Radiofrequency ablation has been used, with good results, in 2 adult patients with dark skin phototypes, although postinflammatory hyperpigmentation occurred and the lesions reappeared.17,18

There have been anecdotal reports of cryotherapy being used to treat facial angiofibromas in 3 isolated cases.19,20 This method is inexpensive and easy to apply and does not require anesthesia, but it requires several sessions and patient collaboration—which is not possible in many cases because of the psychological alterations associated with tuberous sclerosis—and yields limited results.

Electrocoagulation has been used to treat large facial angiofibromas, with good results (Fig. 2). However, the quality of the results depends to a large extent on the dermatologist's experience, and the risk of scarring and other postoperative complications is high. More specific techniques that make it possible to control the electrical power more precisely have therefore been developed. Capurro et al.21 obtained good long-term results in a patient with facial angiofibromas by using timed surgery, an electrosurgical procedure that allows the physician to set the energy and emission-time parameters.

Figure 2.

A, Patient with multiple large facial angiofibromas. B, Result 9 months after treatment with electrosurgery.

(0.25MB).

Dermabrasion has been used by several authors, with good results.22–25 In this technique, the largest lesions are treated with shave excision before the remaining lesions are treated with dermabrasion under general anesthesia. The risk of postinflammatory hyperpigmentation, scarring, and recurrence in the medium to long term is very high. To avoid these complications and minimize the healing time, some authors have proposed the use of cultured epithelial autografts26 or artificial dermis.27 Hori et al.26 used cultured autologous epidermal grafts in 5 adults following the removal of multiple large facial angiofibromas via shave excisions and dermabrasion. Reepithelization was rapid and there were no complications. However, because the process requires general anesthesia and the full cooperation of the patient to ensure graft survival, several patients had to be sedated during the postoperative period. Some regrowth of the lesions occurred 4 to 5 years after the procedure and retreatment was necessary in 2 patients.

The development of laser treatments and their introduction in dermatology has allowed a more precise approach to treating various diseases, with excellent results and fewer adverse effects.

Various types of laser have been used in the treatment of facial angiofibromas. The first types of laser to be used were ablative argon28,29 and carbon dioxide (CO2) lasers.30,31 With the introduction of new equipment such as copper vapor lasers,32 argon lasers, potassium-titanyl-phosphate (KTP) lasers,33,34 and, especially, pulsed dye lasers (PDL),35–38 numerous authors began to treat facial angiofibromas with these types of lasers using the principle of selective photothermolysis. Later, PDL started to be used in combination with other light sources such as with 5-aminolevulinic acid photodynamic therapy39 and fractional resurfacing,40 with good results. Table 1 summarizes all of the studies that have reported more than 2 cases of facial angiofibromas treated with various types of laser.34,35,37,39–42

CO2 lasers have been shown to be effective in both the continuous-wave and superpulsed modes of operation, with similar results (Fig. 3). The ablative effect of CO2 lasers has made it possible to treat larger facial angiofibromas and carry out deeper resurfacing, leading to more effective treatment, but with more complications, such as hypertrophic scarring, which can appear in up to 53.8% of cases.37 General anesthesia is usually necessary, although the procedure can be performed under local anesthesia in some cases of localized lesions. In the study with the longest follow-up period carried out to date,41 lesions recurred in 60.9% of patients and the mean recurrence time was 3 years. Recurrence began as an increase in the volume of the lesions followed by an increase in the number of lesions, and patients younger than 20 years of age had earlier recurrences than older patients. Bittencourt et al.42 treated 10 patients with CO2 laser and classified them in 3 groups according to trends in response and long-term maintenance. Two groups of patients showed a good response to treatment at 6 months; long-term efficacy was maintained in 1 group and lesions reappeared in the other. The third group of patients invariably showed a poor response.

Figure 3.

A, Localized facial angiofibromas on the nose, cheek, and nasolabial fold. B, Result after treatment with CO2 laser. Courtesy of Dr Pablo Boixeda.

(0.16MB).

PDL has been used to treat facial angiofibromas because of the major vascular component of these lesions. Papadavid et al.37 obtained good results in 16 patients who had facial angiofibromas with a predominantly vascular component. Improvement in erythema was observed in more than 90% of patients. However, no decrease in the fibrous component was observed, and as a result more than half of the patients had to be treated with electrosurgery in addition to CO2 laser. The PDL treatment achieved the best results in children, who showed no signs of recurrence after 2 to 5 years of follow-up.

