Publications

Management of Cutaneous Juvenile Hemangiomas

Management of Cutaneous Juvenile Hemangiomas

Edward D. Buckingham, M.D.

Dawn C. Buckingham, M.D.

Marcelo Hochman, M.D., F.A.C.S.

Edwin F. Williams, III, M.D.,F.A.C.S.

Introduction

Past descriptions of vascular lesions often confused vascular malformations and hemangiomas using interchangeable definitions which led to inappropriate treatment and inconsistency in the medical literature. In many classic articles the term capillary hemangioma was used to describe what is now known as a port-wine malformation and the terms strawberry naevi and cavernous hemangioma were used to describe what is recognized today as a true hemangioma. The work of Mulliken and Glowacki systematically delineated the difference between hemangiomas and the multiple varieties of vascular malformations. (1) Waner and Suen suggested further that describing true hemangiomas as capillary or cavernous confuses these terms with earlier descriptions and creates the illusion that these lesions are separate entities when in fact they are not and are only differentiated by their location within the soft tissue. Instead they suggest using the simple classification system of superficial hemangioma to describe those growing within the papillary dermis, deep hemangioma to describe those growing within the reticular dermis or subcutaneous tissue, and compound if the lesion possesses both levels of involvement. (2) This simplified sensible classification which is easily assignable with clinical inspection will be used throughout the remainder of this manuscript. (Table 1)

Hemangiomas are in fact as the suffix "oma" suggests true tumors exhibiting cellular proliferation on histology. They are in fact a cellular proliferation of endothelial cells and associated pericytes. (1,2) Just as the diagnosis and classification of hemangiomas has been confusing, so to has the true natural history and propensity for persistent cosmetic deformity. Additionally, treatment been clouded by numerous reports in the literature of near universal complete spontaneous resolution and conversely arguments that every lesion demands treatment. More recently, thoughtful studies of the natural course of hemangiomas have been completed, algorithms for intervention versus observation proposed, and effective safe treatment plans devised. The following discussion will be presented in two sections. The first section will review the diagnosis and natural history of hemangiomas as appreciated in modern literature and compare this to a review of historical articles. This information will then be used to describe a rational and thoughtful algorithm for observation or intervention and recommend appropriate treatment options. Special emphasis will be given to surgical technique and several cases of late involuting hemangiomas of the face will be presented.

Epidemiology and Natural History of Hemangiomas

Hemangiomas are the most common neoplasm of infancy and childhood, with an estimated prevalence of 10% by one year of age. 30% of hemangiomas will be evident at birth and the majority of others will present within the first few weeks of life. Approximately 40% to 60% of hemangiomas involve the head and neck and 80% are solitary lesions. Within the head and neck a pattern of presentation along embryonic fusion planes has been suggested, and a female sex predilection of 3 to 4:1 exists. The vast majority occurs spontaneously, but quoted risk factors include premature birth weight of 1,000 to 1,500 grams and chorionic villus sampling. (2-6) In the rare patient presenting with four or more cutaneous hemangiomas, consideration should be given to the possibility of visceral involvement and a screening ultrasound should be performed. If further delineation of visceral involvement or a question in diagnosis persists, magnetic resonance imaging will assist in further assessment. The presentation of stridor in an infant with a cutaneous hemangioma should prompt an evaluation of the airway. Additionally, extensive facial Hemangiomas have been associated with Posterior fossa malformations, Arterial anomalies, coarctation of the aorta and Cardiac defects, and Eye abnormalities; the acronym PHACE has been proposed. (7)

Hemangiomas usually present within the first few weeks of life. The diagnosis can nearly always be made by a history and physical exam with description of a small red papule or blue subcutaneous lesion that has been growing with variable intensity since presentation. Superficial hemangiomas will appear as a bright red macular or papular lesion with well-defined borders; (Fig 1a) the macular variety may initially be confused with a port-wine malformation, but time will easily differentiate the two because of the hemangiomas inevitable change in size and the port-wine malformations relatively stable size. Deep hemangiomas because of the intervening dermal layer will appear as a subcutaneous mass with bluish or colorless overlying skin depending on depth. (Fig 1b) At times deep hemangiomas may appear similar to lymphatic malformations to inspection; a careful history will nearly always reveal the correct diagnosis, however, if the diagnosis is in question an ultrasound or magnetic resonance imaging scan will usually serve to differentiate a hemangioma from another vascular entity. (2) Many hemangiomas present with a combination of the above features should be termed compound. (Fig 1c)

A hemangioma's life cycle is characterized by two distinct clinical stages, proliferation and involution. A third stage, post-involution, has been described, however, this is not actually a stage, but instead a lack of completion of the involutional stage. Proliferation occurs during the first 12 months and occasionally as late as 18 months. The growth pattern varies greatly in both timing and severity from one lesion to the next, however, a bimodal growth pattern is frequently observed with the first being during the first few months of life and a second between four and six months of age. (2,6) It is during the first growth phase that functional and cosmetic concerns such as ulceration, nasal and visual obstruction, or frank airway obstruction may occur thus stimulating referral to a specialist. (Fig 2) Histologically, proliferating hemangiomas are characterized by plump proliferating endothelial cells with barely perceptible vascular channels. (1,2)

Proliferation is invariably followed by involution, which by definition follows the completion of proliferation. The onset of involution is characterized clinically by a definite decrease and then cessation in the growth of the lesion. The cutaneous component will change from a bright red color to a darker maroon and eventually patches of an ashen gray color will ensue and spread. (Fig 3) To palpation the tumor will evolve from the original firm tense consistency to a lobular soft compressible mass. Histologically, the plump endothelial cells give way to a gradual flattening until in late involution flat, inactive endothelial cells predominate. At the same time, the vascular channels become more obvious until large ectatic capillary-like vessels are seen. (Fig 4a,b) Variable mast cell infiltration is evident in proliferation and involution. Eventual progressive deposition of perivascular fibro-fatty tissue together with a decrease in the number of vascular channels and production of ectatic vessels manifests clinically as superficial telangectasias and at times a subcutaneous fibro-fatty residuum.(1,2) As with proliferation, involution occurs at drastically differing rates. However, some degree of prediction regarding the rate of involution and completeness of its course is possible. The literature and clinical experience suggests that lesions which are located in the central face or are not significantly involuting by age two or three are more likely to leave a cosmetic deformity. (8)

