Infantile Hemangiomas

Commentary From the Section on Dermatology

The American Academy of Pediatrics (AAP) inaugurated the Section on Dermatology (SOD) in 1986. The SOD dedicates itself to improving the care of infants, children, and adolescents with cutaneous disorders. The SOD is also committed to stimulating research and disseminating knowledge of pediatric dermatology via academy channels. For the 75^th anniversary of Pediatrics, the SOD chose to highlight the tremendous strides that clinicians and scientists have made in the understanding and management of infantile hemangioma over the past few decades. Fifty years ago, there was a tendency to lump a wide variety of cutaneous vascular lesions together under the term “hemangioma.” Over time, it became clear that the classic infantile hemangioma was a distinct benign vascular tumor, with a characteristic appearance and natural history that set it apart from other vascular tumors and malformations. Since that time, there has been an explosion of knowledge regarding infantile hemangiomas, including possible syndromic associations and risks for potential complications. In addition, treatment has evolved from a primarily “hands off” approach, to the use of systemic steroids and, more recently, oral propranolol and other beta blockers, to treat complicated lesions. Although we have learned much, we still have many unanswered questions to explore.

Infantile Hemangiomas

Esteban Fernandez Faith, MD, FAAP¹, Ilona J. Frieden, MD, FAAP²

Affiliations: ¹Division of Dermatology, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University College of Medicine; ²Department of Dermatology, University of California San Francisco School of Medicine

Highlighted Articles From Pediatrics

First Quarter Century: 1948-1973

• Margileth AM, Museles M. Current concepts in diagnosis and management of congenital cutaneous hemangiomas. Pediatrics. 1965;36(3):410-416

Second Quarter Century: 1973-1998

• Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics. 1990;85(4):491-498

Third Quarter Century: 1998-2023

• Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical practice guideline for the management of infantile hemangiomas. Pediatrics. 2019;143(1):e20183475

Infantile hemangiomas (IH) are among the most common birthmarks, and our knowledge about their cause, associated complications, and management has evolved greatly over the past 75 years. The history of this evolution is evident in landmark publications in Pediatrics.

In 1965, Margileth and Museles provided an overview of the diagnosis and management of “congenital cutaneous hemangiomas.”¹ At that time, the term “hemangioma” was used to describe a heterogeneous group of vascular lesions. A major breakthrough in nosology came in 1982 when Mulliken and Glowacki proposed the separation of hemangiomas from vascular malformations based on cellular, histopathologic, and clinical differences.² Previously the terms “strawberry hemangioma” and “cavernous hemangioma” had both been used to describe what we now know as infantile hemangiomas, but other completely different vascular anomalies, such as venous malformations, were also called “cavernous hemangiomas” leading to erroneous predictions of natural history and at times ill-conceived treatments. The clinical observations of Margileth and Museles helped to solidify the knowledge about the characteristic natural history of IH, with noticeable growth early in infancy followed by involution over the ensuing years. Treatment options at the time were limited to surgery, radiation, sclerosing agents, and dry ice; all were accompanied by a high rate of complications. While treatment was pursued in rare cases, the authors had the foresight to recognize critical factors in the decision-making process when managing these patients: (1) size and location, (2) rate of growth, and (3) the parent’s reaction to the birthmark. These factors have stood the passage of time and are still relevant in today’s management of these patients.

In 1990, Enjolras et al reported a series of “alarming hemangiomas.”³ This was a critically important paper because the standard management approach to IH was hands-off, due to their natural history of spontaneous involution. Founders of the field of pediatric dermatology, including Alvin Jacobs and Sidney Hurwitz, wrote and spoke about avoiding unnecessary treatments of IH (eg, X-irradiation and early surgery).⁴ After all, why would you want to treat something that would resolve spontaneously? The case series by Enjolras et al answered that question by emphasizing that not all hemangiomas behaved in such benign fashion.³ The case series illustrated potential severe complications, including visceral involvement, structural anomalies, and cardiovascular complications. At that time, corticosteroids were considered the first-line treatment option for severe hemangiomas. The authors recognized the variable response to corticosteroids, dividing patients into “good” and “bad” responders. While involution was well identified as part of the natural history, the authors also recognized that severe medical morbidities and permanent sequalae might occur, particularly in extensive IH. This case series did include both IH and what later were recognized to be other vascular tumors, particularly Kaposiform hemangioendothelioma (KHE). Their emphasis on the severe morbidities spurred a closer look at these tumors and led Enjolras and others to the realization that KHE was a distinct vascular tumor that was the cause of the Kasabach-Merritt phenomenon, a complication not seen with IH.^5,6

