Multidisciplinary Management of Vascular Anomalies

Whereas vascular malformations result from abnormal vessel embryogenesis in early fetal life, vascular tumors are endothelial neoplasms characterized by cellular proliferation and growth. Malformations may involve a single type of vessel (eg, capillary or lymphatic) or may be of a mixed variety. In clinical practice, malformations are designated by the predominant channel type and resultant rheologic character (ie, fast vs slow flow).

Vascular tumors encompass a broad range of lesions, including angiosarcomas and tufted angiomas, among others. However, the most common vascular tumor remains the hemangioma, a benign and self-limited lesion usually found in infants.;

Currently, various schemas are used to categorize vascular tumors and malformations,[4, 5] stemming from the original classification described by Mulliken and Glowacki,[3] which is based on the pathologic characteristics of the endothelium and the natural course of the lesion. A simplified outline of their original classification of vascular anomalies is as follows[6] :

Vascular tumors include the following:

• Hemangioma - ​Congenital; infantile
• Kaposiform hemangioendothelioma
• Tufted angioma
• Pyogenic granuloma 
• Hemangiopericythoma
• Angiosarcoma

Vascular malformations include the following:

• Capillary
• Lymphatic
• Venous
• Combined - Arteriovenous malformation (AVM); arteriovenous fistula (AVF)

In 2014, the International Society for the Study of Vascular Anomalies (ISSVA) issued an updated official classification of vascular anomalies,[7] which was subsequently reviewed in 2018.[8] In this classification, vascular tumors are broadly divided into the following categories:

• Benign
• Locally aggressive or borderline
• Malignant

Vascular malformations are broadly divided into the following categories:

• Simple malformations
• Combined malformations
• Anomalies of major named vessels
• Malformations associated with other anomalies

The ISSVA classification also specifies individual conditions within these categories.

Hemangiomas

Hemangiomas (see the image below) are true neoplasms. About 30% of them are apparent at birth, and 70% appear in the first few weeks of life; in contrast, vascular malformations are always present at birth, though they are not always readily apparent. The natural course of hemangiomas is one of early and rapid proliferation, followed by involution and spontaneous regression, with only one rare variant that may persist unchanged through an individual’s life.[9] They are more common in girls than in boys (3:1), and their proliferative phase is characterized by endothelial cell hyperplasia due to activation of vasoactive peptides from the mast cells and a mutlilayered basal membrane.

On immunohistochemistry (IHC) studies, hemangiomas stain positively for specific biologic markers, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Lewis Y antigen, and glucose transporter (GLUT)-1, the latter being pathognomonic of infantile hemangioma (see the first image below). Conversely, vascular malformations are congenital dysmorphogenesis and thus are always present at birth, never regress, and often grow slowly over time (see the second image below). Malformations do not show sex predilection, have a normal vascular endothelium, and do not express specific immune biomarkers.

Some vascular malformations can expand and exhibit endothelial proliferation, usually after trauma, with endovascular or operative intervention, or during periods of hormonal change. Hence, as a rule, vascular lesions that persist into adolescence and adulthood are true vascular malformations and should not be referred to as hemangiomas.

Hemangiomas typically have the following three stages, classified on the basis of clinical assessment, microscopic morphology, and IHC markers[10] :

• Proliferation phase (age 8 months to < 1 year)
• Involuting phase (age 1-5 years)
• Involuted phase (age >5 years)

Hemangiomas can be classified into two types, infantile and congenital. Infantile hemangiomas are generally cutaneous, arise in the cervicofacial region (60%), and may appear as focal, segmental, solitary or multiple. They tend to follow a predetermined course of proliferation and involution but exhibit wide variation in the rate, duration, and degree of growth and spontaneous regression. Unlike infantile hemangiomas, congenital hemangiomas present as fully-grown lesions at birth and do not undergo additional postnatal growth.[11]

On the basis of the natural history, the following three subtypes of congenital hemangioma have been identified[8] :

1. Rapidly involuting congenital hemangioma (RICH) - 90% of involution has occurred by the age of 3 months of age, ^[12]  and some lesions may be associated with thrombocytopenia or consumptive coagulopathy
2. Partially involuting congenital hemangioma (PICH)
3. Noninvoluting congenital hemangioma (NICH). 

Most hemangiomas are small and pose only minor clinical problems before they involute and become clinically silent. However, about 20% pose significant problems and require treatment.[13] (See the images below.) This may result from aggressive growth, proximity to vital structures, or complications such as ulceration, bleeding, coagulopathy, or even high-output cardiac failure.[14] Finally, the disfiguring nature of certain lesions may prompt parents to seek intervention early rather than wait for the involution phase.

