Medical,Surgical,and Wound Care Management of Ulcerated Infantile Hemangiomas: A Systematic Review

Abstract

Ulcerated infantile hemangiomas may present a therapeutic challenge, especially if there is concurrent hemorrhage or infection. The aim of this study was to systematically review the published evidence on the treatment of ulcerated hemangiomas, focusing on wound healing as the outcome of interest. We searched MEDLINE, Embase, SCOPUS, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science from inception to July 2016. Seventy-seven studies met our inclusion criteria. One study was a randomized controlled trial, 30 were observational studies, and 46 were case reports or case series. There is significant heterogeneity among the methods used. We reviewed 1239 patients in total. Of the 197 treated with oral propranolol, 191 (97.0%) achieved complete ulcer healing. Thirty-one patients failed corticosteroid therapy (oral, intralesional, or topical) and were subsequently successfully treated with other therapies. Surgical resections were typically performed for larger hemangiomas and those causing complications. None of the therapies discussed appear to offer significant advantages over others. Therefore, treatment decisions should be individualized based on location of disease, extent, symptoms, feasibility, cost, and parental preference.

Keywords

hemangioma pediatric dermatology ulceration wound care treatment

Infantile hemangiomas (IHs) are the most common vascular tumours of childhood, with an incidence of 3% to 10% in all infants.¹ IHs are more commonly seen in females and in preterm infants. They typically exhibit a phase of rapid proliferation shortly after birth, followed by a phase of spontaneous involution that takes years to be completed. Most uncomplicated IHs do not require active intervention. However, ulceration is the most common complication seen in IHs, occurring in up to 15% of IHs.^1,2 Ulceration is almost always an indication for intervention, as it can cause significant pain and increases risk of infection and scarring.²

IHs can be described as superficial, deep, or mixed (having both superficial and deep components). Superficial and mixed hemangiomas are more likely to ulcerate, whereas deep hemangiomas rarely do.³ Larger lesions and lesions located in areas frequently exposed to friction, such as the lip, neck, and perianal regions, are more prone to ulceration.^4,5 IHs tend to ulcerate during the proliferative phase, and early white discoloration of a lesion is predictive of ulceration.⁶

Ulcerated IHs may present a clinical challenge, causing functional limitations (eg, lip hemangiomas cause feeding difficulties), unrecognized infection, or poorly controlled pain. Ulcerated IHs in the perineum are particularly difficult to treat because of repeated contact with urine and stool. Currently, there are multiple options for treatment, which can be broadly categorized into wound care or conservative management, medical therapy, laser therapy, and surgery. The purpose of this study was to systematically review the published evidence on the treatment of ulcerated IHs, focusing on wound healing as the outcome of interest.

Patients and Methods

Search Strategy

Comprehensive literature searches were conducted from inception to July 2016 using each database platform’s command language and appropriate search fields, in the MEDLINE, Embase, SCOPUS, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science databases (Appendix S1). MeSH terms, EMTREE terms, and text words were used for the search concepts of ulcerated hemangiomas, wound care, surgical procedures, and drug interventions. No limits were applied. Because we reviewed all therapeutic interventions that have been used, a broad search strategy was necessary.

Inclusion and Exclusion Criteria

Only ulcerated IHs were included in the study, and other vascular tumours were excluded. Controlled trials, observational studies, case series, and case reports were included if the treatment modality was clearly described, and resolution of ulceration was an end point of the study. In studies where the primary indication for treatment was not ulceration (eg, other primary indications were obstruction or pain), studies were included if they included response of the ulceration to treatment. Exclusion criteria were (1) review articles, (2) no English language version available, (3) patients were over 18 years of age, (4) other types of vascular lesions that were analyzed within the same cohort as IHs, or (5) the outcomes of treatments were not clearly described in the results.

Data Extraction

Two reviewers independently conducted title and abstract screening. Conflicts were resolved through discussion between the reviewers. Data were abstracted from full-text manuscripts by 1 reviewer and double-checked for accuracy by a second reviewer. Data were collected on patient demographics; lesion morphology and characteristics; treatment modality, duration, and outcome; adverse events; and relapse of disease. In studies that examined both ulcerated and nonulcerated lesions, we extracted only the data for ulcerated lesions. Complete healing was defined as complete reepithelialization of the affected area. To assess bias within each study, we defined the level of evidence for each study using the Oxford Centre for Evidence-Based Medicine (CEBM) method.

Analyses

Data analyses were descriptive. The primary end point we assessed was time to complete reepithelialization of ulceration. In consideration of the significant variability in severity of ulceration amongst studies, we have not suggested a timeframe to define therapeutic failure. To obtain total numbers of patients receiving each treatment modality, we have pooled patients from multiple studies. A meta-analysis was not performed, as there were an insufficient number of comparative studies.

Results

Study Selection

Our first search for articles from inception to January 2016 generated 9134 studies. When the search was repeated for studies published between January and July 2016, we retrieved 516 additional results. Following title and abstract screening, we selected 138 studies for full-text review and ultimately included 78 studies in our analysis^1-4,7-81 (Figure 1).

Figure 1.

PRISMA flow diagram of study selection process. n = number of studies.

