Childhood Vascular Tumors Treatment (PDQ®)

Treatment Options Under Clinical Evaluation

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, see the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• NCT04589650 (Study Assessing the Efficacy, Safety, and Pharmacokinetics [PK] of Alpelisib [BYL719] in Pediatric and Adult Patients With PIK3CA-Related Overgrowth Spectrum [EPIK-P2]): This study consists of a screening period, core period, extension period, and long-term extension period to assess the efficacy and PK of alpelisib.
• NCT04258046 (Trametinib in the Treatment of Complicated Extracranial Arterial Venous Malformation): This is a phase II study to assess the safety and efficacy of trametinib in the treatment of children and adults.
• NCT05125471 (Cobimetinib in Extracranial Arteriovenous Malformations [COBI-AVM Study]): This is a phase II study to evaluate the safety and efficacy of cobimetinib in the treatment of children and adults.

References

1. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 69 (3): 412-22, 1982. [PubMed: 7063565]
2. Lokmic Z, Mitchell GM, Koh Wee Chong N, et al.: Isolation of human lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model. Angiogenesis 17 (1): 1-15, 2014. [PubMed: 23884796]
3. Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PubMed: 26055853]
4. van der Vleuten CJ, Kater A, Wijnen MH, et al.: Effectiveness of sclerotherapy, surgery, and laser therapy in patients with venous malformations: a systematic review. Cardiovasc Intervent Radiol 37 (4): 977-89, 2014. [PubMed: 24196269]
5. Soblet J, Limaye N, Uebelhoer M, et al.: Variable Somatic TIE2 Mutations in Half of Sporadic Venous Malformations. Mol Syndromol 4 (4): 179-83, 2013. [PMC free article: PMC3666452] [PubMed: 23801934]
6. Luks VL, Kamitaki N, Vivero MP, et al.: Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 166 (4): 1048-54.e1-5, 2015. [PMC free article: PMC4498659] [PubMed: 25681199]
7. Keppler-Noreuil KM, Rios JJ, Parker VE, et al.: PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 167A (2): 287-95, 2015. [PMC free article: PMC4480633] [PubMed: 25557259]
8. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
9. Hammer J, Seront E, Duez S, et al.: Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study. Orphanet J Rare Dis 13 (1): 191, 2018. [PMC free article: PMC6206885] [PubMed: 30373605]
10. Maruani A, Tavernier E, Boccara O, et al.: Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial. JAMA Dermatol 157 (11): 1289-1298, 2021. [PMC free article: PMC8444064] [PubMed: 34524406]
11. Venot Q, Blanc T, Rabia SH, et al.: Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558 (7711): 540-546, 2018. [PMC free article: PMC7610773] [PubMed: 29899452]
12. Couto JA, Huang AY, Konczyk DJ, et al.: Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet 100 (3): 546-554, 2017. [PMC free article: PMC5339083] [PubMed: 28190454]
13. Dori Y, Smith C, Pinto E, et al.: Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation. Pediatrics 146 (6): , 2020. [PubMed: 33219052]
14. Nakano TA, Rankin AW, Annam A, et al.: Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome. J Pediatr 248: 81-88.e1, 2022. [PubMed: 35605646]
15. Homayun-Sepehr N, McCarter AL, Helaers R, et al.: KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight 6 (15): , 2021. [PMC free article: PMC8410066] [PubMed: 34156985]
16. Foster JB, Li D, March ME, et al.: Kaposiform lymphangiomatosis effectively treated with MEK inhibition. EMBO Mol Med 12 (10): e12324, 2020. [PMC free article: PMC7539180] [PubMed: 32894644]
17. Chowers G, Abebe-Campino G, Golan H, et al.: Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition. Pediatr Res 94 (6): 1911-1915, 2023. [PMC free article: PMC9440952] [PubMed: 35246606]
18. Lekwuttikarn R, Lim YH, Admani S, et al.: Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child. JAMA Dermatol 155 (2): 256-257, 2019. [PMC free article: PMC7186908] [PubMed: 30566190]
19. Nicholson CL, Flanagan S, Murati M, et al.: Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise. Pediatr Dermatol 39 (2): 316-319, 2022. [PubMed: 35014097]
20. Cooke DL, Frieden IJ, Shimano KA: Angiographic evidence of response to trametinib therapy for a spinal cord arteriovenous malformation. J Vasc Anom (Phila) 2 (3): e018, 2021. Available online. Last accessed July 6, 2023..

