Hemangiomas are the most common tumors of infancy and are often presented to pediatricians and dermatologists. Based on a recent study re-analyzing the methodologies used to estimate their occurrence, the incidence is close to 5%.1 Hemangiomas have a much higher occurrence in females, Caucasians, and in premature and twin births. The majority of hemangiomas are harmless lesions that regress spontaneously; however, they can also be disfiguring and endangering. Even if no active treatment is taken, parents are encouraged to observe the progression of the hemangioma through frequent consultations and early support in order to obtain the best possible results. In some cases, an effective early therapeutic regimen is necessary to avoid serious complications, and can otherwise maximize the amount of normal skin, as well as decrease the age at which complete regression is fully reached. What are Hemangiomas? Hemangiomas are benign tumors in which growth of capillary blood vessels occurs through angiogenesis.2 They rarely occur in utero, but instead appear as bluish or red marks within the first 2 weeks of infancy. Following this initial stage, they show rapid growth lasting for up to 12 months, the proliferation phase. In the next phase, the involuting phase, they slowly regress until an average of 5 to 7 years, after which hemangiomas remain unchanged.3 Traditional management of hemangiomas therefore, has been to wait until involution occurs spontaneously. However, complications such as bleeding, infection, ulceration, obstruction of orifices or psychosocial distress may be cues for intervention.4,5 Infantile hemangiomas vary in appearance; they frequently blanch under pressure and exhibit telangiectasia surrounded by a faint halo. However, more importantly, hemangiomas are vessel cell tumors with distinct characteristics that develop as a result of vascular anomalies.6 They can be characterized as superficial, usually consisting of red lobulated papules or plaques on the surface of the skin, or as deep less defined lesions located below the subcutaneous fat, and sometime possessing a bluish tint.2 Some have a combination of these morphological characteristics and thus are called combined lesions.2 The origin of hemangiomas is still unknown, with some hypotheses including defects in local endothelial cells, effects of endothelial progenitor cells or hemangioblasts, as well as embolization of shed placental cells.2 Hemangiomas are commonly located on the head or neck (60%), but can also be found on the trunk (22%) or extremities (18%).7 Although typically benign, they are sometimes life-threatening due to location, size or rapid proliferation. If they are located in the ocular region, they can cause corneal deformation, strabismus due to infiltration of the extraocular muscles or loss of vision.4 Large hemangiomas can cause shunting of blood from the heart and may result in cardiac failure or platelet trapping.8 Additionally, hemangiomas can cause mild but distressing complications such as intermittent bleeding. Phases of Hemangiomas Hemangiomas consist of endothelial cells that have a high proliferation index until the early involuting phase. The proliferation phase has been shown to be associated with an increased expression of fibroblast growth factor and vascular endothelial growth factor, adhesion molecule E-selectin and monocytic chemoattractant protein-2 as consistent with angiogenesis. The involuting phase is characterized by a decrease in cell proliferation, when cells apoptose before the first year.2 The endothelial cells flatten and fatty tissue is deposited between the lobules. Past research has cited a plateau phase, which captures some aspects of proliferation and involution and depicts hemangioma growth as static and in discrete phases.9 However, proliferative factors dominate the proliferation phase, and when apoptotic factors exert a greater influence, involution occurs. This indicates a balance within a continuous dynamic process, in effect describing a more accurate clinical model of hemangioma growth that is on a continuum.9 Management Issues Implications of Diagnosis Delays Due to the heterogeneity of hemangiomas, it is often difficult to determine which patients are at higher risk and which need specialty care.9 This is also largely due to the lack of information tracking the initial growth phase of hemangiomas. However, in a large prospective study, Chang et al discuss the specific growth characteristics of hemangiomas, and thus shed some light on implications for hemangioma management. They found that about 80% of hemangiomas reach their final size in the proliferation phase by 5 months of age.9 However, most infants are not seen by a pediatric dermatologist until 5 months of age. This shows a great inconsistency with the growth cycle of hemangiomas, since by that age, growth is usually completed. Most treatments are best at arresting growth during the proliferation phase, and thus a treatment plan would be more effective earlier. This discrepancy could be largely due to long referral waits. Need for Awareness of Potential Complications If primary care physicians and pediatric dermatologist are made aware of the complications that could arise from treatment postponement in certain hemangiomas, this could help expedite the referral process.9 A thorough initial physical examination is necessary to investigate whether there are complications and if intervention is appropriate. Magnetic resonance imaging can help distinguish depth and extent of involvement of the hemangioma.8 Additionally, the study by Chang et al indicated that there is about a month delay in onset and length of growth for deep hemangiomas when compared to superficial hemangiomas.9 They also exhibit sustained growth of about a month beyond that of superficial hemangiomas.9 Thus, follow-up for deeper hemangiomas needs to also be prolonged. Risk Factors for Complications Since there is such a great spectrum of hemangiomas, it is also essential