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Vascular anomalies are a spectrum of rare diseases classified as vascular tumors or malformations. An updated classification system was adopted at the General Assembly of the International Society for the Study of Vascular Anomalies (ISSVA, April 2014) and recently published. Generally, vascular tumors are proliferative, while malformations enlarge through expansion of a developmental anomaly without underlying proliferation.
Growth and/or expansion of vascular anomalies can cause clinical problems such as disfigurement, chronic pain, recurrent infections, coagulopathies (thrombotic and hemorrhagic), organ dysfunction, and death. Individuals often experience progressive clinical symptoms with worsening quality of life.
Limited treatment options are available; their efficacy has not been validated in prospective clinical trials. Historically, therapies have been mostly interventional and surgical to palliate symptoms. New drugs such as propranolol and sirolimus are now available for the treatment of patients with some of these complex conditions. The first prospective clinical trial using propranolol for infantile hemangioma has been published, as well as the first prospective clinical trial that studied the effectiveness of sirolimus for complicated vascular anomalies.[2,3]
With a prevalence of 4% to 5%, infantile hemangiomas are the most common benign tumors of infancy. Other vascular tumors are rare. The classification of these tumors has been difficult, especially in the pediatric population, because of their rarity, unusual morphologic appearance, diverse clinical behavior, and the lack of independent stratification for pediatric tumors. In 2013, The World Health Organization (WHO) updated the classification of soft tissue vascular tumors. Pediatric tumors were not independently stratified and the terminology was mostly left unchanged, but the intermediate category of tumors was divided into locally aggressive and rarely metastasizing. The ISSVA classification of tumors is based on the WHO classification (refer to Tables 1 and 2) but the ISSVA classification uses more precise terminology and phenotypes that have been agreed upon by the members of ISSVA.
The quality of evidence regarding childhood vascular tumors is limited by retrospective data collection, small sample size, cohort selection and participation bias, and heterogeneity of the disorders.
Benign vascular tumors include the following:
Incidence and epidemiology
Infantile hemangiomas (IH) are the most common benign vascular tumor of infancy, occurring in 4% to 5% of infants. They are not usually present at birth and are diagnosed most commonly at age 3 to 6 weeks.[1,2,3] The lesion proliferates for an average of 5 months, stabilizes, and then involutes over several years.
Infantile hemangiomas are more common in females, non-Hispanic white patients, and premature infants. Multiple hemangiomas are more common in infants who are the product of multiple gestations.[1,4] Infantile hemangiomas are associated with advanced maternal age and placental complications.
Most infantile hemangiomas occur sporadically. However, they may rarely be caused by an abnormality of chromosome 5 and present in an autosomal dominant pattern. In a study that evaluated inheritance patterns of infantile hemangiomas, 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative.
Infantile hemangioma endothelial cells have proven to be clonal in nature.[7,8] Infantile hemangioma proliferation occurs during vasculogenesis (the formation of new blood vessels from angioblasts), as opposed to angiogenesis (the formation of new blood vessels from existing blood vessels). During proliferation, provasculogenic factors are expressed, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), CD34, CD31, CD133, LYVE-1, and insulin-like growth factor (IGF)-2.[9,10,11,12] In involution, infantile hemangiomas express increased apoptosis. During this phase, there are also increased mast cells and levels of metalloproteinase, as well as upregulation of interferon and decreased basic FGF (bFGF).[12,13,14] Throughout their development, endothelial cells in infantile hemangioma express a particular phenotype showing positive staining for glucose transporter (GLUT1). GLUT1 is also expressed on placental endothelial cells but is absent in other vascular tumors such as congenital hemangioma and vascular malformations.
Hypoxia may have a role in the pathogenesis of hemangiomas. As described above, hemangiomas are associated with conditions related to placental hypoxia, and multiple targets of hypoxia [16,17] are demonstrated in proliferating hemangiomas such as VEGF-A, GLUT1, and IGF-2.[9,11,15] The hypotheses suggest that a proliferating hemangioma is an attempt to normalize hypoxic tissue that occurred in utero.
Most infantile hemangiomas are not present at birth but precursor lesions such as telangiectasia or faint discoloration of the skin or hypopigmentation can often be seen. The lesion can be mistaken as a bruise from birth trauma or as a capillary malformation (port wine stain) (refer to Figure 1).[18,19]
Figure 1. The photos on the left depict the precursor lesion (faint color with halo). The photos on the right depict the hemangioma after proliferation (slightly raised with a brighter central color). Credit: Israel Fernandez-Pineda, M.D.
Infantile hemangiomas can be superficial in the dermis, deep in the subcutaneous tissue, combined, or in the viscera. Combined lesions are common. They are most common in the head and neck but can be anywhere on the body. They can be localized, segmental, or multiple in nature.