References

1. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al.: A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med 372 (8): 735-46, 2015. [PubMed: 25693013]
2. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
3. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
4. International Society for the Study of Vascular Anomalies: ISSVA Classification of Vascular Anomalies. Milwaukee, Wi: International Society for the Study of Vascular Anomalies, 2018. Available online. Last accessed June 7, 2022.
5. Wassef M, Blei F, Adams D, et al.: Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 136 (1): e203-14, 2015. [PubMed: 26055853]

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PMC free article: PMC2881732] [PubMed: 20404250]
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
4. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. National Cancer Institute, 2013, Section 28. Also available online. Last accessed August 21, 2023.
5. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. National Cancer Institute, 2013, Section 29. Also available online. Last accessed August 21, 2023.
6. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
7. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.

Infantile Hemangioma

Clinical presentation

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) (see Figure 1).[8,9]

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 and generally appear in the head and neck but can be anywhere on the body.

Infantile hemangiomas can be characterized as follows:

• Local: Most lesions are localized and noted to be in a well-defined area without evidence of a geometric pattern.
• Segmental: Most segmental hemangiomas occur in the head and neck region (PHACE syndrome) but can be seen in the genitourinary area, arm, chest, or legs (PELVIS/LUMBAR/SACRAL syndrome).

  • Diffuse hemangiomas of the face demonstrate defined cutaneous patterns. Several studies have evaluated the distributions of these hemangiomas and found the following four distinct patterns or segments:

    • Segment 1 involves the lateral forehead, anterior temporal scalp, and the lateral frontal scalp.
    • Segments 2 and 3 are located over the maxillary and mandibular area.
    • Segment 4 covers the medial frontal scalp, nose, and philtrum.
  Two papers have noted this observation and suggest the involvement of neural crest derivatives in facial hemangioma development.[10,11] Segmental hemangiomas commonly occur in females and are more likely associated with complications and other syndromes.[12,13]
  For information about PHACE syndrome or PELVIS/LUMBAR/SACRAL syndrome, see the Syndromes associated with infantile hemangioma section.
• Multiple: More than one lesion but noted in the past as greater than five lesions, because of the increased risk of visceral involvement (mostly the liver).

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.[14] 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.

Ulceration is the most common complication of infantile hemangiomas, occurring in 10% to 15% of patients. Ulceration typically occurs during the proliferative phase, and it can lead to bleeding and secondary infections.[15] Most other complications in the proliferative phase result from the impact of the mass on local structures (e.g., visual or auditory compromise, airway obstruction).[16]

Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution. Hemangiomas with a history of ulceration are more likely to cause scarring and potential local anatomical complications.[15] Rare instances of dysesthesias in sites of involuted infantile hemangiomas in the absence of ulceration have been described.[17][Level of evidence C1] 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.[18]

Diagnostic 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 diagnostic ultrasonography is beneficial if there is a deeper lesion without a cutaneous component and reveals a well-circumscribed, hypoechoic, high-flow lesion with a typical Doppler wave characteristic.[37] Additionally, infants with five or more cutaneous hemangiomas should undergo ultrasonography of the liver to screen for hepatic hemangioma.[38]

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 (see Figure 2). They resolve spontaneously and are pathologically GLUT1 positive.[39] 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.[40] Associated soft tissue hypertrophy may persist through childhood.[41]

Figure 2. 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. Airway infantile hemangioma incidence increases with a larger area of bearded involvement.[42]

Airway infantile hemangiomas 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 (30%) had bearded distributions, 2 (15%) had cutaneous hemangiomas, and 7 (55%) had no cutaneous lesions.[43] For information about the treatment of airway infantile hemangiomas, see the Propranolol therapy section.

Ophthalmologic involvement of hemangiomas

Periorbital hemangiomas can cause visual compromise.[44] This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can distort the cornea or obstruct the visual axis. Subcutaneous periocular hemangiomas 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.

