Vasoform Neoplasms and Other Lesions : Part I
Hemangioma and Vascular Malformations
Despite the fact that a sensible biological classification system based on studies correlating physical findings, natural history, and cellular features was described by Mulliken and Glowacki in 1982,1 the confusion in the literature with regard to these lesions has been considerable and the terminology remains a problem among a whole generation of physicians and surgeons.
There are only two major types of vascular lesions: (1) tumors and (2) malformations. The term “hemangioma” is still all too frequently used indiscriminately and incorrectly and applied to vascular lesions that are completely different in behavior and histopathology. Perhaps the worst “culprit” is the term “cavernous hemangioma,” which is usually a venous malformation and only very rarely a deep hemangioma.
Hemangiomas Versus Vascular Malformations
There is continuing controversy between some clinicians and pathologists over the difficult issues involved in separating hemangiomas from vascular malformations. Essentially, hemangiomas are composed of excessive amounts of proliferating benign endothelial cells, producing vascular channels that are similar to normal blood vessels. There is a pericyte around each of these endothelium-lined channels but there are simply too many vessels per unit area in comparison with normal tissue. In contrast, vascular malformations, which have in the past often had the term hemangioma applied to them, are not proliferative lesions but are due to abnormal developments of blood vessels. While they may hypertrophy over a period of time and thereby enlarge, they are not actually neoplastic. These malformations may comprise a single type of vessel (capillary, arterial, venous, lymphatic) or be a combination. Malformations with an arterial component are usually fast-flow, while the other types are slow-flow.
While hemangioma is by far the most common vascular tumor, with ~60% occurring in the head and neck, almost entirely in infants, other rarities include tufted angioma, glomangiopericytoma, angiofibroma, and angiosarcoma.
Very rarely there are exceptions to this clear classification scheme. For example, a “pyogenic granuloma,” which is correctly a small acquired vascular tumor, may occur in an area of capillary or venous malformation.
Papillary Endothelial Hyperplasia
Another vascular variant is endothelial hyperplasia, which may occur as a consequence of stimulation by trauma, ischemia, clotting, embolization, or hormonal influences and can develop in normal vessels anywhere in the body. It has been described in the paranasal sinuses.2 It is a completely benign process and is essentially a distinct form of organizing thrombus that is covered by a thin layer of benign endothelial cells and contains multiple hyaline nodules. It is treated effectively (if necessary) by simple local excision.
Hemangiomas
While the purpose of this book is to describe conditions of the nose and paranasal sinuses, many hemangiomas and vascular anomalies extensively involve the head and neck, covering many anatomical areas. History and careful examination of the head and neck can distinguish between vascular tumors and vascular malformations in over 90% of cases. Imprecise and incorrect terminology must be avoided.
The site, incidence, and clinical features of a particular hemangioma depend on the subtype of hemangioma.
Capillary hemangioma
Hemangioma of infancy
Acquired lobular capillary hemangioma
Cherry “senile” hemangioma
Acquired “tufted” angioma
Intramuscular angioma
Vascular malformations
Venous
Lymphatic
Capillary
Hemangioma of Infancy
Approximately 60% of these lesions occur in the head and neck and they are up to 3 times more common in females than males.3 The commonest site in the upper airways is the subglottic portion of the larynx and this may result in stridor and life-threatening airway obstruction.4 Hemangiomas of infancy have also been reported in the sinonasal tract5,6 and on the dorsum of the nose.7
Diagnostic Features
Clinical Features
These lesions appear at, or shortly after, birth and are the most common tumor in childhood. Single lesions are most common but multiple lesions occur in up to 20% of cases. The lesions progress rapidly, forming prominent, reddish purple nodules that achieve a somewhat rubbery texture as they enlarge (“strawberry” nevus). These lesions begin to regress spontaneously in most cases after the age of 1 year, although this may occur earlier. About half of all patients will have almost complete regression of the lesion by 5 years and virtually all by 12 years of age.8 The clinical history of these patients is an important aspect in the clinical diagnosis and usually contrasts significantly with other vascular malformations that may be present at birth but have no sex predilection and grow or hypertrophy slowly, without any tendency to involution.
The onset and cause of involution in hemangiomas does not seem to be influenced by the time of onset or duration of the proliferative phase, or by sex, race, site, or overall duration.
