Pathogenesis and Clinical Presentation
VMs are a result of an inborn error in vascular embryogenesis leading to the formation
of abnormal endothelium and, as a result, thin-walled, nonfunctional, and ectatic
veins. Greater than 90% of VMs are a result of a sporadic mutation, with the majority
of phenotypes arising from endothelial dysgenesis via the TIE2–PI3K (phosphoinositol-3-kinase)–AKT–mTOR
(mammalian target of rapamycin) pathway ([Fig. 1 ]).[3 ]
[4 ]
[5 ] A gain-of-function somatic mutation in TEK leads to the overexpression of receptor tyrosine kinase TIE2, which is expressed
on venous endothelial cells, resulting in dysplasia of the basement membrane and endothelium.
While only seen in 25% of sporadic VMs, a somatic mutation in PIK3CA leads to unregulated activation of PI3K, which affects cell proliferation, migration,
and survival.[2 ] Mosaic mutations in this pathway are also the cause of VM-predominant overgrowth
entities (known as the PIK3CA-related overgrowth spectrum or PROS), which include
Klippel-Trenaunay syndrome (KTS) and CLOVES (congenital lipomatous overgrowth, vascular
malformations, epidermal nevi, and spine/skeletal anomalies).
Fig. 1 Signal pathway involved in the pathogenesis of venous malformations and targets of
systemic therapy. PI3K-AKT-mTOR signaling pathway and relevant vascular anomalies
associated with each enzyme variant. Sirolimus inhibits mTOR. Alpelisib inhibits PI3K.
AKT, Ak strain transforming oncogene, or protein kinase B; CLOVES, congenital lipomatous
overgrowth, vascular malformations, epidermal PIE 2/RTK, angiopoetin receptor and
y60sine kinase, nevi, and spine/skeletal anomalies; ERK, extracellular receptor kinase;
MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K,
phosphatidylinositol 3-kinase; PIK3CA, phosphatidylinositol 4,5-bisphosphate 3-kinase
catalytic subunit α; RAF, rapidly accelerated fibrosarcoma kinase; RAS, rat sarcoma
oncogene.
Present at birth, VMs generally grow commensurate with the patient, do not spontaneously
regress, and can present at any age. Malformations due to sporadic mutations are usually
unifocal while hereditary forms (such as glomuvenous malformation and, rarely, blue
rubber bleb nevus/bean syndrome) are more commonly multifocal and are associated with
other anomalies. Although VMs can be found at any location, approximately 40% occur
in the head and neck.[6 ] Rapid growth can be observed during teenage years and during pregnancy as sex hormones
promote angiogenesis and proliferation.[7 ] Increase in symptoms can also be seen in response to unrelated major trauma. When
located superficially, they are seen as a blue, soft, and compressible mass that may
be associated with varicosities. Documentation with clinical photographs is critical
and is helpful when assessing treatment response. Unlike lymphatic malformations,
due to increase venous blood flow, these lesions enlarge with Valsalva maneuvers or
when placed in a dependent position. They should be cool to the touch and without
pulsatility or thrill, unlike an arteriovenous malformation. Deeper lesions may not
be evident in infancy and tend to present after puberty. In particular, lesions isolated
to muscle are associated with later presentation and greater morbidity and exercise
limitations.[8 ] Complications include swelling and/or pain from distension, thrombosis or phlebitis,
and joint pain from hemorrhage-related arthropathy with intra-articular involvement.[9 ] When located in the extremities, these symptoms may increase with activity. Rarely,
patients can present with pulmonary emboli in the setting of thrombosis if the malformation
communicates with the deep venous system.[10 ]
Patient Assessment
After physical examination, imaging is performed for further characterization of VM
and is also used to monitor treatment response. Ultrasound (US) is often the first
screening modality at diagnosis. It is inexpensive, does not expose the patient to
ionizing radiation, is readily available, and can be performed in the clinic. On gray-scale
US, VMs appear as heterogeneously hypoechoic masses that are compressible. Tubular
vascular channels may be observed, particularly with high-resolution imaging, but
are not always visualized. Similarly, connections to normal venous drainage may not
be evident. Phleboliths and thrombi, however, should be readily identified. On color-Doppler
imaging, 84% of lesions will show flow, with the majority exhibiting monophasic, slow
flow.[11 ]
[12 ] When flow is extremely slow, it may not be detectable; thus, it is important to
adjust the Doppler scale as low as possible to differentiate these lesions from lymphatic
malformations.
