Evaluation and management of peripheral venous and lymphatic malformations

Evaluation and management of peripheral venous and lymphatic malformations Naiem Nassiri, MD, RPVI,a Jones Thomas, BA,b and Nolan C. Cirillo-Penn, BA,b New Brunswick, NJ The International Society for Study of Vascular Anomalies (ISSVA) broadly categorizes vascular anomalies as vascular tumors or vascular malformations. The latter are congenital lesions that are further categorized by their flow properties and include high-flow arteriovenous malformations, slowflow venous and lymphatic malformations, and congenital mixed syndromes, which can include a combination of malformations. Unlike vascular tumors, vascular malformations never regress and can persist and grow for the duration of the patient’s lifespan. As our understanding of

the natural history, hemodynamics, and treatment outcomes of these lesions has expanded and evolved over the last few decades, certain fundamental diagnostic and therapeutic principles have been established and are considered standard of care. These overarching principles are crucial to adhere to in the overall management of these lesions and are highlighted and expanded on in this report, which focuses exclusively on peripheral slow-flow venous and lymphatic malformations. (J Vasc Surg: Venous and Lym Dis 2015;:1-9.)

Vascular malformations encompass a wide clinical spectrum, ranging from lesions of cosmetic concern to life- or limb-threatening conditions. Each subtype represents a distinct clinical entity with idiosyncratic angioarchitecture, hemodynamics, and natural history. Within each subtype, the anatomic distribution, extent of the lesion, and association with known genetic mutations and affiliated syndromes can further alter the clinical course and affect overall prognosis. Proper nomenclature and clinically oriented organizational schemes, therefore, play a prominent role in the overall management of these complex lesions.

pathogenesis of vascular malformations. This lack of organization has had prognostic and therapeutic implications. Studies have shown improper use of the term “hemangioma” in >70%, which leads to an equivalent proportion of patients receiving an erroneous initial diagnosis.4 This leads to greater than one-half receiving incorrect prognostic information and nearly one-fifth receiving improper initial treatment.4 The latter can have devastating clinical and psychosocial complications. Given the pioneering classification scheme proposed by Mulliken and Glowacki5 and the subsequent criteria set forth by the International Society for Study of Vascular Anomalies (ISSVA),6 these unofficial terms have been abandoned, and their use in describing vascular malformations is discouraged (issva. org/classification; Table). In their seminal paper, Mulliken and Glowacki5 provided proper histologic distinction between hemangiomas and vascular malformations. Hemangiomas are generally benign vascular tumors of endothelial cell origin with specific antigenic profile, tumor markers, and clinical behavior patterns depending on the type of hemangioma6,7 (Table and Fig 1, A). Subcategorization, diagnosis, and management of hemangiomas comprise an extremely detailed topic beyond the scope of this report and will not be discussed further. Vascular malformations do not arise from a neoplastic process but are rather caused by developmental errors during vasculogenesis3,8-10 (Fig 1, B-E). This important histologic distinction was adopted by ISSVA and further expanded to formulate a clinically oriented classification scheme (Table). As outlined in the Table, the ISSVA classification categorizes vascular malformations primarily by their hemodynamics and flow properties. As such, vascular malformations are categorized as slow-flow venous malformations (VMs) and lymphatic malformations (LMs), high-flow arteriovenous malformations and fistulas, and congenital mixed syndromes (Figs 1-3). Vascular malformations can occur as isolated lesions or in combination with other similar flow-pattern vascular malformations.

