Medical management of vascular anomalies of the head and neck

Abstract Depending on impairment, treatment of vascular anomalies is decided on a case‐by‐case basis in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient and management of patients with vascular anomalies increasingly involves the use of medical drugs. The most common vascular tumor is infantile hemangioma where first‐line medical treatment, when necessary, is propranolol. Kasabach–Merritt phenomenon is now largely treated with sirolimus whereas first‐line treatment of coagulation disorders associated with venous malformations is based on low‐molecular‐weight heparins or direct anticoagulants. Sirolimus is the standard treatment for painful inflammatory manifestations of low‐flow vascular malformations such capillary, venous, and lymphatic malformations that can occur singly or in combination but PIK3CA inhibitors, originally developed in oncology, have shown promising results in patients with PIK3CA‐related overgrowth spectrum. Currently, medical treatments are poorly developed for high‐flow malformations such as arteriovenous malformations. However, new research aimed at delineating the different arteriovenous malformations based on molecular findings has given new hope for future development of targeted therapies.


| INTRODUCTION
Vascular anomalies are variable in aggressiveness depending on their type, size, and topography as well as the age of the patient. Some vascular anomalies are responsible for cosmetic discomfort, but others can be life-threatening. In most cases, the management of head and neck vascular anomalies requires a multidisciplinary approach involving surgical and/or laser medical treatment and, in some cases, interventional radiology. Some drug treatments have a proven antiangiogenic effect leading to shrinkage of the vascular anomaly, whereas others are only useful for improvement of functional ability such as anticoagulants used for venous malformations (VMs) that are often complicated by thrombosis. The last decade has been marked by the use of highly efficacious beta-blockers for infantile hemangiomas (IHs) and by the growing interest of mammalian target of rapamycin (mTOR) inhibitors in various aggressive vascular anomalies with slow-flow and/or partial lymphatic differentiation. More recently, identification of the molecular mechanisms associated with vascular anomalies has led to optimism that targeted therapies can be developed.

| Beta-blockers
Since the discovery of the efficacy of propranolol in 2008, 1 oral betablockers have become the first-line medical treatment for complicated IHs. However, the mode of action of beta-blockers remains poorly understood. 2 It has been suggested that propranolol targets several cell types in IH including stem cells, endothelial cells, and/or pericytes by means of β-adrenergic receptor-dependent and -independent mechanisms. A recent proteomic analysis showed that aquaporin-1 (AQP1), a membrane water channel protein modulated in tumor cell migration and invasion, is a major driver of beta-blocker antitumor response. In IH samples, AQP1 was found exclusively in the perivascular layer made of telocytes. Functional in vitro studies showed that AQP1-positive telocytes play a critical role in IH response to propranolol. 3 Propranolol is the only drug officially approved by both the

