Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions of children and adults resulting from abnormal embryologic development of lymphatic vessels. They present as clusters of vesicles full of lymph and blood of various extent. They ooze and bleed, inducing maceration, esthetic impairment, scars, pain, bacterial infections and impaired quality of life. Currently, treatments for CMLMs are disappointing, and their management is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase involved in cell growth and proliferation, cellular metabolism, autophagy and angio-lymphangiogenesis. Topical sirolimus, known to be efficient and well tolerated in cutaneous angiofibromas linked to tuberous sclerosis, has recently been reported effective in few reports of patients with CMLMs. The objective of this trial is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.

This blinded multicentre split body randomized controlled phase 2 trial aims to include 50 patients ≥ 6 years old who have a primary CMLM without an underlying malformation.

The CMLM will be divided into 2 equal areas of the same severity that will be randomly allocated to 0.1% topical sirolimus or topical vehicle for 12 weeks. During the double-blind 12-week period, both topical products will be applied by a nurse to avoid inter-group contamination and for better compliance.

At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for 8 more weeks. Patients will also be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy.

Inclusion Criteria:

• Patients ≥ 6 years
• Updated immunization schedule
• Diagnosis of primary cutaneous microcystic lymphatic malformation (CMLM) confirmed by histopathological or dermoscopic examination, with or without an underlying malformation or a syndromic malformation (Protée syndrome for instance), responsible for impairment (oozing, bleeding and/or pain)
• CMLM ≥ 20 cm2, that can be divided into 2 parts of similar severity
• Informed, written consent of the subject and his/her parents if < 18 years
• Rights to French social security (including CMU)

Exclusion Criteria:

• Patients with lymphatic malformation requiring a continued background therapy (involving deep organs)
• Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
• Previous treatment with oral or topical mTOR inhibitors within 12 months before inclusion
• Previous treatment with oral or topical steroids within 10 days before inclusion
• Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
• Ongoing neoplasia
• Active chronic infectious disease (Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Virus, etc)
• Local fungal, viral (Herpes Simplex Virus, Varicella Zoster Virus, etc) or bacterial infection on the site of the CMLM (based on clinical examination)
• Skin necrosis
• Known allergy to one of the components of the topical sirolimus preparation or vehicle
• Women of child-bearing potential (including teenagers) not using a reliable contraceptive method until the end of the study
• Pregnant or breastfeeding women
• Subject already involved in another therapeutic trial

Patients, parents, nurses and investigators will be blinded for the treatment allocated to each area of the CMLM, during the first step of the study (until week 12, where primary endpoint will be assessed). To ensure the double blinding, both areas will be randomized, and the topical treatments (sirolimus and vehicle) to be applied will have similar packaging. Their appearance is similar, thus the active drug (topical sirolimus) and vehicle cannot be distinguished at drug allocation. Furthermore, the consistency of the creams is similar.