Two institutions in France and Canada performed a retrospective analysis of patients in a vascular anomalies practice. The investigators reviewed the records of all patients with a diagnosis of segmental facial or periorbital focal infantile hemangioma who had clinical photographs and brain magnetic resonance imaging (MRI) available.[45][Level of evidence C1] The study included 122 children (90 girls, 32 boys; mean age, 16.6 months). Forty-five children (36.9%) had a facial infantile hemangioma larger than 5 cm. Twenty-two patients (18.0%) had PHACES or possible PHACES syndrome. Cerebrovascular structural anomalies were seen in 14 of 22 patients with PHACES syndrome and no patients without PHACES syndrome. Brain anomalies were seen in 6 of 22 patients with PHACES syndrome and 1 patient without PHACES syndrome (P < .001). Cardiovascular anomalies were seen in six patients, and ocular anomalies were seen in eight patients. Of these 14 patients, 13 had PHACES syndrome. The authors concluded that clinical concern about associated extracutaneous anomalies is warranted for all children with facial segmental or periorbital focal infantile hemangiomas, including those with small hemangiomas.

Infantile hemangiomas can occur in the conjunctiva (see Figure 3). These hemangiomas can be associated with other ophthalmologic abnormalities and are treated with oral or topical beta-blockers.[46]

Figure 3. 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

PHACE syndrome

Posterior fossa–brain malformations; Hemangiomas; Arterial, Cardiac, and Eye abnormalities (PHACE) syndrome: PHACE syndrome represents a spectrum of diseases and is defined by the presence of large segmental infantile hemangiomas, usually on the face or head, but can include the neck, chest, or arm, in association with one or more congenital malformations (see Figure 4).[47] PHACE syndrome is more common in girls and in full-term, normal birth weight and singleton infants.[13,48-52] The syndrome is not rare among patients with infantile hemangiomas. A prospective study of 108 infants with large facial hemangiomas observed that 31% of patients had PHACE syndrome.[53] Rare cases of PHACE syndrome have been reported in infants with hemangiomas smaller than 5 cm.[45][Level of evidence C1]

Figure 4. 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. Garzon MC, Epstein LG, Heyer GL, et al.: PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 178: 24-33.e2, 2016. PMID: 27659028

Consensus criteria for definite and possible PHACE syndrome were updated at an expert panel meeting, as follows:[47]

PHACE

-

Posterior fossa abnormalities. Posterior fossa malformations include Dandy-Walker complex, cerebellar hypoplasia, atrophy, and dysgenesis/agenesis of the vermis. Effects of these anomalies include developmental delays and pituitary dysfunction.[54]

-

Hemangiomas.[53,55-58]

• A large segmental hemangioma over the face and/or scalp with a surface area of 22 cm² or greater (5 cm × 4.5 cm).
• A large segmental hemangioma of the neck, trunk, or proximal upper extremity.

Infants with two major criteria of PHACE (e.g., supraumbilical raphe and coarctation of the aorta) but lacking cutaneous infantile hemangiomas should undergo complete evaluation for PHACE.

-

Arterial abnormalities. Cerebrovascular anomalies can include carotid artery abnormalities (including tortuosity) and absence, dilation/aneurysm, or narrowing of cerebral vessels. These anomalies, especially related to the carotid arteries, can lead to progressive arterial occlusion and even stroke. The risk categories are as follows:[51,52,59-61]

• Low risk: This category includes patients with arterial anomalies frequently seen in a general screening population. It also includes findings that have either no or very minimal clinical impact on patient outcome, even if rarely seen in the general population. Examples are persistent embryonic arteries, anomalous arterial origin or course, and circle of Willis variants.
• Intermediate risk: Includes patients with nonstenotic dysgenesis, including those with ectatic or segmentally enlarged arteries. It also includes patients with a narrowing or occlusion of arteries proximal to the circle of Willis, with no perceived hemodynamic risk. An evaluation of the patency of the circle of Willis is essential.
• High risk: This category includes patients with one or more of the following:

  -

  Significant narrowing (>25%) or occlusion of principal cerebral vessels within or above the circle of Willis that results in an isolated circulation.

  -

  Tandem or multiple arterial stenoses associated with complex blood flow that may potentially result in diminished cerebral perfusion. Patients with cerebrovascular stenosis in the setting of coarctation of the aorta are likely at higher risk of transient and permanent neurological ischemic events.

  -

  Imaging findings in the brain parenchyma suggestive of chronic or silent ischemia, or progressive steno-occlusive disease. These parenchymal brain MRI findings include existing infarction, chronic or border zone ischemic changes, and presence of lenticulostriate collateral dilation or pial collaterals.

