Samuel M. Lam, M.D.*, and Edwin F. Williams III, M.D.**

*Clinical Instructor, Division of Otolaryngology, Department of Surgery,
Albany Medical College,
Albany, New York

Stratton Veteran Affairs Medical Center,
Albany, New York

**Clinical Associate Professor, Division of Otolaryngology, Department of Surgery,
Albany Medical College,
Albany, New York

Chief of Division,
Facial Plastic & Reconstructive Surgery,
Albany Medical College,
Albany, New York

Medical Director,
Williams Center for Facial Plastic Surgery,
Latham, New York

 

Abstract

            Congenital vascular anomalies have been the subject of much controversy and confusion over the years.  Since 1982, hemangiomas and vascular malformations have been recognized as distinct diseases that exhibit unique properties and behavior that demand an appropriately tailored treatment plan.  This article will briefly review the characteristics of these vascular anomalies, including epidemiology, classification, and clinical presentation and then focus on the current therapeutic options that are available.  The past decade has witnessed a revolution in the understanding and treatment of vascular lesions, marked by more advanced laser therapy, earlier intervention, and an increased sensitivity to the psychosocial dynamics of the disease.

 

Key Words:  Hemangiomas, Vascular Malformations, Current Therapy

Introduction

Much confusion and controversy have shrouded the classification and treatment of benign, congenital vascular anomalies.  Hemangiomas and vascular malformations share the common attribute that they exhibit an abnormal abundance of blood vessels.  Beyond this similarity, these vascular lesions differ fundamentally in histology and physiology.  Early practitioners failed to distinguish between these two types of vascular anomalies, leading to inappropriate and at times harmful care of afflicted children.  In 1982, Mulliken and Glowacki’s seminal treatise proposed that hemangiomas and vascular malformations represent unique disease processes, with the former constituting a true neoplasm by virtue of an increased endothelial turnover.¹ 

The past decade has witnessed a revolution of thought and practice in the treatment of congenital vascular diseases and seen a further refinement of the concepts originally developed by Mulliken and Glowacki.  A better understanding of the natural history of hemangiomas has resulted in a more effective treatment algorithm that may in turn diminish the damaging psychological repercussions of the disease on the child and family.²  Genetic loci **^3,4,  related syndromes^5,6 , and cellular markers⁷ have also been discovered that have shed new light on the clinical behavior of these vascular anomalies.  Laser technology continues to evolve and can now achieve outstanding results with minimal morbidity.  A host of therapeutic modalities has been introduced– including interferon therapy^8-10 and interventional-radiology techniques**¹¹ – that has met with varying success in the treatment of these disparate vascular disorders.

In order to provide a meaningful review of hemangiomas and vascular malformations, the article will be divided equally into respective sections on these two types of vascular anomalies.

Hemangiomas

Epidemiology

            Hemangiomas are the most common neoplasm of infancy and childhood, with an estimated prevalence of 1-3% of all neonates ^12,13 and 10% of infants by 1 year of age.^14,15  Most hemangiomas arise in the head and neck region (60%), and 20% of patients may suffer from more than one lesion.¹⁶  Prematurity is a well-identified risk factor, especially in those neonates that fall below 1500 grams in weight.¹⁷  A predilection for the female sex has also been reported, with a ratio of 3 to 1.¹⁸  Most hemangiomas tend to arise de novo without an antecedent family history, but a few studies have determined an autosomal-dominant pattern of inheritance in a select group of patients.¹⁸  Chorionic villus sampling has also been found to predispose one’s progeny to the development of a hemangioma.¹⁹

