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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 23  |  Issue : 1  |  Page : 28-32

Should all infantile hemangiomas be treated? − Time to learn, unlearn, and relearn


1 Department of Dermatology, LTMMC and LTMGH, Mumbai, Maharashtra, India
2 Department of Dermatology, VM Medical College and Safdarjung Hospital, New Delhi, India
3 Department of Dermatology, Government Medical College, Kota, Rajasthan, India

Date of Submission22-Nov-2020
Date of Acceptance21-Oct-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Sanober Burzin Daruwalla
Department of Dermatology, LTMMC and LTMGH, Sion West, Mumbai - 400 022, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.ijpd_168_20

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  Abstract 


Introduction: The quality of life of both the child and their caretakers has been noted to be adversely affected by visible birthmarks and resultant scarring, particularly in areas that cannot be easily covered. With the current knowledge about the uncertain trend in the progression of infantile hemangiomas (IH), the risks associated with it, and the availability of safe and effective treatment options available, a question arises, that should all hemangiomas be treated? A national survey was conducted to determine dermatologists' opinions throughout the country followed by the analysis and literature review. Methodology: An anonymous questionnaire of 10 questions was shared among dermatologists of the country using a link distributed through the electronic media. The data submitted anonymously by the responders were analyzed after due permission for its use for research and publication was received. Results: A total of 91 clinicians completed the questionnaires. 54.95% of the respondents answered that they would wait and watch in the majority of the cases presenting to them. 83.52% of the responders chose topical timolol as the most common medical treatment modality. 33.71% of the responders reported the resolution of IH in more than 75% of their patients and fibrofatty residue was the most common sequelae reported post the involuntary stage. 65.56% of the responders answered no to the question − “Should all hemangiomas be treated?” Conclusion: Clinical experience backed with research has proved the efficacy of beta-blockers in the resolution of IH beyond doubt. The need to identify, evaluate, and initiate timely treatment is required to avoid missing the window of opportunity to optimize the outcomes.

Keywords: Infantile hemangioma, pediatric dermatology, propranolol, timolol, treatment


How to cite this article:
Daruwalla SB, Khunger N, Kumar A, Dhurat RS. Should all infantile hemangiomas be treated? − Time to learn, unlearn, and relearn. Indian J Paediatr Dermatol 2022;23:28-32

How to cite this URL:
Daruwalla SB, Khunger N, Kumar A, Dhurat RS. Should all infantile hemangiomas be treated? − Time to learn, unlearn, and relearn. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 Jan 28];23:28-32. Available from: https://www.ijpd.in/text.asp?2022/23/1/28/334670




  Introduction Top


Infantile hemangiomas adjudged the most common tumor of infancy is a common occurrence in the dermatology outpatient department. With unpredictable growth characteristics, their identification and managerial decisions also become unpredictable. The old dictum of 30% hemangiomas resolving by 3 years, 50% by 5 years, and 70% by 7 years might have to be taken with a pinch of salt in today's times when the treatment paradigm has changed. Poor recognition of the risk of withholding treatment may encourage parents' unrealistic expectations that the hemangioma shall go away completely. The quality of life of both the child and their caretakers has been noted to be adversely affected by visible birthmarks and resultant scarring, particularly in areas that cannot be easily covered with clothing, such as the face, neck, arms, and hands, as well as other emotionally sensitive areas, such as the breasts and genitalia.[1] The precise risk of a patient having permanent skin changes from an infantile hemangioma is approximately 55%–69% of those left untreated. The most frequent sequelae reported after involution are telangiectasias, fibrofatty tissue, anetodermic skin, less commonly redundant skin, and scar.[2],[3] However, the use of oral propranolol has shown complete regression without sequelae after 6 months of treatment in 60% of cases.[4],[5]

With the current knowledge about the uncertain trend in the progression of infantile hemangiomas (IH), the risks associated with it and the availability of safe and effective treatment options, a question arises, that should all hemangiomas be treated at the time of presentation to the specialist or health-care provider, irrespective of the size, site, or shape? Perhaps, it is a little early in the timeline to propose a big notion as this. However, it is, nonetheless, imperative to communicate to the readers the importance of early recognition and appropriate management in the lesions requiring attention, keeping in mind the nonlinear growth characteristics of IH. For this reason, we conducted a national survey to determine dermatologists' opinions throughout the country.


