FormalPara Key Summary Points

Why carry out this study?

 Port-wine stains (PWSs) can have a significant impact on patients and their families, especially when they are associated with disfigurement and hypertrophy.

 We assessed the efficacy and safety of Hematoporphyrin monomethyl ether-photodynamic therapy (HMME-PDT) in adult patients in order to provide additional evidence on PWSs treatment options other than traditional methods.

What was learned from the study?

 HMME-PDT is an effective and safe treatment for adult patients with PWSs, particularly the purple type.

 Multiple HMME-PDT treatments might improve the response and cure rate.

Introduction

PWSs are congenital low-flow vascular malformations of the skin. Unlike hemangiomas, PWSs do not involute over time, but often continue to progress and evolve into adulthood [1]. At birth, PWSs are typically present as pink-to-red macules or patches; however, they often tend to darken in color with age [2, 3]. Two thirds of the affected individuals develop soft-tissue overgrowth and nodule formation, resulting in disfigurement, asymmetry, and spontaneous bleeding, which creates a tremendous emotional and physical struggle for patients and their families [1, 4,5,6]. In the past, PWSs were treated with surgery, cryotherapy, dermabrasion, isotope therapy, or copper vapor laser with minimal success, in addition to scar formation, and therefore are not widely applied [7]. Although pulsed dye laser therapy (PDL) is considered the gold standard treatment for PWSs, the cure rate is as low as 6%, and up to 30% of patients do not respond to the therapy [8]. Photodynamic therapy (PDT) is a photochemical interaction-based therapy that has recently become a treatment option for PWSs [9]. These photochemical interactions between light, photosensitizer, and oxygen result in the production of highly reactive oxygen-derived free radicals which cause capillary wall damage and vessel closures [10, 11]. Photocarcinorin is a first-generation photosensitizer that has been used to treat PWSs in combination with a light source; however, it has been associated with prolonged photosensitivity and scar formation [12]. Hematoporphyrin monomethyl ether (HMME, hemoporfin) is a novel porphyrin-related photosensitizer first developed in China that consists of two positional isomers of 7(12)-(1-methoxyethyl)-12(7)-(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-di-propionic acid and is clinically preferred over photocarcinorin due to its shorter photosensitivity period (2 weeks) [12, 13]. A previous retrospective study suggested that PDT is as effective as 585 nm PDL for pink PWSs in pediatric patients [14]. Another study suggested that HMME-PDT is an effective and safe treatment for pediatric patients with PWSs [9]. However, HMME-PDT effectiveness in adult patients with PWSs still needs further studies. Hence, we performed the current study to evaluate the efficacy and safety of HMME-PDT in treating adult patients with PWS.

Methods

Study and Patients

A retrospective single-center study was conducted at the Dermatology Department of Guangxi Medical University First Affiliated Hospital, Nanning, China from December 2017 to May 2020. Inclusion criteria were: adults with normal renal and hepatic functions and no previous therapy for PWS with laser, PDT, isotope, topical, or systemic treatment in the last 4 weeks. The exclusion criteria were: known allergy to HMME or its chemical ingredients, scar diathesis, severe hepatic or renal insufficiency. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. Written informed consent was obtained from all participants prior to enrollment. The demographic data of patients was collected and analyzed. Lesion color was determined based on photographs taken before treatment, and the type was identified based on clinical examination of the lesion. All patients were treated twice at 2-month intervals.

Preparations

Hemoporfin powder was obtained from Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co Ltd. All patients received skin tests as previously mentioned [15]. In brief, HMME was diluted in 10 ml of normal saline and 0.1 ml of solution (containing 10 mg HMME) was further diluted with 8 ml of normal saline to a final concentration of 125 µg/ml. Then, 0.1 ml diluent was injected into the inner side of one forearm, and normal saline was injected into the opposite side for a blank control test. A skin test reaction was observed 20 min later. Digital photographs of the lesions were collected and the photosensitizer dosage was calculated (5 mg/kg). The surrounding normal skin was covered with multiple layers of black fabric. No local anesthetics were used prior to the sessions and all patients wore protective goggles.

