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Low-flow vascular malformations of the head and neck: clinicopathology and image guided therapy
  1. Zachary Love1,
  2. Daniel Pierce Hsu2
  1. 1Department of Radiology, University Hospitals Case Medical Center, Cleveland, Ohio, USA
  2. 2Interventional Neuroradiology, University Hospitals Case Medical Center, Cleveland, Ohio, USA
  1. Correspondence to Dr D P Hsu, Interventional Neuroradiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA; daniel.hsu{at}uhhospitals.org

Abstract

Low-flow vascular malformations are congenital lesions secondary to errors in the development of veins, capillaries or lymphatics. The majority of these lesions are sporadic although association with heritable syndromes does occur. Patients with these lesions should be treated and evaluated by a multidisciplinary team comprising medical, radiologic and surgical subspecialties. Percutaneous image guided sclerotherapy is gaining acceptance as a firstline treatment of low-flow vascular malformations.

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Clinicopathology

Vascular malformations

Vascular malformations are localized structural errors in vasculogenesis, angiogenesis or lymphogenesis. According to the classification scheme for vascular anomalies proposed by Mulliken and Glowacki in 1982,1 the endothelial cells of vascular malformations display a normal cell cycle duration. In contrast, the endothelium of vascular tumors displays a characteristic proliferative phase, sometimes followed by an involutional phase, as seen in infantile hemangiomas.2 Vascular malformations can be further characterized by their rheostatic characteristics and endothelial cell of origin. This scheme was adopted and expanded by the International Society for the Study of Vascular Anomalies in 1996 (table 1), which further stratified vascular tumors into: infantile hemangiomas, congenital hemangiomas, lobular capillary hemangiomas, tufted angiomas, kaposiform hemangioendotheliomas and hemangiopericytomas. The scheme is further supported by the finding of molecular genetic differences between malformations and true vascular tumors. For example, in infantile hemangioma, the endothelium constitutively overexpresses the GLUT1 glucose transporter whereas GLUT1 expression is non-detectable in the endothelium of vascular malformations.2

Table 1

Classification scheme of the International Society for the Study of Vascular Anomalies

Vascular malformations are congenital, with up to 90% being recognized at birth,1 and the majority are sporadic.3 The incidence has been estimated at between 0.3% and 0.5% of live births, with no reported gender or ethnic bias.4 These lesions tend to grow with the child and rarely spontaneously resolve. Vascular malformations are subdivided into high-flow and low-flow lesions, depending on the presence of an arterial component. High-flow lesions comprise arterial malformations, arteriovenous malformations, capillary arteriovenous malformations and arteriovenous fistulae. Low-flow vascular malformations have no arterial component and are further characterized by their predominant endothelial cell type: capillary, venous, lymphatic or combined (eg, capillary–lymphatic venous malformation, lymphovenous malformation).

Capillary malformations

Capillary malformations (CM), also known as stains or port wine stains, are common vascular malformations with an incidence estimated at 0.3%.4 These lesions have no reported gender or ethnic bias. CM may be single or multiple, are typically well demarcated, appear pink in infancy and may darken with age. Histologically, these lesions demonstrate ectatic vessels within the dermis. CM commonly occur in the head and neck. Symptoms related to sporadic CM are primarily cosmetic although they can demonstrate severe bleeding following minor trauma.5 The majority of CM in the head and neck occur in the distribution of the trigeminal nerve, most commonly in V1 and V2. In one series, 8% of CM were associated with Sturge–Weber syndrome and unilateral glaucoma.6 CM have further associations with Klippel–Trenaunay (CM, lymphatic malformation, venous ectasia or hypoplasia, and limb overgrowth), Parkes–Weber (CM with multiple micro- arteriovenous fistula and limb overgrowth), macrocephaly capillary malformation and capillary malformation arteriovenous malformation syndromes.3 The latter has been linked to inactivating mutations in RASA1, encoding Ras1, a GTPase activating protein involved in cell growth, proliferation and differentiation in angiogenesis.7

Venous malformations

Venous malformations (VM) are rare congenital lesions with an estimated incidence of 0.01%.3 Approximately 98% of VM occur sporadically,3 with 40% occurring in the head and neck, 40% in the trunk and 20% in the extremities. Distribution can be focal, multifocal or diffuse. VM frequently demonstrate change in size and symptoms with hormonal changes such as those occurring in puberty and menarche. VM appear as bluish to purplish cutaneous lesions which are compressible and characteristically expand with the Valsalva maneuver or dependency. As opposed to arterial malformations, there is no associated thrill or increase in skin temperature.

Histologically, VM display abnormally dilated venous channels lined by a single layer of normal appearing endothelium with a thin, asymmetric and disrupted layer of smooth muscle. The architecture of focal lesions typically results in slow inflow into dilated abnormal channels with slow outflow which predisposes to intralesional thrombosis. However, fast outflow is also seen, especially in diffuse forms with egress via more diffuse networks of draining veins. This can lead to inadvertent systemic administration of sclerosant during sclerotherapy.8