Natural History of Hemangiomas in the Historical Literature

The rate and completeness of involution has been debated for several decades. Many articles published in the mid-20^th century argued that nearly all hemangiomas eventually involuted to the point that no residual deformity existed. (4,8-12) During that same time period other authors advocated aggressive numerous interventions for the treatment of hemangiomas. (13-20) Later, in the 20^th century the earlier evaluations as to the natural history of hemangiomas were reevaluated and this new information has often been quoted as rational for intervention in the management of hemangiomas. (21-22) An analysis of the data from these earlier articles and methods of treatment is warranted to form the basis of a reasonable discussion of whether intervention in the care of hemangiomas is indicated or not. Articles published prior to Mulliken and Glowacki's work often discussed what we now differentiate into hemangiomas and vascular malformations as similar related entities. Even though different definitions were used several authors gathered detailed information regarding the natural history of hemangiomas. Several of these will be discussed in further detail.

Lister in 1938 described beautifully the clinical presentation of "strawberry naevi" as superficial, deep, or involving both regions, as now suggested by Waner and Suen. (2) He followed 92 "naevi" for seven years reporting that 49 of 92 (53%) left no trace which is defined as "no trace... knowing where to look one can just discern a few very faint telangiectases or a stippled scar resembling a faint vaccination mark." 38 were classified as "more or less obvious discoloration of the skin is still visible, but the characteristic signs of retrogression have made their appearance and are progressing." He concludes that of those 92 naevi all "have completely disappeared or are well on the way to doing so..." "No exception has been found to the rule that naevi which grow rapidly during the early months of life subsequently retrogress and disappear of their own accord, on the average about the fifth year of life. It follows that drastic measures for the destruction of these naevi are inadvisable, and treatment should be expectant and conservative." (9)

Wallace studied 290 superficial strawberry naevi and 121 deep cavernous naevi. He divided the results into four groups "1-Impossible to detect site of naevus. 2-Patient left with slightly atrophic skin which causes no disability cosmetic or otherwise.

3-Involution partially complete but some slight infiltration left usually with atrophic skin. No treatment usually required for residual defect but, if necessary, simple surgery suffices. 4-No involution." If the results are tabulated and combined for superficial and deep lesions, 33% of the total of 411 naevi could be described as group 1, 90% group 1 or 2, and 10% as group 3 or 4. He states "Most of the involution occurs within the first two or three years of life but may continue up to the age of 7. Very infrequently when involution is incomplete by the age of 5, further treatment is advised for psychological reasons, but is of trifling consequence compared with the treatment required when the haemangiomata are in full bloom." His article recommended against treatment in most instances. (10)

Simpson followed 170 naevi of which 140 were untreated and 30 were treated, 15 by irradiation, 14 by carbon-dioxide snow, and one by diathermy. His results looked at the presence of residual telangectasia, pallor, or puckering at 5 years and rated them as nil, slight, or severe. He further divided the lesions into dermal, hypodermal, or mixed. The data presentation does not allow determination of which lesions possessed one or more of these residual traits, but at 5 years 57% of dermal, 51% of mixed, and 67% of hypodermal showed no trace of residual. Overall, 55% of lesions showed no trace of residual at 5 years. He states that the results of the treated cases while numbering too few to draw any real conclusions eventually yielded similar results to the untreated cases with the exception of the one treated with diathermy the result of which was "deplorable". His conclusion states, "Because these lesions almost always resolve spontaneously, more than half disappearing by the age of 5 years, no treatment is recommended. (12)

Bowers in 1960 performed perhaps the most objective review and prospective long-term observation of the natural history of hemangiomas and attempted to identify factors which affected the eventual outcome. He divided 169 nevi into two groups, "cured" defined as "gone without a trace, or so inconspicuous that a thin dusting with powder would make it invisible" and "imperfect" defined as "anything short of cured". 83 of 165 nevi (49%) were cured at the end of the 5^th year. At 7 years 72% were reported as cured. He further divided the nevi into an "early" group being those 83 cured by the 5^th year, "late" group being 44 nevi progressing to cured in the 6^th year or later, and "imperfect" being 42 nevi (25%) which were followed for an average of 6.8 years which had not resolved. He felt that many of these lesions may eventually become cured but objectively did not assume so, unlike some of the preceding authors. He then further examined the affect of size, sex, site, multiplicity, subcutaneous component, increase in size after birth, age when improvement began, and ulceration on final outcome. The only factor which appeared to influence outcome was the age when improvement began. "No nevi which yielded a good result... failed to improve by the end of the 4^th year". "By contrast, many of the patients showing imperfect results improved much more slowly; by the beginning of the 3^rd year, a quarter were still unimproved." "One can therefore say with some certainty that a nevus remaining unimproved after the end of the 3^rd year is unlikely to recover completely by about the 7^th, but that early improvement does not always lead to early cure." Interestingly, size and ulceration did not seem to affect outcome however a definite trend existed for poor outcome in lesions of the mucosal lip. (8)

During the time period of the previous four authors' publications a definite difference of opinion existed regarding the management of hemangiomas. Those just presented represented one ideology and others advocated various forms of treatment. Lewis advocated injecting hemangiomas with a sclerosing solution consisting of sodium morrhuate, procaine, and hyaluronidase. No comparison between observed and treated patients was done, however several photographic examples are presented with apparent excellent results most notably in a nasal tip lesion and large central mucosal lip lesion. (13) Kiehn advocated following hemangiomas for the first year except in cases where "growth is infiltrating into the adjacent areas and perhaps threatening invasion of the orbit or nasal cavity, with possible danger to vision, breathing or swallowing". Surgery was planned after involution ensued, however no guidelines were offered to determine which lesions warranted surgery. The author states, "We believe that surgical removal constitutes the most satisfactory method of treating these vascular lesions. (14) Matthews relied primarily on diathermy for strawberry marks (superficial hemangiomas) and sclerosing with super saturated sodium chloride for cavernous (deep) hemangiomas with caution to inject under the skin and never into the skin as if done it will inevitably necrose. He states, "It is my belief that all cavernous lesions should be treated during the first year of active growth, except for the very small ones in harmless sites (as on the trunk and limbs), because of the extreme unpredictability of the subsequent behavior of this group." (15) Other methods of treatment used for hemangioma in the past include hot cautery, carbon dioxide snow, surface radium, radioactive paints (thorium-X), X-rays, interstitial gamma radiation, injection of boiling water or ethamolin froth, or continuous compression. (16-20)

