Update on hemangiomas and vascular malformations ... - Springer Link

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Dec 4, 2008 - Abstract Although the current classification systems of vascular malformations and hemangiomas are increasingly accepted, there are ...
Eur Arch Otorhinolaryngol (2009) 266:187–197 DOI 10.1007/s00405-008-0875-6

REVIEW ARTICLE

Update on hemangiomas and vascular malformations of the head and neck Behfar Eivazi · Mircia Ardelean · Wolfgang Bäumler · Hans-Peter Berlien · Hansjörg Cremer · Ravindhra Elluru · Peter Koltai · Jan Olofsson · Gresham Richter · Bernhard Schick · Jochen A. Werner

Received: 4 November 2008 / Accepted: 10 November 2008 / Published online: 4 December 2008 © Springer-Verlag 2008

Abstract Although the current classiWcation systems of vascular malformations and hemangiomas are increasingly accepted, there are nonetheless several aspects that show us how special and at the same time diYcult it is to diagnose, evaluate, and treat some of those diseases. Close interdisciplinary cooperation of all involved disciplines is essential; the discussion of the adequate individual procedure must be performed in angioma boards, as it is already well established in the context of tumor boards. The interface of angioma therapy and tumor therapy seems to be very close, which is certainly true for the aspect of angiogenesis and of course for the inhibited proliferation as promising therapeutic approach of complex vascular malformations. This leads to another obvious necessity of intensifying experimental

scientiWc research on vascular malformations and hemangiomas, which is a precondition for optimizing or elimination of diVerent current problems and deWcits in the mentioned Weld.

B. Eivazi · J. A. Werner (&) Department of Otolaryngology, Head and Neck Surgery, Philipps University of Marburg, Deutschhausstr. 3, 35037 Marburg, Germany e-mail: [email protected]

R. Elluru · G. Richter Cincinnati Children’s Hospital, Cincinnati, OH, USA e-mail: [email protected]

M. Ardelean Clinic of Pediatric Surgery, Paracelsus Medical University, 5020 Salzburg, Austria e-mail: [email protected] W. Bäumler Department of Dermatology, University of Regensburg, 93042 Regensburg, Germany e-mail: [email protected] H.-P. Berlien Elisabeth Klinik, Abt. Lasermedizin, Lützowstr. 24-26, 10785 Berlin, Germany e-mail: [email protected] H. Cremer Netzwerk interdisziplinäre pädiatrische Dermatologie e.V. (NipD), Dittmarstr. 54, 74074 Heilbronn, Germany e-mail: [email protected]

Keywords Hemangiomas · Vascular malformations · OK 432 · EXIT · Angiogenesis

Introduction Vascular lesions are among the most common congenital and neonatal abnormalities [1, 2]. Until recently, there has been no standard classiWcation for vascular lesions that has

G. Richter e-mail: [email protected] P. Koltai Division of Pediatric Otolaryngology, School of Medicine, Stanford University, 801 Welch Rd, Stanford, CA 94305, USA e-mail: [email protected] J. Olofsson Department of Otolaryngology/Head and Neck Surgery, Haukeland University Hospital, 5021 Bergen, Norway e-mail: [email protected] B. Schick Department of Otorhinolaryngology, Saarland University Hospital, Kirrberger Str., 66421 Homburg, Germany e-mail: [email protected]