Particularly in larger and deeper lesions, magnetic resonance imaging (MRI) is required
for complete evaluation. Sequences for initial assessment must include a fat-suppressed
T2-weighted sequence and a time-resolved angiographic sequence. The larger field-of-view
allows assessment of transpatial and/or intra-articular extension, and involvement
in critical and deeper structures, as well as assessment of the normal draining venous
system. Computed tomography should not be routinely used unless there is need to characterize
osseous involvement, which can manifest as osseous destruction or cortical thinning.
On MRI, these are typically hypo- to isointense on T1-weighted sequences and are markedly
hyperintense on T2-weighted sequences. Foci of hypointensity on T2-weighted imaging
can be due to phleboliths or thrombi, which are confirmed by blooming artifact seen
on gradient-echo sequences. While fluid–fluid levels are more commonly seen with lymphatic
malformations, they can be present in larger VMs due to intralesional hemorrhage.
Finally, VMs have varying degrees of delayed heterogenous enhancement and, depending
on the timing between injection and imaging, some components may appear as nonenhancing.
Some focal VMs have no or minimal egress, making them difficult to distinguish from
lymphatic malformations.
With some extensive lesions, a planning venogram may be considered, as direct venography
offers the best temporal and spatial resolution to assess the variable patterns of
outflow seen with VM. For example, characterization of the deep venous system is critical
prior to pursuing sclerotherapy in patients with extensive limb VMs, such as in KTS;
diversion venography may be necessary, with placement of serial tourniquets over outflow
veins.[13 ] These are similar techniques which may be employed during sclerotherapy.
Prior to intervention, it is important to consider the differential diagnoses. Mimickers
of VM in the pediatric population include vascular tumors, such as hemangiomas, which
should exhibit a solid, soft-tissue component. Lesions such as peripheral nerve sheath
tumors, congenital fibrosarcomas, and spindle cell hemangioendotheliomas have been
mistaken for VM.[14 ] Commonly mischaracterized as a VM, a fibroadipose vascular anomaly (FAVA) or phosphatase
and tensin analog (PTEN) hamartoma can be differentiated by their fat content and
tumor-like appearance on US.
As it is the stasis of blood and dysplastic endothelium that provoke thrombosis, extensive
VM can harbor a localized intravascular coagulopathy (LIC).[15 ] Sclerotherapy can progress LIC into disseminated intravascular coagulopathy (DIC),
which is a medical emergency.[16 ] Patients with larger VM are at greatest risk and it is recommended to evaluate for
decreased fibrinogen and elevated D-dimer levels. If the patient is found to have
LIC, then low-molecular-weight heparin (LMWH) is recommended prior to intervention
or during pregnancy to prevent DIC.[17 ]
[18 ] The use of a direct oral anticoagulant (DOAC), in lieu of LMWH injection, for DIC
prophylaxis has also been described.[19 ]
Treatment
Clinical decision-making is best performed in an interventional radiology or multidisciplinary
clinic, with review of all imaging. After accurate diagnosis, an individual treatment
plan is created with a combination of therapies. It is important to discuss with the
patient and family that the goal of intervention is not complete cure, but rather
to decrease pain, the risk of future complications, and improve function. The need
for staged or repeat treatment should also be discussed. A detailed pain history should
be obtained, preferably with use of standardized pain questionnaires such as the Brief
Pain Inventory or PedsQL.[20 ]
[21 ]
Available treatment modalities for VM include sclerotherapy, surgery (primary excision
or excision after embolization), ablation, and oral pharmacotherapy. Systematic reviews
have not established a benefit of sclerotherapy as an alternative to primary surgery,
mainly due to limitations in study quality.[22 ] However, due to its minimally invasive technique, sclerotherapy is currently the
predominant modality in many centers. The Society of Interventional Radiology recommends
preprocedure antibiotics for the treatment of vascular malformations, a position also
endorsed by the Cardiovascular and Interventional Radiological Society of Europe.[23 ]
Sclerotherapy
General Technique
Effective sclerotherapy requires a comprehensive injury to the abnormal endothelium,
and this relies on two concepts: dwell time and endothelial contact. Percutaneous
sclerotherapy is performed by US-guided access of the lesion with acquisition of blood
return, followed by meticulous fluoroscopic venography and injection of sclerosant.