The available treatment options of the day all had serious side-effects, for example the radio-dermatitis associated with cutaneous radiation and scars of surgery, carbon dioxide snow, and diathermy. Several authors commented on the disastrous results observed with treatment. (9,10) Additionally, the available anesthesia carried its own significant risk. The diagnosis and treatment was also complicated by the confusing variable definitions given to various vascular lesions and a general lack of understanding of the histological basis for the lesions. Given the lack of consistency in diagnosis and description in the literature, lack of dependable reproducible treatment and safe anesthesia, coupled with the evidence that the far majority of hemangiomas eventually completely involuted, a strong opinion developed that the appropriate treatment for hemangiomas was merely observation. This came to be known as benign neglect. With the publication of Mulliken and Glowacki a new understanding developed regarding the origins and differentiation of hemangiomas and vascular malformations. This allowed for consistent definition in the literature and the ability to more accurately follow the course of these differing entities.

Comparison of Historical Works and Recent Publications

Finn, working with Glowacki and Mulliken, produced an article evaluating the clinical application of their new classification system. As part of that article they followed 159 hemangiomas to "complete involution". They described an excellent cosmetic result as "no redundant skin, scar, or telangectasia". (22) Of the 159 patients followed, 96 produced an excellent result (60%), and 63 produced a less than excellent result (40%). 79 of 159 lesions involuted by 5 years of age (50%), and 80 involuted after 5 years of age (50%). These will be called early and late involuters. Of the 79 early involuters 64 produced an excellent result (81%), and 15 produced an "imperfect result" (19%). Of the 80 late involuters 32 produced an excellent result (40%), and 48 produced an imperfect result (60%). In summary, 60% of all lesions produced an excellent result and 40% did not. Half involuted early and half late. 81% of those that involuted early produced excellent results and 19% did not; 40% of those that involuted late produced excellent results and 60% did not. In the authors summary to this article they state that, ""80% of lesions involuting after age 6 do so "imperfectly," with residual scar, redundant skin or telangectasia, as opposed to 38% "imperfect" result for lesions involuting before age 6."" (21) This statement has been often quoted, (6,22) however based upon the data presented in the paper and analyzed herein, its origin is not apparent.

The modern argument for treating hemangiomas rather than benign neglect has been based on the observation that many of the hemangiomas do not regress completely, that is without cosmetic sequelae. Authors have quoted Finn in support of this and also reasoned that the previous works (3,4,8-12) either overestimated the number of hemangiomas that would eventually involute completely or accepted a less than perfect cosmetic outcome. Table 2 summarizes the authors stated results which have been presented. (Table 2) When comparing the results and reviewing the papers, several points emerge. While referring to hemangiomas by different terminology, usually strawberry naevi and cavernous hemangiomas, the authors universally recognized that the lesions were superficial, deep, or compound and that they presented after birth and all involuted to some extent. While the authors had differing cosmetic descriptions of an acceptable outcome, they all recognized that a portion of lesions appeared to innvolute by age 5 and that the remainder did so at a much slower rate. The proportion of early vs. late involuting lesions appears to be around 50%. The number of lesions actually progressing to a perfect outcome is of greater debate, but appears to be between 60% and 75% on critical review. Clearly 100% of lesions, as some authors suggested, do not resolve to a point where no evidence of the lesion exists. (Fig 3) Strikingly, while the authors of these articles all derived different conclusions, comparison of the data reveals quite similar observations. It would appear that the natural history of hemangiomas has not changed and that the number of involuting lesions that leave an imperfect cosmetic result is similar between studies. The difference in opinion relies on the attainable results of the available treatment options of the day and the author's perception of the degree of involution that would occur in the future. Based on these observations it becomes apparent that a proportion of hemangiomas may have a better cosmetic outcome if some intervention were offered. In addition to these findings, studies of the psychological impact of hemangiomas on children and families have emerged and provided additional guidance that should be considered when determining care.

Psychology and Rational for Treatment

Children begin to develop self-awareness at 18 to 24 months of age. A significant body image is well under development by the age of three. (22) A comparison of children aged 3 to 5 affected by head and neck hemangiomas with unaffected children, found a difference between the groups. The study found that children with hemangiomas perception of how others valued them were significantly lower than the unaffected group. Additionally, interviews of the mothers reported strangers raising the question of child abuse, children burying their faces or hiding their lesions with their hair, and family and friends commenting on doing something about it. (23)A further study confirmed the negative psychological impact of hemangiomas on the child and family and relief of these stresses with proper counseling and intervention if warranted. (24) Studies in the past have shown that teachers tend to provide more positive verbal interactions with children considered attractive than those with an anomaly. Evaluation of other cranial-facial abnormalities have highlighted the importance of a psychologist being involved with the health care team to educate physicians, parents, and teachers to the importance of positive involvement with affected children and their peers. (25)

During the period that benign neglect dominated most practitioners philosophies, the methods of treatment available may not have improved the result even in those lesions that did not regress on their own accord. This fact certainly influenced the opinion of earlier authors to support the philosophy of benign neglect. Recent advances in anesthesia, laser technologies, medical treatment, and surgical methods, however, allow effective intervention to treat not only those lesions that would otherwise leave a grossly unacceptable result in years to come, but also permit safe treatment to prevent children from suffering the psychological impact of living with a gross facial or body deformity. Careful thoughtful evaluation of past studies in the authors' opinion now clearly shows that somewhere between 25% (8) and 40% (21) of hemangiomas will leave an unacceptable cosmetic result that could be improved with medical or surgical intervention.

