirect one. […] The appearance of paraneoplastic AN is considered to be the effect of signaling molecules secreted by the tumor. […] The most incriminated in AN progression is transforming growth factor- (TGF-). […] The evolution of paraneoplastic AN is tightly connected to the evolution of cancer, regressing after the surgical ablation of the tumor or in some cytostatic treatments; it could even be a valuable parameter for monitoring of therapy, since it reactivates in case of tumor relapse or development of metastases.

• #55 Current treatment options for acanthosis nigricans | CCID

  https://www.dovepress.com/current-treatment-options-for-acanthosis-nigricans-peer-reviewed-fulltext-article-CCID

  Acanthosis nigricans (AN) is a common dermatologic manifestation of systemic disease that is associated with insulin resistance, diabetes mellitus, obesity, internal malignancy, endocrine disorders, and drug reactions. […] The severity of AN has a positive correlation with fasting insulin levels. AN is likely the result of high levels of insulin binding to insulin-like growth factor 1 receptors (IGF-1Rs) on keratinocytes and fibroblasts. This leads to a proliferation of both cell types and clinically apparent plaques and papillomatosis. […] Treatment of AN should focus on correction of the underlying disease process. Weight reduction in obesity-related AN may resolve hyperkeratotic lesions, while correction of hyperinsulinemia can reduce the burden of AN lesions. […] Oral metformin and combinations of other insulin-mediating medications are effective, as they are therapies aimed at resolving the underlying causes contributing to AN.

• #56 Acanthosis nigricans

  https://www.pcds.org.uk/clinical-guidance/acanthosis-nigricans

  Acanthosis nigricans (AN) is characterised by hyperpigmentation and a velvety thickening of skin predominantly affecting the neck and flexures. […] AN has a number of aetiologies whose likely common mechanism is stimulation of tyrosine kinase growth factor receptor signalling pathways in the epidermis. In insulin resistance syndromes high levels of circulating insulin activate the insulin-like growth factor 1 receptor. […] Insulin resistance secondary to obesity is the most common cause of AN. The changes are weight dependent; lesions may completely regress with weight reduction. […] Malignant acanthosis nigricans is associated with internal malignancy, usually a gastric adenocarcinoma; many other carcinomata have been associated. […] The primary aim is to correct the underlying cause, which, if possible can lead to an improvement in symptoms.

• #57 Current treatment options for acanthosis nigricans | CCID

  https://www.dovepress.com/current-treatment-options-for-acanthosis-nigricans-peer-reviewed-fulltext-article-CCID

  Acanthosis nigricans (AN) is a common dermatologic manifestation of systemic disease that is associated with insulin resistance, diabetes mellitus, obesity, internal malignancy, endocrine disorders, and drug reactions. […] The severity of AN has a positive correlation with fasting insulin levels. AN is likely the result of high levels of insulin binding to insulin-like growth factor 1 receptors (IGF-1Rs) on keratinocytes and fibroblasts. This leads to a proliferation of both cell types and clinically apparent plaques and papillomatosis. […] Treatment of AN should focus on correction of the underlying disease process. Weight reduction in obesity-related AN may resolve hyperkeratotic lesions, while correction of hyperinsulinemia can reduce the burden of AN lesions. […] Oral metformin and combinations of other insulin-mediating medications are effective, as they are therapies aimed at resolving the underlying causes contributing to AN.

• #58 Current treatment options for acanthosis nigricans | CCID

  https://www.dovepress.com/current-treatment-options-for-acanthosis-nigricans-peer-reviewed-fulltext-article-CCID

  While correction of underlying causes remains the mainstay of treatment, it is important to consider cosmetic options to improve patient quality of life that may be affected by the presence of AN lesions. […] Future research in the pathogenesis of insulin-resistant AN and malignancy-related AN will further the development of targeted AN therapies.

• #59 Paraneoplastic Acanthosis Nigricans, Leser-Trélat and Tripe Palms Associated With Gastro-Esophageal Junction Adenocarcinoma: A Case Report | Hagen | Journal of Medical Cases

  https://www.journalmc.org/index.php/jmc/article/view/217/192

  The optimal treatment of paraneoplastic AN differs between individual cases. Some cases are resistant to any form of therapy, even if the patient is successfully treated for the associated malignancy. Fortunately, in some cases, no separate treatment is needed for AN, as it fully regresses when the associated tumor is effectively treated.

• #60 Current treatment options for acanthosis nigricans | CCID

  https://www.dovepress.com/current-treatment-options-for-acanthosis-nigricans-peer-reviewed-fulltext-article-CCID

  While correction of underlying causes remains the mainstay of treatment, it is important to consider cosmetic options to improve patient quality of life that may be affected by the presence of AN lesions. […] Future research in the pathogenesis of insulin-resistant AN and malignancy-related AN will further the development of targeted AN therapies.