The cutaneous appearance of infantile hemangiomas is usually red to crimson, firm, and warm in the proliferative phase. The lesion then lightens centrally and becomes less warm and softer; it then flattens and loses its color. The process of involution can take several years and once involution has occurred, regrowth is uncommon. In two patients treated with growth hormone, regrowth after involution was noted. On further investigation, growth hormone receptors were found on the infantile hemangioma cells. Although preliminary, this may advance the research into the etiology of hemangioma growth.
Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution (refer to Figure 2). In a retrospective cohort study of 184 hemangiomas, the overall incidence of significant sequelae was 54.9%. Sequelae were more common in combined hemangiomas, hemangiomas with a step or abrupt border, and cobblestone surface hemangiomas. Furthermore, this study revealed that the average age to hemangioma involution was 3.5 years.
Figure 2. Examples of different types of sequelae. A, deep hemangioma that regressed without sequelae; B, superficial hemangioma that left only telangiectasia; C, mixed hemangioma that left anetodermic skin; D, mixed hemangioma that left redundant skin; and E, mixed hemangioma that left fibrofatty tissue. Reproduced with permission from JAMA Dermatology. 2016. 152 (11): 1239–1243. Copyright © (2016) American Medical Association. All rights reserved.
Diagnostic and staging evaluation
Infantile hemangiomas are usually diagnosed by the history and clinical appearance. Biopsy is rarely needed and performed only if there is an atypical appearance and/or atypical history and presentation. Imaging is not usually necessary, but if there is a deeper lesion without a cutaneous component, ultrasound imaging is beneficial for diagnosis because it reveals a high flow lesion with a typical Doppler wave characteristic.
Infantile hemangioma with minimal or arrested growth
Infantile hemangioma with minimal or arrested growth (IH-MAG) is a variant of hemangioma that can be confused with capillary malformation because of their unusual characteristics. These hemangiomas are mostly fully formed at birth and are characterized by telangiectasia and venules with light and dark areas of skin coloration (refer to Figure 3). They resolve spontaneously and are pathologically GLUT1 positive. They are mainly located on the lower body but can be present in the head and neck area; if they are segmental, they can be associated with PHACE syndrome.
Figure 3. Patient 4 at (A) presentation and (B) resolution. Patient 5 at (C) presentation and (D) resolution. Ma, E. H., Robertson, S. J., Chow, C. W., and Bekhor, P. S. (2017), Infantile Hemangioma with Minimal or Arrested Growth: Further Observations on Clinical and Histopathologic Findings of this Unique but Underrecognized Entity. Pediatr Dermatol, 34: 64–71. doi:10.1111/pde.13022. Used with permission.
Airway infantile hemangioma
Airway infantile hemangiomas are usually associated with segmental hemangiomas in a bearded distribution, which may include all or some of the following—the preauricular skin, mandible, lower lip, chin, or anterior neck. It is important for an otolaryngologist to proactively assess lesions in this distribution before signs of stridor occur. The incidence of an airway infantile hemangioma increases with increased area of bearded involvement. Airway infantile hemangioma can occur without skin lesions. A retrospective study of the Vascular Anomaly Database at the Children's Hospital of Pittsburgh analyzed 761 cases of infantile hemangioma. Thirteen patients (1.7%) had subglottic hemangiomas; of those 13 patients, 4 patients (30%) had bearded distributions, 2 patients (15%) had cutaneous hemangiomas, and 7 patients (55%) had no cutaneous lesions. (Refer to the Propranolol therapy section of this summary for information about the treatment of airway infantile hemangiomas.)
Ophthalmologic involvement of hemangiomas
Periorbital hemangiomas can cause visual compromise. This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can obstruct the visual axis. The clinician should be aware of subcutaneous periocular hemangiomas, as these lesions can extend into the orbit, causing exophthalmos or globe displacement with only limited cutaneous manifestations. Issues with these lesions include astigmatism from direct pressure of the growing hemangioma, ptosis, proptosis, and strabismus. One of the leading causes of preventable blindness in children is stimulus-deprivation amblyopia caused by hemangioma obstruction. All periorbital hemangiomas or those with any possibility of potential visual impairment should have an ophthalmologic evaluation.
Infantile hemangiomas can occur in the conjunctiva (refer to Figure 4). These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers.
Figure 4. Proposed classification of infantile hemangiomas involving the conjunctiva. Theiler M, Baselga E, Gerth-Kahlert C, et al. Infantile hemangiomas with conjunctival involvement: An underreported occurrence. Pediatr Dermatol. 2017;34:681–685. https://doi.org/10.1111/pde.13305 Copyright © 2017 John Wiley & Sons, Inc.
