Current Classification and Terminology of Pediatric Vascular Anomalies

Transcription

1 Pediatric Imaging Review Kollipara et al. Pediatric Vascular nomalies Pediatric Imaging Review Ramya Kollipara 1 Laura Dinneen 1,2 Kenny E. Rentas 1 Megan R. Saettele 1 Suchit. Patel 1 Douglas C. Rivard 1,2 Lisa H. Lowe 1,2 Kollipara R, Dinneen L, Rentas KE, et al. Keywords: classification, hemangiomas, pediatric imaging, terminology, vascular anomalies, vascular malformations DOI: /JR Received December 26, 2012; accepted after revision March 9, Department of Radiology, University of Missouri-Kansas City, Kansas City, MO. 2 Department of Radiology, Children s Mercy Hospitals and Clinics, 2401 Gillham Rd, Kansas City, MO ddress correspondence to L. H. Lowe (lhlowe@cmh.edu). CME/SM This article is available for CME/SM credit. JR 2013; 201: X/13/ merican Roentgen Ray Society Current Classification and Terminology of Pediatric Vascular nomalies OJECTIVE. The purpose of this article is to review new terminology to diagnose, classify, and refer patients with vascular anomalies for additional imaging, intervention, and treatment. CONCLUSION. In recent decades, much has been learned regarding the histopathology, cause, and treatment of vascular anomalies. s information has been gleaned, a new classification system has emerged that divides vascular anomalies into neoplasms and malformations. Its utility is based on accurate initial diagnosis that correlates consistently with clinical presentation, disease course, and treatment. ecause of a lack of knowledge regarding the origin and histopathology of vascular anomalies, the terminology used has often been confusing. nomalies presenting in different age groups with different clinical courses needing different treatments were often given the same or overlapping names by various imagers and pathologists. Recent advances in knowledge surrounding vascular anomalies have allowed development of the International Society for the Study of Vascular nomalies (ISSV) system, which consistently correlates imaging terminology with patient presentation, histologic diagnosis, clinical course, and treatment. This system has become widely used by clinicians and radiologists, especially those in the pediatric community, who are frequently faced with these important lesions. However, persistent use of older terminology continues to cause confusion leading to inaccurate diagnoses and initial mismanagement [1]. The purpose of this article is to describe in simple terms the ISSV classification of vascular anomalies with emphasis on histopathogenesis, key imaging features, initial treatment options, and correlation of past versus current terminology. Modern Classification and Terminology of Vascular nomalies In 1982, Mulliken and Glowacki [2, 3] proposed a binary classification system of vascular anomalies. The system was later revised and adopted by the ISSV. Now widely ac- cepted, this system divides vascular anomalies into two broad biologic categories: vascular or vasoproliferative neoplasms and vascular malformations (Table 1). Vascular, or vasoproliferative, neoplasms have increased endothelial cell turnover. Perhaps more simply put, vascular neoplasms undergo mitosis. In contrast, malformations are not neoplasms and thus do not exhibit mitosis or increased endothelial cell turnover. Instead, vascular malformations are defined as structural abnormalities of the capillary, venous, lymphatic, and arterial system that grow in proportion to the child [2]. Vascular or vasoproliferative tumors are subdivided on the basis of presence or absence of endothelial cell glucose transporter 1 (GLUT1) isoform protein. Infantile hemangiomas and angiosarcomas express GLUT1 protein, whereas congenital hemangiomas and kaposiform hemangioendotheliomas do not [4]. Vascular malformations are subdivided into slow- versus fast- (or low- vs high-) flow malformations. Slow-flow malformations include various combinations of venous, capillary, and lymphatic elements, whereas fastflow malformations must contain an arterial component [3, 5]. With the changes in classification, various terms used in the past have been replaced with more accurate descriptors. For example, the terms lymphangioma and cystic hygroma (the suffix oma erroneously implying neoplasm) have been eliminated in favor of lymphatic malformation, a term that indicates malformed lymphatic vessels. dditionally, the term cavernous hemangioma is 1124 JR:201, November 2013

2 Pediatric Vascular nomalies TLE 1: Summary of Classification and Treatment of Vascular nomalies Vascular tumors Glucose transporter 1 positive Infantile hemangioma nomaly Glucose transporter 1 negative Congenital hemangiomas Rapidly involuting congenital hemangioma Noninvoluting congential hemangioma Kaposiform hemangioendothelioma ngiosarcoma (Usually GLUT1 negative) Vascular malformations Slow flow (venous or lymphatic) Fast flow (arterial abnormalities, arteriovenous fistula, arteriovenous malformation) not part of the ISSV system because it has been shown that this lesion is not a GLUT1- positive neoplasm with mitosis but is actually composed of malformed venous and lymphatic channels and thus is a vascular malformation [6, 7]. Similarly, the incidental lesions seen in the adult vertebra (T2 bright) and liver (hyperechoic), previously known as hemangiomas, are venous malformations, not GLUT1-positive neoplasms. Thus, with the new system, hemangiomas are no longer divided into capillary versus cavernous but instead are divided into infantile or congenital depending on their GLUT1-positive protein expression and age of presentation [6]. Finally, the CNS lesion known as cavernoma is composed of malformed vessels and thus is more accurately described as a venous vascular malformation [8]. Vascular or Vasoproliferative Neoplasms lthough a wide variety of vascular neoplasms exist, this article will focus on the most common and clinically important lesions. Specific vascular neoplasms discussed include infantile hemangiomas, congenital hemangiomas, rapidly involuting congenital