Small bore (21- or 22-gauge [G]) needles or sheathed needles (peripheral intravenous
[IV] cannula) are commonly used, with short IV connection tubing. High-quality venography
is crucial to safe and effective sclerotherapy, as the distribution, volume, and outflow
of the malformation must be assessed. Based on outflow, VMs can be categorized into
four types ([Fig. 2 ]).[14 ] Outflow is characterized by venography and can be aided by preprocedure imaging,
and determines the complexity of the treatment ([Fig. 3a–c ]). Control of outflow is central to sclerotherapy of VM, as this is necessary to
increase dwell time, avoid nontarget sclerotherapy of normal veins and tissues, and
reduce the risk of thromboembolism from malformations with a direct communication
to the deep venous system.
Fig. 2 Graphic depicting classification of venous malformation based on outflow. Counterclockwise,
type 1 are isolated without drainage, type 2 drain into normal veins, type 3 drain
into dysplastic veins that connect to the deep system, and type 4 are primarily ectatic
veins.
Fig. 3 A 4-year-old male with a type 2 venous malformation of the chest wall. (a ) Ultrasound shows tubular, anechoic channels with slow flow and (b ) linear echogenic, shadowing phlebolith (arrow). The latter is pathognomonic for
a venous malformation. (c ) Upon direct injection of the malformation, a sac-like structure overlying the ribs
opacifies with contrast and shows drainage into a normal caliber vein (arrowhead).
This was successfully treated with 5 mL STS foam.
It is also crucial that lesions never be forcefully injected or overfilled. Lesion
volume and ease of injection are assessed on the venogram, and a volume of sclerosant
reasonably commensurate to lesion volume must be injected. Adequate coverage of the
lesion can be assessed with roadmap (subtracted) fluoroscopy. If the sclerosant is
not radio-opaque, the lesion is first filled with contrast and then the contrast can
be seen being displaced by the sclerosant with roadmap imaging. US, particularly when
the sclerosant is foamed, is useful to assess lesion coverage. Aggressive injection
of the lesion can result in extravasation or arterial reflux, and produce local tissue
injury.
The double-needle technique is often necessary for effective sclerotherapy, and involves
placing two or more open needles at opposite poles of the malformation ([Fig. 4a–c ]). The first is used to inject sclerosant until it is seen to egress through the
other(s). The additional needle(s) allow a path of low resistance for sclerosant to
permeate from one end of the lesion to the other, thus ensuring a more complete distribution.[24 ] The double-needle technique may provide indirect outflow control, as egress can
be directed away from undesirable outflow veins by appropriate needle positioning.
For extremity VM with direct connection to the deep system, constant infusion of heparinized
saline into the deep veins will also guard against sclerosant-induced injury to the
deep veins.
Fig. 4 An 11-year-old male with a type 2 venous malformation of the forehead treated using
a double-needle technique. (a ) Initial frontal venogram over the skull shows drainage into the superior ophthalmic
vein (arrows). Egress of sclerosant was to be avoided. (b ) Two 21-gauge needles were inserted under ultrasound guidance for instillation of
STS foam. Note a hemostat is used to control outflow. (c ) Lateral fluoroscopic image of the skull shows successful injection of the radio-opaque
sclerosant without communication to other veins or the dural venous sinuses.
