Venous Malformations

Abstract

Venous malformations, the most common type of vascular malformation, are slow-flow lesions resulting from disorganized angiogenesis. The International Society for the Study of Vascular Anomalies (ISSVA) classification offers a categorization scheme for venous malformations based on their genetic landscapes and association with congenital overgrowth syndromes. Venous malformations present as congenital lesions and can have broad physiologic and psychosocial sequelae depending on their size, location, growth trajectory, and tissue involvement. Diagnostic evaluation is centered around clinical examination, imaging evaluation with ultrasound and time-resolved magnetic resonance imaging, and genetic testing for more complex malformations. Interventional radiology has emerged as first-line management of venous malformations through endovascular treatment with embolization, while surgery and targeted molecular therapies offer additional therapeutic options. In this review, an updated overview of the genetics and clinical presentation of venous malformations in conjunction with key aspects of diagnostic imaging and treatment are discussed.

Vascular malformations are congenital lesions of disorganized angiogenesis that occur secondary to sporadic mutations in somatic cells. ¹ The incidence of congenital vascular malformations is approximately 1.5%. ² Lesions are typically subdivided into high flow and low flow. High-flow lesions include arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs), while low-flow malformations include venous malformations (VMs), lymphatic malformations (LMs), and capillary malformations (CMs). ¹

VMs are the most common type of vascular malformation, accounting for up to 70% of vascular malformations, and are characterized by dysplastic vessels that are frequently separate from normal adjacent veins, but can be contiguous with the deep-venous system. ^{3 4} These malformations can cause physical symptoms (e.g., pain, swelling), functional limitations, and psychological distress due to their cosmetic appearance. ^{4 5 6} New medical and procedural modalities have emerged for the treatment of VMs. ⁶ Interventional radiologists have become the cornerstone of both the diagnosis and management of VMs. ¹ This review describes the latest understanding of the genetic landscape, clinical presentation, and imaging findings of VMs, as well as relevant diagnostic and technical aspects regarding endovascular therapy.

ISSVA Classification and Genetic Landscape

Sporadic, somatic mutations in proteins regulating the relationships between endothelium and extracellular matrix are implicated in the dysplastic development of vessels observed in VMs. ⁷ The 2018 International Society for the Study of Vascular Anomalies (ISSVA) classification subdivides VMs based on their molecular and genetic landscapes. ⁸ Subtypes of VMs include common VM, familial VM cutaneomucosal (VMCM), blue rubber bleb nevus (Bean) syndrome VM, glomuvenous malformation (GVM), cerebral cavernous malformation (CCM), familial intraosseous vascular malformation, verrucous VM, and others. ⁸ The majority of mutations associated with VMs are sporadic (>98%), although familial subtypes exist. ⁹

The most frequently implicated gene is TEK (TIE2), which has been associated with both the common VM and familial VMCM subtypes. ^{7 8 9 10} PIK3CA has also been involved in this pathway, and is associated with the pathogenesis of common VMs and fibroadipose vascular anomaly (FAVA). ^{7 8 11 12} TEK (TIE2) and PIK3CA are involved in the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway, which regulates cell growth, proliferation, and angiogenesis. Activating mutations in TEK, a receptor tyrosine kinase, may lead to hyperphosphorylation and overactivation of the PI3K/AKT/mTOR pathway. Because the PIK3CA gene encodes the catalytic subunit of the PI3K protein, mutations in this gene may similarly lead to pathway overstimulation. ¹³ Thus, in venous endothelial cells, TEK and PIK3CA mutations can precipitate an increase in abnormal angiogenesis and vessel maturation leading to VM development. ^{7 9 10} Other genes may also be implicated in VM subtypes. For example, GVMs are typically attributed to loss-of-function mutations in glomulin, which may play a role in the differentiation of vascular smooth-muscle cells; these mutations often exhibit an autosomal dominant inheritance pattern. ^{14 15}

