Development of actinic lentigines due to multiple sub-erythemal exposure to UVA1 radiation in Asian skin.

The appearance of actinic lentigines mainly found on face, back of the hands, upper back and décolleté is associated with chronic sun exposure. However, there is no study looking at the role of long UVA specifically in the development of actinic lentigines. This study was conducted in 20 Japanese adult women exposed on the upper back area three times per week for 6 weeks to incremental sub-erythemal UVA1 doses (5 J/cm2 at weeks 1 and 2, 10 J/cm2 at weeks 3 and 4 and 15 J/cm2 at weeks 5 and 6). Clinical assessment, performed on day 0 (before any exposure), and on days 14, 28 and 42, included the evaluation of skin pigmentation (pigmented spots), chromametry of the pigmented skin lesions and measurement of dyschromy. The number of pigmented spots and uniformity of the skin's pigmentation were clearly increased in comparison with baseline, statistical significance of the difference (p < 0.05) being reached at D 28 and D 42 in both cases. In conclusion, repeated sub-erythemal UVA1 exposure induces the development of actinic lentigines. Thus, a suitable protection including long UVA coverage is also needed to prevent from the damages induced by low, sub-erythemal doses of UV exposure.

Can we predict postinflammatory hyperpigmentation after laser treatment based on dermoscopic findings of solar lentigo?

Solar lentigo (SL) commonly occurs as hyperpigmented macules in areas exposed to ultraviolet radiation. It typically shows an increased number of melanocytes in the basal cell layer of the skin, with or without elongated rete ridges. This retrospective study aimed to evaluate the characteristic dermoscopic patterns, reflecting different histopathological features, which might be valuable in predicting the possibility of postinflammatory hyperpigmentation (PIH) occurring after laser treatment. In total, 88 Korean patients diagnosed with biopsy-proven SL (a total of 90 lesions were diagnosed) between January, 2016 and December, 2021 were included. Histopathological patterns were classified into six categories. Dermoscopic features were classified into six categories. Pseudonetwork pattern and rete ridge elongation showed a statistically significant negative correlation. This means that a flatter epidermis is likely to manifest as a pseudonetwork pattern. The erythema pattern showed a significant positive correlation with interface changes and inflammatory infiltration. Bluish-gray granules (peppering), a characteristic dermoscopic finding, showed significant positive correlations with interface changes, inflammatory infiltration, and dermal melanophages. Clinicians considering laser treatment for patients with SL should perform dermoscopic tests before treatment. The pseudonetwork relates to flattened epidermis and fewer Langerhans cells; thus, a lower remission of PIH after laser treatment might be expected. If bluish-gray granules or erythema are observed, inflammatory conditions are likely to be involved. In such cases, regression of the inflammatory response through drug therapy, such as topical corticosteroids, should be a priority option before laser treatment.

Q-switched frequency-doubled Nd:YAG (532 nm) laser versus trichloroacetic acid 35% peeling in the treatment of dorsal hand solar lentigo: An assessor-blind split-hand randomized controlled trial.

BACKGROUND: Solar lentigo (SL) is a benign hyperpigmented spot occurring due to ultraviolet exposure, most commonly in the elderly. We aimed to compare the safety and efficacy of trichloroacetic acid (TCA) peeling with Q-switched laser in the treatment of SLs. METHODS: This assessor-blind split-hand randomized controlled trial included 45 patients with symmetric SLs on the back of their hands referred to the dermatology clinics from March 1 to June 24, 2021. TCA 35% was applied to the back of one hand, and the contralateral hand received Q-switched laser. The interventions were repeated for a total of three sessions 4 weeks apart. Eight weeks after the last treatment session, lesion lightening was graded from 1 to 4. Patient satisfaction with treatment was assessed using a visual analogue scale (VAS). Adverse events were also noted. RESULTS: Of the 45 patients included in the current study with a mean age of 52.71 ± 9.73 years, 11 (24.4%) were male. The Fitzpatrick skin type was II in 11 patients (24.4%), III in 23 (51.1%), and IV in 11 (24.4%). Lesion lightening and patient satisfaction were both significantly better with Q-switched laser compared to TCA peeling (standardized mean difference [SMD] = -1.25, 95% confidence interval [CI] -1.69; -0.79, p < 0.001 and SMD = -1.12, 95% CI -1.56; -0.67, p < 0.001, respectively). Overall, post-inflammatory hyperpigmentation (PIH) occurred in one patient in the laser group and for in the TCA group. Also, erythema and pruritus were observed in all patients of both groups after intervention which were treated with topical repair cream. CONCLUSIONS: Q-switched laser was superior to TCA peeling for the treatment of SLs in terms of lesion lightening and patient satisfaction with a large effect.