hemangiomas, noninvoluting congenital hemangiomas, kaposiform hemangioendotheliomas, and angiosarcomas [9, 10]. The final diagnosis of all vascular anomalies rests with the pathologist, assuming use of the ISSV classification system. To maximize the explanation of the radiologist s role, we have excluded lesions that are very rare and those with such nonspecific imaging features that the diagnosis is nearly always made at biopsy rather than imaging. Some of the vascular tumors not discussed in this manuscript include hemangiopericytoma; tufted angioma; and various forms of hemangioendotheliomas, such as spindle cell, epithelioid, polymorphous, and composite. Treatment Conservative watchful waiting, anti-angiogenic drugs (propranolol, steroids, vincristine), rarely embolization, very rarely liver transplant Same as infantile hemangioma Surgical resection Same as hemangioma Chemotherapy, surgery, or both Sclerotherapy, especially for lesions that are mostly cystic, or surgery, especially for solid lesions and residual masses after sclerotherapy Initial embolization, surgery, or both Histopathogenesis of Vascular Neoplasms: Hypotheses and Observations Vascular tumors arise from angioblasts that give rise to primitive blood vessels, a process known as vasculogenesis [11 13]. Proliferative cellular markers have been identified in proliferating hemangiomas, such as vascular endothelial growth factor (VEGF) [14 16]. Increased mast cells, stem cell differentiation into adipose cells, and apoptosis of vascular lumens have been observed on histopathology of involuting hemangiomas [8, 17, 18]. The placenta and infantile hemangiomas are the only human tissues that express GLUT1 isoform protein [8, 19]. This fact coupled with increased occurrence of hemangiomas in infants who have undergone in utero procedures, along with the similar life cycle of the placenta and hemangiomas, has supported the hypothesis that hemangiomas may actually be due to embolized placental implants [10, 16, 17, 20]. Why then, are congenital hemangiomas GLUT1 negative [4, 12, 21]? This remains difficult to explain but may be related to somatic mutations or environmental differences in the fetal versus infant milieu [22, 23]. Cases of combined congenital and infantile hemangiomas as well as rapidly involuting congenital hemangiomas that later transformed into noninvoluting congenital hemangiomas have been described, implying lesion transformation may be possible [4, 8]. nother interesting recent observation is that some hemangiomas occur in a regional distribution along embryologic prominences and fusion lines [22, 24]. This has caused speculation that they may be of neuroectodermal origin. Some authors have suggested that the common location of hemangiomas on the head and neck is because of the large amount of neuromesenchyme present, which favors migration of hemangioblasts along dermatomes or fusion lines [17]. Infantile Hemangioma Infantile hemangioma, the most common tumor of infancy, presents most often between 2 weeks and 2 months and is most common in premature white girls [25 27]. t initial presentation, infantile hemangiomas may be single or multiple as well as focal, regional, or diffuse in distribution [28]. They present most frequently on the skin, especially the head, neck, trunk, and extremities [17, 27]. The liver is the second most common site of infantile hemangiomas; where they are described as focal, multiple, or diffuse [27]. On histopathology, infantile hemangiomas are GLUT1 positive. Their clinical course consistently progresses from rapid growth (proliferative phase) in the first year of life to gradual regression (involution phase) from ages 1 to 8 years with nearly all lesions resolved by puberty [4, 5, 15, 29]. Many other organ systems besides the skin and liver can be involved; however, it is now JR:201, November

3 Kollipara et al. Fig. 1 1-month-old girl with numerous cutaneous hemangiomas., Longitudinal gray-scale sonogram shows multiple well-circumscribed variably sized hypoechoic hepatic hemangiomas (formerly known as hemangioendotheliomas )., xial color Doppler sonogram reveals extensive hypervascularity. Liver and skin lesions resolved with medical therapy. TLE 2: Key Ultrasound and MRI Features of the Most Common Pediatric Vascular nomalies nomaly Gray-Scale Ultrasound Doppler Ultrasound MRI Vascular tumors Infantile and congenital hemangiomas Vascular malformations slow flow Venous Lymphatic Venolymphatic Vascular malformations fast flow rteriovenous malformation rteriovenous fistulas Well-defined, solid; variable echotexture Multispatial, solid; echogenic; phleboliths Multispatial, multicystic, with or without fluid-fluid levels Combined venolymphatic features Cluster of vessels with no solid intervening mass Intralesional arterial and venous waveforms Intralesional venous waveforms or pattern of no flow No vascular flow except in septa Intralesional arterial and venous waveforms with arterialization of venous waveforms believed that infantile hemangiomas do not arise within osseous structures as was previously thought. On the basis of current histopathology, lesions formerly known as osseous hemangiomas are actually venous malformations [30]. This is shown by the fact that these lesions do not have mitosis and are not GLUT1 positive but instead are formed of malformed venous structures, which is discussed further in the section on vascular malformations later in this article [31]. Color Doppler ultrasound is the imaging modality of choice for infants with possible hemangiomas in any location. It is generally possible to diagnose and characterize lesions sufficiently to determine if additional imaging is required (Fig. 1). Sonography is advantageous because it does not require sedation or radiation exposure. Extensive or complicated hemangiomas require evaluation with MRI to better characterize and determine disease extent [27, 32] (Table 2). CT, although less often used today because of radiation concerns, has the advantage of rapid imaging in urgent situations without requiring sedation. Imaging features seen