to identify features that are most prognostic of complications and the need for treatment, yet this is a great challenge. Haggstrom et al found that morphologic subtype was the strongest predictor for the development of complications.7 Specifically, segmental hemangiomas, which are linear and/or geometrically localized to a certain region, were 11 times more likely to develop a complication when controlling for size.7 This predictor was even more significant when the hemangioma was located on the face. This is largely due to their propensity for ulceration, possibly caused by an error in development in early gestation.7 Furthermore, size and location were also predictors of complications and need for treatment. Whereas the mean size of hemangiomas is 18.9cm2, those with complication were averaging 37.3 cm2, and those requiring treatment were most often located on the face (43% of facial hemangiomas).7 These features should be helpful in determining which hemangiomas are most appropriate for referral and treatment. It is important to note, though, that not all infants need to be referred to a specialist; however, knowledge of the growth characteristics and certain predictors could help ascertain those patients who require referral and/or intervention. Management Techniques Treatment Considerations Most hemangiomas do not require intervention, since by 5 years of age, almost half of hemangiomas complete regression. Regression varies but is typically complete by age 10, with most between 5 and 7 years, as noted earlier. Normal skin is restored in half of the children, even with large protruding hemangiomas. The remaining children often have a cosmetic result better than that offered by surgical procedures.8 Therefore, a detailed account of the natural course of hemangiomas is important to parents in an effort to alleviate anxiety. However, it is still common to have telangiectasia and scarring, especially if ulcerations occur during the proliferation phase.4 In such cases of ulcerated hemangiomas, pulsed dye lasers have been shown to help expedite the healing process.8 Therefore active treatment is useful in cases that do not show signs of involution or those with complications. If hemangiomas are not life-threatening or impairing other vital functions, they can still cause psychological problems. This is due to disfigurement that in turn can cause a negative self-image, lack of self-confidence, and thus a negative trajectory into adolescence. Thus in such cases, proper treatment of hemangiomas is necessary and effective. There are many treatment methods available including laser therapy, systemic and injected corticosteroid therapy, and resection. There is no clear formula for all patients, but treatment regimens are accelerating.6 Importantly, completion of treatment and normalization of the appearance of skin prior to the child’s entrance into school should be stressed. Lasers Laser therapy has been suggested as an intervention strategy during the early stage of hemangioma growth due to its effective arrest of proliferation. Yet due to a natural tendency for hemangiomas to regress, early intervention is a topic of controversy. Furthermore, there are concerns about pulsed dye laser’s limited effectiveness and complications, as well as inconsistent data regarding which hemangiomas benefit best from it.10 However, when lasers are used appropriately they can help minimize the appearance of hemangiomas when compared to observation alone. Due to the limited depth of penetration by lasers, they should be most effective for superficial hemangiomas.4,5 The pumped pulsed dye laser has successfully been used due to its specific design to treat cutaneous vascular lesions without producing a scar. This is achieved by a selective destruction of blood vessels matched to the wavelength of the light absorbed by hemoglobin along with a specifically adapted time frame for the blood vessels.6 This author uses the 595-nm pulsed-dye V-Beam with a spot size of 7 mm and a pulse duration of 1.5ms at 8 to 10 Joules. Treatments are typically performed every 3 to 4 weeks for consistent results. The flashlamp-pumped pulsed dye laser has also been beneficial in managing hemangiomas in the involution phase, specifically for those hemangiomas that are slow to resolve and present a cosmetically vital area, especially for children of school ages.6 Altogether, laser therapy is a valuable tool against hemangiomas when used conservatively and appropriately, especially for ulcerated lesions. Drug Therapy The administration of local or systemic corticosteroids is considered for patients with multiple hemangiomas, rapidly growing ones, or those that are life-threatening. Corticosteroids have been used for more than 40 years and have become the first-line treatment for large hemangiomas that may cause complications. They should be administered during the proliferation phase only. Orally, steroid doses start higher and then taper off over several weeks to months, as a precaution against the possibility of regrowth as well as in avoidance of adrenal problems.8 This is given systemically at the dosage of 2 mg/kg/day to 3 mg/kg/day. Steroids have about an 84% response rate; however, high-dose corticosteroids have side effects including irritability, gastrointestinal upset, adrenal suppression, infection, and immunosuppression.4 Intralesional injections are used to treat focal lesions that cannot be excised, such as those in the periocular region and upper face, at 4- to 6-week intervals with the same response rate as systemic administration. The injection is directed into the hemangioma through different directions with 10 mg/mL as the recommended dosage.8 Some side effects reported include skin atrophy and adrenal suppression.4 Still, corticosteroids are generally well-tolerated with no long term side effects.6 Interferon Therapy Interferon therapy, which inhibits angiogenesis, could be considered for life-threatening hemangiomas due to its high success rate, although