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© Borgis - New Medicine 4/2019, s. 119-126 | DOI: 10.25121/NewMed.2019.23.4.119
Agata Wasilewska1, Małgorzata Badełek-Izdebska1, *Lidia Zawadzka-Głos1, Remigiusz Krysiak2, Jarosław Żyłkowski3
Minimally invasive therapy of lymphatic malformations in patients treated in the Paediatric Teaching Clinical Hospital, University Clinical Centre of the Medical University of Warsaw (DSK UCK WUM)
Małoinwazyjne metody leczenia malformacji limfatycznych na przykładzie pacjentów DSK UCK WUM
1Department of Paediatric Otolaryngology, Medical University of Warsaw, Poland
Head of Department: Lidia Zawadzka-Głos, MD, PhD
2Department of Paediatric Radiology, Medical University of Warsaw, Poland
Head of Department: Michał Brzewski, MD, PhD
3II Department of Clinic Radiology, Medical University of Warsaw, Poland
Head of Department: Professor Olgierd Rowiński, MD, PhD
Streszczenie
Wstęp. Malformacje limfatyczne (ML) są zmianami łagodnymi, powstałymi w wyniku nieprawidłowego formowania naczyń limfatycznych w życiu płodowym. Najczęstszą lokalizacją ML są obszary głowy i szyi. Ze względu na swoją morfologię i lokalizację w pobliżu istotnych struktur naczyniowych i nerwowych, leczenie chirurgiczne jest trudne, obarczone wysokim ryzykiem powikłań i często niedoszczętne.
Cel pracy. Skleroterapia z użyciem bleomycyny jest uznaną małoinwazyjną metodą leczenia ML. W pracy przedstawiamy wyniki leczenia ML okolicy głowy i szyi przy użyciu bleomycyny u dzieci z naszego ośrodka.
Materiał i metody. Od września 2017 do października 2019 roku leczeniu z użyciem bleomycyny poddanych zostało 6 pacjentów w wieku od 3 tygodni do 10 lat z ML głowy i szyi. Zabiegi wykonywano pod kontrolą USG i/lub fluoroskopii. Przeanalizowano liczbę procedur u pacjenta, dawki leku oraz odpowiedź na leczenie i powikłania.
Wyniki. U 4 pacjentów ML była zlokalizowana na szyi, u jednego na szyi i w śródpiersiu, u jednego w okolicy policzka. Dwóch pacjentów zostało poddanych jednemu zabiegowi, u 3 pacjentów wykonano 2 zabiegi, u jednego 3 zabiegi. U 4 pacjentów efekt leczenia był doskonały, u jednego dobry. Efekt leczenia u jednego pacjenta po pojedynczej dawce leku był niezadowalający, dlatego został on zakwalifikowany do kolejnego etapu. Maksymalna jednorazowa dawka bleomycyny wyniosła 10 000 j., nie przekraczano 700 j./kg mc. Nie odnotowano powikłań pozabiegowych.
Wnioski. Wstępne wyniki sugerują, że skleroterapia ML okolicy głowy i szyi przy użyciu bleomycyny u dzieci jest efektywną i bezpieczną metodą leczenia.
Summary
Introduction. Lymphatic malformations (LMs) are benign lesions thought to be caused by the abnormal development of the lymphatic system in utero. Most commonly, LMs affect the head and neck. Because of LM morphology and location close to important vascular and nervous structures, surgical treatment is difficult, associated with a high risk of complications, and often incomplete.
Aim. Bleomycin sclerotherapy is a recognised minimally invasive technique used in the treatment of LMs. We present the outcomes of bleomycin therapy of LMs located in the head and neck area in children receiving therapy in our centre.
Material and methods. Between September 2017 and October 2019, treatment with bleomycin was provided to a total of 6 patients with LMs of the head and neck, aged from 3 weeks to 10 years. The procedures were performed under ultrasound and/or fluoroscopy guidance. The aspects analysed included the number of procedures applied in patients, drug doses, treatment response and complications.
Results. In 4 patients, the LM was located on the neck, in 1 patient ? on the neck and in the mediastinum, and in 1 patient in the cheek region. Three patients underwent 2 procedures, 1 patient ? 3 procedures, and 2 patients ? 1 procedure. The treatment outcome was excellent and good in 4 patients and 1 patient, respectively. However, in 1 patient, the therapeutic effect was unsatisfactory, and a decision was made to administer another course of treatment. The maximum single dose of bleomycin was 10,000 IU; the dose of 700 IU/kg BW was not exceeded. No complications were observed after the procedures.
Conclusions. Preliminary results suggest that bleomycin sclerotherapy of LMs in the head and neck region in children is an effective and safe treatment modality.