Direct outflow control methods involve either temporary or permanent occlusion of
draining veins. Often, a combination of these methods may be necessary, depending
on the robustness of outflow and location of the lesion. Such methods include external
compression (manually or by use of a sterile tourniquet, endovascular balloon occlusion,
injection of glue, percutaneous ligation, and/or deployment of plugs or coils).[25 ]
Endovascular coils or plugs are commonly placed in large outflow veins with appropriate
landing zones ([Fig. 5a–c ]). When sizing coils, it is important to be mindful of the fact that veins are distensible
and may spasm during measurement or deployment. Any distension of the lumen after
deployment may result in embolization; so, it is advisable to oversize by 30 to 50%.
While pushable or detachable coils may be used, the use of an initial detachable coil
as a frame may be beneficial and provide some reassurance against coil embolization.
Fig. 5 A 10-year-old female with CLOVES syndrome. (a ) Venography performed by direct puncture of the persistent lateral vein shows multiple
perforators (arrowheads). (b ) Diversion venography with application of a tourniquet (asterisk) was necessary to
visualize the patent deep system (arrow). (c ) The perforators were coil embolized prior to endovenous laser ablation the following
day, taking care to oversize the coils by 30–50%. CLOVES, congenital lipomatous overgrowth,
vascular malformations, epidermal nevi, and spine/skeletal anomalies.
Endovascular balloon occlusion is most amenable for the treatment of type III VMs,
with short and direct communication to deep veins. The deep veins are accessed separately
from the malformation, and a balloon is positioned over a wire and inflated across
the communication. Sclerotherapy is then performed (if necessary, with glue for more
permanent outflow occlusion, as appropriate), and the balloon is deflated ([Fig. 6a, b ]).
Fig. 6 (a ) A 10-year-old male with a type 3 venous malformation (VM) extending into the bone,
treated using a balloon occlusion technique. Direct injection of the right arm VM
shows egress into the brachial vein (arrow), as well as communication into the medullary
cavity of the humerus (arrowhead). (b ) Placement of a 6 mm × 4 cm balloon (arrow) across the communication via the peripheral
brachial vein prevents outflow and allows for safe sclerosant injection.
Foamed sclerosants are commonly used in VM treatment because they promote both dwell
time and physical contact with the endothelium. Foam, when adequately stable, is able
to displace blood within the VM and expand within the lesion, making more extensive
mural contact than liquid alone. The increased viscosity of a foamed sclerosant relative
to its liquid counterpart also increases dwell time, resulting in prolonged duration
of mural contact in the VM. Although foamed agents are also easily visible on US,
it should be noted that foam will obscure visualization of deep tissues. It is therefore
important to access and treat the deepest components of a malformation first, and
then move progressively more superficially as needed.
Sodium tetradecyl sulfate (STS), polidocanol, and bleomycin may be injected in a foam
formulation. As sclerotherapy is most often performed under fluoroscopy, a contrast
agent may be added to the foam to increase conspicuity. Generation of foam relies
on what is called the “Tessari method” or variations thereof, performed by repeatedly
agitating a mixture of the sclerosant and air through a three-way connector and two
syringes. Typically, a 1:4 mixture is used for polidocanol or STS, and foam has been
described to be more stable when the connector hole is gradually narrowed, as the
microbubbles become progressively smaller.[26 ] Alternatively, a 0.2-µm epidural filter (Perifix; B Braun, Bethlehem, PA) may be
used for this purpose. These agents may also be foamed with water-soluble iodinated
contrast to improve visualization under fluoroscopy and render the foam more stable.[27 ] As both STS and polidocanol molecules consist of long hydrocarbon chains and hydrophilic
heads, their foam can be rendered more stable with oily contrast (Lipiodol; Guerbet,
Villepinte, France). It should be noted that adding contrast would reduce the concentration
of the sclerosant in foam, and that oily contrast will add cost to the procedure.