Treatment Options for Hemangiomas

The decision to treat a hemangioma must be carefully thought out and discussed with the parents of the child. The goal of the evaluation should be to attempt to determine which hemangiomas are likely to involute with a perfect result and which ones will likely leave a cosmetic deformity. Two phases of treatment are possible; during proliferation which will hopefully affect the ultimate size of the hemangioma and induce involution, and during involution. Williams presented a retrospective review of 168 patients with hemangiomas and developed an algorithm for management. This algorithm will be the primary basis for the following discussion. (6) (Fig 5a,b)

Attempting to determine which proliferating hemangiomas will result in cosmetically unacceptable outcomes may be impossible. Fortunately the treatment modalities primarily used during proliferation have few side affects or complications and the goals of therapy are therefore to attempt to reduce the eventual size of the lesion and induce involution. Only those hemangiomas that are life-threatening, of significant functional concern, or are overwhelmingly large warrant more aggressive therapy during proliferation. The treatment options commonly used for proliferating hemangiomas include observation, intralesional steroids, systemic steroids, pulsed dye laser, and surgical debulking. Other therapies, including interferon α2a, interferon α2b, argon laser, and Nd:YAG laser are available options. Enjolras reported on 25 cases of "alarming" hemangiomas treated with systemic steroids. The three patients with liver involvement all died during or following therapy. (26) Interferon α2a and interferon α2b have been recommended for the treatment of these types of complicated hemangiomas including those with airway obstruction or visceral involvement with good response in many patients (27,28). However, spastic diplegia has been reported in several patients with interferon α2a (29) and interferon's use should be reserved to those severe life threatening situations where other modalities are not an option or have failed. Argon, KTP, and Nd:YAG laser are recommended for use by some authors for the treatment of hemangiomas, but since its introduction have been mostly surpassed by the flashed lamp pulsed dye laser due to its effectiveness in the treatment of superficial hemangiomas and unparalleled safety. (30-38) A role may still exist for the use of intralesional laser treatments (31), however the safety of this modality in regards to scar production and damage to deeper anatomic structures has been of concern.

Management of Proliferating Hemangiomas

The decision to treat a proliferating hemangioma is based upon the rate of proliferation, cosmetic significance of the location, presence of ulceration or pending ulceration, or impending or present functional problem. Lesions involving the eyelids or the visual axis deserve special attention and will be discussed in more detail later. Because at least 60% of hemangiomas will involute with no cosmetic deformity perhaps the most important aspect of treating the proliferating hemangioma is determining when to observe. Observation should be considered an active treatment similar to laser and surgery and the term "benign neglect" should be abolished. Lesions which do not fulfill the qualification to warrant further intervention should be followed closely at least every three months and if the lesion is in a cosmetically sensitive area every 2-4 weeks if necessary to attempt to determine its growth characteristics. Open and thoughtful dialogue must occur with the parents and they should be encouraged to call and follow-up as frequently as necessary for their own comfort as well as for the best interest of the child. Never should a physician be coerced into intervening to alter the natural course of a hemangioma because of the parent's demands. It is important to treat the family with educational materials outlining the natural course and reassure them that the treatment goals are in the best interest of the child. Just because modern science has given the tools to intervene safely does not make it a requirement. In Williams' treatment of 168 patients in a high risk tertiary referral environment, only 15 (7.8%) received steroids either intralesional or systemic, 61 (36%) received pulsed-dye laser treatment, and 41 patients (24%) underwent surgery, usually during involution. (6) Interestingly, Bowers in 1960 found a 25% imperfect resolution rate following involution, a nearly exact correlation to the percentage of patients requiring surgical intervention by Williams in 2000. (6,8)

Hemangiomas in the proliferative phase that after interviewing the parents are undergoing rapid growth, have ulcerated, or on inspection are pending ulceration are considered for treatment with the pulsed-dye laser. Additionally, any superficial proliferating hemangiomas of the face or other cosmetically sensitive area should be carefully considered for this treatment. The tunable pulsed-dye laser produces a wavelength of 585 to 600 nm; this wavelength corresponds to the second absorption peak of hemoglobin and the third absorption peak of oxyhemoglobin allowing for selective photothermolysis. At the shorter wavelengths of 585 nm, most of the energy is absorbed by the first 0.5 to 1 mm of tissue thereby limiting the response to the most superficial component of the hemangioma. As the wavelength is increased from 585 to 600 nm, the incident of laser light will reach almost twice the depth, theoretically resulting in a more favorable response for hemangiomas that while still superficial by definition display thickened papular growth. Currently, a wavelength of 595 nm is used to treat most lesions. First generation lasers used a pulse length of 450 to 500 microseconds, significantly shorter than the thermal relaxation time of skin of 700 to 900 microseconds, and therefore very safe. Second generation lasers increased the pulse width to 1500 microseconds in an effort to increase clinical efficacy for larger vessels. This laser has also proven to be extremely safe. The addition of a cryogen spray to the pulse-dye laser allows cooling of the superficial epidermis, while allowing continued penetration of laser energy to the lesion and effective thermal ablation. The dynamic cooling device (DCD) is attached to the handpiece of the pulse-dye laser and delivers a brief (20-30 msec) liquid cryogen pulse. Theoretically, the DCD allows cooling of the epidermis and therefore less thermal injury resulting in reduced risk for scarring and less discomfort. Clinically, when using the device the purpura produced by the start-safe parameters is greatly reduced allowing treatment at a fluence 2 to 3 J/cm² higher than start-safe parameters, theoretically improving results. Experience will determine the appropriate fluence to be used with each lesion, the starting fluence with a 5 mm handpiece is usually approximately 9 J/cm², and this is adjusted upward until the desired degree of purpura is reached. (Fig 6) If a 7 mm handpiece is used the fluence should be started approximately 1 J/cm² lower.

Several articles have been published on the use of the pulsed-dye laser for the treatment of superficial proliferating hemangiomas. (34-38) Glassberg in 1989 published the first article presenting a single case example of a large superficial hemangioma. (34) Haywood treated 39 superficial hemangiomas with cutaneous height above the surrounding skin of no more than 5 mm and no deep component. The mean age at first treatment was 13 weeks, the first sign of involution were seen at an average of 19 weeks and complete resolution was seen in 61.5% of treated hemangiomas at an average age of 39 weeks following a mean of 2.4 treatments. (35) While no control group was provided and so the data must be interpreted with caution, this treatment appears to induce resolution of at least a select group of hemangiomas much earlier than historic data would suggest. Additionally, Lacour used the pulsed-dye laser for the treatment of ulcerated lesions. While the number of patients was small the conclusion was that the lasered lesions healed significantly quicker than ulcers treated conservatively with topical antibiotic ointment and a dressing. (36) The theory explaining the use of the pulsed-dye laser for ulceration is that the ulcer develops because the hemangioma grows at a rate exceeding the epidermal layers ability to cover the lesion. The pulsed-dye laser slows the growth thereby allowing re-epithelialization. Depending on the indication, if laser treatment is recommended it is usually delivered at 4-6 week intervals until the ulceration heals or proliferation is aborted and involution occurs.

