Management of Low-Flow Vascular Malformations: Clinical Presentation, Classification, Patient Selection, Imaging and Treatment.

Cardiovasc Intervent Radiol DOI 10.1007/s00270-015-1085-4

REVIEW

Management of Low-Flow Vascular Malformations: Clinical Presentation, Classification, Patient Selection, Imaging and Treatment Ian McCafferty1

Received: 13 October 2014 / Accepted: 2 February 2015 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015

Abstract This review article aims to give an overview of the current state of imaging, patient selection, agents and techniques used in the management of low-flow vascular malformations. The review includes the current classifications for low-flow vascular malformations including the 2014 updates. Clinical presentation and assessment is covered with a detailed section on the common sclerosant agents used to treat low-flow vascular malformations, including dosing and common complications. Imaging is described with a guide to a simple stratification of the use of imaging for diagnosis and interventional techniques. Keywords Venous intervention Paediatric interventions Embolization Peripheral vascular Vein Vascular malformations

Introduction Vascular malformations are a complex group of developmental abnormalities that present significant challenges in diagnosis and management. The clinical presentation can range from an asymptomatic birthmark to fulminant cardiac failure. The diverse nature of symptoms associated with vascular malformations and their rarity means that patients have often seen multiple specialists before the correct diagnosis is made. Patients often undergo unnecessary biopsy, surgery and to some degree imaging, which

& Ian McCafferty [email protected] 1

Queen Elizabeth Hospital Birmingham (QEHB) & Birmingham Children’s Hospital (BCH), Mindelsohn Way, Edgbaston, Birmingham B15 2GW, UK

in some cases, can mean that the vascular malformation grows and can affect the outcome of further treatment. The management of this complex group of patients should therefore be undertaken within a multidisciplinary team. The exact make-up of the multidisciplinary team depends on the availability and interest locally; however, in our experience, the team has typically included interventional radiologists, plastic surgeons (craniofacial and peripheral), maxillofacial surgeons and dermatologists. Vascular malformations are developmental anomalies that are a result of arrested development at various stages of vasculogenesis or angiogenesis. These can be localised of diffuse and are commonly sporadic. They are present at birth, although they may not become apparent until adolescence or adulthood. They affect males and females equally and persist throughout life, typically with a fluctuating course of symptoms that can be accentuated by pregnancy. Lymphatic malformations are localised developmental abnormalities of the lymphatic system, which results in numerous thin-walled cysts containing lymph. The cysts vary in size and typical are divided into microcystic (cysts less than 2 cm) and macrocystic (cysts greater than 2 cm) variants. One of the more complex components of understanding and managing vascular malformations is the knowledge of the current accepted terminology to describe the different entities within the spectrum of vascular anomalies. A practical classification system that allows a simple differentiation of the subtypes of vascular anomalies to allow implementation of the correct treatment algorithm is essential. This is then further complicated by the existence of a number of syndromes that will not be covered in detail within this review article (see Table 1). The aim of this article is to address a practical classification and terminology and discuss patient evaluation (clinical and imaging) and therapeutic options available for

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I. McCafferty: Management of Low-Flow Vascular Malformations… Table 1 Syndrome based classification Venous and lymphatic malformation syndromes Klippel–Trenaunay Syndrome (KTS) Parkes Weber Syndrome (PWS) Servelle–Martorell Syndrome (SMS) Maffucci Syndrome Proteus Syndrome CLOVES Syndrome Bockenheimer Syndrome Blue Rubber Bleb Naevus Syndrome Gorham–Stout Syndrome

the different types of low-flow vascular malformations. The review will include discussion on the agents available for sclerotherapy, dosage and the techniques available to aid treatment and improve outcomes. The review will include commentary on experience obtained running a multidisciplinary vascular malformation service, with both adult and children’s craniofacial and peripheral clinics for over 15 years in both the Birmingham Children’s Hospital and the Queen Elizabeth Hospital Birmingham. Classification In 1982, Glowacki and Mulliken [1] proposed a ‘‘biological’’ classification of vascular anomalies based on clinical behaviour, histology and histochemistry. The classification was accepted by the International Society for the Study of Vascular Anomalies (ISSVA) and was updated at the inaugural ISSVA meeting in 1992. This classification is now widely accepted, and has help resolve the confusion of terminology in the field of vascular anomalies. The classification was updated at the 20th ISSVA workshop in Melbourne April 2014, incorporating elements of the Hamburg classification system. Broadly speaking, Glowacki and Mulliken divided vascular anomalies into 2 groups: Vascular tumours (underlying endothelial hyperplasia) and Vascular malformations (dysmorphogenesis and abnormal cellular turnover). Vascular malformations are further divided into low flow (capillary, venous, lymphatic and combined) and high flow (arteriovenous malformations, arteriovenous fistula) (see Table 2). For completeness, a brief description of the Hamburg classification [2, 3] is included; it is frequently mentioned in the malformation literature and it is important to understand its elements. It was established following the 7th meeting of the International workshop on vascular malformations in 1988, and clarifies morphological differences within the vascular malformations subset. These morphological differences are explained by the timing of arrested development of the vascular system in various stages of

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angiogenesis (see Table 3). Extratruncal lesions are theorised to maintain their unique embryological characteristics and ability to proliferate when stimulated by trauma, menarche, puberty, pregnancy, female hormones and surgery [4, 5]. They are further subdivided into diffuse infiltrating and localised limited. Truncal lesions do not have the embryonic characteristics and hence do not posses the ability to proliferate. For the purposes of this review on the management and outcomes of Low-flow Vascular Malformations (LFVM), we use the Glowacki and Mulliken classification where LFVM’s are subdivided into Capillary (CM), Venous (VM), Lymphatic (LM) and combined lesions. The lowflow venous malformations have a high recurrence rate, and management should be considered to be a lifelong process for symptomatic lesions. Clinical Presentation Low-flow vascular malformations have a varied clinical presentation depending on whether the lesions are focal or diffuse and which anatomical compartments are involved. It is not uncommon for patients to have been referred to a number of different specialities before a correct diagnosis is made. They have an incidence of approximately 1 in 10,000 [6]. Venous malformations are the commonest of the low-flow vascular malformations with a prevalence of 1 % in the general population [7]. A detailed history and examination commonly reveal the diagnosis and can help differentiate from other sinister differential diagnoses. Clinical features are typically related to the focal mass and patients predominantly present with pain and swelling, which is commonly intermittent. Aesthetic issues are also very common presentation. Clinical examination can separate high-flow (warm, thrill and bruit) from low-flow abnormalities, which in turn can be separated into venous, macrocystic lymphatic and microcystic lymphatic (see Fig. 1). Capillary malformations are the most commonly seen. They are abnormalities of the capillary networks within the skin and mucosal membranes, which may be isolated or herald the presence of extracutaneous disease. Examples of capillary malformations are salmon patches (naevus simplex), port wine stains (naevus flammeus). Port wine stains occur in 0.3 % of newborns and are part of the clinical manifestation of a number of syndromes: Sturge–Weber (SWS); Klippel–Trenaunay (KTS) and Proteus. Capillary malformations are typically treated with laser therapy. Venous malformations (VMs) can occur anywhere in the body but are frequently seen in the head and neck (40 %) extremities (40 %) and trunk (20 %). They present in any anatomical location, tissue or organ, are not confined by anatomical planes and may involve multiple tissue types.