Melanin accumulation in dermal stem cells deteriorates their exosome-mediated skin basement membrane construction in solar lentigo.

Solar lentigo (SL) is a hyperpigmented macule that occurs in sun-exposed areas and is characterized by the accumulation of melanin pigment in the epidermis. On the contrary, melanin-incorporated macrophages have also been identified in the dermis, which is thought to be caused by melanin transfer due to disruption of the basement membrane, but the detailed mechanism remains unclear. In this study, we analysed SL lesions by pathological methods and examined the mechanism of melanin accumulation in the dermis using cultured skin models in vitro. First, we observed a significant decrease in type IV collagen (COL4), a major component of the basement membrane, in SL lesions. The basement membrane is known to be formed by the interaction of keratinocytes and dermal cells. Therefore, we constructed skin models containing fibroblasts or dermal stem cells and examined their effects on basement membrane formation. The results showed a markedly enhanced production of COL4 mediated by dermal stem cell-derived exosomes. The analysis of melanin localization in the SL dermis revealed that CD163-positive macrophages and CD271-positive dermal stem cells both took up melanin pigment. Exosomes of dermal stem cells incorporating melanosomes were less effective in promoting COL4 expression. These findings suggest that while the promotion of COL4 production in keratinocytes by dermal stem cell-derived exosomes is important for maintaining basement membrane homeostasis, this mechanism is disrupted in SL lesions, leading to chronic melanin accumulation in the dermis.

Picosecond 755-nm alexandrite laser treatment for oral lentiginosis in Peutz-Jeghers disease.

We present the case of a 16-year-old boy with Peutz-Jeghers disease with successful treatment of oral lentiginosis with one session of picosecond 755-nm alexandrite laser. To date, only in one other article picosecond laser is used for lentiginosis in Peutz-Jeghers disease. Other therapeutical options include Q-switched 755-nm alexandrite, 1064-nm Nd:YAG, 532-nm KTP-laser, ruby and intense pulsed light, which generally require more sessions, are less pigment-selective and have overall worse results than picosecond laser treatment.

The clinical and electron microscopic evaluation of the impact of pulsed dye laser techniques on solar lentigines (randomized clinical trial).

BACKGROUND: Solar lentigines are skin lesions manifested by benign dark pigmentation causing a cosmetic problem in many patients. Several treatment modalities used for the management of solar lentigines. Side effects and rates of recurrence may be associated with them. OBJECTIVE: Treating solar lentigines with two different techniques of pulsed dye laser (PDL) and evaluation of the results both clinically and via the examination of ultrastructural changes by electron microscopy. PATIENTS AND METHODS: This study was conducted on 22 subjects with solar lentigines and having Fitzpatrick III-IV skin types, was managed by the use of PDL after enrolling them into two groups. Group I (one stacked PDL was used) and Group II (treated by stacked PDL in two sessions, 1 month apart). At baseline and 6 months after treatment, two punch biopsies with a diameter of 2 mm were taken from all patients. All taken biopsies were prepared for light and electron microscopic examinations. RESULTS: Both PDL techniques induced significant better clinical and histological outcomes. No one demonstrated any postoperative complications such as post-inflammatory hyperpigmentation and scarring. CONCLUSIONS: The two techniques of PDL are efficient for solar lentigines treatment.

Mitochondrial Secrets of Youthfulness.

SUMMARY: The genetic basis of youthfulness is poorly understood. The aging of skin depends on both intrinsic factors and extrinsic factors. Intrinsic factors include personal genetics, and extrinsic factors include environmental exposure to solar radiation and pollution. We recently reported the critical role of the mitochondria in skin aging phenotypes: wrinkle formation, hair graying, hair loss, and uneven skin pigmentation. This article focuses on molecular mechanisms, specifically mitochondrial mechanisms underlying skin aging. This contribution describes the development of an mitochondrial DNA depleter-repleter mouse model and its usefulness in developing strategies and identifying potential agents that can either prevent, slow, or mitigate skin aging, lentigines, and hair loss. The ongoing research efforts include the transplantation of young mitochondria to rejuvenate aging skin and hair to provide youthfulness in humans.

Increased melanocytic nevi and lentigines in two patients with harlequin ichthyosis.

An increased number of melanocytic nevi and lentigines have been reported in patients with two types of autosomal recessive congenital ichthyosis (ARCI): lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma. These melanocytic lesions may have clinical and dermoscopic features of atypia, necessitating close surveillance. Here, we report two interesting cases of pediatric patients with harlequin ichthyosis (HI) who developed increased melanocytic nevi and lentigines. These cases are unique in that the patients presented at a younger age and one patient had a darker skin phototype than previously described in the literature.