CLASSIFICATION AND NOMENCLATURE Historically, there has been a great deal of inconsistency in the literature regarding the nomenclature used to describe vascular malformations. In particular, the term hemangioma or derivatives thereof, such as venous angioma, cavernous hemangioma, lymphangioma, and cystic hygroma, continue to be misused in reference to anomalous vascular lesions.1-3 These terms are erroneous because they imply a neoplastic process is involved in the From the Vascular Anomalies & Malformations Program (VAMP) at the Division of Vascular Surgery, Department of Surgery, Rutgers Robert Wood Johnson Medical School, Robert Wood Johnson University Hospital, and Bristol-Myers Squibb Children’s Hospitala; and the Rutgers Robert Wood Johnson Medical School.b Author conflict of interest: none. Correspondence: Naiem Nassiri, MD, Assistant Professor, Vascular Surgery, Department of Surgery, Director, Vascular Anomalies & Malformations Program (VAMP), Rutgers Robert Wood Johnson Medical School, Robert Wood Johnson University Hospital, Bristol-Myers Squibb Children’s Hospital, One Robert Wood Johnson Pl, MEB 541, New Brunswick, NJ 08901 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X Copyright Ó 2015 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvsv.2015.09.001

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Table. Updated 2014 International Society for Study of Vascular Anomalies (ISSVA) classification for vascular anomalies Vascular tumors Benign Infantile hemangioma Congenital hemangioma Rapidly involuting Noninvoluting Locally aggressive Kaposiform hemangioendothelioma Malignant Angiosarcoma Kaposi sarcoma Malignant Angiosarcoma Kaposi sarcoma

Vascular malformations Simple isolated lesions Slow-flow LM VM Capillary malformations High-flow Arteriovenous malformations and fistulas Combined lesions Lymphovenous malformations Capillary VMs Capillary LMs Capillary arteriovenous malformations Congenital syndromes KTS Parkes Weber syndrome Osler-Weber-Rendu/hereditary hemorrhagic telangiectasia CLOVES syndrome Proteus syndrome Phosphatase and tensin homolog hamartoma Bannayan-Riley-Ruvalcaba Cowden syndrome Maffucci syndrome Blue rubber bleb nevus syndrome Sturge-Weber syndrome

CLOVES, Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/Spinal deformities; KTS, Klippel-Trenaunay syndrome; LM, lymphatic malformation; VM, venous malformation.

Combined lesions are more commonly encountered when part of a broader syndrome (Table). The Hamburg classification represents another frequently used organization scheme preferred by some clinicians with an emphasis on the proposed embryogenesis of vascular malformations and their anatomic relationship with major named vascular trunks.7,8 With a stronger emphasis on the hemodynamic profile of vascular malformations, the ISSVA classification has a broader day-to-day clinical applicability and is preferred by most experts in the field. It will be the classification scheme referenced in this review (Table). SLOW-FLOW VASCULAR MALFORMATIONS LMs. LMs represent congenital lymph-filled spaces containing serous, chylous, or serosanguineous fluid, depending on the size and location of the lesion. LMs are arbitrarily termed macrocystic (>2 cm), microcystic (<2 cm), or mixed (most common variant). They can be sporadic or part of a broader syndrome. Syndromes more commonly associated with presence of LM are Klippel-Trenaunay syndrome (KTS) and CLOVES (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/Spinal deformities) syndrome11,12 (Fig 1, D and E). Somatic mosaic mutations in the phosphatidylinositol-4,5bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) have recently been associated with sporadic and syndromic cases of LMs.11 LMs have a predilection for the head and neck (50%), followed by the trunk and extremities (40%), and are least

commonly encountered in the viscera (10%)10,13-15 (Figs 2 and 3). They tend to be lesions of childhood and infancy because changes in the hormonal milieu play a less prominent role in lymphangiogenesis and are not, therefore, necessary environmental triggers for the clinical and symptomatic manifestations of LMs.10,14,16,17 Once discovered, treatment is almost always warranted given the propensity for secondary infection and hemorrhage, which can lead to rapid expansion with exertion of mass effect on adjacent organs, most critically the airway, visceral, and neurologic structures such as the brachial plexus.13,18 Imaging modalities of choice are duplex ultrasound (DUS) imaging and contrast-enhanced magnetic resonance imaging (MRI). DUS features include an avascular, hypoechoic, cystic structure with or without fluid-fluid levels.13,17,19,20 MRI is the gold standard imaging modality and features a T2 isointense-to-hyperintense cystic lesion with characteristic rim enhancement. Lobulations or septations, or both, are also often present13,17,19 (Fig 2, C and D). Microcystic lesions can be more challenging to detect given the intrinsically smaller cystic spaces. They will be hyperintense on T2-weighted series and must be clinically correlated to diagnose accurately.21 First-line treatment is direct percutaneous access of the LM cyst with transcatheter drainage, followed by infusion of sclerosant17 (Fig 3, A and B). An analogy can be made to a fluid-filled balloon. The goal of therapy is percutaneous drainage of the contents of the balloon to obtain maximum collapse and balloon wall apposition in anticipation of infusion of an irritant into the collapsed remnant. This irritant