Syndromes associated with infantile hemangioma
Syndromes associated with infantile hemangioma include the following:
Figure 5. A large segmental infantile hemangioma (plaque-like) in a bearded distribution. This patient has an increased risk of PHACE syndrome, airway infantile hemangioma, and ulceration. A tracheostomy was placed secondary to a very diffuse airway hemangioma. Credit: Denise Adams, M.D.
Consensus criteria for definite and possible PHACE syndrome were developed at an expert panel meeting, as follows:
Diagnosis of PHACE requires clinical examination, cardiac evaluation with echocardiogram, ophthalmologic evaluation, and magnetic resonance imaging (MRI)/magnetic resonance angiogram (MRA) of the head, neck, and mediastinum. Patients need to be monitored for short- and long-term effects as noted above. Other issues include speech and language delay, swallowing dysfunction, hearing loss (conductive and sensorineural), and early-onset migraines.[41,42,43]
A report of two patients with retro-orbital infantile hemangioma and arteriopathy suggested a possible new presentation of PHACE syndrome. For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE may be needed on the basis of central nervous system (CNS) findings.
Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasound or MRI, depending on the age of the patient.
Infants with more than five infantile hemangiomas need to be evaluated for visceral hemangiomas. The most common site of involvement is the liver, in which multiple or diffuse lesions can be noted.[49,50] Often these lesions are asymptomatic, but in a minority of cases, symptoms such as heart failure secondary to large vessel shunts, compartment syndrome, or profound hypothyroidism can occur due to the expression of iodothyronine deiodinase. Multiple or diffuse liver hemangiomas can occur in the absence of skin lesions. (Refer to the Benign Vascular Tumors of the Liver section of this summary for more information.) Other rare potential complications of visceral hemangiomas, dependent on specific organ involvement, include gastrointestinal hemorrhage, obstructive jaundice, and CNS sequelae, caused by mass effects.
Treatment of infantile hemangioma
Treatment options for infantile hemangioma include the following:
Propranolol, a nonselective beta-blocker, is the first-line therapy for infantile hemangiomas. Potential mechanisms of action include vasoconstriction and/or decreased expression of VEGF and bFGF, leading to apoptosis.[54,55] Specific mechanisms of action are under investigation.
The use of propranolol was first noted in two infants treated for cardiac issues in Europe. A change in color, softening, and decrease in hemangioma size was noted. Since that time, the results of a randomized controlled trial have been reported. In 2014, the U.S. Food and Drug Administration (FDA) approved the drug propranolol hydrochloride for the treatment of proliferating infantile hemangioma.
There are many other published reports about the efficacy and safety of propranolol.[57,58,59,60,61] Lack of response to treatment is rare. Propranolol therapy is usually used during the proliferative phase but has been effective in patients older than 12 months with infantile hemangiomas.
Evidence (propranolol therapy):
Based on expert consensus panel recommendations and updated reviews, considerations for the administration of propranolol therapy include the following:[65,66,67]
The pretreatment evaluation (inpatient or outpatient) includes the following:
These complications have been reported in several studies, and severe complications have been rare. The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.
Other selective beta-blocker therapy
Because of the nonselective and lipophilic nature of propranolol with the ability to cross the blood-brain barrier, other beta-blockers are being used for the treatment of infantile hemangiomas. In two small comparison studies, there was no difference in efficacy between propranolol and atenolol.[73,74] In a retrospective study using nadolol, similar results were seen. A prospective study of 76 infants treated with atenolol noted efficacy and safety similar to propranolol.[Level of evidence: 3iiDiv] Additional studies are needed to assess differences between the toxicities of these agents and the toxicities of propranolol. There is some suggestion that the more selective beta-blockers have fewer side effects.
Before propranolol, corticosteroids were the first line of treatment for infantile hemangiomas. They were first used in the late 1950s but were never approved by the U.S. FDA. Corticosteroid therapy has become less popular secondary to the acute and long-term side effects of steroids (gastrointestinal irritability, immunosuppression, adrenocortical suppression, cushingoid features, and growth failure).
Corticosteroids (prednisone or methylprednisolone) are used at times when there is a contraindication to beta-blocker therapy or as initial treatment while a patient is started on beta-blocker therapy.
Topical beta-blocker therapy
Topical beta-blockers are used mainly for the treatment of small, localized, superficial hemangiomas as an alternative to observation. They have also been used in combination with systemic therapy in complicated hemangiomas or to prevent rebound in a hemangioma being tapered off of systemic treatment.[79,80,81]
The topical timolol that is used is the ophthalmic gel-forming solution 0.5%. One drop is applied to the hemangioma two to three times per day until stable response is achieved.