Pain is common in VM and can be related to focal thrombosis, muscle fibrosis, hemarthrosis, arthropathy or associated deformity in the underlying bone or muscle. In the head and neck, deep extension with mucosal involvement can result in oral bleeding. Swelling is common, and local compressive effects can result from extension into adjacent structures such as the orbit, parotid gland, larynx or adjacent musculature. Resulting cosmetic deformity can have profound psychological effects on both patient and parent.9 The cycle of intralesional thrombosis and thrombolysis results in consumption of fibrinogen and production of fibrin split products, with a normal prothrombin time and partial thromboplastin time, termed local intravascular coagulopathy (LIC). Small series have demonstrated a positive d-dimer in 33–42% of patients with VM.10 ,11 LIC has been shown to be associated with large diffuse lesions, truncal location and palpable phleboliths. The presence of LIC can result in disseminated intravascular coagulopathy (DIC) during trauma or surgery.11

Although the vast majority are sporadic, VM can be seen in a number of heritable conditions. The mutations underlying these syndromes may in turn elucidate details of the pathogenesis of sporadic VM. A subset of VM, glomuvenous malformations, account for approximately 5% of VM. These lesions present as painful, non-compressible, multifocal, nodular blue cutaneous lesions, usually in the extremities. New lesions develop throughout the life of the patient. Glomuvenous malformations are associated with loss of function mutations in the globulin gene, causing abnormal differentiation of smooth muscle cells.3 ,4 ,8 Cutaneomucosal venous malformation syndrome displays dominant inheritance and is associated with a mutation in TIE2, causing autophosphorylation of an endothelial cell specific tyrosine kinase, leading to cell proliferation.3 Blue rubber bleb nevus syndrome is a mostly sporadic but sometimes familial disorder which presents with continuous development of painless, nodular, focal, compressible, blue cutaneous lesions throughout life, involving the head, neck and extremities.8 Mucosal involvement of the gastrointestinal tract can result in gastrointestinal bleeding. Cranial nerve palsy due to intracranial involvement has been reported.12 In familial cases this disorder displays autosomal dominant inheritance and has been linked to the 9p locus.13

Lymphatic malformations

Lymphatic malformations (LM) represent a congenital local disturbance in lymphatic development and have formerly been termed by a confusing array of monikers, including cystic hygroma and lymphangioma.14 The incidence is reported at between 0.02% and 0.05%, and represents approximately 3 of 100 000 hospital admissions.14 ,15 Greater than 50% of LM are evident at birth, with 80–90% manifesting prior to 2 years of age.16 Approximately 75% occur in the head and neck15 although they can manifest in the mediastinum, axilla, extremities, retroperitoneum or pelvis with a propensity to cross fascial planes and involve multiple compartments. Spontaneous regression is rare and has been reported at <3–4%.14 ,17 Usual presentation is due to focal mass or tissue overgrowth. Like other vascular malformations, these lesions do not proliferate but grow with the child. However, LM can exhibit an episodic and sudden increase in size due to infection (typically upper respiratory) or hemorrhage into the lesion.

LM are composed of multiple dilated lymphatic cysts or locules, separate from normal lymphatic channels, lined by a single layer of endothelium and containing a thin, tan, proteinaceous fluid.1 These dilated channels are surrounded by disorganized smooth muscle cells and elastin fibers.18 LM can be classified radiologically as macrocystic (cysts ≥2 cm3), microcystic (cysts <2 cm3) or mixed, which has important implications for treatment. It should be noted, however, that one radiographic classification scheme is not universally accepted and many exist. These macroscopic differences are not apparent on histologic sections.18 The presence of lymphatic endothelium can be confirmed by staining with D2-40 antibody.2

Symptoms due to LM are typically due to the mass effect on adjacent structures which can be exacerbated by their episodic enlargement secondary to hemorrhage or infection (figure 1). Infection is especially common in suprahyoid LM with mucosal involvement.15 Airway involvement can present with stridor and apnea. In one series, 5% of patients required tracheostomy at birth due to airway compromise.16 In the orbit LM can present with pain, swelling, proptosis, blepharoptosis and amblyopia. In one series of patients with orbital involvement, 45% had an underlying cerebral developmental anomaly.19 Involvement of the alimentary canal can manifest as macroglossia, dysphagia and dental malocclusion. Long term sequelae include mandibular maldevelopment, skeletal hypertrophy, bite deformity, speech delay and psychological distress due to cosmetic deformity. Bilateral, diffuse and microcystic LM have been associated with lymphocytopenia, which does not appear to be secondary to sequestration within the malformation. Those patients with LM and lymphocytopenia have a greater rate of hospitalization, central line placements and treatment complications.15 ,20

Figure 1

Macrocystic lymphatic malformation with intralesional hemorrhage. (A) Axial T2 weighted image with fat suppression demonstrates a multiloculated cystic mass extending from the left buccal subcutaneous tissues to the left parapharyngeal space. The more medial locules are T2 hyperintense, while the more lateral locules exhibit relative hypointensity, consistent with internal hemorrhage. A follow-up image (B) without interval intervention demonstrates interval decrease in size of the mass and previously demonstrated locules. There has been resorption of the majority of the intralesional hemorrhage although some still contain mixed T2 signal consistent with hemorrhagic clot.

No evidence exists for heritable LM. Cervical LM do occur in association with Klippel–Trenaunay, Turner and Noonan syndromes,21 as well as in trisomy 13 and 18. The lack of heritability of LM suggests that germline mutations leading to LM may not be compatible with life.

Therapy for low-flow vascular malformations

Non-invasive therapies

Patients with vascular malformations benefit from treatment in a multidisciplinary setting. Providers from vascular, orthopedic, plastic/reconstructive surgery, otolaryngology, ophthalmology, diagnostic and interventional radiology, physical and rehabilitation medicine, hematology–oncology, psychiatry and patient advocacy all have crucial roles in the management of these complex patients whose treatment is often prolonged and staged in a stepwise fashion.22 ,23 In particular, initial counseling and an ongoing frank discussion as to the incremental nature of treatment, possible complications, and potential for residual disease despite the possibility of dramatic positive outcome is a requisite.