Although no clinical trials or prospective studies have been carried out, the trends observed in the literature suggest that patients with facial angiofibromas with a large vascular component and lower volume could benefit from PDL treatment, whereas CO2 laser would be especially useful in patients whose lesions have a more pronounced fibrous component.

Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an antiallergic drug that was approved in 1982 for use in Japan and South Korea in the treatment of bronchial asthma. The discovery of the drug's antiproliferative properties—inhibition of growth factors such as transforming growth factor-β, reduction of mast-cell cytokine secretion, and inhibition of metalloproteinase secretion in the extracellular matrix—provided a rationale for its use in the treatment of keloids and hypertrophic scars.43

Wang et al.44 treated 3 adults with tuberous sclerosis with oral tranilast at a dose that increased from 1 to 5mg/kg/d for 3 years. Erythema improved and the size of the facial angiofibromas decreased in 2 patients. A reduction in periungual fibromas was observed in 2 patients, although none of the patients showed improvement in achromic macules. The authors observed no adverse effects. Because the patients were not followed up, it is not known whether the lesions recurred after tranilast was withdrawn.

Podophyllotoxin is an alkaloid derivative that has been used for years in the treatment of genital warts and actinic keratoses. Only 1 case has been reported of podophyllotoxin being used in the treatment of facial angiofibromas associated with tuberous sclerosis.45 A 25% podophyllotoxin solution was applied once monthly for 3 months and a partial response was achieved. There were no adverse effects except a burning sensation on application of the treatment.

Sirolimus is a molecule that belongs to a group known as mTOR inhibitors. It is currently approved for use in the prevention of organ rejection in patients who have undergone a kidney transplant and in drug-eluting coronary stents.

The molecular mechanism of action of sirolimus is partially understood. Sirolimus induces immunosuppression by blocking the cell cycle of T cells at the transition from the G1 phase to the S phase, thereby preventing T cell activation and antibody production. The antitumor effect of sirolimus is based on its ability to normalize abnormally increased mTOR signaling in tumor cells and inhibit angiogenesis by causing levels of vascular endothelial growth factor to decrease.46

Because of the aforementioned antiproliferative effects of sirolimus and its analogs (everolimus, temsirolimus, ridaforolimus), clinical trials of the drug in the treatment of various tumors have been carried out.46–54

Hofbauer et al.55 and Tarasewicz et al.56 reported considerable improvement in facial angiofibromas in 2 patients with tuberous sclerosis who had undergone a kidney transplant following oral administration of sirolimus as a prophylaxis against rejection. This effect was corroborated in a subsequent clinical trial46 in which the authors observed subjective improvement of facial angiofibromas in 57% of patients after 52 weeks of treatment with oral sirolimus. However, because of the potential adverse effects of sirolimus, oral use of this drug would not be justified to treat facial angiofibromas in patients with no other associated abnormalities.

Haemel et al.57 reported the first case of facial angiofibromas treated with topical sirolimus. Supported by an animal model58 and safety data from a clinical trial carried out in patients with psoriasis,59 the authors developed a 1% sirolimus ointment. A decrease in lesion size and erythema was observed after 3 months of treatment with the ointment. A further 59 cases with different dosage regimens and results have subsequently been reported.16,57,60–67

Because of the wide range of formulations and dosages that have been used, and the lack of common measurement systems for evaluating response to treatment, it is extraordinarily difficult to interpret the data from these studies (Table 2). Only in 2 studies16,67 have systematized scales been used to assess erythema, size, extent, and prominence of facial angiofibromas and, of these scales, only the Facial Angiofibroma Severity Index has yielded data with intra- and interobserver reliability.16

Wataya-Kaneda et al.67 carried out the first controlled study of topical sirolimus. The authors evaluated the response of 9 patients who were treated with a 0.03% tacrolimus ointment on half of the face and with 0.03% tacrolimus ointment containing 0.2% rapamycin on the other half. The authors quantified the effectiveness of the treatment by tallying partial scores assigned for the observed improvement in the erythema, size, and thickness of the facial angiofibromas. A score of 2 points was assigned for an improvement of more than 80%, 1 point for improvement of 50% to 80%, and 0.5 points for improvement of 20% to 50%. The final mean score for the 9 patients was 0.5 for the area treated with tacrolimus only and 2.6 for the area treated with sirolimus (P<.001).