Vascular malformations

The pathophysiologic characteristics of vascular malformations are dictated by the type of channels involved (heme vs lymphatic) and the flow characteristics of the resultant lesion. Typically, capillary, venous, and lymphatic lesions tend to be slow-flow, whereas arterial lesions are fast-flow. Any combination of these elements is possible, resulting in an AVM, a capillary-lymphaticovenous malformation (CLVM), or a lymphaticovenous malformation (LVM). (See Presentation.) Venous malformations are most common.

CLVM with overgrowth of the lower extremity, mainly in girls, is referred to as Klippel-Trenaunay syndrome (KTS) (see the first and second images below). Because patients with KTS have deep venous system hypoplasia of the affected leg, they exhibit a pathognomonic dilatation of the superficial saphenous vein, called the marginal vein of Servelle (see the third and fourth images below).

All vessel–type involvement (arteriovenous-capillary-lymphatic malformation) is referred to as Parks-Weber syndrome (see the images below).

The etiology of a particular vascular anomaly can vary greatly, depending on the nature of the lesion. In general, vascular tumors are endothelial neoplasms, the molecular biology of which remains poorly understood and characterized. There has been considerable interest in the mechanisms underlying the formation of hemangiomas, which are the most common of vascular tumors. 

Although data from animal models remain lacking, research performed with human tissues has implicated numerous signal pathways that are altered during the various phases of hemangioma development. These include, among others, the following[15] :

• Basic FGF (bFGF)
• VEGF
• Tissue inhibitor of metalloproteinases 1 (TIMP1)
• Hypoxia-inducible factor (HIF)

Apart from these observational data, however, the mechanistic understanding of hemangioma development remains poor. Some authors have suggested a hereditary component to hemangiomas; however, the data are conflicting with respect to this notion.[16]

It has been suggested that vascular malformations arise from abnormalities in the process of normal vascular development. Specifically, perturbation of early angiogenesis and vasculogenesis may result in abnormal vascular channels, leading to the development of vascular malformations.[17] In contrast with vascular tumors, vascular malformations seem to have a strong hereditary component, with specific lesions observed in the setting of inherited syndromes.

Genetics

Alterations in several signaling molecules and pathways have been identified in specific types of malformations. For example, TIE2,[18] glomus cells,[19] and bFGF[6] have all been implicated in the formation of AVMs (see the image below). Investigators have localized chromosomal mutations underlying several combined vascular formation syndromes (eg, Klippel-Trenaunay-Weber syndrome and Proteus syndrome), further supporting a hereditary component to the development of AVMs.[20, 21]

The majority of mutations leading to vascular malformations are sporadic and post-zygotic, but other autosomal dominant germline mutations have been identified[22] . There are three signaling pathways in which the mutated genes are involved:

1. PIK3CA/mammalian target of rapamycin (mTOR)
2. RAS/mitogen-activated protein kinase (MAPK)
3. G-protein coupled receptor signaling

The PIK3/AKT/mTOR pathway is an antiapoptotic pathway, in which mutations induce excessive and unregulated activation of the AKT pathway.[23]  PIK3CA is one of the most relevant pathways by virtue of its relationship with the PROS (PIK3CA-related overgrowth spectrum) group lesions arising from somatic PIK3CA-activating mutations. It is also relevant to targeted pharmacotherapies, in particular to mTOR/PIK3CA/AKT pathway treatment with sirolimus (rapamycin), further discussed elsewhere (see Treatment).[22]  

The penetrance and expressiveness of the genes involved in these pathways explain the different clinical phenotypes and underline the importance of high-sensitivity molecular diagnosis for targeted pharmacotherapy.[22]

In general, vascular anomalies are rare, and limited data exist regarding their true worldwide incidence and prevalence. However, there is now a growing body of observations detailing the epidemiology and natural history of the more common subtypes of these anomalies (eg, hemangiomas and venous malformations). 

