Laser treatment for Cafe-au-lait Macules: a systematic review and meta-analysis

Cafe-au-lait macules (CALMs) are pigmented lesions found in 2–3% healthy newborns or patients with genetic diseases, such as neurofibromatosis type 1 [1] and Noonan syndrome [2]. They show as pigmented macules or patches [3]. Histologic changes seen in CALMs are subtle and nonspecific. There is increased basilar melanin pigment with either a normal number of melanocytes or melanocytic hyperplasia [4]. CALMs can be morphologically classified including their size, color, location, and border, which have an effect on their treatment response. Besides, CALMs could be a clue of many different genetic diseases including Neurofibromatosis type 1, Legius syndrome [5] and etc. Although CLAMs don’t have any side effects on health, they may cause a great effect on appearance, leading to low self-esteem and shame, so patients with CALMs always have difficulty to integrate into social life.

Nowadays laser is the mainstay treatment for CALMs. The mechanism of laser or light treatment for pigmented lesions is based on the selective photo-thermolysis theory which is proposed by Anderson et al. in 1983. It proposed that melanin in the epidermal is vaporized and broken by absorbing the energy of the laser so that the laser treatments are able to clean epidermal pigmented lesions [6]. Generally, the double-frequency neodymium-doped: yttrium aluminum garnet (532 nm Nd: YAG) laser, the ruby laser (694 nm), the alexandrite (755 nm) laser, and the neodymium-doped: yttrium aluminum garnet (1064 nm Nd: YAG) laser are most used. In practice, as the wavelength of the laser increases, the light is absorbed less but penetrates deeper. Therefore, the 532 nm and 694 nm are the most appropriate wavelengths for epidermal lesions, followed by the 755 nm and then the 1064 nm wavelength.

However, no clinical consensus has been reached on which wavelength is the best choice for treating CALMs and due to the limited sample size, the strength of the available evidence remains open to question. Thus, we conducted this comprehensive and systematic meta-analysis of published data on the efficiency and side effects of the laser treatment for CALMs. At the end of the article, on the basis of summarizing and thinking about previous studies, we put forward new ideas of CALMs treatment.

The yielded result demonstrated the laser treatment without differentiation of wavelengths could reach a satisfactory result with 75% of patients with CALMs presenting a clearance rate of more than 50%. When looking at the efficancy between different wavelength subgroups, QS-1064-nm Nd:YAG laser exhibited the best treatment capability with minimal side effects. However, according to the experience of our center, intense pulsed light (IPL) treatment sometimes achieves better results than QS-1064-nm Nd:YAG laser treatment. We, therefore, believe that the results of this meta-analysis should be referred to with caution and taken into account in conjunction with clinical experience. Further clinical studies with larger sample sizes are warranted to resolve such disagreements. Interestingly, in Yuichi Yoshida study [26], the treatment of pigmented lesions with Neurofibromatosis Type I (NF1) by intense pulsed-radio frequency (IPL-RF) in combination with topical application of vitamin D3 ointment resulted in moderate to good improvement in 6 of 8 cases(75%). This study indicates laser irradiation in combination with the topical application of ointment would be useful as a new modality for refractory CALMs.

This meta-analysis had some limitations, and the results should be interpreted with caution. Firstly, the heterogeneity of pooling clearance data was high, even with the subgroup analysis conducted between different wavelength groups, which indicated that not only the wavelength of lasers affected treatment effects but also many other factors influence the therapeutic efficacy. One one hand, the efficacy of laser treatment is significantly dependent on the customization of the treatment protocol for each individual, which is based on the expert experience and judgment of the dermatologist rather than a standardized criterion. However, the diversity and heterogeneity of reported treatment parameters, including energy, spot size, treatment sessions, and interval time, have made it challenging to perform a thorough sub-group analysis. According to our clinical practice, low fluence, optimal spot size and optimal interval time laser treatment will achieve better treatment results and minimize side effects. Specifically, the low-fluence (LF) QS-1064-nm Nd:YAG laser treatment which had a controlled energy of 1.6–3.5 J/cm², a large spot size of 6–8 mm with multiple-passed could reach the laser toning function [27] and avoided serious epidermal damage and adverse effects like hypopigmentation [30]. In Beak’s clinical trials [15], compared to other QS-1064 nm clinical trials, he selected a relatively medium spot size of 7 mm, lower fluence of 2.2–2.4 J/cm², quite long treatment sessions of 20–50 weeks, and relatively shorter interval of 1 week. 69% of patients in his study improved by > 95%, 26% improved by 76–95%, and 6% improved by 51–75%, which were much better than other clinical trials’ results [18]. On the other hand, the intrinsic properties of CALMs, including their shape, size, location, color, and distribution, are believed to impact the effectiveness of treatment, thereby presenting a potential source of heterogeneity in results. While the shape of CALMs has been established as a crucial determinant of therapeutic outcomes, as evidenced by previous studies [18]. Specifically, CALMs with irregular margins (resembling the coast of Maine) have demonstrated better treatment response compared to those with clearly defined borders (resembling the coast of California) [8]. Nonetheless, the limited availability of initial data linking intrinsic features of CALMs with treatment outcomes precludes a subgroup analysis of their influence on treatment efficacy [18]. Several studies have suggested that smaller CALMs exhibit superior therapeutic responses compared to larger lesions [8]. However, the results have not achieved statistical significance in some investigations [15]. Similarly, while some studies have linked the brown color of CALMs to better treatment outcomes [8], others failed to establish any significant correlation [7]. Facial lesions have also been shown to exhibit better responses to treatment than those found in other areas of the body [18], although these results were also controversy [15]. It is also worth noting that the subjective visual evaluation of CALMs by different dermatologists may affect the assessment of therapeutic efficacy.

Secondly, the sample sizes of the included studies were too small to be divided into different age groups. Given that children had relatively thin skin and lightly colored lesions which may result in better treatment efficacy, further studies with patient-level data could enable more accurate analysis results. Thirdly, the pain was a relatively subjective side effect that was qualitatively but not quantitatively evaluated in resource data, so it was not included in the analysis.

In conclusion, the current systematic review and meta-analysis demonstrated the efficacy and side effects of laser treatment for patients with CLAMs. Among all wavelength lasers, QS-1064-nm Nd:YAG laser treatment resulted in the best clearance rate and the lowest recurrence, hypopigmentation, and hyperpigmentation rate while compared to other wavelength laser treatments. Further large-scale, randomized controlled trials are needed to confirm our current results.

The current meta-analysis was performed according to the recommendations of the latest “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA 2020) [32]. And it was registered in the “International Prospective Register of Systematic Reviews” (PROSPERO) in 2022 (ID: CRD42022339049) and the detailed prespecified protocol is available upon request.