Vascular anomalies a practical approach

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1 Review Article Submitted: Accepted: Conflict of interest None. DOI: /ddg Vascular anomalies a practical approach Martin Theiler 1,2, Regula Wälchli 1, Lisa Weibel 1,2 (1) Pediatric and Adolescent Dermatology, University Children s Hospital of Zurich, Switzerland (2) Department of Dermatology, University Hospital Zurich, Switzerland Summary Vascular anomalies are common clinical problems (around 4.5% of all patients) in pediatric dermatology. A correct diagnosis is possible on clinical grounds in around 90 % of cases; the remaining patients may require radiologic evaluations (duplex ultrasonography, MRI scan) and, rarely, histology. Vascular anomalies are divided into tumors and vascular malformations. This clear division reflects the different biological behaviors of these two groups. The infantile hemangioma represents by far the most common vascular tumor and is characterized by a typical growth cycle consisting of rapid proliferation, plateau phase, and finally slow regression. The discovery in 2008 of the efficacy of beta blockers in this disease is a therapeutic milestone. Vascular malformations can affect all types of vessels (capillaries, veins, arteries and lymphatic vessels). They usually manifest at birth and grow proportionally with the affected child. Some show marked progression especially during puberty. Considerable progress has been made with innovative interventional therapies in recent years, but surgery remains an important option. Basic knowledge of these diseases is important to every dermatologist in order to be able to counsel and manage affected patients correctly. Introduction Vascular anomalies make up a wide spectrum of diseases. They often affect the head and neck, sometimes leading to severe aesthetic impairment. Complications can also occur, and include blindness, hemorrhage, tissue destruction, ulcerations, infections, pain, thrombosis, and coagulation disorders which in rare instances may be fatal. A classification proposed in 1982, based on biological markers [1] contributed substantially to standardization of the nomenclature and thus to improved understanding and therapy of vascular anomalies; it was recognized in 1996 by the International Society for the Study of Vascular Anomalies (ISSVA) in a modified version that included clinical, radiological, histopathological, and hemodynamic features (Table 1) [2]. At the core of this classification is the division of vascular anomalies into tumors and malformations (angiodysplasia). Vascular tumors Infantile hemangioma (IH) Infantile hemangiomas are one of the most common tumors in children with a prevalence of about 5 %, [3]. The disease predominantly occurs in girls, premature infants, and children of multiple pregnancies. The pathogenesis of IH is poorly understood. The endothelial cells in IH patients characteristically express the marker GLUT1, which clearly distinguishes IH from all other vascular tumors occurring in children, especially congenital hemangiomas, and also allows for certain histological diagnosis [4]. Since placental tissue is also positive for GLUT1, some authors have suggested that IH is an expression of a maternal-fetal microchimerism. This explanation has not been confirmed [5]. Due to the rapid proliferation of IH, there has been a strong focus on angiogenesis (proliferation of vessels from existing endothelial cells), although there 397

2 Table 1 Classification of vascular anomalies (International Society for the Study of Vascular Anomalies [ISSVA] 1996 [2]). Vascular tumors Hemangiomas Infantile hemangioma congenital hemangioma Kaposiform hemangioendothelioma Tufted angioma Pyogenic granuloma Vascular malformations Fast-flow malformation Arteriovenous malformation Arteriovenous fistula Low-flow malformation Capillary malformation (port-wine stain) venous malformation lymphatic malformation Complex combined vascular malformation are also signs that the origin of IH may lie in vasculogenesis (development of new vessels from circulating endothelial stem cells) [6, 7]. Molecular mediators also play a key role, especially the VEGF (vascular endothelial growth factor) signalling pathway [8, 9]. Studies are currently underway on the significance of ischemic events in the development of IH. The characteristic growth behavior of IH is important for clinical diagnosis [10]: Not present at birth, or only as precursor lesion (anemic area, telangiectasias), Proliferation phase from 2 6 weeks of age with rapid growth for 3 6 ( 10) months, Plateau phase, Spontaneous regression from age 2 years for several years. It is important to distinguish between localized (superficial, deep, mixed) and segmental plaque-type hemangiomas (Figure 1a, b), because the latter are more commonly associated with other disorders [3]. Although in the majority of patients IH is unproblematic, certain locations require special attention. Problem sites include the eye area (risk: amblyopia, astigmatism), tip of the nose (deformation), lips (often rapid growth, ulceration, deformation), and genital areas (ulceration). In addition, in some situations, there is a risk of associated problems. Plaque-type hemangiomas