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been universally accepted. Even the treatment concepts of hemangiomas and vascular malformations (VMs) are often discussed controversially. Furthermore, only very few centers focus on the treatment or the research of vascular lesions of the head and neck. With this background, it seemed imperative to emphasize and discuss the current knowledge, controversies, and perspectives of the mentioned Welds in the context of a symposium on hemangiomas and VMs of the head and neck with world experts in attendance. The meeting was held in Marburg, Germany, February 22–23, 2008. Most important aspects of the symposium were summarized and published on the basis of the current literature. An introduction to the topic was given by H.-P. Berlien who presented the classiWcation of congenital vascular tumors and malformations. H. Cremer analyzed the special topic of segmental hemangiomas and focused on the poorly understood PHACE syndrome. As the meeting progressed, it became more and more obvious that special centers should be established for the diagnosis and therapy of hemangiomas and VMs of the head and neck, a fact emphasized by J. Olofsson, the current president of the European Federation of OtoRhino-Laryngological Societies (EUFOS). A good example for this is the referral of a fetus with an extended vascular lesion and airway compromise to highly specialized centers described by R. Elluru. The experience of the Cincinnati Children’s Hospital in the Weld of EXIT procedures are considered outstanding. W. Bäumler elaborated current concepts of laser therapy. Special aspects on surgical esthetics were discussed by P. Koltai. A description of the use of OK 432 in the treatment of vascular lesions was provided by M. Ardelean. G. Richter gave a sound perspective on future developments in the Weld of vascular anomalies. Giving a broader perspective to the Weld, B. Schick presented some conclusions on the treatment of juvenile angioWbroma that may be useful for consideration also in the treatment of hemangiomas and VMs. ClassiWcation of congenital vascular tumors and malformations The general term “hemangioma” covers a series of completely diVerent hereditary vascular anomalies. To determine the therapeutic procedure—active or restrained—early diVerentiation is essential. Any classiWcation therefore has to answer the three central questions: what, where, and how. The “Hamburg classiWcation” has become the standard procedure for classiWcation of VMs [3]. Because of the diYcult diVerential diagnosis sometimes, a classiWcation of congenital vascular tumors should be modeled accordingly. Infantile hemangiomas (IHs) are proliferating embryonal tumors that possibly stem from placental tissue or resemble it (they are GLUT 1-positive) and have to be classiWed according to stage, growth pattern, appearance, and organ speciWcity. The prodromal phase of IH only appears days or

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weeks after birth. Color-coded duplex sonography (CCDS) does not yet provide a typical result, but a ballooning of the dermal double lamina structure. In the early or initial phase, IH may partially appear within a few days. Depending on the type of growth, they are diVuse, inWltrating the surrounding tissue or, in case of limited growth, are sharply demarcated. By CCDS, often only a diVuse hyposonic structure will be seen without visible vessels or capillarization. During the proliferation phase, a cutaneously located IH proliferates at a diVerent pace while spreading in size, by exophytic or endophytic subcutaneous growth. With CCDS, hypercapillarizations can now be seen: the stronger they are, the more active the proliferation of the hemangioma. Thus, CCDS is the only method with which to dependably check the activity and aggressiveness of an IH. A maturation phase follows in which proliferation comes to a halt. CCDS shows that microcirculation decreases and drainage veins are formed. The regression phase is usually Wnished by the sixth birthday in cutaneous localized hemangiomas faster than in diVuse inWltrating cutaneous or subcutaneous hemangiomas. CCDS is now hypersonic as an expression of a Wbrolipomatous transformation. Even though a single site is the rule, if there are more than three IH, an ultrasound should be performed to identify occult hemangiomas, particularly in the liver. Strongly vascularized hemangiomas of the ears often cause hypertrophy of ear growth and cartilage destruction. A relocation of the ear canal may trigger infections due to Xuid retention and secondary deafness. This is why all IH of the ear, peri- and preauricular, require otoscopy. Similar precautions have to be taken for the nose with the consequence of skeletal malformations or obstruction of nasal breathing. Perioral localization can hamper food intake, lead to permanent deformation of lips and in extreme cases to abnormalities of the lower jaw and irregular dentition. In perioral localization and involvement of the mucous membranes of the oropharynx or the pretracheal skin, tracheal involvement must be excluded. In IH in the face, residues can lead to functional impairment depending on their size and extension. Here, it is important to initiate by active treatment the regression phase as early as possible. Congenital hemangioendotheliomas (CHEs) are a real GLUT-1-negative vascular tumor and not part of the IH and are classiWed according to their progression, growth pattern, appearance, and organ speciWcity. Depending on their proliferation pattern, entirely diVerent forms must be diVerentiated before establishing the indication for any therapy. During healing, spontaneously or following therapy, they all show the same picture: atrophy of the subcutis and cutis laxa. The rapidly involuting CHE (RICH) is totally matured prenatally and should be clearly diVerentiated from an IH. Contrary to RICH, the noninvoluting CHE (NICH) may be only sparsely developed at birth. CCDS in NICH