-

Cardiac abnormalities. Aortic arch anomalies observed in PHACE syndrome are unusually complex, with involvement of the transverse and descending aorta arch. The arch obstruction is most often long-segment. The obstruction is frequently characterized by areas of arch narrowing with adjacent segments of marked aneurysmal dilatation.

-

Eye abnormalities. Ophthalmologic anomalies can include microphthalmos, retinal vascular abnormalities, persistent fetal retinal vessels, exophthalmos, coloboma, and optic nerve atrophy. These abnormalities are rare and occur in 7% to 10% of patients.[62]

A retrospective review identified midline rhabdomyomatous mesenchymal hamartomas and chin hamartomas in a small number of children with PHACE or LUMBAR syndrome.[63] These are not currently included as minor criteria.

Diagnosis of PHACE syndrome requires clinical examination, cardiac evaluation with echocardiogram, ophthalmologic evaluation, and MRI/magnetic resonance angiogram (MRA) of the head and neck. All patients with intermediate-risk and high-risk central nervous system (CNS) findings should be monitored by a neurologist and/or neurosurgeon. Coarctation of the aorta requires immediate cardiology consultation, and a cardiac MRI/MRA may be warranted. A report of two patients with retro-orbital infantile hemangiomas and arteriopathy suggested a possible new presentation of PHACE syndrome.[58] For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE syndrome may be needed on the basis of CNS findings.

Short- and long-term issues related to PHACE syndrome include the following:[64-66]; [67][Level of evidence C1]

• Headache.

  • May present at an early age.
  • Can be severe.
  • New-onset headaches should be evaluated for vasculopathy and/or cerebral ischemia.
  • Neurology referral is recommended.
  • Vasoconstrictive medications are contraindicated.
• Hearing loss and speech-language delays.

  • Speech-language delays may be a consequence of hearing deficits, prolonged hospitalizations, or may occur because of other neurodevelopmental anomalies.
  • Sensorineural hearing loss is the most common type, and it is usually ipsilateral to the infantile hemangioma, which may involve the ipsilateral cranial nerve VIII.
  • Early detection is crucial.
  • All patients with PHACE syndrome should undergo hearing screening as a newborn and at least one follow-up if initial screening is normal.
• Dysphagia, feeding disorders, speech disorders, and/or language delay.

  • Increased in patients with posterior fossa malformations, lip/oropharynx or airway hemangiomas, hearing loss, and those with a history of cardiac surgery.
  • Patients should undergo an initial speech language evaluation before age 24 months.
  • Patients with feeding difficulties should be referred for evaluation by a pediatric speech-language pathologist at any age.
  • Dysphagia may be secondary to the disease location (lip, oral cavity, and pharynx) or oral motor coordination.
• Endocrine abnormalities.

  • Thyroid dysfunction and hypopituitarism resulting in growth hormone deficiency are the most frequently reported abnormalities.
  • Other manifestations of hypopituitarism, including hypogonadotropic hypogonadism and adrenal insufficiency, have been described.
  • Patients should undergo neonatal screening and repeat studies if symptomatic.
  • Growth hormone deficiency: Most reported cases are associated with hypopituitarism with empty or partially empty sella turcica noted on MRI, but it may also occur without evidence of central nervous system malformations.
  • Neonatal hypoglycemia can be a sign of hypopituitarism and should prompt additional endocrinologic evaluation.
  • Other consequences of pituitary dysfunction include hypogonadotropic hypogonadism, manifesting with delayed pubertal onset and late-onset adrenal insufficiency. These findings emphasize the importance of focused assessment of height, weight, and developmental milestones in the care of children with PHACE.
• Dental abnormalities (enamel hypoplasia).

  • A study of 18 children with PHACE or possible PHACE syndrome revealed that 28% of patients had enamel hypoplasia. All of the affected children had intraoral hemangiomas. Five of 11 (45%) patients with intraoral hemangiomas had enamel defects. Children with enamel hypoplasia are at increased risk of developing caries.
  • Patients should be examined for the presence of intraoral hemangiomas. If they are present, patients should be referred to a pediatric dentist by age 1 year for early screening and management.
• Long-term outcomes and quality of life.