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Fig 1. A, Classic erythematous proliferative tumor (“strawberry birthmark”) associated with hemangioma of infancy. B, Slow-flow venous malformations (VMs) in various anatomic distributions, including the (B1) neck, (B2) paramandibular buccal, (B3) digital, and (B4) plantar distributions. Note cyanotic to purple hue and spongy, compressible appearance. C1 and C2, Scattered, rubbery, cyanotic nodules in blue rubber bleb nevus syndrome. D1, Port-wine stain and (D2) underlying VM infiltrating congenital lipomatous overgrowth in CLOVES (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, and Skeletal/Spinal deformities) syndrome. E, Port-wine stain, bony and soft tissue hypertrophy, and underlying venous anomalies in Klippel-Trenaunay syndrome (KTS).

serves to cause an intense inflammatory and fibrotic reaction, thereby preventing balloon wall re-expansion. Access into the LM cyst can be gained under direct visualization or under US guidance, depending on the location and accessibility of the LM. US visualization during access is required for deeper lesions, those abutting critical organs, and in situations in which leakage of the LM contents, such as chylothorax or chyloperitoneum, can have devastating complications. Access can be obtained via micropuncture technique to facilitate sheath insertion for larger, more complex lesions or via a needle sheath combination (ie, medium-gauge angiocatheter) for smaller, simpler lesions. Sheath insertion can also facilitate wire and catheter manipulation within the cystic cavity for the purpose of destruction of septations and lobulations (Fig 3, A). This is a key maneuver because adequate drainage of the contents of the LM cyst is, by far, the most important technical component of percutaneous therapy because it allows maximal cystic wall apposition and renders the lesion much more susceptible to irritation, inflammation, and eventually fibrosis by the infused sclerosant. Care must be taken to avoid cystic wall rupture during these manipulations because it will preclude safe infusion of sclerosant into the LM and can have devastating consequences,

including adjacent organ injury, infection, and recurrence. Alternatively, multiple punctures can be performed to access various components of a complex, multilobulated macrocystic LM, with each subcompartment drained and sclerosed separately.15,17 Once maximum drainage has been achieved, diagnostic lymphangiography can be performed to ascertain configuration of the cystic remnant, evaluate for the presence of residual septations and lobulations within the LM cyst, ensure cystic wall integrity, and estimate sclerosant volume requirements. The injected contrast medium is then evacuated in preparation for sclerosant infusion.17 Absolute contraindications for sclerotherapy include severe allergic reaction to the embolic agent and untreated superimposed infection. Multiple sclerosing agents are available for offlabel use, including: d

d

d

OK-432, an attenuated strain of Streptococcus pyogenes that is not commercially available in the United States; Doxycycline, a tetracycline, which is effective due to its antivascular endothelial growth factor and antimatrix metalloproteinase properties; Bleomycin, an antineoplastic agent with cumulative dose restrictions owing to the rare risk of pulmonary fibrosis;

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Fig 2. A and B, Isolated, superficial, macrocystic lymphatic malformation (LM) in the right leg. C and D, Note layered, lobulated cystic structure with rim enhancement on T2 weighted magnetic resonance imaging (MRI).

d d

Ethanol, which is highly effective but toxic; and Sodium tetradecyl sulfate (STS; Sotradecol; AngioDynamics, Latham, NY) a detergent-like compound acting as an anionic surfactant.13,15,22,23

