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Home , Hemangioma, Vascular anomaly, Vascular tumor

Treat with confidence. Trusted answers from the American Academy of Pediatrics. Early Diagnosis and Intervention of Vascular Anomalies (Infantile and Malformations)

Bernard A. Cohen, MD, FAAP Professor of Dermatology and Pediatrics Johns Hopkins Center

Linda Rozell-Shannon, PhD President and Founder Vascular Foundation Treat with confidence. Trusted answers from the American Academy of Pediatrics. Disclaimer . Presenter Bernard A. Cohen, MD, FAAP o I have no financial disclosures. o I am a member of the International Society for the Study of Vascular Anomalies (ISSVA). o There is finally a US Food and Drug Administration (FDA)-approved treatment for infantile hemangiomas. o I will discuss off-label use of medications for infantile hemangiomas. o Darrow DH, Greene AK, Mancini AJ, Nopper AJ, American Academy of Pediatrics Section on Dermatology, Section on Otolaryngology–Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile . Pediatrics. 2015;136(4):e1060–e1104. . Statements and opinions expressed are those of the authors and not necessarily those of the American Academy of Pediatrics. . Mead Johnson sponsors programs such as this to give healthcare professionals access to scientific and educational information provided by experts. The presenters have complete and independent control over the planning and content of the presentation, and are not receiving any compensation from Mead Johnson for this presentation. The presenters’ comments and opinions are not necessarily those of Mead Johnson. In the event that the presentation contains statements about uses of drugs that are not within the drugs' approved indications, Mead Johnson does not promote the use of any drug for indications outside the FDA-approved product label. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

What’s new (and old but relevant) on Infantile Hemangiomas (and other assorted vascular lesions) Treat with confidence. Trusted answers from the American Academy of Pediatrics. Webinar Outline . Definitions…vascular tumors of infancy . Pathogenesis, morphology, course . Management of uncomplicated (IH) . High risk lesions…segmental, PHACES . New variants you should know . Rx options for complicated lesions Treat with confidence. Trusted answers from the American Academy of Pediatrics.

First a little quiz… Hemangioma (A) or malformation (B)? Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)?

A B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)? Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)? A Capillary B Venous C Lymphatic D ArteriovenousA Capillary E CombinedB Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence.Hemangioma Trusted answers from the (A) American or Academy malformation of Pediatrics. (B)? HemangiomaTreat with confidence. Trusted answers(A) orfrom themalformation American Academy of Pediatrics. (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined HemangiomaTreat with confidence. Trusted answers(A) fromor the malformation American Academy of Pediatrics. (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)? Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangioma (A) or malformation (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangioma (A) or malformation (B)? A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Hemangioma (A) or malformation (B)? Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangioma (A) or malformation (B)?

A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangioma (A) or malformation (B)? A Capillary B Venous C Lymphatic D Arteriovenous E Combined Treat with confidence. Trusted answers from the American Academy of Pediatrics. vs

Vascular anomalies

Vascular Vascular tumor malformation

Kaposiform Tufted Venous, arterial, Infantile hemangioendo- and AVM, capillary, hemangioma thelioma other tumors lymphatic

Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69(3):412–422; Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol. 1997;13:375–423; and Workshops of the International Society for the Study of Vascular Anomalies (ISSVA): 1996 and April 2014 (www.issva.org/workshops). Treat with confidence. Trusted answers from the American Academy of Pediatrics. Definitions: Distinguish from Vascular Malformations

Infantile Hemangioma Vascular Malformation . Usually not present . Present at birth at birth . Dynamic . Static . Regressing . Persistent . Proliferative . Non-proliferative Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangiomas . Incidence 8–10% at 2 months (<1% of newborns) . Family history 8–10% . Location o Head, neck 50% o Trunk 30% o Extremities 20%

(Data from multiple observational studies over last 5 decades.) Treat with confidence. Trusted answers from the American Academy of Pediatrics. Newer Epidemiologic Data . Female predominance: 2.4:1 o Previously published: 1.4–4:1 . White, non-Hispanic . Twins – usually only 1 affected . Mothers – increased age, placental abnormalities . Prematurity . Low birth weight o #1 risk factor for IH o For every 500-g decrease in birth weight, risk of IH increases 25% o Hemangiomas in 1 in 4 infants <1,000 g

Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicenter prospective study of ulcerated hemangiomas. J Pediatrics. 2007;151(6):684–689; Drolet BA, Swanson EA, Frieden IJ, Hemangioma Investigator Group. Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants. J Pediatr. 2008;153(5):712–715; Darrow DH, Greene AK, Mancini AJ, Nopper AJ, American Academy of Pediatrics Section on Dermatology, Section on Otolaryngology–Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile hemangioma. Pediatrics. 2015;136(4):e1060–e1104. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Pathogenesis . Dysregulation of . Imbalance of pro- and anti-angiogenic factors . Dysregulation of endothelial cell proliferation Treat with confidence. Trusted answers from the American Academy of Pediatrics.