it is expensive, burdensome, and possibly toxic.11 It is administered subcutaneously and daily. Side effects include increased liver enzymes, transient neutroneia, anemia, and possible lasting spastic diplegia4,10,11. Therefore such a treatment should only be considered when systemic corticosteroids show no improvement and the hemangioma is truly a danger. Furthermore the child should follow-up with a neurologist, and liver function should be closely monitored. Although occasionally successful in the hands of several pediatric dermatologists, it is difficult to find a comfortable role for interferon therapy in the armamentarium of therapy for complex hemangiomas. Sclerotherapy Sclerotherapy is effective in non-involuting lesions.8 Superficial lesions and bulky hemangiomas of subcutaneous tissue have shown promise with sclerotherapy without complications. Injections of sclerosing solutions cause tissue irritation and provoke an inflammatory reaction, which causes fibrosis and destruction of vascular channels, and thus sclerotherapy is a great potential therapeutic.8 It is most effective when there is extended contact of the sclerosant with the endothelial lining of the vessel, such as in small vascular spaces.12 Additionally, sclerotherapy is used in conjunction with surgery to decrease the lesion size and its nature to a more fibrous consistency.12 Sclerotherapy is non-invasive, has minimal complications, and can considerably relieve symptoms. Surgery Surgery is usually suggested only if other therapies fail and there is severe bleeding or ulceration.4,5 It might be necessary in the case of periorbital hemangiomas or for those that may cause large deforming lesions of the face. Sometimes surgery is also necessary as late therapy after involution still causes scarring or atrophy, as a means to minimize psychosocial distress.6,10 MRI investigation prior to excision is important for surgical management, and possible preoperative embolization is helpful in reducing the size of the hemangioma and decreasing blood loss.8 Altogether, parents need to be reassured that although hemangiomas go through a proliferation stage of rapid growth, most hemangiomas will involute and the skin will eventually return to normal with minimal or some scarring. However, lesions that threaten vital functions (i.e., periocular), are ulcerative, or whose unchecked proliferation will result in significant scarring often require active management through lasers, systemic or injectable steroids, and/or surgical management. Furthermore, surgery can be suited for small well-localized lesions or in areas where scarring will have a preferable cosmetic result. Risks vs. Benefits The treatment plan is individualized with many factors that should effect decision-making including: size, depth, stage, location, age and likelihood of complication. Thus, therapeutic risks should be weighed against potential advantages and proper referrals to relevant specialists should be highlighted in complicated hemangiomas.11 Further research of angiogenesis will continue to enhance the development of novel therapeutic options for vascular tumors. Conclusion While it is true that the majority of infantile hemangiomas resolve optimally without any treatment at all, it is equally true that the window of opportunity is very small — less than 5 months — for those who do require intervention. In light of the consequences of late diagnosis and intervention, it is imperative that parents and pediatricians be made aware of the potential complications and their risk factors to insure that children are appropriately evaluated and treated before this window of opportunity for optimal outcomes closes. Ms. Barsky is currently a Sc.B/MD candidate at Brown University in Providence, Rhode Island. Dr. Buka is Section Chief, Department of Dermatology, Mount Sinai School of Medicine, New York, New York. DISCLOSURES: The authors have no conflict of interest with any material contained in this article.
ADVERTISEMENT
Management Strategies for Infantile Hemangiomas
Hemangiomas are the most common tumors of infancy and are often presented to pediatricians and dermatologists. Based on a recent study re-analyzing the methodologies used to estimate their occurrence, the incidence is close to 5%.1 Hemangiomas have a much higher occurrence in females, Caucasians, and in premature and twin births. The majority of hemangiomas are harmless lesions that regress spontaneously; however, they can also be disfiguring and endangering. Even if no active treatment is taken, parents are encouraged to observe the progression of the hemangioma through frequent consultations and early support in order to obtain the best possible results. In some cases, an effective early therapeutic regimen is necessary to avoid serious complications, and can otherwise maximize the amount of normal skin, as well as decrease the age at which complete regression is fully reached. What are Hemangiomas? Hemangiomas are benign tumors in which growth of capillary blood vessels occurs through angiogenesis.2 They rarely occur in utero, but instead appear as bluish or red marks within the first 2 weeks of infancy. Following this initial stage, they show rapid growth lasting for up to 12 months, the proliferation phase. In the next phase, the involuting phase, they slowly regress until an average of 5 to 7 years, after which hemangiomas remain unchanged.3 Traditional management of hemangiomas therefore, has been to wait until involution occurs spontaneously. However, complications such as bleeding, infection, ulceration, obstruction of orifices or psychosocial distress may be cues for intervention.4,5 Infantile hemangiomas vary in appearance; they frequently blanch under pressure and exhibit telangiectasia surrounded by a faint halo. However, more importantly, hemangiomas are vessel cell tumors with distinct characteristics that develop as a result of vascular anomalies.6 They can be characterized as superficial, usually consisting of red lobulated