1. Infantile Hemangiomas Victoria Lee, MD Pediatric Surgery Rotation Seattle Children’s Hospital July 5, 2012

2. Vascular tumor or malformation? But first, the basics…

3. Epidemiology Most common vascular tumor of infancy Risk factors – F, white, preterm/LBW

4. Pathogenesis/Natural History Placental hypothesis of origin Growth phase Appear (1 st few weeks)  proliferation (2-12 months) Solid masses of plump, proliferating endothelial cells Involution phase Latter part of 1 st year  variable number of years Apoptosis  fibrofatty tissue and ectatic vasculature

5. Presentation Areas H&N (60%) > trunk (25%) > extremities (15%) Skin > mucous membrane or visceral Morphology Depth – Superficial vs. deep vs. compound Type – Focal vs. segmental vs. multiple

6. Complications General Ulceration Bleeding Location-based Airway Periorbital Ear Tongue, oral cavity, digestive tract Visceral (particularly liver)

7. Diagnosis History and physical examination is the best! Other studies MRI w/ contrast Surgical biopsy/staining for GLUT-1 Additional evaluation US head/abdomen – multiple hemangiomas US liver – large hemangioma MRI of posterior fossa, Angiography of carotid/aortic systems – PHACE syndrome MRI – segmental hemangiomas over lumbosacral midline

8. Vascular tumor or malformation? So what do we do for the child with the hemangioma?

9. The Newcomer - Propranolol Discovered by accident… Mechanism Vasoconstriction Apoptosis Inhibition of angiogenesis

10. Initial observational studies Characteristics Initiation in infancy – 92.9% Dose – 2 mg/kg/d (65%), 3 mg/kg/d (5.3%) Sole agent – 66% Outcomes Favorable outcome, no refractory cases Rebound growth – 21% Adverse events – 18.1 % Conclusions Effective during proliferating phase, unclear in other phases Effective dose 2-3 mg/kg/d, likely as sole therapy Administer until 12 months of age or full involution Side effects less severe than corticosteroids

11. Randomized, Double-Blind, Placebo-Controlled Trial 40 patients 2 groups Propanolol 1 mg/kg/d divided TID x1 wk 2 mg/kg/d divided TID x23 weeks 1 mg/kg/d divided TID x1 wk 0.5 mg/kg/d divided TID x1 wk Placebo Notable exclusion criterion – extracutaneous hemangiomas Follow-up Propanol – 1 discontinued (URI), not analyzed Placebo – 5 discontinued (lack of efficacy, ulceration, visual compromise), analyzed

14. Continued… Conclusions Propranolol safe and effective at 2 mg/kg/d divided TID Treatment course of at least 6 months to avoid rebound growth Tapering over a 2 week period to prevent rebound tachycardia Effective not only in proliferating but also involuting phases Some patients do not respond as well as others Adverse effects – bradycardia, hypotension, bronchospasm, hypoglycemia, peripheral vasoconstriction, GI disturbances, behavioral changes/sleep disturbances, rashes, sweats Limitations Heterogeneous patient population Small sample size

15. Corticosteroids Mechanism – inhibition of vasculogenesis Systemic 2-3 mg/kg/d PO prednisone qd + H2 blocking agent/antacid For at least 1 month and to 9 months of age Adverse effects – behavior disturbances, Cushingoid appearance, growth delay, HTN, GI upset Intralesional 40 mg/mL triamcinolone + 6 mg/mL betamethasone in 1:1 combination delivered with a 1 mL syringe and 30G needle Inject directly into lesion at 6- to 8-week intervals Less adverse effects than systemic Topical Clobetasol, betamethasone Low-risk, low-reward

16. Other Medical Therapy Vincristine Mechanism – acts on microtubules to inhibit mitosis 0.05 mg/kg if 10 kg Adverse effects – peripheral neuropathy, constipation, jaw pain, hematologic abnormalities Interferon alpha 3 million units/m2/d Adverse effects – spastic diplegia

17. Other Modalities Laser photocoagulation Pulse dye laser (PDL) Maximum penetration of 1.2 mm 1-3 passes, repeated at 6 to 8-week intervals, 6-8x Fractional photothermolysis and CO2 laser Excisional surgery

18. So when do we use what?

19. The Stats 60% involute to aesthetically and functionally acceptable point Of 40% that don’t… 50% take less than 6 years to involute 40% involute to a functionally unacceptable result 50% take longer than 6 years to involute 80% involute to a functionally unacceptable result Decision of whether to intervene Location – aesthetically or functionally important Size – large Patient age – older Complications – ulceration, bleeding Decision of how to intervene Phase Subtype Depth

20. Treatment During Proliferation Medical therapy Propranolol – 1 st line Corticosteroids (mainly oral) – 2 nd line Vincristine – 3 rd line Interferon alpha – not recommended PDL – alternative for superficial, thin hemangiomas Surgery – complete excision Last resort Alternative for easily accessible hemangiomas

21. Treatment During Involution Propranolol – unproven Laser photocoagulation – as an adjunct to surgery Surgery – mainstay Maximize preservation of normal skin Maximize aesthetic result Dissection between superficial and deep components and retention of deep component

22. Now, since we’ve done all the prep work, let’s look at a case from this week…

23. HPI 9 month old female, ex 26-week preterm infant Hemangioma on back since birth, recent ulceration/bleeding Relevant PMH/PSH VSD Chronic hypercapnic respiratory failure 2/2 BPD PEX 8 cm wide pedunculated hemangioma on her back with ulceration on the left side of the area Risk factors? Is she a candidate for medical therapy? Why or why not? Is she a candidate for surgical therapy? Why or why not?

24. References Fay A, Nguyen J, Waner M. Conceptual approach to the management of infantile hemangiomas. The Journal of pediatrics. Dec 2010;157(6):881-888 e881-885. Hochman M, Adams DM, Reeves TD. Current knowledge and management of vascular anomalies: I. Hemangiomas. Archives of facial plastic surgery : official publication for the American Academy of Facial Plastic and Reconstructive Surgery, Inc. and the International Federation of Facial Plastic Surgery Societies. May-Jun 2011;13(3):145-151. Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics. Aug 2011;128(2):e259-266. Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. The Annals of otology, rhinology, and laryngology. Oct 2011;120(10):686-695. Pope E, Krafchik BR, Macarthur C, et al. Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics. Jun 2007;119(6):e1239-1247. Sierpina DI, Chaudhary HM, Walner DL, Aljadeff G, Dubrow IW. An infantile bronchial hemangioma unresponsive to propranolol therapy: case report and literature review. Archives of otolaryngology--head & neck surgery. May 2011;137(5):517-521. Starkey E, Shahidullah H. Propranolol for infantile haemangiomas: a review. Archives of disease in childhood. Sep 2011;96(9):890-893.