  Methodology Top


An anonymous questionnaire of 10 questions was sent to dermatologists practicing in the country of India using a link distributed through electronic media. The aim was to ascertain the experience of dermatologists with the management of IH. The data submitted anonymously by the responders were analyzed after due permission for its use for research and publication was received [Table 1].
Table 1: Questionnaire to evaluate experience with the management of infantile hemangiomas

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  Results Top


A total of 91 clinicians completed the questionnaire, of which 81 (89.01%) responders had experience in managing the cases of IH. Fifty clinicians (54.95%) answered that they would wait and watch in the majority of the cases of IH presenting to them. 83.52% of the responders chose topical timolol as the most common medical treatment modality. The question − “Will you choose to go for active nonintervention in a case of an infantile hemangioma presenting at 4 weeks of life, 2 cm × 2 cm in size, over the forehead, not obstructing any vital structure and uncomplicated?” was asked, and 64.44% chose the affirmative, i.e. active nonintervention. Only 33.71% of the responders reported resolution of IH in more than 75% of their patients, and fibrofatty residue was the most common sequelae reported post the involuntary stage. Furthermore, when posed with the question − “Should all hemangiomas be treated?” majority (65.56%) of the responders did not agree and answered the contradiction.


  Discussion Top


The serendipitous use of oral propranolol for the treatment of infantile hemangioma was first reported in 2008.[6] However, it was after approval by the US Food and Drug Administration (FDA) in March 2014, oral propranolol rightfully took over the title of being the first line and gold standard therapy for the management of IH from its predecessor, systemic corticosteroids. Beta-blockers are the mainstay of therapy for IH today due to their greater efficacy and lower potential for toxicity as compared to corticosteroids. A study conducted by Wu et al.[7] compared the curative effect of oral propranolol with an observation group. At the end of 8 weeks, the curative effect of the treatment group was found to have a total efficiency of 98.97% as compared to the total curative efficiency of 31.25% in the observatory group. They also detected a significant decrease in the serum concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinase-9 (MMP-9) in children treated with oral propranolol after 8 weeks of therapy compared with those before treatment. Thus, this signifies that down-regulation of VEGF, bFGF, and MMP-9 maybe one of the mechanisms by which propranolol causes termination or regression of the growth of hemangioma.[7]

Numerous reports since the first description of the use of topical timolol in 2010 have validated its efficacy for the treatment of superficial IHwith minimal adverse effects. Drolet et al.[8] examined timolol plasma concentrations in children receiving ophthalmic preparations applied to skin hemangiomas. Timolol was detected in 86 out of the 92 plasma samples studied and 80% of the samples had a concentration of >0.2 ng/mL, the plasma concentration demonstrated to have measurable systemic beta-blocking activity in adults. However, there were no serious unexpected adverse events reported. Increasing hemangioma thickness was associated with higher plasma concentrations while parameters such as timolol formulation, sex, application site, hemangioma surface area, ulceration, or occlusion did not significantly affect the plasma concentration. In 2016, the hemangioma investigator group retrospectively assessed a large cohort from 9 centers for the effectiveness of timolol and to delineate characteristics associated with a response, and reported adverse events. They recommended the use of topical timolol maleate for thin, superficial IH and as an alternative to systemic β-blockers and watchful waiting.[9] It may also serve as an initial treatment tool to help control the growth of IH when instituted early in the timeline and accelerate involution of the same, thereby reducing the need for systemic agents in later periods of life. However, since topical timolol has not received FDA approval, it's use in many countries, especially when concerns of using an ophthalmic solution for a skin condition is often questioned and debated.