papules or plaques on the surface of the skin, or as deep less defined lesions located below the subcutaneous fat, and sometime possessing a bluish tint.2 Some have a combination of these morphological characteristics and thus are called combined lesions.2 The origin of hemangiomas is still unknown, with some hypotheses including defects in local endothelial cells, effects of endothelial progenitor cells or hemangioblasts, as well as embolization of shed placental cells.2 Hemangiomas are commonly located on the head or neck (60%), but can also be found on the trunk (22%) or extremities (18%).7 Although typically benign, they are sometimes life-threatening due to location, size or rapid proliferation. If they are located in the ocular region, they can cause corneal deformation, strabismus due to infiltration of the extraocular muscles or loss of vision.4 Large hemangiomas can cause shunting of blood from the heart and may result in cardiac failure or platelet trapping.8 Additionally, hemangiomas can cause mild but distressing complications such as intermittent bleeding. Phases of Hemangiomas Hemangiomas consist of endothelial cells that have a high proliferation index until the early involuting phase. The proliferation phase has been shown to be associated with an increased expression of fibroblast growth factor and vascular endothelial growth factor, adhesion molecule E-selectin and monocytic chemoattractant protein-2 as consistent with angiogenesis. The involuting phase is characterized by a decrease in cell proliferation, when cells apoptose before the first year.2 The endothelial cells flatten and fatty tissue is deposited between the lobules. Past research has cited a plateau phase, which captures some aspects of proliferation and involution and depicts hemangioma growth as static and in discrete phases.9 However, proliferative factors dominate the proliferation phase, and when apoptotic factors exert a greater influence, involution occurs. This indicates a balance within a continuous dynamic process, in effect describing a more accurate clinical model of hemangioma growth that is on a continuum.9 Management Issues Implications of Diagnosis Delays Due to the heterogeneity of hemangiomas, it is often difficult to determine which patients are at higher risk and which need specialty care.9 This is also largely due to the lack of information tracking the initial growth phase of hemangiomas. However, in a large prospective study, Chang et al discuss the specific growth characteristics of hemangiomas, and thus shed some light on implications for hemangioma management. They found that about 80% of hemangiomas reach their final size in the proliferation phase by 5 months of age.9 However, most infants are not seen by a pediatric dermatologist until 5 months of age. This shows a great inconsistency with the growth cycle of hemangiomas, since by that age, growth is usually completed. Most treatments are best at arresting growth during the proliferation phase, and thus a treatment plan would be more effective earlier. This discrepancy could be largely due to long referral waits. Need for Awareness of Potential Complications If primary care physicians and pediatric dermatologist are made aware of the complications that could arise from treatment postponement in certain hemangiomas, this could help expedite the referral process.9 A thorough initial physical examination is necessary to investigate whether there are complications and if intervention is appropriate. Magnetic resonance imaging can help distinguish depth and extent of involvement of the hemangioma.8 Additionally, the study by Chang et al indicated that there is about a month delay in onset and length of growth for deep hemangiomas when compared to superficial hemangiomas.9 They also exhibit sustained growth of about a month beyond that of superficial hemangiomas.9 Thus, follow-up for deeper hemangiomas needs to also be prolonged. Risk Factors for Complications Since there is such a great spectrum of hemangiomas, it is also essential to identify features that are most prognostic of complications and the need for treatment, yet this is a great challenge. Haggstrom et al found that morphologic subtype was the strongest predictor for the development of complications.7 Specifically, segmental hemangiomas, which are linear and/or geometrically localized to a certain region, were 11 times more likely to develop a complication when controlling for size.7 This predictor was even more significant when the hemangioma was located on the face. This is largely due to their propensity for ulceration, possibly caused by an error in development in early gestation.7 Furthermore, size and location were also predictors of complications and need for treatment. Whereas the mean size of hemangiomas is 18.9cm2, those with complication were averaging 37.3 cm2, and those requiring treatment were most often located on the face (43% of facial hemangiomas).7 These features should be helpful in determining which hemangiomas are most appropriate for referral and treatment. It is important to note, though, that not all infants need to be referred to a specialist; however, knowledge of the growth characteristics and certain predictors could help ascertain those patients who require referral and/or intervention. Management Techniques Treatment Considerations Most hemangiomas do not require intervention, since by 5 years of age, almost half of hemangiomas complete regression. Regression varies but is typically complete by age 10, with most between 5 and 7 years, as noted earlier. Normal skin is restored in half of the children, even with large protruding hemangiomas. The remaining children often have a cosmetic result better than that offered by surgical procedures.8 Therefore, a detailed account of the natural course of hemangiomas is important to parents in an effort to alleviate anxiety. However, it is still common to have telangiectasia and scarring, especially if ulcerations occur during the