The typical formulation of foam in this setting is two parts of sclerosant, one part
oily contrast, and two parts room air. There is no reported difference in efficacy
between foaming of sclerosant with room air, or carbon dioxide (CO2 ).[28 ] Foam constituted with CO2 has a shorter half-life than that made from room air with faster absorption, and
it may be favored in settings where a large volume of foam must be injected. Needles
smaller than 27 G are also thought to disrupt foam, and thus 25 G or larger needles
are recommended for injection.[29 ]
Sclerotherapy Agents
Systematic reviews have not found any particular agent to be superior for the treatment
of vascular malformations, and this is thought to be due to limitations in study quality.[30 ] The most commonly used sclerosant for VM is STS, and it has been shown to be cost-effective.[30 ] STS is a detergent, and each molecule consists of a hydrophilic head and a long
hydrophobic chain. STS is thought to act as a surfactant, inducing damage of the cell
membrane by removal of transmembrane lipoproteins. STS is available in 1 and 3% formulations
(Sotradecol; Viatris, Pittsburgh, PA) and the 1% formulation may be used for smaller
and more superficial lesions to reduce the risk of skin breakdown. The suggested dose
limit for 3% STS is 0.5 mL/kg, but many practitioners limit the dose to 8 to 10 mL
per session to control hemoglobinuria.
Polidocanol (also known as lauromacrogol 400) is also a detergent sclerosant that
is commonly used to treat acquired venous varicosities, and is available as in liquid
form in 0.5 and 1% concentrations (Asclera; Merz Aesthetics, Raleigh, NC), and as
a more expensive pre-made foam (Varithena; Boston Scientific, Marlborough, MA). Polidocanol
is a milder agent than STS and is thought to have less efficacy in standard sclerotherapy
settings. For vascular malformations, use is reserved for more superficial lesions
or lesions where significant local inflammation needs to be avoided. Sodium morrhuate
is another sclerosant, derived from bile salts of cod liver oil, which is sometimes
used, although less commonly, in the United States.[31 ]
As discussed earlier, n-butyl cyanoacrylate (nBCA) glue (Histoacryl, B Braun; TruFill,
Cordis, Santa Clara, CA) is used primarily to prevent outflow in VMs. Glue can be
used as a primary sclerosant, as polymerization produces an exothermic reaction and
a subsequent inflammatory foreign body response that is injurious to the target vessel
endothelium. Glue is typically directly injected via a 21-G needle at a specific dilution
(15–60%) in oily contrast. The consistency should allow for a degree of desired penetration
while avoiding nontarget embolization into deep veins. In general, glue should not
be used in superficial locations, as it may leave a palpable lump with associated
inflammatory reaction, or in nonsterile locations. This palpable nature, however,
may facilitate surgical excision and in particular, intra-articular VMs may be embolized
exclusively with glue and then excised by an orthopaedic surgeon ([Fig. 7a–c ]). Glue is also provided in a high viscosity formulation with a catheter delivery
system for closure of larger veins discussed later.
Fig. 7 A 16-year-old male with a right knee venous malformation and intra-articular involvement.
(a ) Sagittal T2 fat-saturated MRI demonstrating erosive change and subchondral cyst
formation in the lateral tibia plateau (arrow) and an intra-articular venous malformation
(arrowheads). (b ) Frontal fluoroscopic image after sclerotherapy using 30% n-butyl cyanoacrylate glue
mixed with lipiodol shows intra-articular involvement. Excision was performed by orthopaedics
the following day. (c ) Follow-up radiograph obtained 14 months later shows only a small amount of radio-opaque
glue remains (arrow) and healing of the degenerative changes of the tibia.
Bleomycin, a Streptomyces -derived antibiotic and chemotherapy agent frequently used for Hodgkin's lymphoma
and germ cell tumors, has also shown efficacy for vascular malformations.[32 ]
[33 ]
[34 ] It is chemically similar to pingyangmycin, which is used outside the United States,
and is thought to act by oxidative damage to cells. It has also been found to interact
with the mTOR pathway.[35 ] For slow flow malformations, it is often used in locations where postprocedure inflammation
needs to be limited, such as the oropharynx and the orbit. For VMs, foaming bleomycin
with 25% human serum albumin is a particularly useful technique, and confers the benefits
of foamed sclerosant described earlier, and allows for a greater volume of sclerosant
to be given, as a per-session limit of 15 mg or units (15,000 international units ) is commonly used.[36 ] Idiosyncratic bleomycin-related complications (discussed in the section “Procedure-Related
Complications”) involve the lung and the skin, and are thought to be due to the relative
absence of bleomycin hydrolase in these tissues.[37 ] Important precautionary measures include decreasing Fi O2 during the procedure to room air and minimizing placement of adhesives on the skin.