larger than 5 cm on the head should raise suspicion of PHACES syndrome (Posterior fossa anomalies, Hemangioma, Arterial anomalies [brain, aorta], Cardiac anomalies, Eye anomalies, Sternal defects) [11]. The syndrome affects one-third of children with large hemangiomas on the face [12], usually girls. If there is any suspicion, an MRI of the head and neck, echocardiography, and ophthalmological examination, as well as an abdominal ultrasound should be done. Plaque-type hemangiomas in lumbosacral regions may be associated with spinal dysraphia and various malformations affecting the urogenital region. The acronyms PELVIS (Perineal hemangioma, External genitalia malformations, Lipomyelomeningocele, Vesicorenal abnormalities, Imperforate anus and Skin tag) and SACRAL (Spinal dysraphism, Anogenital, Cutaneous, Renal and urologic anomalies, associated with an Angioma of Lumbosacral localization) syndrome have been suggested [13, 14]. Prompt MRI examination of the affected region is essential. Especially in patients with bilateral IH in the beard region (cheeks, neck), stridor and other respiratory problems should raise suspicion of a possible hemangioma of the airways. Prompt evaluation by a specialist is advised. Patients with more than 5 IH have an increased risk of visceral hemangiomas, usually affecting the liver and rarely other organs. Liver hemangiomas may be divided into focal, multiple, and diffuse lesions [15]. Focal lesions correspond to visceral manifestations of RICH (Rapidly Involuting Congenital Hemangioma, see below). Ultrasound studies are indicated, given the risk of complications such as cardiac insufficiency, abdominal compartment syndrome, and hypothyroidism. Various algorithms Figure 1 Infantile hemangiomas. Multifocal nodular hemangiomas (a) vs. segmental plaque-type hemangioma (b). Possible PHACES association in the latter. 398

3 for the management of liver hemangiomas have been proposed [15, 16]. IH is usually readily diagnosed because of the typical patient history and clinical appearance. The possible differential diagnoses depend on location, depth, and proliferation stage. Precursor lesions may be mistaken for nevus anemicus, nevus depigmentosus, or capillary malformation (nevus flammeus). For superficial lesions, differential diagnostic considerations include pyogenic granulomas, congenital hemangiomas, and other vascular tumors (Table 1). Usually the patient history is the determining factor. The diagnosis of deep IH is a particular challenge, because other subcutaneous masses such as dermoid cysts, nasal gliomas, infantile myofibromas, lipomas, neurofibromas, and of course other vascular anomalies (VM, LM, see below) must be taken into consideration. If there is any uncertainty, imaging studies (duplex ultrasound, possibly MRI) are indicated. IH should be treated if functional complications are anticipated or if there is relevant aesthetic impairment. This applies to % of all hemangiomas [17]. The treatment of choice for IH are non-cardioselective beta blockers [18]. If there is impending functional or significant aesthetic impairment, treatment is usually systemic with propranolol (2 mg/kg/day) for several months [19]. It is essential to refer the patient as quickly as possible to an experienced center for treatment so that the proliferation can be limited. The treatment of infants is usually started in an inpatient or partly inpatient setting. The dosage is steadily increased with monitoring of blood pressure, heart rate, and blood glucose. New monitoring guidelines by the American hemangioma task force on the use of systemic beta blockers in patients with IH are currently in press. The length of treatment is based on the clinical course, generally until at least 12 months of age. We usually treat large and deep hemangiomas longer. Based on experience, about 25 % of patients experience a mild recurrence after discontinuing therapy. In children the side effects of systemic beta blockers are less related to their cardiac effects than to metabolism and bronchoconstriction. Bradycardia and hypertension are rarely problems in normal everyday life. A potential hazard is prolonged hypoglycemia; thus the medication may only be taken with meals. If there is respiratory infection, treatment should be interrupted [20, 21]. For smaller, superficial IH at critical sites, topical beta blockers (timolol, propranolol) may also be useful [22, 23]. Our own studies (unpublished) on timolol gel 0.5 % have shown that it is absorbed in small amounts, but has no systemic pharmacological effects in controlled use on small areas. Caution should be exercised in topical application on larger areas such as in plaque-type hemangiomas on an extremity or in genital regions. Systemic therapy, with monitoring, may be preferred in these situations. In view of the treatment success of systemic and topical beta blockers, the use of cryotherapy to treat IH (only practiced in a few countries, but mentioned in the current AWMF guidelines) is rarely indicated given possible complications (ulcerations, scarring) [24]. Similarly, laser treatments (dye laser, Nd:YAG) for proliferating hemangiomas are less often indicated, but may be still used to treat ulcerated IH [25]. Residual telangiectasias