Classification

Prior to the work of Mulliken and Glowacki, terminology that described hemangioma types was mired in inconsistency and confusion.  A plethora of words abounded to describe various hemangioma morphologies that at times overlapped with descriptions of vascular malformations, such as “strawberry nevus” and “cavernous hemangioma”.  These ill-defined terms have been largely replaced by a systematic nomenclature that seeks to delineate the anatomic dimensions of the lesion.  Hemangiomas that arise only on the surface of the skin and immediate subjacent tissue may be accurately referred to as superficial (formerly known as capillary).  Conversely, a lesion that is situated only in the deeper subcutaneous tissue may be considered a deep hemangioma (formerly known as cavernous).  If both superficial and deep components are present, then the hemangioma may be categorized as compound or mixed.  Field hemangiomas represent multiple hemangiomas that rapidly enlarge and coalesce into a more singular entity.  Visceral hemangiomas are derived within the internal organs, like the liver, colon, and brain.  Diffuse neonatal hemangiomatosis refers to a highly lethal condition in which the newborn is covered with hundreds of hemangiomas that may involve the viscera as well, leading eventually to cardiac failure and ultimately to death within weeks.²⁰  Hemangiomas may also be part of a syndrome known as PHACE(S) (Posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities [and sternal clefting and supraumbilical raphae]).²¹

Clinical Presentation

At birth, a child may exhibit various manifestations of the incipient hemangioma, including an erythematous macule, a telangiectatic mark, a faded area, or no identifiable lesion at all.  Although most hemangiomas are present within the first month of life, it is rare that they are recognizable as such at the time of birth.  Superficial hemangiomas are bright red and non-compressible and may assume a raised or flat contour.  Deep hemangiomas are situated in the subcutaneous tissue and may be well below the skin so that a raised mound provides the only clue to the underlying lesion.  At times, a bluish hue may be visible through the skin as a hint of a deep hemangioma that approaches more closely to the skin’s surface.   In addition, telangiectasias or prominent veins may pepper the skin overlying a deep hemangioma.

The natural history of hemangiomas is characterized by a marked proliferative phase during the first few months of life that usually is sustained to the end of the first year but rarely persists beyond that time.  During this period, the hemangioma may risk ulceration or frank hemorrhage, the former condition may lead to infection and scarring and the latter may usually cease with simple application of pressure.  The greatest concern with rapid growth of the hemangioma lies in its obstructive potential:  in the subglottic airway resulting in stridor or further compromise, situated near the eye leading to amblyopia, or in the external auditory canal causing a conductive hearing loss.  The psychological impact of the expanding hemangioma should not be underestimated and may cause considerable alarm in parents, leading them to seek medical counsel during this time.  After the first year of life, the hemangioma may begin to involute slowly or remain stable and only then slowly diminish in size over the next several years.  If the hemangioma should resolve slowly (a late involuter), then the child may suffer considerable psychological damage during the school years and still be left with a marked cosmetic deformity.  The classification of hemangiomas into early and late involuting types has shaped a newer treatment algorithm that will be discussed in the following section.

Current Therapy

            Since the work of Lister, management of hemangiomas has been plagued with the prevailing dictum of benign neglect.²²  Many practitioners have advocated no therapy at all with the prescription that all hemangiomas will ultimately resolve.  Recent studies have determined that late-involuting hemangiomas only incompletely regress and leave behind an often-significant residuum.^23,24  Neonates and infants may remain unaware of their disfiguring condition, but children 3 years and older are subjected to a burgeoning self-identity and the attendant social stigma that “being different” bears.^25,26  A policy of watchful waiting in a slowly involuting hemangioma may prove detrimental to a child’s psyche and may lead to ostracism from his peers.

Williams et al. have proposed a new treatment strategy based on the proliferative and involuting characteristics of a hemangioma in order to treat select patients on a timely basis and to preclude the potential psychological sequelae of a longstanding hemangioma.²  A proliferative hemangioma that risks ulceration or bleeding or that is rapidly expanding in a cosmetically sensitive area is a candidate for early intervention.  Pulse-dye laser therapy with adjunctive intralesional steroid application has proven to be effective to retard the rate of growth.  A trial of oral steroids may be mandated for a hemangioma that shows signs of impending obstruction, e.g., by encroaching on the airway or vision.  Most hemangiomas begin to involute early, albeit slowly, and should be left to regress spontaneously.  However, a hemangioma that tends toward late involution should receive therapy so as to remove the disease that would most likely fail to involute completely and that would impair the child’s favorable psychosocial maturation.  At this stage, surgical debulking with adjunctive laser therapy is the preferred method of intervention, as steroids have no beneficial role during the involutional phase.