Overview of Studies

Among the 78 studies, 46 were case reports or case series, 16 were retrospective observational studies, 15 were prospective observational studies, and 1 was a randomized controlled trial (RCT). The RCT represents CEBM level 2b evidence,⁷ while all other studies represent level 4 evidence, as there are no comparator groups. It is recognized that the degree of bias in these observational studies is inherently high due to the lack of comparators.

The 5 treatment modalities best described in the literature are topical timolol, oral propranolol, oral atenolol, systemic antibiotics, and pulsed dye laser. The range of median healing times from all studies using these modalities is summarized in Table 1.

Table 1.

Most Common Treatment Modalities for Ulcerated Hemangiomas and Range of Median Healing Times Reported From All Studies.

Treatment Modality	No. of Studies	No. of Patient	Range of Median Healing Times From All Studies
Topical timolol 0.5%	8	46	14 days to 6 weeks
Oral propranolol 1.5-3 mg/kg/d	28	197	10 days to 10 weeks
Oral atenolol	2	54	5.5 to 8.1 weeks
Systemic antibiotics	2	613	40.1 days
Pulsed dye laser	7	200	2.8 to 10 weeks

Systemic Therapy

Twenty-eight studies used oral propranolol as the primary treatment modality. The range of dosing used was 1.5 to 3 mg/kg/d, divided into twice daily or 3 times daily dosing. Amongst the 197 patients treated with propranolol, 191 (97.0%) achieved complete wound healing. Saint-Jean et al⁸ (n = 33) used doses of 2 to 3 mg/kg/d and reported a mean healing time of 5.7 weeks. Tiwari et al⁷ (n = 28) used doses of 2 mg/kg/d and reported a mean healing time of 17.9 ± 2.2 days of uninterrupted treatment. Time to healing for all other studies is reported in Appendix S2. In our review, there were no reports of epithelialized lesions becoming ulcerated while on propranolol therapy. Of these 191 patients successfully treated with propranolol, 10 had previously been trialed on systemic corticosteroids and experienced no wound healing or incomplete healing.^2,8-12 Hyperkalemia was reported in 3 patients, although none were severe enough to necessitate discontinuation of therapy.^13-15 In 1 case, laboratory tumour lysis syndrome due to propranolol therapy was diagnosed on the basis of hyperkalemia and hyperphosphatemia in the absence of clinical symptoms.¹³

Two studies reported the use of atenolol for ulcerated IH. Ji et al¹⁶ used atenolol 1 mg/kg/d, supplemented with oral antibiotics in 9 patients. They reported a mean healing time of 5.5 weeks. Ruitenberg et al¹⁷ (n = 45) used atenolol at a mean dose of 1.3 mg/kg/d for a mean duration of therapy of 45.5 weeks. The mean healing time was 8.1 ± 6.6 weeks. However, 5 of their 45 patients had recurrence of the ulceration after discontinuation of therapy.¹⁷

Tan et al¹⁸ treated 5 patients with captopril 1.5 mg/kg/d divided in 3 doses. All ulcers healed in less than 3 weeks. One patient experienced a mild, transient elevation in serum creatinine.

Corticosteroids were used as primary treatment modalities in only 3 studies. Hasan et al⁵³ used intralesional triamcinolone 4 mg/kg, 2 doses, 5 weeks apart, in 1 patient. This ulcer resolved in 5 weeks. Strand and Smidt⁷⁵ used oral prednisolone 3 mg/kg/d in 1 patient, which produced ulcer healing in 1 month. Thomas et al⁸⁰ used systemic steroids combined with pulsed dye laser in 2 patients. These lesions healed in 6 weeks and 9 weeks, respectively. More interestingly, amongst all of the patients in our analysis, 21 failed oral steroids,^{2,8,9,11,18-26} 3 failed intralesional steroids,¹⁹ and 7 failed topical steroids.^9,22,27-30 Steroid therapy often produced lesion shrinkage but failed to produce ulcer healing. All 31 were subsequently treated successfully with other therapies.

Topical Therapy

Pandey et al³ treated 608 patients with topical antibiotics for smaller ulcerations or both topical and systemic antibiotics for larger ulcerations (>10 cm²). The mean time to healing was 40.1 days (range, 16-96 days). Antibiotics were initiated based on history and clinical suspicion alone; wound cultures were not performed consistently. Three other studies, in which antibiotics were used as adjunctive therapy, performed wound cultures prior to antibiotic treatment.^7,15,27

Topical timolol was used in 8 studies. Seven studies used a 0.5% solution or gel, applied 1, 2, or 3 times daily, and 1 study used a combination solution, containing brimonidine 0.2% and timolol 0.5%, applied twice daily. Of the 46 patients treated, 39 (84.8%) responded, 6 required transition to oral propranolol, and 1 required surgical resection. Mean healing time reported for a cohort of 9 patients (Weibel et al³¹) was 14 days. Weibel et al³¹ measured urine levels of timolol in 6 of their 9 patients. All 6 samples were positive, but no clinically significant adverse effects were observed. Blood levels were not drawn.