I. McCafferty: Management of Low-Flow Vascular Malformations… Table 2 ISSVA 1996 classification of vascular anomalies (update ISSVA 2014) Vascular anomalies Vascular tumours

Benign

Vascular malformations High flow

Low flow

Arteriovenous malformation (AVM)

Capillary malformation (CM)

Infantile haemangioma

Sporadic

Cutaneous (Port wine stain)

Congenital haemangioma Rapidly involuting (RICH)

In HHT In CM-AVM

Telangiectasia (HHT) Cutis marmorata telangiectatica congenital (CMTC)

Non-involuting (NICH) Partially involuting (PICH)

Arteriovenous fistula (AVF)

Angiokeratoma

Sporadic

Tufted angioma

In HHT

Spindle cell haemangiomas

In CM-AVM

Venous malformation (VM) Common sporadic (VM)

Complex combined malformation

Blue rubber bleb naevus syndrome

Capillary–arteriovenous (CAVM)

Glomuvenous malformation (GVM)

Kaposiform haemangioendothelioma

Capillary–lymphatic–arteriovenous (CLAVM)

Retiform haemangioendothelioma

Capillary–venous–arteriovenous (CVAVM)

Familial cutaneous and mucosal venous malformation (VNCM) Cerebral cavernous malformation (CCM)

Composite haemangioendothelioma

Capillary–lymphatic–venous–arteriovenous (CLVAVM)

Epithelioid haemangiomas Pyogenic granuloma Locally aggressive

Papillary intralymphatic angioendothelioma (PILA)

Maffucci syndrome Lymphatic malformation (LM) Common (cystic) LM Microcystica

Dabska tumour

Macrocystica

Malignant

Mixeda

Angiosarcoma

Generalised lymphatic anomaly (GLA)

Epithelioid haemangioendothelioma

LM in Gorham-Stout disease Primary lymphedema Nonne–Milroy disease Primary hereditary lymphedema Complex combined malformation Capillary-venous (CVM) Capillary-lymphatic (CLM) Lymphovenous (LVM) Capillary lymphovenous (CLVM) Vascular malformations associated with other anomalies: Klippel–Trenaunay Syndrome (CM ? VM ± LM ? limb overgrowth) Parkes Weber Syndrome (CN ? AVF ? limb overgrowth) Servelle-Martorell syndrome (limb VM ? bone overgrowth) Sturge–Weber Syndrome (facial ? leptomeningeal CM ? eye ± bone AND soft tissue) Maffucci Syndrome (VM ± spindle cell haemangiomas ? enchondroma) Macrocephaly—CM Microcephaly—CM CLOVES Syndrome (LM ? VM ? CM ± AVM ? lipomatous overgrowth) Proteus Syndrome (CM ? VM ± LM ? asymmetrical somatic overgrowth) Bannayan–Riley–Ruvalcaba Syndrome (AVM ? VM ? macrocephaly ? limb overgrowth) a

Birmingham additions

This is most commonly seen in the periphery, which adds complexity to their presentation and management and can affect treatment outcomes. This has lead some groups to

suggest an additional peripheral limb venous malformation subclassification to aid management stratification (see Table 4). The Birmingham peripheral limb classification

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I. McCafferty: Management of Low-Flow Vascular Malformations… Table 3 HAMBURG (1988) classification of congenital vascular malformations

Table 4 Birmingham classification of venous malformations in periphery

Congenital vascular malformations (CVMs)

Type 1

Species Arterial malformation Venous malformation Arteriovenous malformation Lymphatic malformation Capillary malformation Combined vascular malformation Embryological forms Extra-truncular (defects arising at an early stage of angiogenesis while the vascular structures are in an undifferentiated state and presents as clusters of amorphous vascular tissue. High recurrence rates) Infiltrating/diffuse Limited/localised Truncular (defects arising from pre-existing vascular structures in the maturation period during later stages of angiogenesis. Low recurrence rates) Obstruction/stenosis Aplasia; Hypoplasia; Hyperplasia Stenosis; Membrane; Congenital spur Dilatation Localised (aneurysm) Diffuse (ectasia)

Fig. 1 Typical clinical features of a low-flow venous malformation that affects skin; blue discolouration of the skin with mass effect that exhibits dependency

[8] is one that separates venous malformations as to whether they are localised or diffused; fascia or muscle involvement; bone or joint involvement; trunk extension or whole limb involvement with or without skin involvement. Lesions within the periphery are more likely to be associated with truncal abnormalities. Most commonly the lesion causes a dull ache accentuated by activity, extremes of temperature, valsalva or dependent

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Localised or superficial

Without skin involvement With skin involvement

Type 2

Fascia or muscle infiltration


Type 3

Bone or joint involvement


Type 4

Trunk and limb lesion (chest or abdomen)