It should be emphasized at this point that most hemangiomas do not require therapy, and only a select minority coincide with the enumerated criteria for intervention.  Parents suffer significant psychological distress from the presence of a vascular birthmark.²⁷  However, the timing and rationale for intervention should never be dictated by parental coercion, as this injudicious policy would do a disservice to both the child and insurance carrier, or other third-party payer, to whom the physician is responsible.

            Throughout the history of hemangioma management, many therapeutic options have been advocated or tried with mixed success.  Compression therapy was hitherto popular when few options were available at the time.^28,29,30  However, some authors still rely on this low-risk method of treatment. Cryosurgery was popular in the past but has lost some of its charm.³¹  Many therapeutic modalities that carry a high morbidity profile were also once in vogue, including embolization, sclerosis, chemotherapy, and irradiation.^32,33  Embolization of visceral hemangiomas³⁴ and intralesional chemotherapy³⁵ for refractory cases have still shown some clinical utility. Interferon therapy may also prove helpful in life-threatening or recalcitrant cases.^8-10 but has been associated with neurotoxicity, including spastic diplegia³⁶, and should be used with great caution.  The cornerstones of effective therapy for hemangioma today principally involve steroid, laser, and surgery.

Steroid Therapy

Systemic steroid therapy has been a reliable method of treatment for over 30 years³⁷, but no controlled, prospective studies have been undertaken to evaluate the efficacy, proper dosing, duration of therapy, or tapering regimen.  Steroid therapy, whether systemic (oral and intravenous) or local (intralesional and topical), is only effective during the proliferative phase of hemangioma development and should be used to treat a rapidly proliferating hemangioma in a cosmetically sensitive area that risks imminent ulceration or bleeding or that may lead to obstruction, e.g., near the eye or in the airway.  Usually a rapidly proliferating hemangioma that may ulcerate or hemorrhage may be treated with the pulse-dye laser and with concomitant intralesional kenalog injection.  However, if an obstructive potential exists, then oral steroids may be necessary.

A meta-analysis of systemic steroid therapy determined a response rate of 84% in 10 original case series that met inclusion and exclusion criteria (viz., treatment of a problematic hemangioma, child less than 2 years old, greater than 5 cases, no other simultaneous treatments, proper follow-up, and sufficient data).^**38  The study concluded that administration of higher doses of prednisone (>3 mg/kg/day) resulted in a higher response rate (94%) but a concomitantly higher side-effect profile and that lesser doses (<2mg/kg/day) showed less response, fewer adverse effects and greater rebound rate (70%).  Patients underwent a mean 2-month period of therapy and were maintained on oral steroids until cessation of growth or actual regression was evident.  Tapering schedules were not delineated in most case series and varied considerably in the reported studies.  In conclusion, oral steroid therapy (2-3 mg/kg/day) can be effective in a select group of hemangioma patients who have obstructive or recalcitrant lesions and who demonstrate a response to steroids.

Laser Therapy

            The introduction of the pulse-dye laser has proved to be nothing short of miraculous for the treatment of vascular lesions and has almost entirely replaced the argon laser.  A large series (617 hemangiomas) treated with the pulse-dye laser demonstrated a 96.6% arrest in further growth after a mean of 2.5 treatments (13.8% complete remission, 14.9% significant regression, 67.9% discontinuation of growth).^**39  During rapid proliferation, hemangiomas may require several sessions of laser therapy divided 6 to 8 weeks apart in order to retard the growth rate.  As mentioned, intralesional steroid therapy may be a beneficial adjunct at the time of laser administration.  The indication for laser therapy would include a rapidly proliferating lesion that may ulcerate, bleed, or obstruct.  The pulse-dye laser really only targets the superficial component of the hemangioma.  The ND:Yag and argon lasers have been applied interstitially for the treatment of deeper hemangiomas⁴⁰, but we strongly advise caution as the risk of scar formation may be considerable.  During the involutional period, the laser may remove residual dermal ectasias and telangiectasias, tighten the loosened skin overlying the hemangioma, and serve as a useful adjunct post-surgery to address the aforementioned residual deformities.  Unlike late-involuting hemangiomas, early involuters should be permitted to regress naturally and not be subjected to unnecessary therapy.