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reveals—besides lobular hypersonic areas—arteries and veins running vertically to the surface, and thermography shows a clear but rather weak hyperthermia. As long as NICH is still active, transition to a Kaposi-like hemangioendothelioma (KHE) is possible at any time with the formation of a Kasabach–Merritt syndrome (KMS). The KHE is at birth similar to NICH, but a tough inWltration besides erysipelas (“wasp sting symptom”). Color-coded duplex sonography clearly shows an increased microcirculation, which is not located at the center, as in active IHs, but at the lobuli divided by septa. IH of the face and head may be associated with malformations of the central nervous system, the intra- and extracranial arteries, the heart, the eyes, and sternal clefting (PHACES syndrome). DiVuse growing, inWltrating IHs of the face are described as “segmental” by some authors, although they follow neither dermatome nor nerve supply patterns. This view fails completely for the extremities, the body and the anogenital area, although proliferation in these regions does not diVer from the face. The expression “syndromal hemangiomas” for these IHs is erroneous, and suggests that they form a separate entity of hemangiomas. In reality, these IH do not diVer in their phases or proliferation from other sites or in their relation to organs, but only in their biological activity. KMS does not appear in IH, even in extended complicated IH, but only in KHEs. Both have to be diVerentiated from arterial, venous, lymphatic, and combined VMs, including glomangiomas and the systemic congenital glomangiomatosis such as hamartomatous abnormalities. They show no spontaneous regression but rather steady growth, with the exception of the abortive forms of port-wine stains such as Unna’s nevi, certain forms of cutis marmorata telangiectatica, and isolated monocytic lymphangiomas of the neck such as hygroma colli. VMs have to be classiWed according to their growth pattern, appearance, and organ speciWcity, but also according to embryological disorder and their predominant vascular origin. This means that a common feature of all congenital vascular abnormalities is that they can appear in all organs and regions of the body. Another joint feature is that they can appear in a singular, multiple, or disseminated forms and may vary in their growth pattern, with welldemarcated to diVuse inWltrating shapes. In principle, the techniques of laser applications in congenital vascular tumors and in VMs are similar. Because of the potential for regression in congenital vascular tumors, the aim of laser therapy is only to induce this regression, while in VMs the pathologic vessels must be destroyed. However, with exception of laser vaporization, all photobiological reactions have a delayed eVect. On the other hand, the attitude for VMs is that they should be radically excised like cancers, as they have a high incidence of recurrence and there is always the danger of massive bleeding and the need for

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extensive resection causing mutilation. The wide variety of clinical presentations for these anomalies makes it diYcult to outline speciWc management programs. It is important that the appropriate laser and application form be used. Therefore, treatment of these diYcult vascular lesions must be carefully individualized. While laser treatments in capillary malformations are the Wrst choice therapy, in some arteriovenous (a-v) malformations embolization is the Wrst choice therapy. In venous and lymphatic malformations, laser therapy can be understood as a supplement to surgical excision and sclerotherapy. Segmental hemangiomas of the head and neck Segmental hemangiomas (SHs) are much rarer but—when located in the head area (>50%)—considerably more problematic than localized hemangiomas (LHs). While LHs originate from a central point, the growth of SHs follows developmental segments (Fig. 1), in most cases complying strictly to segmental borders [4]. Segmental hemangiomas in the facial area should immediately be treated with corticosteroids (at the beginning Prednisolone 3–5 mg/kg), then with slow reduction. Total therapy time is about 3–6 months. Generally, laser should only be used in combination with Prednisolone because of increased danger of ulceration. Complications in segmental hemangiomas in the head area are mostly ulcerations. Rarely functional disturbances may also occur, which then have severe consequences. Segmental hemangiomas in the eye area can cause functional blindness. Segmental hemangioma in the chin (“beard”) area or the upper frontal part of the chest are quite often combined with tracheal involvement with associated subglottic hemangiomas in the respiratory tract, which can lead to life-threatening breathing problems. At the slightest signs of breathing diYculties, endoscopy has to be performed. Alarming signs are “noisy breathing” or biphasic stridor and failure to thrive. In such cases, early endotracheal CO2 laser therapy combined with systemic corticosteroids is strongly recommended [5], while also other treatment strategies of subglottic hemangiomas may have very good results. PHACE(S)-syndrome Segmental hemangiomas in the head area are often combined with cerebral, ophthalmological, and/or cardiac malformations [PHACE(S)-syndrome]. PHACE(S)-syndrome stands for as follows: P = posterior fossa malformation; H = segmental hemangioma; A = arterial anomalies; C = co-arctation of aorta; E = eye malformations; S = cleft sternum. Not all of these symptoms have to be present. All

