Infantile haemangiomas (IHs) are the most common benign tumour in infancy, affecting 10% of white children. They are seen more commonly in white children and premature infants 1–3. IH occur more frequently in female individuals, with a female : male ratio of 3 : 1 4. The head and neck region is the most frequently involved area (60%) followed by the trunk (25%) and the extremities (15%) 5.
IH have a predictable natural history. The majority are not present at birth. However, a minority may have a precursor lesion such as a vascular patch or an area of pallor. Soon after birth, IH undergo significant growth (proliferative phase) for several months followed by gradual involution, which usually occurs over several years. Regression is complete in 50% of 5-year-old patients and 90% of 9-year-old patients 6.
It usually has a self-limited course with minimal sequelae, and the mainstay of the therapy is conservative observation. However, even transient cosmetic disfigurement during the long involution phase frequently induces psychological stress in the affected children and their parents 7. Some IH can cause local complications such as ulceration, pain, bleeding, scarring, secondary infection and permanent disfigurement. Others may cause significant functional impairment, vital organ compromise or life-threatening complications. For these complicated IH cases, systemic corticosteroids are generally considered to be the first-line of pharmacological therapy. Although there is a 78–89% response rate 8, a high recurrence rate of up to 36% and adverse effects limit its use 9. Alternative therapeutic options, such as vincristine, 10 interferon α 11 and cyclophosphamide, 12 are used for steroid-refractory and critical patients, but their potential toxicities are a major concern. In ∼10% of cases, depending on their anatomical site, there can be serious or life-threatening complications requiring treatment 13.
At present there are no gold standard systemic treatments for IH 14. Over the last few years, propranolol has become increasingly popular as a successful medication choice with fewer side effects compared with other current treatments. In 2008, a child with obstructive hypertrophic cardiomyopathy was treated with propranolol at 3 mg/kg/day. This child was noted to have a coexisting nasal haemangioma, and there was a coincidental improvement in the haemangioma while the child was on propranolol. The same authors studied a series of 11 patients and found a significant change in both colour and softness of haemangiomas within the first 24 h on propranolol, with improvement in all haemangiomas 15. Propranolol is a nonselective β-adrenergic antagonist that demonstrates equal affinity for both β1 and β2 receptors and therefore acts on multiple tissues.
IHs are composed of a number of cell types including endothelial cells. Recent studies have found that the capillary endothelial cells express β2 adrenergic receptors 16. Propranolol is thought to exert its effects on growing IH by three different molecular mechanisms: vasoconstriction, inhibition of angiogenesis and induction of apoptosis 17.
The autonomic nervous system and epinephrine play key roles in the control of vascular tone. Epinephrine can cause both vasoconstriction and vasodilatation by activating both the α1 receptors and β2 receptors, respectively. β-Blockers without α-antagonistic effects similar to propranolol inhibit epinephrine-mediated vasodilatation, and this leads to vasoconstriction of endothelial cells 18. During the growth phase of IH, there is an increased expression of two major proangiogenic factors: basic fibroblast factor and vascular endothelial growth factor (VEGF). Recent publications have found that the expression of VEGF is reduced by β-blockers, which thus leads to inhibition of angiogenesis 19. Apoptosis is regulated by a number of pathways, with the β1 adrenoreceptor being the probable receptor involved. It has been hypothesized that by blocking the β1 adrenoreceptor, propranolol induces apoptosis at an increased rate 20. In 2011, it was proposed that propranolol acts via the renin–angiotensin system in regulating accelerated involution of proliferating IH by inhibiting the proliferation of CD34/VEGFR-2 endothelial progenitor cells 21,22.
The side effects of propranolol includes bradycardia, hypotension, bronchospasm, hypoglycaemia, peripheral vasoconstriction, gastrointestinal disturbances, behavioural changes/sleep disturbances, profuse sweats and diarrhoea 23–26.
Propranolol should only be used in complicated IH. It is not justified to use propranolol for children with simple IH, particularly for cosmetic reasons given that the majority of these IH resolve spontaneously. Not only would the costs rise but also children would be placed at unnecessary risk from the potential side effects of propranolol 27.