Topical becaplermin 0.01% gel, applied once daily, was used in 5 studies with a total of 21 patients. Nineteen patients experienced ulcer healing, 1 patient partially responded, and 1 was a nonresponder. McCuaig et al⁸¹ (n = 9) reported a healing time range of 2 to 4 weeks. Metz et al²⁰ (n = 8) reported a median healing time of 13.5 days (range, 3-21 days).²⁰ Five patients had previously failed to improve on systemic corticosteroids.^19-21

A single study of 2 patients reported that topical breast milk, applied once daily, used concurrently with propranolol, at 1 mg/kg/d, produced wound healing of ulcerated IH.²⁷ Both patients had previously been given propranolol 1 mg/kg/d, without topical breast milk, for 6 weeks and 1 week, respectively, with persistence of ulceration in both cases. After adding topical breast milk to propranolol, the first patient achieved wound healing at 4 weeks and the latter patient at 20 weeks. These healing times are not significantly shorter than those for propranolol therapy alone. Given the limited sample size, it cannot be determined whether topical breast milk is an effective adjunct therapy.

Laser and Light Therapy

Six studies used 585-nm pulsed dye laser alone, 1 study used 595-nm pulsed dye laser in combination with Nd:YAG laser,³² and 1 study used multiple combinations of pulsed dye laser.³³ Energy fluencies ranged from 4.75 to 11 J/m², and between 1 and 5 treatments were given at intervals of 2 to 4 weeks. Amongst these 8 studies, all 200 patients treated achieved reepithelialization of their ulcers. Morelli et al³⁴ (n = 37), using a 585-nm pulsed dye laser, reported a mean healing time of 2.84 ± 0.22 weeks. Li et al³² (n = 22), using a pulsed dye laser combined with Nd:YAG lasers, reported a mean healing time of 13.5 ± 4.5 days. Kunzi-Rapp⁷⁹ (n = 7) used a combination of pulsed dye laser and oral propranolol. They reported a healing time of 1 to 2 weeks, which is amongst the shortest times reported.

Jorge et al³⁵ treated 2 patients with intense pulsed light and reported a mean healing time of 2 months. Achauer and Vander Kam²⁴ treated 10 patients with argon laser and reported a median healing time of 4 weeks.

Amongst all patients treated with laser and light therapy, new ulceration occurred at untreated sites in 5 patients.^24,35,36

Surgery

Eight investigators performed surgical resections on 12 patients with ulcerated IH. In 5 of these cases, ulceration was the indication for surgery.^29,37 The other indications were severe hemorrhage and progressive heart failure (n = 1),³⁸ risk of bleeding and permanent disfigurement (n = 1),³⁹ cosmetic (n = 1),¹ parental preference (n = 1),⁴⁰ and not reported (n = 2).^41,42 One study used negative pressure wound therapy for wound closure,⁴¹ and another used the TopClosure Tension Relief System (IVT Medical Ltd., Ra’anana, Israel), a noninvasive tissue expander.³⁹ No complications due to surgery were reported in any of the studies.

Wound Care

Only 1 study used wound care exclusively. Oranje et al⁴³ used polyurethane film for 8 cases of hemangioma less than 1 year old. The dressing was changed 3 times a day for the first 3 days and then once daily. All patients had a wound healing time of 2 to 7 weeks.

Other procedural and wound care therapies include ultrasound and negative pressure wound therapy. These therapies have little supporting evidence. Fox et al³⁰ treated 6 cases of ulcerated hemangioma with the combination of propranolol and negative pressure wound therapy.

Observational

Tiwari et al⁷ were the only authors to report an observational arm. They conducted a randomized controlled trial, where the control group was ibuprofen and acetaminophen for pain control, and the study group was propranolol. The mean healing time for the control group (n = 24) was 27.71 ± 2.33 days.

Discussion

Of the 1230 patients reviewed in our study, 613 were treated with systemic antibiotics, 200 with pulsed dye laser, 197 with oral propranolol, 54 with atenolol, 46 with topical timolol, 25 with pulsed dye laser and Nd:YAG laser, 12 with topical becaplermin, 12 with surgical resection, 8 with wound care alone, 5 with captopril, 1 with vincristine, 19 with combination therapies, and 38 with other, less common, treatment modalities (Table 2).

Table 2.

Breakdown of Treatment Modalities Used for Ulcerated Infantile Hemangiomas and Corresponding Adjuvant Therapies, Number of Patients, Ulcer Healing Outcomes, Side Effects, and Recurrence of Ulceration.