CM are primarily treated with pulsed dye laser. This treatment affords approximately 50–75% of patients with port wine stains approximately 70–75% lightening of the lesion.24 ,25 Venous VM can be treated with simple compression, laser photocoagulation,8 radiation, diathermy, percutaneous ablation, surgical resection or sclerotherapy. Pain due to repeated thrombosis has been treated in the past with salicylic acid, although this is of questionable use given that VM are not usually consumptive of platelets.11 A baseline coagulation panel is used to assess for LIC and general bleeding risk. Some groups have had success in the treatment of patients with elevated d-dimer and painful VM with low molecular weight heparin for symptomatic relief. In patients with LIC without pain, low molecular weight heparin may be instituted for 10 days prior and 14 days post-interventional procedure to prevent DIC.

LM and VM can be managed by observation, surgical resection or percutaneous sclerotherapy. Given the frequent rate of infection of LM, many patients require repeated courses of oral or parenteral antibiotic therapy with or without a concomitant course of steroids. Lesions with extension into the oral cavity can cause dental malocclusion, and frequent dental hygiene visits for these patients may help reduce infection. Symptomatic microcystic involvement in the oral cavity, including the tongue and buccal mucosa, is generally treated with surgical resection, although treatment with laser or radiofrequency ablation has been reported.26 Prenatal detection of LM with airway involvement may necessitate EXIT procedure with cesarean partial delivery with continuation of placental circulation for intrapartum staged control of the airway.15

Image guided therapy

General considerations

Early intervention is necessitated in cases where the vascular malformation causes life threatening dysfunction. When this is not the case, observation or treatment delayed past infancy is a viable option.15 When therapy is initiated, symptomatic lesions are targeted first. Image guided sclerotherapy is gaining acceptance as a primary therapy for low-flow VM due to low rates of recurrence and a potentially lower rate of complications and morbidity compared with surgery.

Sclerosants function by causing local endothelial damage which in turn leads to inflammation, thrombosis and ultimately fibrosis and collapse of the malformation channel lumen. Treatment and therapeutic effect extends only to the channels or cysts injected. Some degree of swelling and pain are a predictable part of this process and are not considered complications. It may take weeks to reach full efficacy post-treatment, and it may take multiple treatments to achieve significant lesional reduction and symptom abatement. Ultimately, surgery may be required as an adjunctive procedure to remove scar tissue causing mass effect or cosmetic defect or to excise tissue resistant to sclerotherapy.

Imaging of low-flow vascular malformations

Pretreatment MR or ultrasound is used to define lesion characteristics, lesion extent and relationship to surface and underlying anatomy.23 In general, Doppler ultrasound is the most widely used modality to confirm the hemodynamic characteristics of the lesion whereas MR provides the best information as to lesion extent and relationship to crucial anatomic structures such as nerves and vasculature.27 Low-flow VM are visualized as heterogeneous, compressible soft tissue masses on ultrasound (figure 2). Phleboliths will demonstrate posterior acoustic shadowing. Doppler evaluation will typically show no or monophasic low-flow, and augmentation with compression or Valsalva maneuver may be needed to demonstrate flow. VM are typically hypo- to isointense on T1 weighted sequences, although the presence of thrombosis or hemorrhage may be reflected in a heterogeneous appearance. These lesions demonstrate hyperintense signal of T2 weighted sequences, with areas of internal low signal corresponding to phleboliths, septae or thrombosis (figure 3). Dynamic, post-contrast, T1 weighted images may be obtained to define perfusion and draining venous anatomy. At our institution, time resolved gadolinium bolus MR angiography is utilized to evaluate vascular supply, venous drainage and whether the lesion is high- or low-flow.

Figure 2

Low-flow venous vascular malformation. (A) Characteristic spongiform appearance of venous malformation on gray scale ultrasound. (B) Color Doppler interrogation reveals the compressible echolucent spaces to be vascular (venous). (C) Arterial signal is seen at the periphery of the lesion. (D, E) Contrast enhanced axial CT images demonstrate irregular foci with avid enhancement, as well as phleboliths. Note the bony distortion of the left maxillary sinus and its frontal process. (F, G) Coronal and axial T2 weighted images demonstrate this massive venous malformation to be heterogeneous and trans-spatial. Phleboliths appear as rounded foci of hypointensity. (H) Unsubtracted fluoroscopic image demonstrates phleboliths as rounded radio-opacities scattered throughout the soft tissue mass. (I) Surgical compartmentalization before sclerotherapy allowed for injection of sufficient sclerosant into well defined regions of the large lesion to achieve a therapeutic concentration without reaching toxic dosage levels. (Reprinted from Choi DJ, Alomari AI, Chaudry G, et al. Neurointerventional management of low-flow vascular malformations of the head and neck. In: Neuroimaging clinics of North America, vol 19, 2nd Edn. Amsterdam: Elsevier 2009:199–218, © 2009, with permission from Elsevier.)

Figure 3

Low-flow venous vascular malformation. Axial T1-weighted image without (A) and with contrast (B), axial T2 with fat-suppression (C) and coronal T2 with fat-suppression (D) images reveal a lobular mass (*) with in the right inferolateral lip. The mass displays hypointensity on T1 WI and hyperintensity on T2 WI consistent with venous malformation.