VMs can be associated with congenital overgrowth syndromes, which are also outlined by the ISSVA classification. ^{7 8 11 16 17} PIK3CA-related overgrowth syndromes (PROS) are a subset of syndromes associated with the PIK3CA mutation. ^{11 16} Given the role of the PI3K/AKT/mTOR pathway in cell growth across multiple tissue types, PROS can manifest broadly. ^{11 16} For example, Klippel–Trenaunay syndrome is characterized by VM and CM, with or without LM and bone or soft-tissue limb overgrowth. CLOVES (congenital lipomatous overgrowth, vascular anomalies, epidermal nevi, and spinal anomalies) syndrome is classified as LM, VM, and CM, with or without AVM and lipomatous overgrowth. ⁸ Congenital syndromes with mutations in other genes may also present similar to PROS. These include Servelle–Martorell syndrome, Maffucci syndrome, proteus syndrome, and Bannayan–Riley–Ruvalcaba syndrome. ^{8 11 16} The genetic mutations and clinical syndromes associated with VMs are summarized in Table 1 .

Table 1. Congenital syndromes associated with venous malformations.

Syndrome	Gene mutation	Findings
Blue rubber bleb nevus (Bean)	TEK (TIE2)	VM
Klippel–Trenaunay a	PIK3CA	CM, VM +/− LM, limb overgrowth
CLOVES a	PIK3CA	LM, VM, CM +/− AVM, lipomatous overgrowth
Servelle–Martorell		Limb VM, bone undergrowth
Maffucci	IDH1/IDH2	VM +/− spindle-cell hemangioma, enchondroma
Proteus	AKT1	CM, VM, and/or LM, asymmetrical somatic overgrowth
Bannayan–Riley–Ruvalcaba	PTEN	AVM, VM, macrocephaly, lipomatous overgrowth

Abbreviations: CM, capillary malformation; LM, lymphatic malformation; VM, venous malformation.

Source: Data taken from 2018 ISSVA classification. ⁸

^aPIK3CA-related overgrowth syndrome (PROS).

Clinical Presentation

VMs are always present at birth, although they may not be discernable until later in life. In contrast to hemangiomas of infancy, VMs are not vascular tumors, persist beyond childhood, and continue to grow, with increasing rapidity during hormone peaks (i.e., puberty and pregnancy). ^{1 18} VMs typically present as blue skin discoloration overlying a soft, compressible, nonpulsatile mass that may enlarge with positional changes and/or Valsalva maneuver ( Fig. 1 ). ^{1 4 18 19} Lesions can arise anywhere in the body, but are most commonly found in the extremities (40%) or head and neck (40%). ¹⁸ Lesions may be focal and involve only one layer of tissue, or they may be diffuse and transspatial across muscle, skin, and adipose tissue. Importantly, unlike focal VMs, diffuse VMs are not sequestered from main conducting veins. ⁴ In contrast to other VM subtypes, GVMs typically present as noncompressible pink, blue, or purple cobblestone-appearing nodular lesions that are generally limited to the skin and subcutis. ¹⁵

Fig. 1.

Cutaneous manifestations of venous malformations. Skin findings of venous malformations typically present as soft, compressible, flat, or slightly raised hyperpigmented to blue/purple lesions. Images a-f demonstrate these cutaneous manifestations on the left upper extremity and axilla ( a ), the tongue ( b ), the left lower extremity including the knee and leg ( c ), the dorsum of the right foot ( d ), the plantar surface of the right foot ( e ), and the dorsum of the left foot ( f ) ( a-f , black arrow). Deeper malformations may not show color changes, but present as raised varicosities ( E , white arrow).

VMs may be asymptomatic. However, when symptomatic, VMs can present as localized pain and swelling secondary to venous engorgement following prolonged stasis (e.g., in the morning after prolonged recumbency) or with increasing activity. ^{1 4 18 20 21} Additional symptoms are variable, and depend on size, location, and tissue involvement. ²² Mass effect and local infiltration can lead to nerve entrapment, muscular contracture, and local hemorrhage. ^{4 18 20 21} Due to the potential for skin disfigurement, VMs can also lead to psychosocial distress. ⁶ Rarely, VMs in certain anatomical locations can be life-threatening, such as deep cervical VMs which may increase the risk of airway compromise, or gastrointestinal VMs which can be associated with bleeding. ^{20 21}