Main Treatment Modality	Studies	Adjuvant Therapies	No. of Patients	Ulceration Healed, No. (%)	Previous Ineffective Therapies, No.	Side Effects, No.	Recurrence of Ulceration, No.
Topical
Becaplermin 0.01%	Collins et al¹⁹ Hatfield and Wright⁵² Metz et al²⁰ Sugarman et al²¹ McCuaig et al⁸¹	Occlusive dressing, topical antibiotics, hydrocolloid dressing, oral steroids, hydrogel dressing	19	17 (89)	Oral steroids (5), oral antibiotics (1), topical antibiotics (3), intralesional steroids (3)
Breast milk	Laws et al²⁷	Oral propranolol 1 mg/kg/d	2	2 (100)	Oral propranolol (2), oral antibiotics (2), topical antibiotics (2), topical steroids (1), silicone dressing (2)
Corticosteroids, intralesional	Hasan et al⁵³		1	1 (100)	Oral antibiotics (1), wound care (1)
Eosin 2%	Lapidoth et al⁴⁴	Hydrocolloid dressing	18	18 (100)
Imiquimod	Ho et al⁵⁴ Mascarenhas et al²²		2	2 (100)	Topical antibiotics (1), topical steroids (1), oral steroids (1)
Timolol 0.5%	Beal et al⁵⁵ Boos and Castelo-Soccio⁵⁶ Cante et al⁴⁵ Chang and Kang⁴ Neri et al⁴⁶ Thomas et al²⁸ Tlougan et al⁵⁷ Weibel et al³¹	Topical brimonidine 0.2%, hydrocolloid dressing, oral propranolol (3)	46	39 (85)	Topical antibiotics (2), topical steroids (1), becaplermin (1), zinc oxide barrier (1)	Cool extremities (1), diarrhea (1), sleep disturbance (1)
Wound care polyurethane film	Oranje et al⁴³		8	8 (100)			Mild recurrence (2)
Systemic
Antibiotics	Pandey et al³ Lacour et al³⁶	Topical antibiotics, wound care	613	613 (100)
Propranolol 1.5-3 mg/kg/d	Al Dosari and Riad⁵⁸ Bagazgoitia et al⁵⁹ Ben-Zvi and Gass⁶⁰ Bernabeu-Wittel et al⁶¹ Betlloch-Mas et al⁹ Bouras et al⁶² Cavalli et al¹³ Gidaris et al⁶³ Gulati and Jury¹⁰ Hermans et al⁶⁴ Hong and Fischer⁴⁷ Kim et al² Lanoel et al⁶⁵ Morais et al¹¹ Mousa et al¹⁴ Naouri et al⁶⁶ Nelson et al⁶⁷ Oksiuta et al⁶⁸ Pavlakovic et al¹⁵ Saaiq et al⁶⁹ Sadykov et al⁷⁰ Saint-Jean et al⁸ Sans et al⁷¹ Sharma et al⁷² Tan et al¹² Thomas et al⁷³ Tiwari et al⁷ Vercellino et al⁷⁴	Topical antibiotics, hemostatic dressing, hydrocolloid dressing, topical lidocaine, topical vitamin A, oral antibiotics	197	191 (97)	Occlusive dressing (2), oral steroids (8), topical steroids (1), topical antibiotics (14), alginate dressing (1), systemic antibiotics (3), hyperbaric chamber (1), pulsed dye laser (5), lipido-colloid dressing (3), topical analgesics (12), wound dressings (16), intravenous steroids (1)	Tumour lysis syndrome (hyperkalemia, hyperphosphatemia) (1), temporary drowsiness (6), cold extremities (7), restless sleep (2), poor feeding (2), vomiting/diarrhea (1), hypertension (2), hyperkalemia (1), transient hypotension (1), nightmares (5), esophageal reflux (1), generalized maculopapular rash (3)	2
Atenolol 1 mg/kg/d	Ruitenberg et al¹⁷ Ji et al¹⁶	Oral antibiotics, wound dressings	54	54 (100)		Cold hands/feet (24), sleeping problems (9), gastrointestinal symptoms (6), respiratory symptoms (2)	5
Corticosteroids	Strand and Smidt⁷⁵	Topical benzocaine	1	1 (100)
Captopril 1.5 mg/kg/d	Tan et al¹⁸		5	5 (100)	Oral steroids (3)	Mild elevation in serum creatinine (1)
Vincristine	Fawcett et al²³		1	1 (100)	Oral steroids (1), laser (1)
Lasers and light therapy
585-nm pulsed dye laser	Barlow et al⁴⁸ David et al⁴⁹ Di Maio et al⁷⁶ Hermosa et al³³ Lacour et al³⁶ Morelli et al³⁴ Ward et al⁵⁰	Topical antibiotics	200	194 (97)	Oral antibiotics (9), topical antibiotics (9)	Minor changes in sleeping and feeding (4), pain a few days after treatment	Ulceration recurred at nontreated sites (1)
595-nm pulsed dye laser and Nd:YAG	Hermosa et al³³ Li et al³²		25	25 (100)
Intense pulsed light	Jorge et al³⁵		2	2 (100)			Ulceration recurred at nontreated sites (2)
Argon laser	Achauer and Vander Kam²⁴	Topical antibiotics	10	10 (100)	Oral steroids (1), topical antibiotics (1)		Ulceration recurred at nontreated sites (2)
Surgery
Surgical resection	Alter et al⁴⁰ Bookout et al⁴¹ Chang et al¹ Nakada et al³⁸ Pitta and Gomes⁴² Theologie-Lygidakis et al³⁷ Watanabe et al²⁹ Zhu et al³⁹	Negative pressure wound therapy for postsurgical wound, TopClosure Tension Relief System wound closure	12	12 (100)	Systemic steroids (1), topical steroids (1)	Wound required skin grafting (1)
Other
Ultrasound	Serena²⁵	Oral prednisolone	1	1 (100)	Oral steroids (1), laser therapy (1)
Vacuum-assisted closure	Morais et al⁷⁷	Wound dressings	1	1 (100)	Systemic steroids (1), systemic antibiotics (1)
Combination
Pulsed dye laser and oral propranolol	Rodríguez-Ruiz et al⁷⁸		7	7 (100)
Pulsed dye laser and topical propranolol	Kunzi-Rapp⁷⁹		2	2 (100)
Pulsed dye laser and systemic steroids	Thomas et al⁸⁰		2	2 (100)	Topical antibiotics (1), oral antibiotics (2)
Pulsed dye laser and interferon 100 000 U/kg/d	Thomas et al⁸⁰	Occlusive dressing	1	1 (100)
Interferon 3 million U/m²/d and recombinant human granulocyte-macrophage colony-stimulating factor 3.33 million U ×1	Illum et al²⁶		1	1 (100)	Oral steroids (1), topical antibiotics (1)
Negative pressure wound therapy and oral propranolol	Fox et al³⁰		6	6 (100)	Topical steroids (2), zinc-based ointment (2)

