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High-dose steroid has been the mainstay treatment for problematic proliferating haemangioma since it was serendipitously discovered to induce accelerated regression in the 1960s.1 The mechanism of action of steroid in haemangioma is largely unknown although it is associated with increased mast cell density, reduction of a number of cytokines and enhanced expression of mitochondrial cytochrome b gene.2The recommended starting dose of systemic steroid is oral prednisolone at 2-3 mg/kg/day, as higher dosage (5 mg/kg/day) is associated with increased risk of complications.3Over the last 4 decades, several studies have reported conflicting effectiveness of steroid on haemangioma. One study shows dramatic response occurs in 30%, equivocal result in 40%, with ongoing progression in the remainder.4We report the results and assess the safety profile of steroid therapy as the first-line treatment for problematic proliferating haemangioma, between 1996 and 2007, in our Vascular Anomalies Centre.Methods 233 consecutive patients referred to the Centre for the Study & Treatment of Vascular Birthmarks were identified from our prospective vascular anomalies database 1996-2007. The management of these patients is outlined in Figure 1. Figure 1. Management of the 233 patients with haemangioma Forty-six (36%) of the 129 patients presented with proliferating haemangioma were problematic and required active treatment. 24 patients (20 females, 4 males) received systemic (n=19) or intralesional (n=5) steroid therapy. The mean age was 10 (range 4-29) weeks. The patients were of European (n=16), Maori (n=2) and Pacific Island (n=3) descent. Haemangioma was located in the head and neck region in 19 (79%) patients. Intralesional triamcinolone, up to 4 mg/kg per injection, was used for localised non-periorbital haemangioma in five patients. Treatment was carried out under general anaesthesia using 30 G needle with multiple intralesional injections with small aliquots, as a day case. A repeat injection was performed at 6-weekly intervals as necessary. Oral prednisolone at 2.0-2.5 mg/kg/day was used for diffuse and/or periorbital haemangioma in 19 patients. The dosage was reduced monthly by 0.5 mg/kg/day until a dose of 0.5 mg/kg/day was reached, followed by tapering over 2 weeks. Since 2007, concurrent omeprazole or ranitidine was also given, due to relatively high incidence of gastroesophageal reflux noted during treatment. All patients were jointly assessed by a plastic surgeon and a paediatrician. Patients with periorbital haemangioma threatening vision also underwent ophthalmological assessment. The patients treated with systemic steroid were seen 2 weeks after commencement of treatment and then 4-weekly. Routine blood pressure, weight, height and head circumference measurements, assessment of developmental milestones, as well as cardiorespiratory and abdominal examination were performed. The dose of steroid was adjusted as necessary and any side effect was noted. For those treated with intralesional steroid, follow-up was arranged 2 weeks after treatment and then 4-6 weekly thereafter to assess the response to treatment and the need for further treatment. The response to the treatment was defined as cdramaticd if there was visible reduction of size, palpable softening, and reduction of the colour of the lesion within 6 weeks of treatment. The result was unequivocal if the lesion was unchanged. The treatment was considered a failure if the lesions continued to grow despite treatment. Results The patients were followed up for a mean of 30.2 months (range, 3 months-6.5 years). Two patients in the intralesional steroid group were lost to follow up after a period of 3 and 6 months. A further patient moved overseas shortly after treatment. Intralesional steroid injectionFive female patients with ulcerated proliferating haemangioma in the axilla, upper lip, submental area, forearm, and labia majora underwent intralesional triamcinolone injection. Four of these patients required a second injection, with one also received concurrent Pulsed Dye Laser therapy for optimal result. Accelerated regression with healing of the ulcerated proliferating haemangioma occurred in these patients (Figure 2). The remaining patient underwent debulking surgery because of continued growth of the haemangioma in the upper lip following one injection. No side effect of intralesional steroid therapy was noted during the follow-up period. Overall, the haemangioma in four (80%) of the five patients responded adequately to intralesional steroid therapy. Figure 2. An ulcerated proliferating haemangioma in the axilla of a 5 month-old baby (A) before and (B) 6 weeks after first intralesional triamcinolone injection. Systemic steroid therapyNineteen patients were treated with oral prednisolone for the indications listed in Table 1. The mean age of commencement of steroid therapy was 10 (range 4-29) weeks with the mean duration of treatment of 21.6 (range, 11-38; median, 21) weeks. Fifteen(79%) patients responded to oral prednisolone at 2 mg/kg/day with accelerated regression occurring in 10 (53%) patients and the haemangioma stabilised in 5 (26%) patients. Three of the four patients who failed to respond prednisolone at this initial dose of 2 mg/kg/day responded to an increased dose to 2.5 mg/kg/day with stabilisation of their haemangioma. These three patients received 9-13 weeks of high dose steroid compared to 4-6 weeks of treatment for those who responded well to an initial dose of 2 mg/kg/day. The remaining patient required debulking