proliferation phase.4 In such cases of ulcerated hemangiomas, pulsed dye lasers have been shown to help expedite the healing process.8 Therefore active treatment is useful in cases that do not show signs of involution or those with complications. If hemangiomas are not life-threatening or impairing other vital functions, they can still cause psychological problems. This is due to disfigurement that in turn can cause a negative self-image, lack of self-confidence, and thus a negative trajectory into adolescence. Thus in such cases, proper treatment of hemangiomas is necessary and effective. There are many treatment methods available including laser therapy, systemic and injected corticosteroid therapy, and resection. There is no clear formula for all patients, but treatment regimens are accelerating.6 Importantly, completion of treatment and normalization of the appearance of skin prior to the child’s entrance into school should be stressed. Lasers Laser therapy has been suggested as an intervention strategy during the early stage of hemangioma growth due to its effective arrest of proliferation. Yet due to a natural tendency for hemangiomas to regress, early intervention is a topic of controversy. Furthermore, there are concerns about pulsed dye laser’s limited effectiveness and complications, as well as inconsistent data regarding which hemangiomas benefit best from it.10 However, when lasers are used appropriately they can help minimize the appearance of hemangiomas when compared to observation alone. Due to the limited depth of penetration by lasers, they should be most effective for superficial hemangiomas.4,5 The pumped pulsed dye laser has successfully been used due to its specific design to treat cutaneous vascular lesions without producing a scar. This is achieved by a selective destruction of blood vessels matched to the wavelength of the light absorbed by hemoglobin along with a specifically adapted time frame for the blood vessels.6 This author uses the 595-nm pulsed-dye V-Beam with a spot size of 7 mm and a pulse duration of 1.5ms at 8 to 10 Joules. Treatments are typically performed every 3 to 4 weeks for consistent results. The flashlamp-pumped pulsed dye laser has also been beneficial in managing hemangiomas in the involution phase, specifically for those hemangiomas that are slow to resolve and present a cosmetically vital area, especially for children of school ages.6 Altogether, laser therapy is a valuable tool against hemangiomas when used conservatively and appropriately, especially for ulcerated lesions. Drug Therapy The administration of local or systemic corticosteroids is considered for patients with multiple hemangiomas, rapidly growing ones, or those that are life-threatening. Corticosteroids have been used for more than 40 years and have become the first-line treatment for large hemangiomas that may cause complications. They should be administered during the proliferation phase only. Orally, steroid doses start higher and then taper off over several weeks to months, as a precaution against the possibility of regrowth as well as in avoidance of adrenal problems.8 This is given systemically at the dosage of 2 mg/kg/day to 3 mg/kg/day. Steroids have about an 84% response rate; however, high-dose corticosteroids have side effects including irritability, gastrointestinal upset, adrenal suppression, infection, and immunosuppression.4 Intralesional injections are used to treat focal lesions that cannot be excised, such as those in the periocular region and upper face, at 4- to 6-week intervals with the same response rate as systemic administration. The injection is directed into the hemangioma through different directions with 10 mg/mL as the recommended dosage.8 Some side effects reported include skin atrophy and adrenal suppression.4 Still, corticosteroids are generally well-tolerated with no long term side effects.6 Interferon Therapy Interferon therapy, which inhibits angiogenesis, could be considered for life-threatening hemangiomas due to its high success rate, although it is expensive, burdensome, and possibly toxic.11 It is administered subcutaneously and daily. Side effects include increased liver enzymes, transient neutroneia, anemia, and possible lasting spastic diplegia4,10,11. Therefore such a treatment should only be considered when systemic corticosteroids show no improvement and the hemangioma is truly a danger. Furthermore the child should follow-up with a neurologist, and liver function should be closely monitored. Although occasionally successful in the hands of several pediatric dermatologists, it is difficult to find a comfortable role for interferon therapy in the armamentarium of therapy for complex hemangiomas. Sclerotherapy Sclerotherapy is effective in non-involuting lesions.8 Superficial lesions and bulky hemangiomas of subcutaneous tissue have shown promise with sclerotherapy without complications. Injections of sclerosing solutions cause tissue irritation and provoke an inflammatory reaction, which causes fibrosis and destruction of vascular channels, and thus sclerotherapy is a great potential therapeutic.8 It is most effective when there is extended contact of the sclerosant with the endothelial lining of the vessel, such as in small vascular spaces.12 Additionally, sclerotherapy is used in conjunction with surgery to decrease the lesion size and its nature to a more fibrous consistency.12 Sclerotherapy is non-invasive, has minimal complications, and can considerably relieve symptoms. Surgery Surgery is usually suggested only if other therapies fail and there is severe bleeding or ulceration.4,5 It might be necessary in the case of periorbital hemangiomas or for those that may cause large deforming lesions of the face. Sometimes surgery is also necessary as late therapy after involution still causes scarring or atrophy, as a means to minimize psychosocial distress.6,10 MRI investigation prior to excision is important for surgical management, and possible preoperative embolization