One cannot turn a blind eye to the tremendous degree of disease heterogeneity associated with IH. Even experienced clinicians may find it difficult to predict the degree of growth and the subsequent sequelae of IH.[10] An attempt to characterize the proliferative phase of these hemangiomas has been made. The most rapid growth of superficial IHs typically occurs between 1 and 3 months of age and the large majority of IHs have completed growth by 5 months of age, thereby roughly marking the potential window of opportunity for management.[10],[11],[12] A subset of IH known as IH with minimal or arrested growth lacks the robust proliferative phase characteristic of many IHs but may be associated with complications, such as ulceration or, if segmental, structural anomalies.[12] Hence, risk stratification with timely intervention may prevent unwanted adverse effects. Furthermore, certain characteristics of an infantile hemangioma such as its depth, border, and surface texture, may serve as pointers to ascertain the type of sequelae that shall manifest apart from complications such as ulceration. While deep and combined hemangiomas are found to leave more fibrofatty tissue than superficial hemangiomas, superficial hemangiomas with a cobblestoned appearance on the surface are found to leave more anetodermic skin than those with a smooth surface. IH with a stepped border leave more redundant and anetodermic skin than those with a progressive border.[3] However, these too cannot help accurately determine the outcome an infantile hemangioma may serve.

The survey conducted by us revealed that majority of the practicing dermatologists of our country continue to practice with a conservative approach based on the recommendations proposed initially as reflected by the consensus that majority negated, when posed with the question − “Should all hemangiomas be treated?”[13] The question – “Will you choose to go for active nonintervention in a case of an infantile hemangioma presenting at 4 weeks of life, 2 cm × 2 cm in size, over the forehead, not obstructing any vital structure and uncomplicated?” generated an affirmative response by majority of the respondents, probably still ignorant of the anxiety and stigma the IH might leave in the child in the years to come by. The interpretation of the results generated was purely subject to the authors' bias and is free for individual reasoning. The limitation of the survey was the inability to reach a bigger population and the inability to clarify with more details regarding the type of IH being discussed with the subsequent management strategy and outcome. Furthermore, we could not include other specialties that have an equally important role in the management of hemangiomas.

In many countries across the world like ourselves, separate specialists for managing IH are not available and most of the cases are managed by the clinician the child first presents to. Awareness about the need for a multidisciplinary approach, referral to the pediatrician or child specialist, and education and awareness among the dermatology community is the need of the hour. The infantile hemangioma referral score tool is an easy-to-use tool aimed at primary physicians created with the purpose of facilitating correct and timely referral of patients with IH. A 2-part algorithm with a total of 12 questions helps practitioners in their decisions to refer patients to expert centers to identify children who require early treatment.[14] Risk stratification and high risk IH like those having life-threatening complications, functional impairment, or structural anomalies (e.g. in PHACE syndrome or LUMBAR syndrome) have been the ones that have always warranted immediate attention and mandated the need for treatment. However, given the nonlinear growth characteristics and unpredictable progression, the question that should all IH presenting to the treating clinician be treated to prevent their progression from relatively harmless looking IH to potentially complicated ones or those leaving behind an unfavorable sequelae remains to be answered. In this quest, multiple changes and better approaches are being formulated with the intent to revise provisional best practices as more data becomes available. A recent retrospective study performed through the hemangioma investigator group and the pediatric dermatology research alliance concluded that prolonged monitoring for initiation and escalation of oral propranolol rarely changed management and did not predict future adverse events.[15] Furthermore consensus guidelines from the British Society for Pediatric Dermatology recommended the use of oral propranolol in healthy, term infants over 4 weeks of age in an outpatient setting without the need for specific monitoring.[16] Hereby, the authors propose the concept of initiating early treatment for IH irrespective of the size, site, shape, or age of presentation, with thorough investigations wherever required, supported with the probable limitations faced and likely suggestions proposed [Table 2].
Table 2: Points discussing the potential limitations and suggestions proposed by the authors