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Fig. 1 Infant suVering from a segmental hemangioma (Segment 1) with PHACE syndrome (a). The segments are divided according to Haggstrom et al. [4] (b). c Segmental hemangioma in the beard area (Segment 3) with tracheal involvement

patients with segmental hemangiomas in the head area should undergo sonographic and NMR examinations to exclude PHACE(S)-syndrome. There is a marked dominance of the female gender (about 90%). Possibly there is a X-chromosomal inheritance with lethality of the male sex. Prognosis depends on severity of symptoms. Neurological complications with developmental retardation are not unusual. These patients should be treated and supervised by an interdisciplinary team including pediatricians, neurologists, dermatologists, surgeons, and ophthalmologists. Advanced vascular malformations of the head and neck—is it appropriate to establish specialized centers? Vascular lesions are among the most common congenital and neonatal abnormalities. We have been handicapped by a confusing nomenclature during many decades. The Wrst anatomopathologic classiWcation of vascular lesions as angiomas and lymphangiomas was developed by Virchow and Wegner based on the microscopic appearance into simple, cavernous, and racemic [6, 7]. Mulliken and Glowacki [8] developed a biological classiWcation of vascular anomalies including physical Wndings, clinical behavior, and cellular kinetics into hemangiomas and VMs. Current classiWcation aspects are mentioned in the introduction of the present review. A search in Pubmed (February 19, 2008) yielded 26,406 references to VMs, 8,032 to vascular anomalies, and 289 to VM/classiWcation. The treatment is not so controversial for VMs as for hemangiomas. VMs do not have any spontaneous involution. Laser treatment, embolization followed by surgery, and the use of OK-432 are commonly used. The treatment modality depends on the perfusion and depth of the VM. An important topic for discussion is collaboration within Europe when dealing with rare diseases like hemangiomas and VMs. Few centers in Europe now with about 450 million inhabitants may gain enough numbers of patients to achieve optimal training and expertise to handle these partly very complex patients. Centers of excellence should be created, which should stimulate collaboration, be open

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for discussion of diYcult and advanced cases, and thereby serve as fourth referral centers to provide these children with an optimal initial treatment plan. This may be valid for diVerent rare diseases not only in ORL-HNS. We might, however, take this seriously and do it professionally and perhaps be forerunners in health care organization in the future. Lasers and blood vessels Lasers have been used for more than 40 years to treat vascular disorders. The concept of selective photothermolysis led to the development of the Xash lamp pulsed dye laser (FPDL) to treat cutaneous vascular disorders such as port wine stains (PWS) [9]. Three important laser parameters turned out to be important for a safe and eYcient treatment: wavelength, pulse duration, and radiant exposure (J/cm²). Firstly, the laser light should be selectively absorbed in hemoglobin inside the vessel. This chromophore absorbs in the spectral range of about 400–1,100 nm with maxima at about 400, 580, and 1,000 nm. Secondly, the pulse duration of the laser should be adjusted to the size of the vessel to conWne the heating to the vessel itself. Thirdly, the radiant exposure should be suYcient to heat up the entire vessel to 70°C at least. This parameter is diYcult to adjust, because exact dosimetry of laser radiation ends at the surface of the tissue. Tissue is an optically turbid media and it is a big challenge to describe the propagation of laser light in tissue. The latter is a major prerequisite to perform laser light dosimetry and to optimize laser therapy of blood vessels. When laser light penetrates tissue, the photons are either absorbed or scattered. That is, inside tissue the scattering eVects disperse the laser beam that is applied to the tissue surface. However, it is important to know how many photons reach a blood vessel inside tissue, which should be coagulated. Then, the number of photons absorbed in the hemoglobin of the vessel determines the likelihood of coagulation. In addition, scattering causes a limited penetration depth of light into tissue that depends clearly on the wavelength. The penetration of light, i.e. a suYcient number of