  • An international group of experts published a report of a multicenter study that used cross-sectional interviews and chart review to examine long-term outcomes and quality of life for patients older than 10 years with PHACE syndrome.[68] Individuals were defined as having definite PHACE by previously reported guidelines.[47] This was the largest cohort of adolescents and adults with PHACE. Of 153 individuals who were contacted, 104 participated in the study (68%). The median age was 14 years (range, 10–77 years). This study found that PHACE syndrome was associated with long-term, mild-to-severe morbidities, including infantile hemangioma residua (94.1%), headaches/migraines (72.1%), learning differences (45.1%), and progressive arteriopathy (29.4%). Additional findings from the study are reported in Table 3.
    Most patients with hemangioma residua were satisfied or very satisfied with their appearance (89.5%). Those with surgery and/or ulceration were less likely to report a minimal impact on self-confidence. Of the 68 patients with arteriopathy and available follow-up imaging, 6 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite this finding, the proportion of patients with ischemic stroke was low (2 of 104; 1.9%). Patient-Reported Outcomes Measurement Information System (PROMIS) global health scores were lower than population norms by at least 1 standard deviation. Given the overall prevalence of PHACE, it was not possible to obtain the proper power to accurately assess all outcomes. The authors of the study concluded that primary and specialty follow-up care is important for patients with PHACE into adulthood. Further study is needed to identify precise guidelines for long-term follow-up.[68]

    

    Table

    Table 3. Additional Findings Identified Among the PHACE Syndrome Cohort^a.

LUMBAR/PELVIS/SACRAL syndrome

Infantile hemangiomas located over the lumbar or sacral spine may be associated with genitourinary, anorectal anomalies, or neurological issues such as tethered cord.[69-72] The following criteria have been used to describe segmental infantile hemangioma syndrome in the lumbar, pelvic, and sacral areas. This syndrome has been described in the literature using several acronyms.

LUMBAR

-

Lower-body hemangiomas and other cutaneous defects.

-

Urogenital anomalies or ulceration.

-

Myelopathy.

-

Bony deformities.

-

Anorectal malformations or arterial anomalies.

-

Renal anomalies.

PELVIS

-

Perineal hemangiomas.

-

External genital malformations.

-

Lipomyelomeningocele.

-

Vesicorenal abnormalities.

-

Imperforate anus.

-

Skin tag.

SACRAL

-

Spinal dysraphism.

-

Anogenital.

-

Cutaneous.

-

Renal and urologic anomalies Associated with an angioma of Lumbosacral localization.

Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasonography or MRI, depending on the age of the patient. In several studies, ultrasonography evaluations have failed to identify some spinal abnormalities that were later found on MRI evaluation.[73,74]

Congenital Hemangiomas

Hepatic Vascular Tumors (HVT)

With the development of the new WHO and ISSVA classifications, the terminology of pediatric hepatic vascular tumors has changed.[148-150] The historical Dehner classification of types 1, 2, and 3 liver hemangioendothelioma is no longer favored by pathologists.[151] The term hemangioendothelioma is not considered an isolated entity.

On MRI, hepatic vascular liver tumors are hyperintense on T2 imaging and hypointense on T1 imaging, with postcontrast imaging demonstrating early peripheral enhancement with eventual diffuse enhancement.[76] In practice, these tumors have been classified according to their clinical characteristics and radiological assessment.[76,152]

Lesions are usually divided into the following three categories:[76,152]

• Congenital hemangiomas.
• Infantile hemangiomas.
• Diffuse hepatic infantile hemangiomas.

A more appropriate classification uses an interdisciplinary evaluation, including pathological classification with genomic assessment, radiological imaging evaluation, and clinical history and examination. This is based on the ISSVA and WHO classifications. A study of 33 cases of pediatric hepatic vascular tumors were analyzed by clinicopathologic characteristics from 1970 to 2021.[153] Thirteen cases were identified as hepatic congenital hemangiomas. All were single lesions, and most of these were RICH. Ten patients had hepatic infantile hemangiomas. Three patients had hepatic angiosarcoma, and one patient had hepatic epithelioid hemangioendothelioma. Six patients were excluded from the study, five with vascular malformations and one with vascular dominant mesenchymal hamartoma. The study revealed the importance of an interdisciplinary team approach in the assessment of these tumors.

Congenital hemangiomas

Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH, rarely PICH) (see Figure 6). RICH can present with symptoms of heart failure and mild to moderate coagulopathy but are typically detected by antenatal ultrasonography or as an asymptomatic mass in the newborn period.