Another important hallmark of slow-flow malformations such as VMs is localized intravascular coagulopathy (LIC), in which coagulopathy is confined to the vascular malformation. ^{20 23} LIC is characterized by elevated D-dimer and fibrin degradation products, decreased fibrinogen, factor V, factor VIII, and factor XIII, with or without mild-moderate thrombocytopenia. ^{20 21 22 23} Sequelae include chronic, recurrent microthrombi and bleeding, resulting in calcifications (phleboliths) and pain. ^{20 23} Though LIC rarely causes severe hemorrhage or thrombosis, it may progress to disseminated intravascular coagulation if additional stressors are present. ^{20 21} Importantly, LIC must be differentiated from Kasabach-Merritt syndrome, in which life-threatening thrombocytopenia occurs secondary to platelet sequestration in rapidly growing vascular tumors such as a large hepatic hemangioma or kaposiform hemangioendothelioma. ^{21 24}

Imaging

Multiple imaging modalities are typically used in the evaluation and treatment of VMs. Ultrasound (US) and magnetic resonance imaging (MRI) are preferred due to their lack of nonionizing radiation, given VM predilection for pediatric patients. ^{6 19}

Ultrasonography

US is easily accessible, inexpensive, and is often the preferred first-line modality for the evaluation of superficial VMs. ^{19 22 25} Typical VMs are characterized by a cluster of anechoic tubular structures with monophasic slow-flow on color Doppler ( Fig. 2 ). ^{19 25} However, variations are often seen, including hypoechoic and heterogenous spongiform lesions, and lack of Doppler flow in up to 20% of cases, possibly due to undetectable slow-flow or thrombosis. ²⁶ Calcified phleboliths secondary to thrombosis present as hyperechoic foci with posterior acoustic shadowing. ¹⁹ Contrast-enhanced US is an emerging modality that may be a promising method for detecting small arteriovenous shunts in VMs while minimizing cost and radiation exposure. However, its role in evaluating VMs has not been fully explored. ²⁷

Fig. 2.

Sonographic characteristics of venous malformations. Venous malformations may be within the subcutaneous tissues or intramuscular, and can often be transspatial. ( a ) The typical gray scale appearance of an intramuscular VM with anechoic venous channels (white arrows). ( b ) Compression of the anechoic venous channels (white arrows). Similar findings of pre-compression ( c ) and post-compression ( d ) gray scale ultrasound are shown by the white arrows.

Magnetic Resonance Imaging

Contrast-enhanced MRI is considered the gold-standard modality for the assessment of VMs. ^{4 6 22} MRI provides the best soft-tissue resolution to characterize the size and spatial extent of VMs. Dynamic MR angiography can also provide temporal resolution to evaluate flow. Nonenhanced T1-weighted spin-echo and T2-weighted fat-suppressed or STIR sequences are useful in assessing anatomic detail. ^{6 19} Anatomic features of importance to treatment planning include adjacent tissue involvement; size and number of intralesional, feeding, and draining vessels; and connection to a deep venous system. ^{4 6 19}

VMs are typically T1 hypointense and T2 hyperintense, although heterogenous T1 signal can be seen in the setting of thrombosis or stagnant/very slow flow ( Fig. 3 ). In regions of very slow or absent flow, fluid–fluid levels can be seen which are formed from the separation of plasma and hematocrit. ¹⁹ Gradient echo sequences can be useful to evaluate for the presence of phleboliths. Local subcutaneous tissue overgrowth and muscular atrophy are also well characterized with MRI. ¹⁹

Fig. 3.

Magnetic resonance imaging characteristics of venous malformations. ( a ) T2-weighted fat-saturated axial images of the mid-thigh demonstrate a T2-hyperintense intramuscular lesion with hypointense phleboliths interspersed within (white arrows). Stagnant blood in venous malformations appears fluid intensity on T2-weighted sequences. T1-weighted pre-contrast ( b ) and post-contrast enhanced fat-saturated ( c ) axial images through the mid-thigh demonstrates the intramuscular venous malformation as slightly hyperintense to normal muscle with enhancement after the administration of gadolinium contrast. These findings are typical for the MR appearance of venous malformations. In a different patient, T2-weighted axial images through the calf demonstrate a T2-hyperintense venous malformation with fluid–fluid levels within the gastrocnemius muscle ( d ). Fluid–fluid levels are the result of stagnant/flow that allows for the separation of blood into hematocrit and plasma. Venous-phase time-resolved imaging ( e ) shows late-phase venous filling of aberrant intramuscular venous channels in the gastrocnemius.