In our analysis, propranolol was the most commonly selected systemic agent for ulcerated IH (28 studies). At a dose of 1.5 to 3 mg/kg/d, 191 of 197 (97.0%) wounds healed. Saint-Jean et al⁸ (n = 33) were the only authors to use doses of 2 to 3 mg/kg/d. They reported a mean healing time of 5.7 weeks. Compared to other studies using a maximum of 2 mg/kg/d and shorter healing times, this limited evidence does not suggest that higher doses of propranolol promote faster healing. Pulsed dye laser was the most commonly used local therapy (8 studies). Four of the 8 studies that used pulsed dye laser analysis were published prior to 2008,^{24,34,36,48-50} before propranolol became a therapeutic option. Results were positive with all 225 (100%) wounds healed.

Studies of pulsed dye laser generally reported shorter mean healing times compared to studies of propranolol (Appendix S2). However, due to the heterogeneity in the methods amongst the studies, we cannot conclude whether these differences are significant. Additionally, there is a much larger range in the healing times reported for propranolol, in part because there were 28 studies of propranolol and only 8 studies of pulsed dye laser.

Topical timolol, currently available as a sterile 0.5% ophthalmic solution or gel, is an alternative β-blocker to propranolol. We found that topical timolol was preferentially used for smaller hemangiomas with smaller ulcerated surface areas, for which the benefits of oral propranolol did not outweigh the risks. Weibel et al³¹ detected timolol levels in the urine of all 6 patients whom they tested, suggesting that some systemic absorption does occur.

Corticosteroids demonstrated unfavourable results in our analysis. We found a greater number of patients who failed corticosteroid therapy (n = 31) than patients who were successfully treated (n = 4). Corticosteroid use for IH has decreased in recent years, and our study supports this trend.

Surgical resections were typically performed for larger hemangiomas and those causing complications, such as suffocation, hemorrhage, or disfigurement, where it was deemed unsafe or inadvisable to wait for medical therapy to take effect.

Multiple investigators used topical or oral antibiotics as primary therapy and as adjuvant therapy (Table 2). Antibiotics should be reserved exclusively for IHs that have active infections.

The occlusion of wounds with atraumatic, nonadhesive dressings was the most commonly agreed-on management strategy between wound care experts dealing with ulcerated IH to help relieve pain and improve healing. These goals were achieved with multiple dressings, including silicone dressings and hydrocolloids, which were used in addition to other therapies in multiple studies.^4,20,44-47 Debridement is not always necessary, and if needed, autolytic debridement is preferred.⁵¹

Limitations

There are very few comparative studies published in this clinical area, and there is significant heterogeneity amongst the methods used in the observational studies we do have. It is therefore challenging to determine if any one therapy is truly superior in treating ulcerated hemangiomas. The natural history of infantile hemangiomas, which often spontaneously heal, also adds difficulty to interpreting the data. Furthermore, we recognize that publication bias, which favours the publishing of positive results, has limited the number of negatives studies we have available for analysis.

Conclusion

There was significant variability in the methods and outcomes of the studies we reviewed. None of the therapies discussed appear to offer significant advantages over others. Therefore, treatment decisions should be individualized and based on location of disease, extent, symptoms, feasibility, cost, and parental preference. We encourage future studies to conduct comparative analyses to determine which therapies are superior.

Supplemental Material

Heme_-_Appendix_-_10.21.17_clear – Supplemental material for Medical, Surgical, and Wound Care Management of Ulcerated Infantile Hemangiomas: A Systematic Review

Supplemental material, Heme_-_Appendix_-_10.21.17_clear for Medical, Surgical, and Wound Care Management of Ulcerated Infantile Hemangiomas: A Systematic Review by Jane Y. Wang, Arvin Ighani, Ana P. Ayala, Sadanori Akita, Irene Lara-Corrales and Afsaneh Alavi in Journal of Cutaneous Medicine and Surgery

Footnotes

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Alavi has been a speaker and consultant for AbbVie, Janssen, Novartis, Galderma, Valeant, and Leo. Dr Akita, Dr Lara-Corrales, Mr Ighani, Ms Wang, and Ms Ayala have no conflicts of interest to disclose.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Arvin Ighani

References

Chang

Wong

Rohde

Ascherman

JK.

Management of lip hemangiomas: minimizing peri-oral scars. J Plast Reconstr Aesthetic Surg. 2012;65(2):163-168.

