Complex vascular anomalies

The classification system for vascular anomalies now used by experts worldwide comprises two distinct disease entities that differ in their biologic and pathologic features: vascular tumors and vascular malformations. Vascular tumors include infantile and congenital hemangiomas, tufted angiomas, and kaposiform hemangioendotheliomas. Infantile hemangiomas, the most common vascular anomaly, generally have a predetermined life cycle (proliferation and subsequent involution). GLUT-1, a glucose transporter, is a marker for these specific lesions during all phases of development. Vascular malformations are classified according to their vascular tissue of origin and include capillary, venous, arteriovenous, lymphatic, and mixed malformations. Complex lymphatic malformations and complex mixed malformations, which may have most vascular components, are the most difficult vascular malformations to successfully treat. These lesions are present at birth and often expand or grow in response to trauma, infection, or hormonal changes. Imaging advancements have enabled more accurate assessments and improved management of vascular anomalies. In addition, many lesions are now being managed with targeted pharmacologic therapy. Propranolol and steroids are used for complex or disfiguring tumors, and new anti-angiogenesis inhibitors such as sirolimus are selectively used to treat lymphatic and venous lymphatic malformations that are poorly responsive to sclerotherapy, embolization, and surgical excision. Multimodal therapies are often essential for complex lesions and require the combined expertise of an interdisciplinary team.     

Lymphatic malformations

Lymphatic malformations are low-flow vascular malformations that arise due to errors in vascular development. Lymphatic malformations are benign and usually noted at birth or in the first few years of life. Lymphatic mass lesions are composed of varying size of cysts; this article focuses on discussion of cystic lymphatic malformations. Lymphatic malformations can occur throughout the body especially in lymphatic rich areas such as the cervical and axillary locations as well as the groin, trunk, retroperitoneum, extremities, abdominal or thoracic cavities. Treatment options vary based upon size of cysts and location. A multimodal and interdisciplinary approach is essential to care for patients with lymphatic malformations. Management options include observation, pharmacotherapy, sclerotherapy, and surgical procedures.     

Lymphatic malformations: Diagnosis and management

Lymphatic malformations are benign vascular lesions that arise from embryological disturbances in the development of the lymphatic system. They encompass a wide spectrum of related abnormalities, including cystic lymphatic lesions, angiokeratoma, lymphatic malformations that occur in bones (Gorham–Stout Syndrome), lymphatic and chylous leak conditions, and lymphedema. This article will focus only on lymphatic malformation mass lesions, whereas other related disease entities will be covered elsewhere in this journal issue. Lymphatic malformations occur frequently in lymphatic-rich areas such as the head and neck region, but they can also be found on any anatomical site in the body. In general, lymphatic malformations are categorized into macrocystic, microcystic, or combined depending on the size of the cysts contained within the lesion. Lymphatic malformations can cause both deformation of the anatomical site involved and functional deficits. The goal of this article is to discuss the etiology, epidemiology, treatment modalities, and comorbidities associated with lymphatic malformations.     

Vascular cutaneous anomalies in children: malformations and hemangiomas

The vast majority of cutaneous vascular anomalies in infants and children are either malformations or hemangiomas. Vascular malformations are subgrouped, based on channel morphology and rheology: slow-flow (capillary, lymphatic, venous, or combined-complex types) and fast-flow malformations (ectasia, aneurysm, fistula, or arteriovenous anomalies). Noninvasive radiologic techniques, especially ultrasonography with Doppler flow studies and magnetic resonance imaging, serve to document the extent and flow characteristics. Management depends on the type of malformation: laser for capillary malformations; surgical excision for lymphatic malformations; compression, sclerotherapy, and resection for venous malformations; and embolization and/or surgical resection for arteriovenous fistulae/malformations. Hemangiomas are the most common tumors of infancy. The life cycle is divided into three phases: proliferating, involuting, and involuted. Most hemangiomas do not require treatment, although drug therapy is indicated for endangering or life-threatening hemangiomas. Corticosteroids (either systemic or local) and alpha-2a interferon are currently the most effective agents. Surgical resection of problematic hemangiomas can be undertaken during infancy, the preschool years, or childhood.     