A cross-sectional analysis of skin cancer risk in patients receiving narrow-band ultraviolet B phototherapy: an evaluation of 100 patients.

Narrow-band ultraviolet B (NB-UVB) phototherapy is an effective and widely used treatment modality for psoriasis and other inflammatory skin diseases. The carcinogenic effect of PUVA treatment has been investigated extensively, but there is very scarce data about the role of NB-UVB in the development of skin cancer. The aim of this study was to investigate the potential carcinogenic risk of NB-UVB therapy in various skin disorders. In this cross-sectional study, we evaluated 100 patients who had received whole-body NB-UVB treatment and 100 age- and sex-matched controls. Phototherapy unit database was used to identify patients. A total of 100 patients (53 males and 47 females) treated with NB-UVB and 100 controls were included in the study. The patient group revealed no cases of melanoma or non-melanoma skin cancer, while ten of them were found to have solar lentigines. Basal cell carcinoma in a patient and nine patients with solar lentigines were detected in the control group. There was no statistically significant difference between patient and control groups in terms of skin cancer and solar lentigines. This study does not provide evidence for an increased skin cancer risk in patients treated with NB-UVB phototherapy. However, we have detected the occurence of 10 cases of solar lentigines. Still, definitive prospective longitudinal studies with a greater number of patients and prolonged follow-up are required to specifically address skin cancer risk in relation to NB-UVB phototherapy.

A Prospective Randomized Controlled Study of Oral Tranexamic Acid for the Prevention of Postinflammatory Hyperpigmentation After Q-Switched 532-nm Nd:YAG Laser for Solar Lentigines.

BACKGROUND AND OBJECTIVES: Q-switched (QS) 532-nm Nd:YAG laser is one of the treatment options for solar lentigines (SLs). However, the high incidence of postinflammatory hyperpigmentation (PIH) is concerning, especially in dark-complexioned skin. Tranexamic acid (TA) can decrease melanogenesis and has been used to treat melasma. The aim of this study is to evaluate the efficacy and safety of oral TA for PIH prevention and clearance in patients with SL treated with QS 532-nm Nd:YAG laser. STUDY DESIGN/MATERIALS AND METHODS: Forty patients with SL treated with QS 532-nm Nd:YAG laser were enrolled in this randomized controlled trial. They were randomly assigned to be receive oral TA 1,500 mg daily or placebo for 6 weeks. Results were evaluated by blinded investigators using digital photographs, dermatoscopy, colorimetry, physician grading scores, and patient satisfaction scores at baseline, 2nd, 4th, 6th, and 12th weeks. RESULTS: The incidence of PIH, relative melanin value, lightness index, and clinical improvement scores were not significantly different between the two groups. However, the TA group had a significantly lower incidence of dermatoscopic finding of pigmented granules, which correspond to PIH at 6th and 12th weeks (P = 0.038 and 0.013, respectively). Homogenous light brown pigmentation under dermatoscopy was significantly associated with higher clinical improvement. CONCLUSIONS: Oral TA therapy starting at the first day postlaser treatment is not effective for PIH prevention after QS 532-nm Nd:YAG laser in SL. However, PIH clearance, as assessed dermatoscopically, is significantly improved by oral TA at 6th and 12th week. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Melanocyte Activation Mechanisms and Rational Therapeutic Treatments of Solar Lentigos.

To characterize the pathobiology of solar lentigos (SLs), analyses by semiquantitative RT-PCR, Western blotting, and immunohistochemistry revealed the upregulated expression of endothelin (EDN)-1/endothelin B receptors (EDNBRs), stem cell factor (SCF)/c-KIT, and tumor necrosis factor (TNF)α in the lesional epidermis, which contrasted with the downregulated expression of interleukin (IL) 1α. These findings strongly support the hypothesis that previous repeated UVB exposure triggers keratinocytes to continuously produce TNFα. TNFα then stimulates the secretion of EDNs and the production of SCF in an autocrine fashion, leading to the continuous melanogenic activation of neighboring melanocytes, which causes SLs. A clinical study of 36 patients with SLs for six months treated with an M. Chamomilla extract with a potent ability to abrogate the EDN1-induced increase in DNA synthesis and melanization of human melanocytes in culture revealed a significant improvement in pigment scores and color differences expressed as L values. Another clinical study using a tyrosinase inhibitor L-ascorbate-2-phosphate 3 Na (ASP) demonstrated that L values of test lotion (6% APS)-treated skin significantly increased in SLs and in non-lesional skin with a significantly higher ΔL value in SLs when compared with non-lesional skin. The sum of these findings strongly suggests that combined topical treatment with EDN signaling blockers and tyrosinase inhibitors is a desirable therapeutic choice for SLs.