on cross-sectional imaging modalities include single or multiple well-defined lobulated hypervascular masses with internal arterial and venous flow voids as well as vigorous contrast enhancement [8] (Fig. 2). In infants with extensive hepatic lesions, a decrease in aortic caliber may be observed below the level of the hepatic artery. With involution, infantile hemangiomas become more hetero- T1-weighted intermediate intensity; T2-weighted hyperintense; vigorously enhancing; intralesional flow voids T1-weighted heterogeneous, intermediate intensity; T2-weighted hyperintense, enhancing solid areas T1-weighted intermediate intensity; T2-weighted hyperintense; nonenhancing except septa, with or without fluid levels geneous due to gradual lesion apoptosis and replacement with fatty tissue. Most infantile hemangiomas are easily diagnosed clinically. However, in some infants, diffuse hepatic hemangiomas identified on cross-sectional imaging may be difficult to distinguish from metastatic neuroblastoma. In the past, multiphase CT or MRI with contrast administration was performed to search for centripetal enhancement. The pattern of enhancement was used to suggest a diagnosis of hepatic hemangioma rather than neuroblastoma. However, the enhancement pattern of infantile hemangiomas is highly unreliable and multiphase CT should be avoided because of high radiation exposure. ecause CT and MRI are unlikely to enable a T1-weighted and T2-weighted sequences show serpiginous flow voids without intervening solid tissue 1126 JR:201, November 2013

4 Pediatric Vascular nomalies Fig. 2 4-month-old girl with left facial mass due to infantile hemangioma., xial fat-suppressed T2-weighted MR image shows well-defined hyperintense parotid mass with multiple internal flow voids (arrow)., xial T1-weighted unenhanced fat-suppressed MR image obtained at 4-year follow-up shows poorly defined residual mass with occasional internal flow voids and sparse enhancement (arrows). specific diagnosis, a more sensible initial approach includes a search for a primary neuroblastoma with abdominal sonography and collection of urine catecholamines before CT or MRI [27, 32]. Treatment of infantile hemangiomas depends on the location and number of lesions as well as associated symptoms. lthough most require only watchful waiting, a variety of complications may occur including ulceration, Fig. 3 Prenatal scalp mass caused by rapidly involuting congenital hemangioma, which was seen on fetal sonography in 1-day-old girl. and, xial color Doppler ultrasound images obtained when patient was 3 days old show vascular mass with arterial () and venous () waveforms (arrows). C, xial T2-weighted MR image shows well-defined, T2-hyperintense right occipital scalp mass with central heterogeneity. Without therapy, mass decreased in size approximately 50% by 10 days and almost completely regressed by 22 months. thrombocytopenia, hypothyroidism, heart failure, respiratory compromise, and rarely hemorrhage [33 36]. Laser therapy is available for skin ulceration, the most frequent complication. Thrombocytopenia, hypothyroidism, and heart failure are most common with numerous hepatic hemangiomas. For hemangiomas with some of these dangerous symptoms, treatment begins with antiangiogenic drugs (propranolol, steroids, and less often vincristine) followed by gradually more aggressive treatments, such as embolization and rarely surgery or liver transplantation as a final option [5, 37 39]. Vascular anomaly treatments are summarized in Table 1. Congenital Hemangioma Congenital hemangiomas can be distinguished from infantile hemangiomas on a histopathologic and clinical basis. Whereas infantile C JR:201, November

5 Kollipara et al. hemangiomas are GLUT1 positive, congenital hemangiomas are GLUT1 negative. Furthermore, infantile hemangiomas typically present 2 weeks to 2 months after birth, but congenital hemangiomas are already present at birth because they begin their proliferative phase in utero [27, 40]. Thus, congenital hemangiomas are occasionally found on prenatal imaging [40 42]. For the clinician and radiologist to distinguish between infantile and congenital hemangiomas, the timing of lesion presentation or GLUT1 expression must be known. Two types of congenital hemangiomas are included in the ISSV classification system: rapidly involuting congenital hemangiomas [9] and noninvoluting congenital hemangiomas [4, 10]. y definition, rapidly involuting congenital hemangiomas are present at birth, involute, and regress by age 1 2 years, similar to infantile hemangiomas [4]. Noninvoluting congenital Fig. 4 1-day-old girl with blanching nonpulsatile right chest wall mass and Kasabach-Merritt syndrome (consumptive coagulopathy and thrombocytopenia) due to kaposiform hemangioendothelioma., Frontal chest radiograph reveals soft-tissue swelling along right chest wall. and C, Color Doppler ultrasound images show heterogeneous echogenic mass with arterial () and venous (C) waveforms (arrows). D, Coronal T1-weighted MR image confirms ill-defined heterogeneous chest wall mass with internal flow voids and central hyperintense hemorrhage (arrows). Treatment with vincristine and prednisone lead to total response by 19 months. hemangiomas are also present at birth but do not regress and may steadily grow [4]. Observation of clinical course is typically sufficient to make a diagnosis, and biopsy is rarely needed. Imaging findings for rapidly involuting congenital hemangiomas and noninvoluting congenital hemangiomas are similar to infantile hemangiomas [8]. study of congenital hemangioma found that rapidly involuting congenital hematoma imaging features include, in order of frequency, heterogeneity (62.5%), visible vessels (62.5%), and calcifications (37.5%) [43] (Fig. 3). lthough typically no longer performed as part of the diagnostic workup, angiography of rapidly involuting congenital hemangiomas shows well-defined intensely staining lobular lesions that are surrounded by enlarged systemic arteries [38]. Similar to rapidly involuting congenital hemangiomas, the most common imaging feature in noninvoluting congenital hemangiomas is also heterogeneity (72%) followed by visible vessels (72%) and calcifications (17%) [43]. ecause rapidly involuting congenital hemangiomas regress spontaneously, their treatment is the same as that for infantile hemangiomas [44, 45]. However, surgery is the treatment of choice for noninvoluting congenital hemangiomas because of their lack of regression [46]. Kaposiform Hemangioendothelioma Kaposiform hemangioendothelioma is a rare GLUT1-negative vasoproliferative or vascular tumor that presents at or shortly after birth. Histologically, it is formed of infiltrative nodules composed of vascular and lymphatic vessels. Most commonly, it arises in the trunk, extremities, head, neck, and retroperitoneum with extension into regional lymph nodes and adjacent soft tissues in many cases. Distant metastases C D 1128 JR:201, November 2013