Vascular anomalies: what a radiologist needs to know

Most haemangiomas and vascular malformations are identified according to clinical criteria. A good knowledge of the classification and clinical characteristics of the vascular anomalies is necessary when managing these patients. However, some cases are challenging either because of an atypical presentation (e.g., soft-tissue mass with normal overlying skin) or because of classification difficulties. Doppler US and MRI are the two main imaging modalities that allow classification of the vascular anomalies and are useful in those clinically uncertain cases to establish the correct diagnosis. This aids the choice of the most appropriate treatment and to inform the parents of the prognosis. High-resolution grey-scale and Doppler US allow excellent visualization of most superficial masses. Doppler US is the easiest way to assess the haemodynamics of a vascular lesion and to clarify a doubtful diagnosis between a haemangioma and vascular malformation. MRI is the best technique for evaluating the extent of the lesions and their relationship to adjacent structures. While newly developed drugs from angiogenesis research labs are awaited, radiologists have an important role in the treatment of haemangiomas and vascular malformations. Intervention remains crucial in cases of alarming haemangiomas and venous malformations (VM), lymphatic malformations (LM) and arteriovenous malformations (AVM). A multidisciplinary team, including paediatricians, haematologists, surgeons and radiologists, must manage the problem cases both in terms of diagnostic work-up and therapeutic options. This paper will briefly discuss the imaging findings and treatment of vascular anomalies.     

Identification of Lymphatic Endothelium in Pediatric Vascular Tumors and Malformations

The distinction between lymphatic and other vascular vessels on microscopic sections is a challenging task. D2-40, a novel antibody, has been reported to be selective for lymphatic endothelium. We studied the specificity and sensitivity of D2-40 in pediatric vascular tumors and malformations. Fourteen lymphatic and 11 vascular lesions were randomly selected and stained with D2-40 and CD31 antibodies. The lymphatic lesions included 6 lymphatic malformations, 5 cystic hygromas (macrocystic lymphatic malformation), 2 lymphovenous malformations, and 1 lymphangioma, and the vascular lesions comprised 3 infantile hemangiomas, 3 Kaposiform hemangioendotheliomas, 2 tufted angiomas, 1 pyogenic granuloma, 1 arteriovenous, and 1 venulocapillary malformations. The staining patterns of the vascular channels were compared. In all lesions D2-40 labeled only the endothelium of thin-walled vascular channels morphologically consistent with lymphatic vessels (25 of 25). No staining of the vascular lesions (0 of 11) or of arteries and veins (0 of 25) was observed. All lymphatic lesions had D2-40–positive vessels; however, the percentage of vessels that stained varied. Five lymphatic lesions showed more than 75% D2-40–positive channels, 5 lesions had approximately 50%, and 4 cases showed fewer than 25% D2-40–positive channels. There was a tendency of more consistent D2-40 staining of small versus large lymphatic channels. CD31 constantly labeled arteries, veins, capillaries, and lymphatics in all lesions and all endothelial cells in the vascular lesions. D2-40 is a very specific antibody for lymphatic endothelium, with variable sensitivity. CD31 more reliably identifies lymphatic endothelium. Currently, D2-40 appears to be a good marker to identify lymphatic vessels in pediatric vascular tumors and malformations.     

Cervicofacial vascular anomalies. II. Vascular malformations

Vascular malformations are the second major category of vascular anomalies. In contrast to vascular tumors, they are present at birth and grow commensurately with the child. Although the molecular mechanisms underlying the formation of these lesions remain unclear, lesions are known to result from abnormal development and morphogenesis. Histologic examination of vascular malformations shows no evidence of cellular proliferation, but rather progressive dilation of abnormal channels. Vascular malformations are designated according to their predominant channel type; they may be capillary, venous, lymphatic, arterial, and combined malformations. Malformations with an arterial component are rheologically fast-flow, whereas capillary, lymphatic, and venous malformations are slow-flow in nature. The morbidity of vascular malformations varies greatly both within and among the clinical subgroups cited above. This article describes the clinical presentation, diagnosis, and management of vascular malformations. The more frequently encountered clinical presentations involving the head and neck are highlighted.     

Vascular malformations: a review of 10 years' management in a university hospital

In order to gain insight into the management of patients with vascular malformations (VM) in the University Hospital Nijmegen in the past 10 years, 151 cases managed by different specialists were reviewed. To avoid the usual confusion in terminology, all recorded diagnoses were reclassified according to the biological classification of Mulliken. The sex distribution was equal; 79% of the malformations were diagnosed at birth or in the 1st year of life. The median time between presentation and consultation was 3 years. Sixty-two lymphatic, 26 venous, 24 capillary, 1 arterial, and 38 combined malformations (8 arteriovenous, 30 others) were found. The head and neck region was most frequently involved, followed by the lower and upper limbs and trunk. The pediatric surgeon was the most frequently consulted specialist. Confusing, mutually incompatible terminology and a wide variety of different diagnostic techniques and treatments had been used by the different specialists. To improve the management of patients with vascular malformations, the use of a uniform classification, an increase in basic investigations, and the development and evaluation of protocols for diagnosis and treatment by multidisciplinary teams are necessary.     

