Port-wine stains (PWS), an alternative name for capillary malformations, is a congenital slow-flow vascular anomaly and one of the most common skin vascular abnormalities (1, 2). PWS usually arises from impaired endothelial cell differentiation and progressive dilation of small venule-like capillaries, with its main characteristic being an increased number of dilated capillaries (3, 4). PWS occurs in 0.1% to 2% of newborns, with no gender predisposition (5). PWS typically manifests in children as flat, light pink, or red macules, which over time may undergo changes such as darkening, thickening, and the development of nodules (6, 7). For instance, the color may intensify and turn purplish in adulthood (8). Throughout the developmental and growth journey, PWS presents a dual harm to affected children. Physiologically, it can result in functional damage, such as hyperplasia of the lips or eyelid thickening that inhibits full closure (9, 10). Additionally, PWS may lead to severe diseases such as glaucoma and delayed visual development, resulting in potential vision loss (6, 11). Psychologically, PWS can instill a sense of stigma in the individuals and inflict distress on the family, profoundly undermining the children's overall well-being and quality of life (12, 13). Therefore, there is an urgent need to identify treatments for children PWS patients to alleviate the disease burden and enhance the overall health of children.

A multitude of treatments for PWS have been employed, such as cryotherapy, surgery, and radioisotope therapy (14). However, these methods often result in noticeable scarring and may even carry a possible risk of skin cancer, leading to their current non-recommendation as the primary treatment option (15). At present, the pulsed dye laser (PDL) is regarded as the gold standard for PWS treatment (16). Yet, with the accumulation of clinical experience, the limitations of PDL have become increasingly evident, characterized by suboptimal therapeutic outcomes and a high likelihood of recurrence (15, 17). An effective and safe treatment approach for PWS remains an unmet need. Photodynamic therapy (PDT) as a promising alternative to PDL has been proposed, particularly with hematoporphyrin monomethyl ether (HMME)-mediated PDT, which has become a primary method for treating PWS in China (15, 18). HMME, also known as hemoporfin, is a new generation of porphyrin photosensitizers (19, 20). Compared to the previous generation of PDT drugs (such as Photofrin® and hematoporphyrin derivative), HMME features a more stable structure, higher photodynamic efficiency, stronger photoactivity, faster clearance rate, and lower toxicity, and it has been widely used in PDT for PWS (21). Nonetheless, there are still inconsistent conclusions regarding the application of HMME-PDT in children. For example, Tan's study suggested HMME-PDT was well-tolerated and effective in Chinese children with PWS, recommending it as the first-line treatment for PWS (22). Whereas Gao et al. concluded that the current evidence was insufficient to support HMME-PDT as a preferred treatment for young children (18).

Based on the above research background, more clinical practice or prospective studies are needed in the future to evaluate and explore the use of HMME-PDT in the children population. To the best of our knowledge, current meta-analyses have mostly focused on comparing different treatment methods for treating PWS in the general population, without simultaneously concentrating on the safety and efficacy of HMME-PDT when applied in children (4, 18, 23). Accordingly, addressing the research gap mentioned, our study aims to comprehensively explore the efficacy and safety of HMME-PDT in treating children with PWS.

The research was meticulously planned and executed following the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework (24).

PWS not only inflicts physical and psychological harm on children but also severely impacts the quality of life of their families (42, 43). Although PDL is considered a first-line treatment for PWS, there is currently no unified international standard for the treatment of children with PWS (44). HMME-PDT, a novel treatment method for PWS recently proposed in China, holds great potential (45). Consequently, this study explored the efficacy and safety of HMME-PDT in the children PWS population, with the main conclusions as follows: (1) More than half of the children had efficacy I (improvement ≥ 60%), but less than 20% of children achieved efficacy II (improvement ≥ 75%). (2) The younger the age at which treatment was administered, the better the therapeutic outcome. Furthermore, a greater number of treatment courses, specifically more than three, may yield improved efficacy. Additionally, treatment of PWS located on the face and neck, as well as those with lighter coloration, may demonstrate better outcomes. (3) After HMME-PDT treatment, virtually all children with PWS exhibited edema, over half developed purpura, some experienced crust and hyperpigmentation, and a minority presented with scar and hypopigmentation.