Timolol, a nonselective β-blocker similar to propranolol, is available in a topical formulation for treatment of glaucoma. In 2010, there was a pilot study on the use of topical timolol for IH in the eyelid with good results 28, and since then there has been a great interest in timolol as a safe and an effective treatment for IH.
The aim of the study was to determine the efficacy of topical timolol in treatment of IH.
Patients and methods
This prospective case series study included 20 infants with IHs selected from Dermatology Outpatient Clinic. The duration of the study was 16 weeks. Treatment was given for 12 weeks and follow-up was carried out for 4 weeks after cessation of treatment for detection of any recurrence of lesions. Inclusion criteria were patients with IHs who had not received any treatment for IHs before the study. All types and sizes of IH were included. Informed consent was taken from all parents, and approval from Research Ethics Committee of Alexandria, Faculty of Medicine was obtained. Complete history was taken from all parents and the phase of IH was noted accordingly; lesion was increasing in size (proliferative), no more change in size (stationary) or lesion started to decrease in size or colour (involution). Thorough clinical examination for haemangioma was performed for every patient to detect the site, size, depth, ulceration, bleeding, infection, scarring or disfigurement. IHs were treated with topical timolol maleate, 0.5%. The child’s mother was instructed to apply timolol maleate, 0.5%, ophthalmic solution twice daily, two drops onto the surface of the IH with a gentle spread using a finger. The children were not receiving other medication during treatment.
Two investigators evaluated in consensus the response to treatment by comparing digital photographs at baseline, 4, 8 and final visit at 12 weeks of treatment using a descriptive score of the size and colour of the lesions. The difference in size of IHs was graded from −4 to +4 and the colour of IHs from −4 to +4, where −4 indicated almost double increase in size or colour of lesion and +4 indicated almost complete clearance of the lesion. The assessment of size and colour of the lesions was carried out every 4 weeks. At the end of 12 weeks treatment, the response was evaluated using a global score by the two investigators according to the following criteria: (i) excellent response (≥90%); (ii) partial response (>50 to <90%); (iii) minimal response (<50%); and (iv) no response. Follow-up of the patients was carried out for 4 weeks after treatment to detect any recurrence after improvement. Any side effects were recorded by doctors and parents.
Data were collected and entered into personal computer. Statistical analysis was performed using statistical package for social sciences, version 19 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were represented as mean±SD, whereas qualitative data were represented as frequencies and percentage. Student’s t-test was used for parametric quantitative data to compare between the two types of IH. The level of significance was 0.05.
In the present study, 15 patients were female (75%) and five patients were male (25%). Age of the patients ranged from 2 to 18 months with a mean of 8.8 months. Lesions were in the proliferative stage in eight patients (40%) and in the stationary stage in 10 patients (50%), whereas two patients had lesions in the involution stage (10%).
The lesions were on the ear in three patients, scalp in three patients, neck in three patients, lips in two patients, legs in two patients, thighs in two patients, abdomen in two patients, forearm in one patient, fingers in one patient and cheek in one patient. Lesions were variable in size from small lesion to large ones involving almost the whole forearm or flexor aspect of the leg. Two patients had ulceration in the lesions, whereas three had recurrent attacks of bleeding from the lesions at the time of presentation. Lesions were of mixed (superficial and deep) haemangioma type in 12 patients and superficial haemangioma type in eight patients.
With respect to response to treatment, all patients showed gradual improvement in the size/extent and in colour of lesions during the treatment. The descriptive score showed that both size and colour of IH decreased over time in all patients with variable degrees (Tables 1 and 2).
At the end of treatment, the percentage of improvement was as follows; four patients improved 90%, one patient had 80% improvement, seven patients had 70% improvement and eight patients had 60% improvement. According to the global score, 20% showed excellent response (90% clearance), 80% showed partial response (>50 to <90%) and none showed minimal (poor) response (<50% improvement) (Table 3 and Figs 1–3).
Both superficial and mixed haemangioma showed nonsignificant difference in percentage of improvement (73.75 vs. 70%) (Table 4). All stages of haemangioma improved under treatment. More improvement in haemangiomas was observed in the proliferative stage (78 vs. 65%); yet, the difference was not statistically significant.
