Er:YAG laser combined with botulinum toxin A for patients with local syringomas: A preliminary report

Syringoma is a common but refractory benign skin tumor. Conventional treatment, such as ultra‐pulsed carbon dioxide (CO2) laser or cryotherapy, often requires multiple treatment and can easily cause prolonged erythema, scarring, or depression, which are frustrating, so there is an urgent need to seek a safer and more effective method. In this article, we tried to demonstrate the Er:YAG laser combined with botulinum toxin A (BTXA) as a safer and more efficacious method for treating syringomas. Materials and methods: Twenty‐one patients with local syringomas were treated with erbium laser ablation. Immediately after laser treatment, approximately 10 units of BTXA were sprayed on the wound for 10 min. Result: In total, 21 patients underwent 1.62 ± 0.74 treatments; their Periorbital Syringoma Severity Index (PSSI) score declined from 4.19 (before treatment) to 1.10 (after treatment), and the number of treatments was significantly lower than those reported in previous literature using the erbium laser alone. Conclusion: The Er:YAG laser combined with botulinum toxin A for the treatment of syringoma is a safer and more effective treatment than traditional treatment methods.

Materials and methods: Twenty-one patients with local syringomas were treated with erbium laser ablation.Immediately after laser treatment, approximately 10 units of BTXA were sprayed on the wound for 10 min.Result: In total, 21 patients underwent 1.62 ± 0.74 treatments; their Periorbital Syringoma Severity Index (PSSI) score declined from 4.19 (before treatment) to 1.10 (after treatment), and the number of treatments was significantly lower than those reported in previous literature using the erbium laser alone.Conclusion: The Er:YAG laser combined with botulinum toxin A for the treatment of syringoma is a safer and more effective treatment than traditional treatment methods.

K E Y W O R D S
botulinum toxin, Er:YAG laser, laser ablation, syringoma damage to the surrounding tissues during treatment, which often leads to skin scarring or depression.A fractional laser and radio frequency were also used but could not be completely removed, as reported in the literature.The Er:YAG laser seemed to be a better choice, as it induced less thermal damage with a very thin layer of coagulation. 3cently, several studies reported using botulinum toxin A topical injection for the treatment of syringoma.The results showed good results, but there is a risk of possible drug effects on the periocular muscles, such as eyelid ptosis, brow ptosis, ectropion, or strabismus. 4To date, there is a lack of abundant evidence on the safety of BTXA treatment in periorbital syringoma, so we tried using an Er:YAG laser combined with BTXA transdermal delivery for the treatment of syringomas.

| ME THOD
Twenty-one female patients with periorbital syringomas with Fitzpatrick III or IV were included in the study.Their ages ranged from 21 to 50 years, with scattered-, dense-or fused-type syringomas in the eyelid, forehead, and upper cheek.The treatment was performed in the Plastic Surgery Department of Zhejiang Province Hospital or YiJia Dermatology clinic.
The exclusion criteria included: patients who were under the age of 18 years, had used systemic isotretinoin within the previous 6 months, were treated with a topical agent except topical antibiotic ointment and BTXA, had a propensity for keloids, were pregnant or immunosuppressed, had generalized eruptive syringomas, or had a history of allergy to botulinum toxin type A.
Topical anesthetic (EMLA cream) was used as a local anesthetic and was applied to the treatment areas for 45 min before laser treatment.An intraocular shield was not needed in our treatment, when the lesions lies nearby eyelid margin, an assistant was asked to using a cotton swab containing salt water closing to the eyelid margin for protecting the eyeball.Then, an Er:YAG laser (SP Dynamis device, Fotona, Germany) for tumor ablation was used.The laser parameters were set as follows: a 2-4 mm spot size, a fluence of 5-10 J/ cm 2 , and a pulse width of 100 μs.The irradiation distance was set according to tumor size.When the tumor size was smaller than 2 mm, increasing the irradiation distance could decrease the spot size.For most scattered lesions, the entire lesion was directly removed by laser ablation was stopped once normal dermal tissue was visible, bleeding is not necessary as an end reaction in treatment.For very deeper lesions in eyelid skin, when lesion residue after ablation is approximately 0.5 mm diameter, and the laser is unable to accurately eliminate lesions but instead ablates normal tissue, we also stop laser treatment, so the ablation depth can be slightly lower than the lesion depth for scar reduction.For dense lesions, every ablation wound was arranged at an interval of 3-4 mm.For fused syringomas, the treatment was not done at once, and each ablation was distanced by 3-4 mm.We just choose ablative mode for tumor removal in all types of syringomas.The next treatment was not performed until 1 month later at least, to supply sufficient skin for wound repairing.
All treatments were performed by one doctor.Immediately after laser treatment, BTXA (Botox®; Allergan, Irvine, CA, USA) was applied.A 100-unit vial of BTXA was diluted with 1 mL bacteriostatic normal saline solution, approximately 10 units to 30 units BTXA was sprayed on the lesional area for about 15 min, when the solution was dried up.After treatment, topical antibiotic ointment (Chloromycin eye ointment, China) was applied two or three times per day until the wound healed.