Macrocystic LM appear as multiple, hypoechoic, cystic spaces with intervening septae on grayscale ultrasound; the septae may contain vessels demonstrating flow on Doppler interrogation. Microcystic LM appear as an ill defined hyperechoic mass on gray scale ultrasound imaging. On MR imaging, macrocystic LM appear as fluid filled lesions with a single locule or multiple septated loculations displaying high signal on T2 weighted imaging and low signal on T1 weighted images. Frequently, high signal on T1 weighted images may be seen in the setting of internal hemorrhage (figure 4). Post-gadolinium T1 weighted images show absent or scant septal enhancement. No enhancing soft tissue components should be present in the setting of LM (figure 5).

Figure 4

Macrocystic lymphatic malformation. (A) Axial CT of the neck with contrast reveals an irregular, multiloculated, hypodense mass centered within the left suprahyoid neck with thin internal septations. The mass traverses multiple facial planes extending from the left masticator space to the retropharygeal space, causes anterolateral displacement of the oropharyngeal airway. (B) Axial T2 weighted image with fat suppression re-demonstrates the multiloculated macrocystic architecture, with internal fluid–fluid level consistent with intralesional hemorrhage. (C) Axial T2 weighted TRU-FISP image during MR guided sclerotherapy shows selective cannulation of a locule in the retropharygeal space. (D) Follow-up post-treatment axial T2 weighted image with fat suppression demonstrates two small residual T2 hyperintense locules in the retropharyngeal and left carotid spaces.

Figure 5

Representative MRI images of a patient with a mixed lymphatic malformation (LM). Sagittal (A), coronal (B) and axial (C) STIR (fat suppressed) MRI images before sclerotherapy treatment demonstrating a large mixed macrocystic predominant LM of the right neck extending from the right ear to the back, right supraclavicular fossa, right anterior chest wall and right axilla. (D–F) Sagittal T1 (D) and coronal (E) plus axial (F) STIR MRI images after three sclerotherapy treatments demonstrating significant improvement (86% overall radiographic resolution) with complete resolution of the lesion in the back and near complete resolution of the lesion in the neck. (Reprinted from Nehra D, Jacobson L, Barnes P, et al,43 © 2008, with permission from Elsevier.)

Pretreatment considerations

Patients (except those with small easily accessible malformations and old enough to tolerate a procedure awake) are typically treated under general anesthesia. Preprocedural corticosteroids and Foley catheter placement vary with lesion location and anticipated length of intervention. For those with smaller lesions or predicted short procedure times, ketamine has been used with success by one group.15 In cases where the lesion to be treated involves critical structures such as the airway and orbit, the appropriate services are contacted prior to the procedure in case establishment of an emergency airway or orbital decompression is required. If there is a high likelihood of airway compromise, pretreatment intubation or tracheostomy placement is undertaken.28 Treatment of airway lesions may prolong the time period before extubation, by an average of 3 days.15 In VM in proximity to the facial nerve, one group mapped the course of the facial nerve using electric stimulation prior to therapy. In patients undergoing ethanol sclerotherapy, a pulmonary artery catheter may be placed for hemodynamic monitoring in younger patients,8 those requiring large volumes of sclerosant or those that have exhibited respiratory depression during prior therapy.29

Treatment of venous malformations

Surgery for venous malformations

Surgical resection of VM is indicated where complete resection without resulting functional or anatomic deficit is deemed possible. However, due to the often infiltrative nature of VM, total resection is often not possible. Furthermore, surgical resection of VM can be complicated by massive hemorrhage, damage to the neurovascular bundle, postoperative scarring, disfigurement and recurrence.28

Image guided sclerotherapy for venous malformations

The lesion is cannulated with ultrasound or MR guidance, and aspiration is performed to initially confirm location. If fluoroscopy is used, contrast, ethiodol or CO2 is injected to define the presence of an arterial component and the anatomy, extent and flow rate of the draining veins. The volume of injected contrast can be used to estimate the sclerosant volume. If MR is used, target localization may be precisely correlated to preprocedural imaging. The superior soft tissue resolution and multiplanar capabilities of MR help to avoid critical anatomical structures intraprocedurally.

If large or rapidly draining veins are visualized, these can be treated with endovascular embolization with coils or gelfoam, or by surgical ligation prior to sclerotherapy in order to increase dwell time and decrease the chance of systemic administration of sclerosant. Coil embolization can be performed with or without simultaneous balloon occlusion of draining veins.8 Alternatively, the draining veins can be directly compressed manually or with an inflatable cuff during instillation of sclerosant. Finally, placement of a secondary cannula can provide egress for sclerosant away from draining veins.30 These considerations are particularly important in the region of the orbit where drainage may be via ophthalmic veins, the cavernous sinus or sinus pericranii.

When performed as a preoperative embolization, liquid embolic agents such as n-butyl-cyanoacrylate (n-BCA; Codman Neurovascular, Raynham, Massachusetts, USA) or ethylene vinyl alcohol copolymer (Onyx; ev3, Irvine, California, USA) can be used instead of sclerosant to minimize blood loss prior to surgical excision of VM.5 ,8 ,22

Sclerosants available for the treatment of VM include ethanol, bleomycin and detergents. These agents are considered in detail below. In general, sclerosant is mixed with contrast for real time visualization of treatment extent during the procedure. The skin overlying the lesion is monitored during instillation: induration is indicative of underlying thrombosis, and pallor or duskiness indicates ischemia. In the case of the latter, treatment is temporarily halted and cold compresses are applied to the skin. Treatment is continued until the target volume of sclerosant is administered or until filling of draining veins is visualized. Multiple injections may be undertaken in a single session if the dosage of sclerosant does not exceed the recommended maximum.

