20 Su r g ic a l D iS e a Se S iSSN 2413-6077. iJMMr 2017 Vol. 3 issue 2 dOI 10.11603/IJMMR.2413-6077.2017.2.8381 chOIcE Of TREATmENT OPTIONs fOR cYsTIc LYmPhsTIc mALfORmATIONs IN ThE hEAd ANd NEcK REgION: TREATmENT EXPERIENcE Of 81 chILdREN I. M. Benzar BOGOMOLETS NATIONAL MEDICAL UNIVERSITY, KYIV, UKRAINE Background. Surgery has previously been the only treatment for lymphatic malformations (LMs), but in the head and neck region is challenging due to the risk of scarring, nerve damage, recurrence. Sclerotherapy may be a perfect alternative. Objective. The aim of the study is to determine the efficacy and safety of the OK-432 sclerotherapy in the children with craniofacial LMs. Methods. 81 children with head and neck LM between December 2010 and March 2017were involved into the study. The follow-up period was from 6 to 79 months. According to the size of cysts, LMs were classified into macrocystic, microcystic, and mixed. The result of the treatment of LMs was determined by the percentage of reduction in size as excellent (decrease by more than 90%), good (by 50%–89%), satisfactory (by 20%–49%) and none (by less than 20%). Results. The macrocystic LMs diagnosed in 41.97% of patients, microcystic – in 12.35%, and mixed – in 45.68% of children. OK-432 sclerotherapy only was performed for 83.9% of patients and in 12.3% in combination with surgery. The range of sclerotherapy sessions was from 1 to 11. An excellent result in 96.97% of cases was evidenced in the patients with macrocystic LM. Poor result was proved in the patients with microcystic LMs; the most of them (55.56%) had satisfactory result. In the patients with mixed LM, an excellent and good result was evidenced in 83.33%. After 198 sessions of OK-432 sclerotherapy, complications associated with the treatment occurred in 5 (2.52%) cases. Conclusions. OK-432 sclerotherapy is a safe and effective treatment of head and neck LMs in children. Macrocystic LMs proved the best response to OK-432 treatment. KEY WORDS: lymphatic malformations; sclerotherapy; OK-432; children. Corresponding author: Iryna Benzar, Department of Pediatric Surgery, Bogomolets National Medical University, 28/1 V. Chor- novola, Kyiv, Ukraine, 01135 Phone number: +380951295882 E-mail: iryna.benzar@nmu.ua, ira_benzar@yahoo.com Introduction Cystic lymphatic malformations are benign vascular lesions, which develop as the result of embryological disturbances of lymphatic system. Unfortunately, the terms often used to describe LMs are imprecise. ‘Cystic hygroma’ and ‘lymphangioma’ are often used incorrectly to describe malformations. Both of these terms should be abandoned, as the suffix -oma con- notes a neoplasm [1]. In 1982, a landmark article by Mulliken and Glowacki suggested a classification system designating vascular ano­ malies as either tumours or malformations accor ding to their biologic and pathologic features [2]. This system was adopted by the international society for the study of vascular anomalies (ISSVA) and was last updated in 2014 [3]. Vascular malformations are classified as capillary, venous, lymphatic, arterial, and mixed lesions, depending on their vascular tissue of origin. These lesions are present at birth and have a progressive clinical course. The incidence of LMs is evidenced in about 1 to 6000 to 1 to 16,000 live births, with a frequency of hospita- lization – 3 cases per 100,000 [4, 5]. LMs near the principal lymphatic chains in the neck re- gion are formed when a primordial lymph sac loses or fails to re-establish communication with the central veins (jugular and subclavian) from which it arises [1]. For many years, surgery has been the only treatment for LMs of any anatomical localization. However, the results of the operation were often disappointing, espe- cially in cases of LM of cheek, tongue, oral cavity, neck lateral triangle. The surgical treat- ment of LM in the region of head and neck is accompanied by complications in 12–33% and recurrences in 15–53% of cases. In addition, International Journal of Medicine and Medical Research 2017, Volume 3, Issue 2, p. 20–24 copyright © 2017, TSMU, All Rights Reserved I. M. benzar 21 Su r g ic a l D iS e a Se S iSSN 2413-6077. iJMMr 2017 Vol. 3 issue 2 re section of LM does not inhibit bones overg- rowth in the region of LMs [6, 7, 8]. Recurrence and complications are usually the result of incomplete preoperative examination and in- correctly planned treatment. Incomplete resec- tion provokes rapid growth of malformation, causes postoperative lymphorrhea, and re- current infections [9]. The role of surgical treat- ment in order to achieve an excellent cosmetic result in patients with LMs is questionable. When planning an intervention, it is necessary to clearly understand that LM can sprout fascia, infiltrate different tissues and change normal anatomy. The damage of important nervous and vascular structures is unacceptable in the treatment of benign pathology [10]. LMs usually infiltrate skin and subcutaneous tissue [1], therefore after the operation the asymmetry progresses, and later lymph nodes can sprout post-operative scars. Currently, there is no sufficient evidence in the literature to create treatment algorithms and help determine the best choice of initial therapy, and in recent decades sclerotherapy has become the most common treatment op- tion [5, 11, 12]. According to the results of the literature analysis in the PubMed, Medline, Cochrane databases, three therapeutic agents are widely used for cystic LM local treatment: bleomycin, doxycycline and OK-432 (Picibanil) [13]. The features of endothelial cells