Hemangiomas are the most common tumors of infancy and childhood, observed in 4-12% of infants during the first year of life.[13, 24] They are three to five times more common in females than in males. They are also more common in premature infants, with the risk increasing with lower birth weight.[25] The incidence among nonwhite populations remains unknown; however, hemangiomas in dark-skinned individuals are uncommon.[6]

Epidemiologic data regarding vascular malformations are also scarce. The overall incidence of congenital vascular malformations in the general population is estimated at 1.5%. Approximately two thirds of malformations are of venous predominance and are evenly distributed according to sex and race.[26]

According to the ISSVA and the German Interdisciplinary Society of Vascular Anomalies (DiGGefA), venous malformations are the most common representatives of vascular anomalies (70 %) (see the first image below), followed by lymphatic malformations (12 %) (see the second image below), AVMs (8 %), combined malformation syndromes (6 %) (see the third image below), and capillary malformations (4 %).[2]

In two separate case series, for example, patients with congenital vascular malformations were evaluated at Children's Hospital of Mexico City (1963-1983; 223 children) and the Walter Reed Army and National Naval Medical Centers (1984-1998; 169 children). Of the 392 patients, 257 (65.6%) had malformations of venous predominance. Prevalences of phlebectasia, aplasia or hypoplasia of venous trunks, aneurysms, and avalvulia were also recorded.[26]

Most hemangiomas have a self-limited course, leaving only a mild blemish or nearly imperceptible skin changes at the lesion site. However, the outcome of lesions that require intervention or operative management is heavily influenced by the nature and site of the lesion. For example, facial lesions may result in long-term cosmetic disfigurement. 

Most vascular malformations represent progressive lesions, and long-term outcomes vary according to the nature, size, and location of a specific lesion. Lesions such as AVMs and small vascular malformations are more likely to be "cured" with surgical measures than lesions such as lymphatic malformations and mixed lesions are. With all of these lesions, however, long-term follow-up and vigilance are required to determine the efficacy of therapeutic intervention. 

Although accurate diagnosis of these lesions may be complex, the promptness and precision with which it is achieved represents the basis for appropriate management. Accordingly, it is important to create awareness and spread knowledge of these conditions,[27] as well as to pay attention to their long-term implications (functional, emotional, and aesthetic) for a child's life.

Hemangiomas

Hemangiomas are usually noted in the first 2 weeks of life, though the exact timing depends on multiple factors, including the location of the lesion. Most start as a small cutaneous mark that resembles a bruise or red macular lesion before progressing to a more prominent lesion. Most (60-80%) develop on the craniofacial region, followed by the trunk and extremities. Whereas most cutaneous lesions are isolated, approximately 20% are multiple (see the images below). Such multiple lesions should alert the clinician to the possibility of visceral organ involvement, as is often the case.[13, 28]

The presentation and course are quite variable, depending on the location and depth of the lesion. For example, deeper cutaneous lesions may lack a typical “strawberry” appearance but may instead appear darker with a bluish hue. During the proliferative phase, frequent assessment and documentation are necessary because progression is unpredictable. A small lesion may rapidly blossom into a very large one or may take a much more indolent course. Usually, lesions plateau by age 1 year, marking the end of the proliferative phase. 

During the involuting phase, the growth of the lesion slows and parallels the growth rate of the child. As the lesion matures and begins to regress, it usually lightens in color, often adopting a grayish hue, and becomes softer to palpation. By age 5-7 years, the final traces of color usually disappear, leaving either very little evidence of the lesion or an atrophic fibrofatty patch with telangiectatic vessels. 

In approximately 50% of children, the site of the lesion matures to a normal texture and consistency. However, it is not currently possible to predict the course that a particular lesion may take; no reliable clinical factors predict final cosmetic outcome. In general, facial hemangiomas may lead to long-term cosmetic defects, in that the lesion may destroy hair follicles and may produce mass effects on the facial skeleton, nose, or jaw.[6]  Hemangiomas complicated by chronic ulceration may also leave prominent scars.[29]

Although most hemangiomas resolve without serious long-term complications and require only appropriate diagnosis and expectant management, approximately 20% of them become clinically significant and require more in-depth workup and treatment (see the images below).[13]

Specifically, lesions that involve the head and neck deserve particular attention. Dermatomally distributed facial lesions, in particular, may indicate the presence of PHACE syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, cardiac defects, and eye anomalies). These warrant multiorgan assesment and radiographic evaluation (eg, facial magnetic resonance imaging [MRI]).[30]

Similarly, the presence of numerous hemangiomas (so-called disseminated hemangiomas or hemangiomatosis) may indicate the presence of visceral lesions involving the liver, lung, gastrointestinal (GI) tract, or brain. Screening with ultrasonography (US) or MRI should be considered in these patients. 

Other lesions that warrant early attention are those that involve the airway (usually heralded by a cutaneous cervical lesion), those that involve the eye and related structures, and those in the lumbosacral region, the last of which may indicate the presence of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies)[8] .

In neonates with these lesions, prompt evaluation by appropriate specialists (pediatric surgeon/ophthalmologist) should be sought; therapeutic interventions (eg, tracheostomy) may be required. In the setting of lumbosacral disease, US or MRI might be indicated to rule out underlying spinal cord defects.

