The role of reflectance confocal microscopy in the diagnosis and management of pigmentary disorders: A review.

BACKGROUND: Reflectance confocal microscopy (RCM) has quickly transitioned from a research tool to an adjunct diagnostic bedside tool, providing the opportunity for noninvasive evaluation of skin lesions with histologic resolution. RCM is an optical imaging technique that uses near-infrared excitation wavelengths and safe low-power lasers. En-face images of different skin layers (up to the superficial dermis) are acquired in grayscale based on the reflective indices of tissue components. Melanin has the highest reflective index (contrast) and appears bright on RCM. AIMS: We present a review of the current literature on the use of RCM in the diagnosis and management of pigmentary disorders. METHODS: We reviewed PubMed and Ovid Medline databases from January 2000 to June 2021, using MeSH key terms: "reflectance confocal microscopy, confocal laser scanning microscopy, pigmentary disorders, treatment, melasma, vitiligo, freckles, solar lentigo, lentigo, tattoo, complications, melanoma, skin cancers, pigmented lesions, post inflammatory, melanin, photoaging" to identify studies and review articles discussing the use of RCM in the diagnosis and management of pigmentary disorders. RESULTS: RCM findings of pigmentary disorders were divided into the following categories: (1) disorders of increased pigmentation (post-inflammatory hyperpigmentation, melasma, Riehl's melanosis, solar lentigines, ephelides, hori nevus, naevus of Ota, café-au-lait macules, melanocytic nevus, melanoma, nevus spilus, labial mucosal melanosis, and mucosal melanoma), (2) disorders of decreased pigmentation or depigmentation (post-inflammatory hypopigmentation, vitiligo, nevus depigmentosus, halo nevus), and (3) exogenous pigmentation (tattoo, ochronosis). CONCLUSION: RCM has been explored and proven valuable for the evaluation and management of pigmentary disorders including melasma, vitiligo, solar lentigines, tattoo, and tattoo-related complications.

Treatment of Lentigines: A Systematic Review.

BACKGROUND: Treatments for solar lentigines include topical and physical therapies, including chemical peels, lasers, intense pulsed light, and cryotherapy. A direct comparison of treatment methods and their efficacy is lacking. OBJECTIVE: To compare treatment efficacy and adverse events for different treatment modalities for lentigines. METHODS: Cochrane, MEDLINE, and Embase databases were searched on August 25, 2021. Studies were included if they met our predetermined population, intervention, comparator, outcomes, study design framework. Results are presented in narrative form. RESULTS: Forty-eight articles met the inclusion criteria, representing a total of 1,763 patients. Overall, combination-based treatments showed the greatest frequency of cases with complete response (65%, n = 299/458), followed by laser-based treatments (43%, n = 395/910), topical retinoids (21%, n = 12/57), cryotherapy (15%, n = 25/169), and peels (6%, n = 8/125). Adverse events occurred most commonly while using topical retinoids (82%, n = 23/28), followed by combination-based treatments (39%, n = 184/466), cryotherapy (33%, n = 47/144), laser-based treatments (23%, n = 173/738), and peels (19%, n = 21/110). CONCLUSION: Despite heterogeneity of included study designs, patient populations, treatment regimens, and outcome measures, our results suggest that combination-based treatments and laser-based treatments were the most efficacious treatment modalities. Although cryotherapy was previously considered first-line, our results show that it has substantially lower pooled response rates compared with other treatment modalities.

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.

Efficacy and safety of topical hydrogen peroxide 35% solution versus cryotherapy in the treatment of senile lentigo.

BACKGROUND: Senile lentigines (SLs) are hyperpigmented macules that predominantly affect the elderly. We aimed to compare the efficacy and safety of hydrogen peroxide35% solution with cryotherapy in the treatment of SLs. PATIENTS AND METHODS: This clinical trial included 33 patients with SLs referred to our center. Lesions of each side of the body were randomly allocated to receive 3 sessions of treatment with hydrogen peroxide or cryotherapy at a three-week interval. All patients were followed up 1 week after each round of treatment for the evaluation of side effects, the general effect of the treatment, and the general assessment of response to treatment. RESULTS: Thirty-three patients were included in this study with the mean age of 61.79 ± 4.59 years. Average and excellent effects were significantly higher with cryotherapy after the 2nd and 3rd sessions of treatment, respectively. Positive response to treatment was significantly higher with cryotherapy at all time points. Severe erythema was only observed with cryotherapy. Pigmentation was significantly more frequent with cryotherapy than with hydrogen peroxide at any time point (p < 0.001). Also, blisters were only seen with cryotherapy. Moreover, the pain score was significantly higher with cryotherapy at all time points (p < 0.001). Up to one week after the 3rd session of treatment, no recurrence of lesions occurred in any of the groups. CONCLUSIONS: Cryotherapy appears to be more efficacious for the treatment of SLs compared to hydrogen peroxide 35% solution; however, hydrogen peroxide seems to have fewer side effects.