Treatment options for focal vascular lesions of the liver include the following:

1. Supportive management. Most lesions are asymptomatic and can be monitored through involution using ultrasonography.
2. Embolization. This procedure is considered for severe symptomatic shunting that is unresponsive to treatment for congestive heart failure. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.[154]
3. Surgery. Patients with massive focal symptomatic hepatic congenital hemangioma unresponsive to supportive management or radiological intervention may be surgical candidates for resection. This is a rare circumstance and needs to be evaluated by an interdisciplinary vascular anomaly team. Indication for surgical removal includes rupture, bleeding, and nonresolving coagulopathy. Two patients were reported to require surgical resection after the development of clinically significant ascites as their RICH involuted.[155,156]

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.[76,152] 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.[157]

Figure 6. 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.

Diffuse hepatic infantile hemangiomas

Diffuse liver lesions are very serious (see Figure 7). Complications include hypothyroidism caused by the expression of iodothyronine deiodinase, high-output or congestive heart failure, and abdominal compartment syndrome.[75,76,158,159]

Figure 7. 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:

1. Propranolol: Beta-blockers are the most common treatment for diffuse and some multifocal infantile hemangiomas of the liver. Treatment doses of 2 to 3 mg/kg per day are indicated.[92]
2. Thyroid hormone replacement: Thyroid hormone replacement therapy must be aggressive if hypothyroidism is diagnosed. Treatment with higher doses of hormones may be needed because the deficiency is caused by the aggressive consumption of the hormone by the tumor.[78]
3. Chemotherapy: Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.[76,160,161]
4. Transplant: If a patient does not respond to medical management, a transplant may be indicated.[162] Transplant is considered only for patients with severe diffuse lesions who have multisystem organ failure and there is insufficient time for effective pharmacologic therapy.

There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas.[163,164] It is not clear that all cases were caused by the 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 ultrasonography. For more information, see the Angiosarcoma section.

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 is very high in all newborns but will rapidly fall to normal levels in several months. AFP levels should rapidly diminish, but failure to do so or a rising trend of AFP should elicit concern for hepatoblastoma. There are no prospective studies investigating AFP elevation in patients with hemangiomas.[165,166] Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcomas, metastatic neuroblastomas, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.[167]

Table

Table 4. Distinguishing Features of Pediatric Hepatic Vascular Tumors^a.

Spindle Cell Hemangioma

Epithelioid Hemangioma

Pyogenic Granuloma (Lobular Capillary Hemangioma)

Angiofibroma

Juvenile Nasopharyngeal Angiofibroma

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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.

Clinical presentation

Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area.[3] Most lesions involve the skin (see Figure 8). 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. Primary bone lesions may cause pain or other nonspecific findings, even without an obvious mass on physical examination.[5][Level of evidence C2] Lesions are usually unifocal and growth is expansive and contiguous. Local lymph nodes may be involved, but there are no reports of distant metastasis. Rare multifocal presentations have been reported, mostly in the bone.[1-3]

Figure 8. Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon. The lesion is indurated, firm, and warm with petechiae and purpura. Credit: Denise Adams, M.D.

Fifty to seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon (KMP), which is a life-threatening complication. The risk of developing Kasabach-Merritt phenomenon is highest in patients with congenital lesions, lesions larger than 8 cm, and when kaposiform hemangioendothelioma arises in the retroperitoneum or mediastinum.[3,6] This condition is characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and 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, serious bleeding, and even death. 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 anomalies specialist.[3] The mortality rate is unclear but it has been reported to be as high as 30%.[3,6]