Kim

LHC

Hogeling

Wargon

Jiwane

Adams

. Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas. J Pediatr Surg. 2011;46(4):759-763.

Pandey

Gangopadhyay

Sharma

Kumar

Gopal

Gupta

DK.

Conservative management of ulcerated haemangioma: twenty years experience. Int Wound J. 2009;6(1):59-62.

Chang

Kang

GC.

Efficacious healing of ulcerated infantile hemangiomas using topical timolol. Plast Reconstr Surg Glob Open. 2016;4(2):e621.

Chiriac

Pinteala

Foia

Brzezinski

Ulcerated hemangioma—surveillance only. Folia Med. 2015;57(1):75-77.

Maguiness

Hoffman

McCalmont

Frieden

IJ.

Early white discoloration of infantile hemangioma: a sign of impending ulceration. Arch Dermatol. 2010;146(11):1235-1239.

Tiwari

Pandey

Gangopadhyay

Sharma

Gupta

DK.

Role of propranolol in ulcerated haemangioma of head and neck: a prospective comparative study. Oral Maxillofac Surg. 2016;20(1):73-77.

Saint-Jean

Leaute-Labrze

Mazereeuw-Hautier

et al . Propranolol for treatment of ulcerated infantile hemangiomas. J Am Acad Dermatol. 2011;64(5):827-832.

Betlloch-Mas

Martínez-Miravete

Lucas-Costa

Martin

AIL

Selva-Otalaurruchi

Outpatient treatment of infantile hemangiomas with propranolol: a prospective study. Actas Dermosifiliográficas. 2012;103(9):806.

10.

Gulati

Jury

Propranolol for ulcerated haemangioma in a preterm baby: our experience. Br J Dermatol. 2010;163:126.

11.

Morais

Magina

Mateus

Trindade

Jesus

Azevedo

Efficacy and safety of propranolol in the treatment of parotid hemangioma. Cutan Ocular Toxicol. 2011;30(3):245-248.

12.

Tan

Itinteang

Leadbitter

Low-dose propranolol for infantile haemangioma. J Plast Reconstr Aesthetic Surg. 2011;64(3):292-299.

13.

Cavalli

Buffon

De Souza

Colli

Gelmetti

Tumor lysis syndrome after propranolol therapy in ulcerative infantile hemangioma: rare complication or incidental finding?

Dermatology. 2012;224(2):106-109.

14.

Mousa

Kues

Haas

et al . Successful treatment of a large hemangioma with propranolol. J German Soc Dermatol. 2010;8(3):184-186.

15.

Pavlakovic

Kietz

Lauerer

Zutt

Lakomek

Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics. 2010;126(6):e1589-e1593.

16.

Wang

Chen

et al . Oral atenolol therapy for proliferating infantile hemangioma: a prospective study. Medicine (Baltimore). 2016;95(24):e3908.

17.

Ruitenberg

Young-Afat

de Graaf

Pasmans

Breugem

CC.

Ulcerated infantile haemangiomas: the effect of the selective beta-blocker atenolol on wound healing. Br J Dermatol. 2016;175(6):1357-1360.

18.

Tan

Itinteang

Day

O’Donnell

Mathy

Leadbitter

Treatment of infantile haemangioma with captopril. Br J Dermatol. 2012;167(3):619-624.

19.

Collins

Bolger

Condon

Irvine

Watson

Treatment of ulcerated haemangiomas with recombinant human platelet-derived growth factor. Br J Dermatol. 2004;151(1):260-260.

20.

Metz

Rubenstein

Levy

Metry

DW.

Response of ulcerated perineal hemangiomas of infancy to becaplermin gel, a recombinant human platelet-derived growth factor. Arch Dermatol. 2004;140(7):867-870.

21.

Sugarman

Mauro

Frieden

Siegfried

Treatment of an ulcerated hemangioma with recombinant platelet-derived growth factor. Arch Dermatol. 2002;138(3):314-316.

22.

Mascarenhas

Guiote

Agro

Henrique

Ulcerated infantile hemangioma treated with imiquimod. Dermatol Online J. 2011;17(9):13.

23.

Fawcett

Grant

Hall

Kelsall

AWR

Nicholson

JC.

Vincristine as a treatment for a large haemangioma threatening vital functions. Br J Plast Surg. 2004;57(2):168-171.

24.

Achauer

Vander Kam

VM.

Ulcerated anogenital hemangioma of infancy. Plast Reconstr Surg. 1991;87(5):861-868.

25.

Serena

Wound closure and gradual involution of an infantile hemangioma using a noncontact, low-frequency ultrasound therapy. Ostomy Wound Manage. 2008;54(2):68-71.

26.

Illum

Karlsmark

Svejgaard

Ullman

Yssing

Ulcerated haemangioma successfully treated with interferon alfa-2b and topical granulocyte-macrophage colony-stimulating factor. Dermatology. 1995;191(4):315-317.

27.

Laws

Porter

Taibjee

Clayton

TH.

Topical breast milk may promote healing of ulceration in infantile haemangiomas. Clin Exp Dermatol. 2012;37(8):915-916.

28.

Thomas

Kumar

DD.