This treatment has limited side effects, but infants with a postmenstrual age of younger than 44 weeks and weight at treatment initiation of less than 2,500 grams may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia.[82,83] Close monitoring of temperature, blood pressure, and heart rate in premature and low birth weight infants with infantile hemangiomas at initiation of and during therapy with topical timolol is necessary.
Evidence (topical beta-blocker therapy):
Combined therapy for complicated hemangiomas
Combined therapy is considered either at initiation of treatment in complicated lesions in which there is functional impairment or organ compromise or used at the end of systemic therapy to prevent regrowth of the hemangioma rebound. Further investigation of efficacy and safety is needed for these regimens.
Evidence (combined therapy for complicated hemangiomas):
Treatment options under clinical evaluation for infantile hemangiomas
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Congenital hemangiomas are benign vascular tumors that proliferate in utero. Development of these lesions is complete at birth. Histologically, these lesions are GLUT1 negative, unlike infantile hemangiomas. They are usually cutaneous, but can be found in the viscera. Complications include hemorrhage, transient heart failure, and transient coagulopathy.
To the clinician unfamiliar with these lesions, congenital hemangiomas can be difficult to diagnose. Diagnostic criteria include a purpuric lesion fully formed at birth, frequently with a halo around the lesion, with high flow noted on ultrasound imaging. Essential to the diagnosis is observation of decrease in size over time or stability. These lesions do not enlarge unless there is hemorrhage into the tumor.
Somatic activating mutations of GNAQ and GNA11 have been found to be associated with congenital hemangiomas. Additional research is necessary to assess the significance of these findings, as this may aid in diagnosis and pathophysiology.
Congenital hemangiomas are divided into the following three forms:
Figure 6. Typical appearance of a cutaneous congenital hemangioma at birth. Note the pedunculated mass. This RICH lesion involuted over time but some residual skin changes remained. Credit: Denise Adams, M.D.
Benign Vascular Tumors of the Liver
In the literature, vascular liver tumors are usually classified as liver hemangioendotheliomas, a broad classification no longer in use. These tumors are classified according to their clinical characteristics and radiologic assessment.
Lesions are usually divided into the following three categories:
On MRI, vascular liver tumors are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement.
Focal vascular lesions (congenital hemangiomas)
Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH) (refer to Figure 7). RICH can present with symptoms of heart failure and mild to moderate coagulopathy.
Treatment options for focal vascular lesions include the following:
No medication has proven to be an effective treatment for these lesions, and infants need to be supported during this initial period until involution begins. These lesions may be diagnosed prenatally. In rare situations, maternal treatment with medications such as steroids appeared to be effective but, more likely, natural involution may have been responsible.
Figure 7. Single liver lesion (intrahepatic congenital hemangioma). MRI image of a congenital hemangioma. Note the central enhancement, which is typical for an intrahepatic congenital hemangioma. Credit: Denise Adams, M.D.
Multiple liver lesions (infantile hemangiomas)
Multifocal hepatic lesions are infantile hemangiomas. Multifocal lesions may not need to be treated if the patient is asymptomatic, and they typically follow the same proliferative and involution course as cutaneous hemangiomas. These lesions are monitored closely and if there is growth, propranolol therapy should be considered. If propranolol is needed, doses of up to 2 mg/kg per day are effective.
Diffuse liver lesions (infantile hemangiomas)
Diffuse liver lesions can be very serious (refer to Figure 8). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, congestive heart failure, and compartment syndrome.[49,50,100,101]
Figure 8. Diffuse liver lesions with classical imaging on CT. Note the peripheral enhancement in early contrast phase. Credit: Denise Adams, M.D.
Treatment options for diffuse liver lesions may include the following:
There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas. It is not clear if all cases were transformation of a benign lesion to a malignant phenotype; however, if the lesion does not respond to standard therapy, biopsy should be considered. Further evaluation and consensus is needed to assess whether these patients need to be monitored over a longer period of time with liver ultrasound. (Refer to the Angiosarcoma of the Soft Tissue section of this summary for more information.)
The differential diagnosis of vascular liver lesions always includes malignant liver tumors; thus, alpha-fetoprotein (AFP) should be included in the initial lab work. AFP can be elevated above baseline in congenital and infantile hemangiomas of the liver, but will rapidly fall to normal levels in 1 to 2 months, although there are no prospective studies investigating AFP elevation.[106,107] Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcoma, metastatic neuroblastoma, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.
