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454 SHORT COMMUNICATION Effect of Topical Rapamycin 1% on Multiple Trichoepitheliomas Isabelle DREYFUS 1 , Giuliana ONNIS 1 , Emilie TOURNIER 2 , Olivier DEREURE 3 and Juliette MAZEREEUW-HAUTIER 1 1 Reference Centre for Rare Skin Diseases, (CRMRP), Dermatology Department, CHU Larrey, 24, Chemin de Pouvourville, FR-31400 Toulouse Cedex 09, 2 Laboratory of Pathological Anatomy and Cytology, CHU Oncopole, Toulouse, and 3 Dermatology of Department and INSERM U1058 University of Montpellier, Montpellier, France. E-mail: [email protected] Accepted Jan 15, 2019; E-published Jan 17, 2019 Trichoepitheliomas are benign adnexal neoplasms with follicular differentiation that can occur as isolated sporadic lesions or as part of multiple familial tricho- epitheliomas (MFT) syndrome, a phenotypic variant of Brooke-Spiegler syndrome associated with autosomal dominant mutations of the tumour suppressor gene CYLD (16q12.1) (1, 2). In the MFT setting, trichoepitheliomas appear during childhood as multiple skin-coloured papules or small nodules, usually present with a sym- metrical distribution and localized on the scalp, neck and face (with predominance on the nose, cheeks, forehead, nasolabial folds and inner aspects of the eyebrows). Tri- choepitheliomas progressively increase in number and size over years and usually result in significant aesthetic disfiguring. Brinkhuizen et al. (3) recently demonstrated that, similarly to tuberous sclerosis (4), the pathogenesis of trichoepitheliomas involves an activation of the mam- malian target of rapamycin (mTOR) signalling pathway. We report here the effect of topical rapamycin 1%, an efficient topical treatment of cutaneous angiofibroma, in patients with tuberous sclerosis, on trichoepitheliomas of 5 patients with MFT. CASE REPORTS The patients’ characteristics are summarized in Table SI 1 . All tri- choepitheliomas were histologically confirmed, showing basaloid lobules with keratocysts and infundibular keratinization without epidermal continuity, and with cellular fibroblastic stroma (Fig. 1). All patients were female, with a median age of 45 years (range 26–54 years). Lesions first appeared at the median age of 15 years (range 4–23 years) and were located exclusively on the face (front, nose, nasolabial folds). The number of lesions was between 20 and 500, and their diameter ranged from 2 to 5 mm. Molecular analysis was conducted in one patient showing a heterozygous mutation on exon 19 of the CYLD gene: c.2625dupT (p.Val876Cysfs*14). All patients had received prior topical and/or systemic treatments, including CO 2 laser vaporization, 5% imiquimod cream and oral acitretin (maximum daily dosage 30 mg (0.5 mg/kg/day)). All patients were treated twice daily with a topical formulation of rapamycin 1%, in an emollient cream containing glycerol 15%/ petroleum jelly 8%/liquid paraffin 2%. None of the patients used concomitant treatments. Efficacy and tolerance were evaluated after 2 months (M2, intermediate evaluation) and 5 months (M5, final evaluation) of uninterrupted treatment, using a visual analo- gical scale (VAS) from 0 to 10. Efficacy was rated by 2 different physicians, either during the visits or blindly through digital pho- tograph analysis, and by the patients. According to the physicians’ rating, the median efficacy was 1/10 (range 0–3) at M2, and 3.5/10 https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3116 1 doi: 10.2340/00015555-3116 Acta Derm Venereol 2019; 99: 454–455 Fig. 1. Trichoepithelioma (patient 2). Basaloid lobules showing keratocysts and infundibular keratinization (arrow) without epidermal continuity, and with cellular fibroblastic stroma. Haematoxylin-eosin stain, magnification ×50. (range 0–5) at M5. The clinical response was characterized by a decrease in the density of the lesions, related to a decrease in thickness and size of the lesions, rather than to a reduction in the number of lesions (Fig. 2). According to the patients’ rating, the median efficacy was 6/10 (range 0–6) at M2, and 5.5/10 (range 0–6) at M5. Four patients reported an improvement in the lesions and no new lesions under treatment. Conversely, patient 5 did not report any improvement. Tolerance was considered good by all patients, self-rated at a median score of 9/10 (range 7–10) at M2 and 10/10 (range 4–10) at M5. Four out of 5 patients reported a slight irritation of the skin within the first week of treatment. Two patients reported an increased frequency of headaches during treatment, responding to paracetamol or triptans. None stopped the treatment because of side-effects. Among the 4 patients who had an improvement in their trichoepitheliomas, 2 are currently under treatment (patients 2 and 4). Patient 3 stopped the treatment and was then treated with CO 2 laser. Ten months after stopping topical rapamycin, patient 1 has new lesions, but the size of treated lesions did not change. DISCUSSION A number of therapeutic options have been proposed pre- viously in MFT-related trichoepitheliomas, including sur- gery, dermabrasion, ablative CO 2 laser and cryo­therapy. However, these invasive procedures have a limited ef- ficacy and may be complicated by permanent scarring, hypopigmentation and atrophy. There is also a high risk of relapse (5, 6). Topical imiquimod also proved effective in 2 patients with solitary desmoplastic trichoepithelioma but the lesions relapsed after treatment discontinuation (7). More recently, the effect of topical mTOR inhibitors on MFT-related skin lesions was reported by Tu & Teng (2) in 2 siblings aged 6 and 8 years. A formulation of 1% rapamycin cream was applied on numerous, but small This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.