Ulcerated infantile haemangioma of buttock successfully treated with topical timolol. J Cutan Aesthetic Surg. 2013;6(3):168-169.

29.

Watanabe

Takagi

Sato

Hosaka

Early surgical intervention for Japanese children with infantile hemangioma of the craniofacial region. J Craniofac Surg. 2009;20(suppl 1):707-709.

30.

Fox

Johnson

Storey

Das Gupta

Kimble

Negative pressure wound therapy in the treatment of ulcerated infantile haemangioma. Pediatr Surg Int. 2015;31(7):653-658.

31.

Weibel

Barysch

Scheer

et al . Topical timolol for infantile hemangiomas: evidence for efficacy and degree of systemic absorption. Pediatr Dermatol. 2016;33(2):184-190.

32.

Deng

Successful treatment of ulcerated hemangiomas with a dual-wavelength 595- and 1064-nm laser system. J Dermatolog Treat. 2016;27(6):562-567.

33.

Hermosa

Boixeda

Urech

Turrion

Perez

Jaen

Treatment of ulcerated infantile hemangiomas with pulsed dye laser and Nd:YAG laser. Lasers Surg Med. 2014;46(4):360-361.

34.

Morelli

Tan

Yohn

Weston

WL.

Treatment of ulcerated hemangiomas infancy. Arch Pediatr Adolesc Med. 1994;148(10):1104-1105.

35.

Jorge

Del Pozo

Castineiras

Mazaira

Fernandez-Torres

Fonseca

Treatment of ulcerated haemangiomas with a non-coherent pulsed light source: brief initial clinical report. J Cosmet Laser Ther. 2008;10(1):48-51.

36.

Lacour

Syed

Linward

Harper

JI.

Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas. Arch Dis Child. 1996;74(2):161-163.

37.

Theologie-Lygidakis

Schoinohoriti

Tzerbos

Iatrou

Surgical management of head and neck vascular anomalies in children: a retrospective analysis of 42 patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(1):e22-31.

38.

Nakada

Kawada

Fujioka

et al . Hemangioma of the upper arm associated with massive hemorrhage in a neonate. Surg Today. 1993;23(3):273-276.

39.

Zhu

Yang

Zhao

Fan

Topaz

Early surgical management of large scalp infantile hemangioma using the TopClosure Tension-Relief System. Medicine. 2015;94(47):e2128.

40.

Alter

Trengove-Jones

, H Jr CE. Hemangioma of penis and scrotum. Urology. 1993;42(2):205-208.

41.

Bookout

McCord

McLane

Doughty

Case studies of an infant, a toddler, and an adolescent treated with a negative pressure wound treatment system. J Wound Ostomy Continence Nurs. 2004;31(4):184-192 189p.

42.

Pitta

GBB

Gomes

RR.

Treatment of ulcerated hemangioma: case report. J Vasc Bras. 2009;8(3):263-266.

43.

Oranje

de Waard-van der Spek

Devillers

de Laat

Madern

GC.

Treatment and pain relief of ulcerative hemangiomas with a polyurethane film. Dermatology (Basel, Switzerland). 2000;200(1):31-34.

44.

Lapidoth

Ben-Amitai

Bhandarkar

Fried

Arbiser

JL.

Efficacy of topical application of eosin for ulcerated hemangiomas. J Am Acad Dermatol. 2009;60(2):350-351.

45.

Cante

Pham-Ledard

Imbert

Ezzedine

Leaute-Labreze

First report of topical timolol treatment in primarily ulcerated perineal haemangioma. Arch Dis Child. 2012;97(2):F155-F156.

46.

Neri

Virdi

La Placa

Patrizi

A perineal infantile haemangioma presenting as early ulcerations. Arch Dis Child. 2015;100(5):F393.

47.

Hong

Fischer

Propranolol for recalcitrant ulcerated hemangioma of infancy. Aust J Dermatol. 2011;52:29.

48.

Barlow

Walker

Markey

AC.

Treatment of proliferative haemangiomas with the 585 nm pulsed dye laser. Br J Dermatol. 1996;134(4):700-704.

49.

David

Malek

Argenta

LC.

Efficacy of pulse dye laser therapy for the treatment of ulcerated haemangiomas: a review of 78 patients. Br J Plast Surg. 2003;56(4):317-327.

50.

Ward

Friedlander

Kaplan

GW.

Hemangioma presenting as an ulceration of the scrotum. J Urol. 1998;160(1):182-183.

51.

Yan

AC.

Pain management for ulcerated hemangiomas. Pediatr Dermatol. 2008;25(6):586-589.

52.

Hatfield

Wright

AL.

Becaplermin gel, a recombinant human platelet-derived growth factor, in the treatment of an ulcerated perineal haemangioma. Br J Dermatol. 2006;155:46-46.

53.

Hasan

Tan

Gush

Peters

Davis

PF.

Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105(1, pt 1):117-120.

54.

Lansang

Pope

Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol. 2007;56(1):63-68.

55.

Beal

Chu

Siegfried

EC.

Ulcerated infantile hemangioma: novel treatment with topical brimonidine-timolol. Pediatr Dermatol. 2014;31(6):754-756.

56.