Owing to its relatively limited adverse effect profile (limited to rare bouts of hypoglycemia and skin photosensitivity reactions), high technical success rates (>90%), and low recurrence rates (<10%), doxycycline is often the firstline agent of choice for most peripheral, nonmucosal LMs.10,13,15,17,21 Multiple sessions may be required, and refractory lesions may be targeted by more aggressive sclerosants such as bleomycin and ethanol.18,22,24 Surgical excision and laser photocoagulation of sclerosed remnants serve as other important therapeutic adjuncts.25 In settings of inadequate initial treatment, recurrence is almost always detected within the first postoperative visit. Superficial lesions will demonstrate rapid re-expansion, whereas imaging will be required to document recurrence in deeper lesions. These recurrences will require a staged reintervention to minimize continued rapid expansion. The main cause of re-expansion is often inadequate drainage of the cystic cavity.17

A typical sclerosant dose is 100 to 300 mg of doxycycline powder mixed with sterile water and a contrast agent for a final concentration 10 to 15 mg/mL. Given the pain and discomfort associated with doxycycline infusion, some may choose to add a local anesthetic, such as lidocaine or bupivacaine, to the solution. We prefer to perform these procedures with the patient under general anesthesia to maximize compliance and comfort. Care must be taken to avoid cystic wall disruption if local anesthetic is included to avoid systemic toxicity, particularly with a large volume of sclerosant. The maximum allowable dose per session is 1 g of doxycycline or w100 mL of solution. Such high sclerosant volumes are rarely required except when treating giant intraperitoneal LMs, which may require repeated bouts of sclerotherapy during the same admission.15,17 Smaller, more readily accessible LMs (those requiring <10 mL of sclerosant) can undergo doxycycline infusion without subsequent sclerosant drainage. Larger, deeper macrocystic LMsdparticularly intraperitoneal LMs requiring >10 mL of sclerosantdshould undergo sclerosant drainage 4 to 5 hours after the initial infusion to prevent leakage and adjacent organ irritation. Once the infused sclerosant is drained, additional gravity bag drainage is

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Fig 3. A, Percutaneous catheter access into a lobulated, intraperitoneal, macrocystic lymphatic malformation (LM) and lymphangiogram. The latter ensures adequate breakdown of intrasac lobulations and septations and provides a rough estimate of the volume of the sac. B, Adequate drainage of the contents of the LM cyst is a key step in percutaneous treatment of macrocystic LMs. Note chylous content of this particular intraperitoneal LM. C and D, Microcystic LM of the tongue. These lesions are less amenable to percutaneous drainage and sclerotherapy. Laser photocoagulation with or without surgical excision, followed by reconstruction, is more commonly used under these circumstances.

performed for the next 24 hours. If >25% of the initial cyst volume is drained overnight, further sclerosant infusion can be performed until further cyst volume reduction is achieved. Multiple treatment sessions may be necessary in a staged fashion for adequate treatment of larger LMs. In the absence of secondary complications, such as infection or rapid re-expansion, a lag period of 1 to 3 months is allotted between sessions. Repeat imaging with DUS or MRI, or both, may be necessary to assess remnant volume. With single-session response rates of >80%, macrocystic LMs are much more effectively treated by direct percutaneous drainage and sclerotherapy than microcystic and mixed LMs (response rates of up to 50%).15 Multiple sessions and adjunctive use of other modalities, including laser photocoagulation or surgical excision, or both, may be necessary for adequate treatment of microcystic lesions.25 Surgery is generally not recommended as the first-line therapy for macrocystic LMs due to the propensity for inadequate excision, cystic wall violation and leakage of content, adjacent organ injury, infection, and recurrence.10,13,16 Indeed, recurrence and major complications have been reported in up to 40% to 50% of cases of primary surgical excision of macrocystic LMs.15,17,26-29 Surgery does, nevertheless, serve as an important adjunctive procedure for excision of cystic remnant and residual fibrotic tissue after sclerotherapy in select cases.25 A staged multidisciplinary approach, using the services of an