• #61 Acanthosis Nigricans – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431057/

  Acanthosis nigricans is a cutaneous manifestation of an underlying condition. It usually develops in skin folds, such as the back of the neck, axilla, and groin, where it presents as velvety hyper-pigmented patches with poorly defined borders. 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 or with the use of certain medications like systemic glucocorticoids and oral contraceptives. […] 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.

• #62 Acanthosis Nigricans | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17054

  Acanthosis nigricans is most commonly associated with diabetes and insulin resistance, but rarely it can be a sign of internal malignancy. […] 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. […] 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. […] 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 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.

• #63 Oral malignant acanthosis nigricans associated with endometrial adenocarcinoma | International Journal of Oral Science

  https://www.nature.com/articles/ijos20141

  Thus, the diagnosis of malignant acanthosis nigricans can be made only when there is pathological manifestation and a definite diagnosis of internal carcinoma. […] The etiology and pathogenesis of malignant acanthosis nigricans remains unclear. […] Many pathogenic studies reveal malignant acanthosis nigricans results from carcinoma cells or its products, including transforming growth factor alpha, epidermal growth factor, fibroblast growth factor and melanocyte-stimulating hormone alpha. […] Tissues far from tumor could be affected by these factors via endocrine, autocrine and paracrine.

• #64 Paraneoplastic Acanthosis Nigricans, Leser-Trélat and Tripe Palms Associated With Gastro-Esophageal Junction Adenocarcinoma: A Case Report | Hagen | Journal of Medical Cases

  https://www.journalmc.org/index.php/jmc/article/view/217/192

  Acanthosis nigricans is a skin condition that is characterized by velvety, hyperpigmented and occasionally pruritic plaques, mostly seen in the flexural areas. […] Acanthosis nigricans (AN) is a skin disorder that is characterized by velvety, papillomatous, hyperpigmented and occasionally pruritic plaques, mostly seen in the flexural areas. The disorder in itself is benign and associated with insulin resistance, obesity, erythema nodosum and medication (sex hormones, nicotinic acid). AN can also present as a paraneoplastic syndrome and is associated with several malignancies, mostly adenocarcinomas of gastrointestinal origin. […] The pathologic mechanism that causes paraneoplastic AN is unknown. It has been hypothesized that tumor-produced growth factors such as epidermal growth factor, transforming growth factor-, insulin-like growth factor-1, fibroblast growth factor and melanocyte stimulating hormone- play a central role. It is believed that when these growth factors are produced by the primary tumor and circulate in large quantities, they can cause epidermal cells to proliferate.

• #65 Acanthosis nigricans: diagnosis and treatment. Clínica Universidad de Navarra

  https://www.cun.es/en/diseases-treatments/diseases/acanthosis-nigricans

  Acanthosis nigricans is a dermatological condition characterized by hyperpigmentation and thickening of the skin, which appears mainly in areas of the body with folds and wrinkles, such as the elbows, armpits or neck. […] One of the most common causes is insulin resistance, a pre-diabetic condition that leads the body to produce more insulin than normal to compensate for the cells’ inability to use it properly. The excess insulin stimulates the growth of skin cells, causing the characteristic symptoms of acanthosis nigricans to appear. […] Elevated insulin levels in the blood can stimulate the proliferation of keratinocytes and fibroblasts in the skin, overgrowth of which leads to the hyperpigmentation and thickening characteristic of acanthosis nigricans. […] Importantly, Acanthosis Nigricans, in this context, may be an early cutaneous marker of insulin resistance, even before other clinical signs of metabolic disorders, such as type 2 diabetes, become apparent.

• #66 A Comprehensive Review of Acanthosis Nigricans: Pathogenesis, Clinical manifestation and Management | Bentham Science Publishers

  https://www.benthamdirect.com/content/journals/raiad/10.2174/0127722708314530240919054410

  Acanthosis Nigricans is a dermatological condition characterized by hyperpigmented velvet plaques that can be observed in flexural areas such as the neck, axilla, and groin. […] Pathogenesis is the complex interplay of genetic, hormonal, and environmental factors, with insulin resistance playing a central role. […] AN is closely linked to insulin resistance, characterized by impaired cellular response to insulin, leading to compensatory hyperinsulinemia. […] Acanthosis Nigricans is a skin condition characterized by dark, thickened patches of skin, typically occurring in skin folds and creases. […] Proper diagnosis and management of the underlying conditions are crucial.

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