VEGF & bFGF in serum during proliferative phase and in involuting phase

Storch CH, Hoeger PH. for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163(2):269–274. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangiomas: Morphology . Superficial . Deep (not to be confused with venous malformation) . Most both Superficial Treat with confidence. Trusted answers from the American Academy of Pediatrics. Subcutaneous Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Combined superficial/deep Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangioma Patterns

. Focal (localized)

. Multifocal (multiple localized)

. Segmental Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangioma . Size 1 mm–20 cm

. Number 85% 1 lesion Rare >100 Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangioma: Early Course . Early, pale macule, central . Growth phase (510 patients [Lampe, 1965]) 50% until 6 months 50% until 12 months 80–90% < X 2 5% X 3 2% X 4 . 85% peak by 3 months (most rapid growth 2–7 weeks) . Certain lesions with prolonged growth phase

Brandling-Bennett HA, Metry DW, Baselga E, et al. Infantile hemangiomas with unusually prolonged growth phase: a case series. Arch Dermatol. 2008;144(12):1632–1637, and Darrow DH, Greene AK, Mancini AJ, Nopper AJ, American Academy of Pediatrics Section on Dermatology, Section on Otolaryngology–Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile hemangioma. Pediatrics. 2015;136(4):e1060–e1104. 1 week 2 weeks 3 weeks Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Uncomplicated Infantile Hemangioma: Prognosis . (Generally) independent of o Size o Number o Sex o Location o Growth o Prematurity o Presence of deep component

. But focal vs multifocal vs segmental is important Treat with confidence. Trusted answers from the American Academy of Pediatrics. Uncomplicated Infantile Hemangioma: Management . Complete physical examination . Close observation . Photodocumentation (website) . Avoidance of aggressive therapy . Parent counseling Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangiomas: Complications . Involvement of vital structures o Airway o Eye o Urethra, anus o Gastrointestinal (GI) tract . Infection/ulceration (local, sepsis) . Pain . Cardiac failure ( lesions, and large lesions anywhere) . Body image . Special patterns (eg, segmental) Treat with confidence. Trusted answers from the American Academy of Pediatrics. Risk of Complications . Data from 1,058 cohort o Haggstrom AN, Drolet BA, Baselga E. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118(3):882–887 o Darrow DH, Greene AK, Mancini AJ, Nopper AJ, American Academy of Pediatrics Section on Dermatology, Section on Otolaryngology–Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile hemangioma. Pediatrics. 2015;136(4):e1060–e1104. . Increased risk with large size, facial location, segmental morphology for short term outcome = complication (24%) and treatment (38%) . Rx for ulcer (23%), eye (6.9%), airway (1.8%), auditory canal (1.1%), cardiac (0.4%) Labial hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. Buttock hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. Disfiguring Eye/airway involvement Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. High Risk Subtypes Large, facial segmental PHACES Nasal tip, ear, large facial Disfigurement, scarring Periorbital or retrobulbar Ocular axis occlusion, astigmatism, amblyopia, tear duct obstruction Segmental “beard area” (S3) Airway IH Perioral Ulceration, disfigurement, feeding difficulties Segmental over lumbosacral Tethered cord, genitourinary anomalies, spine PELVIS Perineal, axilla, neck, perioral Ulceration Anogenital area Caudal regression syndromes (PELVIS, SACRAL, LUMBAR) ______Multifocal Visceral involvement (liver, GI) Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122(2):360–367. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Lumbosacral Hemangiomas . Spinal dysraphism . Anomalies of bony and soft tissue cord . Consider ultrasound before 6 months . Magnetic resonance study after 6 months—requires sedation . Many subsets of segmental hemangiomas Treat with confidence. Trusted answers from the American Academy of Pediatrics. Complicated Presentations Cervicofacial (Beard IH) . 63% association with upper airway hemangiomas . 33% of airway hemangiomas with Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a "beard" cutaneous hemangioma distribution. J Pediatr. 1997;131(4):643–646, with permission from Elsevier. . Stridor, cough, cyanosis, hoarseness . ~40% with airway hemangioma will require tracheostomy

Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a "beard" distribution. J Pediatr. 1997;131(4):643–646, and Chatrath P, Black M, Jani P, Albert DM, Bailey CM. A review of the current management of infantile subglottic haemangioma, including a comparison of CO(2) laser therapy versus tracheostomy. Int J Pediatr Otorhinolaryngol. 2002;64(2):143–157.

Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a "beard" distribution. J Pediatr. 1997;131(4):643–646, with permission from Elsevier. Treat with confidence. Trusted answers from the American Academy of Pediatrics.Segmental/field/non- localized hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. PHACES . Posterior fossa vascular malformations . Hemangiomas . Arterial anomalies . Coarctation of aorta, cardiac defects . Eye abnormalities (microphthalmia, optic nerve hypoplasia, cataracts, increased retinal vascularity) . Sternal clefting +/- supraumbilical raphe

Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics. 2009;124(5):1447– 1456. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Higher correlation with Complicated Presentations structural cerebral and Facial Segmental cerebrovascular anomalies

Frontotemporal (S1) V Frontonasal (S4) I Maxillary (S2)

Mandibular (S3)

Higher correlation with ventral and cardiac defects, including coarctation

Waner M, North PE, Scherer KA, Frieden IJ, Waner A, Mihm MC Jr. The nonrandom distribution of facial hemangiomas. Arch Dermatol. 2003;139(7):869–875. Treat with confidence. Trusted answers from the American Academy of Pediatrics. PHACE(S) . Female-to-male ratio: 9:1 . >20% infants with facial IH: segmental hemangioma o 2% of all hemangiomas o ? More common than Sturge-Weber . Diagnosis with hemangioma and 1 extracutaneous finding

Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A. 2006;140(9):975–986. Another Segmental Treat with confidence. Trusted answers from the American Academy of Pediatrics.Hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Segmental Hemangiomas . Complications . Greater need for treatment . Worse outcome . Associated structural anomalies . Segmental lesions: risk for visceral hemangiomas o Liver > GI, brain, mediastinum o 25% mortality

Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138(12):1567– 1576; Metry DW, Hawrot A, Altman C, Frieden IJ. Association of solitary, segmental hemangiomas of the with visceral hemangiomatosis. Arch Dermatol. 2004;140(5):591–596; and Drolet BA, Dohil M, Golomb MR, et al. Early stroke and cerebral vasculopathy in children with facial hemangiomas and PHACE association. Pediatrics. 2006;117(3):959–964. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangiomas: Risk of Slow Regression or Scarring . Parotid . Lip . Tip of nose Treat with confidence. Trusted answers from the American Academy of Pediatrics. Infantile Hemangioma Variants . RICH (rapidly involuting) . NICH (non-involuting) . PICH (partially involuting) . Features of IH, vascular malformations . Glut-1 negative Rapidly Involuting Congenital Hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics. RICH . Develop in utero . No postnatal growth . 50% gone by 7 months . Glut-1 negative – not = IH . Some histologic features of IH Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Non-involuting Congenital Hemangioma Treat with confidence. Trusted answers from the American Academy of Pediatrics. NICH . Develop in utero . May grow somewhat . Glut-1 negative – not = IH . High flow = IH . Persistent . Surgical excision – not recurrence Another Variant Treat withMinimal confidence. Trusted Growthanswers from the American Infantile Academy of Pediatrics. Hemangioma

Suh KY, Frieden IJ. Infantile hemangiomas with minimal or arrested growth: a retrospective case series. Arch Dermatol. 2010;146(9):971–976. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangiomas: Rx . Systemic corticosteroids Edgerton (1967) Esterly (1968) Brown (1972) Feingold (1978) . Intralesional steroids o Central retinal occlusion o Eyelid necrosis o Atrophy, hematoma o Eyelid depigmentation o Growth delay Treat with confidence. Trusted answers from the American Academy of Pediatrics. Systemic Steroids: Other Considerations . Hypertension o Particularly with high doses o Monitoring? o Long-term risk . Growth o Dose, length of Rx o Catch up growth . Behavioral changes/central nervous system development . Adrenal suppression . Fungal infection . Other risks… Treat with confidence. Trusted answers from the American Academy of Pediatrics.

Newly approved stuff… Treat with confidence. Trusted answers from the American Academy of Pediatrics. Therapy: Propranolol

Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. New Engl J Med. 2008:358 (24):2649–2651. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

. Vasoconstriction of supplying o Visible color change in first 48 hours o From decreased release of nitric oxide . Inhibition of angiogenesis o Effects on pro-angiogenic growth factors, VEGF & bFGF, MMP-2 & MMP-9 o Arrest of growth . Induction of apoptosis o Regression of IH

Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Brit J Dermatol. 2010;163(2):269–274.

65 Treat with confidence. Trusted answers from the American Academy of Pediatrics.

July 22, 2008 Treat with confidence. Trusted answers from the American Academy of Pediatrics.

August 13, 2008 (before Rx) Treat with confidence. Trusted answers from the American Academy of Pediatrics.

August 14, 2008 (day 1) Treat with confidence. Trusted answers from the American Academy of Pediatrics.

August 15, 2008 (day 2) Treat with confidence. Trusted answers from the American Academy of Pediatrics.