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photons to cause coagulation, is about 1.5 mm for 585 nm but about 5 mm for 1,064 nm, as proven by histology. Various mathematical models have been developed to predict which lasers parameters should be used to achieve high eYcacy in laser treatment of blood vessels [10]. Light propagation in a turbid medium such as human tissue can be modeled through an analytical solution of the diVusion theory and/or Monte Carlo (MC) simulations. MC simulation is an accurate and Xexible method for modeling photon propagation within heterogeneous mediums; it predicts the movement of photon packages within the medium via statistical analysis. The probability that photons will be scattered, absorbed, or transmitted at each point of time and space is calculated through density function. Alternatively, the photon distribution can be calculated, through the diVusion approximation model. The fundamental assumption in this approach is that unscattered light propagates through a turbid medium, is scattered, and becomes diVuse, creating a new source of diVuse light that propagates through the tissue as in a diVusion process. Meanwhile, the eVect of vessel size and location on response to laser treatment of PWS can be studied by using a new mathematical model that allows calculating the temperature proWle as function of time and space throughout individual vessels of diVerent sizes. The diVusion approximation was used to calculate the photon distribution, and in addition, the simultaneous solving of the heat equation (using Wnite element method, FEM) yields the temperature values inside tissue and in particular blood vessels [11, 12]. Depending on the size of the vessels, diVerent lasers and parameters are predicted and are already used clinically. Small vessels (less than 20 m in diameter) are usually spared from destruction in all kinds of laser treatment. This is caused by an insuYcient temperature increase inside the vessels due to the small number of light-absorbing red cells (hemoglobin). For vessel diameters ranging from 20 to 200 m, visible laser light is applied using frequency-doubled Nd:YAG Laser (532 nm) or FPDL (580–600 nm). The light penetrates the tissue up to 1.5 mm and can coagulate these vessels using pulse durations of 0.5–20 ms. The application of these laser systems yields a reasonable outcome for the treatment of vascular lesion such as PWS, facial teleangiectasia, or hemangioma. Laser light at 400 nm (highest absorption of hemoglobin) is not used in clinical practice, since the penetration of light in this spectral range is limited to less than 0.5 mm. For the treatment of large vessels (0.2–2 mm), near infrared laser light (pulse duration 10–100 ms) is used in clinical practice. Here, the low absorption of infrared light in hemoglobin is compensated by the higher amount of red cells as compared to the small vessels. Because of the large diameter of such vessels and the high absorption coeYcient,

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laser light in the visible spectral range (500–650 nm) would not penetrate the entire vessel leading to incomplete vessel coagulation. Therefore, lasers are used emitting infrared radiation like Nd:YAG laser (1,064 nm) [13]. At this wavelength, light is penetrating the vessel on the one hand, and a suYcient amount of energy is absorbed by the high number of red cells inside the vessel on the other hand. Consequently, the entire vessel can be destroyed, even in deeper areas of the tissue, since the infrared light is penetrating much deeper as compared to the visible light [14]. Surgical esthetics in vascular and lymphatic malformations A surgeon involved in the care of children with vascular and lymphatic malformations is often asked to render judgments about “deformities,” which are considered unattractive. The surgeon may act on those judgments, with the goal of rendering the child more beautiful, probably giving more thought to the craft than to what beauty means. This is not just a consequence of his personal interest but is also a characteristic of our species as a whole: humans have an innate sense of what a beautiful face should be, a knowledge that operates at a subconscious level and drives our eyes, minds, and hands to implement that intuition. Fascination with the human face is universal and has ancient roots in philosophy and art. Plato used the Pythagorean “golden ratio” to deWne the “golden proportions” in which, the width of an ideal face would be two-thirds its length, and a nose would be no longer than the distance between the eyes. Leonardo da Vinci, in his many artistic explorations, identiWed the “golden ratio” among human facial and bodily proportions as the key to beauty. There are many objects that are beautiful to the human eye that conform to the golden ratio; however, the human face, during its trajectory of development, is not subject of this interesting concept. Facial maturation is a process of absolute growth as well as proportional change, and it is these proportional changes that defy easy mathematical analysis. Nevertheless, the concept of proportion seems intuitively important as a fundamental aspect of facial esthetics. In the observations of children, consistency of proportion within similar age groups is what deWnes attractiveness. The contemporary nomenclature for this concept of consistency of proportions is “averageness,” suggesting a cultural inXuence on what is seen as beauty. The implication of this requires consideration of how surgical intervention can alter the arc of growth. A second intuitive aspect of beauty is symmetry. There is a large amount of literature on this subject: simply put, evolutionary theory holds that symmetrical faces are more attractive, hence more likely to be reproductively successful. On the other hand, psychological research has shown that the impact of asymmetry is a matter of degree. All of