surgery for a large haemangioma on the glabella region that caused partial visual axis obstruction. Table 1. Indications for systemic steroid therapy Indications for treatment No. of patients Threat to vision - direct globe compression 1 - corneal deformation 4 - visual axis obstruction 6 Nasal airway obstruction Obstruction of auditory meatus Ulceration 00b1 bleeding Tissue (facial) distortion 9 3 1 5 10 Rebound growth during dose tapering was observed in five patients. In one patient, this was transient and required no further action. Three patients responded well to dose increment of 0.5 mg/kg/day and the remaining patient underwent debulking surgery. Overall, the haemangioma in 17 (89%) patients responded to high dose oral steroid but failed in 2 (11%) patients. Effects on visionNine patients with periorbital haemangioma threatening vision with astigmatism due to corneal deformation (n=5) and/or visual axis occlusion (n=5) and/or globe compression (n=1). At completion of treatment, astigmatism and visual axis obstruction were resolved in all patients (Figure 3). One patient subsequently developed symmetrical hypermetropic astigmatism, unrelated to the haemangioma. There was also an incidental finding of optic nerve coloboma on the affected side. Side effects of steroid therapyOne patient developed adrenal crisis during an intercurrent otitis media requiring hospitalisation and responded well to intravenous hydrocortisone with no long-term sequelae. There was dramatic regression of the haemangioma. Three patients had significant growth retardation during systemic steroid therapy. Their length and weight dropped by 25-50 percentile during initial treatment but this gradually reversed during or after steroid dose tapering and normalised within 1 year of cessation of therapy (Figure 4). Other side effects included mild Cushingoid features (n=2), irritability (n=2), increased appetite (n=3) with one patient having significant weight gain. As some patients had pre-existing gastroesophageal reflux and some were given concurrent omeprazole or ranitidine, the true incidence of steroid-induced gastro-oesophageal reflux is difficult to be ascertained. None of the patient developed hypertension. Figure 3. (A) A 14-week old girl with a right periorbital haemangioma causing globe compression, corneal deformation with mild astigmatism and partial visual axis occlusion, confirmed on (B) sagittal and (C) axial MRI scan. The haemangioma responded dramatically to high-dose prednisolone. A B C Photographs at (D) 4 weeks, (E) 7 months and (F) 4 years after treatment. One year following commencement of treatment, she had equal refraction and visual acuity in both eyes. D E F Figure 4. Growth charts of a patient with growth retardation during high-dose steroid treatment (A - length; B - weight) A B Discussion Over the last 4 decades, there have been several studies reporting the effectiveness of steroid on haemangioma with conflicting results. This is due to the confusion of the nomenclature leading to use of steroid on vascular malformations such as venous malformation. Some studies also include involuting haemangioma. The dosage and duration of steroid therapy also differ widely between studies. The overall 89% response rate in our study compares favourably to that (75%) reported in the meta-analysis4 of the studies that used similar dosage regime of 2-3 mg/kg/day.The higher response rate in our study including a 53% dramatic response rate compared with previous studies of 30%4supports the suggestion that immature haemangioma would respond better to steroid therapy. In the studies using this dosage regime included in the meta-analysis by Bennett M et al,4 there is a 14-37% (mean, 25%) of rebound rates.Rebound growth observed infive of the 15 (33%) patients in our study suggests the need to maintain therapy for longer in younger patients. Three of five patients with rebound growth during dose tapering and those who initially failed to respond were successfully treated with a dose increment. The need of dose increment resulted in an increase of the total duration of treatment from 4-6 to 9-13 weeks. Our study concurs with the findings by Boon et al3 that most complications of high dose systemic steroid therapy for haemangioma are minor and transient. However, our results do not support these authors suggestion that the risk of growth retardation is 4-5 times more likely in children less than 3 months of age or if the duration of treatment is more than 6 months. Only 3 of the 13 (23%) patients in our series who were commenced on steroid therapy aged 3 months or younger developed transient growth retardation. They received 6, 9, and 12 weeks of high dose steroid at 2.0-2.5 mg/kg/day and for a total duration of 19, 21, and 26 weeks of steroid treatment respectively. Furthermore, growth retardation was not observed in the other four patients who had received 26 weeks or more of steroid therapy. Nevertheless, it is pertinent to monitor the growth and development during therapy and the dose of steroid should be tapered as soon as possible. Despite the wide variations in the dosages used and different selection criteria, an overall good response rate of 35-90% to intralesional steroid therapy has been reported.6 The haemangioma in four out of five patients in our study responded dramatically after two intralesional steroid injections and we did not encounter any complication. Chen et al6 reports a 6.4% complication rate including cutaneous atrophy, Cushingoid appearance, and anaphylactic shock. Although intralesional steroid therapy has been used for