Efficacy of surgery combined with photodynamic therapy or triamcinolone acetonide for keloid treatment: An interim analysis of nine cases

Photodynamic therapy emerged in the 1900s and recently, it has been developed as a novel modality for treating tumors, precancerous lesions, hypertrophic skin diseases, vascular diseases and so on. We aimed to compare the efficacy and adverse effects of surgery combined with photodynamic therapy or triamcinolone acetonide injection for keloid treatment. This self‐controlled study included nine patients with keloids. Two keloid sites were selected for each patient: one site received photodynamic therapy (PDT group) and the other site received local triamcinolone acetonide injections (TA group). All the keloids were surgically excised. The Vancouver Scar Scale and pruritus and pain scores were assessed at 3 and 6 months, respectively. At 3 and 6 months postoperatively, the pruritus and pain scores decreased significantly (P < .01) and equally in both groups (P > .05). At 6 months postoperatively, the PDT group showed the following results: complete cure, one patient; significantly effective, four patients; effective, four patients; and ineffective, no patient (efficacy, 100%). The TA group showed the following results: complete cure, one patient; significantly effective, three patients; effective, four patients; and ineffective, one patient (efficacy, 88.9%). Between‐group differences were not significant (P > .05). Hyperpigmentation was observed (n = 2) in the experimental group, whereas menstrual disorders (n = 2), local capillary dilation (n = 1) and subcutaneous atrophy (n = 1) were observed in the TA group. Photodynamic therapy and local triamcinolone acetonide are equally and highly effective in treating keloids with few side effects and when combined with surgery.

and highly effective in treating keloids with few side effects and when combined with surgery.

K E Y W O R D S
local block, photodynamic therapy, surgery, treatment, treatmentkeloid, triamcinolone acetonide 1 | INTRODUCTION "Scar" is a collective term for changes in external appearance that occur as morphological and histopathological characteristics of the normal skin tissue, following trauma or injury. The formation of scars is a normal part of the body's self-renewal process; however, excessive scarring, also known as pathological scarring, is an abnormal manifestation. Keloids are a common type of recurrent or refractory pathological scar that exhibit cancer-like biological characteristics [1]. At present, topical drugs, lasers, compression therapy, surgery and radiotherapy, freezing and other methods are mostly used clinically, but the treatment effect is not satisfactory, and it is easy to recur, and there are side effects such as pigmentation, skin atrophy and thinning, and even rupture and necrosis to varying degrees.
Photodynamic therapy emerged in the 1900s, but it has only recently been repurposed as a novel modality for treating tumors. Increasing dermatological applications of 5-aminolevulinic acid photodynamic therapy have achieved favorable therapeutic effects in treating skin conditions, such as tumors, condyloma acuminata and acne.
In recent years, studies have reported the efficacy of photodynamics in the treatment of keloids, but most of them are individual cases or studies between different individuals. In this self-control study, we aimed to compare the clinical efficacy and adverse effects of two types of combined therapy in patients with keloids: surgical excision with photodynamic therapy and surgical excision with local triamcinolone acetonide injection.

| Participants
In this self-controlled study, patients with keloids on the shoulder or back who sought medical consultation at the dermatological department of our hospital between June 2020 and June 2021 were enrolled. Diagnosis of keloids was confirmed when one or more of the following diagnostic criteria were fulfilled: (i) skin damage that extended beyond the original wound area and involved the adjacent normal skin, (ii) scars that persisted for more than 9 months without signs of spontaneous resolution and (iii) scars that recurred after previous excision [2].
The inclusion criteria for the participants were as follows: individuals aged 18 to 60 years and presence of at least two keloids on the shoulder or back region. The exclusion criteria were as follows: no written informed consent; severely impaired cardiac, hepatic, or renal function; treatment at the selected keloid site in the previous 6 months; contraindications to glucocorticoid injections or photosensitive skin diseases; anticoagulant medication use; hemorrhagic, neurological, mental, hematological, cardiovascular or cerebrovascular diseases; and pregnant or breastfeeding women.
There were no restrictions regarding the sex of the participants. Patients were fully aware of the benefits and drawbacks of study participation and provided written informed consent. The study was conducted in accordance with the principles of the 1975 Declaration of Helsinki, as amended in 1983.