Intervention

Patients received a slow injection of photosensitizer via a venous pump for 10 min, the channel was then flushed with normal saline to ensure its entrance into the blood circulation. Immediately after injection, the treated area was fully exposed in a horizontal plane to a 532 nm LED green light (LED-IE, Wuhan YaGe Photoelectric Technology Co., Ltd) with a power density of 85–95 mW/cm2 for 20–25 min.

Post-Treatment Care

Ice-cold compressions were used to reduce pain and cool the skin. Mild topical corticosteroid cream (desonide) was prescribed for 3–7 days post treatment. Patients were advised to avoid strong light and sunshine, apply sunscreen, wear a hat, sunglasses, and cover up for at least 14 days post treatment.

Clinical Efficacy Evaluation

Digital photographs before and after treatment were taken using the same light source. In addition, standardized digital photos using VISIA skin imaging were taken. After two treatment sessions, three blinded dermatologists (not participating in the study) independently reviewed the photos. Efficacy evaluation standards: excellent efficacy, the color nearly or completely resolved in the treated area (≥ 90% improvement); good efficacy, the color significantly faded in the treated area (≥ 60 to < 90% improvement); fair, the color partially faded in the treated area (≥ 20 to < 60% improvement); no improvement, the color was mostly unchanged in the treated area (< 20% improvement) [16].

Follow-Up

Follow-up was conducted through an online group chat where patients could immediately report post-session reactions such as edema, crusts, or discolorations in the treated areas. Patients were scheduled for visits every 3 months to evaluate their renal and liver function.

Statistical Methods

Data were analyzed using SPSS 22.0 statistical software. For the comparison of response rates across groups, the χ2 and Fisher’s exact tests were used. p < 0.05 was considered statistically significant.

Results

Patients

A total of 72 adult Chinese patients with Fitzpatrick phototype III-IV were enrolled in the study. The average age was 24.36 (18–55 years) and 38.89% were males (28/72). None of the participating patients had received any form of treatment before the HMME-PDT treatment. Lesions were mainly located on the face (58 patients), followed by the forearm and fingers in 8 patients, neck in 4 patients, and extremities in 2 patients. In the majority of participating patients, the size of the skin lesions was within 0–10 cm (65 patients). Lesions were mainly of the purple flat type (65 patients), 5 of the purple hypertrophic type, and 2 of the nodular thickening type (Table 1).

Table 1 Demographic data (n = 72)
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Efficacy

After two HMME-PDT sessions, in the purple flat type group, excellent efficacy was observed in 7 patients (10.77%); good efficacy in 13 patients (20.00%); fair in 47 patients (64.62%), and no improvement in 3 (4.62%). All five patients with the purple and hypertrophic type showed fair efficacy (100%), and no efficacy was observed in patients with nodular thickening type (100%) (Fig. 1).

Fig. 1
figure 1

PWSs before and after two HMME-PDT sessions. A–D  excellent efficacy; E–H good efficacy in a case with purple flat type; I–L fair efficacy in a case with purple flat type; M–P no improvement in a case with nodular thickening type

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There were no differences in excellent and good efficacy response rates between male and female patients (p = 0.604), nor with their lesions’ size (p = 0.546). The excellent and good efficacy response rates in patients aged 20–30 years were higher than those in other age groups, it was the highest in patients with lesions located on the face and neck as compared to lesions on the extremities (p < 0.05), and higher in patients of the purple flat type than those of the purple and hypertrophic types (p < 0.05) (Table 2).

Table 2 Different characteristics of PWS and efficacy
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Adverse Effects

During treatment, all participants showed variable degrees of burning sensation and pain; two patients of the nodular thickening type could not continue the session due to severe pain. Consequently, general anesthesia was used in the next session. A variable degree of pruritus was shown by 66 patients. Those who experienced intensive pruritus were able to continue the treatment after cold spraying.