MRI is limited by cost, availability, and long acquisition times, which are of particular concern in the pediatric population, where sedation or anesthesia may be necessary to obtain diagnostic-quality images.

Venography

Digital subtraction venography (DSV) with US-guided intralesional contrast injection is essential in identifying and characterizing draining veins and specific treatment planning, and is typically performed at the time of treatment. ^{6 19} Draining veins can be categorized into various phenotypes: (1) no visible draining veins, (2) drainage into normal veins, (3) dysplastic draining veins, or (4) venous ectasia. ^{19 25 28} Additional venographic findings may include slow contrast enhancement of tubular channels and potential drainage into a deep venous system ( Fig. 4 ). ⁶ However, limited visualization of other anatomical features, exposure to ionizing radiation, and the invasive nature of DSV limit the role of this modality to complex lesion diagnosis when used outside of treatment sessions. ^{6 19}

Fig. 4.

Venographic findings of venous malformations. ( a ) The typical “mass-like” appearance of an intramuscular venous malformation with a cloud-like opacification pattern. Deep venous drainage is not appreciated on initial venography, making the lesion in a an ideal lesion to treat with sotradecol foam. ( b ) Post-sotradecol embolization. Embolization was stopped just as venous outflow had begun to opacify (white arrow).

Radiography and Computed Tomography

Although not routinely used for the characterization of VMs, radiographs may help evaluate for the presence of phleboliths. Radiography also helps in assessing the presence or absence of associated osseous or general soft-tissue overgrowth or undergrowth, and may suggest more complex diagnoses such as overgrowth syndromes. ¹⁹ CT is infrequently used due to concerns with ionizing radiation, particularly in the pediatric population. It is typically reserved for deeper lesions with concern for osseous involvement, and may visualize phleboliths in lesions not well assessed with US or radiographs. ⁴

Treatment Modalities and Efficacy

VMs are thought to enlarge and become increasingly symptomatic over time, and rarely regress spontaneously. Indications for treating VMs include recurrent swelling, pain, deformity, thromboembolism, or interference with physical activity. ⁵

Lesion size and extent must be considered when planning treatment. Smaller, localized lesions may resolve after a single treatment session or modality, whereas larger, more extensive lesions can require multiple treatment sessions or modalities. Additionally, patient goals of care (e.g., cosmesis, functionality, pain alleviation) should also be taken into consideration when devising a treatment approach. ²² The main forms of therapy for VMs include embolization/sclerotherapy, surgical resection, and molecular targeted therapy ( Table 2 ). ²²

Table 2. Summary of management approaches for venous malformations.

Approach	Agent	Mechanism	Considerations	Efficacy
Sclerosant	STS 1 6 40 42 43	Lysis endothelial cells, promoting coagulation	Administered as embolic foam; low side effect profile including pain, urticaria, skin necrosis, hyperpigmentation	Estimates in literature range from 50–67%
	Ethanol 1 6 22 37 45 46	Endothelial injury leading to thrombosis	Most significant side effect profile of sclerosants	Considered most efficacious sclerosant. Estimated efficacy 74%
	Bleomycin 11 22 31	Disruption of tight junction between endothelial cells	Least inflammatory of sclerosants; advantageous in head/neck VMs	In one study, bleomycin improved symptoms 65% of time compared to 95% for ethanol
Surgical	Resection 22 47 67	Mechanical removal of VM	Will result in scarring; risk of bleeding, can be used after sclerotherapy downsizing	In one study, 74.4% complete resolution of pain, 92.3% improvement in pain
Medical	Sirolimus 10 48 49 50	mTOR inhibitor	Oral administration; blood/bone marrow toxicity	At least >20% response in 11/12 capillary venous lymphatic malformation, 3/3 venous lymphatic malformation
	Alpelisib 51 54 55	PI3KCA inhibitor	Oral administration	Yet to be studied clinically but effective in in vitro and mice models

Abbreviations: mTOR, mammalian target of rapamycin; STS, sodium teracycle sulfate; VM, venous malformation.