Spindle Cell Hemangioma
Spindle cell hemangiomas, initially called spindle cell hemangioendotheliomas, often occur as superficial (skin and subcutis), painful lesions involving distal extremities in children and adults.[109,110] The tumors appear as red-brown or bluish lesions that can begin as a single nodule and develop into multifocal painful lesions over years. The lesions can be seen in Maffucci syndrome (cutaneous spindle cell hemangiomas occurring with cartilaginous tumors, enchondromas) and Klippel-Trenaunay syndrome (capillary/lymphatic/venous malformations), generalized lymphatic anomalies, lymphedema, and organized thrombus.[111,112]
These tumors are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of spindle cell hemangiomas are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass.[111,112]
Treatment of spindle cell hemangioma
There is no standard treatment for spindle cell hemangioma because it has not been studied in clinical trials. Surgical removal is usually curative, although there is a risk of recurrence.[111,112]
Epithelioid hemangiomas are benign lesions that usually occur in the skin and subcutis but can occur in other areas such as the bone, with focal and multifocal lesions.[111,113] Epithelioid hemangiomas may be a reactive process, as they can be associated with local trauma and can develop in pregnancy. Patients usually present with local swelling and pain at the involved site. In the bone, they present as well-defined lytic lesions that involve the metaphysis and diaphysis of long bones.[111,114] They can have a mixed lytic and sclerotic pattern of bone destruction.
On pathologic evaluation, they have small caliber capillaries with eosinophilic, vacuolated cytoplasm and large oval, grooved, and lobulated nuclei. The endothelial cells are plump and are mature, well-formed vessels surrounded by multiple epithelioid endothelial cells within abundant cytoplasm. They lack cellular atypia and mitotic activity.[111,113,114]
A single-institution report reviewed 11 patients with epithelioid hemangiomas (median age, 14.4 years) who were diagnosed between 1999 and 2017. Lesions occurred in the lower extremities (five patients), skull (three patients), pelvis (two patients), and spine (one patient). Five patients had multifocal disease. Patients presented with localized pain and neurologic symptoms, including cranial nerve injury. No significant cytologic atypia was noted, and the endothelial cells were positive for CD31 and ERG, and negative for cytokeratin and CAMPTA1. Median follow-up was 1.5 years. Various modalities of treatments were used, including surgery, endovascular embolization, cryoablation, and medical management. One patient received sirolimus, and another patient received interferon; the lesions of both patients shrank within the first year of follow-up. The youngest patient, aged 2.5 years, had multifocal skull lesions that regressed partially by 1 year later.
Treatment of epithelioid hemangioma
There is no standard treatment for epithelioid hemangioma because it has not been studied in clinical trials. Treatment consists of curettage, sclerotherapy, and resection, or rarely, radiation therapy.[111,114]
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Pyogenic granuloma, known as lobular capillary hemangioma, is a benign reactive lesion that can present at any age, including infancy, although it is most common in older children and young adults. They can present as single or multiple lesions.[116,117,118,119] These lesions can arise spontaneously, in sites of trauma, or within capillary and arteriovenous malformations. Pyogenic granulomas have also been associated with medications including oral contraceptives and retinoids. Most occur as solitary growths, but multiple (grouped) or rarely disseminated lesions have been described. These lesions appear as small or large, smooth or lobulated vascular nodules that can grow rapidly, sometimes over weeks to months and have a tendency to bleed profusely. These lesions are usually cutaneous, but deep-seated/subcutaneous pyogenic granulomas are noted and mimic other vascular lesions.
Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Some untreated lesions eventually atrophy, become fibromatous, and slowly regress.
Treatment of pyogenic granuloma
Treatment often consists of full-thickness excision, curettage, or laser photocoagulation, but recurrence is common. A small case series of four patients with acquired ocular surface pyogenic granulomas were treated with topical timolol 0.5% twice daily for 21 days. In all cases, complete resolution with no recurrence occurred for at least 3 months. More studies are needed to validate these findings. A study of 22 patients with pyogenic granuloma who were treated with topical 1% propranolol ointment with occlusion found that 59% of patients achieved a complete response (mean, 66 days), 18% of patients had stable disease, and 22% of patients did not respond to the treatment. In this study, only skin toxicity was assessed. The authors did not comment on the penetrance of the propranolol formulation or include a safety evaluation of the side effects such as hypoglycemia and the effects on heart rate or blood pressure.
Angiofibromas are rare, benign neoplasms in the pediatric population. Typically, they are cutaneous lesions associated with tuberous sclerosis, appearing as red papules on the face.