| E VA LUATI O N
Blinded observers evaluated the degree of tumor clearance by comparing the baseline photographs with the posttreatment photographs.Standardized photographs were taken from the front and sides of both cheeks using a clinical imaging system (VISIA®-CR; Canfield Scientific, Parsippany, NJ).Photographs were taken at baseline, before each treatment and 2 months after the last treatment.Two dermatologists blinded to the treatments performed objective clinical assessments of the syringomas.They compared the before and after photos in nonchronological order using a Periorbital Syringoma Severity Index 5 (PSSI, Table 1) and global improvement scale (grade 0, no effect or worsened; grade 1, 0%-25%, minimal improvement; grade 2, 26%-50%, moderate improvement; grade 3, 51%-75%, marked improvement; and grade 4, >75%, near total improvement) to evaluate the treatment results.

| RE SULTS
Patient data: We treated 21 patients by this technique, including 20 females and 1 male.Their ages were between 20 and 45 years old, there were 21 cases of syringomas in the eyes, there were 3 cases of syringomas in the forehead, and there were 2 cases of syringomas that involved the cheek.The time of occurrence ranged from 1 year to 15 years.The details are listed in Table 2.
The patients underwent one to three treatments, the average treatment time was 1.62 ± 0.74, the PSSI score decreased from 4.19 (before treatment) to 1.10 (after treatment), and there was a statistically significant difference in the PSSI score before and after treatment (Figure 1).The global improvement scale showing excellent, good, fair, and poor responses was 11 (52%), 7 (33%), 3 (14%), and 0 (0%), respectively, and the average improvement grade was 3.38.
The detailed treatment data are listed in Table 3.
Further analysis of the PSSI score and treatment times showed a positive correlation, with a higher PSSI score for syringomas, and this indicates that there were more serious syringoma, which means more treatment times as well (Figure 2).Among the three types, fused-type syringoma acquired the highest PSSI score (6.0 vs. 4.3 dense and 3.0 scattered) and demanded more treatment (2.75 vs. 1.5 dense and 1.14 scattered, Figure 3).Most patients achieved more than 75% improvement, and the patients appraised the method as more comfortable than previous treatments.Among the three types, scattered-type syringoma had a better global improvement scale (Figure 4).
Seven to ten days after treatment, when the wound healed, no patient complained of obvious erythema or depression.The main side effect was mild to moderate erythema, but the visibility and duration were significantly less than those of CO 2 laser treatment.No patients complained of pain during treatment, and no obvious scars, very slightly hypopigmentation (Figure 7) can see in some patients, one patient have hyperpigmentation after treatment (Figure 6), we conclude the reason is she had a CO 2 laser experience before.In summary, we believe that the Er:YAG laser combined with BTXA treatment is a safe and effective method.However, our study did not proceed with a longterm follow-up to determine the duration of the effect.As Seo 4 reported, the effect can be maintained for more than 2 years.