experienced interventionalist, pediatric surgeon, and plastic surgeon, serves as the best therapeutic option in the management of complicated or refractory cases. VMs. VMs are the most common, comprising >75% of all vascular malformations. It is important to note that the ISSVA classification does not include anomalies of the anatomic veinsdthe so-called truncular venous anomalies according to the Hamburg classificationdbecause these represent embryologic developmental errors that lead to formation of often asymptomatic variants such as duplicated and left-sided vena cava, caval agenesis, and venous compression syndromes.7 Similar to the ISSVA classification, this review focuses on VMs affecting unnamed venous channels that have an unpredictable and variable extent of involvement with major named trunks and present as spongy, compressible masses that can affect nearly any layer of any organ. Unlike hemangiomas, which may involute after a confined proliferative phase, VMs never regress and are present for the duration of the patient’s lifespan. Although congenital, VMs may not become noticed until symptoms develop as a result of injury, activity, thrombosis, and hormonal fluctuations such as occurs during puberty, menses, and pregnancy.3,17 Pain, functional impairments, cosmetic disfigurement, and associated psychosocial issues are major indications for treatment.3,10,17 Diffuse lesions of the extremitiesdparticularly the lower extremities in patients

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with syndromic cases of VMs such KTS, Proteus, and CLOVESdcan involve the joints and are prone to early-onset osteoarthritic changes as a result of chronic hemarthrosis. Careful assessment of gait and function, detailed imaging, and early involvement of orthopedic colleagues are essential supplements to embolotherapy in successful management of these patients.17 Hematologic evaluation at the time of diagnosis, particularly when widespread extensive lesions are encountered, is of paramount importance before treatment is initiated. Fibrinogen and D-dimer levels must be checked routinely because they may signal the presence of localized intravascular coagulopathy (LIC), which may progress to disseminated intravascular coagulopathy (DIC) with aggressive embolotherapy.8,9 Prophylactic administration of low-molecular-weight heparin with frequent D-dimer and fibrinogen level surveillance is often required before any embolic therapeutic intervention. In cases of large, widespread lesions, D-dimer levels can increase significantly after embolization and must be monitored closely and managed with appropriate doses of anticoagulation. Early involvement of an experienced hematologist well versed in the management of the coagulopathic manifestations of vascular malformations is essential for the safe, comprehensive treatment of these patients.8,17,30 VMs are sporadic or part of a broader syndrome. The most common syndrome associated with the presence of VM is KTS, which presents as the triad of port-wine stain, VMs, and often, unilateral limb overgrowth (Fig 1, E). Other associated syndromes include blue rubber bleb nevus syndrome (Bean syndrome), Proteus syndrome, CLOVES syndrome, and Maffucci syndrome3,12,17,19 (Fig 1, B-D). Mutations in the TIE-2 receptor tyrosine kinase, an endothelial cell receptor involved in mesenchymal cell recruitment during vasculogenesis, has been associated with sporadic and syndromic cases of VMs.3,9,10,19,30,31 The resulting defect is a weakened tunica media with abnormal elasticity, increased capacitance, and subsequent incompetence of the venous wall causing stagnant flow and pooling of blood.3,10 Aside from anatomic distribution patterns and extent of involvement, syndromic and isolated cases of VMs have a similar natural history and prognosis, and therapeutic options remain largely similar.10,30 VMs can affect any organ at any layer. Capillary VMs manifest as port-wine stains and are the most common type. When larger venous channels are involved, VMs can present as blue or purple, soft, spongy, compressible tumors or nodules without a pulse, thrill, or bruit (Fig 1, B). If superficial enough, secondary skin changes, such as angiokeratomas, may be present, reflecting localized chronic dermatitic changes. Pain is by far the most common symptom, occasionally exacerbated by the presence of phleboliths. Bleeding is a rare occurrence.3,17 DUS and MRI are the imaging modalities of choice10,17,21,30 (Fig 4, A-D). DUS interrogation of VMs reveals dilated, tortuous channels with an occasional phlebolith (Fig 4, C). Spectral waveform analysis reveals venous flow patterns. DUS also serves an important role in ascertaining the presence and competence of a deep venous system in