Introduction
Vascular anomalies in children are common developmental disorders. Their presentation varies from small, spontaneously resolving lesions to extensive life-threatening abnormalities which cause lasting disfigurement and severe functional impairment. Based on the clinical picture and histological structure, the International Socie-ty for the Study of Vascular Anomalies (ISSVA) classifies vascular anomalies into two categories: 1) vascular tumours (mostly infantile haemangiomas) and 2) vascular malformations (1).
Vascular malformations and haemangiomas have different clinical manifestations. Firstly, malformations are present from birth and grow with the individual. They do not regress, and do not have a tendency to become malignant. They occur with similar frequency in both sexes.
A comparison of the characteristics of haemangiomas and malformations is given in table 1 (2).
Tab. 1. A comparison of the characteristics of haemangiomas and malformations
Vascular malformationHaemangioma
Clinical characteristics
? Always present at birth
? Grows in proportion to the child’s growth
? Never resolves
? Prevalence ?:? 1:1
? Occurs in the neonatal or early infantile period
? Grows faster than the growth of the child during the 1st year
? Involutes after 1 year of age
? Prevalence ?:? 1:6
Biological characteristics
? Flat, normal endothelial cells; normal mast cell count
? Involution: normal endothelial cell turnover; dysplastic vascular channels: venules, veins, capillaries or lymphatic vessels
?  
? Proliferation: abundant, proliferative endothelial cells, numerous mast cells
? Involution: apoptosis and progressive degrees of flattening of endothelial cells Wider but less numerous vessels surrounded by perivascular fibrous fatty tissue
Vascular malformations are benign tumour-like lesions that occur at 4-10 weeks of gestation as a result of abnormalities in the development of vascular tissue. They are characterised by normal cell turnover, and do not undergo spontaneous involution (2, 3).
Depending on the type of vascular channel, they are divided into several categories including: simple vascular malformations: capillary (CM), lymphatic (LM), venous (VM), arterial (AM), and arteriovenous (AVM); mixed vascular malformations: CVM, CLM, LVM, CLVM, AVM-LM, and CM-AVM; arteriovenous fistulas (AVF) (1).
Depending on the rate of blood flow through the lesion, vascular malformations are divided into two subtypes: low-flow (composed of venous, capillary and lymphatic components), and high-flow (composed of arterial components) (2).
Lymphatic malformations, previously referred to as lymphangioma or cystic hygroma, are low-flow malformations. They are composed of malformed dysplastic vessels filled with lymphatic fluid, presenting as dilated channels, and lymphatic cysts (2, 3). Typically, they cause enlargement of the involved organ. They can be located in any major site of lymphatic tissue. Macrocystic malformations (> 2 cm in diameter) are large, soft, smooth clear masses under normal skin. Microcystic malformations (< 2 cm) penetrate the skin or muscles, and present as thin vesicles in the skin or muscle tissue (2). Mixed malformations have both components (the most common type). Macrocystic LMs respond better to sclerotherapy.
The primary locations for LMs include the head and neck region (50-75%), most commonly the posterior triangle of the neck, but also the bottom of the oral cavity as well as the mediastinum, larynx and tongue (2, 3). The second most common location is the torso (chest, axillary fossa) and the extremities. Visceral locations are rare. Malformations may increase in volume significantly during upper respiratory tract infections due to the accumulation of fluid, but also during inflammation, after an injury or haemorrhage into the lesion, with possible effects including airway obstruction or bleeding, and exacerbation of existing problems, e.g. with swallowing or head mobility ? depending on the site of the lesion. Because of specific morphology and location close to important vascular and nervous structures, surgical treatment is difficult, associated with a high risk of complications, and often non-radical.
Vascular malformations are always present at birth. They can be identified by prenatal ultrasound. Despite their congenital nature they may remain clinically silent until puberty and adulthood. They may appear individually or in clusters, as in Klippel-Trenaunay syndrome (KTS) and CLOVES (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Skeletal/Spinal deformities syndrome) (2, 3).
In rare cases, familial occurrence has been reported (two families with congenital venous malformations and a specific mutation within the VMCM-1 gene located on the chromosome 9p) (2), and lymphatic malformations located in the same site in the child and the mother (4).
Diagnostic work-up
The diagnosis is largely based on patient history, clinical findings and radiological evaluation. The most useful diagnostic modalities are Doppler ultrasound and MRI with contrast.
With Doppler ultrasound, lesions are identifiable already in the first trimester of pregnancy (especially macrocystic malformations) and at birth (3, 5). Doppler ultrasound shows an avascular hypoechogenic cystic structure with visible fluid levels.