6 Pediatric Vascular nomalies are uncommon [47]. Kaposiform hemangioendothelioma can present with Kasabach-Merritt syndrome. In this syndrome, platelet sequestration and thrombocytopenia lead to consumptive coagulopathy [48]. Kasabach-Merritt syndrome has a poor prognosis, with a 30% mortality rate [36]. On imaging, kaposiform hemangioendothelioma is classically larger than other vasoproliferative neoplasms, ill-defined, and infiltrative (Fig. 4). It often has impressive flow voids because of its large size and numerous feeding and draining vessels [27]. In the absence of Kasabach-Merritt syndrome, treatment includes wide local excision, embolization, or supportive care, depending on the clinical findings [49, 50]. However, the large size and infiltrative nature of kaposiform hemangioendothelioma make it difficult to treat. ngiosarcoma ngiosarcoma is a rare highly aggressive vascular tumor that is typically GLUT1 negative, with a very poor prognosis. y 2008, 38 cases had been reported, eight in association with hemangiomas [51]. ngiosarcomas tend to be more common in girls, located in the liver, and have an average age of presentation of 3.7 years [52]. On imaging, angiosarcomas are heterogeneous lesions with a variable appearance (Fig. 5). Typically, lesions reveal vigorous enhancement with areas of contrast pooling [8]. Multiple synchronous or metastatic lesions in the liver may be present [51]. The prognosis of angiosarcoma is very poor regardless of treatment. Vascular Malformations esides vascular, or vasoproliferative, tumors the second major category of vascular Fig. 5 2-year-old girl with abdominal pain caused by hepatic angiosarcoma. xial T2- weighted image reveals large well-defined T2-hyperintense mass in right lobe of liver. djacent synchronous or metastatic second mass is also present (arrow). anomalies in the ISSV classification system is vascular malformations [3]. Vascular malformations are subdivided into two major groups, low- or slow-flow and high- or fastflow. Low-flow malformations involve a combination of capillary, venous, and lymphatic elements. High-flow malformations always have an arterial component along with variable combinations of slow-flow elements [53]. Capillary portions of vascular malformations involve the superficial layers of the skin and are obvious and easily evaluated on physical examination. However, the capillary portions of malformations are not easily seen on imaging and thus will not be discussed further in this article [2]. Composed of congenitally malformed vessels, both low- and high-flow lesions tend to grow with the child and can present at any age [54]. Sudden presentations due to rapid enlargement may be secondary to superimposed infection or lesion hemorrhage [8]. Low- or Slow-Flow Vascular Malformations Low-flow malformations are congenital deformities of venous or lymphatic vessels or both [9]. They commonly present before the age of 2 years [27]. The most common site for low-flow malformations is the neck and face followed by the limbs, trunk, internal viscera, bones, and skeletal muscle [31, 55]. Notably, several GLUT1 negative venous malformations presenting in adults are previously called hemangiomas [30]. These adult lesions include lesions have been known as vertebral hemangiomas, hepatic hemangiomas, orbital cavernous hemangiomas, and brain or spinal cavernomas (Fig. 6). ll of the aforementioned masses are histopathologically composed of malformed vessels. They are GLUT1 negative and do not undergo mitosis and thus are vascular malformations [30, 31]. Color Doppler ultrasound and MRI are the most common imaging modalities used to visualize low-flow vascular malformations. Key imaging characteristics include partially solid multicystic multispatial masses with flu- Fig year-old boy with leg weakness caused by venous, or cavernous, malformation of spinal cord (formerly known as cavernoma ). and, Sagittal () and axial () T2-weighted MR images show hyperintense cord edema proximal to well-defined mass with hypointense hemosiderin rim (arrows, ). Lesion did not enhance after contrast administration (not shown). Symptoms improved with conservative therapy. JR:201, November

7 Kollipara et al. id-fluid levels and phleboliths [8]. Phleboliths, which can be seen on conventional radiographs when calcified, are more frequently seen on MRI (Fig. 7). Enhancement of the solid portion of the lesion may also be seen. Table 2 contains a summary of ultrasound and MRI features. The management of slow-flow venous malformations is determined by severity and lesion location. Small masses in benign locations may be managed expectantly. However, treatment is indicated if slow-flow venous malformations are painful, if they interfere with physiologic function by virtue of their location, or if their presence may lead to morbidity. Sclerotherapy is the initial therapy for slow-flow malformations and is especially useful for mostly cystic masses. Surgical excision is helpful for solid or incompletely sclerosed lesions [56, 57]. High-Flow Vascular Malformations High-flow vascular malformations are divided into arteriovenous malformations (VMs) and arteriovenous fistulas (VFs). VMs are