patients with KTS or those with extensive lower limb VMs. DUS has largely replaced ascending phlebography for this purpose.32 Confirmation of an intact, competent deep system affecting the lower extremities can have major therapeutic implications for patients with KTS and allows for a much more aggressive approach to treatment of anomalous superficial veins.10,30,32 Contrast-enhanced MRI is, however, the gold standard imaging modality for VMs with characteristic T-2 hyperintense lesions17 (Fig 4, A and D). Given the inconsistent and unpredictable extent of the association with the systemic circulation, ascending phlebography is unreliable for diagnostic imaging and should not be relied on exclusively for diagnostic purposes.17 No cure currently exists for VMs, and treatment is offered mostly for management of symptoms. The mainstay of treatment for VMs is direct-stick embolization (DSE).3,17,33 VMs affecting the extremities, as well as syndromic cases that include VMs in addition to axial venous reflux with subsequent development of varicose veins (as in KTS), can be conservatively managed with compression therapy.7,34 However, given currently available therapeutic options, compression therapy alone is rarely adequate, and patients almost always seek additional intervention for the alleviation of underlying symptoms.32 Absolute contraindications for DSE include untreated LIC or DIC, active superimposed infection, and known severe allergic reaction to the embolic agent.8,30 DSE involves percutaneous access of the malformed venous conduit with a small-gauge needle or needlesheath combination (angiocatheter). This can be performed with or without US guidance and is followed by venographic evaluation of the extent and configuration of the accessed channel (Fig 4, B). Once endoluminal access is confirmed and the angioarchitecture of the VM is outlined fluoroscopically, a sclerosant is directly infused to produce a localized thrombophlebitis, which is followed by fibrosis and gradual shrinkage of the lesion. Certain sclerosants can be made radiopaque for fluoroscopic monitoring during infusion to minimize the risk of extravasation or nontarget embolization by escape into the systemic circulation. A variety of different sclerosants, such as ethanol, STS, sodium morrhuate, polidocanol, and bleomycin, can be used off-label for embolization.18,30,35-37 Ethanol is by far the most potent embolic agent, with a technical success rates of >90% and extremely rare recurrence rates.17,30 However, its toxic adverse effect profile, with propensity for skin sloughing, neurotoxicity, and central cardiopulmonary complications, has limited its use, particularly in the pediatric population.17,38-40 Detergent-like compounds such as STS and polidocanol have had relatively good technical success rates of 60% to 85%, with recurrence rates of <20% depending on the size and extent of the lesion targeted.3,8,17,30 These agents have long been approved and used for treatment of varicose and reticular veins. They, therefore, have a welldocumented and relatively limited adverse effect profile (allergic reactions, skin ulceration, and nerve damage)

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Fig 4. A, Characteristic magnetic resonance imaging (MRI) features of a superficial slow-flow venous malformation (VM) of the proximal lateral thigh without deep intramuscular involvement. Note T2 hyperintensity without presence of flow-voids. B, Fluoroscopic correlation with MRI findings at the time of direct-stick embolization (DSE). Note intraluminal catheter placement for delineation of the extent of the VM and subsequent infusion of liquid sclerosant. A proximal clamp compressing the overlying skin adequately halts systemic drainage during transcatheter infusion of the sclerosant. C, A superficial slow-flow VM on B-mode ultrasound (US) imaging. Partial thrombosis of portions of the VM was noted on compression. D, T2 hyperintensity on contrast-enhanced MRI (not magnetic resonance venography) is characteristic. Superficial and deep intramuscular components were both noted in this patient with KlippelTrenaunay syndrome (KTS).