Hemangioma of infancy has been associated with multiple cervicofacial hemangiomas.9 Multiple hemangiomas of infancy may also be associated with visceral hemangiomatosis.10
Imaging
Imaging of these hemangiomas does not show any particular features of note other than those of an enhancing soft tissue mass, but it does allow evaluation of the extent of the lesion and some differential from the more typical pathognomonic imaging features of other types of vascular malformations.
Histological Features
Grossly, these lesions vary from tan through red to purple, irregular nodules that are separated from the adjacent dermal and subcutaneous tissues. Initially, during the growth phase, they are composed of cytologically bland, short, spindled cells that are endothelial cells and pericytes forming tight groups of capillaries with minimal lumina. There is obvious mitotic activity and often a prominent, overall “jigsawlike” pattern. There may be associated mast cells within an inflammatory component.
As the lesions mature, the lumen of the vascular channels become more obvious but fibrosis and reduction of the number of vessels commences. Over the long term, with increasing fibrosis, the end result is a fibrofatty residual structure with varying numbers of scattered capillaries.
Immunohistochemical Features
Considerable additional help in diagnosis has been provided by the finding that the cells of hemangioma of infancy characteristically express glucose transporter protein isoform I (GLUT-1).11 In addition, the pericytes around the endothelium-lined channels are positive for SMA (smooth muscle actin).
Differential Diagnosis
The main area of difficulty with hemangioma of infancy, is where it requires separation from so-called “cavernous hemangiomas,” of which the vast majority are venous malformations that clinically do not have the striking appearance of the fully developed hemangioma of infancy and whose dilated large vascular channels with mitotically inactive epithelial cells do not show signs of resolution and do not exhibit expression of GLUT 1. Glomangiopericytomas may occur in infancy but strong GLUT 1 expression would assist with separation of the lesions.
Treatment and Prognosis
Counseling
The value of counseling cannot be overemphasized. Good rapport at a first visit is essential, with adequate time to have a full discussion with the parents. Hemangiomas often present weeks after birth in previously normal, healthy children. Parental fears, frustrations, and misinformation are common. Photographs are essential and accurate information from a coordinated professional team is paramount.
Observation
These rare lesions in the sinonasal tract may not require any treatment as they undergo spontaneous involution. Therefore, most small hemangiomas should simply be observed through their period of proliferation and involution and over 50% will leave normal or only slightly blemished skin of the nose and adjacent face.
Corticosteroids
Corticosteroids, both topical and intralesional, for the smaller lesions are usually the first line of medical therapy, with a response rate of more than 90% of individuals.12 Systemic corticosteroids may be the first line of treatment for problematic, airway-encroaching lesions. Doses of prednisolone of 2 to 3 mg/kg/day may be required, with gradual tapering of the dose over one year. Rebound growth can occur.
Laser Therapy
Laser therapy has been used but does not seem to have any particularly beneficial effect on reducing the growth rate in the initial phase of the lesions.13
Chemotherapy
Interferon alfa therapy has been used in large, extensive lesions involving the face and associated orbital and sinonasal structures. It has a response rate of ~50% but has potential neurological complications limiting its use as a first-line treatment.14 Vincristine has been used as an alternative.15
Irradiation is not indicated.
Propranolol
This nonselective β-blocker appears to have a vasoconstrictive action and downregulates angiogenic factors such as VEGF and bFGF. It also appears to upregulate the apoptosis of capillary endothelial cells and reduces the proliferative phase. It has potential cardiovascular side effects but looks, at present, to be replacing steroids in the management of these infants.16
Surgical Treatment of Hemangiomas of Infancy Involving the Nasal Dorsum
This controversial topic requires considerable care in assessing and treating both the child and the parents. The vast majority of hemangiomas involving the nose ± the adjacent cheeks or the interior of the nasal cavity, develop significantly in the weeks following birth. This naturally produces considerable anxiety and the desire to halt the process and achieve normality for the child. Considerable counseling is required for the parents and reassurance with regard to satisfactory regression with conservative treatment. However, even those that resolve may give rise to residual fibrofatty lesions in the cosmetically important area of the nose and degrees of residual deformity of the underlying nasal bones and cartilages.
Profound swelling of the nasal tip producing a bright red bulbous appearance is particularly disconcerting. Pitanguy and colleagues in 19967 presented a series of 33 patient with nasal tip hemangioma, with at least 85% of them having at least one surgical procedure commencing at an age as young as 7 months. They discuss the merits of a vertical midline approach on the dorsum of the nose but, while they define their final scars in the older children as giving satisfactory results, that was, to say the least, debatable.