Ethanol, provided in concentrations more than 95%, acts by denaturation of proteins
on contact, and is a very potent sclerosant. It is available as a liquid, in concentrations
more than 95%, or in a gel form outside the United States. The increased viscosity
of gel may reduce the risk of nontarget embolization.[38 ] It may be injected straight or mixed with oily or water-soluble contrast in a 3:1
dilution, to provide radio-opacity. Due to its potency, ethanol is associated with
increased rates of local tissue injury (skin and nerves) compared with bleomycin (and
likely so compared with STS).[34 ] As discussed earlier, careful assessment of lesion hemodynamics and vigilant injection
of sclerosant must be performed to reduce these risks. High doses produce systemic
contamination and can result in hemolysis, pulmonary vasospasm, and cardiovascular
collapse.[39 ] With regard to systemic complications, a dose limit of 0.1 mL/kg every 10 minutes
has been suggested safe, with a total dose per session under 1 mL/kg.[40 ]
[41 ]
Endovenous Ablation
Endovenous ablation, which includes laser ablation (EVLA), is reserved for closure
of large malformed veins, and requires an intact deep venous system for physiologic
drainage after closure. It is often used to close persistent embryonic veins in KTS,
to address the risk of catastrophic PE. While most patients with KTS/PROS are thought
to have intact deep systems, diversion venography may be required to document this
prior to closure, if deep veins are not seen on MRI.[13 ]
EVLA is easier to perform in young children. Successful endovenous ablation usually
requires closure of large confluences of the target vein—large tributaries and/or
the central confluence—with coils or plugs, and this may necessitate a 2-day procedure,
with laser ablation performed on day 2. These closures are easier in young children
due to the smaller vein caliber. Laser ablation is also best reserved for the extrafascial
component of the vein, as there is a risk of nerve injury for deeper segments that
are poorly seen with US. EVLA requires tumescence around the vein to a thickness of
1 to 2 cm, and this can be performed with 1% lidocaine with epinephrine 1:100,000
(the maximum dose is 7 mg/kg; normal saline can be used after this limit is met).
A minimum of 1 cm of separation of the vein from the skin should be achieved. We perform
laser ablation using a 1,470-nm wavelength fiber (VenaCure system; Angiodynamics,
Latham, NY), with an initial power of 10 W and an initial energy goal of 100 J/cm,
beginning 2 cm proximal to the central confluence. The amount of energy deposition
may have to be increased for larger diameter veins.[42 ]
[43 ]
[44 ]
[45 ] Additional details for EVLA of VM are discussed in these cited references.
Newer modalities of endovenous ablations include a catheter-based viscous glue (VenaSeal;
Medtronic, Minneapolis, MN) and pharmacomechanical device that employs motorized endovenous
stripping (ClariVein; Merit, South Jordan, UT).[45 ]
[46 ] Although the experience with these devices for VM is new, the potential advantages
of these systems are the lack of thermal injury and decreased need for tumescence.
Cryoablation
Cryoablation has been used to ablate small residual AVM and vascular tumors such as
FAVA and PTEN hamartoma, and is a promising modality for more focal VM. It is well-suited
to treat focal intramuscular VM ([Fig. 8a–c ]). Ablation can be performed with US or CT guidance, and typically involves two freeze
periods separated by a 5- to 8-minute active thaw period. In general, the ice margin
should extend at least 5 mm beyond the lesion. A target freeze period of 10 minutes
is customary, but this may be reduced if adequate coverage of the iceball is seen,
or there is concern about local soft-tissue injury (skin, nerve, or bowel). A separation
of the skin surface and the ice margin of at least 5 mm is recommended to reduce the
risk of frostbite. Adjunct techniques such as physiologic nerve monitoring for motor
evoked potentials, temperature monitoring by thermocouple, or warm saline or CO2 fluid dissection may be useful.[47 ]
[48 ]
[49 ] Due to pain caused by myositis, patients undergoing cryoablation of intramuscular
extremity lesions may benefit from a nerve block for 1 to 2 days after the procedure.