            The carbon-dioxide (CO2) laser may play a useful role in the treatment of laryngeal hemangiomas that encroach on the airway but should be used conservatively to avoid tracheal stenosis.⁴¹  Because the risk of scarring is high for large or circumferential lesions, tracheotomy and systemic steroid therapy may be beneficial in certain cases.*⁴²  Tracheotomy and systemic steroid therapy clearly have their own attendant risks and limitations, including delayed speech and swallowing problems for the former and the many well-known side effects of the latter.  The physician is urged to apply clinical judgment when deciding on a particular course of therapy.

Surgery

            Surgery remains a reliable technique of debulking hemangiomas in a rapid and definitive manner.  During the proliferative phase, hemangiomas rarely require surgical intervention except to alleviate obstructive lesions that fail more conservative measures.  Generally, surgery plays a more useful role during the involutional phase to remove the unsightly residuum that may remain.  A key surgical concept is removal of the bulk of disease but leaving a small (10%) remainder of the lesion behind to accommodate for any further regression that the lesion may undergo in the future.  Usually 6-8 weeks after surgery, the patient may benefit from pulse-dye laser therapy to remove any superficial dermal ectasias or discolorations that are still present.  By approaching the involuted hemangiomas conservatively, the surgeon may avoid larger, unnecessary incisions and prevent a depression due to over-resection.  Most residual hemangiomas may be removed in a straight-forward fashion.  However, infrequently the surgeon may require tissue expanders or serial excisions to resect larger residual deformities that encompass a greater cutaneous surface.  Although tissue expanders have been described with success in the literature⁴³, we believe that children tend not to tolerate these devices well psychologically or physically and may be better served with serial excisions for larger, more difficult hemangiomas.

Kasabach-Merritt Syndrome

            Before concluding this section, we must address the current thinking of the Kasabach-Merritt syndrome, which is characterized by thrombocytopenic coagulopathy.  This phenomenon has been recently found not to be associated with true hemangiomas but with two distinct vascular tumors known as the kaposiform hemangioendothelioma and tufted angioma⁴⁴.  These unique lesions exhibit a violaceous tone and nodular pattern, but each has its own particular histopathologic features.  Kasabach-Merritt carries a high mortality rate, and treatment is often inadequate and inconsistent, relying on multimodality therapy of cytotoxic agents such as vincristine, cyclophosphamide, systemic prednisone, and interferon alfa.⁴⁵

Vascular Malformations

Epidemiology, Classification & Clinical Presentation

            Vascular malformations (VMs) arise from an error in morphogenesis of any combination of the following vascular networks:  arterial, venous, capillary, and lymphatic.  Unlike hemangiomas, these vascular anomalies are present at birth and grow proportionally to the size of the child and do not exhibit any tendency to involute spontaneously.  Hormonal factors, such as puberty or pregnancy, may influence the growth of these vascular lesions, causing acceleration in size during these periods.  Direct trauma or infection may also trigger a rapid expansion.  The predominant vessel type (arterial, venous, capillary or lymphatic) dictates the flow (slow or fast) and thereby the physical attributes of the lesion.  Fast-flow malformations usually have an arterial component and exhibit a propensity to expand, to achieve large volumes, and to pulsate.  Slow-flow lesions encompass capillary, venous and lymphatic types and behave according to the primary vessel present.