periorbital haemangioma,5-7 caution is needed because of the risk of central retinal artery occlusion,8 eyelid necrosis9 and orbital cellulitis. The small number of patients treated with intralesional steroid in our series reflects the small number of cases, i.e., localised and non-periorbital haemangioma, suitable for this treatment. In 2008, L 00e9aut 00e9-labr 00e8zeet al10 serendipitously discovered the dramatic effect of propanolol in inducing accelerated regression of haemangioma. The results of the empirical dosage of 2-3 mg/kg/day of propranolol has been supported by a further report of 30 patients.11 We have confirmed the safety and efficacy of propranolol using a slow dose escalation regimen and shown that the optimal dosage required is a sub-cardiovascular dose of 1.5-2.0 mg/kg/day and that the treatment should be continued until 1 year of age.12 Propranolol has replaced steroid therapy as the first-line treatment for problematic proliferating haemangioma in our Vascular Anomalies Centre. The processes leading to accelerated involution of proliferating haemangioma induced by propranolol is unknown. We have recently shown that haemangioma is a developmental anomaly of the haemogenic endothelium with a neural crest derived phenotype13,14 governed by the renin-angiotensin system and speculate the possibility of using inhibitors angiotensin converting enzyme and that of angiotensin II receptor 2.15 Our Vascular Anomalies Centre is currently conducting a clinical trial using an ACE inhibitor for the treatment of problematic proliferating haemangioma, with promising results.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Acknowledgements

Correspondence

Correspondence Email

Competing Interests

Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plastic Reconstr Surg. 1967;39:76-83. Hasan Q, Tan S, Gush J, et al. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105:117-120. Boon LM, MacDonald D, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104:1616-1623. Bennett M, Fleischer A, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangiomas - An evidence-based evaluation. Arch Dermatol. 2001;137(9):1208-1213. Sloan GM, Reinisch JF, Nichter LS, et al. Intralesional corticosteroid therapy for infantile hemangiomas. Plast Reconstr Surg. 1989;83:459-467. Chen MT, Yeong EK, Horng SY. Intralesional corticosteroid therapy in proliferating head and neck hemangiomas: a review of 155 cases. J Pediatr Surg. 2000;35:420-423. Chantharatanapiboon W. Intralesional corticosteroid therapy in hemangiomas: clinical outcome in 160 cases. J Med Assoc Thailand. 2008;91 Suppl 3:S90-6. Shorr N, Seiff S. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg. 1986;17(4):229-231. Sutula FC, Glover AT. Eyelid necrosis following intralesional corticosteroid injection for capillary hemangioma. Ophthalmic Surg. 1987;18:103. L 00e9aut 00e9-Labr 00e8ze C, Dumas de la Rogue E, Hubiche T, et al. Propanolol for severe hemangiomas of infancy. NEJM. 2008;358(24):2649-2651. Manunza F, Syed S, Lguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants [Correspondence]. Bri J Dermatol. 2010;162:466-468. Tan ST, Itinteang T, Leadbitter P. Low dose optimal propranolol for the treatment of infantile haemangioma. JPRAS. 2010; DOI: 10.1016/j.bjps.2010.06.010. Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cells phenotype predominate proliferating haemangioma. J Clin Pathol. 2010;DOI:10.1136/jcp.2010.079368. Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol. 2010;63:982-986. Itinteang T, Tan ST, Brasch H, Day DJ. Expression of components of the renin-angiotensin system in proliferating haemangioma may account for propranolol induced accelerated involution. JPRAS. 2010;DOI:10.1016/j.bjps.2010.08.039.

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High-dose steroid has been the mainstay treatment for problematic proliferating haemangioma since it was serendipitously discovered to induce accelerated regression in the 1960s.1 The mechanism of action of steroid in haemangioma is largely unknown although it is associated with increased mast cell density, reduction of a number of cytokines and enhanced expression of mitochondrial cytochrome b gene.2The recommended starting dose of systemic steroid is oral prednisolone at 2-3 mg/kg/day, as higher dosage (5 mg/kg/day) is associated with increased risk of complications.3Over the last 4 decades, several studies have reported conflicting effectiveness of steroid on haemangioma. One study shows dramatic response occurs in 30%, equivocal result in 40%, with ongoing progression in the remainder.4We report the results and assess the safety profile of steroid therapy as the first-line treatment for problematic proliferating haemangioma, between 1996 and 2007, in our Vascular Anomalies Centre.Methods 233 consecutive patients referred to the Centre for the Study & Treatment of Vascular Birthmarks were identified from our prospective vascular anomalies database 1996-2007. The management of these patients is outlined in Figure 1. Figure 1. Management of the 233 patients with haemangioma Forty-six (36%) of the 129 patients presented with proliferating haemangioma were problematic and required active treatment. 