Treatment of angiofibroma
Excision of the tumor, laser treatments, and topical treatments, such as sirolimus, have been used.[124,125,126]
Juvenile Nasopharyngeal Angiofibroma
Juvenile nasopharyngeal angiofibromas (JNA) account for 0.5% of all head and neck tumors. Histologically, juvenile nasopharyngeal angiofibromas are benign vascular tumors but they can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, and orbit skull base, with intracranial extension. Some publications have suggested a hormonal influence on juvenile nasopharyngeal angiofibroma, with emphasis on the molecular mechanisms involved.[128,129]
Treatment of juvenile nasopharyngeal angiofibroma
Surgical excision is the treatment of choice but this can be challenging because of the extent of the lesion. A single-institution retrospective review of juvenile nasopharyngeal angiofibromas identified 37 patients with lateral extension. Anterior lateral extension to the pterygopalatine fossa occurred in 36 patients (97%) and further to the infratemporal fossa in 20 patients (54%). In 16 patients (43%), posterior lateral spread was observed (posterior to the pterygoid process and/or between its plates). The recurrence rate was 29.7% (11 of 37 patients). The recurrence rate in patients with anterior and/or posterior lateral extension was significantly higher than in patients with anterior lateral extension only.
Juvenile nasopharyngeal angiofibromas have also been treated with radiation therapy, chemotherapy, alpha-interferon therapy, and sirolimus.[131,132,133,134]
Kaposiform Hemangioendothelioma and Tufted Angioma
Kaposiform hemangioendothelioma (KHE) and tufted angioma are rare vascular tumors that typically occur during infancy or early childhood but have been reported in adults. Both tumors are thought to be a spectrum of the same disease, because both can be locally aggressive and cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. They are discussed here as a single entity, kaposiform hemangioendothelioma.
The exact incidence of kaposiform hemangioendothelioma is unknown but is estimated to be 0.07 cases per 100,000 children per year.[1,2,3] The lesions affect both sexes equally, with most developing in the neonatal period, one-half presenting at birth, and others presenting during childhood or adulthood.
Kaposiform hemangioendothelioma is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. There are often areas of fibrosis, with dilated thin-walled vessels infiltrated around the areas of spindle cells. Mixed with these areas are nests of rounded epithelioid cells of vascular origin and aggregates of capillaries with round or irregularly shaped lumens containing platelet-rich fibrin thrombi. There is usually the presence of abnormal lymphatic spaces, either within or at the periphery of the lesion. The rate of mitosis is variable but usually low. Tufted angioma is characterized by multiple, discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis, so called cannonball pattern. Mitoses are rare.
The pathogenesis is poorly understood. There is some evidence that kaposiform hemangioendothelioma may be derived from lymphatic endothelium, as the spindle cell expresses the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor-3, a receptor required for lymphangiogenesis, and the lymphatic markers D2-40 and PROX1.[5,6,7] There is no evidence of association with human herpesvirus 8 infection as is present in Kaposi sarcoma.
Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area. Most lesions involve the skin (refer to Figure 9). Deeper lesions (retroperitoneum, thoracic cavity, and muscle) can appear as a bluish-purpuric hue on the skin, whereas superficial lesions can be firm, purpuric or ecchymotic, and painful. Lesions are usually unifocal and growth is contiguous. Local lymph nodes may be involved, but they never metastasize. Rare multifocal presentations have been reported mostly in the bone.[1,2,3]
Figure 9. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.
Seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon, which is a life-threatening complication characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and profound hypofibrinogenemia (<1 g/L). D-dimer and fibrin degradation products are elevated. Severe anemia can occur secondary to tumor sequestration. Severe hemorrhage is rare; however, trauma (biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to disseminated intravascular coagulation and serious bleeding and death can occur. Aggressive replacement of blood products, especially platelets, can increase the size of the lesion, causing significant pain and should only be considered with active bleeding and under the direction of a vascular anomaly specialist.
The diagnosis is based on the combination of clinical, histologic, and imaging features. Laboratory evaluation is essential for the diagnosis of Kasabach-Merritt phenomenon. Whenever possible, histologic confirmation should be obtained, because prolonged therapy is often needed. However, if clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy is an option but needs to be planned with an interdisciplinary approach.
Magnetic resonance imaging is the imaging preference. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with soft tissue and dermal thickening and diffuse enhancement with gadolinium. T2-weighted sequences show a diffuse increased signal, with stranding in the subcutaneous fat. Gradient sequences show mildly dilated vessels in and around the soft-tissue mass.
Treatment of kaposiform hemangioendothelioma and tufted angioma
Treatment varies according to severity; there is no evidence-based standard of care. An American and Canadian multidisciplinary expert panel published guidelines for the management of complicated kaposiform hemangioendothelioma. A number of treatment therapies have been reported but none have been uniformly effective.[9,10]
Treatment options for kaposiform hemangioendothelioma include the following:[8,9,10,11,12,13,14,15,16,17]
Initial treatment is most commonly steroids followed by vincristine. A retrospective review identified 37 children with kaposiform hemangioendothelioma whose lesions did not respond to steroids.[Level of evidence: 3iiiDiv] Twenty-six kaposiform hemangioendothelioma lesions achieved complete remission, with platelet counts reaching normal levels within 7.6 ± 5.2 weeks after vincristine treatment.
