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

Early Diagnosis and Intervention of Vascular Anomalies

(Infantile Hemangiomasand Malformations)

Bernard A. Cohen, MD, FAAPProfessor of Dermatology and PediatricsJohns Hopkins Center

Linda Rozell-Shannon, PhDPresident and FounderVascular Birthmarks Foundation


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 hemangioma. 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.


What’s new (and old but relevant) onInfantile Hemangiomas

(and other assorted vascular lesions)


Webinar Outline

Definitions…vascular tumors of infancy

Pathogenesis, morphology, course

Management of uncomplicated infantile hemangioma (IH)

High risk lesions…segmental, PHACES

New variants you should know

Rx options for complicated lesions


First a little quiz…Hemangioma (A) or malformation (B)?


A CapillaryB VenousC LymphaticD ArteriovenousE Combined

Hemangioma (A) or malformation (B)?



A CapillaryB VenousC LymphaticD ArteriovenousE Combined


A Capillary

B Venous

C Lymphatic

D Arteriovenous

E Combined


A Capillary B VenousC LymphaticD ArteriovenousE Combined

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


Vascular Tumor vs Vascular Malformation

Vascularanomalies

Vasculartumor

Infantilehemangioma

Kaposiform hemangioendo-

thelioma

Tufted angioma and other tumors

Vascular malformation

Venous, arterial, AVM, capillary,

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).


Definitions: Distinguish from Vascular Malformations

Infantile Hemangioma

Usually not presentat birth

Dynamic

Regressing

Proliferative

Vascular Malformation

Present at birth

Static

Persistent

Non-proliferative


Infantile Hemangiomas

Incidence 8–10% at 2 months

(<1% of newborns)

Family history 8–10%

Locationo Head, neck 50%

o Trunk 30%

o Extremities 20%

(Data from multiple observational studies over last 5 decades.)


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 IHo 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.


Pathogenesis

Dysregulation of angiogenesis

Imbalance of pro- and anti-angiogenic factors

Dysregulation of endothelial cell proliferation


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

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


Infantile Hemangiomas: Morphology

Superficial

Deep (not to be confused with venous malformation)

Most both


Superficial


Subcutaneous


Combined superficial/deep


Hemangioma Patterns

Focal (localized)

Multifocal (multiple localized)

Segmental


Infantile Hemangioma

Size 1 mm–20 cm

Number 85% 1 lesion

Rare >100


Infantile Hemangioma: Early Course

Early, pale macule, central telangiectasia

Growth phase (510 patients [Lampe, 1965])50% until 6 months50% until 12 months80–90% < X 2

5% X 32% X 4

85% peak by 3 months (most rapid growth 2–7 weeks)

Certain lesions with prolonged growth phaseBrandling-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


Uncomplicated Infantile Hemangioma: Prognosis

(Generally) independent ofo Sizeo Numbero Sexo Locationo Growtho Prematurityo Presence of deep component

But focal vs multifocal vs segmental is important


Uncomplicated Infantile Hemangioma: Management

Complete physical examination

Close observation

Photodocumentation (website)

Avoidance of aggressive therapy

Parent counseling


Infantile Hemangiomas: Complications

Involvement of vital structureso Airway

o Eye

o Urethra, anus

o Gastrointestinal (GI) tract

Infection/ulceration (local, sepsis)

Pain

Cardiac failure (liver lesions, and large lesions anywhere)

Body image

Special patterns (eg, segmental)


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


Buttock hemangioma


Disfiguring Eye/airway involvement


High Risk Subtypes

Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122(2):360–367.

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 spine

Tethered cord, genitourinary anomalies, PELVIS

Perineal, axilla, neck, perioral Ulceration

Anogenital area

_______________________Multifocal

Caudal regression syndromes (PELVIS, SACRAL, LUMBAR)_______________________________Visceral involvement (liver, GI)


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


Complicated Presentations Cervicofacial (Beard IH)

63% association with upper

airway hemangiomas

33% of airway hemangiomas with cutaneous hemangioma

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.

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.Treat with confidence. Trusted answers from the American Academy of Pediatrics.Segmental/field/non-localized hemangioma


PHACES

Posterior fossa vascular malformations Hemangiomas Arterial anomalies Coarctation of aorta, cardiac defects Eye abnormalities (microphthalmia, optic nerve

hypoplasia, cataracts, increasedretinal vascularity)

Sternal clefting +/- supraumbilicalraphe

Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics. 2009;124(5):1447–1456.


Complicated Presentations Facial Segmental

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.

Frontonasal

(S4)

Maxillary (S2)

Mandibular

(S3)

Frontotemporal

(S1)

V

I

Higher correlation with structural cerebral and cerebrovascular anomalies

Higher correlation with ventral and cardiac defects, including coarctation


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 Hemangioma


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 skin 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.


Infantile Hemangiomas: Risk of Slow Regression or Scarring

Parotid

Lip

Tip of nose


Infantile Hemangioma Variants

RICH (rapidly involuting)

NICH (non-involuting)

PICH (partially involuting)

Features of IH, vascular malformations

Glut-1 negative


Rapidly Involuting Congenital Hemangioma


RICH

Develop in utero

No postnatal growth

50% gone by 7 months

Glut-1 negative – not = IH

Some histologic features of IH


Non-involuting Congenital Hemangioma


NICH

Develop in utero

May grow somewhat

Glut-1 negative – not = IH

High flow = IH

Persistent

Surgical excision – not recurrence


Another VariantMinimal Growth Infantile Hemangioma

Suh KY, Frieden IJ. Infantile hemangiomas with minimal or arrested growth: a retrospective case series. Arch Dermatol. 2010;146(9):971–976.


Hemangiomas: Rx

Systemic corticosteroidsEdgerton (1967) Esterly (1968)Brown (1972) Feingold (1978)

Intralesional steroidso Central retinal artery occlusiono Eyelid necrosiso Atrophy, hematomao Eyelid depigmentationo Growth delay


Systemic Steroids: Other Considerations

Hypertensiono Particularly with high doseso Monitoring?o Long-term risk

Growtho Dose, length of Rxo Catch up growth

Behavioral changes/central nervous system development Adrenal suppression Fungal infection Other risks…


Newly approved stuff…


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.


Vasoconstriction of supplying capillaries

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

65

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


July 22, 2008


August 13, 2008 (before Rx)


August 14, 2008 (day 1)


August 15, 2008 (day 2)


August 16, 2008 (day 3)


August 28, 20082 weeks later


September 22, 20081 month later


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


Ongoing experience…

Over 1,000 babies

No serious complications

Our current dosing: 2 mg/kg/d (We are off-label!)


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


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


With permission, Puttgen K.

Topical timolol for superficial IH, PG, etc.

6.29.156.1.15

8.25.15 8.25.15


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.)


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 vascular anomaly, 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.


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.


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.


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