Use of Topical Rapamycin as Maintenance Treatment after a Single Session of Fractionated CO₂ Laser Ablation: A Method to Enhance Percutaneous Drug Delivery

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by pleomorphic features of systemic organs. The skin is the most commonly affected organ system with up to 90% involvement1. Facial angiofibroma is the main feature of this disease, affecting approximately 75% of patients. Angiofibromas appear in early childhood (ages 2~5 years) as red papules and increase in number and size throughout puberty2, 3.

To date, various treatment modalities for angiofibromas have been proposed, including surgical excision, curettage, dermabrasion, electrocautery, and laser ablation4, 5, 6, 7. Despite the use of rigorous approaches to completely remove the lesions, the outcomes have been suboptimal with a high recurrence rate8, 9. In addition to improved understanding of the genetic and molecular pathogenesis of the disease, prominent vascular proliferation due to an increased vascular endothelial growth factor (VEGF) level and mammalian target of rapamycin (mTOR) overactivation were noted in angiofibromas. Rapamycin binds to mTOR with high specificity and represses the VEGF output by inhibiting the hypoxia-inducible factor and endothelial cell proliferation10, 11. Additionally, it suppresses T-cell activity and antibody production, resulting in decreased keratinocyte proliferation and inflammation12.

The use of topical rapamycin has been proposed and shown successful outcomes for both preventing and reducing angiofibroma lesions12. The current general consensus among the considered studies suggests that topical rapamycin is an efficient therapy for facial angiofibromas, providing improvement in 94% of cases8. Unlike pediatric patients who can benefit from preventive measures with the early application of topical rapamycin, adult patients with an already fully developed disease that includes nodular lesions report poor outcomes with monotherapy13.

We describe the case of an adult patient who showed an excellent clinical response after a single session of carbon dioxide (CO₂) laser ablation and continued use of 0.2% topical rapamycin for maintenance.

A 20-year-old Korean male previously diagnosed as having TSC was referred to the dermatology department for the treatment of extensive angiofibromas on his face. His DNA test revealed mutations in TSC2. He presented with scattered and grouped lesions of facial angiofibromas of various sizes and thicknesses. Additionally, periungual fibroma and hypomelanotic macules were noted. Regarding the systemic features of the disease, multiple hamartomas of the heart and kidney were noted.

One year before visiting Scar Laser and Plastic Surgery center, the patient underwent ablative laser treatment for cheek lesions. However, most of the lesions recurred within a few months during the late pubertal period, and wound healing was delayed for large nodules.

He underwent extensive CO₂ laser ablations for all facial lesions. We used a starting fluence between 100 and 150 mJ of continuous CO₂ pulses (eCO₂™; Lutronic, Goyang, Korea), and multiple passes were performed until the lesions were flattened. To improve the absorption of topical rapamycin and wound healing, a fractional CO₂ laser was additionally applied on the whole face. The treated areas were cooled with ice packs for 10~15 minutes, and topical rapamycin was directly applied. Thereafter, a foam dressing was applied for protection and maintained for 1 day. To minimize the risk of post-inflammatory hyperpigmentation (PIH), sunscreen with broad-spectrum ultraviolet (UV) A and UVB protection was prescribed.

The patient returned to the clinic on the following day without any complication. He was encouraged to use topical rapamycin once a day afterward. He regularly visited the clinic every 2~3 months, and no sign of recurrence or irritation was noted at 1 year after laser ablation (Fig. 1). We received the patient's consent form about publishing all photographic materials. Additionally, there were no signs of hypertrophic scarring or delayed wound healing during the follow-up period (Table 1).

Fig. 1
Improvement of facial angiofibroma lesions in a 20-year-old patient with tuberous sclerosis complex during rapamycin therapy after a single session of CO₂ laser ablation. Left panels, labeled 0: before the administration of laser ablation. Pronounced improvement was observed at 1, 3, 6, and 8 months after the start of systemic rapamycin therapy after a single session of CO₂ laser ablation.

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Table 1
Facial Angiofibroma Severity Index (FASI) scores after treatment

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The advent of topical rapamycin has dramatically changed the paradigm of angiofibroma treatment. However, topical rapamycin monotherapy is insufficient for fully developed lesions in adults. Various types of lasers have been popular options, and many studies have reported successful results with CO₂, copper vapor, argon, pulsed dye, potassium-titanyl-phosphate, and Nd:YAG lasers6, 14, 15, 16. For flattened lesions, lasers targeting the vascular structure or melanin pigments may generate sufficient energy to destroy individual lesions with photothermolysis. However, full-thickness ablation of abnormal keratinization and underlying fibrosis is indispensable for bulky lesions. The CO₂ laser is one of the most widely used lasers in dermatology17. CO₂ lasers with a 10,600-nm wavelength target the water component of tissues. As a single CO₂ laser can be modulated to cause tissue reactions of incision, excision, vaporization, and coagulation, it can successfully have a debulking effect even for extensive lesions.

Unlike previous reports showing that the CO₂ laser caused hypertrophic scarring in a considerable percentage of patients6, we did not experience scarring or delayed wound healing in our patient. This outcome can be partially due to the fractionated application of the CO₂ laser after ablation of single lesions. The ablative fractional CO₂ laser can compensate for the lack of specific photothermolysis in CO₂ laser monotherapy. By thoroughly producing microthermal zones on the CO₂-ablated surface, columns of thermal damage cause collagen remodeling and promote wound healing18.

PIH can occur at any age and in any skin type, and it has no sex preference. However, this type of hypermelanosis is more common in patients with Fitzpatrick skin types IV~VI. Previous research showed that the degrees of erythema and pigmentation correlated linearly after UVB irradiation18. Additionally, crusts after laser treatment protect the wound and help prevent the development of PIH after laser treatment. To minimize the risk of PIH, it is necessary to avoid early removal of the crusts and to apply sunscreen with broad-spectrum UVA and UVB protection. We also postulate that topically applied rapamycin could have contributed to normal wound healing after full-thickness ablation. mTOR is a regulator of cell growth and survival, and acts as a mediator of inflammatory and fibrotic processes. In recent in vitro reports, the mTOR signaling pathway was shown to cause proliferation of abnormal fibroblasts, causing pathologic scars19, 20. Therefore, topical rapamycin can induce a synergistic effect of angiogenesis inhibition for the recurrence of angiofibroma lesions and abnormal scarring repression after CO₂ laser ablation. Notably, even with a 0.2% preparation, topical rapamycin did not cause immediate irritation when directly applied on the laser-ablated surface.

Angiofibromas in TSC significantly affect patients' quality of life by causing psychosocial comorbidities. It can be especially burdensome for late adolescent and young adult patients who have already developed extensive lesions throughout puberty. Despite the use of expensive approaches, there is no sustained efficacy in the long term and the risks of complications such as scarring remain. TSC is a predominantly inherited genetic condition that occurs in all races and ethnic groups. We concede with current reports describing the successful outcomes of various laser devices. However, the selection of laser devices can be limited for some institutions. Therefore, we suggest a rather basic but highly effective approach for angiofibroma treatment that can be generally applied with the classic CO₂ device.