Without skin involvement

Type 5

Diffuse whole limb involvement, e.g. Klippel– Trenaunay syndrome

Without skin involvement

With skin involvement With skin involvement

position. There is often a history of intermittent bouts of more severe pain, which is secondary to localised thrombosis and thrombophlebitis. VMs often have associated localised coagulopathy with low fibrinogen and raised fibrin degradation products, which leads to this thrombosis and paroxysmal pain [9]. We, and others, have seen growth in puberty [10], pregnancy and associated with the oral contraceptive pill [4, 11]. Progesterone and oestrogen markers have been shown on endothelial cells of VMs [12]. These and somatic growth factors, which are elevated in puberty, have been postulated to stimulate endothelial growth factors causing growth during these times [10]. There is also an increase in the incidence of thrombophlebitis at these times due to the increased oestrogen levels. Growth has also been reported following trauma and partial resection [10, 13]. The severity of symptoms depends on the size of the lesion, location and proximity to adjacent structures. Superficial lesions often exhibit a bluish/purplish discolouration and can be associated with dilated veins. On examination, the lesions are characteristically soft, compressible, non-pulsatile and demonstrate filling on dependency. Phleboliths can often be palpated in large lesions. Lesions are most likely to progress during adolescence (75 %) although 25 % occur in childhood [14]. Lymphatic malformations (LM’s) more commonly affect the head and neck (48 %) with the trunk and extremities (42 %) and intra-thoracic/intra-abdominal viscera (10 %). 90 % are diagnosed in children younger than 2 years with almost half present at birth [15]. They have 2 typical presentations depending on whether the lesions are microcystic of macrocystic. Macrocystic lymphatic malformations typically have cyst spaces [2 cm and appear as soft nonpulsatile masses with normal overlying skin, which are present at birth. Lesions do not exhibit dependency and are not compressible but demonstrate trans-illumination. Microcystic lymphatic malformations can infiltrate tissues most commonly skin and mucous membranes but also affect bone and organs. There is typically numerous vesicles overlying the affected area and associated with expansion, e.g. swollen

I. McCafferty: Management of Low-Flow Vascular Malformations…

limb. The area covered in a vesicles often bleed tend to leak small amounts of lymph and are commonly complicated by episodes of bleeding and infection which can lead to acute expansion of the affected area. This can lead to serious sequelae dependent of the site affected. Lesions are most likely to progress during adolescence (63.8 %) although 40 % occur in childhood [16].

percutaneous needles. One may choose a different agent if the lesion is predominantly matrix in nature rather than contains multiple large cystic spaces. Those lesions with an abundance of vascular or lymphatic spaces are likely to benefit more from sclerotherapy. US is also ideal to assess the presence and patency of the deep and superficial venous systems prior to sclerotherapy.

Diagnostic Imaging

Magnetic Resonance Imaging (MRI)

The vast majority of low-flow vascular malformations (LFVM’s) can be diagnosed by a detailed history and clinical examination; typically one can also differentiate the majority into lymphatic and venous subtypes. Imaging is therefore there to confirm the diagnosis and extent of involvement, identify rare but significant differential diagnoses and to plan treatment options (conservative, percutaneous sclerotherapy or surgery). Numerous modalities exist to image patients with LFVM’s; for example, plain films may show numerous phleboliths associated with a soft tissue mass and aid the diagnosis of a venous LFVM. Computer tomography (CT) may also show these characteristics, demonstrate the extent of the lesion as a hypodense or heterogeneous mass, which enhance slowly and peripherally (LM’s) and homogenously (VM’s) with the presence of intralesional fat as well as haemorrhage. However, the most useful imaging modalities for the diagnosis and planning of treatment are ultrasound and magnetic resonance imaging. Diagnostic angiography has no role in the management of LFVM’s (see Fig. 2). Direct stick venography will be discussed later.

LFVM’s have often been described as ‘‘iceberg lesions’’ [19] as the portion clinically apparent if often only the tip of the underlying malformation. MRI is the imaging modality of choice as it has superior contrast resolution when compared to CT, it can image in a multiplanar fashion and the lack of ionising radiation is ideal [20, 21]. It has been shown to play a vital role in diagnosing deeper lesions, categorising the type and determining the extent of tissue involvement in LFVM’s (muscles, bone, tendons, subcutaneous tissue and skin) and thereby determine management options [22–26]. The assessment with MRI can give prognostic information and should include a description of the extent—focal, multifocal or diffuse; tissues involved including joint involvement and evidence of prior haemorrhage [27]. The degree of muscular involvement, for example, may be predictive of the risk of contractures either due to involvement or post-sclerotherapy [28]. The basic underlying principle of MRI is to confirm the clinical diagnosis and identify the anatomy/extent of the lesion, in at least 2 orthogonal planes. This allows appropriate planning of treatment and outcome prediction. There are numerous MRI protocols described in the literature but we optimise imaging to identify slow moving fluid—lymph or blood. We use fast spin-echo T1-weighted imaging to define anatomy and the presence of haemorrhage and haemosiderin (some combine this with gradient-echo T1weighted sequences to identify any high flow element) and fat suppression techniques (either fast spin-echo T2weighted or short inversion time inversion recover STIR’s) to increase lesion detection by suppressing the bright fat surrounding and within the bright LFVM (see Fig. 5). These simple sequences can typically diagnose and assess LFVM’s alone and can also aid differentiation of LM’s from VM’s with layering within lymphatic macrocysts. However, it must be remembered that rarely due to extremely slow flowing blood within a VM sedimentation of the red blood cells can mimic this (see Fig. 6). The MRI can also differentiate common differential diagnoses, e.g. a ranula (see Fig. 7). The addition of post-contrast imaging with or without fatsuppressed T1 imaging is useful in differentiating LM’s from VM’s—LM’s enhance peripherally (see Fig. 8) and VM’s enhance homogeneously throughout the lesion (see

Ultrasound-B Mode and Duplex Ultrasound (US) is essential in the management of LFVM’s. High-resolution linear array transducer (5–12 MHz) is used first, often, in outpatients to differentiate the lesion from other tumours and confirm the clinical diagnosis. A malformation typically appears as a low reflective or heterogeneous defined mass lesion, which can be unilocular or multilocular. The cystic areas in LMs are typically non-compressible, whereas VMs are compressible (except in thrombosis) and phleboliths can be detected in 20 % (see Figs. 3, 4), which are pathognomonic of VMs [17]. Duplex US can define the size and help differentiate VM’s from LM’s by demonstrating low velocity flow within the lesion, although up to 20 % of VM’s, no flow is seen [18]. It should be noted that US has limitations with depth penetration and assessment of associated structures such as nerves, bone and defining the extent of lesions not located in the extremities. US plays a critical role in the assessment of the lesions to decide on sclerotherapy agents and accessibility with

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Fig. 2 Low-flow venous malformation demonstrating an arterial blush, but no early venous filling pathognomonic of a high-flow lesion. A The T2 fat-saturated axial image. B Demonstrates the high

signal area with no flow voids and the pre-gadolinium (C) and postgadolinium (D) images demonstrate the typical central enhancement of a venous malformation

Fig. 3 Ultrasound of a low-flow venous malformation demonstrating a macrocystic lesion and a phlebolith pathognomonic of a venous lesion and a matrix rich lesion with very few macrocystic spaces

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treatment [4]. Indications for treatment include the presence of troublesome symptoms, e.g. bleeding, pain, aesthetics and functional impairment and the presence of complications, e.g. infection and coagulation issues.