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.

Cryopeeling versus trichloroacetic acid peeling in the treatment of solar lentigines: Effect on epidermal Langerhans cells.

Trichloroacetic acid (TCA) peeling may be effective in solar lentigines, but with concerns regarding potential tumorigenesis. Cryopeeling would be better with improving the whole sun-damaged skin. We aimed to compare the efficacy and safety of cryopeeling and TCA 35% peeling for treatment of solar lentigines and assess their influence on the number of epidermal Langerhans cells (LC). Twenty-five patients were treated with TCA 35% and cryopeeling on the right and left hands, respectively. Two sessions were done 3 weeks apart. Evaluations were scheduled at weeks 0, 3, and 6. Skin biopsies, taken before and after treatment, were evaluated histologically and immunohistochemically for the number of CD1a + epidermal LCs. Lentigines decreased after cryopeeling from the first session (p < .001), but after the second session with TCA peeling (p = .004). Cryopeeling produced significant lightening, compared with TCA (p = .015). Blistering, hyper/hypopigmentation were reported with cryopeeling, whereas only hyperpigmentation was noted after TCA peeling. The LCs remained at about the pretreatment number after cryopeeling (p = .058), though they decreased after TCA (p = .002). Cryopeeling provided faster and superior improvement of lentigines compared with TCA peeling. Furthermore, TCA seems to suppress LCs raising the concern for carcinogenic potential.

Laugier-Hunziker syndrome: complete clearance of mucosal lentigines with a single session of Q-Switched Nd:YAG laser.

Background: Laugier-Hunziker (LH) syndrome is a rare condition in which melanocyte overactivity produces lentiginous lesions of the lips and buccal mucosa. Objective: Given the paucity of reports on therapeutic options in LH syndrome, this case is herein reported to show the response to treatment with the Q-Switched Nd:YAG laser in a 32-year-old man with LH Syndrome. Methods: The Q-Switched Nd:YAG laser was used to treat the lentiginous lesions on the mucosal surface of the lower lips using a single pass at 532 nm. Results: There was complete clearance of the mucosal lentiginous lesions with a single laser session, and recurrence was not observed after 12 months. Conclusion: The Q-Switched Nd:YAG laser is an effective treatment option for cosmetic benefit in LH Syndrome.

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.

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.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo.

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation. Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16INK4A. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts. To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed. Results:In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation. Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation. SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation. Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment. Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts. Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation. These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.

Prospective study of removing solar lentigines in Asians using a novel dual-wavelength and dual-pulse width picosecond laser.

OBJECTIVES: Quality-switched (QS) lasers are known to be an effective treatment for removing solar lentigines, however, high incidence of post-inflammatory hyperpigmentation (PIH) is a concern in darker skin types. The objective of this study was to evaluate the efficacy and safety of a dual-wavelength and dual-pulse width picosecond Nd:YAG laser for removing solar lentigines in Asians. METHODS: This was a prospective, IRB-approved study. Twenty cases with solar lentigines on the face were enrolled for treatment and evaluated at 1- and 3-month after the final treatment. Results were assessed by blinded evaluators using a 5-grade percentage improvement scale and Melanin index (MI) measured by a reflectance spectrophotometer. A patient self-assessment questionnaire was also administered using a 5-grade improvement scale. Additional treatment was performed if the improvement was less than 75% or the lentigo partially remained after 4 weeks. Histological evaluation was performed to compare the differences between the current picosecond laser and a QS Nd:YAG laser 532-nm using light and electron microscopy. RESULTS: Forty-three lesions in 20 females, skin type III or IV, age 53.7 ± 9.75 were treated and evaluated. The laser setting was: 532-nm, 750 picoseconds, average fluence of 0.35 ± 0.06 J/cm [2] using a spot size of 3 or 4 mm. Forty lesions (93.02%) achieved over 75% clearance with a single treatment and the other three lesions (6.98%) needed two treatments. PIH occurred only in 4.65% of lesions. The average score of the blinded evaluators' assessment was 4.77 and 4.58 on a 5-grade percentage improvement scale. The patients' self-assessment rating was 4.76 and 4.67 on a 5-grade scale at 1- and 3-month follow-up, respectively. The improvement rate of relative MI (MI in the lesion minus that of the normal area) was 77.60 ± 36.27% and 76.93 ± 20.95% at 1-and 3-month follow-up. Histology showed vacuolar formation by both lasers in the epidermis that were different sizes between lasers. Electron microscopy showed destruction of melanosomes with surrounding tissue damage with the QS laser and without particular damage with the picosecond laser. CONCLUSIONS: To the best of our knowledge, this is the first study using a picosecond Nd:YAG laser 532-nm for removing solar lentigines in darker skin types that includes histological evaluation. Although there are many options to treat solar lentigines, our results suggest that picosecond laser with preferable endpoint determination can be a safer and more effective treatment over conventional treatments in Asian patients. Lasers Surg. Med. 50:851-858, 2018. © 2018 Wiley Periodicals, Inc.

