Acanthosis nigricans (AN) is a skin disorder characterised by hyperpigmentation, hyperqueratosis, and the presence of multiple papillomatosis that affects mainly in symmetrical form the cutaneous folds, appearing as dark, coarse, thick, and velvety plaques, usually in intertriginous areas such as the groin, axilla, and neck folds. [1] [2]
According to aetiology, AN is classified into two great groups: benign and malignant. [1] AN is likely the most readily recognised skin manifestation of diabetes and is present in up to 74% of obese adult patients, and can be predictive of the existence of hyperinsulinemia. Prevalence of AN varies by ethnicity: lowest in whites (0.5%), higher in Hispanics (5%), and even higher in African Americans (13%). This review examines the underlying pathophysiological mechanisms of acanthosis nigricans and evaluates the efficacy and safety of tretinoin 0.025% as a topical treatment modality.
Pathophysiology of Acanthosis Nigricans
Metabolic and Endocrine Mechanisms
The pathophysiology of AN involves disruptions in insulin, IGF1 (insulin-like growth factor 1), leptin, fibroblast growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR), leading to keratinocyte and fibroblast proliferation. [3] AN is connected to insulin, IGF1, leptin, and growth factor receptors and is an independent marker for metabolic disorders. [3] Excessive energy intake results in cell overload that triggers mechanisms to protect cells from further energy accumulation by reducing insulin sensitivity, and hypertrophied adipocytes and macrophage infiltration causes local inflammation that may result in general inflammation that induces insulin resistance. [4]
The pathophysiology of AN is linked to the activation of epidermal growth factor receptors. [5] Insulin resistance (IR) is a metabolism disorder that may contribute to the pathophysiology of acanthosis nigricans, with AN potentially serving as a cutaneous marker of IR. [6] Both underlying conditions present with insulin resistance.
Histopathological Features
The pathophysiology of AN is multifactorial, resulting in proliferation of epidermal keratinocytes and dermal fibroblasts, with resultant histopathological changes including epidermal acanthosis with papillomatosis, hyperkeratosis, mild increase in pigmentation, with a pauci-inflammatory dermis. [2] Specifically, histological examination typically reveals hyperkeratosis, papillomatosis, increased pigmentation of the basal cell layer and mild acanthosis, with a sparse inflammatory infiltrate of mononuclear cells in the upper dermis. [7]
Associated Systemic Conditions
Heredity, obesity, endocrine disorders, certain drugs, and malignancy are associated with AN. Type 2 diabetes–related AN has an insidious onset and initially presents as hyperpigmentation, and there is a possible genetic predisposition or increased sensitivity of the skin to hyperinsulinemia in different ethnic groups. In hyperandrogenism, the dermatologic spectrum of manifestations primarily includes hirsutism, acne vulgaris, androgenetic alopecia, acanthosis nigricans, acrochordons, and hyperhidrosis, with cutaneous features often being the earliest clinical indicators and tightly associated with androgen receptor (AR) activation, local enzymatic conversion, and downstream metabolic and inflammatory pathways. [8]
Despite the association of insulin resistance (IR) in the pathophysiology of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), AN appears to predict a higher steatosis grade in adults with overweight and obesity, supporting the clinical applicability of AN as a screening tool for MASLD. [9]
Clinical Classification and Presentation
AN is a hyperpigmented velvety thickening of skin folds, presenting predominantly in the neck, axilla, and groin areas, with possible additional presentations including skin tags and hyperkeratosis. Cutaneous paraneoplastic syndromes associated with acanthosis nigricans occur predominantly in patients with solid tumors, and the clinical manifestations of these dermatoses may precede, coincide with, or follow the diagnosis of cancer, with the presence of a cutaneous paraneoplastic syndrome often associated with a poor prognosis. [10]
In acral AN, also called acral acanthotic anomaly, the lesions are localized to the knee, ankle, phalangeal joints and tarsophalangeal joints and appear to be more common in persons with a dark complexion and affects acral areas without prominent affection of axilla and other flexures. [7]
Tretinoin 0.025% Treatment: Efficacy and Mechanisms
Clinical Efficacy
Both 0.025% and 0.05% tretinoin creams were efficacious in acanthosis nigricans treatment with 17.1 ± 8.0% improvement and 18.4 ± 9.8% improvement after 8 weeks treatment by reflectance spectrophotometry measurement, respectively, with generally no significant differences in efficacy, improvements in ANSC (Acanthosis nigricans scoring chart), investigator- and patient-global evaluation scores, and local cutaneous irritations between the two groups. [11]
There was a statistically significant difference between 10% urea and 0.025% tretinoin in the treatment of acanthosis nigricans (p < 0.01), with efficacy of 10% urea and 0.025% tretinoin treatment showing 11.4 ± 5.7% and 20.1 ± 9.7% improvement, respectively, and the efficacy of 0.025% tretinoin was significantly better than 10% urea in the treatment of acanthosis nigricans. [12] The treatment efficacy using the investigator’s global evaluation found that 36.8% of participants treated with 10% urea and 63.2% of participants treated with 0.025% tretinoin had more than 75% skin improvement. [12]
In another comparing tretinoin against retinol peels, all treatment groups demonstrated statistically significant improvement, with participants in the topical tretinoin group achieving a slightly better reduction of Acanthosis Nigricans Area Severity Index (ANASI) score with a mean ANASI score of 10 at final follow-up, followed by 10% retinol peel with mean ANASI score of 12 and 4% retinol peel with mean ANASI score of 11, and patient satisfaction score was found to be higher among the participants in the topical tretinoin group. [13]
Comparative Effectiveness with Other Topical Agents