Embolization and Sclerotherapy

Sclerotherapy is an endovascular treatment modality, which has emerged as a safe and efficacious first-line therapy for VMs. ²² US-guided direct needle puncture into a VM channel is first performed to facilitate intralesional digitally subtracted venography which is used to characterize lesion anatomy and venous drainage pathways. Several sclerosant materials can be used to embolize VMs. ^{6 11} The goal of embolization in the management of VMs is either definitive nonsurgical cure or preoperative size optimization to minimize blood loss during surgical resection. ²² Prior to sclerotherapy, complications should be discussed, which include pain and swelling that often worsens before clinical improvement, infection, bleeding, nerve or vascular compression, and skin injury and necrosis that may require surgical skin grafting. ²² Relative contraindications for embolization and sclerotherapy include proximity to major nerves, the airway, or orbit; extensive cutaneous involvement; deep venous involvement; severe consumption coagulopathy; a patent foramen ovale; or chronic pulmonary embolic disease with decreased cardiopulmonary reserve. ⁵ However, the advent of using bleomycin for the treatment of VMs has made difficult-to-treat lesions safe from a percutaneous approach. ^{29 30 31 32 33 34 35 36}

Sclerosants

Sodium Tetradecyl Sulfate

Sodium tetradecyl sulfate (STS) is a commonly used embolic in the treatment of VMs. It is an anionic surfactant detergent which destabilizes phospholipid membranes and promotes cellular lysis. It also induces a negative charge along the cellular membrane of endothelial cells, promoting coagulation. ^{6 22 37} The most common indications for STS sclerotherapy include varicose veins, telangiectasias, hemangiomas, LMs, and VMs. ^{38 39 40}

STS is most often used in 3 or 1% formulations, with the latter reserved for superficial/cutaneous vascular lesions. ¹ Based on FDA-approved guidelines, the maximum dosage of a single treatment of 3% STS is 10 mL. ³⁷ When used as the primary agent for sclerotherapy, STS is typically administered in multiple treatment sessions spaced 6 to 8 weeks apart so that the embolic effect has ample time to occur and allows for better assessment of treatment efficacy over time. ¹ STS can be administered in liquid or foam form, although it is most commonly prepared using the Tessari method into an embolic foam containing three parts air, two parts 3% STS, and one part ethiodized oil (lipiodol). The iodine in lipiodol is radiopaque, making it an ideal sclerosant for use under fluoroscopy. ^{1 37 41}

The efficacy and low side effect profile of STS in treating VM has been described in retrospective reviews and case reports. ^{40 42 43} In a retrospective review of STS sclerotherapy in peripheral VMs, 48 of 72 (67%) patients reported improvement of symptoms, with 11 of 48 (23%) becoming asymptomatic and 19 of 35 (54%) patients demonstrating decrease in size of the VM on MRI. ⁴³ Another retrospective analysis evaluated clinical outcomes of foam STS therapy in VMs and found improvement in pain in 45 of 91 lesions (49.5%) and mass reduction in 58 of 91 (53%) based on MRI findings. ⁴² No major complications were reported in either study. ^{42 43} Additionally, in a case series of 13 patients with head and neck VMs who were treated with intralesional 3% STS, 10 of 13 patients (77%) had a 50% or greater decrease in size, with complete resolution in 4 of these patients. The side effect profile in this case series was minimal with all pain and edema well-controlled on oral analgesics and intramuscular injection of dexamethasone; two patients developed superficial ulcerations that healed uneventfully, and one patient developed mild ecchymosis. ⁴⁰ Adverse effects of STS use may include pain, urticaria, skin necrosis, and hyperpigmentation, and are generally mild. ⁶ There are no reported long-term carcinogenic effects with STS use. ⁴⁴