General Measures 1. 2. 3. 4.

5. 6.

Explanation of the diagnosis and likely clinical course Custom-made compression garments for VM’s. Treatment of associated complications: infection, anaemia, thrombophlebitis and localised DIC. Involve other specialities for specific requirements: orthopaedics for leg length discrepancy or joint involvement, haematology for coagulation issues. Screening of family members for inherited malformations. Referral of complicated cases to experienced tertiary centres where the patient can be treated by an organised multidisciplinary team.

Observation and Conservative Management

Fig. 4 Ultrasound of a low-flow lymphatic malformation demonstrating a macrocystic malformation (A) and a complex lesion (B) secondary to haemorrhage

Fig. 5). This is usually performed in a static phase; however, some authors advocate the use of 3D time-resolved MRA and rapid dynamic contrast-enhanced imaging to look at arterial inflow, equilibrium and venous outflow phases [29– 31]. This allows assessment of flow characteristics, anatomy (including venous drainage) and enhancement [9, 32, 33]. These techniques, however, have a far more important role in the assessment and management planning of high-flow malformations. VMs can occur anywhere, and the administration of contrast is extremely useful in atypical anatomical sites to aid the diagnosis (see Fig. 9). Contrast is paramount when the clinical history and examination is atypical as the enhancement pattern can help in identifying the differential diagnoses (see Fig. 10), e.g. tumour [11, 34, 35]. However, this does add significant imaging time and cost, and may not be required in the investigation of all VM cases. Management principles A multidisciplinary team approach is essential for the appropriate management of LFVM’s. Not all LFVM’s are amenable to treatment and not every lesion requires

The majority of LFVM’s that are seen in a multidisciplinary team require assessment and advice. One explains the diagnosis, natural history and expected level of risk related to size, location, depth and proximity to adjacent structures before considering active treatment [36, 37]. Clinical follow-up, advice regarding thrombophlebitic events (see Fig. 11), compression bandages and a contact details suffice in most. Surgery Surgery has traditionally been used to treat both LM’s and VM’s; however, excision based on limited knowledge of the biology of these lesions has lead to poor surgical outcomes [36, 38, 39]. There is no role for surgery in microcystic LM’s, although surgery has been frequently used for macrocystic LMs. There is a high incidence of complications following surgery (12–33 %), which include airway obstruction, scarring, haematoma and infection [40–42]. Surgery is never radical at first attempt in these cases and needs to be staged [43, 44], and recurrence rates are very high (15–53 %). Surgical excision can be used for focal VM abnormalities, debulking procedures and peripheral malformations where percutaneous sclerotherapy can have significant risks of terminal ischaemia. This can lead to significant functional improvement but an experienced surgeon treating LFVM’s who understands the risks of incomplete resection and the proliferative nature of

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I. McCafferty: Management of Low-Flow Vascular Malformations… Fig. 5 MRI characteristics of low-flow venous malformation. T2 fat-saturated sequences demonstrate the lesion best (A, B). This is true for both venous and lymphatic malformations. In B, the presence of a small low signal focus consistent with a phlebolith (arrow) diagnoses a venous lesion. And this can be confirmed with the use of gadolinium that demonstrates a central enhancement pattern (C, D)

extratruncal LFVM’s [37, 45, 46]. Roh et al. demonstrated a 75 % improvement in patient’s symptoms for debulking procedures where sclerotherapy had failed or was deemed unsafe [47]. Surgery is also used following percutaneous sclerotherapy when treatment has been incomplete or when aesthetic prejudice requires correction [38]. Recurrence after surgery is high around 22 % for LFVMs [48].

endothelial linings of LFVMs and induce fibrosis. Each agent has its own unique technique and safety profile and it is essential to have a full understanding of these agents in order to manage these patients. The common agents used are discussed below.

Percutaneous Sclerotherapy

There are numerous agents described in the literature for treating low-flow vascular malformations. A number of these agents are used specifically for either lymphatic or venous low-flow malformations, although some can be used in both subsets. For the purposes of this review, only the commonest agents described in the literature are described. These include sodium tetradecyl sulphate, ethanol, polidocanol and bleomycin [50–58]. It must be noted that

Percutaneous sclerotherapy with ultrasound and fluoroscopic guidance is now universally accepted as a treatment option for both VM’s and LM’s. Sclerotherapy is the only option available in the poor surgical candidate with extensive multi-compartment involvement [49]. A variety of sclerosant agents exist, which aim to destroy the

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Treatment Agents


Fig. 6 MRI of a lymphatic malformation (A, B) in the axilla demonstrating layering within the lesion macrocysts due to separation of the proteinaceous liquid. This traditionally has been a feature to

differentiate LM from VM but in very slow flow venous lesions layering an also be seen (C, D). This is felt to represent sedimentation of the red cells

Fig. 7 A differential diagnosis of a low-flow vascular malformation. Features suggest a lymphatic malformation with high signal intensity of the T2 fat saturation sequences and post-gadolinium the lesion shows only peripheral enhancement. The lesion was a ranula

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at present there has been no prospective randomised controlled studies comparing the sclerosing agents currently in use. There is no consensus as to which sclerosant agent is best but each agent has its own unique administration technique and complication profile [59; see Table 5: Common treatment agents].