Post-treatment considerations

Postprocedurally, the access cannulas are removed and antibiotic ointment is applied. In general, patients are admitted for overnight observation and pain control. Same day discharges are utilized in adults and older children, smaller lesions and lesions not associated with critical structures such as the airway or orbit. Postprocedure edema peaks at approximately 24 h, and may continue for up to 2 weeks. Elevation of the head of the bed and treated area, application of ice packs and administration of steroids can be used to treat swelling. Morphine, tramadol or ketorolac can be employed for postprocedural analgesia during admission.

Hemoglubinuria secondary to hemolysis requires aggressive hydration, especially following sclerotherapy with ethanol. Placement of a Foley catheter preprocedure allows monitoring of urine output. Hemoglobinuria can be monitored visually and generally clears 6 h postprocedure.8

At the time of discharge the patient is typically given a prescription for adequate analgesia and a corticosteroid taper, if necessary. Close clinic or telephone follow-up is scheduled to monitor for skin necrosis and superinfection. If multiple therapy sessions are planned, they can be spaced 6–12 weeks apart to allow assessment of efficacy.5 ,8 The endpoints of therapy are clinical resolution of symptoms or lack of clinical response as well as no targetable tissue within the lesion.

Ethanol

Absolute ethanol8 is the most well characterized and potent of the available sclerosants. On injection, denaturation of endothelial proteins leads to rapid thrombosis and disruption of the vascular histology to the level of the intima. Ethanol is diluted 10:1–10:2 with ethidiol,5 or to a final concentration of 60–100%.29 After initial venogram, the ethanol is instilled and allowed to dwell for 5–10 min. A follow-up venogram is used to define residual filling. Total maximal dose is 1 mg/kg or 60 ml. Doses greater than 0.75 mg/ml induce intoxication. Because of pain induced by the treatment and potentially serious complications associated with systemic administration, ethanol is administered with general anesthesia and critical care nursing support. Due to the risk of cardiovascular collapse,31 pulmonary hypertension and pulmonary embolism, some groups monitor pulmonary artery pressure during instillation and halt therapy in the event of increased pulmonary artery pressure, hypotension, increased end tidal CO2, decreased oxygen saturation, or bradycardia or other arrhythmia.8 ,29 Complication rates have been reported in 10–28% of patients.28 ,29 ,32 ,33 Necrosis of skin overlying may be related to transmural necrosis of vascular channels with diffusion into surrounding tissues. Nerve palsy has been reported in patients undergoing sclerotherapy of head and neck lesions and is generally transient, although in rare cases it is permanent. Other reported complications include: hyperthermia, hypoglycemia, transaminitis, skin necrosis or blistering, hemoglobinuria, pulmonary hypertension, pulmonary embolism, DIC, arrhythmia, CNS depression, cardiovascular collapse and death. Cardiovascular collapse may be related to large volume lesions with rapidly draining systemic veins.29

In a series of 60 patients with VM of the head and neck treated with ultrasound and fluoro guided ethanol sclerotherapy (mean 2.6 sessions/patient), Su reported 68% complete response (>90% volume reduction), 25% marked response (>50% volume reduction), 7% moderate response (<50% volume decrease) and 0% no response by post-treatment MRI. Complications occurred in 10% of cases and included skin necrosis, transient facial nerve palsy and hemoglobinuria. Following sclerotherapy, 7% of patients went on to surgery for cosmesis.28 There was no recurrence in a mean follow-up of 8 months.

In a series of 158 patients with VM not limited to the head and neck treated with percutaneous ethanol sclerotherapy (mean 3 sessions/patient), 16% of patients had a good response, defined as combined marked improvement by self-assessment and ≥30% decrease in size on MRI. In this series, female gender, no or delayed visualization of draining veins and well defined margin on MRI were associated with improved outcomes. A total of 27% of patients experienced one or more complications including nerve palsy (13%), skin necrosis (8%), hemoglobinuria (8%), transaminitis (2%), transient pulmonary hypertension (1%) and arrhythmia (1%).29

Lee et al treated 87 patients with craniofacial VM with ethanol sclerotherapy, with subgroup analysis based on disease extent by imaging. Of the 81% of patients with imaging follow-up, 32% had an excellent response (>75% volume reduction), 52% a good response (>25% volume reduction) and 16% a poor response (25% volume decrease) by post-treatment MRI or whole body blood pool scintigram. Patients with localized disease had better imaging outcomes and required fewer treatment sessions than those with diffuse disease in subgroup analysis. Complications occurred in 5% of cases and included hypoxemia, transient pulmonary hypertension and transient nerve palsy. Following sclerotherapy 8% of patients went on to surgery for cosmesis. No recurrence was reported over a mean follow-up time of 35 months.34

Detergents

Detergents used in sclerotherapy of VM include sodium tetradecyl sulfate (STS), polidocanol, sodium morrhuate and ethanolamine. STS is FDA approved in the USA for the treatment of varicose veins.5 Polidocanol has FDA approval for sclerosis of uncomplicated spider and reticular veins.35 These agents are thought to have a milder spectrum of complications than ethanol; only one case of reversible cardiac arrest has been reported for sclerotherapy with a detergent (polidocanol).36 Detergents may be mixed with either lipophilic or hydrophilic contrast agents. General anesthesia may be necessary in cases of pediatric patients and airway involvement, but in general detergent sclerosis has little associated pain and can be performed on an ambulatory basis. Reported complications include cardiovascular collapse, skin pigmentation, skin necrosis, anaphylaxis and hemoglobinuria.