One of the more problematic complications of cutaneous hemangiomas remains ulceration of the skin, affecting approximately 5% of infants.[31] Ulceration most commonly arises in lesions that involve the extremities, lips, or perineum. Most ulcerative lesions can be treated with local wound care. Laser treatment and even resection may be considered if the ulceration is extensive.

Although most vascular tumors encountered in clinical practice are hemangiomas, other, rarer lesions (eg, pyogenic granuloma and kaposiform hemangioendothelioma) should also be considered when a neonate with a vascular lesion is evaluated. It is essential to identify these rare tumors at an early stage; treatment of the lesion and possible associated syndromes (eg, Kasabach-Merritt syndrome) may be required. 

Venous malformations

Venous malformations, the most common form of vascular malformation, are composed of thin-walled, endothelial-lined, dilated, spongelike channels, with a notable absence of smooth muscle. They are typically blue-gray in color and compressible and grow slowly over time (usually growing as the child grows). Lesions may be small and varicose or large and extensive, involving the extremities, face, or trunk. Visceral involvement may occur. Cutaneous lesions may visibly expand with a Valsalva maneuver (a potential diagnostic aid during physical examination).

Phlebothrombosis is a common complication, resulting in pain, swelling, and stiffness of joints and muscles. The location and size of a specific lesion dictate the extent of clinical pathology. In general, the mass effect of a growing lesion leads to local symptoms. For example, craniofacial lesions may cause obstructive ocular and aerodigestive complications (eg, exophthalmia and sleep apnea, respectively). Lesions in the skin and soft tissue may cause extensive disfigurement. Deeper lesions that involve muscle or bone may eventually lead to a loss of musculoskeletal function and even pathologic fractures due to bony destruction. 

Workup of venous malformations should include coagulation studies, in that extensive venous malformations have also been associated with coagulopathies. Computed tomography (CT) angiography (CTA) or MRI may also be required to determine the extent of involvement of a venous malformation. (See the image below.) These noninvasive studies have displaced the former standard, venography.

Indications for treatment of these lesions include cosmetic disfigurement, pain, and functional impairment. The mainstay of therapy remains a combination of compression, sclerotherapy, and surgical resection.

Capillary malformations

Capillary malformations (also known as port-wine stains) can occur anywhere on the body, with a prevalence of 0.3% at birth.[32]  These lesions often manifest as discolorations of the neonatal skin and may darken over time, accompanied by a nodular expansion. Capillary malformations on the face may follow a dermatomal distribution, though more than half cross dermatomes or occur bilaterally.[33]  Lesions may involve the mucosal membranes and may cause significant distortion of the face with bony overgrowth and gingival hyperplasia.

The presence of capillary malformations should alert the physician to the possibility of anatomically associated central nervous system (CNS) defects, such as ectopic meninges, AVMs of the spinal cord (Cobb syndrome), lipomeningocele, tethered cord, or spinal dysraphism. Lumbosacral lesions may also be accompanied by spinal cord abnormalities and neurogenic bladder dysfunction.[34, 35, 36]

Sturge-Weber syndrome must be considered in the presence of facial capillary malformations. This syndrome is characterized by facial capillary malformations and ipsilateral ocular and leptomeningeal vascular anomalies.[33]  

Leptomeningeal vascular anomalies may be of venous, capillary, or mixed types and can cause various neurologic symptoms, such as seizures and hemiplegia. Choroidal anomalies are also often present, necessitating frequent ophthalmologic evaluation.

Lymphatic malformations

Lymphatic malformations are usually noted at birth or within the first few years of life, and may manifest in numerous forms. These lesions may be isolated, may encompass a large anatomic area, and may involve multiple organs (see the image below). Their classification is based on radiologic and histologic evaluation and resultant grouping into microcystic, macrocystic, and combined forms. Historically, these lesions have commonly been referred to as lymphangiomas and cystic hygromas; however, these terms are now regarded as outdated and should no longer be used by experts in the field.[6]

Lymphatic malformations may occur in any location, but are typically found in the cervicofacial region (see the images below), mediastinum, chest, axilla, perineum, buttock, and retroperineum.[37]  The lesions can range from small spongelike blemishes, to large bulky masses that cause severe disfigurement. The overlying skin may appear normal, may exhibit bluish discoloration, or, in the case of dermal involvement, may be riddled with tiny dark-red vesicles caused by intravesicular bleeding.