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us have minor asymmetries, which have little bearing on attractiveness. However, major disproportions between the two sides of the face are noticeable and are generally considered unattractive. The surgical corollary to the value of symmetry is the importance of the normal side as the template for reconstruction. Along with averageness and symmetry, sexual dimorphism is the third well-established facet of a biologically based standard of beauty. However, in children, gender diVerentiation is not yet a signiWcant esthetic factor. Then again, function, which seems to me to be very important in any consideration on facial esthetics, is surprisingly not stressed in the “biological basis of beauty” literature. The human face has many vital and phylogenetically ancient functions: sight, sound, touch, taste, smell. Movement is just as old and just as important from an esthetic perspective. Movement facilitates communication, conveys emotion, and expresses the spirit that is in each of us. Movement also reinforces the perception of proportion and emphasizes symmetry, strengthening their value. The surgical insight that this demands is an understanding and respect for the complex and unpredictable relationship between the facial nerve and the congenital lesions that aZict the face of children. There is logic to beauty. It is clear that the human eye has a keen appreciation of proportion, symmetry, and movement. It indicates health, the likelihood of successful mating, and the creation of healthy oVspring. Beauty seems to be “hardwired” into the human brain by natural selection. Our challenge as surgeons is to understand how the eye Wnds beauty and how we can bend this knowledge to the will of our hands. Further information can be found in the appended reference list [15–20]. Current value of OK 432 in lymphangiomas Lymphangiomas although benign lesions give complications by expanding into surrounding structures. Lymphangiomas of the head and neck may cause alteration of vision, breathing, swallowing, or even disWguration. The genesis of lymphangiomas is still not Wnally clariWed [21]. In recent times, molecular research on lymphangiomas is increasingly performed [22] to probably Wnd new therapeutic approaches. Aggressive surgery in lymphangiomas associates signiWcant morbidity as nerves and vessels lesions. “In toto” excision is possible only in about 40% of the cases. To overcome the functional deWcit and cosmetic disappointing results, alternative therapies as laser therapy, and sclerosing therapy became more common in the last years. The use of bleomycin, cyclophosphamide, Wbrin glue, and alcohol (Ethibloc) has limited success. Sclerotherapy with OK-432 was introduced by Ogita et al., in 1987, to treat unresectable lymphangiomas [23].

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OK-432 (Picibanil, Chugai Pharmaceutical, Tokyo) is a biological preparation of lyophilized cells of Streptococcus pyogenes (Group A, Type 3, Su strain) treated with benzylpenicillin. It has been used initially as immunotherapy for malignant tumors. An intracystic injection of OK-432 produces a local inXammatory reaction, which leads to resolution of the lesion. The white blood cells induced and activated by OK-432, and the cytokines produced by these cells increased the endothelial permeability, and thus the accelerated lymph drainage and increased lymph Xow led to shrinkage of the cystic spaces. To prepare the solution to be injected, 0.1 mg of OK-432 is diluted in 10 ml of physiological saline (0.9%). So each milliliter of solution contains 0.01 mg of OK-432. At Wrst injection, the patient is generally admitted for 24 h because of possible penicillin allergy. A topical anesthetic (EMLA) is applied at the puncture place 1 h preoperative. The procedure is done in the operating room mostly under anesthesia and ultrasound guidance. In macrocystic lesions, after punctation of the cyst, the intracystic Xuid is aspirated and through the same needle (18–22 gauge) OK-432 solution is injected. The aspirated Xuid will be replaced by the same quantity of OK-432 solution up to 10 ml (0.1 mg). In the case of bigger cysts, all Xuid will be aspirated, but not more than 10 ml OK-432 solution will be injected at the Wrst therapy. If there is not suYcient shrinkage a second injection follows 5–6 weeks later: up to 20 ml OK-432 (0.2 mg) will be injected if necessary. In microcystic lesion, OK-432 solution is injected into the lesion at few sites until the lesion expands slightly. Our recent experience comprises nine children with head and neck lymphangiomas treated by sclerotherapy with OK-432 from August 2000 till April 2007. There were six boys and three girls. The youngest patient was 10 days, and the oldest 13 years old at the Wrst injection. The lesions were of macrocystic type in six and mixed (macro- and microcystic) in three patients. Lymphangiomas were cervical-axillar unilateral in four, cervicofacial giant (up to 30 £ 15 cm) in two patients, cervical-axillar bilateral, mediastinal, pulmonary, splenic and upper extremities lesions in one, cervicofacial bilateral inWltrating the tongue and mediastinum in one, and orbital in one patient. Six patients were treated by injection therapy with OK432. Other three children underwent a combined therapy consisting of partial surgical resection and OK-432 intralesional injections. The resection was done before and after injections in two patients, and only after sclerotherapy in one patient. In both patients having surgery before sclerotherapy the lesions recurred; in one of them, lymphangioma became even bigger after surgery. One of operated patients was a girl with cervicofacial bilateral lesions, inWltrating the tongue and mediastinum. The cervicofacial and mediastinal lesions markedly regressed after injection. Because of