Ethanol

Intravascular injection of absolute ethanol induces endothelial injury and protein denaturation, leading to thrombosis. ^{1 22} While highly effective, ethanol is among the most cytotoxic of sclerosing agents, with a relatively high complication rate, estimated at approximately 10%. ^{6 22} Complications include nerve injury, pain, skin necrosis, deep vein thrombosis and pulmonary embolism, pulmonary hypertension, and severe cardiopulmonary instability. ^{22 37} Due to the risks involved with systemic ethanol toxicity, which can lead to significant hemodynamic instability, general anesthesia, as well as careful postprocedural cardiovascular monitoring for 24 to 48 hours, must be used in all ethanol sclerotherapy cases. ⁴⁵ In a systematic review of sclerotherapy for VMs, 13 case series regarding ethanol sclerotherapy across 681 patients were reviewed, with a calculated weighted average clinical success rate of 74%. ⁴⁶ Historically, ethanol was commonly used to treat VMs but has had a markedly decreased role in the contemporary management of VMs due to its high side effect profile. ¹

Bleomycin

Bleomycin is an antibiotic derivative that induces DNA strand breaks, possibly by chelating metal ions which eventuate in the production of denaturant free radicals. ^{11 22 29} In this manner, bleomycin disrupts tight junctions between endothelial cells and promotes endothelial sclerosis through fibroblast transformation. ^{11 22 29} Bleomycin is considered less inflammatory than other sclerosants and is therefore particularly useful in head and neck VMs in which rapid airway edema and orbital swelling are important concerns. ^{1 30}

Bleomycin's overall response rate for VMs ranges from 70 to 100%, with complete response in 20 to 57%. ²² In a randomized controlled trial, Zhang et al found that bleomycin was less effective in reducing VM size (41/63 patients) than ethanol (71/75 patients; p  < 0.05). However, there were fewer adverse events in the bleomycin group with only 5 cases of skin necrosis, compared to 14 cases of skin necrosis, 17 cases of localized swelling requiring further treatment, 3 cases of muscle fibrosis, and 1 case of embolic stroke in the ethanol group ( p  = 0.0001). ³¹ In a retrospective review, Nevesny et al demonstrated that bleomycin had a greater than 50% volume reduction in VM lesion size in up to 64% of cases. ³² Additionally, in a prospective study, Lee et al demonstrated a greater than 40% reduction in vasculature in 82.4% of cases. ³³ In a retrospective review of 32 patients who underwent serial bleomycin intralesional injections over an 8-year period, more than 50% reduction in VM size was demonstrated in 96.3% of lesions. ³⁴

Bleomycin has also shown efficacy in electrosclerotherapy for VMs resistant to prior invasive therapy; electrosclerotherapy involves application of high-voltage electrical impulses which leads to a reversible increased permeability thereby increasing intracellular concentrations of bleomycin during intralesional injection. ³⁵ In a case series, there was a median decrease of 86% in MRI-derived lesion volume following bleomycin electrosclerotherapy. ³⁵

Systemic bleomycin therapy carries a risk of toxicity in the form of pulmonary fibrosis; however, a meta-analysis of more than 1,300 patients who underwent bleomycin sclerotherapy for the treatment of vascular malformations had no instances of pulmonary fibrosis and had a lower adverse event rate compared to other sclerosants. ³⁶ Dosing for children ranges from 0.5 to 1 unit/kg up to 15 kg body weight and for adults from 10 to 15 units, with a maximum cumulative lifetime dose of 100 to 150 units. ³⁶

Surgical Management

Surgical management of VMs can be considered as an additional therapeutic option, especially for local control or removal of scar tissue after sclerotherapy has been used for downsizing. ²² Surgical excision can be used as monotherapy when the VM is small, accessible, and does not involve any vital structures, but is more likely to leave residual scarring and may affect cosmetic outcomes. ²²

Preoperatively, imaging is paramount for surgical planning, with US and contrast-enhanced MRI serving as modalities of choice. Additionally, a multimodal, staged approach is often used in surgical management, as preoperative or intraoperative sclerotherapy and/or laser therapy can also reduce perioperative complications of surgical resection. ⁴⁷ For example, circumferential airway and mediastinal VMs require careful planning and incorporation of multiple modalities; control of mucosal disease must be accomplished, often through a combination of laser therapy and bleomycin sclerotherapy, which is advantageous due to its minimal inflammatory effect (i.e., decreasing the risk of airway edema). ⁴⁷ Laser therapy and bleomycin sclerotherapy can be performed simultaneously, followed by surgical excision in 6 to 8 weeks. ⁴⁷ The main risks of surgical resection, especially when compared to sclerotherapy, are scarring, disfiguration, bleeding, and nerve injury. ⁴⁷

