Targeted Medical Therapies for Vascular Anomalies: A Clinical Review.

Vascular anomalies are a diagnostic and therapeutic challenge. They require dedicated interdisciplinary management. Optimal patient care relies on integral medical evaluation and a classification system established by experts in the field, to provide a better understanding of these complex vascular entities. A dedicated classification system according to the International Society for the Study of Vascular Anomalies (ISSVA) and the German Interdisciplinary Society of Vascular Anomalies (DiGGefA) is presented. The vast spectrum of diagnostic modalities, ranging from ultrasound with color Doppler, conventional X-ray, CT with 4 D imaging and MRI as well as catheter angiography for appropriate assessment is discussed. Congenital vascular anomalies are comprised of vascular tumors, based on endothelial cell proliferation and vascular malformations with underlying mesenchymal and angiogenetic disorder. Vascular tumors tend to regress with patient's age, vascular malformations increase in size and aresubdivided into capillary, venous, lymphatic, arterio-venous and combined malformations, depending on their dominant vasculature. According to their appearance, venous malformations are the most common representative of vascular anomalies (70 %), followed by lymphatic malformations (12 %), arterio-venous malformations (8 %), combined malformation syndromes (6 %) and capillary malformations (4 %). The aim is to provide an overview of the current classification system and diagnostic characterization of vascular anomalies in order to facilitate interdisciplinary management of vascular anomalies. · Vascular anomalies are comprised of vascular tumors and vascular malformations, both considered to be rare diseases.. · Appropriate treatment depends on correct classification and diagnosis of vascular anomalies, which is based on established national and international classification systems, recommendations and guidelines.. · In the classification, diagnosis and treatment of congenital vascular anomalies, radiology plays an integral part in patient management.. · Sadick M, Müller-Wille R, Wildgruber M et al. Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies. Fortschr Röntgenstr 2018; 190: 825 - 835.

Background Vascular malformations (VM) are malformed vessels with highly active endothelial walls and irregular flow of blood and lymphatic fluids. This increases the risk for intralesional and/or systemic thrombosis. Patients with vascular malformations have more pain than the general population. VM are complex group of developmental abnormalities that present significant challenges in diagnosis and management. The clinical presentation can range from an asymptomatic birthmark to fulminant cardiac failure. Objective To assess the prevalence of pain in patients with low flow vascular malformations and its relation to thrombosis. Patients and Methods This is a cross-sectional (pilot study) that include 30 patients of children and adolescents with venous, veno-lymphatic, and lymphatic vascular malformations at Children’s Hospital Ain Shams University to study the prevalence of pain in these patients and its relation to thrombosis through D-dimer levels. Results This study included 30 patients with low flow vascular malformations out of which 16 (53.3%) patients had venous malformations, 8 (26.7%) had complex malformations and 6 (20.0%) had lymphatic malformations. Pain was reported by 25 (83.3%) patients from which 13 (52.0%) were having venous malformation, 8 (32.0%) were having complex malformations and 4 (16.0%) were having lymphatic malformation, although pain was reported more in patients with venous malformations yet there was no significant difference the three groups (P = 0.241). Patients with pain had higher D-dimer level than those who didn’t have pain which was statistically significant (P = 0.027). Conclusion Pain is common symptom in patients with low flow vascular malformations especially in patients with venous malformations and it is related to high D-dimer level.

