Vascular Malformations: Current Progress Toward Drug Therapy

INTRODUCTION

Vascular malformations are congenital disorders of vasculogenesis that affect approximately 0.5% of the population. Although benign, lesions cause significant morbidity, primarily because they enlarge over time. A common problem is psychosocial distress because most involve the integument resulting in a deformity. Other complications include: bleeding, pain, ulceration, loss of function, organ failure, and death.

Vascular malformations are differentiated from vascular tumors based on endothelial proliferation.¹ Vascular malformations classically have been considered quiescent lesions with minimal cellular turnover. Vascular tumors, in contrast, have significant endothelial division. Because of this discrepancy in cellular proliferation, vascular tumors, similar to other neoplasms, have been able to be treated with drugs. For example, infantile hemangioma responds to beta-blockers and corticosteroids, while kaposiform hemangioendothelioma is managed with sirolimus or vincristine.

Physicians who focus on patients with vascular malformations recognize that these lesions are not static. Vascular malformations do exhibit cellular activity and growth, although less than vascular tumors. Drug development for vascular malformations has been limited because: (1) embryological structural problems are not believed to be amenable to pharmacotherapy, (2) drugs used for vascular tumors in the past were not effective for malformations (e.g., propranolol, prednisone), and (3) the mechanisms by which vascular malformations enlarge are unknown.

Over the past several years tremendous growth in our understanding of the pathophysiology of vascular malformations has occurred. Our group has focused on understanding the biology of vascular anomalies in order to develop improved therapies. The first step in solving the mystery of vascular malformations is to determine their genetic basis. Technological advances in next generation sequencing and bioinformatics has allowed the identification of low-level mutations in many somatic diseases, including vascular malformations (Table 1).

Table 1.

Genetic mutations associated with vascular malformations.

Vascular Malformation	Mutation
Capillary Malformation (CM)	GNA11 GNAQ PIK3CA
Lymphatic Malformation (LM)	PIK3CA
Primary Lymphedema	CCBE1 FOXC2 SOX18 VEGFR3
Venous Malformation (VM)	PIK3CA TIE2
Cerebral Cavernous Malformation	CCM1/KRIT1 CCM2/Macalvernin CCM2/PDCD10
Fibroadipose Vascular Anomaly	PIK3CA
Glomuvenous Malformation	Glomulin
Verrucous Venous Malformation	MAP3K3
Arteriovenous Malformation (AVM)	BRAF HRAS KRAS MAP2K1
Capillary Malformation-Arteriovenous Malformation	EPHB4 RASA1
Hereditary Hemorrhagic Telangiectasia	ACVRL1/ALK1 ENG GDF2 SMAD4
Parkes Weber Syndrome	EPHB4 RASA1
PTEN Hamartoma-Tumor Syndrome	PTEN
Overgrowth Syndromes
Maffucci	IDH1/IDH2
PIK3CA-Related Overgrowth Spectrum (PROS)   CLOVES   Klippel-Trenaunay   Facial Infiltrating Lipomatosis   Megalencephaly-Capillary Malformation	PIK3CA
Proteus	AKT1

Currently, the mutations responsible for most types of vascular malformations have been identified.² Variants typically effect tyrosine kinase signaling along either the RAS or PIK3CA pathways. Mutations usually are enriched in the endothelial cells. Although the mutations and cell-type driving the pathophysiology of the malformations are known, the mechanisms by which the mutation causes the malformation and results in its growth are being studied.

Now that the mutations for vascular malformations have been identified, investigators can test potential drug therapies on cell function in-vitro as well as attempt to develop in-vivo animal models. Although numerous types of vascular malformations exist, almost all of them fall under 4 major categories (capillary malformation, lymphatic malformation, venous malformation, arteriovenous malformation [Figure 1]) that mirror the types of vasculature (capillaries, lymphatics, veins, arteries). Vascular malformations also contribute to overgrowth syndromes.

Figure 1.

Major types of vascular malformations and an example of an overgrowth syndrome. (A) Capillary malformation. (B) Venous malformation. (C) Lymphatic malformation. (D) Arteriovenous malformation. (E) CLOVES syndrome.

