Key points
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Most vascular anomalies are associated with mutations, most commonly somatic, disrupting tyrosine kinase receptor signaling through the PIK3/AKT and RAS/MAPK/MEK pathways.
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Molecularly targeted medical therapeutics are important treatment considerations in the interdisciplinary management of complicated vascular anomalies.
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Sirolimus, a potent mammalian target of rapamycin inhibitor, has been demonstrated to be a safe and efficacious treatment for complicated vascular anomalies in numerous studies.
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Currently, most nontargeted and molecularly targeted medications, other than alpelisib, are used off-label and on a compassionate basis for complicated management of vascular anomalies.
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Cost of genetic testing and procurement of molecularly targeted medications remain challenges in the care of complicated vascular anomalies.
Introduction
Optimal management of complex vascular anomalies aims to not only treat acute issues, such as infection or effusion, but also prevent potential future complications and improve physical functioning and quality of life. Historically, medical treatment for vascular anomalies focused on managing complications with supportive measures, such as pain control, antibiotics, dental hygiene, and compression garments. In addition to the creation of a formal classification system of vascular anomalies by the International Society for the Study of Vascular Anomalies, the serendipitous discovery of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, as an efficacious treatment for complicated vascular anomalies, boosted interest in the field, propelling clinical and basic science research, and began to shift the treatment paradigm. ,
The study of the pathophysiology and molecular biology of vascular tumors and malformations has rapidly expanded. In the last decade, germline and somatic mutations in the endothelial receptor intracellular signaling pathways, phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3)/AKT and RAS/MAPK/MEK, have been identified in numerous vascular anomalies. Overactivation of tyrosine kinase receptor signaling through the PIK3/AKT and RAS/MAPK/MEK pathways causes disruption of normal cellular activities, resulting in cellular proliferation, survival advantage, and angiogenesis, which is thought to be the mechanism driving the development and/or progression of vascular anomalies. Although optimal management of patients with complex vascular anomalies requires an interdisciplinary approach, these genomic discoveries have led to new therapeutic options and the increasing importance of the hematologist/oncologist within multidisciplinary vascular care teams. This article discusses the use of molecularly targeted medications and anti-angiogenesis agents in the management of complicated vascular anomalies. Table 1 lists the known associated genetic mutations for the various vascular anomaly phenotypes. Fig. 1 illustrates the molecular targets of medications within the PIK3CA/AKT and RAS/MAPK/MEK pathways.
| Diagnosis/Phenotype | Genetic Mutations |
|---|---|
| Lymphatic malformation, sporadic | PIK3CA |
| Klippel-Trenaunay syndrome (capillary lymphatic venous malformation or capillary venous malformation with overgrowth of affected extremity) | PIK3CA |
| CLOVES syndrome | PIK3CA |
| Megalencephaly–capillary malformation (MCM) or Megalencephaly–capillary malformation–polymicrogyria syndrome (MCAP) | PIK3CA |
| Generalized lymphatic anomaly (GLA) | PIK3CA |
| Kaposiform lymphangiomatosis (KLA) | NRAS |
| Venous malformations, sporadic | PIK3CA, TIE2/TEK |
| Glomuvenous malformation | GLMN |
| Multiple cutaneous and mucosal venous malformation (VMCM) | TIE2/TEK |
| Blue rubber bleb nevus syndrome (BRBNS) | TIE2/TEK |
| Arteriovenous malformations, extracranial and sporadic | MAP2K1, KRAS, NRAS, BRAF |
| Arteriovenous malformation, intracranial and sporadic | KRAS, BRAF |
| Phosphatase and tensin homolog hamartoma | PTEN |
| Fibroadipose vascular anomaly | PIK3CA |
| Vein of Galen aneurysmal malformation, subtype of cerebral AVM | EPHB4 |
| Capillary malformation–arteriovenous malformation type 1 (CM-AVM1) | RASA1 |