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24. Fernandez-Pineda I, Lopez-Gutierrez JC, Ramirez G, et al.: Vincristine-ticlopidine-aspirin: an effective therapy in children with Kasabach-Merritt phenomenon associated with vascular tumors. Pediatr Hematol Oncol 27 (8): 641-5, 2010. [PubMed: 20863161]
25. Fernandez-Pineda I, Lopez-Gutierrez JC, Chocarro G, et al.: Long-term outcome of vincristine-aspirin-ticlopidine (VAT) therapy for vascular tumors associated with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 60 (9): 1478-81, 2013. [PubMed: 23609996]
26. Kai L, Wang Z, Yao W, et al.: Sirolimus, a promising treatment for refractory Kaposiform hemangioendothelioma. J Cancer Res Clin Oncol 140 (3): 471-6, 2014. [PubMed: 24464150]
27. Hammill AM, Wentzel M, Gupta A, et al.: Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer 57 (6): 1018-24, 2011. [PubMed: 21445948]
28. Blatt J, Stavas J, Moats-Staats B, et al.: Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer 55 (7): 1396-8, 2010. [PubMed: 20730884]
29. Ji Y, Chen S, Xiang B, et al.: Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer 141 (4): 848-855, 2017. [PubMed: 28486787]
30. Adams DM, Trenor CC, Hammill AM, et al.: Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies. Pediatrics 137 (2): e20153257, 2016. [PMC free article: PMC4732362] [PubMed: 26783326]
31. López V, Martí N, Pereda C, et al.: Successful management of Kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon using vincristine and ticlopidine. Pediatr Dermatol 26 (3): 365-6, 2009 May-Jun. [PubMed: 19706115]
32. Oza VS, Mamlouk MD, Hess CP, et al.: Role of Sirolimus in Advanced Kaposiform Hemangioendothelioma. Pediatr Dermatol 33 (2): e88-92, 2016 Mar-Apr. [PubMed: 26864138]
33. Wang Z, Yao W, Sun H, et al.: Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol 46 (11): 956-961, 2019. [PubMed: 31489702]
34. Ji Y, Chen S, Zhou J, et al.: Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial. Blood 139 (11): 1619-1630, 2022. [PubMed: 35030255]
35. Zhang G, Chen H, Gao Y, et al.: Sirolimus for treatment of Kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon: a retrospective cohort study. Br J Dermatol 178 (5): 1213-1214, 2018. [PubMed: 29388191]
36. Mariani LG, Schmitt IR, Garcia CD, et al.: Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. Pediatr Blood Cancer 66 (8): e27810, 2019. [PubMed: 31087627]
37. Ying H, Qiao C, Yang X, et al.: A Case Report of 2 Sirolimus-Related Deaths Among Infants With Kaposiform Hemangioendotheliomas. Pediatrics 141 (Suppl 5): S425-S429, 2018. [PubMed: 29610165]
38. Russell TB, Rinker EK, Dillingham CS, et al.: Pneumocystis Jirovecii Pneumonia During Sirolimus Therapy for Kaposiform Hemangioendothelioma. Pediatrics 141 (Suppl 5): S421-S424, 2018. [PubMed: 29610164]
39. Ji Y, Chen S, Yang K, et al.: Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet J Rare Dis 15 (1): 39, 2020. [PMC free article: PMC6998257] [PubMed: 32014025]
40. Schaefer BA, Wang D, Merrow AC, et al.: Long-term outcome for kaposiform hemangioendothelioma: A report of two cases. Pediatr Blood Cancer 64 (2): 284-286, 2017. [PubMed: 27701822]

Pseudomyogenic (Epithelioid Sarcoma–Like) Hemangioendothelioma

Retiform Hemangioendothelioma

Papillary Intralymphatic Angioendothelioma

Composite Hemangioendothelioma

Kaposi Sarcoma

References

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24. Soldado F, Fontecha CG, Haddad S, et al.: Composite vascularized fibular epiphyseo-osteo-periosteal transfer for hip reconstruction after proximal femoral tumoral resection in a 4-year-old child. Microsurgery 32 (6): 489-92, 2012. [PubMed: 22511340]
25. Jackson CC, Dickson MA, Sadjadi M, et al.: Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8. Pediatr Blood Cancer 63 (3): 392-7, 2016. [PMC free article: PMC4984265] [PubMed: 26469702]
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27. El-Mallawany NK, Kamiyango W, Slone JS, et al.: Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study. PLoS One 11 (4): e0153335, 2016. [PMC free article: PMC4833299] [PubMed: 27082863]
28. Rees CA, Keating EM, Lukolyo H, et al.: Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review. Pediatr Blood Cancer 63 (8): 1325-31, 2016. [PMC free article: PMC7340190] [PubMed: 27082516]
29. Macken M, Dale H, Moyo D, et al.: Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children. Pediatr Blood Cancer 65 (2): , 2018. [PubMed: 28988435]
30. Silverstein A, Kamiyango W, Villiera J, et al.: Long-term outcomes for children and adolescents with Kaposi sarcoma. HIV Med 23 (2): 197-203, 2022. [PMC free article: PMC9121366] [PubMed: 34634187]
31. Régnier-Rosencher E, Guillot B, Dupin N: Treatments for classic Kaposi sarcoma: a systematic review of the literature. J Am Acad Dermatol 68 (2): 313-31, 2013. [PubMed: 22695100]
32. Tsao MN, Sinclair E, Assaad D, et al.: Radiation therapy for the treatment of skin Kaposi sarcoma. Ann Palliat Med 5 (4): 298-302, 2016. [PubMed: 27701876]
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34. Lebbe C, Garbe C, Stratigos AJ, et al.: Diagnosis and treatment of Kaposi's sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer 114: 117-127, 2019. [PubMed: 31096150]