Fig. 8 Typical MRI features of a macrocystic lymphatic malformation in the left axilla. On the T2 fat-saturated images the lesion is seen as a high signal intensity lesion due to its static fluid content (A) and the white arrows demonstrate the peripheral wall enhancement (B)

Fig. 9 An example of a low-flow venous malformation affecting bone (left acetabulum). An expansile cystic appearances on CT (A), typical high signal intensity on the T2 fat saturated MRI (B) and

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Sodium Tetradecyl Sulphate (STS-Fibrovein: STD Pharmaceutical, UK) Originally 3 % STS was injected percutaneous directly into the malformation typically following a venogram to outline the abnormality, using a contrast displacement technique. However, more recently, foam STS has become the standard treatment with some evidence suggesting superior sclerotherapy [60], where microbubbles of air are coated with STS creating enormous increase in the surface area displacing blood from the lesion and permitting better contact of the agent to the endothelium [61]. It is the contact with the endothelium that is important to cause damage. The Tessari technique [62] is commonly used to create the foam; in this technique, 2 leur lock syringes are attached via a three-way tap (see Fig. 12). Neat STS is then mixed with a volume of air

classical homogeneous enhancement following Gadolinium contrast administration (C, D)


Fig. 10 Low-flow vascular malformations (B) have a typical appearance on MRI and can confidently be diagnosed with an appropriate accompanying clinical history, however, other conditions

can mimic the MRI findings, e.g. Ewings sarcoma (A). In a Ewings sarcoma, the history is typically short and post-gadolinium images demonstrate a more heterogeneous enhancement

and agitated through the three-way tap in typical mixes of 1:1 and 1:2 (STS:air) with or without contrast (iodinated or lipiodol). The STS to air mix is only important for the stability of the foam [63], although it does affect the bubble size, and a compromise has to be made between stability, STS concentration and amount of air administered. It should be noted that STS is deactivate by a relatively small volume of blood; 0.5 ml of blood will deactivate 1 ml of 3 % STS significantly reducing the systemic effects [64]. A robust hydration protocol can significantly reduce the risk of renal complications [65, 66]. Complications of TIA & stroke have been described in the treatment of varicose veins [6], caused by emboli and macrobubbles [67], although no reported cases have been described in treatment of low-flow vascular malformations. A patent foramen ovale (PFO) is a relatively common occurrence in the adult population with some suggesting 20 % [6]; however, the vast majority are left to right shunts. Interestingly one standard technique used to identify the presence of PFO’s is the use of bubble-echo using agitated saline (foam) to demonstrate and quantify the shunts [68].

Ethanol Ethanol can be used to treat malformations in a direct (percutaneous) stick, transarterial or transvenous administration. Injections should be performed very cautiously; only after contrast injection has confirmed an appropriate position within the malformation, due to the significant complications that are associated [69]. Bleomycin In human tissue, it exhibits a dual effect inducing DNA degradation in under-coiled strand regions and has a specific sclerosing effect on endothelium [70]. It is commonly used to treat Germ cell tumours and lymphomas [71, 72] and in 1977, Yura used Bleomycin to treat cystic hygroma (macrocystic lymphatic malformations) successfully [70]. Subsequently, other authors found success with bleomycin for the treatment of both macrocystic and microcystic lymphatic malformations [73–76]. Intralesional percutaneous injection of bleomycin was also used in a number of different congenital vascular malformations including haemangiomas and low-flow venous malformations with reports of significant improvement in 52 % and complete resolution in 32 % [50]. Muir published his 5-year experience in over 160 patients in 2013

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Fig. 11 Thrombosis can complicate venous malformations causing swelling and pain. MRI T1-weighted sequences demonstrate high signal intensity within the malformation consistent with haemorrhage

(A arrowed) and demonstrate a low intensity filling defect with a high signal intensity rim (B) which demonstrates enhancement postgadolinium injection (C, D)

demonstrating success in a variety of congenital malformations [58].

OK432 (Picibanil) OK432 has a long history having first been used clinically in 1967 and is typically used for the treatment of macrocystic lymphatic malformations [80, 81]. It is injected into the lymphatic malformation according to a method described by Ogita [82] with 0.1–0.2 mg of OK432 injected every 2 months for an initial 3 treatment sessions. Injection causes marked swelling and sclerosis that does not spread outside the target lesion.

Doxycycline Doxycycline can be administered by percutaneous injection of via a catheter. Depending on the size of the lesion, treatment typically takes 3–6 sessions. It has been shown to be a safe and affective sclerosant for treating lymphatic malformations in children and has a wide safety profile with significantly less neurotoxic effects and skin necrosis compared to ethanol [77, 78]. It has also been recommended for the use in abdominal lymphatic malformations where it appears to be safe in the peritoneal cavity [79]. Its use has also been combined with STS 3 % with the suggestion that a detergent sclerosant used first allows better penetration of the doxycycline afterwards and better results.

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Sclerotherapy Procedure and Adjuvant Techniques Pretreatment assessment is vital to assess which liquid sclerosant agent to use. As previously discussed, MRI can accurately identify the exact anatomical location of the LFVM and can help predict complications. US has two main roles to aid therapy; firstly to aid decision making by

(Bleo-Kyowa; Kyowa Hakko Kirin UK Ltd.)

Bleomycin

Is a cytotoxic anti-tumoral antibiotic discovered by Umezawa in 1966. Its cytotoxicity is mediated by DNA cleavage triggering single and double strand breaks. Apoptosis occurs rapidly in rapidly growing haemangiomas and immature rapidly growing cells

Can cause trans-mural vessel necrosis and diffusion into adjacent tissues causing significant non-target effects

Maximum doses up to 100 mg (clinician decision)

Record cumulative doses

Under 1 year age 0.5–1 mg/kg

Maximum single dose 15 mg per session

Constitute 15 mg of Bleomycin powder with 15 mls of sterile saline—15 mg/ ml

Only used by experienced operators

Continuous pulmonary artery pressure recording advised

Maximum single session dose 60 mls never exceeded

1 mg/kg total dose

Conscious sedation adequate in adults

Targeting matrix components and spaces

Image guided injections (ultrasound)

More commonly mixed with contrast (iodinated or lipiodol)

Injected neat using contrast washout techniques

Patient require a GA

Conscious sedation adequate for adults with peripheral lesions consider GA for head and neck

Occasionally used as an emulsion with lipiodol contrast agent

Pulmonary fibrosis is a major complication related to cumulative dose. In dose range 50–150 mg 4 % incidence with zero mortality, however 250–350 mg range 5 % incidence with 0.9 % mortality LFLM’s (macrocystic) LFVM’s (matrix rich or 2nd line)

Flu-like illness, pain and swelling, ulceration, cellulitis

Pain and swelling (significant at times resulting in compartment syndrome), extensive tissue necrosis, permanent nerve injury, central nervous system depression, hypoglycaemia, hypertension, haemolysis, pulmonary embolism, pulmonary vasospasm, cardiac arrhythmias and death [124–128]

LFLM’s (microcystic)

LFLM’s (macrocystic)

LFVM’s

TIA and stroke (see text)

Potential rare

Routine lung function tests prior to Bleomycin therapy (underlying pulmonary disease may increase risks of pulmonary fibrosis)

In superficial lesions the dose can be diluted to 0.66 mg/ ml

Ethanol levels correlate directly with amount injected [122, 123]

Narrow safety margin

Commonest agent used worldwide for LFVM’s

Stability of foam relates directly to the foam mix 1:3 [ 1:2 etc

Wide safety margin

Widely used in management of varicose veins

Manufactured since 1966 (UK)

Aggressive sclerosant causing instant precipitation of endothelial proteins, rapid thrombosis and vessel occlusion

(dehydrated alcohol 100 % w/v—Sandoz Canada)

0.5–1 % used in superficial VMs

0.5 mls/kg (maximum single dose 30 mls) [38]

Ethanol

(Fibrovein STD Pharmaceutical, UK)

Available in 0.2, 0.5, 1 and 3 %.