after involution of IH (from age 4 5 years onward) respond very well to pulsed dye laser. For residual scarring and excess tissue after involution surgical treatment may be necessary for aesthetic reasons (from age 3 5 years, depending on affected site). Congenital hemangiomas (CH) Congenital hemangiomas are rare vascular tumors that are fully formed at birth and may already be diagnosed antenatally on ultrasound. In contrast to IH, they are GLUT1- negative, which underscores them being a separate entity [26]. They may be divided into two main forms, the more common RICH (Rapidly Involuting Congenital Hemangioma), which undergoes involution within a few months, and the persistent NICH (Non Involuting Congenital Hemangioma). Transitional types, with partially regressive lesions, are also possible. Clinically, CH typically present as circumscribed, blue nodules with superficial telangiectasias and an anemic halo (Figure 2). Treatment initially consists of regular clinical follow-up and if there is no regression, then later surgical intervention. Possible complications in patients with large RICH include cardiac insufficiency (high-output failure), which requires appropriate measures. Figure 2 RICH. Typical subcutaneous blue tumor with anemic halo on the scalp. 399

4 Figure 3 AVM of the segment V1, reminiscent of a common CM (a). Typical presentation of a CM on the left cheek (b). The other rare vascular tumors occurring in pediatric patients, such as kaposiform hemangioendothelioma and tufted angioma, which are sometimes associated with severe coagulation disorders (Kasabach-Merritt phenomenon) are beyond the scope of this article. The interested reader is referred to the literature [27 30]. Vascular malformations Vascular malformations are divided into 3 groups according to the vessels involved and their flow pattern: fast-flow, slow-flow, and complex-combined vascular malformations (Table 1). Vascular malformations are histologically characterized by an increase of dysplastic and dilated vessels. They are present at birth and grow proportionally as the child develops. The cause in the much more common, sporadically occurring forms is presumably local defects during vasculogenesis and angiogenesis. In recent years, several familial sub-types have been genetically de-coded (see below) [31]. Capillary malformation (CM) Capillary malformation (CM), also known as nevus flammeus or a port-wine stain, is completely visible at birth as a sharply demarcated, homogeneous, erythematous, usually unilateral macule, usually located on the face or neck (Figure 3b). Capillary malformations occur sporadically in 0.3 % of all newborns and exhibit proportional growth. In most cases, they cause only aesthetic impairment without any associated disorders. If left untreated, they have a tendency to become darker with increasing age and develop cavernous changes and pyogenic granulomas [32]. There may also be hyperplasia of the underlying soft tissue. The most important examination in a newborn with a nevus flammeus with involvement of the eyelids is an ophthalmological examination (within the first 10 days of life) for early detection of related glaucoma. If glaucoma is detected, immediate drug or surgical management is needed. Otherwise, regular follow-up is necessary throughout childhood, especially during the first two years. If the nevus flammeus affects the frontotemporal region (V1 segment) there is the additional possibility of Sturge- Weber syndrome (SWS). This disorder is characterized by the triad of CM in the V1 segment, ipsilateral leptomeningeal angiomatosis, and glaucoma. Children with the disorder often have a history of seizures during infancy, often severely delayed development, and motor impairment (hemiparesis). In case of such a CM, in addition to an ophthalmological evaluation, a cranial MRI at age 6 12 months is indicated. In patients with unilateral V1 involvement, the risk of SWS is %, while in patients with bilateral V1 involvement it is nearly 100 % [33]. The combination of CM with a large pigmented nevus is known as phakomatosis pigmentovascularis. Affected children may have merely cutaneous involvement but extracutaneous anomalies are also not uncommon. These may affect CNS, eyes, or other organs. The traditional classification divides these disorders into 5 types with the sub-types A (isolated cutaneous) and B (syndrome-related); this classification was revised and simplified in 2005 by Happle [34]. An association between CM and a large Mongolian spot is the most common type and based on the new classification is referred to as phakomatosis caesioflammea. 400