UV irradiation-induced DNA hypomethylation around WNT1 gene: Implications for solar lentigines.

Wnt/ß-catenin signalling promotes melanogenesis in melanocytes and also induces melanocytogenesis from melanocyte stem cells (McSCs). Previous study reported that WNT1, a ligand which activates Wnt/ß-catenin signalling pathway, was more highly expressed in the epidermis at SLs than in normal skin areas, suggesting that WNT1 causes hyperpigmentation. To elucidate the mechanism by which WNT1 expression is increased in SLs, we examined the methylation of 5-carbon of cytosine (5mC), that is 5-methylcytosine (5mC) level, in a region within the WNT1 promoter; the methylation of the region was known to negatively regulate WNT1 gene expression. We used an immortalized cell line of human interfollicular epidermal stem cells to analyse the effect of UVB irradiation on DNA methylation level of WNT1 promoter and found that UVB irradiation caused demethylation of WNT1 promoter and promoted WNT1 mRNA expression. It was also found that UVB irradiation reduced the expression of DNA methyltransferase 1 (DNMT1), an enzyme responsible for maintaining methylation patterns during cell division. Pathological analysis of SLs and non-SL regions in the human skin revealed that both DNMT1 expression and 5mC level were decreased at SLs compared to non-SL skins. Furthermore, bisulphite sequencing showed that the methylated CpG level in WNT1 promoter was also lower at SLs than in non-SL skins. Thus, in the skin exposed to a high amount of UV rays, excessive expression of WNT1 is thought to be caused by the demethylation of WNT1 promoter, and the upregulated WNT1 promotes melanocytogenesis and melanogenesis, then resulting in SL formation.

Efficacy and safety of intense pulsed light with a KTP filter for the treatment of solar lentigines.

BACKGROUND: Optical energy-based devices, including intense pulsed light (IPL) and potassium titanyl phosphate (KTP) lasers achieve reduction of pigmented and vascular lesions in a relatively similar number of treatments. This study aimed to evaluate the efficacy and safety of an IPL with a "KTP-like" filter emitting a wavelength of 525-585 nm for the treatment of solar lentigines on the hands and face. METHODS: This was a single center, prospective, open-label clinical trial including 16 healthy Caucasian subjects (15 females, mean age, 55 years; skin types II and III) with hand and facial solar lentigines. Subjects were treated with three IPL treatment sessions with a KTP-like filter conducted at monthly intervals. Follow-up evaluations were performed 1, 3, and 6 months after the last treatment session. Overall pigmentation improvement, pigmentation clearance per lesion, adverse events, and subject tolerability to treatment were evaluated. RESULTS: Significant improvements in facial and hand pigmentation were noted at all follow-up visits (P < 0.0001). One month after the last treatment session, good to excellent outcomes were noted in 74.6% of treated facial areas and 90% of treated hand regions. Although the effect of treatment gradually declined in both treatment regions over the 6-month follow-up period, over 60% of subjects demonstrated good to excellent results at the study end. Clinical effectiveness was further confirmed by the reduction in Melanin Index (MI) following each treatment as compared to baseline. Downtime and complications were minimal. CONCLUSIONS: IPL treatment with a KTP-like filter is a well-tolerated and effective method for reducing facial and hand pigmentation. Lasers Surg. Med. 51:500-508, 2019. © 2019 Wiley Periodicals, Inc.

CCN1/Cyr61 Stimulates Melanogenesis through Integrin α6ß1, p38 MAPK, and ERK1/2 Signaling Pathways in Human Epidermal Melanocytes.

Fibroblast-derived melanogenic paracrine mediators are known to play a role in melanogenesis. To investigate the effect of CCN1 (also called CYR61 or cysteine-rich 61) on melanogenesis, normal human epidermal melanocytes were treated with recombinant CCN1 protein. Our findings show that CCN1 activates melanogenesis through promoting melanosome maturation and up-regulation of MITF, TRP-1, and tyrosinase via the integrin α6ß1, p38 MAPK, and ERK signaling pathways. Furthermore, we found that UVB irradiation stimulates the secretion of CCN1 from normal human dermal fibroblasts, and CCN1 knockdown in fibroblasts attenuates melanogenesis in melanocyte-fibroblast co-culture system. Moreover, using immunohistochemistry and immunofluorescence staining, we discovered that CCN1 is overexpressed in the dermis of both solar lentigines and Riehl's melanosis lesions. These findings suggest that CCN1 is a fibroblast-derived melanogenic paracrine mediator that is secreted under UVB irradiation, and it may play an important role in the development of hyperpigmentation diseases such as Riehl's melanosis.