Pain, skin staining, blistering, erosion, and localised loss, transient nerve defects (commonly due to compression), haemoglobinuria and renal impairment (see Fig. 13)

LFVM’s

Typically administered as foam, using the Tessari method as a 1:2 or 1:3 (STS/air) mix

3 % commonest strength used

Anionic detergent based sclerosant. Endothelial damage by decreasing the surface tension resulting in thrombosis and fibrosis

Sodium tetradecyl sulphate—STS LFLM’s (macrocystic)

Notes

Complications

Uses

Technique

Dosage

Mechanism of action

Name

Table 5 Common agents used in the treatment of low flow vascular malformations


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Post-injection flu-like illness with pyrexia, pain, swelling, leukocytosis, thrombocytosis and elevated C-reactive protein

Pre-procedure Assessment Patients should be nil by mouth for 4 h for solids and 2 h for clear fluids. The majority of patients with LFVM’s in the craniofacial area and in the pediatric population will have a GA; those in the periphery are typically treated with intravenous sedation. All patients should have a cannula placed and an IVI started to prevent dehydration. In patients with large lesions in whom renal complications may occur, an active pre-hydration protocol should be used. Low molecular weight heparin is used for 2 weeks prior to the procedure if the VM is extensive and the patient has low fibrinogen levels. This is to reduce the localised coagulopathy and reduce the risk of treatment failure (Fig. 13).

1 KE has 0.1 mg of freeze dried streptococci containing 1 9 108 cells [117]

OK432 measured in Klinische Einheit (KE) units

(Chugai Pharmaceutical Co, Tokyo, Japan)

1–2 KE (0.1–0.2 mg) every 2 months

Image guided injection after drainage of cystic component Is a lyophilized biological preparation containing cells of streptococcus pyogenes (Su strain) treated with benzylpenicillin. Heating in the presence of penicillin at 370 increases antitumoural activity of the Su strain and eliminates its toxin producing ability. The cells remain intact but proliferative activity is lost [131] Picibanil (OK432)

LFLM’s (macrocystic)

Haemolytic anaemia, hypoglycaemia in neonates and neuropraxia

3–6 treatments often required

Conscious sedation adequate in adults

Image guided injections via needle or small pigtail catheter Dose range 100–1000 mg per session (10 mg/ml)

Is a tetracycline antibiotic originally reported as an effective sclerosant agent in lymphatic malformations in 1995 by Molitch [129]. Exact mechanism is unclear but animal models demonstrate a cellular reaction with deposition of fibrin [130] Doxycycline

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defining the degree of cystic spaces and to assess ultrasound-guided accessibility, and second with agents that are used as foam, ultrasound is used to assess treatment completion by identifying foam (microbubbles) within all cystic spaces.

Beware in patients allergic to penicillin as anaphylactic reactions can occur

Can be used in combination with other agents e.g. STS

Complications occur in approximately 10 % with prolonged swelling and skin blistering the commonest LFLM’s (macrocystic)

Safe profile

Complications Uses Technique Dosage Mechanism of action Name

Table 5 continued

Notes


Direct Stick Phlebography (DSP) Many operators advocate DSP in venous LFVM’s prior to installation of a liquid sclerosant. Digital subtraction venography is performed via a needle introduced into the lesion with US guidance and is used to assess the morphology and venous drainage in a dynamic manner (see Fig. 14). This is important in assessing drainage into the deep veins. A number of classification systems have been described in the literature, which categorises venous LFVM’s, by their morphology and drainage characteristics; Goyal [69] and Fayad [83] described MRI classifications and Puig and Dubois [13, 84] described a classification system (see Table 6) based on drainage patterns seen on DSP. This system, which we use, correlates well with outcomes; types 1 and 2 have high success rates with type 4 having lower success rates (60 % excluded) and higher complications. Sclerotherapy Procedure The exact technique used depends entirely on the nature of the underlying LFVM and the operator’s preference. In our institution, microcystic LM’s are treated primarily with Bleomycin, in the manner previously described, using a 25G spinal needle and US guidance to ensure that bleomycin is instilled in the entire lesion in equal aliquots. Doxycycline in used as a second line sclerosant. In macrocystic LM’s, a ‘‘2 needle’’ technique is used (see Fig. 15), usually with a relatively large cannula, e.g. 20G, placed with US so that the tips lie at opposite ends of the lesion [4, 84]. This allows the sclerosant agent to either be installed via the dependent cannula until it exhausts from the non-dependent cannula or allow the agent to be washed ‘‘in and out’’ the LM on multiple occasions to allow greater sclerosant contact with the


Fig. 12 Tessari technique for making foam sclerosant. Two leur lock syringes are connected via a three-way tap, with the tap turned so only the two syringes are connected the plunger is depressed numerous times developing the white foam

endothelium. This technique significantly reduces the risk of cyst rupture and extravasation of sclerosant, e.g. STS which would lead to significant local complications. If this is used as foam, then US is ideal to check that all cystic spaces have been treated (microbubble US contrast); and if not, further needle placements can be made and treated. If Doxycycline is used, then the ‘‘2 needle technique’’ can be used to install the treatment dose; however, some operators have described using pigtail catheters (6–10F) to install treatment doses, administered over 2–3 days, before removing the pigtail. Other operators more recently have suggested better results using an STS wash to ‘‘degrease’’ prior to administration of doxycycline or ethanol [85]. If OK432 (Picibanil) is the agent of choice, this technique is unnecessary and the agent is injected directly into the cysts in divided doses with US guidance using 1–3KE dose. In VM’s, there are a number of techniques, used dependent on the Puig classification [84], to maximise sclerosant contact with the endothelium and cause fibrosis. If the VM is type 1, then direct puncture with several small gauge needles to cover the lesion ± DSP is sufficient prior to installation of liquid sclerosant. Use of a tourniquet has been recommended by a number of authors [54, 86–90] and is used for a number of reasons. A tourniquet to 60 mmHg will enhance the visualisation of the type 1 VM and allow easier US-guided access; it also will control type 2/3 VM lesion outflow veins to prevent loss of sclerosant and therefore improve efficiency [62, 91–93]. Care should be taken not to overfill VM’s under tourniquet control, and needles should only be withdrawn once the tourniquet has been released to prevent significant extravasation and local complications. An ideal dwell time of sclerosant is between 2 and 10 min [84, 88, 94]. All liquid sclerosant agents are radiolucent and therefore not visible on fluoroscopy. There are a number of ways, however, to identify the sclerosant;