By far the most common of the VMs, capillary malformations (port-wine stains [PWS]) occur in an estimated 3 children per 1000 births, with approximately 80% occurring in the head and neck region and with an equal sex distribution.⁴⁶  PWS manifests as a flat lesion with a red to pink hue which may lighten during the first year but then tends to darken throughout life turning a deeper shade of red or blue and may even become thicker or more nodular as the individual matures.⁴⁷  Two related syndromes have been linked with PWS:  Sturge-Weber and Klippel-Trenaunay.  Sturge-Weber, or encephalotrigeminal angiomatosis, refers to a PWS that is distributed in the first trigeminal division (V1), with or without V2 or V3 involvement, and with central nervous system (CNS) abnormalities.  CNS defects include cerebral atrophy, leptomeningeal angiomas, and cortical calcifications that may lead to seizures, mental retardation and hemiparesis.  Magnetic resonance imaging (MRI) should be conducted after 6 months of age to screen the high-risk neonate, who, by our experience, usually has V1 involvement that circumscribes the eyelid and often V2 extension as well.  In addition, ocular examinations should be undertaken to determine whether glaucoma is present with the syndrome.  Klippel-Trenaunay syndrome, or angio-osteohypertrophy, is characterized by a PWS that usually involves a unilateral, lower extremity marked by hypertrophy, varicose veins, lymphedema and phleboliths. ⁴⁸

 

            Venous malformations are characterized by a dark blue hue and may be situated in the skin, subcutaneous tissue, or mucosa.  They tend to be compressible and may have nodular areas that constitute phleboliths scattered throughout.  Lymphatic malformations, formerly known as lymphangiomas, typically arise in the head and neck.  They may be deeply infiltrative above the hyoid and more circumscribed in nature below the hyoid.  Arteriovenous malformations are principally found in the cephalic region and show signs of rapid arterial flow, including warmth and the presence of a bruit or thrill.  One of the most dreaded complications that may occur with this fast-flow lesion is high-output cardiac failure.

Current Therapy

            Vascular malformations represent a dissimilar group of disorders that mandate a treatment plan predicated on the vessel type(s) and related clinical manifestation.  Port wine stains represent the most common form of VM, and the extent of literature concerning PWS is commensurate to its prevalence.  Accordingly, most of the current treatment options that will be discussed focus on management of PWS.

Capillary Malformations (Port Wine Stains)

            Prior to the introduction of laser therapy, the only method of treatment for PWS was simply cosmetic camouflage.  Initially, the argon laser showed promise in the treatment of vascular diseases, but the incidence of scarring and the advent of the pulse-dye laser have largely relegated the argon to historical interest.  Now with the pulse-dye laser that selectively targets the vascular chromophore in PWS, patients have found a new hope in minimizing their deformity with little morbidity.  However, patients should be properly informed that their lesion will fade but not completely vanish with the pulse-dye laser.  Numerous studies have documented the proven reliability of the pulse-dye laser in treating PWS.*^49,50 Some studies have investigated the role of a 532-nm KTP laser in the treatment of resistant PWS and found clinical efficacy**⁵¹, but scarring has been reported with this laser type.**^51,52  Intense pulsed light has also proven to be highly effective and safe for the treatment of PWS according to one study.⁵³  The authors recommend discretion in the use of lasers other than the pulse dye, which is a proven and safe gold standard of therapy.

            Recent studies have emphasized the psychological aspect as much as the efficacy of treatment.^54,55,56,57  Most studies have demonstrated the ostracizing effects of the PWS and the benefit of intervention to the psychological welfare of the afflicted individual.  One small study contended that the patients in the series (n=9) revealed no subjective benefit to treatment despite objective physical improvement.⁵⁵   As the child matures, he/she not only confronts the psychosocial trauma of bearing the unsightly mark but also may develop a lesion that is more difficult to treat as age and hormonal factors darken and thicken the PWS.  For all these reasons, it is imperative to institute early laser therapy to counteract the detrimental psychological and physical forces and to continue therapy based on the responsiveness to the treatment and the tolerance and desire of the patient and family to undergo further cycles of therapy.

Other Vascular Malformations

            A comprehensive review of all the options that are available to cope with vascular malformations lies beyond the scope of discussion.  The mainstay of therapy for other types of vascular malformations remains complete surgical extirpation.  Incomplete attempts only make future surgery both necessary and more difficult and can foil any successful pre-embolization efforts.  Embolization for arteriovenous malformations should be seriously considered in order to minimize intraoperative blood loss as well as the extent and complexity of surgery.^**11  Patients should be counseled on the morbidity of embolization and surgery against that of no intervention and should weigh the options intelligently.