A significant complication of lymphatic malformations remains intralesional hemorrhage, which can affect as many as 13% of cases.[38]  This is often heralded by rapid growth of the lesion, predisposing the area to infection. If bleeding occurs, antibiotic therapy should be started immediately.[6]  However, prophylactic treatment with antibiotics is not currently recommended.

Notably, faciocervical lymphatic malformations may result in significant ophthalmologic symptoms, dental problems, or airway compromise, the last of which may necessitate tracheostomy.[39, 40]

Management of lymphatic malformations centers on the prevention of bleeding, infection, and mass effect. The mainstays of treatment are sclerotherapy and surgical excision. (See the images below.)

Arteriovenous malformations

AVMs are usually diagnosed at birth and may be mistaken for other types of malformations (eg, capillary malformations). As their name implies, AVMs consist of arteriovenous structures that allow shunting to occur. The lesions are defined by the presence of feeding and draining vessels. Consequently, the natural history of the lesion is one of progression.[41, 42, 43]

AVMs may first be evident as small discolored areas on the skin and progress at different rates depending on their flow (ie, fast vs slow). Fast-flow lesions typically evolve quickly, resulting in worsening erythema, bruits, and thrills. Trauma may exacerbate the lesions, and rapid growth may be observed during puberty.[6]  As the arteriovenous shunting worsens, local ischemic signs may manifest (ulceration, pain, bleeding). Extensive lesions may lead to high-output cardiac failure as the heart attempts to maintain perfusion in the presence of a large arteriovenous shunt. 

Schobinger summarized the natural history of congenital AVMs as evolving through four distinct clinical stages, as follows[44] :

• Stage 1 (quiescence) - This is characterized by a pink violaceous mark and the presence of an arteriovenous shunt detectable by echo Doppler US
• Stage 2 (expansion) - As in stage 1, but clinically pulsatile, with obvious presence of tortuous vessels
• Stage 3 (destruction) - As in stage 2, along with damage to surrounding tissue (eg, dystrophic skin changes), ulceration, bleeding, and continuous pain 
• Stage 4 (decompensation) - Similar to stage 3, but associated with cardiac failure due to voluminous shunting 

AVMs can occur almost anywhere in the body. Intracranial lesions are most common, followed by head and neck, extremities (lower more often than upper), trunk, and visceral. Among AVMs that involve the extremities, those associated with fistulous shunts of the femoral vessels are most common. Many investigators choose to reserve the term AVF for the acquired traumatic variant involving a solitary fistula.

Patients with an AVM involving the brain may have a dramatic presentation, including neurologic symptoms. Pelvic AVMs are usually extensive and manifest as vaginal bleeding or symptoms related to compression of other pelvic organs. Congenital visceral fistulas can involve the lung, kidney, and alimentary tract. Alimentary tract AVMs are usually part of congenital telangiectatic syndromes and often present with GI bleeding .[45, 46]

Multimodality imaging with US (Doppler), CTA, magnetic resonance angiography (MRA), and even angiography may be required to fully characterize a lesion. Because many AVMs are not localized and infiltrate deeply into several tissue planes, such imaging may be necessary to determine the best course of treatment.[47]  Treatment is individualized on a case-by-case basis, taking into consideration the location and extent of the lesion. A multidisciplinary approach is required, with embolization, sclerotherapy, and surgical resection as single or combined treatment alternatives (see the images below).

Combined malformations

Lesions with multiple combinations of vascular elements are grouped into this category. Capillary-lymphaticovenous malformations (seen in Klippel-Trenaunay syndrome) often involve the lower extremities, resulting in disfiguring hypertrophy of the involved limb (see the images below). Functionality of the limb may also be affected, requiring surgical debulking, if appropriate. The syndrome is more common in females.

Other combined malformations include those that manifest in individuals with Sturge-Weber syndrome. Limbs are typically affected and exhibit enlargement with skin changes. Treatment may include expectant management and embolization, if appropriate. 

The workup of vascular anomalies relies heavily on history, physical examination, and overall clinical assessment. Typically, laboratory studies are not required in the workup and diagnosis of these anomalies. However, in patients with multiple venous malformations, Kasabach-Merritt syndrome, and combined malformations, coagulation studies are warranted because coagulopathies are often present. 