5 If there is suspicion of a nevus flammeus, the differential diagnosis should include salmon patch (see below) and an initial plaque-type hemangioma. In addition, in children arteriovenous malformations (AVM) may be mistaken for banal CM. Signs of AVM include excessive warmth of the lesion and possibly a palpable thrill. If there is suspicion, duplex ultrasound may be useful. For nevus flammeus, the treatment of choice is the pulsed dye laser [35]. The response to therapy is better in younger patients and for lesions on the face. In addition, psychological aspects support early initiation of treatment in patients with facial CM, typically after age one. Several laser treatment sessions are necessary (usually 4 to 6) to considerably lighten up a lesion. In small children treatment should be performed using short general anesthesia. For older children, topical anesthesia may be adequate, although one must use a local anesthetic without vasoconstrictive properties (e.g., Ametop gel 4 %). In some patients, the lesion will darken again later, making repeated laser treatments necessary. Salmon patch (stork bite) In infants true CM may be confused with a salmon patch (nevus simplex). This is a transitory functional CM in about 40 % of newborns which presents as an irregularly bordered, symmetrical, pink macule on the middle of the neck, middle of the forehead, philtrum, or upper eyelids. Larger lesions can occasionally occur; it has been suggested that these be referred to as nevus simplex complex [36]. A large salmon patch may also occur in association with Beckwith-Wiedemann syndrome or macrocephaly-capillary malformation. Salmon patches usually go away completely within the first three years of life, although they occasionally persist on occipital regions [37]. Dye laser treatment may be used in older children with persistent lesions. Figure 4 CMTC. Characteristic, slightly atrophic, bluish, reticular macules on the right leg. used later. In patients with severe hypotrophy of the affected extremity, an orthopedic evaluation is advised. Cutis marmorata telangiectatica congenita (CMTC) CMTC is a variant of a capillary malformation which occurs sporadically and has a highly characteristic appearance at birth. The lesions consist of reticulated or band-like, purplish macules (livedo reticularis), usually on an extremity and often with associated tissue hypotrophy, which usually affects the circumference of the legs more than their length; there is no progression over the course of disease (Figure 4). Diagnostic criteria for CMTC have been published recently [38]. Associated developmental anomalies affecting other organs can occasionally occur in individual patients, but a search for them is not part of routine practice [37]. CMTC lightens considerably during the first years of life and usually does not require treatment. If necessary, dye laser may be Venous malformation (VM) Similar to CM, VM are also slow-flow lesions. The clinical appearance consists of irregularly bordered bluish, soft plaques. On palpation these occasionally present with small hard nodules (phleboliths). VM can occur anywhere on the body, primarily on the head and neck (Figure 5a). VM are normally visible at birth but may first be noticed later; during puberty the lesions may progress and become more prominent [39]. Unlike IH or CM, VM often affect the mucosa (tongue, lips) and deeper tissues such as the muscles, intestines, or bones. In patients with VM near a joint, a dreaded complication is recurrent hemarthrosis which may result in joint destruction [37]. The diagnosis should include an assessment of clotting parameters including D-dimer and fibrinogen. Increased 401

6 Figure 5 Typical VM on the left cheek (a); in contrast combined micro- and macrocystic LM (b); superficial LM (Lymphangioma circumscriptum) (c). D-dimer levels are suggestive of a venous component of a vascular malformation [40]. Larger VM in particular may lead to chronic localized intravascular coagulopathy (LIC). Various trigger factors such as surgery, sclerotherapy, immobilization, and pregnancy may lead to disseminated intravascular coagulopathy (DIC) with a risk of hemorrhage. Low-molecular heparin administered perioperatively can minimize the risk of bleeding and pain related to VM [41]. Deep venous thrombosis and embolisms are very rare, but may occur after puberty. The majority of VM (94 %) occur sporadically, but there are also hereditary types such as mucocutaneous VM (MCVM) (1 %) due to TIE2 mutations or glomuvenous malformation (GVM) (5 %) due to glomulin mutations [31]. GVM are often suspected based on their characteristic clinical appearance. In general, the lesions are multifocal, superficial, sometimes cobblestone-like plaques, which are typically painful, have a more fi rm consistency compared to classic VM, and do not empty with elevation [42]. Differential diagnosis should include other vascular malformations (lymphatic malformation [LM], complexcombined malformations); in the neck area one should recall congenital cysts and with deeper lesions the rare possibility of a tumor. For the diagnosis of VM, assessment of the areas involved and treatment planning, imaging studies must usually include duplex ultrasound and MRI. Histological analysis confirms the diagnosis of GVM. The treatment of choice for VM is percutaneous intralesional sclerotherapy or, if possible, surgical excision [39]. In very extensive VM with involvement of deep tissues the treatment options are often limited. Compression therapy is an important additional measure for pain reduction and to increase comfort in general. Arteriovenous malformation (AVM) AVM most often affect the head and neck area, followed by the extremities and trunk. Initially, they present as flat pink spots and sometimes imitate harmless CM (Figure 3a). Over time blood flow increases, the lesions grow larger, and on palpation feel hot [43]. The direct arteriovenous vessel shunt (nidus) leads to progressive dilation of the surrounding vessels. The progressive nature of AVM is reflected in the Schobinger classification [44]: Stage I: warm pink macules Stage II: pulsation and vibration Stage III: trophic changes of the skin with ulcerations, bleeding, and pain Stage IV: cardiac insufficiency Puberty, pregnancy, or infections may trigger rapid progression of AVM. AVM are distinguished clinically from other vascular malformations by excessive warmth, a sometimes palpable vibration, as well as possible pulsing sounds on auscultation (bruits). Doppler ultrasound reveals high flow velocities, which may be confirmed on MRI. 402