is helpful in reducing the size of the hemangioma and decreasing blood loss.8 Altogether, parents need to be reassured that although hemangiomas go through a proliferation stage of rapid growth, most hemangiomas will involute and the skin will eventually return to normal with minimal or some scarring. However, lesions that threaten vital functions (i.e., periocular), are ulcerative, or whose unchecked proliferation will result in significant scarring often require active management through lasers, systemic or injectable steroids, and/or surgical management. Furthermore, surgery can be suited for small well-localized lesions or in areas where scarring will have a preferable cosmetic result. Risks vs. Benefits The treatment plan is individualized with many factors that should effect decision-making including: size, depth, stage, location, age and likelihood of complication. Thus, therapeutic risks should be weighed against potential advantages and proper referrals to relevant specialists should be highlighted in complicated hemangiomas.11 Further research of angiogenesis will continue to enhance the development of novel therapeutic options for vascular tumors. Conclusion While it is true that the majority of infantile hemangiomas resolve optimally without any treatment at all, it is equally true that the window of opportunity is very small — less than 5 months — for those who do require intervention. In light of the consequences of late diagnosis and intervention, it is imperative that parents and pediatricians be made aware of the potential complications and their risk factors to insure that children are appropriately evaluated and treated before this window of opportunity for optimal outcomes closes. Ms. Barsky is currently a Sc.B/MD candidate at Brown University in Providence, Rhode Island. Dr. Buka is Section Chief, Department of Dermatology, Mount Sinai School of Medicine, New York, New York. DISCLOSURES: The authors have no conflict of interest with any material contained in this article.
Hemangiomas are the most common tumors of infancy and are often presented to pediatricians and dermatologists. Based on a recent study re-analyzing the methodologies used to estimate their occurrence, the incidence is close to 5%.1 Hemangiomas have a much higher occurrence in females, Caucasians, and in premature and twin births. The majority of hemangiomas are harmless lesions that regress spontaneously; however, they can also be disfiguring and endangering. Even if no active treatment is taken, parents are encouraged to observe the progression of the hemangioma through frequent consultations and early support in order to obtain the best possible results. In some cases, an effective early therapeutic regimen is necessary to avoid serious complications, and can otherwise maximize the amount of normal skin, as well as decrease the age at which complete regression is fully reached. What are Hemangiomas? Hemangiomas are benign tumors in which growth of capillary blood vessels occurs through angiogenesis.2 They rarely occur in utero, but instead appear as bluish or red marks within the first 2 weeks of infancy. Following this initial stage, they show rapid growth lasting for up to 12 months, the proliferation phase. In the next phase, the involuting phase, they slowly regress until an average of 5 to 7 years, after which hemangiomas remain unchanged.3 Traditional management of hemangiomas therefore, has been to wait until involution occurs spontaneously. However, complications such as bleeding, infection, ulceration, obstruction of orifices or psychosocial distress may be cues for intervention.4,5 Infantile hemangiomas vary in appearance; they frequently blanch under pressure and exhibit telangiectasia surrounded by a faint halo. However, more importantly, hemangiomas are vessel cell tumors with distinct characteristics that develop as a result of vascular anomalies.6 They can be characterized as superficial, usually consisting of red lobulated papules or plaques on the surface of the skin, or as deep less defined lesions located below the subcutaneous fat, and sometime possessing a bluish tint.2 Some have a combination of these morphological characteristics and thus are called combined lesions.2 The origin of hemangiomas is still unknown, with some hypotheses including defects in local endothelial cells, effects of endothelial progenitor cells or hemangioblasts, as well as embolization of shed placental cells.2 Hemangiomas are commonly located on the head or neck (60%), but can also be found on the trunk (22%) or extremities (18%).7 Although typically benign, they are sometimes life-threatening due to location, size or rapid proliferation. If they are located in the ocular region, they can cause corneal deformation, strabismus due to infiltration of the extraocular muscles or loss of vision.4 Large hemangiomas can cause shunting of blood from the heart and may result in cardiac failure or platelet trapping.8 Additionally, hemangiomas can cause mild but distressing complications such as intermittent bleeding. Phases of Hemangiomas Hemangiomas consist of endothelial cells that have a high proliferation index until the early involuting phase. The proliferation phase has been shown to be associated with an increased expression of fibroblast growth factor and vascular endothelial growth factor, adhesion molecule E-selectin and monocytic chemoattractant protein-2 as consistent with angiogenesis. The involuting phase is characterized by a decrease in cell proliferation, when cells apoptose before the first year.2 The endothelial cells flatten and fatty tissue is deposited between the lobules. Past research has cited a plateau phase, which captures some aspects of proliferation and involution and depicts hemangioma growth as static and in discrete phases.9 However, proliferative factors dominate the proliferation phase, and when apoptotic factors exert a greater influence, involution occurs. This indicates a balance within a continuous dynamic