Propranolol therapy has been reported as a treatment option for kaposiform hemangioendothelioma. Its use is based on the positive results of propranolol for other more benign vascular tumors. Results have been mixed, with a report of improved effectiveness using higher doses of propranolol.[18,19] Preliminary results indicate that propranolol should be reserved for patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon and with smaller, less complicated lesions.
Secondary to promising case reports, case series and a prospective clinical trial, sirolimus may be considered an alternative first-line therapy for kaposiform hemangioendothelioma.[14,15,20] There are limited studies investigating its effect on kaposiform hemangioendothelioma/tufted angioma without Kasabach-Merritt phenomenon.
Reports that support the use of sirolimus include the following:
A case report described two children with kaposiform hemangioendothelioma and Kasabach-Merritt syndrome who died of pulmonary infections after treatment with sirolimus. Another child who received sirolimus and prednisolone developed Pneumocystis jirovecii pneumonia. Additional studies are needed to determine the long-term efficacy and safety of sirolimus for the treatment of vascular tumors associated with Kasabach-Merritt phenomenon.
Surgical excision may be possible for lesions that are smaller, have failed medical management, or are life threatening. Embolization may be performed in conjunction with surgery or medical therapy; usually it is a temporizing measure.
The mortality associated with this tumor is primarily from the extensive coagulopathy associated with Kasabach-Merritt phenomenon.
Even with therapy, these lesions do not fully regress and can recur; worsened symptomatology (pain, inflammation) can occur with age, especially around the time of puberty.
Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues. These lesions prove to be a difficult dilemma for the practitioner because they have a varied clinical spectrum and response to therapy.
Treatment options under clinical evaluation for kaposiform hemangioendothelioma
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Intermediate vascular tumors (rarely metastasizing) include the following:
Incidence and outcome
Pseudomyogenic hemangioendothelioma is a rare, newly designated, distinct vascular tumor. It is characterized as an intermediate-grade tumor with moderately aggressive local spread and rare distant metastatic disease.
Pathology and biology
Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindle and epithelioid cells with abundant eosinophils, cytoplasm, and coexpression of keratins and endothelial markers.[1,2,3] The etiology for this tumor is unclear, although a balanced translocation t(7;19) resulting in the SERPINE1-FOSB fusion gene was reported.
Clinical presentation and diagnostic evaluation
The tumor usually presents in young men aged 20 to 50 years.[1,2] Multifocal disease occurs in 70% of patients. Sites of involvement include the dermis, subcutis, and bones. Patients usually present with pain or a soft tissue mass.[1,5]
Treatment of pseudomyogenic hemangioendothelioma
Most patients are treated with surgery, including amputation with multifocal bony disease. In reported cases, chemotherapy has produced responses.[6,7] Recently, the mammalian target of rapamycin (mTOR) inhibitors have been considered as treatment options.[7,8]
Pathology and clinical presentation
Retiform hemangioendotheliomas are slow growing, exophytic, flat tumors found in young adults and occasionally children. They are usually located in the limbs and trunk. Histologically, they are located in the dermis and subcutaneous tissue. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. They do not express lymphatic markers but stain positive for endothelial markers.
Local recurrences are common, but distinct metastases are extremely rare.
Treatment of retiform hemangioendothelioma
Surgical excision with adequate surgical tumor margins and monitoring for local recurrence is the treatment for this tumor. There are case reports of the use of radiation therapy and chemotherapy for inoperable and recurrent tumors.[11,12,13,14]
Papillary Intralymphatic Angioendothelioma
Papillary intralymphatic angioendothelioma, also known as Dabska tumor, can occur in the adult and pediatric population. The lesions occur in the dermis and subcutis on all body parts and there have been some reports of lymph node involvement. They can be large or small raised purplish firm nodules.
Pathologically, they reveal intravascular growth of well-differentiated endothelial cells in a columnar configuration. They have thickened hyaline walls with hobnailed endothelium. Vascular endothelial growth factor receptor type 3, a marker for lymphatic endothelium, is positive in most cases. There is minimal cytologic atypia. Some are associated with vascular malformations.
Treatment of papillary intralymphatic angioendothelioma
Surgical excision is the treatment of choice.
Composite hemangioendothelioma is a very rare vascular tumor classified because of the combined benign and malignant vascular components. Usually, combined epithelioid and retiform variants are noted but some tumors have three components (epithelioid, retiform, and spindle cell). Angiosarcoma foci have been noted. Pathology reveals positivity for CD31, factor VIII, and vimentin.[18,19] Rarely, D-240 is positive with a Ki-67 index of approximately 20%.