contrast can be added to facilitate visualisation; however, this will lead to some sclerosant dilution and may reduce effectiveness [95, 96]. Examples include iodinated contrast with 3 % STS in a 1:2 or 1:3 ratio [88]; lipiodol with ethanol in a 1:9 ratio [89] and 3 % STS with air and lipiodol or iodinated contrast in a 2:1:1 or 3:1:1 ratio. Alternatively if the VM has been opacified by contrast DSP, then the use of road-mapping when administering sclerosant will allow visibility. In our institution, our first line agent for treating VM’s is 3 % STS and we deliver this as a foam, using the Tessari method [62], under US guidance, typically through 3-4 23G butterfly needles. DSP is performed to identify and confirm intralesional placement and exclude any major venous drainage and not to over distend the malformation. Tourniquet control is not routinely used unless there is significant venous outflow, which is seen on DSP, or when the foam is injected under US control. If large draining veins are identified that cannot be controlled by manual compression or the use of a tourniquet, e.g. craniofacial lesions then percutaneous administration of coils, glue, direct ethanol injection (0.2–0.5 mls) or angioplasty balloons accessed via jugular or femoral veins [4]. US and fluoroscopy can be used to assess that foam sclerosant has been administered to all parts of the VM (see Fig. 16), and if need be introduce new needles to complete treatment. If the VM involves overlying skin, then 0.5–1 % STS is used. Post-procedure A compression bandage is applied in a similar fashion to that used for the treatment of varicose veins and is left on for 24 h [17]. Patients have analgesia and steroids prescribed, and the intravenous fluids are continued until adequate urine output is seen. The administration of non-steroidal anti-inflammatories is avoided in the first 48 h in VM’s especially when using ethanol or 3 %

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I. McCafferty: Management of Low-Flow Vascular Malformations… Fig. 13 Complications from STS foam sclerotherapy occur. Image A demonstrates the skin changes that can occur if too superficial injection is performed which can include necrosis. 3 months later, the skin changes have significantly improved although staining can be permanent (B). Haemoglobinuria is also common after STS sclerotherapy and can lead to renal failure if not treated with pre-hydration. The image shows serial urine samples following a significant (0.5 mls/kg–20 mls) STS sclerotherapy (C)

STS, due to the potential risks of renal impairment secondary to haemoglobinuria. Although we do not routinely use antibiotics orally or topically, some authors have recommended them when treating LM’s [4]. Follow-Up and Outcomes Sclerotherapy frequently requires a course of treatment, rather than a single session, to obtain satisfactory patient symptom improvement; typically, this is between 3 and 5 sessions. Repeat treatments are ideally spaced between 6 and 8 weeks apart [88, 97, 98] and best arranged as a course. At our institution, following a patient satisfaction survey from 5 years of our malformation service, we found that a more aggressive approach at the first session offered the better satisfaction outcome, albeit with a slightly higher initial minor complication rate, e.g. skin blistering (see Fig. 17). There were no long-term complication sequelae.

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This finding suggests that it is only at the first treatment session that all the cystic spaces are likely to communicate, thereby allowing sclerosant to freely fill all parts of the lesion with the minimal number of needle insertions. Later treatments were compromised by a degree of lesion compartmentalisation [10]. Patients should be given the details of a contact in the vascular malformations service to whom to liaise with if there are any immediate complications or issues. Patients are then typically reviewed at their subsequent sclerotherapy treatment session or in outpatients if the treatment course has been completed. Clinical review should include lesion measurements, US evaluation and clinical photography (see Fig. 18). If there has been little symptomatic improvement and/or the lesion morphology has changed, e.g. become more matrix rich, then consideration should be given to changing the sclerosant agent [10].


Fig. 14 US-guided insertion of needles into the low-flow malformation is followed by direct stick venography to identify the venous morphology of the malformation to determine the amount of

Table 6 Puig and Dubois classification of venous LFVM’s Type

Description

Sclerotherapy outcome

Type 1

Isolated, well circumscribed lesion with negligible drainage into a normal venous circulation

Highest success rate

Type 2

Isolated, well circumscribed lesion with drainage into a normal venous system via normal veins

High success rate

Type 3

Isolated, well circumscribed lesion with drainage via and into dysplastic veins

50 % exclusion rate

Lesion is composed of ectatic and dysplastic veins

60 % exclusion rate

Type 4

High complication rates Highest complication rate

There is no agreed follow-up in terms of imaging, probably because treatment is solely based on symptomatic improvement rather than changes in lesion morphology and size improvement on MRI. Generally the interpretation of symptom improvement is subjective, although a validated quality of life questionnaire (QoL) would be extremely useful tool for assessment of treatments. MRI imaging whilst informative to assess the lesion morphology changes and degree of fibrosis often does not correlate in a linear fashion with the patient’s symptom improvement or failure [85]. However, a repeat MRI at 6/12 to assess response seems reasonable in appropriate cases [13]. LFVM’s are rarely cured, and therefore, outcomes are based on patient satisfaction and symptom improvement. There are no randomised control trials comparing surgery versus sclerotherapy versus conservative or with regards to usage of different sclerosant agents and therefore no

sclerosant to administer. Venography demonstrates a typical venous malformation with no significant venous drainage into deep veins