While the pulse dye laser is useful for superficial hemangiomas it is ineffective for deep hemangiomas or the deep component of compound hemangiomas due to the inability to penetrate tissue to the necessary depth. Intralesional laser therapy with the KTP or Nd:YAG laser has been suggested for this use, but scarring and damage to underlying structures has been a concern. (31) The primary treatment modality for deep and compound hemangiomas that are either rapidly proliferating in a cosmetically sensitive area or a functional threat is systemic or intralesional steroids. The preferred mode of delivery is author dependent. (6,22,33) Systemic steroids may also be indicated for certain wide-spread superficial hemangiomas in conjunction with pulsed-dye laser. Intralesional steroids are delivered into the bulk of the tumor using kenalog 10 mg/mL for a total of 10 to 15 mg depending on the size of the lesion. This usually correlates to about 2-3 mg/kg. (6) When performing intralesional steroid injection in conjunction with pulsed-dye laser, the laser treatment should be carried out first so that any bleeding encountered from the injection does not interfere with accurate effective laser pulses. Injecting with a 1 cc syringe and a 27 or 30 gauge needle is recommended; the needle should pass through normal skin en route to the central aspect of the hemangioma as this normal skin bleeds less than an entry through the thinned epidermis involved with the hemangioma. This treatment is repeated every 4-6 weeks as needed until the lesion's growth stabilizes, decreases, or requires other intervention from failure to respond. Intralesional steroid use for periocular hemangiomas is controversial due to the reported risk of central retinal artery occlusion, eyelid necrosis, and atrophic scarring; this will be discussed further when discussing management of periocular hemangiomas.

With regard to systemic steroids, Bennett performed an extensive review of the use of systemic corticosteroids for the treatment of cutaneous hemangiomas. The meta-analysis was careful to exclude vascular malformations, involuting hemangiomas as steroids are only useful for proliferating hemangiomas, those associated with Kasabach-Merritt syndrome as this phenomenon is probably related to tufted angiomas and kaposiform hemangioendothelioma and not juvenile hemangiomas (39), visceral hemangiomas, and those undergoing multiple simultaneous treatments. (40) While admittedly this retrospective review has limitations as pointed out in the article, several useful conclusions were apparent. Administration of prednisone more than 2 to 3 mg/kg/day, resulted in a 75% response. Dosage greater than 3 mg/kg/day resulted in 94% response, but greater adverse effects, 51%. Lesser dosing resulted in fewer adverse effects, but also fewer responses and rebound growth occurred in 70% of patients. (40) Potential side effects include Cushingoid features, growth retardation, gastroesophageal reflux, peptic irritation and ulceration, fluid and electrolyte disturbances, hypertension, hyperglycemia, behavioral disturbances, and immune suppression. (41) Despite these possibilities no life-threatening adverse effects were observed and many authors reported no adverse effects. (40)

Sadan reported possibly the highest dosage of steroid use for the longest time course. They treated 60 infants; the first sixteen were treated with 3 mg/kg/day and the next 44 were treated with 5 mg/kg/day. After 2 weeks of treatment the dose was tapered gradually and discontinued after 6 to 8 weeks and in one patient after 12 weeks. A significant increase in response was seen with 5 mg/kg dosing. Side effects were reported as moon facies in 32 of 60 which all disappeared with completion of therapy. In two patients receiving prolonged therapy interference with growth was observed, but swift "catch-up" growth was evident a few months later and bone age became consistent with chronologic age. Osteoporosis developed in one patient who received two courses of prednisone therapy. Changes in behavior were present in all the infants and consisted of irritability, frequent crying, and an increased appetite appearing after the second or third week of treatment and continuing for a week or two. After discontinuation of therapy mood and appetite returned to normal. (42) The apparent dose related response of steroids clearly needs to be studied further in a prospective manner; however the use of oral corticosteroids even at high doses appears safe. The mechanism of action of corticosteroids on hemangiomas is not understood and while several theories have been proposed regarding the direct or indirect action on vasoconstriction or angiogenesis, this mechanism deserves further study as well.

Many proposed regimens of steroid dosage and tapering have been used and as stated the optimum regimen is unknown. A regimen that has proven effective and safe is as follows. A starting dose of prednisone 4 mg/kg per day in a single dose if possible is used. The patients' hemangiomas are then reevaluated in 1 week for steroid response. If shrinkage or stabilization is noted at this time, the treatment is maintained at the initial dose for 3 weeks. If no response is seen an increase in dosage to 5 mg/kg per day may be attempted and reexamined in one week. On follow-up exam at 3 weeks, the steroid is tapered over 4 to 8 weeks. The patients are observed closely by their primary care physicians or pediatricians for anti-reflux management (appropriate doses of a H₂ blocker or proton pump inhibitor are recommended) and frequent well-baby checks. All patients are observed by an endocrinologist as well. A follow-up exam is performed every 4 weeks or sooner if parents note problems. During treatment, no live vaccines are given and parents are informed that the infants are immunocompromised. If during tapering rebound proliferation is noted the dosage should be increased to the next highest level for an additional week and then tapering should be attempted again. One month after steroid treatments are discontinued, the patients are reevaluated. If the hemangioma exhibits proliferation, systemic steroid treatments are resumed at a dose of 4 mg/kg per day. The hemangiomas are reevaluated at 1 week and, if improvement has occurred, systemic steroids are tapered over 4 weeks. (Fig 7a,b)

Management of Periorbital Hemangiomas

Surgical management of proliferating hemangiomas is usually reserved for cases involving the periorbital area which do not respond to steroid or laser therapy and are a functional concern. Hemangiomas are the most common tumors of the orbit in children. In addition to their cosmetic significance, they carry a more ominous threat of visual disability. Because of this threat, treatment in proliferation, either medical or surgical is often warranted. Amblyopia, visual impairment because of interruption in development of the neural visual pathways, has been reported in 43-60% of patients with hemangiomas located in the eyelids or orbit. (43) The amblyopia may be due to many factors; the first is visual deprivation due to the pupil being covered by the tumor/eyelid which blocks the visual axis. The brain receives minimal visual stimulus from this eye and the visual pathways fail to develop properly. The second factor may be anisometropia which is a difference in the refractive error between the eyes caused by the tumor indenting the sclera or cornea and causing astigmatism. Normally, the cornea is of equal radius of curvature from the center point to its edges. In astigmatism, the radius of curvature of the cornea is greater in one dimension than the dimension at a right angle. Anisometropia, if not treated with corrective lenses such as glasses, may result in the patient suppressing the images from the affected eye resulting in amblyopia. Additionally, the hemangioma may cause amblyopia by directly affecting the extraocular muscle or its nerve resulting in strabismus which is deviation of the eye. While vision loss from amblyopia is the most common complication of a periorbital hemangioma, other complications include proptosis, optic atrophy, ptosis, and dermatologic sequalae.