There is no doubt that the major deformity of the large dorsal nasal hemangioma is distressing even for children as young as 3 or 4 years of age, and certainly once they commence any form of schooling. Intralesional or systemic steroids may be used on a monthly basis and laser treatment may be added if the lesion is flat and superficial, but the parents need to understand that it may not provide significant benefit if there is a notable, deeper component. Multiple laser sessions may be required. At present, the majority of experienced surgeons perform any necessary excision in the 3- to 5-year age group prior to them attending schooling. This gives the majority of hemangiomas of infancy time to commence involution and avoids unnecessary excision. Access by external rhinoplasty approaches and even midfacial degloving may remove the need for any notable additional scarring and allow for any augmentation procedures at a later date, particularly after the nose ceases to grow.
Acquired Lobular Capillary Hemangioma
Synonyms
These are many and varied, and a review of the older literature can be very confusing! The terms pyogenic granuloma, granuloma pyogenicum, capillary hemangioma, nasal granuloma gravidarum, epulis gravidarum, and cavernous hemangioma have all been used.
Site, Incidence, and Specific Clinical Features
These lesions commonly occur in the head and neck and the fingers, but in the sinonasal tract the septal mucosa, particularly Little′s area, and the tip of the turbinates are the sites most often involved (Fig. 9.1). Again, some examples have been reported in the paranasal sinuses.17 These lesions can occur at almost any age but with peaks noted in males younger than 18 years of age and females during their reproductive years. Many of these women are pregnant at the time of presentation and the lesion is referred to in past literature by a wide variety of names such as granuloma gravidarum. The nasal lesions most commonly present with epistaxis with or without accompanying nasal obstruction; they may additionally be ulcerated, but rarely painful (Fig. 9.2).
Histological Features and Differential Diagnosis
The lobular capillary hemangioma is the underlying lesion of virtually all these previously described pathologies named under “synonyms” above. It is an exophytic growth that may have surface ulceration and an inflammatory cell infiltration with lymphocytes, plasma cells, histiocytes, and neutrophils (i.e., granulation tissue–like changes). Beneath any surface ulceration there is a diagnostic lobular arrangement of capillaries at the base. The lobules consist of discrete clusters of endothelial cells and the lumina vary from indistinct to prominent.18 The lesion may be delineated at its periphery and base by an epithelial collar. With time, the lesion fibroses and the vessels reduce.
These histopathological changes are not observed in the infantile hemangioma and, immunohistochemically, GLUT 1 is not expressed.11,19 The hemangioma of infancy and acquired lobular capillary hemangioma usually occur in different age groups and are distinguished clinically and histopathologically, but both must be differentiated on rare occasions from the naevus flammeus (“port wine stain”) that presents at birth as a large, red, macular lesion. In the Sturge-Weber syndrome (see later), this is located in the distribution of the ophthalmic branch of the trigeminal nerve. In contrast to the two forms of hemangioma, naevus flammeus is a capillary vascular malformation.
Treatment and Prognosis
The marked variation in sex distribution that is seen in the larger reports of these lesions suggests a hormonal factor and certainly both progesterone and estrogen are known to alter the vascularity of the nasal mucosa.20 Lobular capillary hemangiomas will spontaneously regress in pregnant women following delivery.21 Trauma has been suggested as playing a role in the past but there is no strong evidence for this and when the lesions are fully excised by a variety of simple nasal surgical or endoscopic procedures, they do not recur. Recurrence is documented, however, with attempted reduction by cautery, electrocoagulation, or cryotherapy. The neodymium-YAG laser has the well-recognized advantages of precision and hemostasis for removing these local vascular lesions, but the larger lesions on the lateral wall of the nose, involving particularly the anterior end of the turbinate, are still commonly pedunculated and can be excised endoscopically without notable difficulty.
Cherry (“Senile”) Hemangioma
These skin lesions are most common on the trunk and upper limbs and usually present following puberty; they are asymptomatic lesions that gradually increase in size to form erythematous papules a few millimeters across. While they may occur in the head and neck, they have not been described in the sinonasal tract.22
Acquired “Tufted” Angioma
Acquired “tufted” angiomas present as dull red plaques or nodules that occur in the skin of the head and neck and upper trunk. They grow slowly and most commonly present in children by the age of 5 years. They are asymptomatic lesions that commonly regress, although more slowly than the hemangioma of infancy. They have not been described in the sinonasal tract. The histopathology of the nodules showing ectatic, thin-walled vessels forming a cellular tuft, usually in the middle and deep dermis, separates them clearly (along with the clinical history in most cases) from infantile hemangioma and acquired lobular capillary hemangioma.