congenital lesions that can be single, multiple, or part of a genetic disorder, such as hereditary hemorrhagic telangiectasia syndrome. They occur most often in the cranium, bone, muscle, and subcutaneous fat. On the other hand, VFs are acquired and most frequently occur in the brain [5]. Histologic specimens of both VFs and VMs reveal dysplastic arteries that drain into arterialized veins. VMs contain a nidus between the arterial and venous portions of the malformation that bypasses the normal capillary system, whereas VFs have more of a direct connection between the arterial and venous components, without a nidus [58]. ll cross-sectional imaging studies have the ability to show the key features of high flow vascular malformations, including a masslike cluster of arterial and venous structures with little to no intervening solid tissue. The vascular nature of the lesion can be seen on color Doppler ultrasound with spectral tracing, contrast-enhanced CT, or MRI (Fig. 8). s with hemangiomas and slow-flow malformations, ultrasound is the initial study of choice. diagnosis can generally be made that can guide further imaging and referral. MRI is helpful to determine the extent of malformation, and CT can be used in urgent situations or in lesions with osseous involvement [5]. lthough CT has the risk of ionizing radiation exposure, MRI carries the risk of sedation. Thus, CT can be useful to adequately evaluate lesions in young children who may be able to cooperate for a short CT examination but not for a more lengthy MRI study. Imaging characteristics are summarized in Table 2. Treatment of high-flow vascular malformations usually begins with diagnostic conventional catheter angiography to assess vessel characteristics and pathways. This is followed by embolization, the treatment of choice for high-flow vascular malformations. Surgery or a combination of therapies may be necessary in some cases [5, 27]. Regional and Diffuse Syndromes Vascular anomalies may occur alone or as part of a regional or diffuse syndrome. Familiarity with specific imaging findings is useful for accurate diagnosis and treatment. lthough the treatment of vascular anomalies in these syndromes may be the same as that which has been described and is summarized in Table 1, many children have combined malformations that require a combination of therapies [59]. Regional syndromes with associated neoplasms, such as PHCES (posterior fossa malformations, facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarctation, eye anomalies, and sternal clefting or supraum- C Fig year-old girl with pain and swelling of entire right arm due to venolymphatic malformation., Radiograph shows forearm mass with multiple discrete rounded soft-tissue phleboliths and associated adjacent ulnar remodeling. and C, xial () and sagittal (C) T2-weighted fat-suppressed MR images reveal multispatial, mixed solid and multicystic lesion with fluid-fluid levels (curved arrow, ), phleboliths (arrow, ), and intraosseous extension (arrowhead, C) JR:201, November 2013

8 Pediatric Vascular nomalies bilical raphe) and LUMR (lower body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies), present with hemangiomas combined with congenital anomalies in facial and lumbopelvic dermatomal distributions [8] (Table 3 and Fig. 9). Described in 1978 and 2010, respectively, PHCES and LUMR syndromes [60, 61] support the recent observation that some hemangiomas occur in nonrandom regional distributions along embryologic fusion or dermatomal lines [22, 24]. In children with facial infantile hemangiomas, PHCES syndrome is more likely present if the hemangioma is segmental or larger than 5 cm [62]. Treatment and prognosis depend on the type and extent of anomalies present. variety of regional syndromes associated with low- or fast-flow vascular malformations have been described (Table 4). Sturge- Weber syndrome, the most common of these, Fig year-old girl with warm pulsatile leg mass due to arteriovenous malformation. and, Gray-scale () and color Doppler () ultrasound images reveal hypervascular cluster of tubular structures with arterial and venous wave forms. Note lack of intervening solid tissue. C, Dynamic contrast-enhanced MR angiogram shows intensely enhancing mass mostly fed by profunda femoris (arrow) and drained by saphenous vein (arrowhead). is thought to result from nonhereditary defective regression and maturation of the primitive venous plexus [59]. It presents at birth with a facial capillary malformation (formerly port-wine stain), and seizures occur in 80% of children by 1 year [63]. Mental retardation and glaucoma occur in 50% and 30% of children, respectively [63, 64]. Ipsilateral (70%) pial capillary malformations occur in the parietal; occipital; and, least often, frontal lobes of the brain [65]. Choroidal malformations of C the globe are also common. The classic imaging finding of Sturge-Weber syndrome is gyriform calcification, the tram track sign [66]. This finding is rarely present in children under 2 years old. Thus, contrast-enhanced MRI is essential to diagnose Sturge-Weber syndrome. MRI shows pial and choroidal enhancement, choroid plexus enlargement, and atrophy (Fig. 10). Sturge-Weber syndrome is progressive with no cure [67]. Klippel-Trenaunay syndrome is the second most common regional syndrome with lowflow vascular malformations. It is thought to be caused by an anomaly of the ischial venous system leading to persistent malformed venous channels. Klippel-Trenaunay syndrome presents with a regional capillary malformation, congenital varicose veins, and overgrowth [68]. Imaging also shows delayed contrast enhancement. Complications include venous thrombosis, pulmonary embolism, sepsis, infection, hematuria, and coagulopathy [69, 70]. Parkes-Weber syndrome, although rare, is the most common regional syndrome with high-flow vascular malformations. It may be confused with Klippel-Trenaunay syndrome because of overlapping clinical manifestations, such as limb overgrowth. However, Parkes-Weber syndrome has periarticular VMs, warmth of the involved