MRI is the leading imaging modality in the diagnosis and follow-up of patients with vascular malformations. Arteriography is the criterion standard for the evaluation of high-flow vascular anomalies, particularly for arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs).[2]

Hemangiomas

Most hemangiomas can be managed without imaging studies. However, magnetic resonance imaging (MRI) is warranted in the following circumstances:

• Lesions consistent with PHACE syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, cardiac defects, and eye anomalies) should undergo imaging to evaluate the carotids and cerebral vasculature
• The presence of multiple cutaneous lesions warrants screening with ultrasonography (US) or MRI to assess concomitant visceral lesions 
• Lumbosacral lesions require imaging of the spinal cord (US or MRI) to rule out synchronous cord lesions
• Preoperative imaging may be required at the discretion of the surgeon 

Venous malformations

Magnetic resonance angiography (MRA) or computed tomography (CT) angiography (CTA) may be required to delineate the full extent of complex venous malformations. Such information may be useful for assisting in treatment and operative management. 

Capillary malformations

Imaging of the spinal cord should be considered in the presence of capillary malformations; developmental defects of the central neural axis are common with these lesions. 

Lymphatic malformations

Large lymphatic malformations may be diagnosed in utero with US.[37] Such malformations are classified according to their radiographic and histologic characteristics. Hence, multimodality imaging is often used for proper delineation. MRI and Doppler US yield insight into the extent and flow characteristics, respectively. 

Arteriovenous malformations

US with Doppler imaging is a very useful tool to confirm the diagnosis of suspected AVM. Further imaging with MRI can delineate the full extent of the lesion and involvement of other structures. Angiography may also be useful to aid in embolization and preoperative planning. Hardwicke et al described a case in which office-based thermography was used adjunctively in the assessment of an AVM of the hand.[48]

Vascular anomalies are quite diverse in nature and encompass many types of lesions; accordingly, indications for treatment are nuanced and variable. In general, the decision to intervene should take into consideration the type of lesion, the associated symptoms, and the desires of the patient and family. 

Most hemangiomas are small tumors that eventually undergo involution. However, treatment may be warranted if the tumor is large, grows rapidly, is complicated by severe ulceration, is in a threatening location, or might otherwise cause complications. Most are currently managed with propranolol as the first line of treatment (see Medical Therapy).

Indications for treatment of venous malformations include appearance, impairment of function, and protracted pain. 

Capillary malformations are largely treated for cosmetic reasons; however, excision may be warranted in patients who develop fibronodular hypertrophy or who have extensive facial involvement. 

Treatment of lymphatic malformations should be geared toward preventing infection and bleeding, correcting cosmetic deformity, and improving the function of affected areas.[49]

Quiescent arteriovenous malformations (AVMs) may be managed expectantly; however, pain, bleeding, ulceration, and extensive enlargement are all indications for treatment. Symptomatic lesions that are not amenable to surgical treatment may be considered for palliative embolization therapy.

Treatment is indicated to mitigate the sequelae of combined malformations, including hypertrophy, lymphatic weeping, pain, and loss of functionality.

Hemangiomas

Since 2008[50] and after the report of a consensus protocol in 2013,[51]  propranolol has been used as first-line treatment of hemangiomas, with caution exercised in infants with hemodynamic disorders, care taken to prevent hypoglycemia, and attention paid to confirming that the benefits of treatment outweigh the risks in patients with hemangiomas associated with PHACE (posterior fossa, hemangioma, arterial, cardiac, eyes) syndrome.

The starting dosage for propranolol is 0.5 to 1 mg/kg/day; if tolerated (with heart rate and blood pressure checked after one to three doses), it can be increased to 2 mg/kg/day.[52]

Treatment of hemangiomas with corticosteroids and interferon alfa has fallen out of favor because of the common adverse effects related to their use (cushingoid syndrome for the former, neuropathy for the latter). Lauromacrogol has been used in sclerotherapy for refractory hemangioma.[53]

Venous malformations

Initial treatment of venous malformations consists of elastic compression aids to reduce swelling and pain. Daily aspirin may also be administered to prevent thrombotic complications. Sclerotherapy, most often with ethanol, has been a mainstay of treatment.[54]  Lauromacrogol has also been used as a sclerosing agent for vascular malformation.[53]

Sclerotherapy should be performed with general anesthesia, guided by ultrasonography (US), fluoroscopy, or both. With repeated therapy, the success rate for improving function and reducing symptoms can reach 84%.[55]

In 2014, the International Union of Phlebology issued an updated guideline expressing a current consensus on the diagnosis and management of venous malformations.[56]

Capillary malformations

Cosmetic camouflage and laser photocoagulation are the current first-line treatments for capillary malformations.[6] Flashlamp pulsed dye lasers are most often used, though the results of such therapy are mixed. Multiple treatments are usually required, and nearly half of all lesions will darken within 5 years of treatment.[57]

Lymphatic malformations

Macrocytic lesions may be effectively treated with sclerotherapy. Both bleomycin and OK-432 (attenuated group A Streptococcus pyogenes) were effective as intralesional sclerotic agents. [58, 59]  A 2008 series by Burrows et al evaluated the use of doxycycline as an effective sclerosing agent for lymphatic malformations.[60]

Carbon dioxide, argon, and yttrium-aluminum-garnet (YAG) laser therapy can also be used to treat mucosal lesions, though malformations treated with this therapy often recur, requiring repeat treatment.