U.S. Food and Drug Administration and the European Medicines
Agency for the treatment of IHs (see Table 1 for guidelines) based on a pivotal randomized study published in 2015. 4 Oral propranolol is dramatically effective in treating IHs: when treatment is given early, at the onset of the proliferative phase, the tumor growth is stopped.
Propranolol works rapidly and is particularly effective for treatment of subglottic IHs 5,6 and periorbital IHs 7 that are responsible for visual axis obstruction. The indication and initiation of propranolol must be performed in an experienced center with monitoring of blood pressure and heart rate 1 h and then 2 h after first the dose, and then treatment is given on an outpatient basis. The recommended dose of propranolol is 3 mg/kg/day in two divided doses. In clinical studies, complete or almost complete disappearance of the IH was observed in 60% of cases after 6 months of treatment 4 and in up to 75% of cases if the treatment was given until 1 year of age. 8 When stopping propranolol, a relapse of the IH was observed in 10% to 15% of cases, and most often the regrowth was moderate and responsive to a further course of propranolol if necessary. 9,10 Relapses are frequently observed in large facial IHs, and the standard of care is to maintain treatment until 1 year of age in these patients. A recent study on large facial IHs showed that the median length of propranolol treatment was 16 months with a median age at treatment cessation of 21 months, and this was extended to 25 months if the V3 segment was involved (i.e., location in the beard area). 10 Unlike corticosteroids, resistance to treatment is rare and late treatment of IHs beyond the proliferative phase is also possible. 11 The acceptability and tolerance of propranolol is usually good in infants. 12 The main side effects reported in infants are hypoglycemia in fasting situations, worsening of bronchospasm during outbreaks of bronchiolitis, and sleep disturbances. Bradycardia is more rarely observed, and asymptomatic hypotension and diarrhea are sometimes present at the start of treatment. Propranolol is also the first-line medical treatment for PHACE syndrome, 13 as short-and long-term safety data have been found to be reasonable. 10,13 Other beta-blockers including nadolol, 14 acebutolol, 15 and atenolol 16 have worked successfully in small series of IH patients. To date, however, there is not sufficient data to conclude these beta-blockers are superior, nor a have better tolerance, moreover none of these molecules have a marketing authorization for this indication. Topical beta-blockers have been applied on IHs, especially timolol which has been formulated as eye drops. The first open studies were encouraging and showed a potential effect on superficial IH, 17 however, a recent randomized study demonstrated a limited benefit of timolol in resolving IH when given during the early proliferative stage. 18 The conclusion is that the value of topical beta-blockers in the management of complicated IH forms remains limited. In addition, other studies have shown that timolol is transcutaneously absorbed and significative blood levels have been found in infants 19  kaposiform hemangioendothelioma, and tufted angiomas (TAs), interest of propranolol seems anecdotal, 20 except in angiosarcomas in association with radiotherapy and/or chemotherapy. 21 Propranolol is unnecessary in LMs and VMs. 22 Concerning arteriovenous malformations (AVMs), propranolol may help to reduce flow and ameliorate patient comfort 23 and encouraging results on epistaxis has been reported in hereditary telangiectasia. 24

| mTOR inhibitors
Sirolimus, also called rapamycin, was discovered in the 1970s as a substance produced by Streptomyces hygroscopicus. Sirolimus was initially considered an antibiotic, then later used as an immunosuppressant. Current guidelines for sirolimus use are described in Table 2. It acts by inhibiting mTOR, a serine/threonine kinase regulated by phosphoinositide 3-kinase (PI3K) and Akt, key elements of many cellular processes such as proliferation, apoptosis, and angiogenesis. Sirolimus thus has antiproliferative, immunosuppressive, antiangiogenic, and antilymphangiogenic properties. 25 Sirolimus is currently used in oncology, especially in angiolipomas and astrocytomas linked to tuberous sclerosis. Other mTOR inhibitors, also referred to as rapalogs, include everolimus, temsirolimus, and deforolimus.
The first publication reporting the efficacy of sirolimus in vascular anomalies concerned a child with hypertrophic syndrome associated with a germline mutation of the PTEN gene. 26 More than a hundred publications have followed, mainly on vascular tumors complicated by thrombocytopenia and/or the Kasabach-Merritt phenomenon, 27 and low-flow vascular malformations (LM and VM). [28][29][30][31] Recently, a randomized clinical trial showed that sirolimus treatment led to a decrease in LM volume as well as improvement of oozing and bleeding and an increased quality of life. 32 In cases of combined LM/VM, sirolimus significantly reduced pain, oozing, and bleeding, however, benefits were much lower than for cases with VM alone. 32 Sirolimus has not been as effective in the treatment of AVMs. 33  The side effects commonly reported during treatment with sirolimus in vascular anomalies are rarely severe; the most common are oral mucositis, digestive disorders (abdominal pain, anorexia), headaches, and asthenia. Rare cases of hypersensitivity pneumonitis have been reported, as well as cases of arterial hypertension and induced lymphoedema, presumably by inhibition of lymphangiogenesis. 36 Biological disturbances may also occur: anemia and cytopenia, which may require discontinuation of treatment; microcytosis, which occurs frequently (probably linked to the interaction of sirolimus with iron metabolism); and elevation of blood lipids and glucose, which is usually without clinical consequences. The duration of treatment of vascular anomalies with sirolimus is at least 6 months, but the time course is not codified and is currently discussed between doctors, parents, and child.
In the event of prolonged treatment, some teams advise Pneumocystis prophylaxis (cotrimoxazole or pentamidine).
Topical sirolimus is not marketed, 37