skin, lymphedema, and rarely high-output cardiac failure [71]. Periarticular VF stains seen on catheter, CT, or MR angiography help distinguish Parkes-Weber syndrome from Klippel-Trenaunay syndrome [72]. variety of rare diffuse syndromes with low-flow malformations have been described (Table 4). lue rubber bleb nevus, or ean, syndrome, is reported in 200 patients and presents with multiple 0.1- to 0.5-cm blueblack rubbery skin nevi (venous malformations) [73 75]. Imaging findings are highly suggestive, including multiple variable-sized polypoid masses on contrast enema or CT with scattered phleboliths [76]. Proteus syndrome, a rare disorder of uncertain cause, is named after the Greek god TLE 3: Regional Syndromes ssociated With Vascular Neoplasms PHCES Posterior fossa abnormalities Hemangioma (cranial nerve V distribution) rterial anomalies (especially intracranially) Cardiac anomalies, coarctation Eye anomalies Sternal defects LUMR Lower body hemangioma Urogenital anomalies Myelopathy ony deformities norectal and arterial anomalies Renal anomalies JR:201, November

9 Kollipara et al. Fig. 9 4-month-old girl with left V1 (ophthalmic) distribution hemangioma associated with posterior fossa malformations, facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarctation, eye anomalies, and sternal clefting or supraumbilical raphe (PHCES) syndrome., Sagittal T1-weighted MR image shows large posterior fossa cyst with hypoplastic cerebellum., xial fat-suppressed contrast-enhanced T1-weighted image reveals well-defined vigorously enhancing mass with internal flow voids in left superior orbit (arrow). C, xial image from 3D time-of-flight MR angiography shows distended tortuous vessels of left Circle of Willis (arrow). TLE 4: Description of Regional and Diffuse Syndromes ssociated With Vascular Malformations Syndrome Regional syndromes with slow-flow vascular malformations Sturge-Weber Klippel-Trenaunay Regional syndromes with fast-flow vascular malformations Parkes-Weber Diffuse syndromes with slow-flow vascular malformations lue rubber bleb nevus (ean) Proteus Gorham-Stout Maffucci Epidermal nevus (Solomon) annayan-riley-ruvalcaba Diffuse syndromes with fast-flow vascular malformations Hereditary hemorrhagic telangiectasia Wyburn-Mason Cobb Proteus who could change form. This syndrome was previously thought to be a phosphatase and tensin homolog suppressor gene (PTEN) hamartomatous syndrome; however, recent research suggests it is due to a mutation of KT1 kinase [77, 78]. The presentation and imaging features of Proteus syndrome are highly variable. However, the onset of puberty is associated with rapid progression of symptoms [79]. Early diagnosis is useful to direct therapy and attempt to hinder pubertal exacerbations [80]. Gorham-Stout syndrome, also a rare disorder of unknown cause, has been reported in fewer than 200 patients [81]. It presents with serous or chylous pleural effusions and regional pain. On imaging, unexplained osteolysis, soft-tissue swelling, and chylous effusions should prompt Malformation Facial and intracranial capillary malformation, venous malformation, or VM Limb, trunk capillary, or venous-lymphatic malformation and overgrowth Capillary VM with overgrowth; lymphatic malformation Multiple venous malformations of the skin, musculoskeletal system, and gastrointestinal tract Capillary or venous malformations, hamartomas, asymmetric limb or digit overgrowth in various body parts, lipoma, pigmented nevi Spontaneous osteolysis and lymphatic malformations; intracranial Enchondromatosis, multiple venous-lymphatic malformations VM; epidermal nevi; and varied abnormalities of eyes, skin, nervous, skeletal, cardiac, and genitourinary systems Skin, intracranial malformations, macrocephaly, ectoderm dysplasia, fatty masses, gastrointestinal hamartomas, PTEN mutation Skin, mucous membrane, and gastrointestinal telangiectasias; VM of lungs, liver, brain, and spinal cord VM or VF of brain or retina with same-segment facial malformation VM or VF of spinal cord with same-segment skin vascular malformation Note VM = arteriovenous malformation, PTEN = phosphatase and tensin homolog suppressor gene, VF = arteriovenous fistula. consideration of Gorham-Stout syndrome. It has no cure, although some reports indicate that interferon and steroids may be beneficial [81]. Table 4 summarizes additional diffuse syndromes with vascular malformations, including Maffucci, epidermal nevus, and annayan-riley-ruvalcaba syndromes. Hereditary hemorrhagic telangiectasia, or Osler-Weber-Rendu syndrome, is the most C 1132 JR:201, November 2013

10 Pediatric Vascular nomalies Fig month-old boy with left facial capillary malformation (so-called port-wine stain) in first and second divisions of cranial nerve five secondary to Sturge-Weber syndrome. xial T1-weighted contrast-enhanced MR image shows parietooccipital enhancement (arrow) and enlarged, enhancing left choroid plexus (arrowhead). common diffuse syndrome with high-flow malformations. It is an autosomal dominant disorder caused by abnormal growth factor (TGF)-β which controls mesenchymal and soft-tissue cell differentiation, proliferation, and cell death [59, 82, 83]. Three of the following criteria are required for diagnosis: recurrent epistaxis; a first-degree relative with the syndrome; multiple vascular malformations of the oral cavity, digits, nose, or lips; or VMs or VFs of the lungs, brain, liver, or osseous marrow. VMs are visualized with imaging [83]. Other rare diffuse syndromes with fast-flow malformations include cerebral arteriovenous metameric syndromes, such as Wyburn-Mason and Cobb syndromes. Cerebral arteriovenous metameric syndromes are believed to involve failure of a body segment to form, which simultaneously leads to absent nerves, skin, and blood vessels in the region [84, 85]. Wyburn- Mason syndrome involves the brain and Cobb syndrome, the spinal cord. oth show VMs, VFs, and cutaneous vascular malformations in the affected body area [84, 85]. Treatment depends on symptoms but often requires multispecialty long-term planning [59]. Conclusion In