Conclusions

            Many advances have been made in the understanding and treatment of vascular anomalies, including improved laser therapy, knowledge of disease biophysiology, and sensitivity to the psychological repercussions on the child and family.  This progress has informed the timing and technique with which care givers have therapeutically intervened.  More active and earlier therapy has been administered to a select minority of hemangioma patients who demonstrate a rapidly proliferating hemangioma in a cosmetically sensitive area or that risks ulceration and hemorrhage or who show a late- involuting lesion that may not completely resolve and only serve to worsen the child’s psychosocial integration.  Port wine stains have been successfully treated with the pulse-dye laser and those afflicted with these lesions have been the favored subject of much psychological analysis.  Advances in all fronts are expected in the management of vascular anomalies and should alleviate the considerable burden of disease carried by the child and family alike.

References and recommended reading

1.  Mulliken JB, Glowacki J:  Hemangiomas and vascular malformations in infants and children:  a classification based on endothelial characteristics.  Plast Reconstr Surg 1982, 69:412-22

2.  Williams EF 3^rd, Stanislaw P, Dupree M, et al.:  Hemangiomas in infants and children.  an algorithm for intervention.  Arch Facial Plast Surg 2000, 2:103-11

**3.  Vikkula M, Boon LM, Mulliken JB:  Molecular genetics of vascular malformations.  Matrix Biol 2001, 20:327-35

**A study of the mutated genes, identified in families with vascular anomalies showing an autosomal-dominant inheritance pattern, and the role that these genes have in the regulation of angiogenesis.

4.  Walter JW, Blei F, Anderson JL, Orlow SJ, et al.:  Genetic mapping of a novel familial form of infantile hemangioma.  Am J Med Genet 1999, 32:77-83

5.  Metry DW, Herbert AA:  Benign cutaneous vascular tumors of infancy:  when to worry, what to do.  Arch Dermatol 2000, 136:905-14

6.  Mueller-Lessman V, Behrendt A, Wetzel WE, et al:  Orofacial findings in the Klippel-Trenaunay syndrome.  Int J Paediatr Dent 2001, 11:225-9

7.  Takahashi K, Mulliken JB, Kozakewich HPW, et al:  Cellular markers that distinguish the phases of hemangioma during infancy and childhood.  J Clin Invest 1994, 93:2357-64

8.  Soumekh B, Adams GL, Shapiro RS:  Treatment of head and neck hemangiomas with recombinant interferon alpha 2B.  Ann Otol Rhinol Laryngol 1996, 105:201-6

9.  Bauman NM, Burke DK, Smith RJ:  Treatment of massive or life-threatening hemangiomas with recombinant alpha(2a)-interferon.  Otolaryngol Head Neck Surg 1997, 117:99-110

10.  Illum N, Karlsmark T, Svejgaard E, et al.:  Ulcerated haemangioma successfully treated with interferon alfa-2b and topical granulocyte-macrophage colony-stimulating factor.  Dermatology 1995, 191:315-7

**11.  Simons ME:  Peripheral vascular malformations:  diagnosis and percutaneous management.   Can Assoc Radiol J 2001, 52:242-51

**A good review of the varied clinical aspects of vascular malformations and the pros and cons of interventional radiologic therapy.

12.  Pratt AG:  Birthmarks in infants.  Arch Dermatol 1967, 67:302-5

13.  Jacobs AH, Walton RG:  The incidence of birthmarks in the neonate.  Pediatrics 1976, 58:218-22

14.  Holmdahl K.  Cutaneous hemangiomas in premature and mature infants. Acta Paediatr 1955, 44:370

15.  Jacobs AH.  Strawberry hemangiomas:  the natural history of the untreated lesion.  Calif Med, 1957:86:8

16.  Margileth AM, Museles M.  Cutaneous hemangiomas in children:  diagnosis and conservative management.  JAMA 1965, 194:523-6