Ocular indications for treatment include induced amblyopia, compression of the optic nerve, or corneal exposure secondary to severe proptosis. Compression of the optic nerve and corneal exposure are indications for immediate treatment usually in the form of surgical debulking. The threat of visual loss from amblyopia is serious, though usually not an emergency. Visual function of the infant should be monitored at least monthly with assessment of the visual acuity and a cycloplegic retinoscopy by an ophthalmologist until either the hemangioma begins to regress or evidence of refractive asymmetry, or strabismus appears. If the astigmatism is greater than1.5 diopters, it should be treated with corrective lenses. Once amblyopia is suspected, the visual axis is obstructed, or the lesion enlarges rapidly treatment of the tumor should be considered. (43) There is mounting evidence that for the complete regression of the induced astigmatism intervention before one year of age is preferable; however more clinical data are needed to confirm this. (44) Treatment for ocular hemangiomas threatening visual loss generally consists of steroid treatment or surgical excision. Steroid administration generally falls into two categories, intralesional injection and systemic administration. Systemic steroids have been associated with a slower onset of action than intralesional injection (two to three weeks) and rebound upon tapering which necessitates prolonged administration with increased risks of infection, growth retardation, and cushingoid features. (43)

The use of oral steroids has been previously discussed and so this section will focus on intralesional steroids and their complications. Intralesional injection of steroid is the preferred method in the ophthalmic literature for medical management of amblyogenic eyelid hemangiomas as it has an 80 to 88% response rate and fewer systemic risks. (44,45) The total amount injected varies with the size of the tumor, but is usually between 1-2ml. (43) Intralesional corticosteroids deliver a high local concentration while minimizing systemic adsorption. The onset of action is usually two to three days with tumor blanching and is usually considerable within 2-4 weeks. Additional injections are required in most patients in four to eight weeks. Injections are usually given under general anesthesia. Post injection swelling is common but usually resolves within 24 hours. (43)

There are numerous reported complications of this therapy including retrobulbar hemorrhage, penetration of the eye with the needle, and the most feared complication central retinal artery occlusion. The incidence of central retinal artery occlusion is extremely rare with only a few reported cases in the literature; the majority of these are unilateral, but it has been reported bilaterally. (46,47) Some believe injection is best performed while visualizing the retinal vasculature. (48)The mechanism of central artery occlusion has been related to injection pressure, particle size, and volume injected. Egbert et al. found that fellowship trained pediatric ophthalmologists with extensive experience administering intralesional steroids routinely exceeded systemic arterial pressures during the injection of hemanangiomas with a 50/50 mixture of triamcinolone diacetate (40 mg/ml) and betamethasone acetate (6 mg/ml). However, 71 injections were performed without any adverse sequalae. (49) Also, it was noted that retrograde flow was necessary, but not sufficient to cause ocular embolization. In order for retinal embolization to occur, retrograde flow with sufficient volume of the injection must be present. (49) Egbert summarized five steps to minimize retinal embolization 1) aspirate before injecting to avoid intravascular injection, 2) treat multiple areas of the hemangioma with small volumes, 3) limit the total volume injected "volumes of 0.8ml to 1.5ml were sufficient to cause shrinkage of periocular tumors between 4 ml and 8 ml," 4) use indirect ophthalmoscopy to observe the retinal vasculature, and 5) do not apply pressure to the tumor or patch the eye, and a shield should be placed around the tumor to prevent inadvertent pressure to the lesion. (49) Particle size has also been implicated as a contributor to embolization. The range of commonly used steroid preparation particle sizes is 10 to 50 microns, compared with 6 to 7 microns for erythrocytes. (43,47) Accumulation of multiple steroid particles may result in aggregates of up to 200 microns. Aging of the medication, exposure to air or an incompatibility between solutions may result in flocculation when mixed theoretically contributing to aggregation. (43) To avoid this Haik recommends "use only unopened vials of medication and mix only medications known to be compatible." Additionally, it is recommended to thoroughly agitate the both the bottle and the syringe immediately before injection. Other rare complications of steroid injection include eyelid necrosis, subcutaneous deposits, hypopigmentation, local fat atrophy, transient adrenal suppression, and cushingoid appearance.

Surgical excision for periocular hemangiomas has been recommended by authors both as primary treatment and for medical treatment failures. (44,45,50) Rapid resolution of the anisometropia has been shown with excision of the hemangioma. This rapid resolution was identified as very important in masses resulting in deprivation amblyopia which has more severe visual consequences and may require more rapid resolution than that afforded with medical treatment. (50) Additionally, it has been shown that lesions treated with surgical excision earlier in infancy are more likely to have the anisometropia and amblyopia resolve. (44)