| Treatment methods
Two keloids were selected from the shoulder or back of each patient; one site was randomly assigned to the PDT group (photodynamic therapy) and the other site was assigned to the TA group (local triamcinolone acetonide injections). Complete excision of the keloids was performed under local anesthesia in both groups, with absorbable sutures used for subcutaneous tissue closure to minimize tension.
Immediately after surgery, photodynamic therapy was administered using the following protocol: 5-aminolevulinic acid was dissolved in a gel to prepare a 20% solution. The prepared solution was applied to the incision site, which was sequentially covered with cling wrap and lightproof black film. After 3 hr, the cling wrap and lightproof black film were removed. The excision site was then irradiated with 633 ± 10-nm wavelength light at 85 J/cm 2 for 25 min using a light-emitting diode therapy device (LED-IB; Wuhan Yage Optic and Electronic Technique Co, Ltd).
The TA group received triamcinolone acetonide injections at the surgical site and the skin adjacent to the incision. Triamcinolone acetonide injectable suspension (40 mg/mL, 0.5 mL) and lidocaine (2%, 0.5 mL) were drawn into a syringe and injected through the incision site into both sides of the wound. The injections were spaced 0.5 cm apart and 0.05 mL of triamcinolone acetonide was injected at each point until blanching was observed. Two weeks postoperatively, the sutures of both groups were removed, and photodynamic therapy and triamcinolone acetonide injections were administered again. The final treatment was administered 4 weeks postoperatively.

| Follow-up observations
All patients were followed up at 2 and 4 weeks and at 3 and 6 months postoperatively to assess their general condition and evaluate adverse effects. The Vancouver Scar Scale and pruritus and pain scores of the patients were determined at 3 and 6 months postoperatively [1].

| Criteria for assessment of clinical effectiveness
At 6 months postoperatively, clinical effectiveness was assessed based on the following indicators: (i) complete cure: disappearance of ≥80% of the lesion, flat and pliable local incision, and absence of pain and pruritus; (ii) significantly effective: disappearance of ≥50% of the lesion, presence of pain and pruritus, and pale red appearance in the local skin region; (iii) effective: local recurrence not extending beyond the original wound area and presence of pain and pruritus that improved after treatment and (iv) ineffective: local recurrence that extended beyond the original wound area and presence of pain and pruritus that did not improve after treatment.

| Statistical methods
All data were statistically analyzed using SPSS version 19.0 (IBM Corp., Armonk, NY). Quantitative data were compared using the rank-sum test and categorical data were compared using the chi-square test. P < .05 was considered significant.
After three treatment sessions, the Vancouver Scar Scale and pruritus and pain scores of the PDT and TA groups at 3 and 6 months postoperatively were significantly lower than the corresponding pretreatment scores (P < .01). However, the intergroup differences were not significant (P > .05) ( Table 1 and Figure 1).
The 6-month postoperative efficacy assessment results for the PDT group were as follows: complete cure, one patient; significantly effective, four patients; effective, four patients; and ineffective, no patients (effective treatment rate, 100%). The results for the TA group were as follows: complete cure, one patient; significantly effective, three patients; effective, four patients; and ineffective, one patient (effective treatment rate, 88.9%). The between-group difference in treatment efficacy was not significant (P > .05), as demonstrated in Figures 2 and 3.
The adverse effects of the two types of treatment were as follows: (i) in the PDT group, obvious local hyperpigmentation was observed in two patients after the three treatment sessions, but reduction in hyperpigmentation T A B L E 1 Vancouver Scar Scale item scores and pruritus and pain scores of the two groups before treatment and at 3 and 6 months postoperatively was observed at 6 months postoperatively and (ii) in the TA group, local capillary dilation was observed in one patient at 3 months postoperatively, and two patients experienced menstrual disorders with an approximately 2-week delay in menstrual bleeding that spontaneously resolved without intervention, and atrophy of the subcutaneous tissue was observed in one patient.