| Capillary malformation–arteriovenous malformation type 2 (CM-AVM2) | EPHB4 |
| Hereditary hemorrhagic telangiectasia syndrome (HHT) | ACVRL1, ENG, SMAD4, GDF2/BMP9 |
| Capillary malformation, sporadic | GNAQ, GNA11 |
| Sturge-Weber syndrome | GNAQ |
| Facial infiltrating lipomatosis | PIK3CA |
Mammalian target of rapamycin inhibitors: sirolimus/everolimus
Sirolimus, also known as rapamycin, is a specific inhibitor of mTOR, a serine/threonine kinase in the PIK3/AKT pathway that regulates protein synthesis and cell growth through downstream signaling. Before use in vascular anomalies, sirolimus was used to treat individuals with tuberous sclerosis and lymphangioleiomyomatosis or LAM, conditions caused by TSC1 and TSC2 mutations that affect the PIK3/AKT pathway. Sirolimus was first used under compassionate-care protocol in a patient with kaposiform hemangioendothelioma, severe Kasabach-Merritt phenomenon (KMP), and multiorgan failure who was refractory to all previously known effective treatments, including corticosteroids, vincristine, cyclophosphamide, bevacizumab, and embolization. With sirolimus treatment, the patient had complete resolution of KMP as well as significant improvement in pain, lesion size, and functional abilities. Hammill and colleagues also reported similar benefits in 4 other individuals with various complex vascular anomalies. Subsequently, a phase 2 clinical trial evaluating the safety of efficacy of sirolimus treatment in multiple complicated vascular anomalies revealed an overall response rate of 85% at 1 year of treatment with low toxicity. Although radiologic disease improved in approximately half of the patients, most had improved clinical symptoms and/or quality of life. Given these encouraging results, the use of sirolimus quickly expanded, proving efficacious in a wide variety of vascular tumors and malformations and demonstrating additional benefits when used in combination with surgery and interventional procedures.
As demonstrated in the phase 2 clinical trial, sirolimus is efficacious for the treatment of complex microcystic and macrocystic lymphatic malformations by inhibiting overactive PIK3/AKT signaling caused by the gain-of-function PIK3C A mutations in lymphatic malformations. Numerous studies, along with case series and reports, have demonstrated similar benefits for lymphatic malformations and combined malformations with a lymphatic component. Reduction of malformation size, cutaneous lymphatic lesions, malformation-associated infections, bleeding complications, and pain, along with improved quality of life, have all been reported with systemic sirolimus treatment. With minimal to no systemic absorption, topical sirolimus, now commercially available in the United States, has also shown benefit in treating cutaneous manifestations of lymphatic malformations by lessening the number or size of lymphatic vesicles as well as lymphatic leakage or bleeding from the skin. From the author’s clinical experience, some patients experience skin irritation or a sensation of burning, but alteration of the vehicle, that is, cream, ointment, or similar, can sometimes resolve this issue.
In the head and neck area, sirolimus has demonstrated importance in the multidisciplinary management of cervicofacial lymphatic malformation, as shown in Fig. 2 . One case series of 8 infants with cervicofacial lymphatic malformations, refractory to sclerotherapy and/or surgery, responded positively to sirolimus therapy with modest to significant response with acceptable side effects. Similarly, another case series of 19 patients with cervicofacial lymphatic malformations demonstrated similar efficacy with a reduction in malformation volume and improved or resolved mucosal vesicles while on sirolimus. In a retrospective, multicenter review of 13 patients with an extensive lymphatic malformation of the head and neck region, who previously underwent placement of tracheostomy and subsequently received sirolimus treatment, Holm and colleagues found that tracheostomy was able to be reversed in 62% of the patients with a median duration of 18 months of sirolimus treatment before tracheostomy removal. Sirolimus therapy has also shown significant improvements in macroglossia and oral/tongue bleeding secondary to lymphatic or venous lymphatic malformation. , Topical administration of sirolimus is currently being investigated for lingual microcystic lymphatic malformations (NCT04128722).
