A 15% Trichloroacetic Acid + 3% Glycolic Acid Chemical Peel Series Improves Appearance of Hand Lentigines: An Evaluator-Blinded, Split-Hand Prospective Trial.

BACKGROUND: Improving the appearance of lentigines on the hands is a key component to hand rejuvenation. Soft tissue fillers revolumize hands, but do not address pigmentary changes. OBJECTIVE: This study investigated the effiacy of a 15% trichloroacetic acid (TCA) + 3% glycolic acid (GA) combination peel in improvement of appearance of hand lentigines. METHODS: A prospective evaluator-blinded, split-hand study was performed using a 15% TCA + 3% GA peel to treat patients with hand lentigines. Subjects received a total of 3 treatments at 4-week intervals on 1 hand, with the other hand serving as an untreated control. Final photographs were taken 12 weeks after the last treatment. Two blinded board-certified dermatologists graded improvement in hand lentigines using a 5-point scale. RESULTS: Eighteen of 20 patients completed the study (90%). The mean age was 64.4 years (SE 1.6, range 51-71). The mean pain scores were 3.8 (SE 0.4) on a 10-point scale (1 = no pain, 10 = extremely painful). Blinded evaluators correctly identified the after-treatment photographs in 16 patients (88%). Physician and patient-graded mean improvement of lentigines was significant for treated versus control hands ( p < .01). No adverse events were noted. CONCLUSION: A series of three 15% TCA + 3% GA peels are effective and safe in the treatment of hand lentigines.

Odyssey toward an understanding of acquired postinflammatory lentiginosis.

PURPOSE OF REVIEW: Acquired postinflammatory lentiginosis is a phenomenon that has been previously termed 'induction of lentiginosis in assorted dermatoses' or the ILIAD phenomenon. RECENT FINDINGS: Although some cases have been described as arising exclusively in those who applied topical calcineurin inhibitors (TCIs), other patients have presented with similar findings in other nonatopic disorders (contact dermatitis, psoriasis, lichen planus, focal dermal hypoplasia), and without antecedent use of TCIs. SUMMARY: Inflammatory skin disorders can produce localized areas of cutaneous lentiginosis, particularly as the inflammation retreats in response to treatment. This post-inflammatory lentiginosis or ILIAD phenomenon may be potentiated by use of topical and systemic anti-inflammatory medications, including TCIs, topical corticosteroids, methotrexate, and systemic biologic agents. Although this phenomenon has not been associated with melanocytic neoplasia, ongoing periodic monitoring for dysplastic changes is reasonable.

A Role for NRF2-Signaling in the Treatment and Prevention of Solar Lentigines.

BACKGROUND: Photoaging is premature skin aging resulting from oxidative stress generated by exposure to solar radiation. A key clinical feature is solar lentigines, areas of hyperpigmentation on sun-exposed skin. Skin pigmentation is determined by cross-talk between keratinocytes and melanocytes, which is exquisitely sensitive to oxidative stress. Toll-like receptor (TLR) signaling and NF-E2-related factor 2 (NRF2) signaling, an endogenous antioxidant system, serve as a bridge between the oxidative stress response and immune regulation. Moreover, TLR-mediated induction of IL-6 production has been shown to prevent ultraviolet (UV)-induced hyperpigmentation. METHODS: Shave biopsies of solar lentigines were obtained from 14 individuals. An additional 7 subjects applied broccoli sprout extract (BSE) containing sulforaphane daily or vehicle on photodamaged skin. Immunofluorescence staining was used to determine total and phosphorylated NRF2 in the lentiginous skin. Dermoscopy and Fontana & Masson staining were used to assess the effect of topical BSE on UV-induced pigmentation. Similar topical treatments were performed in a mouse model of UVB-induced hyperpigmentation utilizing WT, Nrf2-/-, or K14-Cre-ERT2IL-6Rαfl/fl C57BL/6 mice. RESULTS: NRF2 expression is altered in solar lentigines, and UV-induced skin pigmentation in humans could be ameliorated with topical BSE. Corresponding mouse models replicated the authors' clinical findings and identified a potential mechanistic link to IL-6Rα signaling in keratinocytes. CONCLUSION: The authors' findings suggest that dysregulation of NRF2 signaling is involved in the pathogenesis of UV-induced skin pigmentation and pharmacological activation of NRF2 may represent a potential therapeutic target in photoaging.

Familial gastrointestinal stromal tumors, lentigines, and café-au-lait macules associated with germline c-kit mutation treated with imatinib.