Epithelioid Hemangioendothelioma

Angiosarcoma

References

1. Mehrabi A, Kashfi A, Fonouni H, et al.: Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 107 (9): 2108-21, 2006. [PubMed: 17019735]
2. Haro A, Saitoh G, Tamiya S, et al.: Four-year natural clinical course of pulmonary epithelioid hemangioendothelioma without therapy. Thorac Cancer 6 (4): 544-7, 2015. [PMC free article: PMC4511336] [PubMed: 26273413]
3. Sardaro A, Bardoscia L, Petruzzelli MF, et al.: Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol Rev 8 (2): 259, 2014. [PMC free article: PMC4419652] [PubMed: 25992243]
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5. Adams DM, Hammill A: Other vascular tumors. Semin Pediatr Surg 23 (4): 173-7, 2014. [PubMed: 25241094]
6. Xiao Y, Wang C, Song Y, et al.: Primary epithelioid hemangioendothelioma of the kidney: the first case report in a child and literature review. Urology 82 (4): 925-7, 2013. [PubMed: 23726166]
7. Reich S, Ringe H, Uhlenberg B, et al.: Epithelioid hemangioendothelioma of the lung presenting with pneumonia and heart rhythm disturbances in a teenage girl. J Pediatr Hematol Oncol 32 (4): 274-6, 2010. [PubMed: 20445417]
8. Cournoyer E, Al-Ibraheemi A, Engel E, et al.: Clinical characterization and long-term outcomes in pediatric epithelioid hemangioendothelioma. Pediatr Blood Cancer 67 (2): e28045, 2020. [PubMed: 31724797]
9. Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999. [PubMed: 10022152]
10. Ackermann O, Fabre M, Franchi S, et al.: Widening spectrum of liver angiosarcoma in children. J Pediatr Gastroenterol Nutr 53 (6): 615-9, 2011. [PubMed: 21832953]
11. Raheja A, Suri A, Singh S, et al.: Multimodality management of a giant skull base hemangioendothelioma of the sphenopetroclival region. J Clin Neurosci 22 (9): 1495-8, 2015. [PubMed: 25986183]
12. Ahmad N, Adams DM, Wang J, et al.: Hepatic epithelioid hemangioendothelioma in a patient with hemochromatosis. J Natl Compr Canc Netw 12 (9): 1203-7, 2014. [PubMed: 25190690]
13. Otte JB, Zimmerman A: The role of liver transplantation for pediatric epithelioid hemangioendothelioma. Pediatr Transplant 14 (3): 295-7, 2010. [PubMed: 20331517]
14. Stacchiotti S, Provenzano S, Dagrada G, et al.: Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol 23 (9): 2735-44, 2016. [PubMed: 27334221]
15. Semenisty V, Naroditsky I, Keidar Z, et al.: Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma-a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 15: 402, 2015. [PMC free article: PMC4437555] [PubMed: 25967676]
16. Engel ER, Cournoyer E, Adams DM, et al.: A Retrospective Review of the Use of Sirolimus for Pediatric Patients With Epithelioid Hemangioendothelioma. J Pediatr Hematol Oncol 42 (8): e826-e829, 2020. [PubMed: 31714437]
17. Orbach D, Van Noesel MM, Brennan B, et al.: Epithelioid hemangioendothelioma in children: The European Pediatric Soft Tissue Sarcoma Study Group experience. Pediatr Blood Cancer 69 (10): e29882, 2022. [PubMed: 35841307]
18. Cioffi A, Reichert S, Antonescu CR, et al.: Angiosarcomas and other sarcomas of endothelial origin. Hematol Oncol Clin North Am 27 (5): 975-88, 2013. [PubMed: 24093171]
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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 in the care of their 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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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:

• Denise Adams, MD (Children's Hospital Boston)
• Sally J. Cohen-Cutler, MD, MS (Children's Hospital of Philadelphia)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD
• Michael Jeng, MD (Stanford Medicine Children's Health)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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.

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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]

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