| Discussion
Histopathological features of pathological scars include an increased number of fibroblasts in the dermis, disordered arrangements of collagen fibers and formation of collagen nodules among certain collagen fibers, which may be accompanied by angiogenesis. While the etiology of pathological scars remains unclear, several researchers have demonstrated that it is mainly related to fibroblasts, cytokines and blood supply; individual differences and wound care have also been identified as key factors [3][4][5].
Keloids, a type of pathological scar, also have an unclear etiology. Although various treatment methods exist, including local blockage, excision and local radiation therapy; none are truly effective in the treatment and prevention of keloid recurrence [4][5][6][7]. As such, surgical therapy is commonly performed in clinical settings. However, the use of surgical excision as single-modality therapy triggers collagen deposition during the woundhealing process, resulting in a high recurrence rate. Although most researchers consider surgery as the first line of therapy for medium and large keloids, they recommend its use as a part of combination therapy rather than as monotherapy.
Following surgery, keloid treatment should focus on preventing recurrence, which offers multiple benefits, such as enhanced therapeutic effects, significantly shorter treatment duration, reduced adverse drug effects and lower recurrence rates [4,[8][9][10]. Photodynamic therapy is a novel and noninvasive method to treat pathological scars, which involves the local application of a photosensitizer (5-aminolevulinic acid) at the lesion site under occlusion, which is absorbed and converted to protoporphyrin IX by local and actively proliferating cells, such as fibroblasts. Upon exposure to light of certain wavelengths, protoporphyrin IX reacts with oxygen molecules, producing reactive oxygen species and free radicals that damage actively proliferating cells [10][11][12].
Other studies have indicated that photodynamic therapy exerts anti-infective, anti-inflammatory and antiimmune factor-like effects on keratinocytes and fibroblasts and can inhibit angiogenesis in tissues [13,14]. Photodynamic therapy also reduces the expression of collagen types I and III, increases the expression of matrix metalloproteinase-3 and tropoelastin [15], and induces superoxide anion-dependent autophagic cell death [16], thereby inhibiting scar formation. Various in vitro and in vivo studies have further demonstrated the therapeutic effects of photodynamic therapy on keloids [17][18][19][20][21][22]. Although there have been many studies reporting photodynamic research in the treatment of keloids, the efficacy is mixed and most of them are reported in individual cases. There are fewer self-controlled studies and fewer self-controlled studies of combined surgery. At present, local triamcinolone acetonide injection is the most commonly used treatment modality for keloids in clinical settings, as it promotes collagen and fibroblast denaturation and induces apoptosis [23,24].
In the present study, the PDT group was administered photodynamic therapy using 20% 5-aminolevulinic acid immediately after surgical excision, to enable adequate drug penetration into the tissues to achieve optimal effects on the fibroblasts, which may undergo rapid growth shortly after the surgery. Currently, different treatment frequencies have been adopted in clinical settings. After considering the findings of previous studies and practical experience, we selected a treatment frequency of once per fortnight, with treatment performed three times in each patient. Our observations revealed that these three photodynamic therapy sessions resulted in the inhibition of scar formation. The same treatment frequency was adopted for the TA group, who received classical triamcinolone acetonide injection therapy to achieve more contrasting significance [23,24].
A major challenge in keloid treatment is the high tendency for recurrence; therefore, we performed follow-up at 3 and 6 months after surgical excision. At 6 months postoperatively, the effective treatment rates of the PDT and TA groups were 100% and 88.9%, respectively. However, our results indicated that differences in the F I G U R E 2 Appearance of keloid scars, A, before the combined photodynamic therapy and surgery, B, 6 months after the combined photodynamic therapy and surgery, C, before the combined triamcinolone acetonide injection and surgery and D, 6 months after the combined triamcinolone acetonide injection and surgery F I G U R E 3 Appearance of keloid scars, A, before the combined photodynamic therapy and surgery, B, 6 months after combined photodynamic therapy and surgery, C, before the combined triamcinolone acetonide injection and surgery and D, 6 months after the combined triamcinolone acetonide injection and surgery treatment effects of both groups at 3 and 6 months postoperatively were not significant.
Keloids not only adversely affect esthetic appearance but also cause pruritus and pain, thereby affecting the patient's quality of life. In the present study, one patient complained that the pain had severely affected sleep quality. Therefore, in addition to reducing scar size and improving esthetics, the alleviation of pruritus and pain is also a key treatment goal. A previous study indicated that photodynamic therapy significantly reduced the expression of runt-related transcription factor 3 (RUNX3) in keloid tissues, which is closely associated with sensations of pain and pruritus in scars [19]. The pain and pruritus scores of patients after each treatment session revealed that these symptoms were significantly alleviated within 2 weeks following the first treatment session and remained mild until 6 months postoperatively in both groups. Two patients in the PDT group experienced pruritus after the photodynamic therapy; however, the symptoms spontaneously resolved within a few days.
Photodynamic therapy may result in adverse effects when used alone, including burning pain, redness and swelling, ulceration, or hyperpigmentation in the lesions and surrounding tissues. Hyperpigmentation is an inevitable adverse effect when photodynamic therapy is used for the treatment of various skin problems. In the PDT group, hyperpigmentation occurred in two patients but subsequently resolved at 6 months postoperatively. One patient in the TA group exhibited obvious capillary dilation on the skin surface, two patients experienced menstrual disorders and one patient exhibited atrophy of the subcutaneous tissue after three triamcinolone acetonide treatment sessions. As no other possible factors were present in this study, we deduced that these adverse effects were related to steroid treatment, as they were also commonly associated with local application of glucocorticoids [4,24].

| CONCLUSION
Although the pathogenesis of keloids and the underlying therapeutic mechanisms of many treatment methods are unclear, we remain steadfast in our efforts to discover and apply newer and more promising therapies, such as photodynamic therapy. The results of this comparative study indicate that photodynamic therapy not only provides favorable therapeutic effects but also has fewer adverse effects. Long-term photodynamic therapy studies involving larger cohorts aimed at enhancing treatment outcomes for keloid patients are required in the future. The findings of this study revealed that compared with local injection of triamcinolone acetonide, photodynamic therapy is a promising treatment method.

AUTHOR CONTRIBUTIONS
Qi Jing and Lin Xing-xiao were involved in investigation, writing, review and editing. Li Cheng-xin and Xie Fang were involved in conceptualization. Hao Yong-hong, Liu Peng-xiang and Tang Li-chuan were involved in investigation.