24 patients (20 females, 4 males) received systemic (n=19) or intralesional (n=5) steroid therapy. The mean age was 10 (range 4-29) weeks. The patients were of European (n=16), Maori (n=2) and Pacific Island (n=3) descent. Haemangioma was located in the head and neck region in 19 (79%) patients. Intralesional triamcinolone, up to 4 mg/kg per injection, was used for localised non-periorbital haemangioma in five patients. Treatment was carried out under general anaesthesia using 30 G needle with multiple intralesional injections with small aliquots, as a day case. A repeat injection was performed at 6-weekly intervals as necessary. Oral prednisolone at 2.0-2.5 mg/kg/day was used for diffuse and/or periorbital haemangioma in 19 patients. The dosage was reduced monthly by 0.5 mg/kg/day until a dose of 0.5 mg/kg/day was reached, followed by tapering over 2 weeks. Since 2007, concurrent omeprazole or ranitidine was also given, due to relatively high incidence of gastroesophageal reflux noted during treatment. All patients were jointly assessed by a plastic surgeon and a paediatrician. Patients with periorbital haemangioma threatening vision also underwent ophthalmological assessment. The patients treated with systemic steroid were seen 2 weeks after commencement of treatment and then 4-weekly. Routine blood pressure, weight, height and head circumference measurements, assessment of developmental milestones, as well as cardiorespiratory and abdominal examination were performed. The dose of steroid was adjusted as necessary and any side effect was noted. For those treated with intralesional steroid, follow-up was arranged 2 weeks after treatment and then 4-6 weekly thereafter to assess the response to treatment and the need for further treatment. The response to the treatment was defined as cdramaticd if there was visible reduction of size, palpable softening, and reduction of the colour of the lesion within 6 weeks of treatment. The result was unequivocal if the lesion was unchanged. The treatment was considered a failure if the lesions continued to grow despite treatment. Results The patients were followed up for a mean of 30.2 months (range, 3 months-6.5 years). Two patients in the intralesional steroid group were lost to follow up after a period of 3 and 6 months. A further patient moved overseas shortly after treatment. Intralesional steroid injectionFive female patients with ulcerated proliferating haemangioma in the axilla, upper lip, submental area, forearm, and labia majora underwent intralesional triamcinolone injection. Four of these patients required a second injection, with one also received concurrent Pulsed Dye Laser therapy for optimal result. Accelerated regression with healing of the ulcerated proliferating haemangioma occurred in these patients (Figure 2). The remaining patient underwent debulking surgery because of continued growth of the haemangioma in the upper lip following one injection. No side effect of intralesional steroid therapy was noted during the follow-up period. Overall, the haemangioma in four (80%) of the five patients responded adequately to intralesional steroid therapy. Figure 2. An ulcerated proliferating haemangioma in the axilla of a 5 month-old baby (A) before and (B) 6 weeks after first intralesional triamcinolone injection. Systemic steroid therapyNineteen patients were treated with oral prednisolone for the indications listed in Table 1. The mean age of commencement of steroid therapy was 10 (range 4-29) weeks with the mean duration of treatment of 21.6 (range, 11-38; median, 21) weeks. Fifteen(79%) patients responded to oral prednisolone at 2 mg/kg/day with accelerated regression occurring in 10 (53%) patients and the haemangioma stabilised in 5 (26%) patients. Three of the four patients who failed to respond prednisolone at this initial dose of 2 mg/kg/day responded to an increased dose to 2.5 mg/kg/day with stabilisation of their haemangioma. These three patients received 9-13 weeks of high dose steroid compared to 4-6 weeks of treatment for those who responded well to an initial dose of 2 mg/kg/day. The remaining patient required debulking surgery for a large haemangioma on the glabella region that caused partial visual axis obstruction. Table 1. Indications for systemic steroid therapy Indications for treatment No. of patients Threat to vision - direct globe compression 1 - corneal deformation 4 - visual axis obstruction 6 Nasal airway obstruction Obstruction of auditory meatus Ulceration 00b1 bleeding Tissue (facial) distortion 9 3 1 5 10 Rebound growth during dose tapering was observed in five patients. In one patient, this was transient and required no further action. Three patients responded well to dose increment of 0.5 mg/kg/day and the remaining patient underwent debulking surgery. Overall, the haemangioma in 17 (89%) patients responded to high dose oral steroid but failed in 2 (11%) patients. Effects on visionNine patients with periorbital haemangioma threatening vision with astigmatism due to corneal deformation (n=5) and/or visual axis occlusion (n=5) and/or globe compression (n=1). At completion of treatment, astigmatism and visual axis obstruction were resolved in all patients (Figure 3). One patient subsequently developed symmetrical hypermetropic astigmatism, unrelated to the haemangioma. There was also an incidental finding of optic nerve coloboma on the affected side. Side effects of steroid therapyOne patient developed adrenal crisis during an intercurrent otitis media requiring hospitalisation and responded well to intravenous hydrocortisone with no long-term sequelae. There was dramatic regression of the haemangioma. Three patients had significant growth retardation during systemic steroid therapy. Their length and weight dropped by 25-50 percentile during initial treatment but this gradually reversed during or after steroid dose tapering and normalised within 1 year of cessation of therapy (Figure 4). Other side effects included mild Cushingoid features (n=2), irritability (n=2), increased appetite (n=3) with one patient having significant weight gain. As some patients had pre-existing gastroesophageal reflux and some were given concurrent omeprazole or ranitidine, the true incidence of steroid-induced gastro-oesophageal reflux is difficult to be ascertained. None of the patient developed hypertension. Figure 3. (A) A 14-week old girl with a right periorbital haemangioma causing globe compression, corneal deformation with mild astigmatism and partial visual axis occlusion, confirmed on (B) sagittal and (C) axial MRI scan. The haemangioma responded dramatically to high-dose prednisolone. A B C Photographs at (D) 4 weeks, (E) 7 months and (F) 4 years after treatment. One year following commencement of treatment, she had equal refraction and visual acuity in both eyes. D E F Figure 4. Growth charts of a patient with growth retardation during high-dose steroid treatment (A - length; B - weight) A B Discussion Over the last 4 decades, there have been several studies reporting the effectiveness of steroid on haemangioma with conflicting results. This is due to the confusion of the nomenclature leading to use of steroid on vascular malformations such as venous malformation. Some studies also include involuting haemangioma. The dosage and duration of steroid therapy also differ widely between studies. The overall 89% response rate in our study compares favourably to that (75%) reported in the meta-analysis4 of the studies that used similar dosage regime of 2-3 mg/kg/day.The higher response rate in our study including a 53% dramatic response rate compared with previous studies of 30%4supports the suggestion that immature haemangioma would respond better to steroid therapy. In the studies using this dosage regime included in the meta-analysis by Bennett M et al,4 there is a 14-37% (mean, 25%) of rebound rates.Rebound growth observed infive of the 15 (33%) patients in our study suggests the need to maintain therapy for longer in younger patients. Three of five patients with rebound growth during dose tapering and those who initially failed to respond were successfully treated with a dose increment. The need of dose increment resulted in an increase of the total duration of treatment from 4-6 to 9-13 weeks. Our study concurs with the findings by Boon et al3 that most complications of high dose systemic steroid therapy for haemangioma are minor and transient. However, our results do not support these authors suggestion that the risk of growth retardation is 4-5 times more likely in children less than 3 months of age or if the duration of treatment is more than 6 months. Only 3 of the 13 (23%) patients in our series who were commenced on steroid therapy aged 3 months or younger developed transient growth retardation. They received 6, 9, and 12 weeks of high dose steroid at 2.0-2.5 mg/kg/day and for a total duration of 19, 21, and 26 weeks of steroid treatment respectively. Furthermore, growth retardation was not observed in the other four patients who had received 26 weeks or more of steroid therapy. Nevertheless, it is pertinent to monitor the growth and development during therapy and the dose of steroid should be tapered as soon as possible. Despite the wide variations in the dosages used and different selection criteria, an overall good response rate of 35-90% to intralesional steroid therapy has been reported.6 The haemangioma in four out of five patients in our study responded dramatically after two intralesional steroid injections and we did not encounter any complication. Chen et al6 reports a 6.4% complication rate including cutaneous atrophy, Cushingoid appearance, and anaphylactic shock. Although intralesional steroid therapy has been used for periorbital haemangioma,5-7 caution is needed because of the risk of central retinal artery occlusion,8 eyelid necrosis9 and orbital cellulitis. The small number of patients treated with intralesional steroid in our series reflects the small number of cases, i.e., localised and non-periorbital haemangioma, suitable for this treatment. In 2008, L 00e9aut 00e9-labr 00e8zeet al10 serendipitously discovered the dramatic effect of propanolol in inducing accelerated regression of haemangioma. The results of the empirical dosage of 2-3 mg/kg/day of propranolol has been supported by a further report of 30 patients.11 We have confirmed the safety and efficacy of propranolol using a slow dose escalation regimen and shown that the optimal dosage required is a sub-cardiovascular dose of 1.5-2.0 mg/kg/day and that the treatment should be continued until 1 year of age.12 Propranolol has replaced steroid therapy as the first-line treatment for problematic proliferating haemangioma in our Vascular Anomalies Centre. The processes leading to accelerated involution of proliferating haemangioma induced by propranolol is unknown. We have recently shown that haemangioma is a developmental anomaly of the haemogenic endothelium with a neural crest derived phenotype13,14 governed by the renin-angiotensin system and speculate the possibility of using inhibitors angiotensin converting enzyme and that of angiotensin II receptor 2.15 Our Vascular Anomalies Centre is currently conducting a clinical trial using an ACE inhibitor for the treatment of problematic proliferating haemangioma, with promising results.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Acknowledgements

Correspondence

Correspondence Email

Competing Interests

Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plastic Reconstr Surg. 1967;39:76-83. Hasan Q, Tan S, Gush J, et al. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105:117-120. Boon LM, MacDonald D, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104:1616-1623. Bennett M, Fleischer A, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangiomas - An evidence-based evaluation. Arch Dermatol. 2001;137(9):1208-1213. Sloan GM, Reinisch JF, Nichter LS, et al. Intralesional corticosteroid therapy for infantile hemangiomas. Plast Reconstr Surg. 1989;83:459-467. Chen MT, Yeong EK, Horng SY. Intralesional corticosteroid therapy in proliferating head and neck hemangiomas: a review of 155 cases. J Pediatr Surg. 2000;35:420-423. Chantharatanapiboon W. Intralesional corticosteroid therapy in hemangiomas: clinical outcome in 160 cases. J Med Assoc Thailand. 2008;91 Suppl 3:S90-6. Shorr N, Seiff S. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg. 1986;17(4):229-231. Sutula FC, Glover AT. Eyelid necrosis following intralesional corticosteroid injection for capillary hemangioma. Ophthalmic Surg. 1987;18:103. L 00e9aut 00e9-Labr 00e8ze C, Dumas de la Rogue E, Hubiche T, et al. Propanolol for severe hemangiomas of infancy. NEJM. 2008;358(24):2649-2651. Manunza F, Syed S, Lguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants [Correspondence]. Bri J Dermatol. 2010;162:466-468. Tan ST, Itinteang T, Leadbitter P. Low dose optimal propranolol for the treatment of infantile haemangioma. JPRAS. 2010; DOI: 10.1016/j.bjps.2010.06.010. Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cells phenotype predominate proliferating haemangioma. J Clin Pathol. 2010;DOI:10.1136/jcp.2010.079368. Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol. 2010;63:982-986. Itinteang T, Tan ST, Brasch H, Day DJ. Expression of components of the renin-angiotensin system in proliferating haemangioma may account for propranolol induced accelerated involution. JPRAS. 2010;DOI:10.1016/j.bjps.2010.08.039.

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

High-dose steroid has been the mainstay treatment for problematic proliferating haemangioma since it was serendipitously discovered to induce accelerated regression in the 1960s.1 The mechanism of action of steroid in haemangioma is largely unknown although it is associated with increased mast cell density, reduction of a number of cytokines and enhanced expression of mitochondrial cytochrome b gene.2The recommended starting dose of systemic steroid is oral prednisolone at 2-3 mg/kg/day, as higher dosage (5 mg/kg/day) is associated with increased risk of complications.3Over the last 4 decades, several studies have reported conflicting effectiveness of steroid on haemangioma. One study shows dramatic response occurs in 30%, equivocal result in 40%, with ongoing progression in the remainder.4We report the results and assess the safety profile of steroid therapy as the first-line treatment for problematic proliferating haemangioma, between 1996 and 2007, in our Vascular Anomalies Centre.Methods 233 consecutive patients referred to the Centre for the Study & Treatment of Vascular Birthmarks were identified from our prospective vascular anomalies database 1996-2007. The management of these patients is outlined in Figure 1. Figure 1. Management of the 233 patients with haemangioma Forty-six (36%) of the 129 patients presented with proliferating haemangioma were problematic and required active treatment. 24 patients (20 females, 4 males) received systemic (n=19) or intralesional (n=5) steroid therapy. The mean age was 10 (range 4-29) weeks. The patients were of European (n=16), Maori (n=2) and Pacific Island (n=3) descent. Haemangioma was located in the head and neck region in 19 (79%) patients. Intralesional triamcinolone, up to 4 mg/kg per injection, was used for localised non-periorbital haemangioma in five patients. Treatment was carried out under general anaesthesia using 30 G needle with multiple intralesional injections with small aliquots, as a day case. A repeat injection was performed at 6-weekly intervals as necessary. Oral prednisolone at 2.0-2.5 mg/kg/day was used for diffuse and/or periorbital haemangioma in 19 patients. The dosage was reduced monthly by 0.5 mg/kg/day until a dose of 0.5 mg/kg/day was reached, followed by tapering over 2 weeks. Since 2007, concurrent omeprazole or ranitidine was also given, due to relatively high incidence of gastroesophageal reflux noted during treatment. All patients were jointly assessed by a plastic surgeon and a paediatrician. Patients with periorbital haemangioma threatening vision also underwent ophthalmological assessment. The patients treated with systemic steroid were seen 2 weeks after commencement of treatment and then 4-weekly. Routine blood pressure, weight, height and head circumference measurements, assessment of developmental milestones, as well as cardiorespiratory and abdominal examination were performed. The dose of steroid was adjusted as necessary and any side effect was noted. For those treated with intralesional steroid, follow-up was arranged 2 weeks after treatment and then 4-6 weekly thereafter to assess the response to treatment and the need for further treatment. The response to the treatment was defined as cdramaticd if there was visible reduction of size, palpable softening, and reduction of the colour of the lesion within 6 weeks of treatment. The result was unequivocal if the lesion was unchanged. The treatment was considered a failure if the lesions continued to grow despite treatment. Results The patients were followed up for a mean of 30.2 months (range, 3 months-6.5 years). Two patients in the intralesional steroid group were lost to follow up after a period of 3 