process, in effect describing a more accurate clinical model of hemangioma growth that is on a continuum.9 Management Issues Implications of Diagnosis Delays Due to the heterogeneity of hemangiomas, it is often difficult to determine which patients are at higher risk and which need specialty care.9 This is also largely due to the lack of information tracking the initial growth phase of hemangiomas. However, in a large prospective study, Chang et al discuss the specific growth characteristics of hemangiomas, and thus shed some light on implications for hemangioma management. They found that about 80% of hemangiomas reach their final size in the proliferation phase by 5 months of age.9 However, most infants are not seen by a pediatric dermatologist until 5 months of age. This shows a great inconsistency with the growth cycle of hemangiomas, since by that age, growth is usually completed. Most treatments are best at arresting growth during the proliferation phase, and thus a treatment plan would be more effective earlier. This discrepancy could be largely due to long referral waits. Need for Awareness of Potential Complications If primary care physicians and pediatric dermatologist are made aware of the complications that could arise from treatment postponement in certain hemangiomas, this could help expedite the referral process.9 A thorough initial physical examination is necessary to investigate whether there are complications and if intervention is appropriate. Magnetic resonance imaging can help distinguish depth and extent of involvement of the hemangioma.8 Additionally, the study by Chang et al indicated that there is about a month delay in onset and length of growth for deep hemangiomas when compared to superficial hemangiomas.9 They also exhibit sustained growth of about a month beyond that of superficial hemangiomas.9 Thus, follow-up for deeper hemangiomas needs to also be prolonged. Risk Factors for Complications Since there is such a great spectrum of hemangiomas, it is also essential to identify features that are most prognostic of complications and the need for treatment, yet this is a great challenge. Haggstrom et al found that morphologic subtype was the strongest predictor for the development of complications.7 Specifically, segmental hemangiomas, which are linear and/or geometrically localized to a certain region, were 11 times more likely to develop a complication when controlling for size.7 This predictor was even more significant when the hemangioma was located on the face. This is largely due to their propensity for ulceration, possibly caused by an error in development in early gestation.7 Furthermore, size and location were also predictors of complications and need for treatment. Whereas the mean size of hemangiomas is 18.9cm2, those with complication were averaging 37.3 cm2, and those requiring treatment were most often located on the face (43% of facial hemangiomas).7 These features should be helpful in determining which hemangiomas are most appropriate for referral and treatment. It is important to note, though, that not all infants need to be referred to a specialist; however, knowledge of the growth characteristics and certain predictors could help ascertain those patients who require referral and/or intervention. Management Techniques Treatment Considerations Most hemangiomas do not require intervention, since by 5 years of age, almost half of hemangiomas complete regression. Regression varies but is typically complete by age 10, with most between 5 and 7 years, as noted earlier. Normal skin is restored in half of the children, even with large protruding hemangiomas. The remaining children often have a cosmetic result better than that offered by surgical procedures.8 Therefore, a detailed account of the natural course of hemangiomas is important to parents in an effort to alleviate anxiety. However, it is still common to have telangiectasia and scarring, especially if ulcerations occur during the proliferation phase.4 In such cases of ulcerated hemangiomas, pulsed dye lasers have been shown to help expedite the healing process.8 Therefore active treatment is useful in cases that do not show signs of involution or those with complications. If hemangiomas are not life-threatening or impairing other vital functions, they can still cause psychological problems. This is due to disfigurement that in turn can cause a negative self-image, lack of self-confidence, and thus a negative trajectory into adolescence. Thus in such cases, proper treatment of hemangiomas is necessary and effective. There are many treatment methods available including laser therapy, systemic and injected corticosteroid therapy, and resection. There is no clear formula for all patients, but treatment regimens are accelerating.6 Importantly, completion of treatment and normalization of the appearance of skin prior to the child’s entrance into school should be stressed. Lasers Laser therapy has been suggested as an intervention strategy during the early stage of hemangioma growth due to its effective arrest of proliferation. Yet due to a natural tendency for hemangiomas to regress, early intervention is a topic of controversy. Furthermore, there are concerns about pulsed dye laser’s limited effectiveness and complications, as well as inconsistent data regarding which hemangiomas benefit best from it.10 However, when lasers are used appropriately they can help minimize the appearance of hemangiomas when compared to observation alone. Due to the limited depth of penetration by lasers, they should be most effective for superficial hemangiomas.4,5 The pumped pulsed dye laser has successfully been used due to its specific design to treat cutaneous vascular lesions without producing a scar. This is achieved by a selective destruction of blood vessels matched to the wavelength of the light absorbed by hemoglobin along with a specifically adapted time frame for the blood vessels.6 This author uses the 595-nm pulsed-dye V-Beam with a spot