Intramuscular Hemangioma
These rare vascular lesions arise within skeletal muscle, most commonly in adolescents and young adults of both sexes, and affect the lower extremities most commonly, followed by the head and neck. They have been recorded in the masseter muscle, trapezius, sternocleidomastoid, temporalis, and periorbital muscles.23 They do not affect the sinonasal tract.
Vascular Malformations
Venous Malformations
Site, Incidence, and Clinical Features
Venous malformations are the most common type of vascular malformation and may be present at birth and in similar areas of the head and neck to the capillary hemangioma of infancy. However, they may become apparent in children and adults of all ages and occur in an almost equal male-to-female ratio. It is likely that the majority of previously so-called cavernous hemangiomas are congenital venous vascular malformations due to abnormal vessel morphogenesis. They do not grow and merely hypertrophy, increasing in size only as the individual grows. They show no evidence of regression with age and indeed may swell at times related to minor degrees of inflammation.
While they principally occur in skin and subcutaneous tissues and thereby involve the dorsum of the nose in some patients, venous malformations can also involve muscle and deeper structures of the larynx, all areas of the neck, oral cavity, skull base, central nervous system, temporal bones, sinonasal area, and orbit (Figs. 9.3 and 9.4). Cutaneous lesions appear as variable areas which are usually bluish and sometimes nodular and they blanch and compress with pressure. Equally, they may increase and expand notably during a Valsalva maneuver.
All deep extensive malformations involving the nose, sinuses, oropharynx, and larynx may compress and deviate the upper airway to cause insidious obstructive sleep apnea (Figs. 9.5 and 9.6). Cervical facial lesions are often unilateral, resulting in marked facial and neck asymmetry in addition to upper airway obstruction.
Intraorbital venous malformations may expand the orbital cavity and communicate to adjacent areas via the superior and inferior orbital fissures, thereby extending into the nose, sinuses, and adjacent regions. They may result in dependant exophthalmia or occasionally anophthalmia when the patient stands.
Multiple cavernous hemangiomas are associated with the autosomal dominant condition known as blue rubber bleb nevus syndrome.24 With such an enormous range in the size and involvement of these lesions, adequate imaging is necessary for documenting their nature and extent.
Imaging
In the head and neck, venous malformations may clinically and histologically resemble lymphatic malformations and may be a mixture of the two elements. Radiologically, the venous lesions frequently demonstrate phlebolith formation (organized calcified thrombi). Plain radiographs may demonstrate these in up to 50% of venous lesions. Both CT and ultrasonography may be useful but MRI is the best imaging modality to identify and characterize these lesions. It is able to distinguish between the slow flow lesion—exhibiting low signal intensity on T1 weighting and high signal intensity on T2 weighting. The lesions may be well defined or infiltrative and their total extent may be significantly underestimated on clinical examination. Angiography is rarely required for these lesions and many do not have any form of specific feeding vessel (contrary to the accepted clinical view). Angiography may be performed if interventional radiological treatment is envisaged.
Histological Features
Cavernous lesions vary between being poorly circumscribed to rather more definitive lobular masses but contain multiple, dilated vascular spaces with thin walls and surrounding fibrous connective tissue, usually with only minimal amounts of interspersed smooth muscle. The vascular spaces are frequently engorged with blood and thrombosis of these low-flow areas is common, with the resulting formation of a phlebolith. There may additionally be abnormal lymphatic and capillary channels and these lesions may become inflamed at times, displaying chronic inflammatory cells. They are truly vascular malformations rather than hemangiomas if there is no pericyte around each endothelium-lined blood channel and no signs of proliferation. These pericytes will be positive for SMA (smooth muscle actin).
Treatment
Treatment may vary between none at all through a wide range of therapeutic modalities depending on the site, size, and symptoms. Treatment options include elastic compression, sclerotherapy, surgical resection, or combinations thereof, depending on the site. Treatment may be required for cosmetic appearance, functional airway problems, impairment of speech, and, at times, recurrent pain. Low-dose aspirin taken daily does provide some prophylaxis against pain associated with thrombosis and phlebolith formation.