recent decades, much has been learned about the origin, histopathology, and treatment of vascular anomalies. Modern classification using the ISSV system divides anomalies into two general categories: vascular neoplasms and vascular malformations. ecause this system allows more consistent and accurate diagnoses as well as predictable correlation of lesions to their clinical course and treatment protocols, it has been widely embraced by clinicians and radiologists who most often deal with vascular anomalies. References 1. Hassanein H, Mulliken J, Fishman SJ, Greene K. Evaluation of terminology for vascular anomalies in current literature. Plast Reconstr Surg 2011; 127: Mulliken J, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982; 69: Mulliken J, Glowacki J. Classification of pediatric vascular lesions. Plast Reconstr Surg 1982; 70: Mulliken J, Enjolras O. Congenital hemangiomas and infantile hemangioma: missing links. J m cad Dermatol 2004; 50: Legiehn GM, Heran MK. Classification, diagnosis, and interventional radiologic management of vascular malformations. Orthop Clin North m 2006; 37: [vii-viii] 6. Hand JL, Frieden IJ. Vascular birthmarks of infancy: resolving nosologic confusion. m J Med Genet 2002; 108: Frieden IJ, Haggstrom N, Drolet, et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, pril 7 9, 2005, ethesda, Maryland, US. Pediatr Dermatol 2005; 22: Lowe LH, Marchant TC, Rivard DC, Scherbel J. Vascular malformations: classification and terminology the radiologist needs to know. Semin Roentgenol 2012; 47: Eifert S, Villavicencio JL, Kao TC, Taute M, Rich NM. Prevalence of deep venous anomalies in congenital vascular malformations of venous predominance. J Vasc Surg 2000; 31: North PE, Waner M, Mizeracki, et al. unique microvascular phenotype shared by juvenile hemangiomas and human placenta. rch Dermatol 2001; 137: Cohen MM Jr. Vasculogenesis, angiogenesis, hemangiomas, and vascular malformations. m J Med Genet 2002; 108: oye E, Yu Y, Paranya G, Mulliken J, Olsen R, ischoff J. Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 2001; 107: Nguyen V, Furhapter C, Romani N, Weber F, Sepp N. Infantile hemangioma is a proliferation of beta 4-negative endothelial cells adjacent to HL- DR-positive cells with dendritic cell morphology. Hum Pathol 2004; 35: Zhang L, Lin X, Wang W, et al. Circulating level of vascular endothelial growth factor in differentiating hemangioma from vascular malformation patients. Plast Reconstr Surg 2005; 116: Takahashi K, Mulliken J, Kozakewich HP, Rogers R, Folkman J, Ezekowitz R. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994; 93: Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl cad Sci US 2002; 99: Lo K, Mihm M, Fay. Current theories on the pathogenesis of infantile hemangioma. Semin Ophthalmol 2009; 24: Yu Y, Fuhr J, oye E, et al. Mesenchymal stem cells and adipogenesis in hemangioma involution. Stem Cells 2006; 24: North PE, Waner M, Mizeracki, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000; 31: Friedlander SF, Ritter MR, Friedlander M. Recent progress in our understanding of the pathogenesis of infantile hemangiomas. Lymphat Res iol 2005; 3: Walter JW, North PE, Waner M, et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 2002; 33: Waner M, North PE, Scherer K, Frieden IJ, Waner, Mihm MC Jr. The nonrandom distribution of facial hemangiomas. rch Dermatol 2003; 139: Chang EI, Thangarajah H, Hamou C, Gurtner GC. Hypoxia, hormones, and endothelial progenitor cells in hemangioma. Lymphat Res iol 2007; 5: Haggstrom N, Lammer EJ, Schneider R, Marcucio R, Frieden IJ. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 2006; 117: ruckner L, Frieden IJ. Hemangiomas of infancy. J m cad Dermatol 2003; 48: ; quiz, Holmdahl K. Cutaneous hemangiomas in premature and mature infants. cta Paediatr 1955; 44: Slovis T. Caffey s pediatric diagnostic imaging, 11th ed. Philadelphia, P: Mosby Elsevier, Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic JR:201, November

11 Kollipara et al. subtypes, and their relationship to race, ethnicity, and sex. rch Dermatol 2002; 138: Donnelly LF, dams DM, isset GS 3rd. Vascular malformations and hemangiomas: a practical approach in a multidisciplinary clinic. JR 2000; 174: Greene K, Rogers GF, Mulliken J. Intraosseous hemangiomas are malformations and not tumors. (letter) Plast Reconstr Surg 2007; 119: ; author reply, ruder E, Perez-tayde R, Jundt G, et al. Vascular lesions of bone in children, adolescents, and young adults: a clinicopathologic reappraisal and application of the ISSV classification. Virchows rch 2009; 454: Rivard DC, Lowe LH. Radiological reasoning: multiple hepatic masses in an infant. JR 2008; 190(6 suppl):s46 S Kalpatthi R, Germak J, Mizelle K, Yeager N. Thyroid abnormalities in infantile hepatic hemangioendothelioma. Pediatr lood Cancer 2007; 49: Kassarjian, Zurakowski D, Dubois J, Paltiel HJ, Fishman SJ, urrows PE. Infantile hepatic hemangiomas: clinical and imaging findings and their correlation with therapy. JR 2004; 182: Ruppe MD, Huang S, Jan de eur SM. Consumptive hypothyroidism caused by paraneoplastic production of type 3 iodothyronine deiodinase. Thyroid 2005; 15: Sarkar M, Mulliken J, Kozakewich HP, Robertson RL, urrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997; 100: Denoyelle F, Leboulanger N, Enjolras O, Harris R, Roger G, Garabedian EN. Role of propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol 2009; 73: Konez O, urrows PE, Mulliken J, Fishman SJ, Kozakewich HP. ngiographic features of rapidly involuting congenital hemangioma (RICH). Pediatr Radiol 2003; 33: Léauté-Labrezè C, Dumas de la Roque E, Hubiche T, oralevi F, Thambo J, Taieb. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358: Krol, Macrthur CJ. Congenital hemangiomas: rapidly involuting and noninvoluting congenital hemangiomas. rch Facial Plast Surg 2005; 7: Gorincour G, Kokta V, Rypens F, Garel L, Powell J, Dubois J. Imaging characteristics of two subtypes of congenital hemangiomas: rapidly involuting congenital hemangiomas and non-involuting congenital hemangiomas. Pediatr Radiol 2005; 35: Marler JJ, Fishman SJ, Upton J, et al. Prenatal diagnosis of vascular anomalies. J Pediatr Surg 2002; 37: Rogers M, Lam, Fischer G. Sonographic findings in a series of rapidly involuting congenital hemangiomas (RICH). Pediatr Dermatol 2002; 19: erenguer, Mulliken J, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Dev Pathol 2003; 6: oon LM, Enjolras O, Mulliken J. Congenital hemangioma: evidence of accelerated involution. J Pediatr 1996; 128: Lopez-Gutierrez JC, Diaz M, Ros Z. Giant rapidly involuting congenital hemangioma of the face: 15-year follow-up. rch Facial Plast Surg 2005; 7: Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Folpe L, Weiss SW. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. m J Surg Pathol 2004; 28: Enjolras O. Color atlas of vascular tumors and vascular malformations. West Nyack, NY: Cambridge University Press, Vin-Christian K, McCalmont TH, Frieden IJ. Kaposiform hemangioendothelioma: an aggressive, locally invasive vascular tumor that can mimic hemangioma of infancy. rch Dermatol 1997; 133: Zukerberg LR, Nickoloff J, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood: an aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. m J Surg Pathol 1993; 17: Nord KM, Kandel J, Lefkowitch JH, et al. Multiple cutaneous infantile hemangiomas associated with hepatic angiosarcoma: case report and review of the literature. Pediatrics 2006; 118:e907 e Deyrup T, Miettinen M, North PE, et al. Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. m J Surg Pathol 2011; 35: Legiehn GM, Heran MK. Venous malformations: classification, development, diagnosis, and interventional radiologic management. Radiol Clin North m 2008; 46: [vi] 54. urrows PE, Mulliken J, Fellows KE, Strand RD. Childhood hemangiomas and vascular malformations: angiographic differentiation. JR 1983; 141: Hein KD, Mulliken J, Kozakewich HP, Upton J, urrows PE. Venous malformations of skeletal muscle. Plast Reconstr Surg 2002; 110: Pappas DC Jr, Persky MS, erenstein. Evaluation and treatment of head and neck venous vascular malformations. Ear Nose Throat J 1998; 77: , Pascarella L, ergan JJ, Yamada C, Mekenas L. Venous angiomata: treatment with sclerosant foam. nn Vasc Surg 2005; 19: Stapf C, Mohr JP, Pile-Spellman J, Solomon R, Sacco RL, Connolly ES Jr. Epidemiology and natural history of arteriovenous malformations. Neurosurg Focus 2001; 11:e1 59. Nozaki T, Nosaka S, Miyazaki O, et al. Syndromes associated with vascular tumors and malformations: a pictorial review. RadioGraphics 2013; 33: Iacobas I, urrows PE, Frieden IJ, et al. LUM- R: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. J Pediatr 2010; 157: Pascual-Castroviejo I. Vascular and nonvascular intracranial malformation associated with external capillary hemangiomas. Neuroradiology 1978; 16: Oza VS, Wang E, erenstein, et al. PHCES association: a neuroradiologic review of 17 patients. JNR 2008; 29: Comi M. Presentation, diagnosis, pathophysiology, and treatment of the neurological features of Sturge-Weber syndrome. Neurologist 2011; 17: Thomas-Sohl K, Vaslow DF, Maria L. Sturge- Weber syndrome: a review. Pediatr Neurol 2004; 30: enedikt R, rown DC, Walker R, Ghaed VN, Mitchell M, Geyer C. Sturge-Weber syndrome: cranial MR imaging with Gd-DTP. JNR 1993; 14: Wasenko JJ, Rosenbloom S, Duchesneau PM, Lanzieri CF, Weinstein M. The Sturge-Weber syndrome: comparison of MR and CT characteristics. JNR 1990; 11: Welty LD. Sturge-Weber syndrome: a case study. Neonatal Netw 2006; 25: Oduber CE, van der Horst CM, Hennekam RC. Klippel-Trenaunay syndrome: diagnostic criteria and hypothesis on etiology. nn Plast Surg 2008; 60: Huang WJ, Creath CJ. Klippel-Trenaunay-Weber syndrome: literature review and case report. Pediatr Dent 1994; 16: Jacob G, Driscoll DJ, Shaughnessy WJ, Stanson W, Clay RP, Gloviczki P. Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 1998; 73: Roebuck DJ. Klippel-Trenaunay and Parkes-Weber syndromes. JR 1997; 169: Ziyeh S, Spreer J, Rossler J, et al. Parkes Weber or Klippel-Trenaunay syndrome? Non-invasive diagnosis with MR projection angiography. Eur Radiol 2004; 14: Fernandes C, Silva, Coelho, Campos M, Pon JR:201, November 2013

12 Pediatric Vascular nomalies tes F. lue rubber bleb naevus: case report and literature review. Eur J Gastroenterol Hepatol 1999; 11: Nahm WK, Moise S, Eichenfield LF, et al. Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation. J m cad Dermatol 2004; 50(5 supp):s101 S Wong CH, Tan YM, Chow WC, Tan PH, Wong WK. lue rubber bleb nevus syndrome: a clinical spectrum with correlation between cutaneous and gastrointestinal manifestations. J Gastroenterol Hepatol 2003; 18: Kassarjian, Fishman SJ, Fox VL, urrows PE. Imaging characteristics of blue rubber bleb nevus syndrome. JR 2003; 181: Lindhurst MJ, Sapp JC, Teer JK, et al. mosaic activating mutation in KT1 associated with the Proteus syndrome. N Engl J Med 2011; 365: Tan WH, aris HN, urrows PE, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet 2007; 44: iesecker LG, Happle R, Mulliken J, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. m J Med Genet 1999; 84: Yamamoto, Kikuchi Y, Yuzurihara M, Kubota M, O Uchi T. case of Proteus syndrome with severe spinal canal stenosis, scoliosis, and thoracic deformity associated with tethered cord. Japanese J Radiol 2012; 30: Patel DV. Gorham s disease or massive osteolysis. Clin Med Res 2005; 3: Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet 2010; 128: McDonald J, ayrak-toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med 2011; 13: hattacharya JJ, Luo C, Suh DC, lvarez H, Rodesch G, Lasjaunias P. Wyburn-Mason or onnet-dechaume-lanc as cerebrofacial arteriovenous metameric syndromes (CMS): a new concept and a new classification. Interv Neuroradiol 2001; 7: Clark MT, rooks EL, Chong W, Pappas C, Fahey M. Cobb syndrome: a case report and systematic review of the literature. Pediatr Neurol 2008; 39: FOR YOUR INFORMTION This article is available for CME/SM credit. To access the examination for this article, follow the prompts associated with the online version of the article. JR:201, November