| DISCUSS ION
According to a precise study, the depth of syringoma was 0.4-1.2mm, which is obviously deeper than the periorbital skin dermis reticular layer, so the risk of scarring may be unavoidable for deep lesions or accumulated-type or lump-type lesions.The clinical ablation results were not just due to the difference in device but also related to the clinician's experience. 6Therefore, minimizing the depth of injury is the most important point in treatment.For laser treatment, reducing or avoiding laser-induced thermal damage to the surrounding tissues was the main consideration.Sang 7 tried using a CO 2 laser with the pinhole method in the treatment of periorbital syringoma.
After the second treatment session, only 34.5% of patients had marked clinical improvement, and the patient pictures revealed obvious scar residue.Considering that the large residual thermal damage of the CO 2 laser could result in prolonged erythema or scar formation, we thought the erbium laser was a better choice for removing a syringoma.The erbium laser created only a thin coagulation zone of 20 μm, 8 so it could clear tumor tissue thoroughly and accurately.The tissue removal was easy for isolated or lower lesions.However, for deeper or fusion lesions, more than five treatments are needed, and the long process may be unacceptable for patients.Yukie Kitano 8 attempted to remove dense syringomas with an Er:YAG laser by a method called many ablation units.One ablation unit had an ovoid  There are some literatures reported on drug therapy of syringoma, including topical retinoids, tranilast, and topical atropine. 1Oral tranilast was reported with good improvement after 3 and 8 months treatment.The possible rationale is tranilast which could suppress collagen synthesis by inhibiting the release of transforming growth factor-b and interleukin (IL)-1b from fibroblasts or monocytes/macrophages, 9 and the mechanism also reported in BTXA scar treatment. 10Besides, Sánchez 11 report that topical atropine can release the pruritus and reduce the size of lesions in eruptive syringomas by inhibiting sweat secretion, the function also reported in BTXA too.
Hyun-Min 4 reported using a CO 2 laser combined with BTXA for syringoma, requiring significantly fewer treatment sessions and higher clinical improvements compared with treated with a CO 2 laser only.
Indicating drug therapy has some effect on syringoma.
Considering that there was a lack of abundant clinical expe-  patients improved more than 50%, and 2.3% of the patients had scarring.Considering that CO 2 laser ablation produces a thicker coagulation zone than the Er:YAG laser and that Marilin 8 demonstrated that a thick coagulation zone limits drug penetration, a thin coagulation zone prevents oozing and bleeding and may function as a reservoir through which drugs may be gradually released into the tissue.In addition, deeper ablation holes are rapidly filled with interstitial fluid, providing a more favorable environment for The relationship between syringoma score and treatment times.

F I G U R E 3
The relationship between syringoma types and treatment times.

F I G U R E 4
The relationship between syringoma types and global improvement scale scores.
hydrophilic drugs than for hydrophobic drugs.In general, we speculated that Er:YAG laser ablation had a better BTXA penetration than CO 2 ablation.
Many studies have shown that BTXA can reduce the proliferation and migration of human scar fibroblasts and reduce scar formation. 9 Li found that the scar reduction effect occurred in a dose-dependent manner, and the dose must be higher than 1 U/9 mm to initiate clinical efficacy.Gugerell's research revealed that a high concentration of BTXA (20 U/mL) inhibited angiogenesis. 10According to our experience, 100 U/mL BTXA could reduce scar formation in facial surgery.Therefore, we continued the dose of 100 U/mL, and no adverse reactions were found during treatment.
In our study, the patients underwent one to three treatments, respectively, the average times was 1.62 ± 0.74, and the treatment times were significantly less than the Er:YAG laser alone.Also, the number of patients showing excellent, good, fair, and poor response was 11 (52%), 7 (33%), 3 (14%), and 0 (0%), respectively, and the average improvement grade was 3.38, which was lower than the Er:YAG laser alone, partly because the ablation depth was insufficiently in some of the initial cases treated.When a patient is treated three times, we suggest that the treatment be stopped for several months for skin repair.
Compared with other treatment protocols, the method used in this article emphasized removing a single lesion as completely as possible.For dense or fusion lesions, we chose to completely remove partial lesions once, which was significant for avoiding recurrence.In addition, we emphasize scar-free healing.The patients in the study had no obvious scar formation and only mild erythema at the follow-up 1 month after surgery, which did not affect the patient's daily life, and the patient's satisfaction was great.