Ulceration in the lesion healed during treatment with a scarring, whereas no more attacks of bleeding occurred during the treatment.
The treatment was well-tolerated. Local side effects after application of timolol were noticed in two patients (10%) only in form of local irritation with itching, which did not necessitate cessation of treatment. No systemic side effects were detected in any patient.
During the follow-up period, there was no recurrence of lesions in any patient, whereas two patients continued treatment and showed further improvement.
In the present study, topical timolol was used in the treatment of IH. It was applied twice daily for 12 weeks. Treatment was well-tolerated without systemic side effects; only local irritation was noticed in 10% of patients, which did not need cessation of treatment. Treatment was effective in all patients. None of patients showed minimal (<50% improvement) or no response. During the follow-up period, no recurrence was noticed in any patient; yet, two patients continued treatment with further improvement in the lesions.
The successful outcomes for timolol in IH were previously reported in case reports 28–31. In 2010, Guo and Nin 28 demonstrated that the application of topical β-blocker solution produced significant reduction in a large capillary haemangioma and resulted in the clearance of the child’s visual axis within a few weeks of treatment. No local or systemic adverse effects were noted. In the same year, Pope and Chakkittakandiyil 29 performed a pilot study on six patients with uncomplicated IHs in the head and neck area who were treated with timolol maleate, 0.5%, gel. This study showed that timolol maleate, 0.5%, gel is effective and safe for the treatment of IHs. Patients with superficial IHs and those treated for longer periods showed better response to timolol. Early intervention during the rapid proliferative phase (age 1–6 months) may result in better and faster resolution of IHs. These results are similar to results of the present study in which response to timolol continued over time, and better results were obtained when treatment was started in the proliferative phase. In a case report 30 of a 1-month-old boy who had a capillary haemangioma on his left eyelid, treatment was carried out with topical timolol. After 2 weeks of treatment, the haemangioma was significantly reduced in size, thickness and colour. The topical timolol application was continued for 5 months, with practical resolution of the lesion. The child tolerated the topical treatment well, and close clinical monitoring did not show adverse effects suggestive of systemic absorption of a β-blocker. Timolol had been reported in the treatment of a large ulcerating haemangioma with PHACE syndrome 31. An 18-month-old girl, born after a full-term normal delivery, presented with a large, ulcerated haemangioma on the right side of the face. The patient showed a dramatic response to topical timolol 0.5% ophthalmic lotion applied over the haemangiomas. There was a decrease in redness within 3 days and almost complete resolution of the haemangiomas by 8 weeks. Pruritus was the only side effect observed after 4 weeks of application. Close clinical monitoring did not show adverse effects suggestive of systemic absorption of a β-blocker 31.
In another study, 20 patients with IH treated with timolol 0.5% ophthalmic solution were described. More or less similar results were obtained. The treatment was effective in all superficial IHs after 1–4 months. A quick direct inhibitory effect on the growth of IHs followed by a slower regression was observed. The children had to be treated during the whole proliferative phase. In contrast to results of the present study, deep IHs on the nose (two patients) and lower eyelid (one patient) showed no response 32.
In a study comparing timolol maleate 0.5 and 0.1% gel-forming solution for IH, it was found that predictors of better response were superficial type of haemangioma, 0.5% timolol concentration, and a duration of use longer than 3 months. This study further demonstrated the efficacy and tolerability of topical timolol maleate and gradual improvement with longer treatment in patients with superficial IH 33.
Little is known about percutaneous absorption of timolol 34. It is important to proceed with caution and encourage clinical trials. In particular, it is prudent to be cautious when using topical timolol on large, ulcerated or mucosal or perimucosal haemangiomas, where the skin barrier function is compromised and when occlusion is likely 35.
The results of the present study suggest that topical β-blocker administration provides a safe and an effective new treatment modality for IH. Treatment was found effective in all types of IH with minimal side effects.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2014 Egyptian Women's Dermatologic Society
beta blockers; haemangioma; topical timolol