Molecular Therapies

Sirolimus/Rapamycin

Sirolimus, also known as rapamycin, inhibits the serine/threonine kinase, mTOR, which acts as a molecular switch to promote cell cycle processes. Sirolimus has also been demonstrated in mice models to inhibit an endothelial cell tyrosine kinase receptor that is responsible for VM expansion. ¹⁰ Multiple studies have demonstrated oral sirolimus to be effective in managing complicated vascular anomalies, with improvements in pain, bleeding, lesion size, and functional impairment, with a low side effect profile. For these reasons, sirolimus is being increasingly used for the treatment of not only VMs but almost all vascular malformations. ^{48 49 50} Of note, these studies typically involved administering sirolimus for compassionate use in patients with vascular anomalies which were refractory to multiple other therapies. ^{48 49 50}

Although not currently FDA-approved for the treatment of vascular malformations, in a phase II clinical trial, 61 patients with complicated vascular anomalies were treated with a continuous dose of oral sirolimus which started at 0.8 mg/m ² per dose twice a day with target serum trough levels of 10 to 15 ng/mL. The study found that 11 of 12 patients with capillary venous LMs and 3 of 3 patients with venous LMs who completed six courses of therapy demonstrated a partial response, which was defined as either a more than 20% reduction in size of target lesion, improvement in self-reported quality of life, or improvement in functional assessment. Adverse effects included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%, with no toxicity-related deaths reported and no long-term toxicities. ⁴⁸

Alpelisib and Targeted Novel Therapies

While sirolimus is the most advanced and well-studied pharmacotherapy for VMs, other targeted novel therapies deserve discussion. ⁵¹ One of these potential drugs includes alpelisib which is a potent inhibitor of the phosphoinositide 3-kinase catalytic subunit (PI3KCA), an enzyme known to activate pathways involved in VM formation. ⁵¹ Initially studied for its potential role in anticancer therapy, alpelisib has also been shown to restore abnormal phenotypes of VM-causative mutations (including PI3KCA) in vitro. ^{52 53 54} In a study by Castel et al, mice models with VMs caused by activated PIK3CA mutations were treated with alpelisib; both systemic and topical administration induced a statistically significant decrease in VM volume and cellular proliferation. ⁵⁵ Finally, while alpelisib has not been tested clinically for VM, a case report from Garreta Fontelles et al describes a patient with CLOVES syndrome and PI3KCA mutation, with an associated left chest wall cystic lymphangioma, who was administered systemic alpelisib for compassionate use following surgical debulking and sirolimus treatment. ⁵⁶ In this patient, alpelisib significantly reduced the size of the lesion and halted its progression into the gluteal region. ⁵⁶

Limited safety data exist on alpelisib and only in the context of being an investigational cancer drug in adult patients; however, the current description of side effects includes mild hyperglycemia, nausea, diarrhea, and skin reactions with the overall profile being deemed acceptable for continued clinical studies. ^{57 58} Large clinical trials for alpelisib must be performed to assess both the side effect profile and the efficacy, especially in pediatric patients with VMs.

Another drug currently under investigation is dactolisib, or BEZ-235, which is a dual inhibitor of both the PI3KA and mTOR pathways; dactolisib was originally studied for the purposes of treating cancer but has since been discontinued due to limited levels of clinical activity. ^{59 60} While not clinically studied in human VMs, dactolisib has been shown to induce vascular regression in PI3KA mouse models of VMs. ⁵⁹ The endothelium-specific receptor tyrosine kinase (TIE-2) pathway and inhibition has also been investigated. ¹⁰ The TIE-2 inhibitor demonstrated weak in vitro inhibition of TIE-2-associated VM mutations and minimal to no effect on VM growth in mice models. ¹⁰