Foaming of detergents with either carbon dioxide or air results in an increase in sclerosant volume and surface area, which may increase sclerosant efficacy. Foam is produced by the Tessari method.37 Instilled foam is left within the lesion. In a prospective, randomized controlled trial comparing ultrasound guided sclerotherapy with foamed versus liquid polidocanol or ethanolamine in 89 patients with VM, the majority in the head and neck, 90% of patients had partial or complete response at 6 months in the foamed group versus 63% in the liquid group (p=0.002).38 Reported complications were hemoglobinuria (7%), skin necrosis (3%) and acute kidney injury (1%), with a trend toward lower complications in the foam sclerosant group.

In another series of 50 patients with VM not limited to the head and neck, ultrasound guided sclerotherapy using 0.25–4% polidocanol foam resulted in complete resolution in 38% of patients, size reduction of ≥50% in 30% of patients, size reduction of 0–50% in 26% of patients and no change in 8% of patients, as determined by physical examination, MR or ultrasound imaging. Of those patients presenting with pain, 36% had complete resolution and 64% had reduction in symptoms. Of those presenting with episodic hemorrhage, 89% had complete resolution of symptoms and 11% had a decrease in symptoms. Reported complications were transient skin pigmentation (8%) and skin necrosis (6%).39

A case series reported by Kaji,40 involving 26 patients with VM of the head and neck treated with ultrasound guided, digital subtraction angiography or MR directed sclerotherapy using ethanolamine oleate demonstrated 49% excellent, 39% good, 12% fair and 0% poor results based on postprocedure clinical assessment. However, these results are inclusive of seven LM. Five of these lesions were also treated with transarterial embolization of feeding vessels prior to sclerotherapy. Mean volume reduction for low-flow VM was approximately 42%. Reported complications included hemoglobinuria, skin blistering, ulceration and scarring, laryngeal edema and trismus.

Bleomycin

Bleomycin is an antibiotic and antitumor agent originally derived from Streptomyces verticillus in 196641 which also causes an inflammatory response in endothelial cells, making it an effective sclerosant. Bleomycin can be administered in oil or aqueous form, providing flexibility when mixing with contrast agents. There are some reports that this agent leads to less post-treatment edema, which may increase utility in lesions involving the orbit or airway.5 There is some residual concern over use of this agent due to association with pulmonary fibrosis in the setting of chemotherapy; however, the threshold dose for pulmonary fibrosis and interstitial pneumonia is 450 mg while doses for sclerotherapy are typically 0.5–1 mg/kg for pediatric patients and 1–15 mg in adults,41 and these entities have not been reported in the setting of sclerotherapy. Reported complications include skin ulceration, skin pigmentation, laryngeal edema, flu-like symptoms, cellulitis, nausea and vomiting, and focal alopecia.41 ,42

A case series of 31 patients with 32 VM of the head treated with fluoro guided sclerotherapy with bleomycin (mean 3.5 sessions) resulted in 0% complete resolution, 34% marked (>50%) decrease in size, 31% minimal (≤50%) decrease in size, 34% stable size and 0% increase in size by postprocedure MR. Patients felt the lesions were improved in 91% of cases. Complications were seen in 12.5% of patients and comprised transient skin pigmentation, nausea and cellulitis.42

In a larger case series of 95 patients with VM and hemangiomas not limited to the head and neck, Muir et al treated 32 patients with VM using percutaneous bleomycin sclerotherapy. Complete resolution of the lesion was seen in 32% of patients and significant improvement was seen in 52% of patients by clinical assessment. The number of patients requiring subsequent surgical revision or experiencing recurrence was not recorded for this subgroup.41

Treatment of lymphatic malformations

Surgical therapy for lymphatic malformations

Surgical therapy for the treatment of LM is a complex issue due to the insinuating nature of the disease coupled with the complex and vital anatomy of the head and neck. It has been shown that the more complex and expansive the LM, the more likely it is to have both presurgical as well as postsurgical complications. The staging system for LM proposed by de Serres is based on both laterality and relation of the lesion with respect to the hyoid.16 Both rate of recurrence and postsurgical complications, which included infection, cranial nerve palsy (temporary and fixed) and postoperative seroma, were seen to increase with increasing stage, and ranged from 0% (infrahyoid/unilateral) to 100% (bilateral, supra-/infrahyoid disease). It should be noted that this group included in their analysis late, complications which were of result residual. These complications, such as feeding difficulties, airway obstruction, infection, and malocclusion, would have very likely occurred whether or not surgery had been performed.