Boos

Castelo-Soccio

Experience with topical timolol maleate for the treatment of ulcerated infantile hemangiomas (IH). J Am Acad Dermatol. 2016;74(3):567-570.

57.

Tlougan

Gonzalez

Orlow

SJ.

Abortive segmental perineal hemangioma. Dermatol Online J. 2011;17(10).

58.

Al Dosari

Riad

. Ulcerated nasal infantile haemangioma treated by oral propranolol. Dermatol Online J. 2013;19(5):18298.

59.

Bagazgoitia

Torrelo

Gutierrez

JCL

et al . Propranolol for infantile hemangiomas. Pediatr Dermatol. 2011;28(2):108-114.

60.

Ben-Zvi

Gass

JK.

Propranolol for ulcerating infantile haemangiomas. Br J Dermatol. 2013;168(1):e5.

61.

Bernabeu-Wittel

Pereyra-Rodriguez

Mantrana-Bermejo

Fernandez-Pineda

De Agustin

Conejo-Mir

Propranolol for the treatment of severe hemangiomas of infancy: Results from a series of 28 patients. Actas Dermosifiliograficas. 2011;102(7):510-516.

62.

Bouras

Dehbi

Elfatouaki

et al . Propranolol therapy for infantile haemangiomas: a case series of 33 infants. J Am Acad Dermatol. 2013;68(4)(suppl 1):AB5.

63.

Gidaris

Economou

Hatzidemetriou

Gombakis

Athanassiou-Metaxa

Use of propranolol in infantile haemangiomas: report of five cases and review of the literature. Hippokratia. 2011;15(1):81-83.

64.

Hermans

van Beynum

Schultze Kool

van de Kerkhof

Wijnen

van der Vleuten

CJ.

Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls. J Am Acad Dermatol. 2011;64(5):833-838.

65.

Lanoel

Tosi

Bocian

et al . Perianal ulcers on a segmental hemangioma with minimal or arrested growth. Actas Dermosifiliograficas. 2012;103(9):820-823.

66.

Naouri

Schill

Maruani

Bross

Lorette

Rossler

Successful treatment of ulcerated haemangioma with propranolol. J Eur Acad Dermatol Venereol. 2010;24(9):1109-1112.

67.

Nelson

Zimmerman

Alexander

Hennessy

Sidman

Outpatient propranolol is safe and effective in infants with hemangioma: single center experience and case report of successful use in a seven-year-old. Pediatr Blood Cancer. 2011;56(6):965.

68.

Oksiuta

Matuszczak

Debek

Dzienis-Koronkiewicz

Hermanowicz

Treatment of rapidly proliferating haemangiomas in newborns with propranolol and review of the literature. J Matern Fetal Neonatal Med. 2016;29(1):64-68.

69.

Saaiq

Ashraf

Siddiqui

Ahmad

Salman Zaib

Successful propranolol treatment of a large size infantile hemangioma of the face causing recurrent bleeding and visual field disruption. World J Plast Surg. 2015;4(1):79-83.

70.

Sadykov

Podmelle

Sadykov

Kasimova

Metellmann

HR.

Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region. Int J Oral Maxillofac Surg. 2013;42(7):863-867.

71.

Sans

Dumas-De-la-roque

Boralevi

et al . Propranolol for severe infantile haemangiomas. Br J Dermatol. 2009;161:117-118.

72.

Sharma

Fraulin FOG, Dumestre

Walker

Harrop

AR.

Beta-blockers for the treatment of problematic hemangiomas. Can J Plast Surg. 2013;21(1):23-28.

73.

Thomas

Kumar

DD.

Ulcerated infantile haemangioma of leg successfully treated with propranolol. J Cutan Aesthetic Surg. 2011;4(3):211-213.

74.

Vercellino

Romanini

Pelegrini

Rimini

Occella

Dalmonte

The use of propranolol for complicated infantile hemangiomas. Int J Dermatol. 2013;52(9):1140-1146.

75.

Strand

Smidt

AC.

Pain management for ulcerated infantile hemangiomas. Pediatr Dermatol. 2012;29:124-126.

76.

Di Maio

Baldi

Dimaio

Barzi

. Use of flashlamp-pumped pulsed dye laser in the treatment of superficial vascular malformations and ulcerated hemangiomas. In Vivo. 2011;25(1):117-123.

77.

Morais

Magina

Reis

et al . Reticular hemangioma of the lower extremity associated with congenital structural anomalies: therapeutic approach. Medicina Cutanea Ibero-Latino-Americana. 2013;41(1):38-42.

78.

Rodríguez-Ruiz

Tellado

del Pozo Losada

Combination of pulsed dye laser and propranolol in the treatment of ulcerated infantile haemangioma [in Spanish]. An Pediatr (Barc). 2016;84(2):92-96.

79.

Kunzi-Rapp

Topical propranolol therapy for infantile hemangiomas. Pediatr Dermatol. 2012;29(2):154-159.

80.

Thomas

Hornung

Manning

Perkins

JA.

Hemangiomas of infancy - Treatment of ulceration in the head and neck. Arch Facial Plast Surg. 2005;7(5):312-315.

81.

McCuaig

Cohen

Powell

et al . Therapy of ulcerated hemangiomas. J Cutan Med Surg. 2013;17(4):233-242.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.39 MB