17. Amir J, Metzker A, Krikler R, et al:  Strawberry hemangioma in preterm infants.  Pediatr Dermatol 1993, 1:58-68

18.  Blei F, Walter J, Orlow SJ, et al:  Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait.  Arch Dermatol 1998, 134:718-22

19.  Burton BK, Schulz CJ, Angle B, et al:  An increased incidence of hemangiomas in infants born following chorionic villus sampling (CVS).  Prenat Diagn 1995, 15:209-14

20.  Stratte EG, Tope WD, Johnson CL et al:  Multimodal management of diffuse neonatal hemangiomatosis.  J Am Acad Dermatol 1996, 34:337-42

21.  Frieden IJ, Reese V, Cohen D:  P.H.A.C.E. syndrome:  The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities.  Arch Dermatol 1996, 132:307-11

22.  Lister WA, Camb MD:  The natural history of the strawberry nevus.  Arch Dermatol 1960, 59-71

23.  Enjolras O, Riche MD, Merland JJ, et al: Management of alarming hemangiomas in infancy:  a review of 25 cases.  Pediatrics 1990, 85:491-98

24.  Finn MC, Glowacki J, Mulliken JB:  Congenital vascular lesions:  clinical application of a new classification.  J Pediatr Surg 1983, 18:894-900

25.  Dieterich-Miller CA, Cohen BA, Liggett J:  Behavioral adjustment and self-concept of young children with hemangiomas.  Pediatr Dermatol 1992,9:241-245

26.  Dieterich-Miller CA, Safford PL:  Psychosocial development of children with hemangiomas:  home, school, health care collaboration.  Child Health Care 1992,21:84-89

27.  Kunkel EJ, Zager RP, Hausman CL, et al:  An interdisciplinary group for parents of children with hemangiomas.  Psychosomatics 1994, 35:524-32

28.  Magnus DJ: Continuous compression treatment of hemangiomata:  evaluation in two cases.  Plast Reconstr Surg 1972, 49:490-93

29.  Miller S, Smith R, Shochat S:  Compression treatment of hemangiomas.  Plast Reconstr Surg 1976, 58:573-9

30.  More AM:  Pressure in the treatment of giant hemangioma with purpura.  Case report and observations.  Plast Reconstr Surg 1964, 34:606

31.  Reischle S, Schuller-Petrovic S:  Treatment of capillary hemangiomas of early childhood with a new method of cryosurgery.  J Am Acad Dermatol 2000, 42:809-13

32.  Li FP, Cassady JR, Barnett E:  Cancer mortality following irradiation in infancy for hemangioma.  Radiology 1974, 113:177-8

33.  Al-Rashid RA:  Cyclophosphamide and radiation therapy in the treatment of hemangioendothelioma with disseminated intravascular clotting.  Cancer 1971, 27:364-8

34. Argenta LC, Bishop E, Cho KJ, et al:  Complete resolution of life-threatening hemangioma by embolization and corticosteroids.  Plast Reconstr Surg 1982, 70:739-44

35. Sarihan H, Mocan H, Yildiz K, et al:  A new treatment with bleomycin for complicated cutaneous hemangioma in children.  Eur J Pediatr Surg 1997, 7:158-62

36.  Barlow CF, Priebe CJ, Mulliken JB, et al:  Spastic diplegia as a complication of interferon alfa-2a treatment of hemangiomas of infancy.  J Pediatr 1998, 132:527-530

37.  Fost CF, Esterly NB:  Successful treatment of juvenile hemangiomas with prednisone.  J Pediatr 1968, 72:351-7

**38.  Bennett ML, Fleischer AB Jr, Chamlin SL, et al:  Oral corticosteroid use is effective for cutaneous hemangiomas:  an evidence-based evaluation.  Arch Dermatol 2001, 137:1208-13.

**A meta-analysis of 10 case series evaluating the efficacy of oral steroid therapy in the treatment of problematic hemangiomas.