Tretinoin 0.05% was significantly more effective for axillary lesions in terms of treatment response and patient satisfaction (p = 0.02 and p = 0.008, respectively), though neither tretinoin nor glycolic acid 70% was significantly effective for neck lesions, with tretinoin 0.05% shown to be more efficacious in treating axillary lesions of acanthosis nigricans, despite causing minimal side effects. [14]
A systematic review comparing topical treatment options found that tretinoin was more effective for reducing dark pigmentation, especially on the neck, and patients were more satisfied with it than with glycolic acid, with tretinoin recommended for predominant hyperpigmentation. [15] Both urea and tretinoin may be effective treatments for AN, with choice of therapy potentially individualized—tretinoin for predominant hyperpigmentation, urea for erythema or lower irritation tolerance, salicylic acid as a tolerable alternative, and trichloroacetic acid peel when stronger procedural options are suitable. [15]
Safety Profile and Adverse Effects
The 0.025% and 0.05% tretinoin demonstrate similar efficacy and safety profiles in the management of AN, with both concentrations being well tolerated with mild degree of local cutaneous irritation. [11] Overall, side effects with all tretinoin treatments were mild and went away on their own. [15]
Case Applications and Real-World Use
In a case of a five-year-old boy with type 1 diabetes mellitus presenting with atypical acanthosis nigricans skin lesions as tiny non-scaly brownish papules on the medial aspects of the upper thighs, daily tretinoin cream was started and proven beneficial. [16] In a case of unilateral nevoid AN in a 19-year-old female with asymptomatic brownish pigmented plaques on the medial side of the left submammary area, she was treated with topical tretinoin and her skin lesions were almost cleared 9 months after her first visit to the clinic. [17]
Methodological Comparison of Treatment Studies
The treatment efficacy studies on tretinoin for acanthosis nigricans have employed consistent methodological approaches. An 8-week, randomized double-blinded study used narrowband reflectance spectrophotometry to measure skin improvement through melanin (M) and erythema (E) indices at follow-up visits at weeks 2, 4, and 8, with improvements in Acanthosis nigricans scoring chart (ANSC), investigator- and patient-global evaluation (IGE and PGE), and adverse cutaneous irritations also scored. [11] An 8-week trial, double-blind, randomized, comparative study used the Mexameter MX18 for assessing treatment efficacy and the global evaluation scale to evaluate the overall success rate at weeks 2, 4, and 8 of the study. [12] A systematic review of randomized controlled trials assessed topical urea (10–20%), tretinoin (0.025–0.05%), salicylic acid (10%), and chemical peels such as glycolic acid (35–70%) and trichloroacetic acid (15%) over 8 weeks to 2 months, primarily on the neck and axilla, with outcomes including melanin and erythema indices (M/E), ANASI/ANSC scores, Investigator’s and Participant’s Global Evaluation (IGE/PGE), and adverse events. [15]
Research Gaps and Future Directions
Several important research gaps remain in the treatment of acanthosis nigricans with tretinoin. While insulin resistance is present in AN patients, the association between IR and AN severity is not significant enough to qualify AN as a screening tool for IR, highlighting the need for further exploration of the AN-IR relationship. [6] Neither tretinoin nor glycolic acid was significantly effective for neck lesions in some trials, though tretinoin was more efficacious for axillary lesions, suggesting that anatomical location may influence treatment response in ways that require further investigation. [14]
Additionally, the choice of therapy for AN may be individualized based on comparative effectiveness results, with tretinoin recommended for predominant hyperpigmentation and urea for alternative presentations. [15] Long-term follow-up data comparing sustained efficacy of tretinoin treatment versus other modalities are limited, and the mechanisms by which retinoids reduce melanin production and improve keratinocyte morphology in AN warrant deeper investigation.
Synthesis and Conclusion
Acanthosis nigricans represents a multifactorial dermatological manifestation intimately linked to metabolic dysfunction, with hyperinsulinemia, insulin resistance, and dysfunction of growth factor signaling pathways serving as central pathophysiological mechanisms. The disorder is characterized histopathologically by epidermal acanthosis with papillomatosis and hyperkeratosis, accompanied by increased melanin in the basal layer, reflecting the proliferation of both epidermal and dermal compartments.
Tretinoin at concentrations of 0.025–0.05% is effective for treating acanthosis nigricans, with tretinoin being most effective for reducing dark pigmentation especially on the neck, and patients being more satisfied with it than with glycolic acid. [15] The evidence supports tretinoin 0.025% as a well-tolerated, efficacious topical agent that achieves approximately 17–20% improvement in AN severity over 8 weeks of treatment, with similar efficacy profiles between 0.025% and 0.05% concentrations. The mechanism of tretinoin action in AN appears to involve normalization of keratinocyte differentiation and reduction of melanin production, though the precise mechanisms warrant further investigation.
Tretinoin demonstrates particular effectiveness in treating axillary and neck involvement when applied nightly, with mild and reversible adverse effects limited primarily to local cutaneous irritation. The evidence suggests that tretinoin should be considered a first-line topical treatment for AN characterised by predominant hyperpigmentation, though comprehensive management requires simultaneous attention to underlying metabolic dysfunction through weight loss, glucose control, and management of insulin resistance. Dermatologists may intervene by referring to primary care or by addressing underlying causes such as obesity and hyperinsulinemia, emphasising the importance of weight loss. [3] Future research should focus on identifying predictors of treatment response, optimising dosing schedules and formulations, and determining optimal combination approaches integrating topical retinoids with systemic metabolic management strategies.
Disclaimer: This content is for general information only and does not replace advice from your doctor, specialist, or pharmacist.
References:
