Vascular malformations are a complex group of lesions that are present at birth and enlarge commensurate with the child. They may be apparent at birth, early childhood, or not develop until adult life. Vascular malformations are comprised of masses of blood vessels with no defined limit or endothelial proliferation. They do not involute or regress; instead, they grow commensurate with the child and are often poorly demarcated from surrounding tissues, frequently infiltrating tissue planes. They are typically slow flow lesions, although they may cause compression of adjacent vital structures and high output cardiac failure in some complex cases. Vascular malformations encompass a wide anomaly and have been classified in various methods, descriptors, and language can be confusing, often hindering effective communication. Although vascular malformations are relatively rare, they can be associated with significant morbidity affecting appearance, function, organ or limb growth, and in some cases, lead to life-threatening bleeding. A comprehensive classification system assists with effective communication between clinicians and researchers and can identify how the lesion will alter over time or if treatment is required. This will improve the understanding of specific types of vascular malformations and enable the development of better treatment strategies.
Definition of Vascular Malformations
Vascular anomalies have undergone a complete overhaul in classification since their original description. Until recently, they were classified as either hemangiomas, which were rapidly involuting or proliferating lesions present at birth and typically resolve with time, or vascular malformations which were referred to as lesions present at birth that persist and often times increase in size and complexity over time. This was a poor and simplistic classification of complex lesions with a vast array of clinical behavior and treatment algorithm. In 1996, Mulliken and Glowacki attempted to classify vascular lesions based on their clinical behavior and histopathology into tumors or malformations. This was an improvement over previous classification, but was still not an adequate or practical classification system for patient care and management. In 1999, the International Society for the Study of Vascular Anomalies established a new classification in the hope of achieving a common language for all clinicians and investigators involved in the care and study of patients with vascular anomalies. This was based on a simplified clinicohistopathologic categorization (Figure 1).
Vascular malformations are congenital anomalies that are often progressive throughout life. They are comprised of an abnormally formed vascular channel that diverts or shunts blood away from the normal capillary beds and creates a high flow or low flow vascular lesion. This can result in tissue overgrowth or rarely a reduction in blood flow to the involved area. Vascular malformations are not tumors, though they have often been referred to as such. They do not have a true proliferative cell element and thus do not have a defined biologic endpoint. They are best looked at and treated as a structural abnormality or defect. The accurate diagnosis and classification of the type of malformation is essential in its management.
Importance of Understanding Vascular Malformations
All too often when we think of the effects of vascular malformations, we think of them as slight embarrassing birthmarks, mainly a cosmetic inconvenience. If we think more deeply into it, each malformation can be looked at as an anomaly in the skin. Anomalies in the skin are what doctors of any type should notice as an indicator to look further into a problem. A medical student may be taught that if a patient has sclera icterus (where the white of the eyes turns yellow), then this is an indicator to look for liver problems. Similar simple clues exist with vascular lesions. If physicians do not have a broad understanding of these lesions, they will not recognize them as unique entities. This will lead to misconceptions of diagnosis and treatment. The majority of medical practitioners will only ever come across one or two vascular malformations in their entire career. This, coupled with the fact that there are four types of malformations that are easily misdiagnosed, means that the probability of a physician encountering a patient with a vascular malformation and recognizing it is rather slim. The resulting confusion of these lesions with other entities such as infantile hemangiomas and vascular tumors is often the worst with VM, and it can have significant consequences. A recent study from the Netherlands showed that the mean delay in diagnosis for patients with VM was 7.6 years. During this period, these patients were treated as though they had a different skin condition, usually with unsatisfactory recourse. Often times, the wrong treatment will do more damage than no treatment.
Causes of Vascular Malformations
Development of venous malformations, in particular, has been shown to be affected by changes in blood flow caused by an injury to the area such as trauma, surgery, radiotherapy, or an adjacent neoplastic tumor. This is due to changes in flow causing veins to distend and also regress to form cavernous tissue. A likely example of indirect genetic and environmental interaction is that of infantile hemangioma. This common childhood benign tumor has been recently demonstrated to be the biologic response of hemangioma stem cells to injury at the site by acquisition of the mutation for the GLUT1 glucose transporter protein that allows for uncontrolled angiogenesis of the lesion.
Environmental factors in the development of vascular malformations are still an area of research, and as yet, there is limited evidence for many possibilities, though some seem plausible from evidence found in animal models.
Genetic variants or mutations are hypothesized to be a contributing factor in the majority of vascular malformations. Recent advances in molecular genetic techniques have helped to identify somatic mutations that affect the endothelial cells that line blood vessels, causing pathways involved in cell cycle regulation and cell migration to become dysregulated, resulting in the formation of the malformed blood vessel. These mutations can be inherited from a parental germline or can occur sporadically in the affected individual. Vascular malformations can also arise due to chromosomal defects that affect certain genes required for the development of the vascular system. Normally, a specific gene may have a limited role in a particular type of vascular tissue, and thus it’s the loss or gain of function of a certain gene that causes any given malformation.
Genetic Factors
Finally, a variety of genes in the MAPK pathway have been shown to cause arteriovenous malformations when mutated. Mutation in these genes smaller lesions have been shown to form due to reduced expression of the affected gene, which causes an abnormal growth of cells of the affected lineage. These mutations are responsible for the varying sizes of arteriovenous malformations and can present labyrinth-like anomalies in the case of mutations in some of the extracellular regulated kinases (ERKs).
The GNAQ and GNA11 genes encode for G alpha subunits of heterotrimeric G proteins that are known to be involved in the regulation of angiogenesis. Mutations in these genes result in an overactivation of GNAQ and GNA11, which lead to a downregulation of RGS2 and an increase in the Rho pathway, resulting in an alteration of gene expression. Activating mutations in this pathway are known to cause capillary malformations, which are generally seen in the eye or central nervous system.
The most well-known and common occurrence of a trisomy of a chromosome which results in a vascular malformation is an extra copy of chromosome 11. An extra copy of chromosome 11 is linked to capillary malformations and is seen in patients with Turner syndrome. These patients suffer from an extra copy of the X chromosome, and due to one of the X chromosomes being heavily inactivated, there is effectively a trisomy of chromosome 11. This results in the malformation on one side of the body, termed the Sturge Weber syndrome.
Vascular malformations are a result of dysregulated vascular growth and can arise from genetic mutations. There are three known phenomena which can lead to a genetic cause of vascular malformations: (1) trisomy of specific chromosomes, (2) activating mutations in the GNAQ or GNA11 genes, and (3) somatic activating mutations in genes in the mitogen-activated protein kinase pathway (MAPK pathway).
Environmental Factors
In addition to intrinsic genetic factors, an extrinsic environmental influence may be implicated in some types of vascular malformation. The simple malformations (VM) are thought to result from a focal arrest of the capillary bud differentiation programme. This may be triggered by localized tissue damage such as that caused by trauma or inflammation. A VM is often seen to develop at the site of a previous soft tissue injury such as a blunt impact or contusion, and it is common to find an association with a venous varix linked to a local traumatic episode. A high flow VM arteriovenous malformation (AVM) may be induced by raised expression of vascular growth factors in response to tissue hypoxia caused by chronic anemia or congenital heart disease. These growth factors, principally vascular endothelial growth factor (VEGF), drive abnormal proliferation and differentiation of a dysmorphogenic vascular network. Diffuse congenital microfistulae and capillary malformations (CM) are more likely to represent an intrinsic genetic anomaly and to have no environmental causation. Klippel-Trenaunay syndrome exhibits the somatic GNAQ R183Q mutation, whereas sporadic port wine stains commonly have a causative GNA11 mutation. These genetic mutations result in altered function and constitutive activation of G alpha q signaling proteins, which gives a simple and direct explanation for the CM phenotype. In rare cases where CCM is induced by an angiogenic stimulant, the biological behavior and target of the angiogenic factor will determine the type of CCM lesion.
Developmental Abnormalities
Developmental abnormalities associated with vascular malformations have largely been categorized into two different subtypes. The first represents an abnormality of differentiation, in which a histologically normal endothelial cell forms an aberrant lesion of blood vessels. The second abnormality represents an aberrant differentiation in which an endothelial cell derives from a stem cell or progenitor cell that has differentiated down a lineage-specific pathway to form an abnormal endothelial cell. These growths closely resemble neoplasms, or true tumors, but are not induced by a clonal population of cells. Recently, it has been documented that a significant number of vascular tumors and malformations occur as part of complex genetic syndromes, such as Sturge-Weber syndrome, Klippel-Trenaunay-Weber syndrome, and hereditary hemorrhagic telangiectasia. Many of these lesions have unique genetic signatures, and understanding these genetic abnormalities may help in developing specific treatments or cures for these lesions.
Types of Vascular Malformations
Arteriovenous Malformations (AVMs)
Treatment in the past consisted of AVM excision, ligation, or embolization. However, this often caused a recurrence of the AVM and significant morbidity. In addition, because of the nature of AVMs, these procedures can lead to incomplete treatment and paradoxically exacerbate the AVM. Complete removal of the AVM is very difficult, especially if normal vessels are close by, and there is an inherent risk of iatrogenic trauma to normal vessels. High morbidity rates and knowledge of the complex nature and natural history of AVMs have shifted treatment away from direct surgical methods towards more conservative and progressive treatments. AVMs are commonly categorized as Spetzler-Martin grade I, II, III, or IV depending on the size, venous drainage, and adjacent eloquent brain cortex. Grade I and II are usually less aggressive and can potentially be managed with radiation therapy or follow-up observation. Grade III and IV are better treated with particle embolization, a process in which particles are inserted through a catheter and directly into the AVM. This method is performed in several sessions to avoid neurological complications by halting treatment if there are changes in exam findings or symptoms. Upon the confirmation of sufficiency and eradication of the AVM, the patient can be treated with supportive therapy (e.g. physiotherapy) to reduce any treating complications.
Arteriovenous malformations (AVMs) consist of knot-like tangles of arteries and veins. They occur in less than 1% of the population and can exist in many organs of the body. AVMs tend to grow over time and can become a serious health risk, often because of their tendency to rupture and bleed (hemorrhage). AVMs of the brain, skin, and spine are of particular concern. Spinal AVMs can lead to incomplete and painful defecation because of the altered blood flow that can cause damage to the spinal cord. Hemorrhage and other complications of AVMs can lead to various neurological symptoms and skin damage. High output cardiac failure is also a risk for patients with extensive AVMs.
Venous Malformations
Unlike arteriovenous malformations (AVMs), which involve a tangling of arteries and veins, venous malformations are solely made up of veins, most commonly in the skin and subcutaneous tissues. A venous malformation can present in a variety of ways. Many are asymptomatic and are found incidentally. Some present with increased pain and tenderness, which usually indicates microthrombosis of the lesion. Others can present with localized swelling, limiting function of an extremity or organ. Occasionally, vesicles and bullae will form, leading to chronic skin changes. A rare but potentially life-threatening complication is consumption coagulopathy, caused by chronic bleeding from the malformation. This can present with anemia and abnormal coagulation tests and can be associated with a high output heart failure if the malformation encompasses a large area. High output heart failure can also occur from a large malformation that has created an arteriovenous shunt. An ultrasound is the best way to diagnose a venous malformation. It usually appears as a lesion with low-level internal reflectivity and can have phleboliths. MRI or MR venography is indicated if there is concern for a deeper lesion or involvement of a joint. Treatment options include compression stockings, sclerotherapy, and surgery. The best choice often depends on the location and extent of the malformation.
Lymphatic Malformations
Management of lymphatic malformations remains a treatment challenge. Surgery has traditionally been the mainstay of treatment but is often complicated by a high rate of recurrence and surrounding tissue damage, which leads to functional and/or cosmetic deformities. OK-432 (Picibanil) injection has been shown to be safe and effective for the treatment of macrocystic and microcystic lymphatic malformations; however, it is not available in many countries. Other treatment modalities such as laser therapy and sclerotherapy have also been used, but the optimum management of lymphatic malformations has yet to be determined.
Lymphatic malformations (LMs) are rare, non-life-threatening, congenital vascular malformations. They affect all age groups, but 90% become apparent before the age of 2 years. Lymphatic malformations consist of cysts of varying size, which are filled with lymphatic fluid. These cysts are lined with endothelium and are most commonly found in the head and neck (50-70%), axilla or upper extremity (20%), and less commonly in the trunk and lower extremities. The etiology of LMs remains unknown, but they are thought to arise from sequestrations of lymph sacs, which fail to communicate with the rest of the lymphatic system. LMs are often isolated but can be associated with other vascular malformations or syndromes.
Capillary Malformations
These superficial capillary malformations, also known as port wine stains, are composed only of the smallest blood vessels. They are nearly always present at birth and are found in 3 out of every 1,000 children. Rarely causing any symptoms, they can be of significant cosmetic concern and cause emotional distress. They also have the potential to develop thromboses or disseminated intravascular coagulation later in life. The skin may darken and develop nodules and hypertrophy called a Cobb’s syndrome, with a severe variant known as Klippel-Trenaunay syndrome which may also involve varicose veins and bony and soft tissue hypertrophy. Port wine stains occur sporadically but also have autosomal dominant and sporadic inheritance patterns. They are due to an abnormal embryonic development of the neuroectoderm and mesoderm which results in reduced perivascular innervation and atrophy or absence of the capillary.
Treatment Options for Vascular Malformations
Medications
Corticosteroids have been widely used to treat symptoms associated with VM. They are particularly effective in reducing pain or swelling due to inflammation around a lymphatic or venous malformation. However, their use is often associated with unacceptable side effects and corticosteroids should be used with caution. High doses of steroids can produce metabolic, immunologic, and orthopedic side effects, and long-term use is associated with problems such as avascular necrosis of bone and osteoporosis. Nowadays the trend is to use alternative medications more selectively and for shorter durations. In the case of corticosteroids, this may mean using the lowest possible dose to control symptoms, and switching to medications with fewer side effects as soon as they become available.
Medications can be useful in treating some symptoms of vascular malformations, but they do not eliminate the malformations. Most VM lesions are relatively quiescent and often there is no need for therapeutic intervention. However, in certain situations, the natural history of a particular lesion or a constellation of symptoms may indicate the use of a medication to alleviate pain, prevent clotting in a venous malformation, stop bleeding from any kind of lesion, or decrease the size of a lesion. For example, aspirin therapy may be indicated for a patient with a venous malformation located in a site at high risk for significant bleeding. Dosages vary widely depending on the medication, the patient’s age and size, and the particular VM being treated. Close observation of the lesion and careful documentation of symptoms are essential for accurate assessment of response to therapy.
Interventional Radiology Procedures
Several of the latest tricks can be utilized to block off an abnormal vascular lesion, without the necessity to inject anything directly into it. Embolization is a general term used to describe the blockage of an artery. It is becoming more and more frequently utilized in the treatment of children with vascular lesions. Various substances can be injected through a tiny catheter, from coils to glue, to tiny particles known as PVA (polyvinyl alcohol) or onyx. These block the flow of blood into the abnormal vessels, resulting in it shrinking, and often a dramatic improvement in symptoms such as pain or swelling. By choosing the correct method and materials, it allows the procedure to be precisely tailored to best suit individual patients.
Interventional radiology is a subspecialty of radiology in which minimally invasive procedures are performed using image guidance. It uses the most advanced imaging techniques to obtain images inside the body, such as ultrasound, x-rays, MRI (magnetic resonance imaging), and other innovative methods. These images are used during the procedures to direct catheters (thin tubes) and other small instruments through the blood vessels or other pathways to treat a variety of conditions. Its procedures are virtually painless and associated with less risk and shorter recovery time compared to open surgery. Interventional radiology procedures are performed by specially trained interventional radiologists.
Surgical Interventions
Surgical therapy represents the most direct means of removing a vascular malformation and is still the most effective method of eliminating a symptomatic lesion, especially if it is of low flow. There are many surgical options and the choice of technique will depend upon the type of malformation, its anatomical location, the clinical symptoms, the risks of causing further complications, and the expertise and preferences of the surgical team. High flow arteriovenous lesions should not generally be treated by surgery unless endovascular or other preoperative methods are employed to reduce the flow within the lesion, since simple excision is likely to cause massive and uncontrollable hemorrhage. The simplest and often most effective surgical method of treating slow flow vascular malformations is by direct puncture of the lesion with a hypodermic needle and expression of its contents. This method is suitable for small isolated lesions and is generally curative in that it seldom causes recurrence. The needle and syringe method may be used with particularly good effect for the treatment of venous malformations. A more invasive form of surgery is excision of the vascular lesion in toto. This is particularly suitable for solitary lesions that are discrete from normal anatomical structures, but general acceptance of this method is not common because of the risks of causing unacceptable damage to the patient.