Newer therapies

More accurate diagnosis, improved treatment guidance, and various emerging therapies have been made possible by refinements in the classification and terminology of vascular anomalies.[23]

Advances in the discovery and understanding of the pathways involved in the pathophysiology of vascular malformations have led to the development of several targeted molecular inhibitors of these pathways.[23]

The newer agent that has been the subject of the most study to date is sirolimus (rapamycin[61] ; a mammalian target of rapamycin [mTOR] inhibitor), which is used for venous, lymphatic, and complex malformations. Another emerging agent is alpelisib (a PIK3CA inhibitor),[23] which is used for PIK3CA-mutated vascular malformations.[61]

Over the past few decades, sclerotherapy has become increasingly popular as the initial management of lymphatic malformations, by virtue of its safety, efficacy, and cost-effectiveness when compared with surgery; this development highlights the importance of interventional radiology within the multidisciplinary management of patients with these malformations.[62]

The efficacy and safety of sclerotherapy depend directly on the angioarchitecture, the sclerosing agent used, and the dwell time of the sclerosant within the malformation.[63]

The most commonly used sclerosing agents can be classified according to their mechanism of action[63] , as follows:

• Direct induction of endothelial injury and thrombosis of the malformation - Ethanol, ethanolamine, and pingyangmycin
• Induction of a nonspecific inflammatory reaction within the malformation (less potent) - Sodium tetradecyl sulfate and bleomycin

Hemangiomas

Surgical resection may be appropriate for lesions that are refractory to medical management and that continue to present problems (eg, ulceration). Resection may be performed at any of the three stages of the life cycle. As a general rule, resection should be deferred until the involuted phase (late childhood), when the lesion has matured and the anesthetic risk to the child is decreased. However, specific indications have been suggested for resection at all phases, as summarized by Marler and Mulliken[6] :

• Infancy (proliferative phase) - Indications for resection include obstruction (visual or subglottic), deformity (eg, periorbital distortion), bleeding, ulceration, involvement of the scalp (to prevent alopecia of the effected region), and anticipation of a scar caused naturally by the lesion that would be more marked than that caused by surgical intervention
• Early childhood (involuting phase) - Large protuberant lesions are resected in this phase, as children of this age generally become aware of physical appearance; excision may be performed at this point if resection is considered inevitable, the resultant scar is similar to that achieved by waiting to excise in the involuted phase, and the scar may be easily hidden
• Late childhood (involuted phase) - Indications for resection in this phase include damaged skin, abnormal contour, and distortion of skin or surrounding structures 

Early tracheostomy may be warranted for lesions that threaten the airway. 

Because no two lesions or patients are alike, optimal timing and technique of surgical excision should be determined on a case-by-case basis

Venous malformations

Sclerotherapy is the primary interventional treatment for venous malformations; however, surgical excision may be offered for selected lesions. Small localized lesions are the best candidates for surgical intervention. In general, sclerotherapy should be used to shrink lesions prior to surgical excision. 

Capillary malformations

Small fibrovascular lesions can easily be excised in most locations. More extensive excision and grafting of select capillary malformations may also be performed. Facial lesions with concomitant disfigurement may require excision with full- or split-thickness grafts accompanied by contour resection and correction of maxillofacial distortion.[64, 65]

Lymphatic malformations

Surgical resection is the mainstay of treatment for lymphatic malformations. In general, resection should be deferred until late infancy or early childhood to minimize anesthetic risk and to allow easier dissection of neurovascular structures often associated with complex lesions. 

Often, lymphatic malformations encompass vital structures, precluding complete excision. Staged approaches are often used. The approach to resection varies with lesion location. Generally, total excision of the lesion is attempted, with careful identification and preservation of involved major nerves (eg, preservation of the brachial plexus when an axillary lesion is excised). 

Resections tend to be involved, and wound complications (eg, infection, drainage, swelling, and seroma formation) are common. 