The critical period for the development of amblyopia has been reported after 13 days of occlusion therapy at 18 months of age, (51) and after as little as one week of patching in children younger than 2 years of age. (52) Thus complete occlusion of the visual axis demands immediate intervention. Plager states that the "best" surgical candidates are those with well circumscribed tumors, without dermal involvement, and anterior in the orbit. Surgery on lesions with an active surface component, the skin is not freely moveable over the lesion, is avoided because of the possibility of skin necrosis and need for grafting in a cosmetically sensitive area. (44) The surgical technique involves a skin incision in the lid crease or transconjunctival, followed by sharp dissection around the extent of the tumor, which is aided by an easily identifiable surgical plane in most cases. The tumor is generally removed en bloc. However, when a portion of the tumor is adherent to the surrounding normal orbital structures and can not be shelled out it is left behind. (45) Feeder vessels are identified, cauterized, and divided. Walker excised 12 periorbital hemangiomas and stated, "The lesions treated were primarily isolated, orbital masses. Lesions with large areas of skin involvement were not believed to be amenable to excision due to the risk of skin necrosis and dehiscence after devascularization of the tissues directly underneath the skin." Surgical techniques in other locations purposefully leaving hemangioma on the undersurface of skin flaps has allowed safe removal of tumors with superficial involvement without risk of skin loss and may be applied to periorbital excisions allowing broader indications for surgical intervention in the future. (Fig 8) The risk of blood loss for periorbital tumors may be greater than other locations. When planning surgical excision for hemangiomas posterior to the orbital septum, it may be prudent to have preoperative directed-donor blood products readily available in case a transfusion is necessary. (45) The average blood volume for a 15-lb infant is approximately 500 ml. Thus the patient may require a transfusion even with controlled intraoperative bleeding. (44) Traditionally hypotensive anesthesia was recommended. (43) However, recent reports and experience have not deemed this necessary. (44,45) Excisions of true juvenile hemangiomas outside the orbit rarely if ever require blood components even if performed during proliferation. The consideration to have blood components available should consider the location of the hemangioma in the orbit, the size of the child and therefore available blood volume, and the stage, proliferation or involution, of the hemangioma. Additionally, the two patients that received blood products in Walker's study both had directed donor transfusions of packed red blood cells available and were performed electively for intra-operative blood loss of 50 and 60 cc in a 16 month old and 3.5 month old respectively. However, due to the confined surgical access of the bony orbit and inability to compress the tumor for hemostasis, preoperative preparation for blood loss especially in young infants is warranted. (Fig 9a-f)

Management of Involuting Hemangiomas

Involution will begin usually no later than 12 months but occasionally as late as 18 months of age. As the lesion enters involution it becomes necessary to observe the process for 8 to 12 months. As explained earlier hemangiomas will involute at different rates with approximately 50% doing so by age 5 and 50% more slowly than that. (Fig 10) As the hemangioma is monitored during early involution it becomes apparent from serial photography and parent questioning whether the lesion is remaining stable in size or has begun to regress. Those that show regression by the age of two are classified as early involuters and those not showing regression are classified as late involuters. Those lesions which are determined to be early involuters are monitored approximately every 6 months until age 4- 41/2 when if substantial deformity still exists surgical therapy is offered for atrophic skin or fibro-fatty residuum or laser therapy is offered for telangectasias to attempt to resolve the abnormality completely prior to entrance in primary school. Approximately 20% of early involuting lesions will fall into this category while 80% will resolve completely without any abnormal residuum. (21) Hemangiomas that have not shown any regression in size after 8 to 12 months are determined to be late involuters. These are offered surgical excision or laser treatment around the age of two because a majority of these lesions will leave a substantial cosmetic deformity by the time of entrance to primary school. By intervening at the age of two the child has not yet begun to fully develop a body image and little recognition of the treatment will likely persist past early childhood. The overall goal of intervention in the natural cycle of the hemangioma is to identify as readily as possible those lesions which will most likely leave a cosmetic deformity as the child progresses to school age where it is likely to cause psychological detriment, and then to intervene in such a manner to leave the child with little if any noticeable remnant of the ordeal either physically or mentally.

When undertaking surgical excision of a hemangioma several surgical principles are important to consider. First and foremost unlike other vascular lesions, in particular tufted angiomas, hemangioendotheliomas, and arterial and venous malformations, juvenile hemangioma excisions more resemble that of a benign tumor than a vascular lesion. While no capsule exists around the hemangioma, an easily definable surgical plane does. This plane can be followed and with careful identification and management of a few feeding vessels very little bleeding should be encountered. Bipolar cautery is recommended and while laser or "hot" scalpels may be used they are certainly not necessary tools. Blood products are not necessary with the exception of perhaps a very large proliferating hemangioma related to the orbit as described. Placement of incisions should be done to include any abnormal atrophic scar tissue from previous ulceration and so that they lie in the junction of facial units, subunits, or relaxed skin tension lines. The incision line can often be shortened with the use of an M-plasty at one or both extremes of the incision. (Fig 11) An advantage is gained when excising hemangiomas in the two to three year old time frame because the tumor itself acts as a tissue expander and adequate tissue is nearly always available to be advanced as necessary to primarily close the excision. When the hemangioma has an extensive superficial component and the entire lesion cannot be excised without violating aesthetic lines or making an unduly large incision it is always better to leave hemangioma behind and rely on the natural involutional process to complete the result. Routinely approximately 10% of the hemangioma is left behind and allowed to undergo involution to prevent over-resection and tissue void. The pulsed-dye laser can be used post-operatively to effectively create tissue by converting telangectatic skin or skin with residual hemangioma to normal appearing skin. (53) (Fig 12) Mulliken recently published an article describing the use of a purse-string stitch to excise the hemangioma initially and gather the surrounding tissue taking advantage of the tissue expander phenomenon. Following this if necessary a second operation was planned to remove the scar created by the purse string. This method served to reduce the length of the scar necessary to remove the lesion and a theoretical decrease in scar length was calculated to equal 72%. (54) This method may prove useful for lesions placed in the central cheek or forehead as many of the examples in the paper illustrate; however its use when incisions may be placed in facial unit junctions may be of less benefit. (Fig 13)

Once the surgical plan has been made, the tissue is injected with local anesthetic with a vasoconstricting agent. The incision is usually carried down through skin and into the substance of the hemangioma where it is transected by using a small hemostat to bluntly separate the tissue and a bipolar cautery to divide. No attempt is made to raise a skin flap over the substance of the hemangioma since the dermis is often involved leading to an overly thin flap with the risk of necrosis. Once the deep aspect of the hemangioma is encountered an easily dissectible tissue plane is the rule. The lesion is then separated from the surrounding tissue and any feeding vessels appropriately dealt with. As the superficial aspect of the lesion is encountered again a portion is intentionally left on the undersurface of the skin flap and no attempt to identify a tissue plane is made. Any undesirable tumor bulk that is left on the undersurface of the skin flaps is then thinned to a safe thickness with a scissor and the residual cauterized with a bipolar cautery to induce further involution. (Fig 14) It appears and has been mentioned by other authors as well (56) that surgery appears to influence the speed of involution even on any residual left after a debulking, although this cannot be substantiated by any scientific study.