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only moderated regression of the tongue (microcystic type lymphangioma), a wedge resection under tracheostomy was necessary. Near total/total shrinkage after two to three injections was achieved in the seven patients: six with macrocystic type and one with mixed type lymphangioma. Other two patients with mixed form lymphangioma had a regression of 75–80% of their lymphangiomas. The adverse reactions of OK-432 injection are fever, which subside with antipyretic drugs, local swelling, and redness of the skin. Other side eVects are general malaise, anorexia, and nausea. Because of postinjectional swelling, injection of lymphangiomas surrounding the airways may be hazardous [24]. In such cases, children must be admitted and followed 2–3 days after injection. The macrocystic forms of lymphangioma respond well to sclerosing therapy with OK-432. It is our experience that OK-432 is eYcient in up to 90% of macrocystic forms of head and neck lymphangioma. The response may be good (more than 50% regression) also in microcystic types. Previously, the published results [23, 25, 26] showed with some exceptions [24, 27] the same good results, but also the authors of [27] recommend OK-432 injection therapy alone for macrocystic types and surgical excision after pretreatment with OK-432 for microcystic types. Resection of the remaining tumors, necessary mostly in microcystic forms, proved to be easier, after partial shrinkage induced by OK-432. In conclusion, OK-432 injection is an eYcient therapy for macrocystic forms of head and neck lymphangiomas. OK-432 injection combined with partial resection seems to be a good choice to treat the extensive microcystic lesions. Future investigations will have to show to what extent other substances such as e.g. tetracyclins may achieve good longterm results in the treatment of lymphangiomas [28]. Current value of EXIT procedure in giant malformations One of the most challenging diagnostic and treatment situations that can arise in the Weld of vascular anomalies is intrauterine identiWcation of a fetus with large cervical mass. The challenges are twofold: (1) to determine the nature of the cervical mass and how it will impact the longterm survival of the fetus; (2) to determine if the cervical mass compromises the airway and how to manage the baby during delivery. Adding to these clinical challenges are the risks to the health and well being of the mother. At Cincinnati Children’s Hospital, when suspicion of a fetal cervical mass arises, the mother is referred to the fetal surgery program. The fetal surgery program is a multidisciplinary team composed of pediatric surgeons, otolaryngologists, obstetricians, neonatologists, geneticists, cardiologists, and radiologists. The team approach is invaluable, as it