Management of visceral vascular anomalies

Visceral vascular anomalies are common in patients with vascular malformations in other parts of the body and can include lymphatic, venous, and arteriovenous malformations. Depending on the organ or organs involved they may present differently and pose different treatment challenges. Defining the malformation and understanding its extent is paramount in devising management regimens. Medical, interventional, and surgical therapies are often required in combination to treat these complex lesions. There are new and promising advances in the development of therapeutic agents targeting the PI3K/AKT/mTOR pathway. Due to the complex nature of these lesions a coordinated, multi-disciplinary approach is necessary to manage and mitigate symptoms and complications of this diverse group of vascular malformations.     

Lymphatic malformations: percutaneus treatment with bleomycin

Lymphatic malformations are developmental abnormalities of the lymphatic system, which tend to complicate during their evolution. In the last decade, therapy with sclerosing agents has gained popularity over surgery due to its effectiveness, fewer complications, and excellent cosmetic results. We present a series of 24 patients treated with percutaneous bleomycin injection. Results were excellent (volume reduction ≥ 95%, without symptoms) in 12 patients, good (volume reduction between 50% and 95%, without symptoms) in 5 patients, fair (volume reduction <50%, without symptoms) in 4 patients, and poor (no change in volume from baseline and persistence of symptoms) in 3 patients. These results were directly related to the type of lymphatic malformation. The complications found had little clinical relevance. Sclerotherapy with bleomycin is an effective and safe treatment for patients with unicystic or macrocystic lymphatic malformations. It could also be used in patients with microcystic or cavernous lymphatic malformation undergoing surgery to reduce both the malformation size and postoperative lymphorrhea, and in postoperative symptomatic patients whose malformation could not be totally resected.     

Clinical and sonographic features of pediatric soft-tissue vascular anomalies part 2: vascular malformations

Vascular malformations are a heterogeneous group of entities, many of which present in the pediatric age group. Sonography plays a major role in the management of children with these vascular anomalies by providing information that helps in diagnosing them, in assessing lesion extent and complications, and in monitoring response to therapy. The interpretation of sonographic findings requires correlation with clinical findings, some of which can be easily obtained at the time of scanning. This has to be combined with the use of appropriate nomenclature and the most updated classification in order to categorize these patients into the appropriate management pathway. Some vascular malformations are part of combined vascular anomalies or are associated with syndromes that include other disorders, frequently limb overgrowth, and these are now being reclassified based on their underlying genetic mutation. Sonography has limitations in the evaluation of some vascular malformations and in these cases MR imaging might be considered the imaging modality of choice, particularly for lesions that are large, that involve multiple compartments or are associated with other soft-tissue and bone abnormalities. In this article, which is part 2 of a two-part series, the authors review the most relevant clinical and sonographic features of arteriovenous, capillary, venous and lymphatic malformations as well as vascular malformations that are part of more complex conditions or associated with syndromes, including Parkes–Weber syndrome, phosphatase and tensin homologue (PTEN) hamartoma tumor syndromes, Klippel–Trénaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi and skeletal anomalies) syndrome, fibro-adipose vascular anomaly and Proteus syndrome.     

Complex lymphatic anomalies

Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham–Stout disease have been segregated with distinctive bone lesions and peri-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies.     

Urgent and emergent embolization of lesions of the head and neck in children: indications and results

Indications for and results and complications of embolization of lesions of the head and neck were analyzed retrospectively. The procedures were performed since 1980 on an emergent or urgent basis in 30 infants and children by an experienced interventional neuroradiologist in Bicetre, France. Indications for embolization included hemorrhage, occular occlusion, respiratory obstruction, CNS complications or potential complications, interference with nutrition, and functional impairment related to the effect of the lesion on the developing facial skeleton and teeth. The specific lesions included seven hemangiomas (palpebral, subglottic, and nasal) and 20 vascular malformations (maxillofacial, auricular, dural, cerebral [including three vein of Galen malformations] and spinomedullary). Embolization was efficacious in 28 of 30 patients. Hemangiomas (potentially involutive tumors) responded dramatically with arrest of the proliferative phase and shrinking of the mass. Combined hemovascular lymphatic malformations (hemolymphangiomas) of the tongue demonstrated a variable decrease in size. High-flow evolutive arteriovenous malformations involving the teeth and dura were controlled but required multiple embolizations. One infant with a vein of Galen arteriovenous malformation died. Three local complications occurred in two patients. No cerebral ischemic or femoral artery complications occurred.     

Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations

Successful treatment of vascular anomalies has eluded the physician until now, despite various treatments utilised. Bleomycin has been successfully used in intralesional injection treatment of cystic hygromas and haemangiomas, based specifically on a high sclerosing effect on vascular endothelium. In a prospective study of 95 patients, the effectiveness of intralesional bleomycin injection (IBI) treatment in haemangiomas and vascular malformations was evaluated and documented. Complete resolution or significant improvement occurred in 80% of all patients treated. Complete resolution occurred in 49% of haemangiomas, 32% of venous malformations, and 80% of cystic hygromas. Significant improvement occurred in 38% of haemangiomas, 52% of venous malformations, 13% of cystic hygromas and 50% of lymphatic malformations. Of the six patients who presented with a painful lesion, four experienced complete resolution and two had significant improvement to treatment. Local complications encountered were superficial ulceration occurring in 2 patients, and cellulitis in 1 of the 95 patients. Systemic complications were flu-like symptoms in three patients and partial, transient hair loss in two patients. None of the patients presented with haematological toxic effects or signs of pulmonary involvement (fibrosis, hypertension). IBI is an effective treatment in haemangiomas and vascular malformation lesions, obviating the need for invasive primary surgery or systemic treatment regimens in 80% of cases, and allowing for limited need of secondary surgical or adjunctive procedures in cases with a moderate result.     

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in theG6PC gene encoding the phosphatase of the microsomal glucose-6-phosphatase system. GSD Ia is characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and short stature. Other forms of GSD I (GSD I non-a) are characterized by the additional symptom of frequent infections caused by neutropenia and neutrophil dysfunction. GSD I non-a is caused by mutations in a gene encoding glucose-6-phosphatase translocase (G6PT1). We report on the molecular genetic analyses of G6PC and G6PT 1 in 130 GSD Ia patients and 15 GSD I non-a patients, respectively, and provide an overview of the current literature pertaining to the molecular genetics of GSD I. Among the GSD Ia patients, 34 different mutations were identified, two of which have not been described before (A65P; F117C). Seventeen different mutations were detected in the GSD I non-a patients. True common mutations were identified neither in GSD Ia nor in GSD I non-a patients,Conclusion: Glycogen storage disease type Ia and and type I non-a are genetically heterogenous disorders. For the diagnosis of the various forms of glycogen storage disease type I, molecular genetic analyses are reliable and convenient alternatives to the enzyme assays in liver biopsy specimens. Some genotype-phenotype correlations exist, for example, homozygosity for oneG6PC mutation, G188R, seems to be associated with a glycogen storage disease type I non-a phenotype and homozygosity for the 727G>T mutation may be associated with a milder phenotype but an increased risk for hepatocellular carcinoma. Published online: 27 July 2002     

Vascular malformations

Vascular malformations are rare but important skin disorders in children, which often require multidisciplinary care. The goal of this article is to orient pediatricians to the various types of vascular malformations. We discuss the clinical characteristics, diagnostic criteria, and management of capillary, venous, arteriovenous, and lymphatic malformations. Associated findings and syndromes are also discussed briefly.     

Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature

We studied the genotype/phenotype correlation in a cohort of glycogen storage disease type (GSD) 1b patients. A total of 25 GSD1b patients, 13 females and 12 males, age range: 4.3–28.4 years, mean:14.6±6.8 years; median: 15 years, representing the entire case load of Italian GSD1b patients, were enrolled in the study. Molecular analysis of the glucose 6-phosphate translocase (G6PT1) gene was performed in all patients. We analysed the presence of a correlation among both the clinical features associated with GSD1b (neutropenia, frequency of admission to the hospital for severe infections) and the presence of systemic complications (liver adenomas, nephropathy, bone mineral density defect, polycystic ovaries, short stature, inflammatory bowel disease) and the mutations detected in each patient. Nine patients were homozygous or compound heterozygous for mutations causing stop codons. In particular, three patients were homozygous for the same mutation (400X); of these patients, one showed chronic neutropenia with severe and frequent infections and severe inflammatory bowel disease, another patient cyclic neutropenia associated with rare bacterial infections and mild bowel involvement and the last one normal neutrophil count. Two patients were homozygous for the mutation 128X; one of these patients did not show neutropenia, whereas the other one had severe neutropenia needing frequent hospital admission and was under granulocyte-colony stimulating factor treatment. In three patients no mutations were detected. Conclusion:no correlation was found between individual mutations and the presence of neutropenia, bacterial infections and systemic complications. These results suggest that different genes and proteins modulate neutrophil differentiation, maturation and apoptosis and thus the severity and frequency of infections. The absence of detectable mutations in three patients could suggest that a second protein plays a role in microsomal phosphate transport.     

