Topical retinoid therapy for acanthosis nigricans: In the thick of it

By Warren R. Heymann, MD
Dec. 11, 2019
Vol. 1, No. 39

At the risk of overgeneralizing, in my experience there are two types of patients with acanthosis nigricans (AN) — those who are devastated by it, and those are unaware that they have it.

This commentary will focus on utilizing topical retinoids for treating AN.

AN is characterized by thick velvety hyperpigmented plaques of the intertriginous, flexural, and (less commonly) extensor extremities. It is not a disease, per se, but rather a sign associated with systemic disorders, notably obesity, diabetes mellitus, insulin resistance, other endocrinopathies (polycystic ovary disease, Cushing syndrome, Addison disease, hypothyroidism, acromegaly), internal malignancies (paraneoplastic AN -usually adenocarcinomas — especially gastric, breast, lung, and endometrium), and medications (niacin, glucocorticoids, estrogen, testosterone, growth hormone). There are also rare, familial forms of AN. (1, 2)

Histologically, AN is characterized by minimal acanthosis, papillomatosis, epidermal hyperkeratosis, and an increased number of basal melanocytes. Hyperpigmention is usually the result of epidermal hyperkeratosis, but in some cases it may be due to an increased number of melanosomes within the stratum corneum. (3)

Although incompletely understood, the pathophysiology of AN involves multiple cytokines and signaling pathway crosstalk. Insulin or an insulin-like growth factor (IGF) have been implicated as promoters of enhanced epidermal cell propagation. Other mediators include fibroblast growth factor (FGF, notably in inherited AN) and tyrosine kinase receptors. In paraneoplastic AN, malignant cells secrete cytokines (notably transforming growth factor-α) that pathologically affect fibroblasts and keratinocytes. Additionally, α-melanocyte stimulating hormone may contribute to increased melanocyte pigmentation. (2) The cornerstone of treating AN, of course, is eliminating any precipitating cause, if possible (losing weight, discontinuing any implicated medications, treating an endocrinopathy, excising a malignancy, etc.). Aside from retinoids (topical and oral), calcipotriene, keratolytics (urea, salicylic acid), podophyllin, chemical peels (trichloroacetic acid), metformin, rosiglitazone, octreotide, and the alexandrite laser have been utilized. (1)

Topical retinoids are considered first-line treatment for AN. According to Balak, the pleotropic cellular effects of retinoids are mediated by two types of nuclear receptors: the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), both of which are present in three isoforms (α, β, and γ). Three generations of retinoids are distinguished: first, the nonaromatic retinoids, including tretinoin, isotretinoin, and alitretinoin; second, the mono‐aromatic retinoid acitretin; and third, the poly‐aromatic retinoids bexarotene, tazarotene, and adapalene. (4) All-trans and 13-cis retinoic acid bind all three retinoic acid receptors; adapalene and tazarotene interact preferentially with RAR β and RAR γ. (6)

Admittedly, I stopped prescribing topical retinoids for AN decades ago because patients complained that the irritation vastly exceeded any perceived benefit. I was intrigued by Treesirichod et al, who performed an 8-week, randomized, split-neck, comparative study between topical 0.1% adapalene gel and 0.025% tretinoin cream for the treatment of neck hyperpigmentation associated with AN. Regarding treatment efficacy, 90.0% and 85.0% of participants had more than 75% improvement for 0.1% adapalene and 0.025% tretinoin treatment sides, respectively. The major adverse reaction was mild cutaneous irritation for both drugs, which was mostly observed in the first two weeks, gradually improving by the end of the study. The authors concluded that there was no significant difference between topical 0.1% adapalene gel and 0.025% tretinoin in the treatment of AN. (5)