size of 7 mm and a pulse duration of 1.5ms at 8 to 10 Joules. Treatments are typically performed every 3 to 4 weeks for consistent results. The flashlamp-pumped pulsed dye laser has also been beneficial in managing hemangiomas in the involution phase, specifically for those hemangiomas that are slow to resolve and present a cosmetically vital area, especially for children of school ages.6 Altogether, laser therapy is a valuable tool against hemangiomas when used conservatively and appropriately, especially for ulcerated lesions. Drug Therapy The administration of local or systemic corticosteroids is considered for patients with multiple hemangiomas, rapidly growing ones, or those that are life-threatening. Corticosteroids have been used for more than 40 years and have become the first-line treatment for large hemangiomas that may cause complications. They should be administered during the proliferation phase only. Orally, steroid doses start higher and then taper off over several weeks to months, as a precaution against the possibility of regrowth as well as in avoidance of adrenal problems.8 This is given systemically at the dosage of 2 mg/kg/day to 3 mg/kg/day. Steroids have about an 84% response rate; however, high-dose corticosteroids have side effects including irritability, gastrointestinal upset, adrenal suppression, infection, and immunosuppression.4 Intralesional injections are used to treat focal lesions that cannot be excised, such as those in the periocular region and upper face, at 4- to 6-week intervals with the same response rate as systemic administration. The injection is directed into the hemangioma through different directions with 10 mg/mL as the recommended dosage.8 Some side effects reported include skin atrophy and adrenal suppression.4 Still, corticosteroids are generally well-tolerated with no long term side effects.6 Interferon Therapy Interferon therapy, which inhibits angiogenesis, could be considered for life-threatening hemangiomas due to its high success rate, although it is expensive, burdensome, and possibly toxic.11 It is administered subcutaneously and daily. Side effects include increased liver enzymes, transient neutroneia, anemia, and possible lasting spastic diplegia4,10,11. Therefore such a treatment should only be considered when systemic corticosteroids show no improvement and the hemangioma is truly a danger. Furthermore the child should follow-up with a neurologist, and liver function should be closely monitored. Although occasionally successful in the hands of several pediatric dermatologists, it is difficult to find a comfortable role for interferon therapy in the armamentarium of therapy for complex hemangiomas. Sclerotherapy Sclerotherapy is effective in non-involuting lesions.8 Superficial lesions and bulky hemangiomas of subcutaneous tissue have shown promise with sclerotherapy without complications. Injections of sclerosing solutions cause tissue irritation and provoke an inflammatory reaction, which causes fibrosis and destruction of vascular channels, and thus sclerotherapy is a great potential therapeutic.8 It is most effective when there is extended contact of the sclerosant with the endothelial lining of the vessel, such as in small vascular spaces.12 Additionally, sclerotherapy is used in conjunction with surgery to decrease the lesion size and its nature to a more fibrous consistency.12 Sclerotherapy is non-invasive, has minimal complications, and can considerably relieve symptoms. Surgery Surgery is usually suggested only if other therapies fail and there is severe bleeding or ulceration.4,5 It might be necessary in the case of periorbital hemangiomas or for those that may cause large deforming lesions of the face. Sometimes surgery is also necessary as late therapy after involution still causes scarring or atrophy, as a means to minimize psychosocial distress.6,10 MRI investigation prior to excision is important for surgical management, and possible preoperative embolization is helpful in reducing the size of the hemangioma and decreasing blood loss.8 Altogether, parents need to be reassured that although hemangiomas go through a proliferation stage of rapid growth, most hemangiomas will involute and the skin will eventually return to normal with minimal or some scarring. However, lesions that threaten vital functions (i.e., periocular), are ulcerative, or whose unchecked proliferation will result in significant scarring often require active management through lasers, systemic or injectable steroids, and/or surgical management. Furthermore, surgery can be suited for small well-localized lesions or in areas where scarring will have a preferable cosmetic result. Risks vs. Benefits The treatment plan is individualized with many factors that should effect decision-making including: size, depth, stage, location, age and likelihood of complication. Thus, therapeutic risks should be weighed against potential advantages and proper referrals to relevant specialists should be highlighted in complicated hemangiomas.11 Further research of angiogenesis will continue to enhance the development of novel therapeutic options for vascular tumors. Conclusion While it is true that the majority of infantile hemangiomas resolve optimally without any treatment at all, it is equally true that the window of opportunity is very small — less than 5 months — for those who do require intervention. In light of the consequences of late diagnosis and intervention, it is imperative that parents and pediatricians be made aware of the potential complications and their risk factors to insure that children are appropriately evaluated and treated before this window of opportunity for optimal outcomes closes. Ms. Barsky is currently a Sc.B/MD candidate at Brown University in Providence, Rhode Island. Dr. Buka is Section Chief, Department of Dermatology, Mount Sinai School of Medicine, New York, New York. DISCLOSURES: The authors have no conflict of interest with any material contained in this article.