and 6 months. A further patient moved overseas shortly after treatment. Intralesional steroid injectionFive female patients with ulcerated proliferating haemangioma in the axilla, upper lip, submental area, forearm, and labia majora underwent intralesional triamcinolone injection. Four of these patients required a second injection, with one also received concurrent Pulsed Dye Laser therapy for optimal result. Accelerated regression with healing of the ulcerated proliferating haemangioma occurred in these patients (Figure 2). The remaining patient underwent debulking surgery because of continued growth of the haemangioma in the upper lip following one injection. No side effect of intralesional steroid therapy was noted during the follow-up period. Overall, the haemangioma in four (80%) of the five patients responded adequately to intralesional steroid therapy. Figure 2. An ulcerated proliferating haemangioma in the axilla of a 5 month-old baby (A) before and (B) 6 weeks after first intralesional triamcinolone injection. Systemic steroid therapyNineteen patients were treated with oral prednisolone for the indications listed in Table 1. The mean age of commencement of steroid therapy was 10 (range 4-29) weeks with the mean duration of treatment of 21.6 (range, 11-38; median, 21) weeks. Fifteen(79%) patients responded to oral prednisolone at 2 mg/kg/day with accelerated regression occurring in 10 (53%) patients and the haemangioma stabilised in 5 (26%) patients. Three of the four patients who failed to respond prednisolone at this initial dose of 2 mg/kg/day responded to an increased dose to 2.5 mg/kg/day with stabilisation of their haemangioma. These three patients received 9-13 weeks of high dose steroid compared to 4-6 weeks of treatment for those who responded well to an initial dose of 2 mg/kg/day. The remaining patient required debulking surgery for a large haemangioma on the glabella region that caused partial visual axis obstruction. Table 1. Indications for systemic steroid therapy Indications for treatment No. of patients Threat to vision - direct globe compression 1 - corneal deformation 4 - visual axis obstruction 6 Nasal airway obstruction Obstruction of auditory meatus Ulceration 00b1 bleeding Tissue (facial) distortion 9 3 1 5 10 Rebound growth during dose tapering was observed in five patients. In one patient, this was transient and required no further action. Three patients responded well to dose increment of 0.5 mg/kg/day and the remaining patient underwent debulking surgery. Overall, the haemangioma in 17 (89%) patients responded to high dose oral steroid but failed in 2 (11%) patients. Effects on visionNine patients with periorbital haemangioma threatening vision with astigmatism due to corneal deformation (n=5) and/or visual axis occlusion (n=5) and/or globe compression (n=1). At completion of treatment, astigmatism and visual axis obstruction were resolved in all patients (Figure 3). One patient subsequently developed symmetrical hypermetropic astigmatism, unrelated to the haemangioma. There was also an incidental finding of optic nerve coloboma on the affected side. Side effects of steroid therapyOne patient developed adrenal crisis during an intercurrent otitis media requiring hospitalisation and responded well to intravenous hydrocortisone with no long-term sequelae. There was dramatic regression of the haemangioma. Three patients had significant growth retardation during systemic steroid therapy. Their length and weight dropped by 25-50 percentile during initial treatment but this gradually reversed during or after steroid dose tapering and normalised within 1 year of cessation of therapy (Figure 4). Other side effects included mild Cushingoid features (n=2), irritability (n=2), increased appetite (n=3) with one patient having significant weight gain. As some patients had pre-existing gastroesophageal reflux and some were given concurrent omeprazole or ranitidine, the true incidence of steroid-induced gastro-oesophageal reflux is difficult to be ascertained. None of the patient developed hypertension. Figure 3. (A) A 14-week old girl with a right periorbital haemangioma causing globe compression, corneal deformation with mild astigmatism and partial visual axis occlusion, confirmed on (B) sagittal and (C) axial MRI scan. The haemangioma responded dramatically to high-dose prednisolone. A B C Photographs at (D) 4 weeks, (E) 7 months and (F) 4 years after treatment. One year following commencement of treatment, she had equal refraction and visual acuity in both eyes. D E F Figure 4. Growth charts of a patient with growth retardation during high-dose steroid treatment (A - length; B - weight) A B Discussion Over the last 4 decades, there have been several studies reporting the effectiveness of steroid on haemangioma with conflicting results. This is due to the confusion of the nomenclature leading to use of steroid on vascular malformations such as venous malformation. Some studies also include involuting haemangioma. The dosage and duration of steroid therapy also differ widely between studies. The overall 89% response rate in our study compares favourably to that (75%) reported in the meta-analysis4 of the studies that used similar dosage regime of 2-3 mg/kg/day.The higher response rate in our study including a 53% dramatic response rate compared with previous studies of 30%4supports the suggestion that immature haemangioma would respond better to steroid therapy. In the studies using this dosage regime included in the meta-analysis by Bennett M et al,4 there is a 14-37% (mean, 25%) of rebound rates.Rebound