A term, large-for-gestational age boy is transferred from an outside hospital with a right anterior chest wall mass noted since birth. His mother is a healthy 33-year-old gravida 4, para 4 woman with good prenatal care and normal prenatal laboratory values who had an uncomplicated pregnancy and elective cesarean delivery. None of the patient’s siblings or family members have had similar masses.On physical examination the patient is well-appearing and moving all 4 extremities spontaneously without obvious limitations. Vital signs on admission to the hospital are normal. There is a nontender, boggy, fluctuant, flesh-colored, grapelike mass from his right nipple to the midaxillary line that extends to the right upper arm, with dimpling of the skin throughout the right upper extremity (Fig 1). No bruit is heard over the lesion. There is no palpable bony abnormality. Radial pulses are 2+. Capillary refill is less than 2 seconds. His lungs are clear to auscultation. The cardiovascular examination reveals a normal heart rate, rhythm, S1, and S2 and no murmurs. The abdomen is soft, nontender, and nondistended, with no palpable masses or hepatosplenomegaly.Chest radiography is normal. Complete blood cell count with differential count is normal. Ultrasonography of the right superolateral chest shows a multiloculated fluid collection with undulating borders measuring 6 × 1.7 cm. Magnetic resonance imaging (MRI) with contrast of the chest and right upper extremity reveals a multiloculated macrocystic mass in the superficial right chest wall, additional cysts in the right arm, and a partially cystic right mediastinal mass (Figs 2 and 3). MRI also shows multiple cysts in both kidneys (Fig 4). Review of the findings from MRI and genetic testing reveal the diagnoses.The differential diagnosis includes lymphatic malformation, venous malformation, vascular tumor, arteriovenous malformation, arteriovenous fistula, and capillary malformation. The patient was diagnosed as having lymphatic malformation. In addition, rapid genome sequencing revealed de novo pathogenic variant of PKD1 mutation, supporting an incidental second diagnosis of autosomal dominant polycystic kidney disease (ADPKD).Lymphatic malformations are a type of vascular anomaly. The International Society for the Study of Vascular Anomalies stratifies vascular anomalies into vascular tumors (benign, locally aggressive or borderline, and malignant) and vascular malformations (simple, combined, anomalies of major named vessels, and vascular malformations associated with other anomalies). (1)(2) Lymphatic malformations are low-flow, nonmalignant vascular malformations of the lymphatic system with dilated lymphatic channels or cysts thought to occur during lymphatic development.Lymphatic malformations can affect 1 location or can be loculated and/or multifocal (eg, lymphangiomatosis). (3) Lymphatic malformation is an umbrella term that includes all subtypes of lymphatic malformations, including cystic lymphatic malformations (macrocystic, microcystic, or mixed), generalized lymphatic anomalies such as kaposiform lymphangiomatosis, channel-type lymphatic malformation, acquired progressive lymphatic anomaly (acquired progressive lymphangioma), and primary lymphedema. Lymphatic malformations can affect any area of the body but most commonly occur in the head and neck regions, followed by the extremities. (4) They are classified as macrocystic, microcystic, or mixed. Most are noted at birth or within the first 2 years after birth.Superficial lymphatic malformations or deep vascular lesions may have no skin discoloration. In contrast, superficial arterial, capillary, or venous vascular anomalies can appear red, pink, violaceous, or blue, depending on the mix of oxygenated (arterial) or deoxygenated (venous) blood. Superficial lymphatic malformations can have clear vesicles or pitting of the skin or appear bruised if bleeding occurs within the malformation. Venous malformations are often bluish, soft, and compressible papules. Capillary malformations are often pink, red, or purple flat macules or patches. High-flow malformations, such as arteriovenous malformations and arteriovenous fistulas, can have a palpable bruit or thrill. Vascular anomalies can cause overgrowth and swelling in the affected area, which could cause pain.Lymphatic malformations can be associated with other anomalies. Gorham-Stout syndrome, also known as vanishing bone disease, is a rare condition characterized by proliferation of lymphatic vessels adjacent to single or multiple bones, leading to osteolysis and resorption of bone, oftentimes the ribs, spine, pelvis, skull, clavicle, or jaw. (5) Several PIK3CA-related overgrowth spectrum conditions also have lymphatic malformations, such as Klippel-Trenaunay syndrome, a rare congenital syndrome characterized by cutaneous capillary malformations (port-wine stain), vascular or lymphatic malformations, and limb overgrowth. (1)(6) Many patients with lymphatic malformations have an activating somatic PIK3CA gene mutation. (7) This was not the case for our patient.Diagnosis of vascular malformation or neoplasm is often made clinically and confirmed by imaging. For initial imaging, the 2019 American College of Radiology Appropriateness Criteria for Clinically Suspected Vascular Malformation of the Extremities deems magnetic resonance angiography with and without contrast, MRI with and without contrast, computed tomographic (CT) angiography with contrast, and duplex Doppler ultrasonography as appropriate for suspected vascular malformation of the extremity presenting with physical deformity. (8) However, because our patient also had a suspected abnormality in the chest wall, MRI or magnetic resonance angiography with and without contrast would be the best initial study to better