Follow-Up

Patients are being followed-up to date (≥ 1 year). All patients showed variable degrees of edema; purpura in the treated area was observed in 36 patients; crusting was observed in 11 patients, and 1 patient showed urticaria (Fig. 2). No other obvious systemic adverse reactions were observed. The majority of adverse reactions subsided within 2 weeks with general management. Patients’ liver and kidney function remained within normal values during the period of follow-up.

Fig. 2
figure 2

Post-treatment adverse effects: A, B intensive edema; C purpura; D crusting and purpura

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Recurrence was seen in three patients with flat purple type; one patient (~ 14.3%) from the excellent efficacy group 6 months after the session and two patients (~ 15.4%) from the good efficacy group 5–8 months after the session.

Discussion

We performed a retrospective analysis of 72 patients to investigate the efficacy of HMME-PDT in the treatment of PWS in adult Chinese patients with skin type III–IV. The results of our research showed that HMME-PDT is an effective and safe treatment for adult individuals with PWS, particularly the purple type.

Previous studies have shown that regardless of the lesion site, size, or type, the total effective rate of HMME-PDT treatment of PWSs in different age groups can be as high as 97.78% and 99.75% [17, 18].

Li-qiang et al. used HMME-PDT therapy to treat PWS in Chinese pediatric patients: 29.27% of patients showed an excellent efficacy (cured) after two HMME-PDT treatments, 41.46% showed good efficacy, and 19.51% showed alleviation (fair) where most of the patients were of the pink type [9]. Unlike the pediatric study, the majority of lesions in our study were of the purple flat type, and we gained an overall lower rate of excellent and good efficacy (10.77% and 20.00%, respectively). Yuan et al. achieved higher excellent and good efficacy (37.0%, 94.2%, respectively) treating adult patients with HMME-PDT; however, a copper vapor laser was used and the sample size was larger than the current study [14].

After two HMME-PDT sessions, we observed an overall higher response rate compared with ≥ 3 sessions of PDL in lesions from similar age groups and skin types reported in a previous study [19]. Irrespective of the small sample size, K. Gao et al. [20] reported a lower improvement response (fair) in a side-by-side comparison of PDL and PDT treatment of purple flat PWS lesions in adults (8–33% and 30–45%, respectively), demonstrating that PDT is at least as effective as and, in some cases, superior to PDL. In fact, Y. Han et al. recently reported that HMME-PDT is an alternative option for treating PDL-resistant PWSs [21]. In this study, compared with Gao et al. [20], we achieved better responses from a similar age group and lesion type (10.77% excellent, 20.00% good, and 64.62% fair).

According to our findings, patients with lesions on the face or neck had better efficacy rates than patients with lesions on the extremities. Gan et al. had similar findings and hypothesized that lesions located in thinner skin areas have easier irradiation penetration [9]. In this study, patients aged 20–30 years old showed better efficacy than those in other age groups. Furthermore, we found no correlation between the size of the skin lesion and the efficacy of the treatment.

The adverse effects observed during treatment included a burning sensation and pain, which could subside after applying a cold spray or treatment suspension. Local adverse effects after treatment included edema, which could be relieved with ice compression and greatly subsided within 7 days. Purpura usually resolved within 21 days, itching was relieved with oral antihistamines, and crusting would spontaneously fade 2 months later. Interestingly, none of the patients had post-treatment scar formation, and we have not observed any other systemic adverse reactions to date. It should be noted that the treatment needs strict post-treatment care, which might be easier to achieve with adult patients.

Recurrence was observed in three patients several months after treatment, where they received additional (1 ~ 2) sessions and have observed no recurrence to date. In our experience, multiple HMME-PDT treatments can improve the response rate.

The main limitations in our study were the small numbers of patients in some subgroups and the evaluation depending mainly on visual assessment. Therefore, the use of objective assessment tools such as chromameter and controlled trials with a larger sample size is needed to help investigate the real value of HMME-PDT and to further analyze the relationship between age, type, location, frequency, and number of therapy sessions in adult patients with PWS.

Conclusion

The current study demonstrates that HMME-PDT is an effective and safe treatment for PWS in adult patients, especially the purple type. Recurrence is possible; therefore, additional HMME-PDT sessions might be required for better efficacy in persistent PWS lesions.