This tumor usually occurs in the dermis and subcutis of the distal extremities but has been found in other areas such as the head, neck, and mediastinum. They have been reported in all age groups.
Composite hemangioendotheliomas recur locally and rarely metastasize.[18,19] Regional lymph nodes are the most likely site of metastasis and need imaging evaluation.
Treatment of composite hemangioendothelioma
Surgical removal is the treatment of choice, although radiation therapy and chemotherapy have been used for metastatic disease.[20,21]
Kaposi sarcoma (KS) is a rare malignant vascular tumor associated with a viral etiology (human herpesvirus 8). The skin lesions were first described in 1872 by Moritz Kaposi. The incidence has increased worldwide secondary to the HIV-AIDS epidemic. It is an extremely rare diagnosis in children. Epidemic and iatrogenic forms of Kaposi sarcoma in children result from profound acquired T-cell deficiency that results from HIV infection and rare immune disorders.
A retrospective study has investigated the presentation of Kaposi sarcoma in children in endemic areas of Africa. Children usually present with cutaneous lesions, lymphadenopathy, and intrathoracic and oral lesions. Cutaneous lesions initially appear as red, purple, or brown macules, later developing into plaques and then nodules.[23,24,25]
Kaposi sarcoma is exceedingly rare in the pediatric population and is usually associated with immunocompromised states such as HIV infection or solid organ transplant.
Treatment of Kaposi sarcoma
Children with Kaposi sarcoma have responded to treatment with chemotherapy regimens, including bleomycin, vincristine, and taxanes, although there are no prospective clinical trials. Other treatment options have been based on adult studies (see below).
Because Kaposi sarcoma is rare in the pediatric population, there are no evidence-based studies. Even in adults, the evidence and quality of studies is inferior and it is difficult to recommend particular treatment regimens. Fifty-six Malawian children aged 3 to 12 years with Kaposi sarcoma were treated with six courses of vincristine, bleomycin, and oral etoposide. This was a high-risk population because 48 of the patients (86%) were HIV positive, of whom 36 (77%) were on antiretroviral therapy. Quality of life improved in 45 patients (80%). Eighteen patients (32%) had a complete remission. At 12 months, the overall survival rate was 71%, and the event-free survival rate was 50%.[Level of evidence: 3iiA]
In a systematic review of treatment for classic Kaposi sarcoma, 26 articles published from 1980 to 2010 were reviewed; articles describing populations at high risk secondary to previous transplantation and endemic and epidemic Kaposi sarcoma were excluded. All articles had a minimum of five patients per intervention. A greater than 50% decrease in the size of the lesions or lymphedema was considered a response. The quality of the articles was considered poor, primarily because of lack of uniform staging criteria and variable means of assessing response. The following response rates for systemic treatments were noted:
For local therapies, the following response rates were reported:
(Refer to the PDQ summary on Kaposi Sarcoma Treatment for information about the treatment of Kaposi sarcoma in adults.)
Malignant vascular tumors include the following:
This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[1,2,3,4,5,6,7]
The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.
Histopathology and molecular features
A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported. These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.
Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.
The number of pediatric patients reported in the literature is limited.
Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[3,8,9] Clinical presentation depends on site of involvement, as follows:
Treatment of epithelioid hemangioendothelioma
Treatment options for epithelioid hemangioendothelioma include the following:
For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus. The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[3,11,12,13,14]
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for epithelioid hemangioendothelioma
Angiosarcoma of the Soft Tissue
Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million people; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.
Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[16,17,18,19] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.
Established risk factors include the following:
Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.
Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).
Treatment of angiosarcoma of the soft tissue
Treatment options for angiosarcoma of the soft tissue include the following:
Localized disease is cured by aggressive surgery. Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[18,21,22,23] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis. Data on liver transplantation for localized angiosarcoma are limited.[Level of evidence: 3iiA]
Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.
Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative. Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months  and a median overall survival (OS) rate of 14 months to 18 months. In both adults and children, 5-year OS rates between 20% and 35% are reported.[18,19,29]
In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.[16,26] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[17,29]
Treatment options under clinical evaluation for angiosarcoma of the soft tissue
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, a surgeon experienced in vascular tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Anwar et al. as reference 48.
Added duration of treatment as a consideration for the administration of propranolol therapy. Also added text to state that there are no consensus guidelines for the treatment duration of propranolol. Also added text about the results of a prospective, multi-institutional study that assessed efficacy, safety, and treatment duration of propranolol in high-risk patients (cited Baselga et al as reference 70).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Vascular Tumors Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Vascular Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-vascular-tumors-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26844334]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2019-11-25
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