BACKGROUND: Familial lentiginosis syndromes are characterized by a wide array of manifestations resulting from activation of molecular pathways which control growth, proliferation, and differentiation of a broad range of tissues. Familial gastrointestinal stromal tumors (GISTs) are often accompanied by additional features like hyperpigmentation, mastocytosis, and dysphagia. They have been described with mutations in c-kit (most commonly), platelet-derived growth factor receptor A, neurofibromatosis-1, and succinate dehydrogenase genes. MATERIALS AND METHODS: We report on molecular characterization and tumor histopathology of two siblings in whom lentigines and café-au-lait macules were present along with multifocal GIST. Immuhistochemical analysis of CD34 and CD117 was performed on GIST biopsy samples from both siblings, while c-kit mutational analysis was done by PCR and direct sequencing on DNA from peripheral blood leukocytes of all family members and from paraffin-embedded gastric biopsy specimens of affected siblings. RESULTS: Histopathology revealed positive expression of CD117 and CD34. Mutational analysis showed the germline c.1676T>C mutation in c-kit exon 11, (p.(Val559Ala)), in the peripheral blood of both siblings and a second exon 11 mutation, c.1669T>A (p.(Trp557Arg)) in the tumor biopsy of one of them. Initiation of imatinib treatment resulted in striking resolution of their hyperpigmentation and a stable gastrointestinal disease in one of them. CONCLUSIONS: A c-kit mutational test in familial GISTs is indicated before initiation of imatinib therapy, as it can help predict tumor response to treatment.

Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo.

AIMS: Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice. Here, we describe a clinical study to evaluate the safety and efficacy of ATRA-MN in subjects with seborrheic keratosis or senile lentigo. MAIN METHODS: ATRA-MN was applied to the lesion site of each subject for 6h once per week for 4weeks. The skin irritation reaction was scored to assess adverse reactions and blood tests were performed to evaluate the presence of systemic adverse reactions. To assess the treatment effect using ATRA-MN, the desquamation and whitening ability of the investigational skin was observed. KEY FINDINGS: Desquamation of the stratum corneum was observed following four ATRA-MN applications at 1-week intervals, but ATRA-MN applications did not induce severe local or systemic adverse effects. SIGNIFICANCE: These results showed that ATRA-MN treatment is promising as a safe and effective therapy for seborrheic keratosis and senile lentigo.

The Effect of MCP-1/CCR2 on the Proliferation and Senescence of Epidermal Constituent Cells in Solar Lentigo.

Solar lentigo (SL) is a representative photoaging skin disorder. Alteration of the main epidermal constituent cells-keratinocytes and melanocytes-in relation to the photoaged dermal environment or chemokine/cytokine network is suggested as its pathogenesis. Among these, we focused on monocyte chemoattractant protein-1 (MCP-1), as it is known to be associated with tissue aging. For the first time, we report that the MCP-1 receptor, CCR2, is expressed in normal human melanocytes. In SL tissue, there was an increase of CCR2+Melan A+ melanocytes with positivity to Rb protein compared to peri-lesional normal skin. MCP-1 induced the proliferation of normal human melanocytes without a significant change in the melanin content. MCP-1 treatment in normal human keratinocytes showed an increase in senescence-associated ß-galactosidase staining and p53 and p21 protein expressions. In summary, MCP-1 may participate in the development of SL by affecting epidermal constituent cells, for example, by inducing melanocyte proliferation and keratinocyte senescence.

Photodynamic Photorejuvenation: A Review.

INTRODUCTION: Topical photodynamic therapy (PDT) is acknowledged to be a safe and efficient therapeutic option for the selective destruction of actinic keratosis and superficial carcinomas. Over the past 15 years, topical PDT has also been shown to be a possible method for "photorejuvenation." MATERIALS AND METHODS: An extensive review was performed of in vitro and in vivo (animals, organ transplant recipients, or immunocompetent patients) studies. RESULTS: The studies point to a high level of efficacy. Tone, lentigos, skin roughness, and moreover texture and fine wrinkles because of the effects of dermal remodeling are improved. Adverse effects are generally described as mild to moderate, without scarring, along with a fast recovery time. Patients with fair phototypes and a history of sun exposure and actinic damage of varying severity are the best candidates for this technique. Photodynamic photorejuvenation sessions can both rejuvenate their skins and also treat their visible or incipient UV-induced lesions. New protocols either with daylight use and/or previous intensification by laser or microneedling seem promising. CONCLUSION: The photodynamic rejuvenation technique seems to show excellent short-term efficacy and tolerability.