How many forms of glycogen storage disease type I?

 Glucose-6-phosphatase is a multicomponent enzymatic system of the endoplasmic reticulum, which catalyses the terminal steps of gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and inorganic phosphate. Glycogen storage diseases type I (GSD I) are a group of metabolic disorders arising from a defect in a component of this enzymatic system, i.e. the glucose-6-phosphate hydrolase (GSD Ia), the glucose-6-phosphate translocase (GSD Ib) and possibly also the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id). The genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase have both been cloned and assigned to human chromosomes 17q21 and 11q23, respectively. Investigation of patients with GSD I shows that those with GSD Ia are mutated in the glucose-6-phosphate hydrolase gene, whereas those diagnosed as GSD Ib, GSD Ic or GSD Id are mutated in the glucose-6-phosphate translocase gene, and are therefore GSD Ib patients, in agreement with the fact that they all have neutropenia or neutrophil dysfunction. This suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable. Conclusion In practice therefore appears to be only two types of GSD I (Ia and Ib), which can be differentiated by (1) measurement of glucose-6-phosphatase activity in fresh and detergent-treated homogenates and (2) by mutation search in the genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase. Received: 20 July 1999 and in revised form: 1 October 1999 / Accepted: 1 October 1999     

Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure

Abstract:  GSD-I, III, and IV are congenital disorders of glycogen metabolism that are commonly associated with severe liver disease. Liver transplantation has been proposed as a therapy for these disorders. While liver transplantation corrects the primary hepatic enzyme defect, the extrahepatic manifestations of GSD often complicate post-transplantation management. Upon review of the English-language literature, 42 children <19 yr of age were discovered to have undergone liver transplantation for complications associated with GSD (18 patients with GSD-Ia, six with GSD-Ib, one with GSD-III, 17 with GSD-IV). An additional two children followed at our institution have undergone liver transplantation for GSD complications (one with GSD-Ia and one with GSD-III) and are included in this review. The risks and benefits of liver transplantation should be considered prior to performing liver transplantation in these metabolic disorders, particularly in GSD-Ia. As liver pathology is not the major source of morbidity in GSD-Ib and GSD-IIIa, liver transplantation should only be performed when there is high risk for HCC or evidence of substantial cirrhosis or liver dysfunction. Liver transplantation remains the best option for treatment of GSD-IV.     

The use of rapamycin to treat vascular tumours and malformations: A single-centre experience

ObjectivesTo assess the safety and efficacy of rapamycin in treating children with vascular tumours and malformations.Study designWe performed a retrospective review at a large tertiary care paediatric centre to assess the efficacy and safety of using rapamycin to treat vascular tumours and malformations. Response to therapy was defined by patient-reported symptom improvement, radiological reduction in size of lesions, and/or improvement of laboratory parameters.ResultsForty-two patients (7 with vascular tumours and 35 with vascular malformations) have been treated with rapamycin. Despite 33 of 42 patients being diagnosed in the first year of life, the median age of initiating rapamycin was 11 years. Of the 38 children treated for a minimum of 4 months, 29 (76%) exhibited a clinical response. Twenty-one patients had follow-up imaging studies and of these, 16 (76%) had radiographic decrease in lesion size. Median time to demonstration of response was 49 days. All five children with vascular tumours and all three children with vascular malformations under the age of 4 years showed a clinical response. Response rate was lower for children ≥ 4 years of age (0/2, 0% for vascular tumours; 21/28, 75% for vascular malformations). No patient experienced an infection directly related to rapamycin or discontinued rapamycin due to toxicity.ConclusionsRapamycin is safe and efficacious in most children with select vascular tumours and malformations. Young children appear to respond better, suggesting that early initiation of rapamycin should be considered.