Efficacy and Safety of Topical Pidobenzone 4% as Adjuvant Treatment for Solar Lentigines: Result of a Randomized, Controlled, Clinical Trial.

BACKGROUND/OBJECTIVE: This study aims at the evaluation of the efficacy and safety of a combination therapy based on pidobenzone 4% and fractional CO2 laser or cryotherapy in the treatment of solar lentigines and the prevention of eventual posttreatment hyperchromia. METHODS: Efficacy was clinically evaluated by grading the pigmentation level with the Skin Tone Color Scale (STCS), and by grading patients' impression through a Visual Analog Scale (VAS). RESULTS: Our study shows that the associated treatment was safe and that it improves the therapeutic results on solar lentigines and prevents postiatrogenic hyperpigmentation compared with physical therapy alone. CONCLUSION: The combination of cryotherapy and pidobenzone 4% has been found to be the most useful treatment.

A Prospective Trial Comparing Q-Switched Ruby Laser and a Triple Combination Skin-Lightening Cream in the Treatment of Solar Lentigines.

BACKGROUND: Quality-switched (QS) laser therapy is a safe and well-established treatment option for removing solar lentigines. Triple combination therapy (TCT) with the active pharmaceutical ingredients hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03% is often used for skin-lightening. OBJECTIVE: This prospective, open-label trial compares the efficacy and safety of a QS Ruby laser (QSRL) and a TCT in the treatment of solar lentigines. METHODS: In total, 15 patients with symmetrically distributed solar lentigines on the back of both hands were included. The lesions on the back of the right hand were treated in one or 2 sessions with a QSRL, the ones on the back of the left hand with a TCT for 7 weeks accompanied by UV protection. Clinical results were evaluated 4 weeks, 8 weeks, and 20 weeks after baseline. RESULTS: Treatment with QSRL provided significant lightening (p = .01) compared with TCT. Both procedures were generally well-tolerated. Comparing the side effects, the laser produced significantly more crusting and hyperpigmentation than the TCT. CONCLUSION: Both QSRL and TCT were capable in reducing solar lentigines in Fitzpatrick skin Type I to IV with an acceptable side effect profile. The QSRL provides faster, superior, and long lasting lightening compared with TCT.

Effects of topical application of B-Resorcinol and Glycyrrhetinic acid monotherapy and in combination with fractional CO2 laser treatment for benign hand hyperpigmentation treatment.

BACKGROUND: Hand solar lentigines are frequent benign lesions of elderly population, requiring longtime treatments with topical agents or laser to lighten. AIMS: The aim of this study was to evaluate and compare the efficacy of CO2 fractional laser photothermolysis followed by topical application of B-Resorcinol and Glycyrrhetinic acid vs. only topical B-Resorcinol and Glycyrrhetinic acid application for hand solar lentigines treatment. METHODS: Hand solar lentigines of eleven volunteers were divided into two groups: Group A spots received CO2 fractional laser photothermolysis followed by 4 weeks topical application of B-Resorcinol and Glycyrrhetinic acid, and Group B spots received only 4 weeks topical treatments. All hands were photographed, and hand solar lentigines scanned with dermatoscope at the beginning of the study (T0 ), 1 month after laser treatment (T1 ), and at the end of the study (T2 ) to document spots dimensions and color. A blinded dermatologist evaluated dermoscopic T0 and T2 images. The considered variables were assessed for significance by the nonparametric Mann-Whitney U-test. RESULTS: In all volunteers, investigators and blinded dermatologist's evaluation hand solar lentigines features improved, with no statistical differences in the two groups. CONCLUSION: Topical application of B-Resorcinol and Glycyrrhetinic acid is effective to lighten hand solar lentigines after 4 weeks of treatment, with or without a previous fractional laser photothermolysis.

A Multimodal Approach to Rejuvenation of the Lower Face.

BACKGROUND: Facial aging is multifactorial, including changes in all the anatomical layers of the face including bone, fat, connective tissues and skin. METHODS: An evaluation of the multifactorial causation of facial aging pointed to the need for a multifactorial approach to restoration and rejuvenation of the aging human face. RESULTS: The varied aetiologies of the expressions of facial aging require more interventions than a unipolar approach. Combinations of neuromodulators, three and two-dimensional fillers and energy based devices were discussed. Surgical interventions were also discussed but were not addressed in this paper. CONCLUSIONS: A multimodal approach to lower facial rejuvenation and restoration is discussed as the most effective and appropriate method to achieve noninvasive aesthetic treatment success.