Silicone sheet containing all-trans retinoic acid and hydroquinone for the treatment of epidermal melanosis.

BACKGROUND: Although bleaching treatment using all-trans retinoic acid (RA) and hydroquinone (HQ) improves epidermal melanosis, the application of two medications and the irritant dermatitis induced by RA inconvenience patients. To overcome these problems, we developed a silicone sheet containing RA and HQ. OBJECTIVE: To compare the efficacy of a silicone sheet containing RA and HQ with that of conventional bleaching treatment. METHOD: Silicone sheets containing 1% RA and 5% HQ were applied at night during the bleaching phase of 4 weeks, followed by application of sheets containing 5% HQ during the healing phase of 4 weeks. Hemifacial epidermal melanosis, for which the sheets were applied, was compared with a contralateral face which was treated conventionally using RA and HQ. Twenty-four Japanese women who were enrolled in this study and followed up for more than 6 months were analyzed. RESULTS: RA/HQ sheets improved epidermal melanosis, as did the conventional bleaching method, but irritant dermatitis occurred less in patients treated using silicone sheets. CONCLUSION: RA/HQ sheets, which are easily applied to face skin, can improve epidermal melanosis to the same extent as conventional bleaching.

Efficacy of hydroquinone-free skin-lightening cream for photoaging.

BACKGROUND: Hyperpigmentation and solar damage remains a difficult problem to treat with topical agents. AIMS: To evaluate a novel skin-lightening complex (SLC) comprising four actives targeting melanin formation at multiple levels, namely disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine, in an oil-in-water emulsion cream. PATIENTS/METHODS: Skin-lightening complex was evaluated in 80 female subjects of skin types I-III with at least moderate mottled hyperpigmentation. After a wash-out period of 1 month with a sunscreen, the subjects added a cream containing the SLC for 12 weeks twice daily to entire face and continued the sunscreen use. RESULTS: Whereas there was no significant change during the wash-out period, the primary endpoint mottled hyperpigmentation decreased by 32% after the 12-week treatment period with the SLC cream. Secondary endpoints such as severity and number of lentigines, skin tone, and skin brightness also improved. In all, 57% of the subjects showed at least a moderate response, 17% did not improve, and 3% got worse after the treatment. CONCLUSIONS: The SLC cream was well tolerated, in particular when comparing with exfoliating or peeling agent containing skin-lightening products. When used with a daily sunscreen, this study confirms that the SLC represents an alternative to hydroquinone, retinoids, and many other skin-lightening actives.

NB-UVB (311-312 nm)-induced lentigines in patients with mycosis fungoides: a new adverse effect of phototherapy.

BACKGROUND: Lentigines are a common pigmentary disorder in adults and in patients treated by psoralen and ultraviolet A (PUVA) radiation. Their appearance following treatment with narrow-band ultraviolet B (NB-UVB) radiation has been reported in only two patients. OBJECTIVE: To describe the clinical and histological features of NB-UVB-induced lentigines their relation to dosimetry and the course of the eruption in patients with mycosis fungoides (MF). METHODS: The files of all patients with MF treated in our department in 2003-2010 were searched to identify those in whom lentigines appeared following monotherapy with NB-UVB radiation. RESULTS: Of the 73 patients with early stage MF identified, 10 met the study criteria. Lentigines were detected in skin previously involved by MF in seven patients, and in both involved and uninvolved skin in three patients. They appeared during therapy in three patients, after a mean of 56 exposures (range 50-61), and several months (mean 7.8) following completion of treatment in seven patients, after a mean of 69 exposures (range 32-157). Histopathological study of lesions from five patients revealed basal hyperpigmentation relative to adjacent normal-looking skin. Two lesions had a slight increased number of normal-looking melanocytes on immunohistochemical staining with melanoma cocktail. One lesion had elongated rete ridges. The lesions persisted throughout follow-up (mean 26.7 months) in 8 patients. CONCLUSIONS: Patients with MF treated with NB-UVB may acquire lentigines. As opposed to PUVA-induced lentigines which are a known common side-effect of long-term treatment, NB-UVB-induced lentigines are uncommon but appear earlier, even after a few months of treatment.

Analytic assessment under ultraviolet light of actinic lentigines under bleaching treatment.