evaluate deeper lesions than ultrasonography and better evaluate soft tissue contrast than CT angiography.The presence of renal cysts initially raised concern for underlying lymphangiomatosis. Lymphangiomatosis is the term used to describe lymphatic malformations in multiple organs. (3) It can affect any region of the body, although it is most common in the neck, axilla, retroperitoneum, and mediastinum. Renal lymphangiomatosis in pediatric patients is rare but should be included in the differential diagnosis for conditions such as ADPKD, nephroblastomatosis, lymphoma, and hydronephrosis with perinephric urinoma. (9) Several case reports describe initial misdiagnosis of renal lymphangiomatosis as ADPKD. Imaging and genetic testing can help differentiate between renal lymphangiomatosis and ADPKD. In renal lymphangiomatosis, renal cysts are central in the renal sinus, whereas in ADPKD, renal cysts are peripheral and parenchymal, as was seen with this patient. (9) In addition, the patient’s rapid genome sequencing reveals de novo pathogenic variant of PKD1 mutation, which supports a diagnosis of ADPKD being a separate etiology for renal cysts from that underlying the lymphatic malformations in the chest and right upper extremity. Differentiation between renal lymphangiomatosis and ADPKD can affect the treatment regimen and prognosis. A case report describing an infant with biopsy-proven bilateral renal lymphangiomatosis with 1-year follow-up suggests a self-limiting course in some patients, although it can expand before regression. (10) Successful treatment for renal lymphangiomatosis with sclerotherapy has been described. (3)(9)A case report describing an adult with comorbid lymphangiomatosis and ADPKD hypothesized a link between ADPKD and lymphangiomas as cystic pathologies sharing common genetic and congenital processes; however, no genetic mechanism has been identified. (11)ADPKD is the most common hereditary kidney disease, with a prevalence of 1:1,000 to 1:2,500. Patients with ADPKD develop cysts in the kidney parenchyma, which often leads to end-stage kidney disease by age 50 to 60 years. Our patient’s incidental diagnosis of ADPKD is atypical for several reasons. There was no family history, he developed cysts in the neonatal period, and his presenting complaint was lymphatic malformations. Our patient had a de novo PKD1 mutation, the most common mutation seen in ADPKD. Patients with PKD1 mutations have a less favorable kidney prognosis than patients with PKD2 mutations, who have end-stage kidney disease in their 70s and 80s. The Predicting Renal Outcomes in Polycystic Kidney Disease score combines predictive genetic factors with clinical information to predict risk of progression to end-stage kidney disease for patients with ADPKD in patients older than 35 years. (12) ADPKD is typically diagnosed using renal ultrasonography in patients with an affected first-degree relative. Genetic analysis can be useful in very young patients without a family history of ADPKD, as in our patient, who was found to have a de novo PKD1 mutation.Symptoms from lymphatic malformations vary depending on location of involvement and extent of invasion. Management varies depending on location, size and symptoms (including compression or obstruction of adjacent structures), infection, and interference with quality of life, including cosmetic concerns. Generally, microcystic lymphatic malformations are more challenging to treat than are macrocystic lymphatic malformations because they are less accessible for aspiration or sclerosing. (1)Observation for potential spontaneous regression can be appropriate for small lymphatic malformations without compromise of other systems. (13) Compression dressing is a conservative, first-line option for symptomatic treatment of lymphatic malformations limited to the extremities to prevent pain or growth of the malformation. (4) Treatment options for large or symptomatic lymphatic malformations include sclerotherapy, endovenous laser ablation, radiofrequency ablation, and surgical resection. Drug therapy with sirolimus, sildenafil, or propranolol has been described in case reports. Antibiotics should be used to treat infected lymphatic malformations.Clinical trials in adults with ADPKD show that angiotensin-converting enzyme inhibitors and possibly vasopressin antagonists decrease renal cyst growth. (14) A randomized controlled trial with tolvaptan, a selective vasopressin antagonist, for pediatric ADPKD is underway for children aged 12 to 17 years; results are not yet available. (15) Schaefer et al suggest angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for management of hypertension and proteinuria in the setting of pediatric ADPKD. (15) In addition, there is limited evidence that statin therapy slows the progression of structural kidney disease in children and young adults with ADPKD. (16)The patient was evaluated by a multidisciplinary team including surgery, hematology/oncology, nephrology, genetics, and interventional radiology; he was referred for sclerotherapy but was lost to follow-up.Five months later he presented with cough and was diagnosed as having a parainfluenza infection. Chest radiography revealed airway compromise; CT showed that the intrathoracic extent had dramatically increased, resulting in mediastinal shift and tracheal narrowing (Fig 5). Dark, sanguineous fluid was drained from the lesion, and sclerotherapy was performed using bleomycin. The postsclerotherapy radiograph showed mass reduction and improved lung expansion.Persistent hypertension was treated with enalapril. Repeated renal ultrasonography, compared with postnatal imaging, showed an enlarging right cyst and a new left cyst. Intrathoracic sclerotherapy was repeated 40 days later. Further treatment will be required.

