New Use of Rapamycin Stent in Non-Responding Facial Lymphatic Malformation

Introduction: Vascular anomalies represent a diagnostic and therapeutic difficulty. A lymphatic malformation (LM) corresponds to a low-flow vascular malformation. Sclerotherapy is the preferred treatment. Recently, angiogenesis inhibitors such as Rapamycin have been used with promising results. Case Report: A pediatric patient presented with a large facial LM and poor response to Sildenafil and sclerotherapy. After a persistent enlargement of the lesion, with painful ocular occlusion a new sclerotherapy was performed obtaining partial improvement. As a rescue treatment an IRS was installed. The patient achieved a rapid and evident response, with better ocular aperture and pain control. Discussion: LM correspond to vasculogenesis disorders with persistent growth over time. They can present high morbidity. The complications in the facial area are infection, hemorrhage, exophthalmos, and amblyopia. Rapamycin is a potent angiogenesis inhibitor. Rapamycin stents have been safely used in cardiology. They provide local concentration with less adverse effects. There are no reports on their use in lymphatic malformation. The patient had a favorable and persistent response. Conclusion: IRS should be considered as a therapeutic alternative in severe nonresponding lymphatic malformation. The necessity of a multidisciplinary approach is fundamental


Introduction
Vascular anomalies represent a diagnostic and therapeutic difficulty. The classification system of the International Society for the Study of Vascular Anomalies (ISSVA) divides them in two groups: tumors and vascular malformations based on clinical, genetic and pathological findings [1]. Lymphatic malformations (LM) -low flow vascular malformations-are classified as macrocystic, microcystic or mixed [1][2][3]. The incidence of LM reaches 1.2-2.8 per 1,000 births and 2.8 patients per 100,000 hospital admissions [1]. They are located in the head and neck area in 70% of the cases, and their growth is proportional to the patient's development unless infection, trauma or hormonal changes are present [1,4]. Imaging is an essential diagnostic tool, based on the presence of thin-walled cysts of variable size, generally clustered in the affected area.
Depending on the location, depth and size of the lesion, the most useful tests are ultrasound (US) and magnetic resonance (MRI). [2]. The classic therapeutic approach includes sclerotherapy or surgical excision, depending on each case. However, in some cases an optimal result is not accomplished [5]. Recently, angiogenesis inhibitors agents such as Rapamycin (Sirolimus) have been used with promising outcomes. In particular cases when LM or venouslymphatic malformations have not responded to other treatments, oral Rapamycin has been reported to be successful [1,6]. Herein, we report a clinical case of LM nonresponding to conventional management treated with an intralesional biological therapy: Rapamycin stent. To the best of our knowledge, there are no previous reports on the use of this kind of stent in LM.

Discussion
Vascular anomalies represent a diagnostic and therapeutic challenge. According to the ISSVA classification, they can be divided in tumors and malformations, based on clinical, pathologic and genetic features [1]. Lymphatic malformation (LM) corresponds to a low-flow vascular malformation, with an incidence of 2.8 patients per 100,000 hospital admissions [1]. Frequent in head and neck location, 90% detected before the age of 2 years [4]. LM corresponds to vasculogenesis disorders with persistent growth over time. On histology, it is formed by cysts lined by an endothelium containing amorphous lymph [1]. The LM have a wide clinical spectrum. The cysts can be few and small or in the other side present with a severe hypertrophy and deformation with the subsequent complications and functional limitation. Spontaneous regression is rare [4]. They can present high morbidity and mortality according to their size and location area, with functional impairment, aesthetics changes, pain and other complications such as altered feeding [3]. Among The proposed treatment depends on the severity of LM. It has to be personalized and that is why it is important to have a of a multidisciplinary group of specialists in charge of these patients. In macrocystic LM sclerotherapy and surgery can be used [1,7]. Either alone or combined with embolization is a valuable treatment. To date, interventional radiology is the top line treatment for vascular malformations in many reference centers [7]. Large microcystic or mixed malformation are a therapeutic problem, sometimes progressing with the treatment. Rapamycin is a potent mTOR inhibitor (mammalian target of Rapamycin), is a serine/threonine protein kinase, which modulates the signaling pathway of angiogenesis and cell proliferation, decreasing the vascular endothelial growth factor. mTOR is suspected to play a role in the pathogenesis of some vascular anomalies. In 1970 sirolimus (Rapamycin) an inhibiting mTOR compound was identified. In 2015 this drug was approved by the Food and Drug Administration to treat lymphangioleiomyomatosis.
The literature suggests that Sirolimus is an effective therapy for LM but has many side effects and its bioavailability is extremely variable with complex plasmatic monitoring being required; so, a local controlled release increases the profile of safety and efficacy [6].
It appears as a useful therapy in extensive nonresponding LM, expanding the therapeutic possibilities [1].
The use of a bioresorbable polymer of a sirolimus-eluting stent is a daily practice in interventional cardiology. Rapamycin stents have been extensively used in cardiology with safety protocols according to the FDA [8,9]. However, to the best of our knowledge, there are no reports on the use of Rapamycin stents in the treatment of vascular malformations. In our case the unsatisfactory evolution of the patient after conventional treatment with progression of tumor size, pain, visual compromise, and life quality led us to an innovative treatment option and the interventional radiologist suggested the introduction of the percutaneous Rapamycin stent.
The patient responded favorably with the Rapamycin stent, improving her optical field, functionality and aesthetics. A strict quarterly follow-up has been pursued for nine months until now, with no adverse effects reported.

Conclusion
In conclusion, the use of local Rapamycin through stents as carriers should be considered as a therapeutic alternative in the treatment of extensive non-responding LM. To date the patient has exhibited persistent stable evolution and adequate tolerance, avoiding the side effects of systemic rapamycin therapy. The necessity of a multidisciplinary approach is fundamental specially in severe cases of LM. Its permits the adequate follow up, treatment planning and orientation of the patient and family group.