Fig. 8 A 10-year-old female with a painful shin type 2 venous malformation. (a ) Fluoroscopic image obtained during direct injection shows egress into the saphenous
vein (arrow). Outflow could not be controlled with direct compression or balloon occlusion;
therefore, sclerotherapy was not performed. The lesion was treated with cryoablation.
(b ) Color Doppler US before and (c ) grey scale US during shows adequate coverage with the ice ball (arrows). (Case courtesy
of Dr. Anne Marie Cahill.)
Surgical and Adjunct Methods
Systematic reviews have not established surgery or sclerotherapy to be superior as
standalone interventions, and primary extirpation of VM can result in significant
morbidity and deformity. However, for certain lesions that are focal and/or respond
poorly to sclerotherapy (e.g., glomuvenous malformation, blue rubber bleb nevus, or
verrucous hemangioma), primary surgical resection is often the better option. Similarly,
venous stripping can be performed for prominent superficial veins in lieu of endovenous
ablation, as long as they do not have large connectors to the deep system.[45 ]
Surgery can be beneficial as an adjunct to percutaneous intervention. A common scenario
for this is the excision of intra-articular or superficial VM after sclerotherapy
or embolization with glue. For deeper lesions, glue may require excision if there
is an intractable delayed hypersensitivity reaction (discussed later). Finally, external
neodymium-doped yttrium aluminum garnet (Nd:YAG) laser therapy, typically performed
by the plastic surgeon, may be useful in conjunction with sclerotherapy to treat superficial
stigmata of VM.[50 ]
Drug Therapy and Conservative Measures
The elucidation of signal transduction defects in vascular anomalies—defects that
produce dysregulated proliferation and angiogenesis—has resulted in a role for oncologic
pharmacotherapy. Sirolimus, or rapamycin, which targets the mTOR pathway, is the index
agent in this class. It is currently the primary medication available for VM, although
direct PI3K inhibitor alpelisib may be an additional agent that targets this pathway
([Fig. 1 ]). As the treatment duration is indefinite, and serum level titration requires frequent
monitoring and dose adjustment, pharmacotherapy is reserved for lesions that are morbid
and extensive, wherein the prognosis for lesion control by surgery and/or sclerotherapy
is otherwise poor.
Conservative measures for control of symptoms from VM can be used in conjunction with
any interventions, including oncologic pharmacotherapy. These are especially recommended
for extensive malformations such as Bockenheimer or phlebectasia, and may include
the use of anticoagulants (LMWH or DOAC, often prescribed through consultation with
the hematologist) to control painful thrombus formation, and nonsteroidal analgesics
when needed.[19 ] Compression garments are also a mainstay of therapy for extensive lesions. Garments
may be customized to the patient through consultation with the physical therapist;
a pressure rating of 20 to 30 mm Hg is commonly used for VM, but a pressure of 15 mm
Hg may allow for greater comfort and compliance, with similar therapeutic benefit.[51 ]
Procedure-Related Complications
Site infection and blistering are the most common complications encountered in practice.
Patients are advised to contact the interventional radiology team with concerns and
submit photos via phone by SMS or e-mail. Skin blistering is common after STS sclerotherapy
of superficial VM, and conservative wound care (nonadherent dressings with antibiotic
ointment) is performed. If there is a concern for cellulitis, the patient is started
on a 7-day course of oral antibiotic, frequently a first-generation cephalosporin
(cefazolin) or clindamycin. Patients are advised to demarcate the erythema with a
marker and follow progression or regression daily. If there is a poor response to
oral antibiotics, the patient will come to the department for US assessment for abscess
and possible admission for IV antibiotics.
For superficial blistering, supportive care and reassurance is continued until resolution.
Skin breakdown indicates an inflammatory injury and presents as a large erosion and
associated erythema. In the absence of infection, skin breakdown can be managed conservatively
with wet-to-dry dressings and oral analgesics, with plastic surgery consultation for
severe cases. The onset of skin necrosis is rapid, and it presents as black eschar
([Fig. 9a ]). Plastic surgery consultation for possible skin graft is required.