Sclerotherapy
Sclerotherapy has been used in various degrees over many years, the main aim of the injection of any agent being to induce inflammation and obliteration of the affected venous channels. It may be effective in small cutaneous and mucosal lesions and for larger lesions in the sinonasal area it may be necessary to undertake this under general anesthesia with an experienced interventional radiologist using real-time fluoroscopic and often ultrasonic monitoring. Unfortunately, multiple treatments may be required to shrink large venous malformations because recanalization of venous channels and local complications such as blistering, necrosis and bleeding, nerve injury, and dissemination of the sclerosing agent are possible. The reported success rates are variable, but up to three-quarters of patients may have marked improvement or cure.25
Endoscopic or Open Surgery
Small intranasal lesions may be excised endoscopically but larger lesions involving the nasal cavity and adjacent sinuses may require open approaches such as lateral rhinotomy or midfacial degloving. Large cervicofacial lesions extending to involve the nose, sinuses, and nasopharynx, in addition to multiple other areas of the head and neck, may present a massive surgical challenge either in the child or in the adult and should be reviewed by a multidisciplinary team comprising surgeons from different disciplines with special interest and experience in these problems. Large-scale surgery is occasionally necessary as a consequence of severe upper respiratory tract problems, feeding problems, dental malalignment, visual disturbance, and neurological impairment, but many patients, even with notably deep lesions, may not require any intervention and achieve a normal life span.
Several reports have described endoscopic resection of cavernous hemangiomas in the sinonasal region, notably a study by Song et al in 2009.26 They described a series of 22 patients, comprising 13 capillary hemangiomas, 8 cavernous (probably venous malformations) and 1 mixed. All were excised endoscopically, with preoperative embolization used in three cases. None recurred with a follow-up of 8 to 48 months (mean 21 months).
Lymphatic Malformations
Lymphatic malformations vary in the same way from small localized lesions to massive lesions of the head and neck and may be microcystic or macrocystic, the latter large macrocystic lesions being given the name “cystic hygroma” for many years and the term “lymphangioma” being used for the microcystic lesions. The management of these lesions follows a similar pattern to the venous malformations and may require sclerotherapy or a wide variety of surgical procedures from the most minor to the most major.
Sclerotherapy
Sclerotherapy has its maximum effect for macrocystic lesions, particularly those with a single compartment in the lesion that can be aspirated, injected with sclerosant, and then compressed. Both intralesional bleomycin and OK-432 (a lyophilized mixture of attenuated group A Streptococcus pyogenes of human origin) have been reported to give good results.27,28
Lasers
Argon, neodymium-YAG, and carbon dioxide lasers have all been used in an attempt to coagulate both venous and lymphatic anomalies but their use is limited to the more superficial aspects of the lesions and may only be of real use in small lesions.
Open Surgery
Neonates with extensive cervicofacial venous, lymphatic, or mixed malformations may present with respiratory obstruction secondary to involvement of the nose, sinuses, tongue, oral cavity, or pharyngolarynx, and immediate tracheostomy may be required. Subsequent resection may be deferred until infancy or early childhood; certainly the dissection of delicate neurovascular structures is a little easier in the older child, but complete removal of all of the lesion is rarely possible.
Staged excision has been recommended, removing different components from anatomical sites at different times, but previous scarring from an adjacent area may make these procedures more difficult and certainly reoperation on a previously operated area can be particularly complicated. A downside of previous sclerotherapy, particularly if it was inappropriately used in microcystic lesions, can be to make any subsequent operation considerably more difficult as the malformation is more adherent to surrounding structures.
Capillary Malformations
Capillary malformations are usually sporadic but genetic research in the last decade has studied familial cases with an autosomal dominant inheritance pattern due to a gene RASA1 on chromosome 5q.29,30 A subgroup of the families with this mutation also have arteriovenous malformations and fistulas. Interestingly, the defect in hereditary benign telangiectasia has also been mapped to the same chromosome.31
Capillary malformations can occur anywhere in the body and vary from small areas of minor cutaneous erythema to extensive areas of involved skin—commonly referred to in the past as a port-wine stain. Approximately half of all facial capillary malformations are confined to one of three trigeminal dermatomes but there may be overlapping or crossing of the midline.32 The sinonasal and oral mucous membranes may be involved.
The lesions are usually evident at birth and generally darken with age; they may develop nodular expansion and underlying maxillary or mandibular expansion. They may be accompanied by nasal and labial hypertrophy and hyperplasia of the gums.
Treatment
Involvement of the nose and sinonasal tract by capillary malformations may require a range of treatments extending from cosmetic camouflage make-up; through multiple applications of laser photocoagulation, resection, and skin grafting; to contour bone resection with orthognathic procedures to correct maxillary overgrowth.