Trifarotene, a novel first‐in‐class fourth‐generation topical retinoid, is a selective RAR γ agonist. In multiple mouse models trifarotene exhibited superior comedolytic, anti‐inflammatory, and depigmenting activity compared with other topical retinoids. Theoretically, by being a selective RAR‐γ agonist trifarotene could avoid RAR‐β‐mediated skin irritation. (4,6). In 12-week trials for moderate facial and truncal acne, trifarotene was statistically significant for efficacy; local irritation (erythema, scaling, dryness, stinging, burning) was manageable in the first weeks of treatment, improving thereafter. (7)

First impressions count. In fifth grade, my class was assigned Ernest Hemingway’s Pulitzer Prize winning Old Man and the Sea. I was bored silly and vowed never to read his work again. Decades later, when visiting Papa Hemingway’s cat-riddled study in Key West, it occurred to me that I was rather presumptuous and may not have had the maturity to recognize genius. I bought a copy of For Whom the Bell Tolls — his depiction of guerilla warfare of the Spanish Civil War is the most riveting writing I have ever read. My initial impression of retinoids for AN may have also been presumptuous. I plan on giving topical retinoids another try, and especially look forward to utilizing trifarotene, when available.

Point to Remember: Despite their local side effects, topical retinoids may be effective for acanthosis nigricans. Perhaps the new selective, fourth-generation retinoid, trifarotene, should be assessed for this cosmetically challenging disorder.

Our Expert’s Viewpoint

John J. DiGiovanna, MD
Senior Research Physician
National Cancer Institute
Center for Cancer Research

I love Dr. Heymann’s analogy between his evolving opinions about acanthosis nigricans (AN) treatment and reading Hemingway. Not only because it reminded me of the fecund felines at the Hemingway House in Key West (definitely worth a visit), but because it illustrates that while the novelist effectiveness probably did not change — perceptions can.

Just as Dr. Heymann, I also lost faith in topical retinoid treatment of AN, largely because, despite their motivation, I never found patients who considered the benefit sufficient to continue long term. But in a study (5) performed without controls, a measurable change was detected when compared to pre-treatment. Uncontrolled studies are not solid evidence. Measurable, but minimal, change may not be sufficient for clinically significant efficacy, especially when measured by the person paying for the tube. Perhaps the retinoid effect on AN did not change, but the evidence on which we are basing our perception is different. A “published study” sounds like it should be good evidence. And keeping an open mind and re-evaluating new data keeps our thinking resilient. While I continue to inform patients with AN that there is “some evidence” that topical retinoids may help, my enthusiasm has not changed. My assessment is that the more solid evidence is with Dr. Heymann’s initial expert clinical impression, my own experience, and that of the patients who could not find a way to make this treatment worth their effort.

1. Patel NU, Roach C, Alinia H, Huang WW, Feldman SR. Current treatment options for acanthosis nigricans. Clin Cosmet Investig Dermatol 2018; 11: 407-413.

2. Popa ML, Popa AC. Tanase C, Gheorghisan-Galateanu AA. Acanthosis nigricans: To be or not to be afraid (Review). Oncol Lett 2019; 17: 4133-4138.

3. Kutlubav Z, Engin B, Bairmov O, Tüzün Y. Acanthosis nigricans: A fold (intertriginous) dermatosis. Clin Dermatol 2015; 33: 466-470.

4. Balak DMW. Topical trifarotene: A new retinoid. Br J Dermatol 2018; 179: 231-232.

5. Treesirichod A, Chaithirayanon S, Wongjitrat N. Comparison of the efficacy and safety of 0.1% adapalene gel and 0.025% tretinoin cream in the treatment of childhood acanthosis nigricans. Pediatr Dermatol 2019; 36: 330-334.

6. Aubert J, Piwnica D, Bertino B, Blanchet-Réthoré S, et al. Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor- γ agonist trifarotene. Br J Dermatol 2018; 179: 442-456.

7. Tan J, Thiboutot D, Popp G, Gooderham M, et al. Randomized phase 3 evaluation of trifarotene 50 µg/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol 2019; 80: 1691-1699.