Over half of the children showed an improvement of more than 60%, demonstrating that HMME-PDT possessed a certain efficacy in the treatment of children with PWS. This was consistent with the findings of Chai and Tan, both of whom concluded that HMME-PDT showed good potential in the treatment of children with PWS (22, 27). Age was closely related to the growth and development of PWS (28). The study found that in both efficacies I and II groups, the proportion of efficacy in children aged 0–3 years was higher than in other age groups. The above result was similar to that of Lin et al., who found that efficacy decreases with age (46). Age has been correlated with the color, thickness, and nodularity of PWS lesions, with children tending to have thinner skin with better irradiation penetration and therefore better treatment outcomes (4, 47). Moreover, when analyzing the data by gender, observing the proportion of females achieving efficacy I (improvement ≥ 60%) was higher than that of males. However, in the efficacy II group (improvement ≥ 75%), a higher proportion of males was noted. Tan's study found that females had better treatment outcomes (22). Yet, in reality, few scholars have focused on the gender differences in HMME-PDT treatment for children with PWS, and conclusions regarding gender differences in efficacy cannot be firmly established. Therefore, future clinical or prospective studies are needed to examine the differences in treatment outcomes related to gender.

Consistent with the research by Huang and Chen et al., our study found that children with PWS who underwent a greater number of HMME-PDT treatment courses experienced better therapeutic outcomes (28, 30). The study by Lin et al. also indicated that the efficacy of 2 consecutive treatments was significantly higher than that of a single one (46). Furthermore, a subgroup analysis was conducted on the efficacy of PWS treatment at different anatomical locations. The results indicated that PWS located on the face and neck responded better than extremities or trunk, with a higher proportion of children showing improved outcomes. It was hypothesized that this may be due to the generally thinner skin on the face and neck, allowing light to penetrate more easily and thus facilitating the resolution of the lesions following treatment (4, 48). Similar to the research by Sun et al., their study found that the therapeutic effect of HMME-PDT was greatly influenced by the location of the PWS (35). But somewhat differently from ours, they believed that the efficacy on the face was not very effective. Furthermore, Zhang's research suggested that there was no significant difference in the therapeutic effect of PWS on the face, neck, and other parts of the body (17). The aforementioned differences were likely attributable to variations in the study populations, and the sample size also exerted a certain degree of influence. Ultimately, stratified analysis based on different types of PWS revealed that, consistent with the research by Zhang et al., purple or hypertrophic PWS types respond less favorably to HMME-PDT compared to pink or red types (17). It is widely acknowledged that the depth and thickness of blood vessels are the most critical factors affecting the treatment outcomes of PWS, with purple PWS often presenting thicker nodules, thus leading to poorer therapeutic results (15, 30).

In this survey, although almost all children experienced edema following HMME-PDT treatment, no severe adverse events were observed. Moreover, minor adverse reactions were likely to occur in most studies. For instance, in the research by Li et al., the side effects following HMME-PDT treatment were primarily manifested as edema, crusting, and excessive pigmentation (49). Besides, edema has been reported to be common in children and adults after PDT (4). In addition, the occurrence of purpura after treatment is also a normal and anticipated reaction, as it typically signifies that the abnormal blood vessels have been damaged and do not require special treatment (50). However, if further reactions occur, such as the skin turning grayish, medical intervention may be necessary (51). Hyperpigmentation and hypopigmentation also occurred partially in the children's population in this study, but there was no cause for concern as these reactions usually subsided within 2–6 months (48). Alternatively, concerning the recurrence of PWS, statistical analysis could not be performed due to the absence of data on recurrence in the original literature. In the included literature, studies by Tan (eight weeks after treatment), Zhang (with an average follow-up of 21.3 months), and Yu (with follow-ups ranging from 2–3 years) demonstrated no observed recurrences during the follow-up periods after HMME-PDT treatment (22, 25, 39). This suggested to some extent that the capillaries in PWS may suffer permanent damage that was difficult to repair after HMME-PDT, thereby preventing the recurrence of the condition (22). Although there was a study reporting no recurrences over an 18-year follow-up period post-PDT treatment, long-term follow-up studies specific to HMME-PDT were relatively scarce (52). Future long-term studies are essential to confirm the recurrence and progression of PWS in children patients treated with HMME-PDT. In summary, the aforementioned conclusions indicated that adverse events associated with HMME-PDT treatment for children with PWS were mild and transient. HMME-PDT is relatively safe for children with PWS. However, in the future, clinicians should consider taking appropriate measures early on when applying HMME-PDT to treat children with PWS, in order to address the mentioned reactions and safeguard the satisfaction of the patients as much as possible.