outcome data. The choice of agent is therefore a personal decision dependent on experience. The development of agreed outcome measures and multicenter collaboration would greatly enhance the knowledge in this field and lead to a better understanding of the correct sclerosant to use in specific circumstances and identify those lesions less likely to respond to therapy. VM’s have the greatest risk of progression in adolescence (70 %) with a smaller group progressing in childhood (26 %). This is felt to represent hormonal influences as a factor for growth. In VM’s, clinical outcomes are generally divided into arbitrary categories related to symptom improvement with MRI imaging size assessment. Ethanol and STS are the commonest sclerosant’s described in the literature. Ethanol appears to have the highest success rates quoted, up to 98 % with no recurrences within 18 months [51, 99] but is a challenging agent to use due to a relatively narrow safety window and high complication rates [4, 99]. Ethanol has a higher minor and major complication rate when compared to 3 % STS (12–30 vs. 0–10 %). STS also has high success rates 68–86 % [54, 88], and both ethanol and 3 % STS have high [75 % patient satisfaction when used to treat facial VM’s [51, 52, 53]. Berenguer et al. [48, 98, 100] in 1999 described 75 % response rates with ethanol and STS sclerotherapy to VM’s with no significant difference in outcomes related to morphology or location with only number of sessions and male sex being predictors of success. This is different to the Birmingham experience where layer involvement was significant in predicting outcomes. Mendonca et al. demonstrated response rates were lower in peripheral (limb) than craniofacial VM’s [8], and Kok et al. demonstrated superficial lesions responded better than

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Fig. 15 The technique of sclerotherapy depends to some degree the underlying type. In A, several needles are placed into the venous malformation to access all areas; in B, larger needles are placed in a

lymphatic malformation to act as an exhaust and prevent over pressurising the system

Fig. 16 Sclerotherapy using foam can be monitored using ultrasound where the foam (gas bubbles) can be visualised as a contrast media with ultrasound and areas not treated can easily be seen (A, B). Direct

stick venography demonstrates the correct location for treatment and after foam sclerotherapy the air outlines the treated malformation (C, D)

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I. McCafferty: Management of Low-Flow Vascular Malformations… Fig. 17 Immediate posttreatment pictures demonstrate the marked swelling of affected areas with inflammatory changes in the skin associated with sclerotherapy (A, C). Follow-up pictures show the clinical improvement (B, D)

Fig. 18 Pictures pre and post-sclerotherapy to a venous malformation

deeper lesions. Markovic et al. [101] reviewed a 6-year experience of foam STS sclerotherapy demonstrating a 92.9 % response rate with cellular microcystic morphological appearances having poor performance. It was suggested that these lesions are more suitable for surgery; however, Muir et al. [50, 58] have demonstrated excellent results treating such lesions with bleomycin sclerotherapy. Intramuscular VM’s often present with a mass and pain and whilst traditionally treated with surgery have significant morbidity after surgery. Sclerotherapy has high response

rates with upto 92 % of patient demonstrating improvement [102] and surgery being reserved for sclerotherapy failures of lesions that are focal and limited to a single muscle. Yun et al. addressed predictors of response to treatment with a review of 158 patients with a detailed questionnaire. He found that the female sex, no draining veins on venography (Puig type 1) and well-defined margins on MRI as positive predictors [103–106]. Sclerotherapy has also been shown to be highly successful in higher risk areas. Stimpson et al. [107] described 83 % response rates for the trans-oral and percutaneous access to treat oral and pharyngeal VM’s with no significant complications. Due to the post-sclerotherapy, swelling prophylactic tracheostomy must be considered for laryngeal VM’s. LM’s have the greatest risk of progression in adolescence (63.8 %) although 40 % progress in childhood [16]. Spontaneous regression occurs in\2 %. Macrocystic LM’s have a higher success rate than microcystic with effective sclerotherapy treatment rates ranging from 88 to 100 % and complication rates ranging from 2 to 22 %. Typically complications are local and include skin loss, blistering, nerve damage and scarring [77, 108, 109]. The results and complications depend to a degree, on which sclerotherapy agent is used. Ethanol due to its higher risk of nerve injury

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and skin necrosis [4] is only useful for treating localised small lesions. STS has been shown to be effective when used alone or in combination with ethanol to treat macrocystic LM [103, 104, 110–113]; Kok et al. demonstrated benefit rates of 84.3 % with the use of 3 % STS [114]. OK432 and Doxycycline treatments have been shown to be a safe and effective treatment [77, 78, 108, 112, 115] with similar success rates of 82–83 % with the OK432 patients requiring on average more treatment sessions 1.9 versus 1.0 (although overall treatment times were similar), and had more post-operative swelling [31, 116, 117]. A multicenter phase 2 trial comparing OK432 treatment with conservative measures reported in 2009 demonstrated a 63 % complete and 94 % partial response rates to OK432 and \2 % spontaneous regression in the conservative group [113]. Patient evaluation surveys have also confirmed anatomical location and morphology to be important factors in predicting response with ethanol having the highest complication rate [118]. Sclerotherapy has also been shown to be beneficial in high-risk areas, e.g. orbital [119], pharyngeal/tracheal [113] and abdominal lesions. Hill et al. [120] demonstrated sclerotherapy with STS and ethanol for macrocystic LM’s and doxycycline for microcystic LM’s safe and effective results with drainage and treatment of orbital LMs. In abdominal LM’s, doxycycline has been shown to be safe and effective with low morbidity when treating abdominal LM with mean doses of 608 mg/session and 1230 mg total doses [103]. Microcystic LM’s present more of a treatment challenge and multiple agents have been used with varying degrees of success, and all studies report significantly lower response rates in microcystic LM’s versus macrocystic LM’s [50, 58, 78, 118, 120, 121]. Bleomycin, however, seems to have good patient tolerance with a good safety profile and is demonstrating high success rates [50, 58, 107], and this agent may become the agent of choice in these lesions.

Conclusion The management of low-flow vascular malformations is complex and requires a multidisciplinary approach. Treatment should be aimed at those lesions that are symptomatic or causing significant morbidity. Whilst surgery can be an option in selective cases, direct stick sclerotherapy is a preferred option as it is least invasive and can be repeated on numerous occasions, this is particularly important in venous malformations, which have a high recurrence rate. A detailed knowledge of the sclerosing agents is extremely important to personalise treatment plans depending on size and morphology in adult and pediatric populations.

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Conflict of interest Author declare that they have no conflicts of interest.

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Iatrogenic percutaneous vascular injuries: clinical presentation, imaging, and management.

Vascular malformations of the orbit: classification and the role of imaging in diagnosis and treatment strategies*.

Management of vascular malformations.

Re: "Vascular malformations of the orbit: classification and the role of imaging in diagnosis and treatment strategies".

Mediastinal venous vascular malformations: report of two cases, with discussion of imaging findings and classification systems.

Prenatal imaging and postnatal presentation, diagnosis and management of congenital lung malformations.

Surgical management of brain stem vascular malformations.

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