Fig. 9 Complications of sclerotherapy. (a ) A 3-year-old with an upper lip venous malformation (VM) treated with STS foam. Photograph
obtained shortly after treatment shows a dark eschar at the site of intervention from
skin necrosis. The wound did not heal with conservative management and the patient
required debridement and reconstruction by plastic surgery 3 weeks after treatment.
(b ) A 2-year-old with a biopsy-proven tufted angioma of the left upper arm treated with
interstitial bleomycin injection. Photograph obtained 14 months after treatment shows
square hyperpigmented foci (arrows) at the site of ECG lead placement. (c ) A 14-year-old with a left heel VM treated by direction injection of 30% n-butyl
cyanoacrylate. Photograph obtained 2 months later shows a small lump reflecting spontaneous
glue extrusion. Once the glue was completely expelled, the site healed without further
intervention.
Skin hyperpigmentation has been described in approximately 1% of patients treated
with bleomycin and is often focal, and can be treated with topical hydroquinone 4
to 10% ([Fig. 9b ]).[34 ] Diffuse and severe changes (flagellate) have been described even with doses of 15
units and may be intractable.[52 ] Hyperpigmentation from bleomycin may be exacerbated by adhesives present on the
skin during the procedure, and efforts are made to minimize the amount of adhesives
(e.g., trimming electrocardiogram leads, using minimal paper tape for the eyes, and
avoiding adhesive dressings).[53 ] Focal hyperpigmentation has also been encountered with STS.
Bleomycin-related lung injury is a well-recognized complication. Pulmonary fibrosis
is associated with total doses of 300 to 400 units, and has not yet been described
with sclerotherapy. However, an acute pulmonary toxicity is also possible and is less
well-known, and this may be catastrophic and result in respiratory failure or death.[54 ]
[55 ] Fortunately, the incidence of this is rare, and is thought to be due to oxidative
damage in alveoli with a poor capacity to metabolize bleomycin.[37 ] Maintaining Fi O2 at room air during the procedure and postprocedure vigilance are advised.
Sclerotherapy-related nerve injury has been described with STS, but risks are likely
higher with ethanol than with any other agent.[34 ]
[56 ] Resulting neurologic deficits described in the literature have been self-limited,
and motor deficits may be improved by physical therapy. Vigilant planning and injection
are recommended to reduce this risk, with particular attention with VM in the head
and neck.[57 ]
Glue boluses remain inert for most patients, but may rarely become infected and require
antibiotics. Allergy to nBCA is rare, but may produce severe pruritus. Reported cases
have been managed with oral and topical antihistamines.[58 ] Chronically infected or inflamed glue may eventually extrude through the skin ([Fig. 9c ]).
Glue or coils may also embolize to deep veins or the lungs during the procedure. Vigilant
embolization with adequate outflow control is recommended to guard against this. Small
volumes of glue pulmonary emboli are usually well-tolerated, but coils should be retrieved
by snare whenever possible. If there is concern for deep venous injury and a risk
of DVT, the patient is placed on LMWH twice per day or a DOAC for 2 weeks with US
follow-up; if deep vein injury has occurred, anticoagulation will continue until follow-up
in clinic in 6 to 8 weeks.
Extensive VM in the distal extremities (forearm or calf) may be prone to compartment
syndrome after sclerotherapy. A preprocedure fascial release may be indicated for
patients at high risk; otherwise overnight observation and expectant management are
recommended.
As discussed previously, large VMs are often in a state of LIC due to their dysfunctional
endothelium, and sclerotherapy can induce DIC. Rates of DIC in appropriately anticoagulated
patients is low, but the patient should be assessed for signs and symptoms of DIC
as appropriate.[15 ]
[16 ]
[59 ] Hemoglobinuria is a noted complication of sclerotherapy with higher doses of STS
and ethanol, but is usually transient and addressed by adequate hydration, unless
excessive amounts are used.[60 ]