| CON CLUS ION
The clinical results suggest that the Er:YAG laser combined with BTXA therapy is a fast, safe, and effective method for syringoma F I G U R E 5 A 39-year-old female with a 5-year-old syringoma on the eyelid.(A) The first treatment was using an ultrapulsed carbon dioxide laser.To avoid insufficient scar ablation depth, the removal of syringoma was not effective.(B) The second treatment was using an Er:YAG laser combined with BTXA.The clinical improvement of the syringoma was grade 3.

F I G U R E 6
A 42-year-old female with a 9-year-old syringoma on the eyelid, forehead, and cheek.before (A, C, E, G), 2 months after one session of Er:YAG laser combined with BTXA (B, D, F, H).The global improvement scale score was 3.
Case report 1 (Figure 5) A 39-year-old female with a 5-year fused-

TA B L E 2
Patients data.2-4 mm in diameter.The ablation depth depended on the tumor depth.As a result, 98% of patients improved more than 75%, and there was no scar formation.The disadvantage was the number of treatment sessions.For large-scope plaque-type syringoma and treatments up to seven sessions, patients needed to bear more economic and time costs.
in BTXA injection of periocular syringoma, especially for large fused-type.Besides, eccrine hidrocystomas are cystic masses, and syringomas are surrounded by a sclerotic stroma.Seo 4 tried using the CO 2 multiple-drilling method combined with botulinum toxin for the treatment of periorbital syringomas.The multiple-drilling method could remove only a small portion of the tumor tissue and could enhance the delivery of topical agents through the skin.After two sessions of treatments, 49% of the F I G U R E 1 Periorbital Syringoma Severity Index score before and after treatment.The score decreases significantly after treatment (*** means P < 0.001).TA B L E 3 Treatment data.
type syringoma on the eyelid with a PSSI score of 4. (A) The first treatment used an ultra-pulsed CO 2 laser.To avoid scarring, the removal of syringoma was not deep enough.(B) The second treatment was using an Er:YAG laser combined with BTXA.After treatment, the PSSI score was 0, the global improvement scale score was 4, and no visible scars were present, but the lower eyelids has some hyperpigmentation.Case report 2 (Figure6) A 42-year-old female with a 9-year-old scattered-type syringoma on the eyelid, fused-type on the forehead and cheek, the PSSI score was 6. (a, c, e, g), 2 months after one session of Er:YAG laser combined with BTXA (b, d, g, f), the majority of the tumor was removed, but some erythema existed after treatment, and there was no visible scar formation, the PSSI score was reduced to 2, the global improvement scale score was 3. The patient was satisfied with the clinical improvement and was not willing to undergo a second treatment.Case report 3 (Figure7) A 59-year-old female with about 15-year-old scattered-type and dense-type syringoma on the eyelid with a PSSI score 5 (a, b, c, d). 1 month after two session of Er:YAG laser combined with BTXA treatment (e,f,g,h), the majority of the tumor was removed, but there was partly tumor tissue residue in both side of tear trough, the PSSI score was reduced to 2, no obvious hyperpigmentation or hypopigmentation existed.The patient was very satisfied with the clinical improvement.
TA B L E 1