Special Considerations

Klippel–Trenaunay Syndrome

Klippel–Trenaunay syndrome (KTS) clinically presents as a triad of malformations: port wine stain, underlying low-flow vascular (venous or lymphatic) malformations, and bone or soft-tissue limb overgrowth of the affected extremity. ¹¹ The most characteristic finding in KTS is the persistence of the lateral embryonic vein of Servelle, which extends from the dorsum of the foot to the thigh, typically draining into the internal iliac vein, via posterior route to the pelvis. Standard imaging for KTS includes an MRI of the entire affected limb, the contralateral limb for comparison, and trunk for deeper vascular malformations (LM, VM) if present. ¹¹

Management of patients with KTS focuses on symptom alleviation and prevention of life-threatening complications (e.g., gastrointestinal bleeding, thromboembolic phenomena). Initially, these patients can be managed conservatively with compression stockings and lifestyle modifications. More invasive options for management include endovascular closure and bland embolization of embryonic veins, sclerotherapy of VMs, and laser therapy of lymphatic vesicles.

Endovascular closure of embryonic veins can involve embolization or sclerotherapy of the lateral vein of Servelle. This technique should only be performed when a patent deep venous system is present; typically, a preprocedural MR venogram of the entire affected limb should be performed to visualize the embryonic vein of Servelle, and an associated deep venous system. In the interventional suite, arteriography should be performed to ensure that there is no evidence of high-flow malformation, as this would reflect a separate diagnosis from KTS, such as Parkes-Weber syndrome, which carries a similar phenotype to KTS but an overgrowth syndrome associated with high-flow AVM and mutations involving the RASA1 gene. ¹¹ Both coil embolization and sclerotherapy can be performed upon the lateral vein of Servelle via antegrade venous access, or with retrograde venous occlusion techniques. Completion and follow-up venography is important to ensure successful enduring closure, along with continued patency of a deep femoral system. ¹¹

In a case report, Lim et al described an endovascular technique in which micropuncture access peripheral to a large dilated venous channel is obtained with ascending venography performed to confirm the lateral margin position of an incompetent truncal vein. A presence of a deep venous system was obtained, and the outflow channels that drained the lateral marginal vein were embolized with detachable coils. After control of the outflow tracts, a mechanochemical ablation (MOCA) was performed using 3.5 mL of 1.5% STS with completion venography and duplex US confirming no residual flow through the lateral marginal vein. ⁶¹ The MOCA technique has a dual mechanism: a rotating wire tip provides mechanical damage to the endothelium and the sclerosing agent causes chemical damage. ⁶² In a prospective study of 13 MOCA procedures on 11 patients, Lambert et al demonstrated that primary occlusion without any adverse events were achieved by this technique with partial recanalization and symptom recurrence only occurring in 2 of 11 patients (18%) at 14- and 18-month follow-up. These patients would undergo a second MOCA procedure without any recanalization or symptom recurrence during their next follow-up period. ⁶²

Venous Malformations of the Head and Neck

VMs of the head/neck are strongly associated with sleep-disordered breathing symptoms; in a cohort of pediatric patients with head/neck vascular malformations, up to 47% had such symptoms. ⁶³ As such, special precautions must be taken in pediatric patients to manage the airway. Continuous positive airway pressure (CPAP) can be administered for airway obstruction related to vascular malformations, which can bridge patients to definitive therapy. ⁶

STS is commonly used and highly effective in the treatment of head and neck region VMs. ^{40 64 65} However, because STS can cause significant inflammation and airway edema, airway precautions are recommended, which may include a prolonged period of postprocedural intubation in the intensive care unit. ^{6 66} Bleomycin, considered to be a less inflammatory sclerosant, is advantageous in head and neck malformation management, when the risk of airway edema and compromise is high. ³⁰

Conclusion

VMs are disorders of embryogenesis with unique genetic landscapes that can lead to broad physical and psychosocial impacts. The roles of imaging, particularly US and MRI, and interventional radiology are critical in the diagnosis and management of VMs. Endovascular sclerotherapy is considered first-line therapy for a wide array of VMs, with surgical, medical, and multimodal management offering utility in specific patient subsets. Further research is needed to optimize management of VMs, including the roles of contrast-enhanced US in diagnostic workup, the choice and dosing of sclerosants, and the identification of novel targets for molecular therapy.

Funding Statement

Funding None.