growth observed infive of the 15 (33%) patients in our study suggests the need to maintain therapy for longer in younger patients. Three of five patients with rebound growth during dose tapering and those who initially failed to respond were successfully treated with a dose increment. The need of dose increment resulted in an increase of the total duration of treatment from 4-6 to 9-13 weeks. Our study concurs with the findings by Boon et al3 that most complications of high dose systemic steroid therapy for haemangioma are minor and transient. However, our results do not support these authors suggestion that the risk of growth retardation is 4-5 times more likely in children less than 3 months of age or if the duration of treatment is more than 6 months. Only 3 of the 13 (23%) patients in our series who were commenced on steroid therapy aged 3 months or younger developed transient growth retardation. They received 6, 9, and 12 weeks of high dose steroid at 2.0-2.5 mg/kg/day and for a total duration of 19, 21, and 26 weeks of steroid treatment respectively. Furthermore, growth retardation was not observed in the other four patients who had received 26 weeks or more of steroid therapy. Nevertheless, it is pertinent to monitor the growth and development during therapy and the dose of steroid should be tapered as soon as possible. Despite the wide variations in the dosages used and different selection criteria, an overall good response rate of 35-90% to intralesional steroid therapy has been reported.6 The haemangioma in four out of five patients in our study responded dramatically after two intralesional steroid injections and we did not encounter any complication. Chen et al6 reports a 6.4% complication rate including cutaneous atrophy, Cushingoid appearance, and anaphylactic shock. Although intralesional steroid therapy has been used for periorbital haemangioma,5-7 caution is needed because of the risk of central retinal artery occlusion,8 eyelid necrosis9 and orbital cellulitis. The small number of patients treated with intralesional steroid in our series reflects the small number of cases, i.e., localised and non-periorbital haemangioma, suitable for this treatment. In 2008, L 00e9aut 00e9-labr 00e8zeet al10 serendipitously discovered the dramatic effect of propanolol in inducing accelerated regression of haemangioma. The results of the empirical dosage of 2-3 mg/kg/day of propranolol has been supported by a further report of 30 patients.11 We have confirmed the safety and efficacy of propranolol using a slow dose escalation regimen and shown that the optimal dosage required is a sub-cardiovascular dose of 1.5-2.0 mg/kg/day and that the treatment should be continued until 1 year of age.12 Propranolol has replaced steroid therapy as the first-line treatment for problematic proliferating haemangioma in our Vascular Anomalies Centre. The processes leading to accelerated involution of proliferating haemangioma induced by propranolol is unknown. We have recently shown that haemangioma is a developmental anomaly of the haemogenic endothelium with a neural crest derived phenotype13,14 governed by the renin-angiotensin system and speculate the possibility of using inhibitors angiotensin converting enzyme and that of angiotensin II receptor 2.15 Our Vascular Anomalies Centre is currently conducting a clinical trial using an ACE inhibitor for the treatment of problematic proliferating haemangioma, with promising results.

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Competing Interests

Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plastic Reconstr Surg. 1967;39:76-83. Hasan Q, Tan S, Gush J, et al. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics. 2000;105:117-120. Boon LM, MacDonald D, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104:1616-1623. Bennett M, Fleischer A, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangiomas - An evidence-based evaluation. Arch Dermatol. 2001;137(9):1208-1213. Sloan GM, Reinisch JF, Nichter LS, et al. Intralesional corticosteroid therapy for infantile hemangiomas. Plast Reconstr Surg. 1989;83:459-467. Chen MT, Yeong EK, Horng SY. Intralesional corticosteroid therapy in proliferating head and neck hemangiomas: a review of 155 cases. J Pediatr Surg. 2000;35:420-423. Chantharatanapiboon W. Intralesional corticosteroid therapy in hemangiomas: clinical outcome in 160 cases. J Med Assoc Thailand. 2008;91 Suppl 3:S90-6. Shorr N, Seiff S. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg. 1986;17(4):229-231. Sutula FC, Glover AT. Eyelid necrosis following intralesional corticosteroid injection for capillary hemangioma. Ophthalmic Surg. 1987;18:103. L 00e9aut 00e9-Labr 00e8ze C, Dumas de la Rogue E, Hubiche T, et al. Propanolol for severe hemangiomas of infancy. NEJM. 2008;358(24):2649-2651. Manunza F, Syed S, Lguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants [Correspondence]. Bri J Dermatol. 2010;162:466-468. Tan ST, Itinteang T, Leadbitter P. Low dose optimal propranolol for the treatment of infantile haemangioma. JPRAS. 2010; DOI: 10.1016/j.bjps.2010.06.010. Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cells phenotype predominate proliferating haemangioma. J Clin Pathol. 2010;DOI:10.1136/jcp.2010.079368. Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol. 2010;63:982-986. Itinteang T, Tan ST, Brasch H, Day DJ. Expression of components of the renin-angiotensin system in proliferating haemangioma may account for propranolol induced accelerated involution. JPRAS. 2010;DOI:10.1016/j.bjps.2010.08.039.

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