In a recent controlled clinical trial,63 28 patients were treated with a formulation containing sirolimus and polyvinylidene fluoride (PVDF), an agglutinating polymer used as a vehicle to make the formulation more occlusive and favor the absorption of the active ingredient. Subjects were randomized and assigned to 1 of 3 treatment groups: 0.015% sirolimus, 0.003% sirolimus, or PVDF only. The formulation was applied once daily for 24 weeks. No statistically significant differences between the treatment groups were found. However, of the 23 patients who completed the study, 73% in the treatment groups reported that they “got better” while using the treatment versus 38% in the placebo group. None of the patients had detectable sirolimus plasma levels in the blood or abnormalities in their complete blood counts. One patient had an episode of aspiration during a seizure and developed pneumonia, which subsequently progressed to septic shock. However, this study had important limitations. The authors did not define the initial severity of the lesions, use researcher-assessed methods for measuring efficacy, or carry out intermediate controls during treatment in order to monitor clinical course in the patients.

Given that no commercialized topical sirolimus preparations exist, physicians have developed compounds at different concentrations by crushing and sifting commercially available sirolimus tablets (Rapamune).60 The use of sirolimus in powder form has considerably improved the physical properties of sirolimus formulations and reduced their cost.68 Some authors have applied the commercially available oral sirolimus solution (1mg/ml) to facial angiofibromas, either alone61,64–66 or in combination with emollients.62

Topical treatment with sirolimus has been found to decrease the size of facial angiofibromas and accelerate the resolution of erythema (Fig. 4), and it has been suggested that this treatment is more effective in younger patients.60,61 However, studies with larger sample sizes are needed in order to substantiate the observed trends.

Figure 4.

A and C, Multiple facial angiofibromas in patients with tuberous sclerosis. B and D, Improvement in erythema, size, and extent of the lesions after 9 months of treatment with 0.4% sirolimus ointment.

(0.11MB).

The literature on sirolimus shows that the drug has a good safety profile. Only 6 cases of local irritation have been reported. Of these cases, 4 were related to the direct application of the oral sirolimus solution (1mg/ml) and the other 2 were related to the sirolimus-PVDF formulation. No systemic adverse effects have been observed and the sirolimus plasma levels have been below the limits of detection in 49 of the 50 patients who were tested. Sirolimus has only been found in the blood of 1 patient, and the amount detected was well below therapeutic levels and the toxicity range.61

Because the use of sirolimus and everolimus has been associated with the possible impairment of the wound healing process,69,70 it has been recommended that topical sirolimus not be applied on wounds.

It was initially suggested that the incidence of lymphomas and skin cancer is higher than normal in patients treated with oral sirolimus.71 However, this claim has been refuted by various studies that have shown that patients who have received long-term treatment with sirolimus have a lower overall incidence of cancer72 as well as lower rates of lymphoma73 and nonmelanoma skin cancer,74 specifically.

There are no data on the possibility of facial angiofibromas growing back after suspension of treatment. Only 1 study has reported recurrence of erythema (1 month after withdrawal of the formula).67

Topical sirolimus has also been used in 2 patients with hypomelanotic macules associated with tuberous sclerosis, and clearance of the lesions was achieved after 3 months of treatment.75

Other mTOR inhibitors have also been shown to be effective in the treatment of facial angiofibromas. In a clinical trial of everolimus for the treatment of subependymal giant-cell astrocytomas, 13 of 15 patients reported subjective improvement of facial angiofibromas.50 There have been no studies on the possible topical use of everolimus.

The development of new mTOR inhibitors such as temsirolimus and ridaforolimus, currently used in the treatment of various types of cancer,48,49 could play a role in controlling cutaneous manifestations of tuberous sclerosis.

The authors declare that no experiments were performed on humans or animals for the purpose of this study.

The authors declare that they have followed the protocols of their hospitals concerning the publication of patient data and that all patients included in this study were appropriately informed and gave their written informed consent.

The authors declare that no patient data are disclosed in this article.