Arteriovenous malformations

Treatment of AVMs consists of a combination of embolization, sclerotherapy, and surgical resection. Angiography is required for intervention, in that it delineates the extent of the lesion and clearly outlines the feeding and draining vessels. Surgical ligation of feeding vessels should not be performed, because doing so only induces recruitment of new vessels into the lesion. Such ligation not only fails to solve the problem but also—even worse—prevents further endovascular access, thereby precluding therapeutic interventions.[6]

Embolization may be performed with coils, particles, or glue via an arterial approach. Sclerotherapy may be delivered in the nidus of the lesion with concomitant occlusion of feeding and draining vessels. Various sclerosing agents (eg, absolute ethanol and N-butyl cyanoacrylate [NBCA]) have been described.[66] Combinations of embolization and sclerotherapy may be used to treat lesions that may not be amenable to surgical resection; however, these measures provide only temporary improvement, in that new vessels are readily recruited into the lesion.

All AVMs are high-flow lesions. Thus, it is essential to ensure that the sclerosant does not escape the lesion through the draining vessels. This can give rise to one of the most feared complications, embolization of nontarget organs, which can range from asymptomatic and clinically irrelevant to problematic (eg, large cutaneous ulcers) to or disastrous (eg, blindness, organ failure, or even death due to massive pulmonary absorption). The author has had to place a balloon catheter in the drainage jugular vein while injecting NBCA into a high-flow malformation of the mandible on a 12-year-old boy in order to keep the plastification agent from leaking into the heart and the systemic circulation.

If a lesion is deemed appropriate for surgical excision, preoperative embolization is usually recommended to aid in resection. Select lesions (eg, small malformations on the extremities) may be excised without preoperative embolization. Operative intervention is indicated to facilitate complete excision and to minimize operative blood loss and recurrence. Staged procedures are usually not performed, though for extensive, complex lesions, staged endovascular treatment (sclerosis, embolization, or plastification) followed by single or staged surgical resection procedures represents a therapeutic alternative. (See the images below.)

Excision should include the nidus of the lesion, as well as any involved skin or deeper tissues. Wide excision is often necessary, with the extent of the resection based on delineation of the lesion by preoperative imaging, bleeding patterns at the resection margin (ie, consistent with normal dermal vasculature or extensive bleeding indicative of the malformation), and frozen sections of the resection margin. Large excisions may necessitate grafting or tissue transfer for adequate wound closure. Fluorescence-guided surgery with indocyanine green and infrared lamps has been advocated, with varying results.

Deep intracranial and complex craniofacial AVMs present a unique therapeutic challenge, in that surgical excision is often impossible. Embolization is the usual treatment for such lesions. Radiotherapy has been also successfully employed to treat such intracranial lesions[67] ; the International Radiosurgery Association has published guidelines for its use in this setting.[68]

In 2013, the International Union of Angiology published a consensus document on the management of AVMs.[69]

Combined malformations

Proper management of combined and complex malformations requries a high level of expertise in their treatment. Different segments of the malformation can be managed with distinct therapeutic approaches. In a given patient, the multidisciplinary team could opt for embolization of the arterial component of the lesion; sclerotherapy or surgical resection for the venous or lymphatic component; laser therapy for the capillary cutaneous component; and staged surgical resection, mTOR inhibitors, or both for limb overgrowth. Treatment should be specifically tailored for each particular patient.

Permanent or temporary growth arrest of the noninvolved lower limb has been used in order to avoid limb-length discrepancy, thereby aiding the gait and helping to prevent limping. 

Complications of therapy depend on the nature of the lesion and the type of intervention carried out.

Systemic corticosteroid therapy used to treat hemangiomas may produce the expected complications of such therapy (eg, gastric irritation, temporary growth retardation, and cushingoid appearance). Local intralesional administration may be complicated by damage to surrounding structures such as the eye.[70]  As noted (see Medical Therapy), corticosteroids currently are less commonly used to treat hemangiomas than they once were.

In general, treatment of malformations with sclerotherapy may result in local complications, including nerve injury, cutaneous necrosis, blistering, and injury to surrounding structures.[71]  (See the images below.)

Laser therapy or phototherapy often fails to resolve lesions permanently; recurrence rates are high.

Short-term complications of surgical excision may include bleeding and infection. Protracted wound problems may also occur, depending on the nature of the lesion. Edema, pain, seromas, and prolonged drainage may occur at resection sites. Functional loss (of limbs and hands) and need for repeat excisions (as with lymphatic malformations) may also be potential complications of surgical management.

In general, vascular anomalies constitute a chronic and complex group of lesions that require long-term follow-up and care. Although no treatments can be said to be curative for all problematic lesions, most malformations can be treated to achieve mitigation of symptoms if the correct diagnosis is made early and the proper interventions implemented. Patients should be observed in multidisciplinary clinics, if appropriate, and consultation with a surgeon should be sought early.