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optimizes communication and aVords the optimal assembly of expertise and technical resources. Furthermore, parents can be given a diagnosis and comprehensive treatment plan in a single clinical setting. The goal of the team should be to assess and treat both the mother and the fetus. The two most common causes of a cervical mass in a fetus are teratomas and vascular anomalies [29]. Obtaining a speciWc diagnosis prior to delivery of the fetus can be very diYcult [29, 30]. Typical diagnostic test utilized include a high resolution ultrasound and/or an ultrafast magnetic resonance imaging (MRI). These radiological modalities allow evaluation of fetal anatomy and tissue characteristics of the cervical mass. Findings of polyhydramnios, absence of a stomach bubble, and loss of airway patency suggest a large cervical mass. Cervical teratomas are usually midline, composed of both solid and cystic components, and frequently contain calciWcations. Vascular anomalies are predominantly cystic, enhance with contrast on MRI, and are usually localized to the lateral neck [29, 30]. Distinguishing between a cervical teratoma and a vascular anomaly prior to delivering the baby can be of critical importance, as a fetus born with a vascular anomaly can have life-threatening comorbidities [29]. SpeciWcally, large vascular anomalies can cause congestive heart failure and fetal hydrops, and can have signiWcant associated coagulopathies [31]. Coagulopathies should be anticipated before delivery so that appropriate resuscitative measures can be planned and administered immediately upon birth. The ex-utero intrapartum treatment (EXIT)-to-airway procedure is a technique used to deliver a fetus with a large cervical mass and impending airway compromise. The general principle of the procedure is to partially expose the fetus from the uterus, keeping intact uteroplacental circulation to allow oxygen delivery to the baby until an airway can be established [32, 33]. Uteroplacental circulation is maximized by maintaining uterine relaxation, and maintaining maternal blood. The priorities for the EXIT procedure are the safety of the mother and establishing a fetal airway [32, 33]. The EXIT procedure is not the equivalent of a Caesarean (C)-section. C-sections involve minimal anesthesia time, to avoid fetal anesthetic exposure and newborn cardiac depression [32]. Additionally, in a C-section, the goal is to maintain uterine tone to prevent maternal hemorrhage. In contrast, EXIT procedures require some fetal anesthesia as well as fetal analgesia [33]. Furthermore, anesthesia is maintained fairly deep to allow uterine relaxation, despite the increased risk of maternal hemorrhage. The key to success of the EXIT to airway procedure is planning. The airway is established by proceeding through a carefully planned algorithm [33]. The algorithm begins with consideration of direct laryngoscopy, Xexible bronchoscopy, rigid bronchoscopy, tracheotomy with or without

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retrograde intubation, or resection of the cervical mass to allow a tracheotomy. Planning includes review of the radiological exams, a team approach to discussing the airway anatomy and airway management algorithm, and assembly of all needed equipment and personnel. The majority of babies, even with large cervical masses, can be intubated using an endotracheal tube with a stylet under direct laryngoscopy [33]. All airway management options have intrinsic advantages and disadvantages, and require expertise. The advantage of rigid bronchoscopy with a telescope is that the larynx can be visualized directly. If an endotracheal tube has been placed over the telescope, the endotracheal tube can be slid over the telescope into the tracheal airway under direct visualization. The disadvantage of a rigid telescope or a ventilating bronchoscope is that these instruments require a straight view of the larynx from the mouth. Flexible bronchoscopes allow direct visualization of the larynx and can be navigated through a tortuous upper airway. However, entering the larynx with a Xexible bronchoscope in a child with abnormal anatomy can be technically diYcult [33]. Other options in airway management include a tracheotomy, though this can be quite challenging in a child with a large cervical mass. In some cases, the cervical mass may need to be excised prior to performing the tracheotomy. Fetal cervical anatomy can be confusing because of the small caliber of structures, and distortion of structures and hyperextension of the neck caused by the mass. A temporary tracheotomy can be used to perform a retrograde intubation if the clinical situation dictates [33]. In conclusion, the EXIT to airway procedure provides a means for successfully delivering a fetus with a large cervical mass and avoiding potential airway compromise. The EXIT to airway technique converts a possible catastrophic emergency into a controlled planned procedure. The indications for EXIT procedures are expanding and are continually being reWned. Finally, EXIT procedures are best executed using a multidisciplinary approach. Future treatment concepts for hemangiomas and vascular malformations Despite the classiWcation system for vascular birthmarks described by Mulliken and Glowacki [8], the scientiWc Weld of vascular anomalies remains relatively nascent. A glance at the literature demonstrates that nearly 60% of articles pertaining to vascular anomalies are either case reports or clinical series. The remaining majority are retrospective reviews with fewer than 6% of studies dedicated to prospective investigation (5%) or basic science (