MRI with contrast as a complementary examination to ultrasound scanning (3, 5) additionally evaluates the extent of the lesion and its position relative to the surrounding structures. T2 images reveal iso- or hyperintense cystic lesions with a characteristic peripheral enhancement. A lobular structure or septa between cysts can be seen especially in macrocystic lesions (3).
The management of lymphatic malformations is often challenging to the treating physician. Small, limited and superficial lesions can be treated surgically with good results. However, the surgical treatment of extensive lesions poses a greater challenge. The following therapeutic modalities have been reported in the literature:
1. Surgical resection (radical, if possible), while conserving important vascular/neural structures (microcystic lesions). Multi-stage surgical treatment in most cases, treatment (frequently non-radical) especially in the suprahyoid location (recurrence rate 85%; high risk of complications) (2, 3, 6),
2. Laser therapy ? CO2, Nd:YAG in limited mucosal lesions.
3. Observation (postinfectious “autosclerotherapy” process).
4. Aspiration ? ad-hoc management (haemorrhaging, infections).
5. Sclerotherapy ? obliteration of low-flow cystic lesions by intralesional administration of alcohol, doxacillin, cyclophosphamide, acetic acid, triamcinolone, OK-432 (Picibanil) or bleomycin (3, 6-8). Vascular endothelial damage results in decreased fluid production, fluid absorption, formation of adhesion and fibrosis, ultimately leading to a reduction in the volume of the malformation (3, 6-8). It represents a minimally invasive first-line therapy. The method is both more efficient and more effective, and furthermore it is associated with a lower risk of complications than surgical management (6). Partial aspiration of the fluid content prior to the intralesional injection of bleomycin has been shown to yield good results. The best effects are observed in the treatment of macrocystic LMs (3).
Bleomycin is an antibiotic chemotherapeutic agent with anti-cancer activity. One of the side effects of bleomycin is its destructive activity on vascular endothelial cells through non-specific inflammatory response, which causes fibrosis and closure of the malformation (6-9). Bleomycin is commonly used as a substance closing off the spaces within lymphatic malformations.
Aim
The aim of the study was to review the effects of treatment of lymphatic malformations in the head and neck region by intralesional bleomycin injections.
Material and methods
A total of 6 children with diagnosed lymphatic malformations in the head or neck region were hospitalised in the Department of Paediatric Otolaryngology, Medical University of Warsaw, between September 2017 and October 2019, to receive intralesional bleomycin injection treatment. The aspects analysed in the study included the age and sex of the patients, the number of procedures applied, as well as drug dose, treatment response and complications. At the start of treatment, the youngest patient was 3 weeks old, and the oldest 10 years and 10 months old. The group consisted of 4 girls and 2 boys.
The patients were selected for treatment on the basis of lymphatic malformation diagnosed by ultrasound and MRI. The procedures were performed under ultrasound and/or fluoroscopy guidance (fig. 1, 2).
Fig. 1. Lymphatic malformation in fluoroscopy. Photo after contrast administration. Patient S.N.
Fig. 2. Lymphatic malformation in fluoroscopy. Photo after contrast administration. Patient W.I.
In 4 patients, the lesion site was on the neck. In 1 patient, the malformation was located on the neck and in the mediastinum, and in another patient it was present in the cheek region.
The technique involves the injection of bleomycin prepared in the sterile drug laboratory in syringes, diluted with saline to 5 ml of the solution, into the lumen of the lymphatic malformation under ultrasound visualisation as well as/or X-ray scopy. The procedures are performed under general anaesthesia because of their long duration and the lack of patient cooperation.
Follow-up ultrasound scanning is carried out at least 6 weeks after the procedure. If necessary, the next stage of treatment is scheduled after at least 2 months of follow-up.
Results
1. Three patients underwent 2 procedures, 2 patients ? 1 procedure, and 1 patient ? 3 procedures. The treatment outcome was excellent in 3 patients, good in 2 patients and unsatisfactory in 1 patient.
2. The maximum single dose of bleomycin was 10,000 IU; the dose of 700 IU/kg BW was not exceeded.
No immediate perioperative or distant postoperative complications were noted.
Patient G.J.

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Piśmiennictwo
1. ISSVA classification for vascular anomalies. Approved at the 20th ISSVA Workshop, Melbourne, April 2014, last revision May 2018.
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otrzymano: 2019-11-26
zaakceptowano do druku: 2019-12-17

Adres do korespondencji:
*Lidia Zawadzka-Głos
Klinika Otolaryngologii Dziecięcej Warszawski Uniwersytet Medyczny
ul. Żwirki i Wigury 63A, 02-091 Warszawa
tel.: + 48 (22) 317-97-21
laryngologia@litewska.edu.pl

New Medicine 4/2019
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