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  Conclusion Top


There seems to be hesitancy in part of the dermatologist when it comes to the treatment of hemangiomas. The need to identify, evaluate, and initiate timely treatment or propose referral to a specialist early in the disease timeline is required in today's time to avoid missing the window of opportunity to optimize outcomes. What are we afraid of? Clinical experience backed with meta-analysis and multiple studies has proved the efficacy of beta-blockers in the resolution of IH beyond doubt. Further research in this light is required before a definite consensus can be made. For real progress to be made, it is perhaps time we unlearn and learn anew what we thought we knew before.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tanner JL, Dechert MP, Frieden IJ. Growing up with a facial hemangioma: Parent and child coping and adaptation. Pediatrics 1998;101:446-52.  Back to cited text no. 1
    
2.
Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PH. Untreated hemangiomas: Growth pattern and residual lesions. Plast Reconstr Surg 2011;127:1643-8.  Back to cited text no. 2
    
3.
Baselga E, Roe E, Coulie J, Muñoz FZ, Boon LM, McCuaig C, et al. Risk factors for degree and type of sequelae after involution of untreated hemangiomas of infancy. JAMA Dermatol 2016;152:1239-43.  Back to cited text no. 3
    
4.
Darrow DH, Greene AK, Mancini AJ, Nopper AJ; Section on Dermatology, Section on Otolaryngology-Head and Neck Surgery; Section on Plastic Surgery. Diagnosis and management of infantile hemangioma. Pediatrics 2015;136:e1060-104.  Back to cited text no. 4
    
5.
Luu M, Frieden IJ. Haemangioma: Clinical course, complications and management. Br J Dermatol 2013;169:20-30.  Back to cited text no. 5
    
6.
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;358:2649-51.  Back to cited text no. 6
    
7.
Wu S, Wang B, Chen L, Xiong S, Zhuang F, Huang X, et al. Clinical efficacy of propranolol in the treatment of hemangioma and changes in serum VEGF, bFGF and MMP-9. Exp Ther Med 2015;10:1079-83.  Back to cited text no. 7
    
8.
Drolet BA, Boakye-Agyeman F, Harper B, Holland K, Lewandowski A, Stefanko N, et al. Systemic timolol exposure following topical application to infantile hemangiomas. J Am Acad Dermatol 2020;82(3):733-6.  Back to cited text no. 8
    
9.
Püttgen K, Lucky A, Adams D, Pope E, McCuaig C; Hemangioma Investigator Group, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics 2016;138:e20160355.  Back to cited text no. 9
    
10.
Krowchuk DP, Frieden IJ, Mancini AJ, Darrow DH, Blei F, Greene AK, et al. Clinical practice guideline for the management of infantile hemangiomas. Pediatrics 2019;143:e20183475.  Back to cited text no. 10
    
11.
Tollefson MM, Frieden IJ. Early growth of infantile hemangiomas: What parents' photographs tell us. Pediatrics 2012;130:e314-20.  Back to cited text no. 11
    
12.
Chang LC, Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, et al. Growth characteristics of infantile hemangiomas: Implications for management. Pediatrics 2008;122:360-7.  Back to cited text no. 12
    
13.
Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al. Initiation and use of propranolol for infantile hemangioma: Report of a consensus conference. Pediatrics 2013;131:128-40.  Back to cited text no. 13
    
14.
Léauté-Labrèze C, Baselga Torres E, Weibel L, Boon LM, El Hachem M, van der Vleuten C, et al. The infantile hemangioma referral score: A validated tool for physicians. Pediatrics 2020;145:e20191628.  Back to cited text no. 14
    
15.
Püttgen K, Hansen L, Lauren C, Stefanko N, Mathes E, Olsen G, et al. Limited utility of repeated vital sign monitoring during initiation of oral propranolol for complicated infantile hemangioma. J Am Acad Dermatol 2021;85:345-52.  Back to cited text no. 15
    
16.
Solman L, Glover M, Beattie PE, Buckley H, Clark S, Gach JE, et al. Oral propranolol in the treatment of proliferating infantile haemangiomas: British Society for Paediatric Dermatology Consensus Guidelines. Br J Dermatol 2018;179:582-9.  Back to cited text no. 16
    



 
 
    Tables

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