Hemangiomas of the nasal tip and lip pose an additional challenge to excision and reconstruction. Bowers demonstrated with near significance that hemangiomas of the lip fail to involute more often than other areas. (8) Zide presented several surgical excisions of difficult non-involuting lip hemangiomas and made several observations.(55) Many of the same surgical principles already mentioned apply, but have specific application to the lip anatomy. As hemangiomas grow within the red or white lip expansion of the lip occurs. Removal of the lesion requires that both the vertical and horizontal proportion of the red and white lip be adjusted to their normal anatomical relationship. Once again conservatism is the rule and over-resection should be avoided. Usually the hemangioma will involve the tissue superficial and/or deep to the orbicularis muscle and will not invade through the muscle. It is advisable to not resect orbicularis muscle unless absolutely necessary as this often leads to volume loss within the lip which cannot be easily replaced. (Fig 15, 16, 17) Placement and reconstruction of the white roll is essential in lip reconstruction as malposition of this border is obviously perceptible. Zide also makes note of several aspects of lip hemangioma treatment which are difficult to reconstruct including convexity of the tissue below the lower lip white roll, abnormal skin surface after involution, and bulk deficiency. (55)

Perhaps no other region may be affected or invite ridicule and social isolation more than the nasal tip. Hemangiomas in the nasal region tend to proliferate rapidly often reaching large size relative to the native nasal skeleton and will often splay if not cause frank deformity to the lower lateral cartilages. These lesions will often be classified as late involuters and because of the psychological impact of allowing involution to go on into the late elementary school ages, they are often amenable to surgical excision. Thompson compared eight patients with nasal tip hemangiomas managed without surgery with eleven patients with surgery via various methods and concluded that conservative management provided superior results. (56) Since that time however greater understanding of nasal anatomy and subunits has been gained and applied to reconstructive nasal surgery. Several approaches to the excision of nasal hemangiomas have been described with varying advantages, disadvantages, and results. (56-60) The procedure chosen must be able to accomplish the following goals. The incisions must be placed within the aesthetic subunit junctions of the nose, they must provide access for complete removal of the hemangioma, and they must allow for both horizontal and vertical trimming of the redundant nasal soft tissue envelope for repositioning. Care must be taken when performing the dissection to preserve adequate thickness to the nasal soft tissue flap for survival. Once again it is not necessary to define a tissue plane between the skin and the hemangioma. Conversely, the deep aspect of the lesion will provide an identifiable dissection plane above the nasal cartilaginous skeleton that must be preserved. Once the hemangioma is removed the alar cartilages should be repositioned and sutured to place the domes in anatomical approximation. Following this the soft tissue envelope is repositioned, trimmed, and sutured into position. (Fig 18,19)

Conclusion

Pediatric vascular lesions including hemangiomas and other vascular malformations have been called by many different names and confused in the literature for many years. This confusion in terminology also led to misdiagnosis and inconsistency of treatment. Mulliken and Glowacki fortunately clarified the different endothelial characteristics of these lesions allowing them to be classified as true hemangiomas or vascular malformations. This microscopic classification scheme hence has allowed the clinical course and treatment of hemangiomas to be followed with clarity. Unfortunately, hemangiomas are still at times referred to in the literature as capillary or cavernous, terms from the past which were used to describe differing vascular lesions. Hemangiomas are a single clinical entity whose presentation only differs because of their depth within the soft tissue. The terminology of superficial, deep, and compound to differentiate these different clinical presentations of the same pathological entity is therefore sensible.

Hemangiomas are the most common neoplasm of infancy and early childhood, and their clinical course is usually completely benign both functionally and cosmetically. However, historical papers describing the natural history of hemangiomas prior to the advent of newer medical, laser, and surgical treatments probably overestimated the complete resolution of these lesions. When these studies are compared to more recent projects the natural history of hemangiomas appears unchanged, but the interpretation of the data is quite different. It becomes apparent on review that during the involutional stage of the hemangioma two groups emerge, those which will resolve by the age of 5 and those that will not. About 50% of hemangiomas will fall into each group, which it is recommended should be referred to as early and late involuters. Additionally, a difference in cosmetic outcome exists between groups with approximately 20% of early involuters verses 60% of late involuters leaving a cosmetically imperfect result. With newer medical technologies the expectation of attainable outcomes should be elevated. Psychological studies of children with facial hemangiomas bolster the argument that in certain cases intervention in the natural history of the hemangioma should be undertaken.

Intervention during proliferation should be offered for rapidly proliferating lesions in cosmetically sensitive areas, ulceration or pending ulceration, or impairment of function. The most urgent reason to intervene during proliferation is impending visual impairment. The available options for intervention are currently many and have been even more numerous in the past, however the mainstay of therapy consists of oral or intralesional corticosteroids, pulsed dye laser, and surgical excision. Once a hemangioma has begun to involute determination should be attempted to place the lesion into the category of early or late involution. It must be emphasized that 60 to 75% of hemangiomas will involute without any cosmetic sequela and for that reason every attempt should be made to identify those lesions which do not need any further intervention. However once it becomes apparent that a cosmetically undesirable outcome is likely, surgical or laser therapy should be offered. Surgery if undertaken is not an unduly hemorrhagic affair. Definable surgical planes are readily apparent and complete excision is not necessary or even desirable. Minute amounts of blood loss are easily controlled with standard surgical techniques. Surgical planning is paramount and principles of facial units, subunits, and relaxed skin tension lines should be observed. Abnormal skin through which ulceration or atrophic scarring exists should be excised without effort to include all skin involved by the superficial component of the hemangioma. The normal involutional process which may be encouraged by surgery and the use of the pulsed dye laser post-operatively will actually produce additional normal skin as time passes.

Hemangiomas should not be routinely disregarded and assumed to resolve of their own accord. Physicians must be reeducated regarding the usefulness of active intervention for these tumors even if that intervention consists of thoughtful monitoring and family education. When indicated referral to a physician experienced in treatment should be commonplace early in the evolution of the process and not only when an unacceptable residuum exists in an already impacted child.

References

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