**39.  Hohenleutner S, Badur-Ganter E, Landthaler M, et al:  Long-term results in the treatment of childhood hemangioma with the flashlamp-pumped pulsed dye laser:  an evaluation of 617 cases.  Lasers Surg Med 2001, 28:273-7

** A large series of children who demonstrated a high percentage of tumor regression or cessation of growth using the pulse-dye laser, a finding which was correlated with a patient questionnaire.

40.  Burstein FD, Simms C, Cohen SR, Williams JK, Paschal M.  Intralesional laser therapy of extensive hemangiomas in 100 consecutive pediatric patients.  Ann Plast Surg 2000, 44:188-94
41.  Sie KC, McGill T, Healy GB:  Subglottic hemangioma:  ten year’s experience with the carbon dioxide laser.  Ann Otol Rhinol Laryngol 1994, 103:167-72

*42.  Dinehart SM, Kincannon J, Geronemus R:  Hemangiomas:  evaluation and treatment.  Dermatol Surg 2001, 27:475-85

*A good comprehensive review article that addresses the relevant clinical aspects of the disease.

43.  Chang CJ, Achauer BM, VanderKam VM:  Reconstruction of head and neck hemangiomas with tissue expansion in the pediatric population.  Ann Plast Surg 1997, 38:15-8

44.  Enjolras O, Wassef M, Mazoyer E, et al:  Infants with Kassabach-Merritt syndrome do not have “true” hemangioma.  J Pediatr 1997, 130:631-640

45.  Powell J:  Update on hemangiomas and vascular malformations.  Curr Opin Pediatr 1999, 11:457-63

46.  Miller AC, Pit-Ten Cate IM, Watson HS:  Stress and family satisfaction in parents of children with facial port-wine stains.  Pediatr Dermatol 1999, 16:190-7

47.  Geronemus RG, Ashinoff R:  The medical necessity of evaluation and treatment of portwine stains.  J Dermatol Surg Oncol 1991, 17:76-9

48.  Dohil MA, Baugh WP, Eichenfield LF:  Vascular and pigmented birthmarks.  Pediatr Clin North Am 2000, 47:783-812

*49.  Namba Y, Mae O, Ao M:  The treatment of port wine stains with a dye laser:  A study of 644 patients.  Scand J Plast Reconstr Surg Hand Surg 2001, 35:197-202

*A study of a large series of patients who successfully underwent treatment of their port wine stains using the pulse-dye laser.  A good review of the different characteristics and response to laser therapy for PWS depending on the size and location of the lesions.

50.  Scherer K, Lorenz S, Wimmershoff M et al:  Both the flashlamp-pumped dye laser and the long-pulsed tunable dye laser can improve results in port-wine stain therapy.  Br J Dermatol 2001, 145:79-84

**51.  Chowdhury MM, Harris S, Lanigan SW:  Potassium titanyl phosphate laser treatment of resistant port-wine stains.  Br J Dermatol 2001, 144:814-7

**An interesting and objective study that reports improvement in pulse-dye laser resistant cases of PWS.  30 patients were evaluated using an erythemameter, videomicroscopy and photography.

52.  Chan HH, Chan E, Kono T, Ying SY, Wai-Sun H:  The use of variable pulse width frequency doubled Nd:Yag 532 nm laser in the treatment of port-wine stain in Chinese patients.  Dermatol Surg 2000, 26:657-61

53.  Angermeier MC:  Treatment of facial vascular lesions with intense pulsed light.  J Cutan Laser Ther 1999, 95-100

54.  Lanigan SW:  Acquired port wine stains:  clinical and psychological assessment and response to pulsed dye laser therapy.  Br J Dermatol 1997, 137:86-90

55.  Gupta G, Bilsland D:  A prospective study of the impact of laser treatment on vascular lesions.  Br J Dermatol 2000, 143:356-9

56.  Troilius A, Wrangsjo B, Ljunggren B:  Patients with port-wine stains and their psychological reactions after photothermolytic treatment.  Dermatol Surg 2000, 26:190-6

57.  Strauss RP, Resnick SD:  Pulsed dye laser therapy for port-wine stains in children:  Psychosocial and ethical issues.  J Pedatr 1993, 122:505-10.