Background:Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.Methods:We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.Results:These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.Conclusions:Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.Funding:R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial number:NCT03941782

Vascular anomalies are separated into vascular tumours and vascular malformations. Vascular malformations are named according to the affected type of vessels, that is venous, capillary, arteriovenous or lymphatic malformations. Up to now, sclerotherapy, embolisation and/or surgery are the treatments of choice, yet they do not often offer a curative treatment. Thus, there is an important need to develop novel disease‐specific therapeutic approaches. Inherited forms of vascular malformations led to the identification of several genes that are mutated encoding dysfunctional proteins. Demonstration that tissular second hits are commonly involved in inherited forms to explain development of lesions led to study somatic mutations in sporadically occurring forms. Since the primary discovery demonstrating that venous malformations are due to somatic mutations in TIE2/TEK, most types of vascular anomalies now have a known genetic cause. Thereby, the signalling pathways involved have been unravelled, leading to a better understanding of the aetiopathogenesis of vascular anomalies. As – like in cancers – the RAS/MAPK/ERK and the PI3K/AKT/mTOR signalling are enhanced in most vascular anomalies, treatment with cancer drugs interfering with these pathways could represent novel treatment options. Key Concepts Vascular anomalies are classified into tumours and malformations. The latter are further divided according to the affected vessels to capillary, venous, arterial, lymphatic and combined malformations. Treatment options are mostly restricted to sclerotherapy, embolisation and/or surgery. Most vascular anomalies are caused by genetic mutations, either germ line or somatic. Altered signalling involves RAS/MAPK/ERK, BMP9/10/ALK, PI3K/AKT/mTOR and VEGF/VEGFR3 pathways. Same pathways are also involved in cancers. Making repurposing of cancer drugs that interfere with these pathways, such as the mTOR inhibitor rapamycin, of interest for the treatment of vascular anomalies.

BackgroundThe histological differentiation of individual types of vascular anomalies (VA), such as lymphatic malformations (LM), hemangioma (Hem), paraganglioma (PG), venous malformations (VeM), arteriovenous malformations (AVM), pyogenic granulomas (GP), and (not otherwise classified) vascular malformations (VM n.o.c.) is frequently difficult due to the heterogeneity of these anomalies. The aim of the study was to evaluate digital image analysis as a method for VA stratificationMethodsA total of 40 VA tissues were examined immunohistologically using a selection of five vascular endothelial-associated markers (CD31, CD34, CLDN5, PDPN, VIM). The staining results were documented microscopically followed by digital image analyses based quantification of the candidate-marker-proteins using the open source program ImageJ/Fiji.ResultsDifferences in the expression patterns of the candidate proteins could be detected particularly when deploying the quotient of the quantified immunohistochemical signal values. Deploying signal marker quotients, LM could be fully distinguished from all other tested tissue types. GP achieved stratification from LM, Hem, VM, PG and AVM tissues, whereas Hem, PG, VM and AVM exhibited significantly different signal marker quotients compared with LM and GP tissues.ConclusionAlthough stratification of different VA from each other was only achieved in part with the markers used, the results of this study strongly support the usefulness of digital image analysis for the stratification of VA. Against the background of upcoming new diagnostic techniques involving artificial intelligence and deep (machine) learning, our data serve as a paradigm of how digital evaluation methods can be deployed to support diagnostic decision making in the field of VAs.