and are the agents most commonly used for treatment of VMs.8,30 They can be delivered as foam by mixing and agitating air into the compound solution (ie, Tessari method) or as a liquid preparation, depending on physician preference and experience.8,30 Reported experience remains limited to case series and retrospective reviews. As such, no level I evidence exists on the method of embolization and sclerosant agent of choice; therefore, experience and familiarity with technique are the most reliable determinants of clinical outcomes.3,8,17,30 Our practice is to use a liquid preparation of STS of 1% to 3%, depending on the extent and location of the lesion. The procedure is performed under general anesthesia to help maximize patient compliance and comfort. The solution is prepared by mixing 2.5 mL of STS with 0.2 mL of lipiodol oil (Guerbet USA, Bloomington, Ind) and agitated. This technique renders the solution radiopaque for the purposes of fluoroscopic monitoring during the infusion to prevent nontarget embolization. When extremity lesions are treated, a sterile tourniquet is applied proximal to the affected area under treatment and insufflated to mean arterial pressure. This allows for venous congestion of the lesion under treatment without disrupting systolic arterial perfusion and also helps

minimize nontarget embolization and escape of sclerosant into the central circulation. Furthermore, when possible, an intravenous catheter is inserted distal to the targeted treatment area for continuous heparinized saline infusion during DSE for dilution of any escaped sclerosant into systemic circulation. Upon completion of DSE, we continue the heparinized saline infusion as well as tourniquet insufflation for an additional 5 minutes to help minimize nontarget embolization into major draining veins. After the procedure, the patients are observed for 24 hours in the hospital for evaluation of any neurosensory deficits, overlying skin changes, and to assess level of pain. The patient is evaluated after discharge from the hospital at intervals of 2 weeks, 6 weeks, 3 months, and 6 months. Patients are reassured and reminded that symptoms may actually worsen within the first 2 weeks after the procedure given the intrinsic inflammatory response associated with this technique. Typically, a minimum of 6 weeks is required before any real assessment of postoperative improvement can be made. We generally avoid local reintervention earlier than 90 days unless plans have been made for a staged, multidisciplinary approach such as embolization, followed by surgical excision.

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In experienced hands, major complications associated with DSE are extremely rare (<5%).8,30 These can include allergic reactions, nontarget embolization with subsequent development of venous thromboembolism, central cardiopulmonary toxicity, extravasation of sclerosant with neurotoxicity, skin ulceration, compartment syndrome, and DIC. In our experience, the hemoglobinuria occasionally reported in some series after DSE is extremely rare and tends to be a manifestation of LIC or DIC, or both.41 Judicious use of imaging modalities during DSE, a staged, conservative approach to treatment, familiarity with nuances of each embolic agent and necessary adjunctive modalities, and collaboration with dedicated and experienced colleagues serve to provide optimal outcomes while minimizing complications. Although surgical excision of focal, isolated lesions can be performed successfully, surgical excision is most effective as a secondary adjunct after DSE.3 It is important to re-emphasize that no cure exists currently for these lesions. Focal isolated lesions can be treated without recurrence, but widespread lesions are almost impossible to eliminate.17 As such, under these circumstances, treatment is geared toward symptom control and preservation of function. Although excellent relief of symptoms is achieved with almost all available embolic agents, recurrence of these larger, more widespread VMs is inevitable throughout the patient’s lifespan (up to 40% recurrence).17,30 Recurrence tends to be extremely rare in the immediate postoperative period if adequate embolization has been performed initially. Symptom recurrence can be due to the expansion of new VM conduits or recanalization of previously treated channels. The latter tends to occur months to years later after the initial successful DSE. In the setting of recurrence, repeat DSE is generally recommended before contemplation of other therapeutic modalities such as surgical debulking. SUMMARY Vascular malformations are congenital lesions that develop as a result of developmental errors during vasculogenesis. They must be distinguished from hemangiomas, which represent hamartomas of endothelial cell origin. Nomenclature and classification schemes are important because treatment options vary widely. Slow-flow vascular malformations include VMs and LMs that can occur sporadically or as part of a broader syndrome. Endovascular treatment by DSE has evolved into the first-line and often sole therapy for most VMs and LMs. Experience with technique and familiarity with various embolic agents are main determinants of clinical outcomes. A collaborative, multidisciplinary approach, often led by an experienced interventionalist within a dedicated center of excellence, is critical for safe, comprehensive management of these complex lesions. Other essential members of such a team include radiologists, hematologists, and reconstructive surgeons. Although these specialties often remain at the core of most vascular malformation programs, collaboration and cooperation with nearly all medical specialties is required based on the idiosyncratic features of each patient’s unique clinical condition.