August 16, 2008 (day 3) Treat with confidence. Trusted answers from the American Academy of Pediatrics. August 28, 2008 2 weeks later Treat with confidence. Trusted answers from the American Academy of Pediatrics. September 22, 2008 1 month later Treat with confidence. Trusted answers from the American Academy of Pediatrics. Our Experience: Methods . Retrospective analysis in 70 patients with function- threatening or disfiguring cutaneous hemangiomas treated with propranolol o Response to therapy o Complications (hypoglycemia, hypotension, cool hands and feet, etc.) o No serious adverse effects o Drop in blood pressure with first dose but not clinically important Treat with confidence. Trusted answers from the American Academy of Pediatrics. Ongoing experience… . Over 1,000 babies . No serious complications . Our current dosing: 2 mg/kg/d (We are off-label!) Treat with confidence. Trusted answers from the American Academy of Pediatrics. New stuff… . First drug ever approved for treating IH . Great safety and efficacy data . Most exciting drug discovery and implementation in my career . Easy to access Treat with confidence. Trusted answers from the American Academy of Pediatrics. Hemangeol (propranolol hydrochloride 4.28 mg/mL) . Phase II/III clinical trial . 60.4% complete or nearly complete resolution compared to 3.6% placebo . 88% improved at week 5 . Most common adverse drug reactions: ~10% sleep disorders, aggravated upper respiratory infections, diarrhea, vomiting . <2% stopped medication for safety Topical timolol for superficial IH, PG, etc.

Treat with confidence.6.1.15 Trusted answers from the American Academy6.29.15 of Pediatrics.

8.25.15 8.25.15

With permission, Puttgen K. Treat with confidence. Trusted answers from the American Academy of Pediatrics. More Cool Stuff… . Topical beta-blockers . Collaboration with pedsplastics on rebounding IH . Scalp, periocular, nasal tip lesions . Identification of IH requiring early intervention . Other segmental IH . Risk factors for hemangiomas . Hemangiomatosis and visceral lesions . Vascular malformations (oral sirolimus, topical sirolimus, etc.) Treat with confidence. Trusted answers from the American Academy of Pediatrics. Impact of Vascular Anomalies on the Family System Linda Rozell-Shannon (April 2017) . For new parents, having an infant is stressful, but when that infant is diagnosed with a potential disfiguring , parents will experience additional stress. . Wandering from doctor to doctor to find an accurate diagnosis and appropriate treatment plan can result in symptoms of acute stress, disruption to normal family routines, and feelings of helplessness and hopelessness by the entire family, primarily the parents. . Additionally, the stress from the uncertainty over how large or disfiguring these lesions can become can interfere with maternal bonding as the mother becomes fixated on treatment, missing significant milestones in the infant’s normal development. . To further complicate the matter, insurance companies routinely deny the treatment of benign vascular anomalies leaving the families feeling helpless and hopeless. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

. Studies conducted to assess the impact of having an infant with a facial vascular anomaly concluded that there was an interference with normal maternal bonding, the fear of the unknown negatively impacted the family system, and inconsistent information from physicians and potential denial of treatment by insurance providers resulted in symptoms of acute stress. . Due to the lack of consistent information regarding the diagnosis and treatment of these lesions, families often seek outside sources, such as not for profits, that provide accurate information and support to the affected families. . Outdated medical information that promotes a “benign neglect” philosophy further complicates the fact finding of parents who learn about early treatment options on the internet through organizations such as the Vascular Birthmarks Foundation. . Online medical advice provided by vascular anomalies experts provides hope to the families but is often impeded by insurance companies who deny out of network treatment. As a result, families experience cyclical highs and lows as they wander from doctor to doctor and internet resources to internet resources trying to find appropriate treatment options. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

. What can be done???? . Affected families need to know they are not alone. Support groups, such as the Vascular Birthmarks Foundation, exist, which can connect families newly diagnosed with families who have successfully navigated the diagnosis and treatment process. . Affected families need to know there are treatment options available, and these options should be presented and discussed, weighing pros and cons. . Outdated benign neglect protocol needs to be abandoned for a more appropriate approach to early intervention. . Babies need to be referred early for treatment, following the 4-week well baby check up. . If needed, practitioners need to provide documentation for the medical necessity for treatment. . Last, but not least, physicians need to be cognizant and sensitive to the fact that having an infant with a potentially problematic and disfiguring vascular anomaly can interfere with maternal bonding, as well as the entire family system. In some instances, families may need to be referred to a social worker or appropriate mental health expert to resolve any psychosocial issues. Treat with confidence. Trusted answers from the American Academy of Pediatrics. Treat with confidence. Trusted answers from the American Academy of Pediatrics.

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