Capillary Malformation (CM)

Capillary malformation is the most common type of vascular malformation, affecting approximately 1/300 individuals. Lesions are present at birth as pink cutaneous stains. CMs darken, the skin thickens, tissues beneath the lesion become enlarged, and pyogenic granulomas can develop. First-line therapy is pulsed-dye laser to lighten the malformation; overgrowth of tissues is managed with resection. Unfortunately, CMs re-darken and enlarge following treatment. Almost all CMs are sporadic and most are caused by mutations in GNAQ.^3,4 Diffuse lesions involving an extremity may result from GNA11 or PIK3CA variants.^5,6 The cell-type enriched for the somatic mutations is the endothelial cell lining the blood vessels which is thus driving the pathophysiology of this lesion.⁴ Although the mutations responsible for CMs are known, the biology by which the mutation causes the lesion and results in its growth remains unclear. Animal models of CM do not exist and targeted drug therapy has not been investigated experimentally or clinically.

Lymphatic Malformation (LM)

LMs result from abnormal lymphatic development and cause bleeding, infection, pain, ulceration, and destruction of tissues. Treatment includes sclerotherapy, laser, or resection. LMs are caused by mutations in PIK3CA.⁷ Primary lymphedema also is a type of LM and germline mutations in approximately 20 genes are known to cause this condition: VEGFR3, VEGFC, CCBE1, FOXC2, GJC2, GJA1, PTPN14, SOX18, HGF, KIF11, PTPN11, SOS1, GATA2, IKBKG, RASA1, 15q locus, ITGA9, KRAS, RAF1, HRAS.⁸ LM was the first vascular malformation to be successfully treated with targeted drug therapy using the mTOR inhibitor sirolimus (rapamycin) which blocks the PIK3CA signaling pathway.^9–11

LMs currently are the most common type of vascular malformation treated with pharmacotherapy (Figure 2A). Initially, only patients with very problematic lesions that had failed traditional treatments received the drug. Because sirolimus has a favorable toxicity profile, however, the indications for treating patients with this medicine have expanded. Sirolimus is now considered as first-line therapy in some patients and is used to reduce recurrence following sclerotherapy and resection. Recently, a genetically engineered mouse model of LM was developed and PIK3CA inhibitors showed efficacy.¹² Because PIK3CA mutations are the most prevalent variants in the field of vascular anomalies, pharmacotherapeutic development targeting this gene has received the most attention.

Figure 2.

Current treatment of vascular malformations with pharmacotherapy. (A) Successful management of a tongue lymphatic malformation before (above) and after (below) oral sirolimus (photos courtesy of Cameron Trenor, MD). (B) Patient with an AVM treated with oral trametinib which improved her symptoms and slowed the progression of the lesion.

Venous Malformation (VM)

Several germline and somatic mutations result in VMs and many exhibit a genotype-phenotype relationship. Mutations in the tyrosine kinase receptor TIE2 cause both autosomal dominant cutaneomucosal VMs as well as most sporadic VMs.^13–15 Cerebral cavernous malformation (CCM) involves the brain and may be sporadic or autosomal dominant. CCM can be associated with hyperkeratotic cutaneous lesions and are caused by mutations in CCM1/KRIT1, CCM2/macalvernin, or CCM2/PDCD10.¹⁶ A glomulin mutation leads to autosomal dominant glomuvenous malformation (GVM). GVMs are small, multifocal, typically cause pain, and do not respond well to sclerotherapy.¹⁷ A MAP3K3 variant causes somatic verrucous venous malformations (VVM) that is a hyperkeratotic lesion usually affecting an extremity.¹⁸ Somatic VMs also result from PIK3CA mutations which usually are located subcutaneously.¹⁹ Fibroadipose vascular anomaly (FAVA), which was previously thought to be an intramuscular VM, results from PIK3CA variants.⁷

VMs enlarge, especially during puberty, and are managed by sclerotherapy and resection. Like all vascular malformations, they can re-grow following treatment. A favorable cell-based animal model exists for VM that has been used for drug testing.²⁰ Endothelial cells containing disease-causing mutations injected subcutaneously into immunodeficient mice create VMs that reasonably recapitulate the human phenotype. Sirolimus has shown efficacy against VMs in both animal models and humans.^20–22

Arteriovenous Malformation (AVM)

Arteriovenous malformation is an abnormal connection between arteries and veins without a normal capillary bed. Oxygen delivery to tissues is reduced and patients suffer from pain, bleeding, ulceration, deformity, and rarely congestive heart failure. AVM is the most active “tumor-like” malformation and grows, especially during puberty. AVM can be the most challenging type of vascular malformation to treat. Management includes embolization and resection. Unfortunately, AVMs have a high recurrence rate following these interventions.