At our institution, in vivo facial nerve mapping (FNM) is used during vascular anomaly (VAN) surgeries involving the facial nerve (FN) to create an FN map and prevent injury. During mapping, FN anatomy seemed to vary with VAN type. This study aimed to characterize FN branching patterns compared to published FN anatomy and VAN type. Retrospective study of surgically relevant facial nerve anatomy. VAN patients (n = 67) with FN mapping between 2005 and 2018 were identified. Results included VAN type, FN relationship to VAN, FNM image with branch pattern, and surgical approach. A Fisher exact test compared FN relationships and surgical approach between VAN pathology, and FN branching types to published anatomical studies. MATLAB quantified FN branching with Euclidean distances and angles. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) analyzed quantitative FN patterns amongst VAN types. VANs included were hemangioma, venous malformation, lymphatic malformation, and arteriovenous malformation (n = 17, 13, 25, and 3, respectively). VAN FN patterns differed from described FN anatomy (P < .001). PCA and HCA in MATLAB-quantified FN branching demonstrated no patterns associated with VAN pathology (P = .80 and P = .91, one-way analysis of variance for principle component 1 (PC1) and priniciple component 2 (PC2), respectively). FN branches were usually adherent to hemangioma or venous malformation as compared to coursing through lymphatic malformation (both P = .01, Fisher exact). FN branching patterns identified through electrical stimulation differ from cadaveric dissection determined FN anatomy. This reflects the high sensitivity of neurophysiologic testing in detecting small distal FN branches. Elongated FN branches traveling through lymphatic malformation may be related to abnormal nerve patterning in these malformations. NA Laryngoscope, 130:2708-2713, 2020.

Haemangiomas in children usually involute spontaneously and surgical treatment is exceptional. Vascular malformations do not regress spontaneously and resection may become necessary. We present a series of surgically treated face and neck vascular anomalies during a 9-year period, assessing the epidemiology, presenting signs and symptoms, diagnostic modalities, indications for surgery, treatment methods and clinical outcome post-treatment. The medical and pathological records of all patients with cervicofacial vascular anomalies treated surgically at our department from 1997 to 2005 were retrospectively reviewed in relation to current evidence. Forty-one patients were identified. Of these, 9 patients had haemangiomas and the remaining 32 had a variety of vascular malformations. Cervicofacial vascular anomalies were most commonly located at the lip. Atypical looking vascular anomalies like masseteric intramuscular haemangiomas and parotid malformations were diagnostic problems. All 41 had surgical excision of their vascular anomalies for troubling symptoms, cosmesis or diagnostic purpose. For cervicofacial arteriovenous malformations, 28% were classified as Schobinger stage I, 50% stage II, and the remainder stage III. Combined embolisation-resection was used to treat 6 arteriovenous malformations (stage II to III) and of these, 3 required flap reconstruction. Accurate diagnosis distinguishing between cervicofacial haemangiomas and vascular malformations is key to best treatment. The diagnosis can usually be made by history and physical examination aided by early magnetic resonance imaging (MRI). Although cervicofacial haemangiomas can be managed conservatively or with medical therapy, surgery is indicated for preventing psychological distress and in cases of chronic aesthetic alteration resulting from partial regression. Aesthetic concerns and prevention of psychosocial distress point to early excision of venous malformation as the treatment of choice. Lymphatic malformations are best treated by excision. Outcome after excision of localised cervicofacial haemangiomas and low-flow vascular malformations is excellent. Large extensive low-flow malformations as well as those located at the lips may require multiple procedures including reconstruction; patients should be informed that the outcome is generally not as good. Combined embolisation-resection is definitive treatment for arteriovenous malformations and flap reconstruction may prevent their recurrence. Tissue expansion is a useful reconstructive tool after the excision of large vascular anomalies.

Educational Exhibit Abstract No. 290 - Percutaneous sclerosis of low-flow vascular malformations: technical considerations and comparison of sclerosants

Vascular anomalies are classified broadly into vascular tumors and vascular malformations.1 Vascular malformations are further subdivided based on the histology of the lesion and whether the lesion is ‘high flow’...

The genetics of vascular birthmarks

Clinicoradiologic predictors of sclerotherapy response in low-flow vascular malformations