| Interferon alpha 2a and 2b
Interferon alpha is an antiangiogenic agent that decreases the proliferation of endothelial cells. Indications are currently limited to severe and complicated IH or vascular tumors not responding to propranolol nor corticosteroids 38 or LMs with osteolysis. 39 The dosage varies from 1 to 3 million units/m 2 /day by subcutaneous injection and duration of the treatment varies between 6 and 12 months. Fever and muscle aches (flulike symptoms) are common side effects, 38 especially early in treatment.
Less common side effects include hepatic and hematologic toxicity, hypothyroidism, and depressive syndrome, and in children severe neurotoxicity with spastic diplegia and developmental delay have been reported.

| Vincristine
Vincristine is an antiangiogenic agent that interferes with mitotic microtubules and induces apoptosis of tumor cells. Prior to 2008, it was indicated in severe complicated IH that was unresponsive to corticosteroids or in Kasabach-Merritt phenomenon. 40

| Thalidomide and lenalidomide
Thalidomide and lenalidomide are potent immunosuppressive and antiangiogenic agents effective in the treatment of inflammatory diseases and various cancers (e.g., myeloma, lymphomas, and epithelioid hemangioendothelioma). Some specialized centers use thalidomide for AVMs with and reported effectiveness against pain and bleeding, 41 however, this drug has severe side effects such as neuropathy and teratogenicity.

| Targeted therapies
Recently, identification of specific genetic mutations in vascular anomaly patients has made it possible to develop targeted therapies, 41

| Steroids
For many years, corticosteroids have been the first-line treatment for complicated IHs and are still used as second-line therapy if betablockers are contraindicated. 49 Corticosteroids are less effective than beta-blockers and responsible for many side effects such as high blood pressure, slowdown of growth, and opportunistic infections. In Kasabach-Merritt phenomenon and inflammatory outbreaks of LMs, corticosteroids have been gradually replaced by sirolimus. 27,32

| Tranexamic acid
Tranexamic acid is an antifibrinolytic agent that helps stabilize the clot. It can be used topically for controlling bleeding in vascular anomalies such as congenital hemangiomas 50 or superficial lymphangiectasias of the tongue, however, it should be used orally with caution as it can promote thrombosis.

| MEDICAL MANAGEMENT STRATEGY
In practice, the drug treatment of AVMs (Table 3)  LMWH treatment is sometimes essential to avoid clotting imbalance after surgery or interventional radiological procedures.
For high-flow malformations such as AVMs, no drug treatment has a proven efficacy against these potentially devastating disorders.
Beta-blockers or sirolimus can be used for palliative care to reduce flow and improve patient comfort. Currently, progress is being made in delineating the different types of AVM based on molecular findings which may lead to the development of targeted therapies. For example, a clinical study with the MEK inhibitor trametinib is currently being conducted. It is likely that in the future AVMs will be treated with a targeted drug therapy given before and/or after surgery or embolization similar to the way some cancers are now being managed.

CONFLICT OF INTEREST
The author has declared that no competing interest exists as regards the conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ORCID
Christine Léauté-Labrèze https://orcid.org/0000-0002-4110-2607 F I G U R E 2 Same high-risk infantile hemangioma at 12 months of age (10 months of propranolol therapy). No visual impairment is noted, if necessary, residual telangiectasia can be treated later with a vascular laser.