Autosomal dominant hereditary AVMs can occur. Hereditary hemorrhagic telangiectasia (HHT) causes epistaxis, telangiectasias, and visceral AVMs and results from mutations in ENG, ACVRL1/ALK1, SMAD4, or GDF2.²³ Capillary malformation-arteriovenous malformation (CM-AVM) and Parkes Weber syndrome (PWS) are caused by germline variants in RASA1 and EPHB4.^24–26 Germline PTEN mutations result in PTEN hamartoma-tumor syndrome; 50% of patients have AVMs that are typically multifocal, intramuscular, and have extra adipose tissue.²⁷

Almost all AVMs are sporadic and most extracranial and intracranial lesions are caused by mutations in MAP2K1 and KRAS, respectively.^28,29 Extracranial AVMs can result from HRAS, BRAF, and KRAS variants as well.^30–32 Mutations in BRAF also have been found to cause intracranial AVMs.³³ Although a genotype-phenotype association has not been present in intracranial AVMs, a relationship is emerging with extracranial AVMs. Lesions caused by HRAS variants have extra adipose tissue.³⁰ KRAS mutations are more likely to cause intramuscular fast-flow vascular anomalies (IFVA) and lesions that appear similar to congenital hemangiomas.^31,34 AVM MAP2K1 mutations are located in the endothelial cell and activate signaling causing tissue overgrowth by a cell non-autonomous mechanism.^28,35,36 The activating effects of the mutation in endothelial cells can be mitigated by treating the cells with a MAP2K1 inhibitor.³⁵ Consequently, patients in our center and others are being treated with a FDA-approved MAP2K1 inhibitor (trametinib) that was developed to treat melanoma and lung cancer (Figure 2B). Results in our experience as well as published data show that for the first time a drug can prevent the growth of AVM as well as cause it to become smaller.^37,38

Vascular Malformation Overgrowth Syndromes

Capillary, venous, lymphatic, and arteriovenous malformations can be a major component of overgrowth syndromes. Proteus syndrome (progressive, asymmetrical overgrowth of the skeleton, cerebriform nevi of the hands or feet, epidermal nevi, vascular malformations, cerebral anomalies, skull hyperostosis, and megaspondylodysplasia) results from an AKT1 mutation.³⁹ Maffucci syndrome (multiple enchondromas and soft-tissue VMs) is caused by variants in IDH1/IDH2.⁴⁰

The most common overgrowth conditions result from PIK3CA mutations and are classified under the term PROS (PIK3CA-related overgrowth spectrum).^41,42 CLOVES syndrome (congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies), Klippel-Trenaunay syndrome (capillary-lymphatic-venous malformation of an extremity causing overgrowth), and facial infiltrating lipomatosis result from a PIK3CA mutation.^7,43,44 The mutation is present throughout all structures and is enriched in non-endothelial cells.⁴⁵ Megalencephaly-capillary malformation (MCM) causes neurologic abnormalities and patients typically have a CM involving the upper lip, trunk, or extremity.⁴⁶ PROS conditions are being treated successfully in our center and others with sirolimus and PIK3CA inhibitors.^47–49

Conclusions

It is a very exciting time in the field of vascular anomalies. Vascular malformations are at the crossroads of plastic surgery, basic research, innovation, and interdisciplinary collaboration. Molecular discoveries have been translated into clinical practice. We now use genetic testing to identify lesions with an unclear diagnosis, as well as to screen patients for potential drug treatment. We are at a point in time where we are transitioning from managing vascular malformations with resection, embolization, sclerotherapy, and laser to pharmacotherapy. Several FDA approved medications used off-label for vascular malformations have shown efficacy. In the future, drugs for vascular malformations will be a routine part of their management (Figure 3). Medications will be used to prevent these lesions from enlarging, as well as reducing their risk of recurrence following “traditional” interventions.

Figure 3.

Future of drug treatment for vascular malformations. Our goal is to develop pharmacotherapy for patients that will prevent the enlargement of their lesion. In the future, this patient will receive medicine in childhood (left) that will stop his AVM from growing to cause significant morbidity in adulthood (right).