Percutaneous image guided sclerotherapy of lymphatic malformations

Percutaneous sclerotherapy is gaining acceptance as a firstline therapy for LM, particularly for macrocystic variants. The procedure can be performed under ultrasound, fluoroscopic or MR guidance (figure 6), Generally, cannulation of the target cyst is performed with a 20 gauge angiocatheter or needle. Cyst fluid is aspirated prior to instillation of an equal volume of sclerosant. For larger cysts, 5 F access can be established, and aspiration and sclerosis can be alternated over several days until drainage is minimal. Sclerosants include ethanol, doxycycline, OK-432, bleomycin, alcoholic solution of zein, acetic acid, hypertonic saline, fibrin sealant and detergent. Depending on lesion location and resulting risk to vital structures from edema, the patient may be discharged the day of treatment or admitted for observation. Due to the high risk of infection, antibiotics can be given periprocedurally and may be continued for 7–10 days postprocedure.8 ,22 Edema in the immediate postprocedure period can be treated with diuretics and steroids. At discharge, mild oral analgesia is typically sufficient. Follow-up imaging and clinical assessment, and additional therapy sessions if needed, can be scheduled 6–8 weeks following therapy. Generally, macrocystic variants show an excellent response to sclerotherapy whereas microcystic disease demonstrates a poor response. Therapy is continued until the patient is satisfied with the clinical outcome and/or there is a lack of targetable cysts by imaging. Subsequent surgical resection may be necessary for redundant tissue or residual disease.43

Figure 6

MR guided sclerotherapy of a macrocystic lymphatic malformation. (A) Axial T2 weighted image demonstrates two hyperintense locules within the left retropharyngeal space. Intraprocedural T2 weighted axial TRU-FISP image demonstrates selective cannulation of the more medial retropharyngeal locule, followed by complete aspiration of the locule contents (B, C). Subsequent axial TRU-FISP (D) and T1 weighted FLASH (E) images after injection of an equal volume of sclerosant (ethanolamine oleate) containing gadolinium confirms containment of the sclerosant within the targeted locule.

Doxycycline

Doxycycline is a derivative of tetracycline and is an effective sclerosant with a history of use for pleurodesis, pericardiodesis and in the treatment of postoperative lymphoceles.43 The mechanism by which doxycycline induces endothelial inflammation leading to sclerosis is unknown. Doxycycline can be used at a concentration of 10 mg/ml in sterile saline, with a maximum dose of 200 mg per session.43 After instillation, the sclerosant is allowed to dwell for at least 6 h or until resorbed.

In a small case series of 11 patients with macrocystic or mixed LM of the head and neck treated with ultrasound guided or blind sclerotherapy (mean of 2 treatments/patient), patients with macrocystic variants achieved 100% clinical and 93% radiographic resolution, defined by a decrease in the largest diameter of the dominant cyst, whereas patients with mixed macro/microcystic LM demonstrated partial clinical resolution and an average of 73% radiologic response. In this small study, no complications were noted. Over a mean follow-up period of 8 months, two patients (18%) experienced recurrence in the setting of upper respiratory infection.43 Two patients (18%) required follow-up surgery for revision of redundant skin and removal of residual solid components of the lesion.

A second case subseries of 17 patients with microcystic LM of the head and neck treated with ultrasound guided instillation of 20 mg/ml doxycycline showed 100% complete cyst ablation at the 1 month ultrasound or MR follow-up. In the larger trial of 31 patients which included macrocystic LM treated with STS and ethanol, 6% of patients experienced perioperative infection over a mean follow-up of 1–60 months.44

Administration of doxycycline carries the potential risk of tooth discoloration, although this has not been documented in the setting of sclerotherapy. In addition, acidosis and hypoglycemia are potential but undocumented complications in this setting.15

Detergents

Detergents have a more limited history as sclerosants in the setting of LM but incur a similar consideration of benefits and risks as when they are used in the treatment of VM.

In a case series reported by Shiels et al, 28 patients with macrocystic and mixed disease of the head and neck, comprising 54 macrocysts, were treated with ultrasound guided cannulation and fluoro guided sclerotherapy of STS followed by ethanol (mean number of treatments 1.1). Using this dual drug approach, with instillation of 3% STS (50% cyst volume, 2 min dwell time) followed by 98% ethanol (100% cyst volume, 15 min dwell time), 100% of cysts were completely ablated, 93% in a single session.44 As described above, the larger series also included microcystic LM treated with doxycycline; total complication rate for the entire series was 6% due to two patients with postoperative8 infection requiring antibiotic therapy. One of these patients (3%) went on to surgical resection.

Due to the potential for less postprocedural swelling, some groups have used detergents in the treatment of intraorbital LM to minimize the potential for compartment syndrome (figure 7). In a case series of six patients with unilateral intraorbital macrocystic LM treated with direct injection of STS, reduction in lesion size was observed in all patients. One patient (17%) experienced intralesional hemorrhage 2 weeks post-treatment.45

Figure 7

Sclerotherapy of an orbital lymphatic malformation. This patient had recurrent acute bleeds into an intraorbital lymphatic malformation, causing severe proptosis. He had undergone numerous surgical debulking procedures, with recurrence of the proptosis. (A) Axial MR image (T1 weighted with gadolinium and fat saturation) before sclerotherapy shows septated hyperintense mass filling the superomedial left orbit. The high signal was secondary to the presence of blood. (B) Digital subtraction image of the orbit, lateral projection, after cannulation of the lymphatic malformation and contrast medium injection. The fluid and contrast medium were aspirated, and approximately 1 ml of 3% sodium tetradecyl sulfate was injected. The procedure was repeated 1 week later because of rebleeding. After the second procedure, proptosis resolved. (C) Axial MR image (T1 weighted with gadolinium and fat saturation) obtained 2 months after sclerotherapy shows significant reduction in the size of the malformation. (Reprinted from Burrows PE, Mason KP,8 © 2004, with permission from Elsevier.)