AUTHOR CONTRIBUTIONS Conception and design: NN Analysis and interpretation: NN Data collection: NN, JT, NC Writing the article: NN, JT, NC Critical revision of the article: NN Final approval of the article: NN Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: NN REFERENCES 1. Sundararajan SH, Nassiri N. Regarding “Cavernous hemangioma of the external carotid artery”. J Vasc Surg 2014;60:1412. 2. Clemens RK, Pfammatter T, Meier TO, Alomari AI, Amann-Vesti BR. Vascular malformations revisited. Vasa 2015;44:5-22. 3. Nassiri N, O TM, Rosen RJ, Moritz J, Waner M. Staged endovascular and surgical treatment of slow-flow vulvar venous malformations. Am J Obstet Gynecol 2013;208:366.e1-6. 4. Hassanein AH, Mulliken JB, Fishman SJ, Greene AK. Evaluation of terminology for vascular anomalies in current literature. Plast Reconstr Surg 2011;127:347-51. 5. Mulliken JB, Glowacki J, Thomson HG. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:412-22. 6. International Society for the Study of Vascular Anomalies. ISSVA classification of vascular anomalies. Available at: issva.org/classification. Accessed March 18, 2015. 7. Lee BB, Laredo J, Lee TS, Huh S, Neville R. Terminology and classification of congenital vascular malformations. Phlebology 2007;22: 249-52. 8. Lee BB, Baumgartner I, Berlien P, Bianchini G, Burrows P, Gloviczki P, et al. Diagnosis and treatment of venous malformations. Consensus document of the International Union of Phlebology (IUP): updated 2013. Int Angiol 2015;34:97-149. 9. Blei F. Medical and genetic aspects of vascular anomalies. Tech Vasc Interv Radiol 2013;16:2-11. 10. Burrows PE. Vascular malformations involving the female pelvis. Semin Intervent Radiol 2008;25:347-60. 11. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovée JV, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 2015;166:1048-54. e1-5. 12. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet 2007;16:R140-9. 13. Chaudry G, Burrows PE, Padua HM, Dillon BJ, Fishman SJ, Alomari AI. Sclerotherapy of abdominal lymphatic malformations with doxycycline. J Vasc Interv Radiol 2011;22:1431-5. 14. Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations: part I. J Am Acad Dermatol 2007;56:353-70; quiz: 371-4. 15. Burrows PE, Mitri RK, Alomari A, Padua HM, Lord DJ, Sylvia MB, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol 2008;6:209-16. 16. Gloviczki P, Duncan A, Kalra M, Oderich G, Ricotta J, Bower T, et al. Vascular malformations: an update. Perspect Vasc Surg Endovasc Ther 2009;21:133-48. 17. Burrows PE. Endovascular treatment of slow-flow vascular malformations. Tech Vasc Interv Radiol 2013;16:12-21. 18. Mohan AT, Adams S, Adams K, Hudson DA. Intralesional bleomycin injection in management of low flow vascular malformations in children. J Plast Surg Hand Surg 2014;49:1-5. 19. Dompmartin A, Vikkula M, Boon LM. Venous malformation: update on etiopathogenesis, diagnosis and management. Phlebology 2010;25: 224-35. 20. Paltiel HJ, Burrows PE, Kozakewich HP, Zurakowski D, Mulliken JB. Soft-tissue vascular anomalies: utility of US for diagnosis. Radiology 2000;214:747-54.

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Submitted Mar 18, 2015; accepted Sep 2, 2015.