BACKGROUND: Actinic (solar) lentigines are melanotic tumors frequently developed during photoaging on the dorsum of the hands. Bleaching (whitening) agents are commonly offered to fade their darker aspect. In general, regular colorimetric methods show poor sensitivity to disclose any bleaching effect. METHOD: The present randomized controlled study on 24 women was designed to objectively assess the clinical efficacy of a combination of bleaching agents on actinic lentigines. In the endeavor of improving sensitivity, the ultraviolet light-enhanced visualization (ULEV) method was used to derive analytical measurements of lentigo areas and darkness. The test product was a commercially available formulation associating glycolic acid, kojic acid, lipohydroxyacid, and a Vitreoscilla extract. The Analysis® Olympus and Adobe Photoshop® quantitative methods were applied to the ULEV pictures. RESULTS: Data indicated a rapid bleaching effect arising as early as after 1 month of daily applications. The effect progressively increased over 3 months of therapy. CONCLUSION: The presently described analytical method appears to be sensitive to document some bleaching effects on actinic lentigines.

A preliminary study of the local treatment of preneoplastic and malignant skin lesions using methyl jasmonate.

BACKGROUND: Jasmonates are plant stress hormones. These small hydrophobic compounds exhibit anti-cancer activities, in vitro and in vivo, against cancer cells of various histological origins. Moreover, they show a selective activity against transformed cells and affect drug-resistant cells as well. AIM: The aim of this study was to evaluate the activity of a powerful jasmonate derivative, that is methyl jasmonate. MATERIAL AND METHODS: Methyl jasmonate was applied topically on cancerous and pre-cancerous skin lesions from eight patients. RESULTS: Methyl jasmonate did not cause any meaningful local or systemic side effects. Three patients exhibited positive responses. Two patients had complete recovery and one had a recurrence of the lesion three months post treatment. CONCLUSIONS: Methyl jasmonate is a potentially promising novel topical treatment for prcancerous and cancerous skin lesions. Methyl jasmonate should be evaluated in a larger series of patients.

Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) harbor gain-of-function mutations of the c-kit tyrosine kinase receptor. Imatinib mesylate is an inhibitor of c-kit and is indicated in the treatment of chronic myeloid leukemia and GISTs. Reported adverse effects of imatinib include hypopigmentation, depigmentation, and hyperpigmentation. Although the exact mechanism by which these occur is unclear, it is likely that inhibition of c-kit leads to downstream inhibition of the tyrosinase gene promoter and thus to inhibition of pigment production. OBSERVATIONS: A 45-year-old woman with a history of multiple dysplastic nevi and lentigines was diagnosed as having familial GIST syndrome. Treatment with imatinib mesylate was started in an attempt to decrease the tumor load. Three months after treatment initiation, the patient noted a decrease in the number of pigmented lesions, lightening of the skin in her genital area, and graying of her terminal hair. CONCLUSIONS: The potential association between a specific genetic mutation and pigmentation changes secondary to imatinib therapy may account for the variety in presentation of this potential side effect. Further genetic studies paired with melanocyte-specific or c-kit-specific stains of affected tissue are warranted to better understand the relationship between the genetic mutation and the effect of imatinib on pigmentation.

Analytic quantification of the bleaching effect of a 4-hydroxyanisole-tretinoin combination on actinic lentigines.

BACKGROUND: Solar lentigines represent a common feature of photoaging, particularly on the back of the hands. Bleaching agents are usually proposed to lighten the shade of the lesions. METHODS: The study was randomized and designed to assess the effect of a bleaching solution containing 2% mequinol (4-hydroxyanisole, 4HA) and 0.01% tretinoin (Solagé). The formulation was applied twice daily for 3 months on solar lentigines present on the back of one hand. The lesions on the other hand were treated with the ethyl alcohol vehicle which served as a control. Clinical diagnosis was confirmed using dermoscopy. In addition, objective measurements of the hypermelanosis were performed at 1-month intervals during and after treatment. Clinical assessments were used as well as narrow-band reflectance spectrophotometry, image analysis of video-recorded ultraviolet light-enhanced visualization (ULEV method) and photodensitometry of the corneomelametry test. RESULTS: The multipronged assessment of the lesional color demonstrated a significant lightening effect of the 4HA/tretinoin solution. This was demonstrated after 2 months of treatment and was maintained at least 2 months after stopping treatment. CONCLUSION: Both the visual ratings and the objective bioinstrumental methods indicate the rapid lightening effect of the 4HA/tretinoin formulation. After stopping treatment, the rate of repigmentation appeared to have slowed compared to the depigmentation phase.