Background. The term Kasabaha-Merit syndrome is often used as a eponym for general description of the for coagulation disorders in different vascular lesions in both children and adults. However, subsequent studies show that for certain types of vascular tumors and vascular malformations different types of coagulopathy occur. The aim of the study is to determine which vascular anomalies are at risk for coagulopathy. Methods: 64 patients aged from 1 month to 15 years with vascular anomalies were enrolled in prospective investigation. Of the 26 patients with vascular tumors 20 have hemangiomas, including 6 liver hemangiomas, 2 have kaposhiforme hemangioendothelioma, 1 tufted angioma, and 3 PHACE syndrome. Vascular malformations have 38 patients, 15 of them have cystic lymphatic malformations, 8 have primary lymphedema, 11 have venous malformations, 2 have arteriovenous malformation, and two have CLOVES syndrome. Measurement of D-dimer levels, platelet count, and fibrinogen in blood, witсh was drawn from a peripheral vein not involved by the vascular anomalies. Results. None patients with hemangiomas had any coagulation disorders. Very low platelet count so called Kasabach-Merritt phenomenon had two patients younger than one year with rare local aggressive tumor kaposiform hemangioendothelioma. 14 year old patient with huge tufted angioma of extremities had normal platelet count. Among the 11 patients with venous malformations (VM) 6 (54.5%) had elevated D-dimer levels. Patients with multiple gastrointestinal venous malformations had very high D-dimer lever (≥4 µg/ml) associated with low fibrinogen level. Patients with large unifocal truncal VM and VM of perineum and pelvis had D-dimer levels above 1 µg/ml and normal fibrinogen level. In contrast, patients with small localized VM of limbs and children with lymphatic malformations had normal coagulations tests. Conclusions. Children with vascular anomalies have risk of coagulopathy. Very low platelet count is specific for kaposhiform hemangioendothelioma and tufted angioma and is age dependent. Elevated D-dimer level is highly specific for VMs and don’t depends of patients age only of VMs size.

Dear Editor, We read the article “Pure spinal epidural cavernous hemangioma” by Zhong et al. [4] published recently in Acta Neurochirurgica with great interest and found that some discussion is pertinent. In 1982, Mulliken and Gloweki [3] classified vascular anomalies into two categories of hemangiomas (infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, and tufted angioma) and vascular malformation (arteriovenous, venous, lymphatic, and capillary malformations). In 1996, the International Society for the Study of Vascular Anomalies approved this classification system to establish a common language for the many different medical specialists who are involved in the management of these lesions. Previously, there was no precise classification and naming of hemangioma and vascular malformation. They were mostly referred to as hemangioma or lymphangioma together, and were primarily named according to the lesion’s morphology. For example, hemangioma included capillary hemangioma, cavernous hemangioma, racemose hemangioma; lymphangioma included capillary, cavernous and cystic. Since patients with hemangioma or vascular malformations can be treated in different clinical departments, even the same lesion can also get different names, as wine-color stains are referred as PWS in some departments. In 1982, Mulliken and Gloweki put forward that there should be a re-classification according to the cell biological and pathological characteristics, and made it clear that the two types of lesions as tumor and deformity should be distinguished. They were divided into two categories of hemangiomas and vascular malformations according to whether the proliferations of endothelial cells were found in the pathologic tissues. Hemangioma was the embryonic vascular endothelial cell proliferation characterized by benign tumor. This is quite different from the original traditional classification that was based on morphology and pathology. The occurance of hemangioma in neonates is about 3 %, which often occurs in the neonatal period and then enters the proliferative phase. Generally, it should get timely treatment once it is found. Ninety percent of vascular malformations are there at birth, but with no proliferation phase, they will grow proportionally with the increase in age [1]. Previous traditional classification rules defined wine-color stains, cavernous hemangioma, and racemose hemangioma as all belonging to vascular malformation, but they are now named as capillary malformations, venous malformation and arteriovenous malformations respectively. Due to errors in classification, many vascular malformations are mistaken as hemangioma, and many patients received false and ineffective treatment. The term “cavernous hemangioma” refers to a venous malformation. It consists of dilated sinusoidal channels lined by quiescent endothelium. The magnetic resonance imaging features of vascular malformations include: T2-weighted images that performed as high-intensity signal, T1-weighted images performed as the iso-intensity signal, just as that recorded in the article; magnetic resonance imaging can reveal the spinal epidural venous malformation, intra-lesion hemorrhage and thrombosis. Magnetic resonance imaging can demonstrate the breadth of lesions and the relationship between lesions and adjacent tissues; it can also help to provide the potential treatment plans. M. Zhu :Y. Luo : L. Qiu (*) Department of Diagnostic Ultrasound, West China Hospital of Sichuan University, No.37 Guo Xue Xiang, Chengdu 610041, Sichuan, China e-mail: vigour_sky@163.com

Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies. The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994 and 2017. Search terms included "vascular anomaly," "mutation," "gene," "hemangioma," "pyogenic granuloma," "kaposiform hemangioendothelioma," "capillary malformation," "venous malformation," lymphatic malformation," "arteriovenous malformation," and "syndrome." Articles that identified both germline and somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation. The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein-coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in more than one gene. Mutations were most commonly enriched in endothelial cells. Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics and molecular pathophysiology.