HMME, as a second-generation photosensitizer, possesses enhanced photodynamic effects, higher targeting specificity, lower toxicity, and reduced skin phototoxicity (25). In our study, HMME used as a photosensitizer in PDT for pediatric patients with PWS, demonstrated relatively good improvement effects. Most studies also suggested that HMME-PDT was a safe and effective method for the clinical treatment of PWS, indicating that HMME had certain advantages in treating PWS-related lesions to a certain extent (25, 41). There exist photosensitizers with longer absorption wavelengths, such as indocyanine green (ICG) (53). Although studies have shown that ICG may be a promising photosensitizer for PDT, its application in the treatment of PWS is currently very limited in clinical practice and remains in the stage of clinical research and exploration (54). Significantly, while longer wavelengths are more effective in targeting deeper lesions, the current focus on the development and application of photosensitizers is predominantly in oncological treatments, with a scarcity of exploration in the context of PWS (55). Moreover, current research on various photosensitizers and their penetration depth in the treatment of PWS was very limited. Future scholars should focus on this area to promote further advancement in the field of PWS treatment.

Additionally, all cases of HMME-PDT for PWS treatment have been conducted in China, and our study has shown promising efficacy in children (18). Numerous studies have also demonstrated satisfactory outcomes across various populations. For instance, a study by Sun et al., which included 2,952 subjects aged from 8 months to 56 years, indicated that HMME-PDT for PWS is highly effective, with high cure rates and mild local reactions, making it a preferred treatment method (35). Yu et al.'s research similarly confirmed the effectiveness, safety, and good patient tolerance of HMME-PDT for PWS (25). However, Gao et al.'s study suggested that, across all age groups, the clearance rate of PDL was generally higher than that of HMME-PDT (18). PDL exerts its effect by emitting yellow light (such as 585 nm or 595 nm), which is preferentially absorbed by hemoglobin, leading to the selective closure of dilated capillaries in the upper dermis and subsequently causing the color of PWS to gradually lighten (56). Studies have shown that during PDL treatment, while blood vessels are damaged, local hypoxia is also induced, leading to the upregulation of hypoxia-inducible factor (HIF-1α) (19). HIF-1α triggers the transcription of vascular endothelial growth factor (VEGF) (57). VEGF, through the VEGF receptor-2 (VEGFR-2) signaling pathway, regulates angiogenesis, ultimately leading to the revascularization and reconstitution of blood flow in PWS vessels (58, 59). However, HMME-PDT involves the intravenous administration of the photosensitizer HMME, which accumulates and resides within the dilated capillaries (34). Subsequently, light of an appropriate wavelength is applied to generate oxygen-derived free radicals, selectively destroying the vascular walls of PWS without harming the surrounding tissues, thereby exerting a more effective therapeutic action (60). Therefore, although PDL is currently the standard treatment for PWS, recent studies have pointed out recurrences and patient resistance, leading to suboptimal treatment progress (61). Some studies even recommend HMME-PDT as the first-choice treatment for PWS over PDL (22). Peng et al.'s single-center retrospective study also indicated that HMME-PDT may be more effective in treating purple and red PWS than PDL, with the overall treatment effect for purple PWS being greater than that for red PWS (34). Notably, HMME-PDT requires high technical proficiency from physicians, and precise operation is necessary to avoid suboptimal outcomes. Therefore, HMME-PDT should be applied under the guidance of experienced doctors, adhering to expert consensus (62). In summary, given the ongoing debate about the efficacy and safety of HMME-PDT, larger-scale studies are needed in the future to further verify its exact effects in treating PWS.

This study addresses the efficacy as well as the safety of HMME-PDT for the treatment of PWS in children, for which, according to the search, there are no targeted studies of the mentioned research field for the time being. We expect this review to provide strong evidence for the medical care of children with PWS and to help reduce the physical and psychological damage to children as well as the emotional burden on families. However, our study also has certain limitations. Firstly, previous treatment history and the size of the lesions could potentially affect the therapeutic outcomes, but due to the limitations of the original literature, it was not possible to conduct a detailed analysis. Secondly, the majority of the included studies reported short-term efficacy, with a lack of long-term outcomes. Thirdly, all HMME-PDT studies conducted thus far have been carried out in China, hence caution should be exercised when generalizing these findings to other populations. Hence, more high-quality clinical studies dedicated to exploring the value of HMME-PDT for the treatment of children with PWS are needed in the future.

The meta-analysis discovered that over half of the children treated with HMME-PDT for PWS had an improvement ≥ 60% (efficacy I), with better outcomes observed in younger children who received longer courses of treatment, and facial/neck PWS and pink/red PWS improved better after treatment. Although most patients experienced edema after HMME-PDT therapy, there were no severe adverse reactions. Future large-scale, comprehensive prospective studies could be employed to validate the aforementioned findings, and clinicians should consider a multitude of factors when applying HMME-PDT for the treatment of children with PWS.