The following decades witnessed critical advances in our knowledge about IH. Identification of distinct clinical patterns and morphologies, syndromic associations (PHACE and LUMBAR syndrome), risk of complications, and advances in basic science greatly improved the management of these patients.^7-9 Larger studies continued to uncover important information about the epidemiology of IH. Prematurity, low birth weight, and multiple gestation were identified as factors associated with the development of IH. Advanced maternal age, pre-eclampsia and placenta previa have also been associated with a higher incidence of IH.¹⁰ Apart from providing a clearer demographic profile for patients with IH, these findings helped to theorize at least part of the pathogenesis of IH. Similar to other conditions seen in premature babies, hypoxia has been linked to the migration and proliferation of circulating endothelial progenitor cells leading to the development of IH.

In 2008, the non-selective beta-blocker propranolol was serendipitously observed to be a highly effective treatment for IH.¹¹ This observation led to literally hundreds of scientific articles including a pivotal clinical trial resulting in the FDA approval of propranolol in 2014, the first approved treatment for this common tumor of infancy.¹² Beyond that, it sparked great interest in the science of beta-blockers for vascular anomalies and in other neoplastic conditions. Since the discovery of the benefits of propranolol for IH, other beta-blockers (topical timolol, atenolol, nadolol) have become additional (off-label) therapies currently available for the management of these patients. Propranolol has also been incorporated as an adjunctive treatment for a wide variety of other neoplasms.¹³

A major landmark in IH management came in 2019 when the AAP developed its first clinical practice guideline for the management of IH.¹⁴ A multidisciplinary group critically appraised the published literature to date and developed evidence-based guidelines for the evaluation and management of IH. This comprehensive publication covers all aspects of IH, including pathogenesis, natural history, clinical presentation, and management recommendations. Importantly, it provides risk stratification to aid in the decision making process and stresses the importance of timely evaluation and intervention when indicated. It is an invaluable tool for primary care providers who see these patients firsthand and highlights the importance of communication with hemangioma specialists to ensure optimal clinical outcomes.

From the historical perspective, from Margileth and Museles’ report in 1965 to the AAP guidelines in 2019, it is evident that we have made great progress in the management of this common condition. While most IH require no treatment, there are a significant minority where active intervention is needed. We now have tools for risk stratification, a better understanding of the timing of growth and involution of IH, and far better treatments. These advances allow us to better care for patients, but many questions, such as how beta-blockers work and how to more accurately predict which IH will thicken, causing a threat of permanent skin changes, remain. For the most common vascular tumor of infancy, medicine has come a long way; yet there is still more to uncover.   

References

1. Margileth AM, Museles M. Current concepts in diagnosis and management of congenital cutaneous hemangiomas. Pediatrics. 1965;36(3):410-416
2. 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
3. Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics. 1990;85(4):491-498
4. Jacobs AH. Strawberry hemangiomas; the natural history of the untreated lesion. Calif Med. 1957;86(1):8-10
5. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr. 1997;130(4):631-640
6. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with Kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg. 1997;100(6):1377-1386
7. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132(3):307-311
8. Iacobas I, Burrows PE, Frieden IJ, et al. LUMBAR: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. J Pediatr. 2010;157(5):795-801.e791-797
9. Greenberger S, Yuan S, Walsh LA, et al. Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J Invest Dermatol. 2011;131(12):2467-2476
10. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. 2007;150(3):291-294
11. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649-2651
12. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372(8):735-746
13. Peixoto R, Pereira ML, Oliveira M. Beta-Blockers and cancer: where are we? Pharmaceuticals (Basel). 2020;13(6)
14. Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical practice guideline for the management of infantile hemangiomas. Pediatrics. 2019;143(1):e20183475