OK-432

OK-432 is a lyophilized mixture of group A Streptococcus pyogenes initially developed as an immunotherapeutic agent in the treatment of gastric and lung carcinomas with first use as a sclerosant in the treatment of LM described in a case report in 1987.46 Use in the USA has been limited to FDA supported trials as OK-432 does not carry FDA approval. Direct injection of this avirulent streptococcal strain into LM has been shown to increase intralesional cytokine levels, namely tumor necrosis factor, interleukin 6 (IL-6), IL-8, interferon γ and vascular endothelial growth factor in patients with a total or near total response to treatment with OK-432.47 ,48 In addition, OK-432 has been utilized in the treatment of multiple other cystic lesions of the neck, including ranula and branchial cleft cysts.49 ,50 In the USA, a prospective, randomized phase II trial of OK-432 versus delayed treatment was conducted to evaluate lesional response to therapy versus spontaneous regression in 182 patients with LM.17 In all patients treated with OK-432, 68% had a complete or substantial response. In this trial, 94% of patients with solely macrocystic disease had a complete or substantial response, 63% of patients with mixed macro-microcystic LM had a complete or substantial response, and none of the patients with microcystic disease responded to OK-432 therapy. Follow-up (2.9 years) in the treated patients revealed a 9% recurrence rate. Minor side effects of inflammation including fever, pain and erythema were seen for up to 2 weeks postprocedure. Major adverse events such as infection requiring readmission, airway obstruction and severe edema occurred in just over 8% of treated patients.

Bleomycin

Bleomycin is also utilized in sclerotherapy of LM and carries the same considerations for administration, dosage, benefits and complications previously discussed.

In a case series of 70 patients with LM, 90% with macrocystic disease not limited to the head and neck and treated with intralesional bleomycin injection, 47% of patients achieved excellent results (total or near total resolution clinically), 36% achieved good results (>50% reduction in lesion volume by examination) and 17% had poor results (<50% reduction in lesion size). Five patients in the good results group had recurrence (7%), and these patients and five in the poor results group (14%) went on to surgical resection. Common complications included erythema, swelling, pain and fever in 43% of patients, which largely resolved in 24–48 h. Leucopenia (4%), intralesional hemorrhage (4%) and persistent swelling (1%) were also noted. Two patients (3%) with extensive LM involving the airway died of septicemia, pneumonia and respiratory failure after partial surgical resection followed by bleomycin sclerotherapy.51

A case series of 200 patients with LM of the head and neck treated with intralesional injection of bleomycin-A5 in saline demonstrated complete lesion resolution in 87% of patients (1–8 treatments), 13% subtotal lesion response or recurrence over a follow-up period of 2–10 years. Complications included anorexia (10%) and mild fever (12%).52

Alcoholic solution of Zein (Ethibloc)

Alcoholic solution of Zein (Ethibloc; Ethicon, Norderstedt, Germany) is a biodegradable thrombogenic solution of ethanol, corn protein, oleum papavaris and sodium diatrizoate that has been used in Europe and Canada as a sclerosant in the treatment of LM but does not have FDA approval for use in the USA.

A case series of 14 patients with macrocystic or mixed LM of the head and neck treated with instillation of a 10% cyst volume of Ethibloc demonstrated an excellent response (undetectable clinically, >95% volumetric decrease on CT) in 64% of patients and a satisfactory response (clinical and radiographic volume decrease of 50%) in 36% of patients over a follow-up period of 6–51 months. Reported complications in this series included minor local inflammatory response and initial increase in lesion size in all patients (100%) and fever (36%). External leakage of Ethibloc occurred in 71% of patients a mean of 2 months after treatment, and was considered by the authors to be associated with a favorable response to treatment.53

In a larger case series of 65 patients with macrocystic and mixed LM not limited to the head and neck treated with ultrasound guided sclerotherapy using a volume of Ethibloc equal to 10% of the lesion volume (median 2 sessions/patient), 49% achieved excellent results (≥95% decrease in lesion size), 35% satisfactory results (≥50% decrease in lesion size and asymptomatic) and 16% had poor results (<50% decrease in lesion size or symptomatic) in the subset of patients with predominantly macrocystic disease. In the subset of patients with predominantly microcystic disease, in which only the macrocystic component was treated, 23% achieved excellent results, 54% satisfactory results and 23% had poor results. Eight per cent of patients went on to subsequent surgical resection. Over a mean follow-up of 3.5 years, 100% of patients had moderate localized inflammatory reaction lasting <4 days, 80% developed self-limiting external leakage of the Ethibloc a mean of 2 months post-therapy, 16% had inflammatory reaction 2–4 weeks post-treatment, 12% developed culture positive infection, 3% had persistent drainage from the lesion and one patient (2%) developed salivary fistula.54

Summary

Low-flow vascular malformations are congenital lesions secondary to errors in the development of veins, capillaries or lymphatics. The majority of these lesions are sporadic, although association with heritable syndromes does occur. Patients with these lesions should be treated and evaluated by a multidisciplinary team comprising medical, radiologic and surgical subspecialties. As an emerging treatment strategy, current practice is dependent on individual practitioner training, practice environment and experience; however, percutaneous, image guided sclerotherapy is gaining acceptance as a firstline treatment of low-flow vascular malformations.

Acknowledgments

Joe Molter prepared images for publication.

References

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; not externally peer reviewed.

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