Sturge-Weber Syndrome
This syndrome consists of a facial capillary malformation with ipsilateral leptomeningeal and ocular anomalies (Fig. 9.7). The leptomeningeal abnormalities may be capillary, venous or arteriovenous. Large pial vascular lesions may cause delayed motor and cognitive development with epilepsy and contralateral hemiplegia. Regular ophthalmic assessment in infants and children is necessary as choroidal involvement may result in retinal detachment, glaucoma, and blindness.
Syndromes Associated with Hemangiomas and Vascular Malformations
The numerous syndromes (at least 15 to date) associated with these vascular lesions33 are beyond the scope of this book but further illustrate the need for all children and young adults to be seen by experienced multidisciplinary teams with specialist expertise to facilitate accurate diagnosis, expert imaging, and good patient and family communication and support. A full overall assessment is frequently essential and patients with large, complex lesions may require combined therapies over long periods.
Treatment of Hemangiomas and Vascular Malformations; Personal Series
We have a series of 21 cases of vascular malformations in adults, two-thirds of which have been venous malformations (Table 9.1). The capillary vascular malformations presented at an earlier age (mean of 37.3 years) compared with a mean of 49.8 years in the venous group; there was no particular sex difference either within the two groups or between them, with men and women equally affected. Eleven patients had lesions affecting the nasal cavity, structures either on the lateral wall or septum, and were mainly capillary vascular malformations. The venous lesions, as expected, tended to be more extensive, involving soft tissues and bone and affecting the midface, skull base, and orbit. However, all were amenable to surgical excision, which was complete and curative in all but two, both of whom had massive mixed venous/lymphatic malformations and who had had many previous surgical interventions elsewhere. A third patient had had a resection undertaken in our institution 14 years earlier.
Surgery ranged from endoscopic resection in 52% to midfacial degloving (19%), lateral rhinotomy (14%), craniofacial resection (10%), and an osteoplastic flap (5%). Embolization has not been required in any case and to date there have been no recurrences with a follow-up of 12 months to 18 years (mean 9.5 years).
Key Points
There are essentially two types of vascular lesions, which are either tumors or malformations.
The term “hemangioma” should not be used indiscriminately.
Numerous symptoms are associated with these vascular lesions and many children and young adults require review by experienced multidisciplinary teams.
Large, complex lesions may require combined therapies over a prolonged period.
References
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Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: results of a 1-year analysis. Lancet 2002;360(9332):521–527 14. Werner JA, Dünne AA, Folz BJ, et al. Current concepts in the classification, diagnosis and treatment of hemangiomas and vascular malformations of the head and neck. Eur Arch Otorhinolaryngol 2001;258(3):141–149 15. Perez J, Pardo J, Gomez C. Vincristine—an effective treatment of corticoid-resistant life-threatening infantile hemangiomas. Acta Oncol 2002;41(2):197–199 16. Zimmermann AP, Wiegand S, Werner JA, Eivazi B. Propranolol therapy for infantile haemangiomas: review of the literature. Int J Pediatr Otorhinolaryngol 2010; 74(4):338–342 17. Sheppard LM, Mickelson SA. Hemangiomas of the nasal septum and paranasal sinuses. Henry Ford Hosp Med J 1990;38(1):25–27 18. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma. 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Berenguer B, Burrows PE, Zurakowski D, Mulliken JB. Sclerotherapy of craniofacial venous malformations: complications and results. Plast Reconstr Surg 1999;104(1):1–11, discussion 12–15 26. Song CE, Cho JH, Kim SY, Kim SW, Kim BG, Kang JM. Endoscopic resection of haemangiomas in the sinonasal cavity. J Laryngol Otol 2009;123(8):868–872 27. Okada A, Kubota A, Fukuzawa M, Imura K, Kamata S. Injection of bleomycin as a primary therapy of cystic lymphangioma. J Pediatr Surg 1992;27(4):440–443 28. Greinwald JH Jr, Burke DK, Sato Y, et al. Treatment of lymphangiomas in children: an update of Picibanil (OK-432) sclerotherapy. Otolaryngol Head Neck Surg 1999;121(4):381–387 29. Eerola I, Boon LM, Watanabe S, Grynberg H, Mulliken JB, Vikkula M. Locus for susceptibility for familial capillary malformation (“port-wine stain”) maps to 5q. Eur J Hum Genet 2002;10(6):375–380 30. Eerola I, Boon LM, Mulliken JB, et al. 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