7 Treatment of AVM is extremely difficult. For early- stage, smaller AVM, primary surgical excision may be a viable option. For larger, painful lesions, the treatment of choice is prompt selective embolization of the nidus, if possible followed by secondary surgical resection [43]. Lymphatic malformation (LM) high-flow complex combined vascular malformations (Parkes-Weber syndrome) capillary malformation with hemihypertrophy extensive venous malformation extensive lymphatic malformation Proteus syndrome/clove syndrome capillary malformation macrocephaly syndrome LM may be divided into two types: macrocystic (also known as lymphangioma, and on the neck as cystic hygroma) and microcystic LM [45]. These may occur in combination at any site, although they often appear on the neck or jaw, manifesting at birth or during infancy. Cutaneous involvement is evident as lymphangioma circumscriptum with groups of watery or hemorrhagic vesicles (Figure 5c). Microcystic LM appear on the extremities as pseudotumors; on the face, larger lesions may cause disfigurement and lead to damage of the jaw and bulbus oculi (Figure 5b). LM of the neck region often lead to obstruction of the upper airways, possibly requiring a tracheostomy [46]. There may also be involvement of the thorax with chylothorax and pericardial effusion [47]. The volume of LM increases with infection or trauma. Intracystic hemorrhage is also common. Spontaneous lymphogenous cellulitis is possible and requires prompt antibiotic therapy [45]. The differential diagnosis of LM is similar to that of VM. Ultrasound and MRI studies may be used to confirm a presumptive clinical diagnosis. They are important for treatment planning as well. In addition, histology using lymphatic markers (e.g., D2-40) may be useful in uncertain situations. Macrocystic LM may be treated with sclerotherapy. Surgical interventions are a secondary option. Lymphangioma circumscriptum may be treated with CO 2 laser. Microcystic LM are generally difficult to manage, because they are difficult to treat with sclerotherapy. Successful treatment has recently been reported with the mtor inhibitor rapamycin (sirolimus); mtor inhibitors will probably be used more often in the near future [48]. Vascular malformation with hemihypertrophy In closing, vascular malformations with associated hemihypertrophy of an extremity deserve mentioning. These often involve complex combined vascular malformations. A classic example is Klippel-Trenaunay syndrome (KTS). A nomenclature that precisely identified the various vascular components has become the most widely employed system internationally though [37]. The differential diagnosis of vascular malformations with hemihypertrophy includes the following diseases: slow-flow complex combined vascular malformations (Klippel-Trenaunay syndrome) Conclusion Vascular anomalies are a mixed group of disorders with different prognoses. The spectrum extends from minimal aesthetic impairment to severe functional loss or even, in rare instances, death. Basic knowledge of these lesions is important for all dermatologists. Diagnosis is often possible based on clinical presentation and uncomplicated types may be observed and treated by private practice physicians. This applies in particular to unproblematic IH, for which careful photo documentation and close monitoring (child s age in months = control interval in weeks) are sufficient. If the diagnosis is uncertain, imaging studies (duplex ultrasound and MRI) can be of help. Patients with more extensive lesions, which may lead to complications, should be promptly referred to a specialized clinic where the necessary diagnostic and treatment procedures may be performed without delay. The development of drug therapies (e.g., beta blockers, rapamycin) in recent years has enhanced the role of dermatology in the treatment of vascular anomalies. Correspondence to Dr. med. Lisa Weibel Kinder- und Jugenddermatologie Universitäts-Kinderklinik Steinwiesstrasse Zürich, Switzerland lisa.weibel@kispi.uzh.ch References 1 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol 1997; 13: Holland KE, Drolet BA. Infantile hemangioma. Pediatr Clin North Am 2010; 57: North PE, Waner M, Mizeracki A, Mihm MC, Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31: Pittman KM, Losken HW, Kleinman ME, Marcus JR, Blei F, Gurtner GC, Marchuk DA. No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation. J Invest Dermatol 2006; 126:

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