lining the LMs cysts determine the effectiveness of the OK-432 for the treatment of LM. The mechanism of action of the drug is based on the induction of inflam­ mation with subsequent activation of cytokines and apoptosis of cells that form the inner layer of the cysts [14]. In the cyst fluid the level of inflammatory mediators increases that confirms the inflammation in response to the injection of the drug [15]. The effectiveness of the OK-432 sclerotherapy in the treatment of cystic LMs has been described in small series of some medical centres [16, 17]. Since 2011 OK-432 is successfully used in Ukraine [18]. Objective of the study is to analyse the treatment experience of 81 child patients with lymphatic malformations (LM) in the head and neck region, and to determine the efficacy and safety of the OK-432 sclerotherapy in this cohort of patients. Methods During the period from December 2010 to March 2017, 126 patients with isolated LMs or LMs in combination with other congenital vascular malformations were treated in the OKHMATDYT National Specialized Children Hospital. The study includes 81 clinical cases of LMs that are localized in the head and neck region, representing 64.29% of all patients with LMs during the established period of time. The follow up period was from 6 to 79 months. There were 44 (53.7%) male and 37 (45.1%) female patients. The following visualization methods were used to confirm the diagnosis of cystic LMs: ultrasound scan in grey-scale and colour Doppler was performed at the primary patient's exa- mination and in dynamics, MRI was per formed before treatment and at the stages of treatment, CT in urgent situation. According to the results of MRI, the size and structure of LMs and also their topographical relationship with neighbou- ring organs and tissues were deter mined as particularly mediastinum with retro pharyngeal space involvement associated with LMs to the level of the hyoid bone. LMs were classified as macrocystic, microcystic, or mixed (macrocystic- microcystic), which has been proven useful in other sclerotherapy studies [19]. The classification was determined radio graphically by MRI and ultrasound examination according to the cysts size: macrocystic (formed by cysts with a volume of more than 2 cubic centimetres (cc)), microcystic (cysts volume – less than 2 cc), and mixed, in which the microcystic component exceeds 50%. The size of LMs was determined using the ellipse square formula. The size of LMs up to 100 cm2 was evaluated as small, 100–199 cm2 – middle, 200–299 cm2 – large and more than 300 cm2 – gigantic. The result of the treatment of LM was determined by the percentage of reduction in the lesion size [3, 10] as excellent (decrease by more than 90%), good (50–89%), satisfactory (20–49%) and unsatisfactory (less than 20% reduction in size). The statistical analysis was performed using IBM SPSS Statistics, version 23. The data is pre- sented as an average of 95 percent confidence interval or standard deviation. The qualitative data (age, sex, localization, size, etс.) were analysed in a univariate analysis with the Pear- son’s correlation coefficient χ2 test. The logistic regression model was used for variants that significantly predict the outcome of the treat­ ment and/or the course of the disease. Statis- tical significance was defined as p<0.05. Results Diagnosis of LMs were established prenatal- ly in 12 (14.81%) patients, at birth in 43 (53.08%), I. M. benzar 22 Su r g ic a l D iS e a Se S iSSN 2413-6077. iJMMr 2017 Vol. 3 issue 2 during the first year of life in 12 children (14.81%), at the age of one to three years in 4 (4, 94%) and in 10 (12.35%) children, the clinical signs of the disease were manifested at the age above three years. Clinical signs of cystic LM in the head and neck region were: the asymmetry of face and neck due to mass in all children, compression of upper airway requiring tra cheo- stomy before sclerotherapy (n=4, 3.6%), transient stridor during the first year of life (n=8, 7,1%), macroglossia, disarticulation (n=5, 4,5%), disturbance of occlusion (n=6, 5,4%), recurrence lymphorrhoea in the children with mucosal and skin lesions (n=4, 3.6%), excessive salivation (n=3, 2.7%), visual impairment (n=1, 0.9%), lym- phedema of upper limb (n=1, 0.9%). 68 patients were treated primary, 13 children underwent surgical interventions previously. There pa ti- ents were treated conservatively with propra- nolol within 6–12 months without any clinical result. According to the visualization of LMs using ultrasound and MRI, the topographic features of LM and relationship to adjacent organs were established. The lesions were localized in suprahyoid region in 37 (45.68%) children, and in infrahyoid region – in 44 (54.32%) cases. Bilateral mass were observed in 23 (28.39%) children, in other patients LMs were localized on the one side of middle line. 34 (41.97%) patients had macro cystic LMs, in 10 (12.35%) children microcytic LMs were diag- nosed, and in 37 (45.68%) children LMs were mixed. The size of LMs ranged from 23 to 517 сm2, in average 135.87 см2. In 37 (45.68%) patients LMs were small; in 29 (35.80%) they were middle, in 7 (8.64%) LMs were large and in 8 (9.88%) LMs were gigantic. In 22 (2716%) children mediastinal involvement was diag- nosed. In children with head and neck LMs sclero therapy, surgical and combined treat- ments were performed. Three patients (3.7%) underwent surgical resection of LMs for the following reasons: recurrent inflammation requiring re­hospita­ lization and antibiotic therapy (n=2), difficulty in diagnostic due to sudden onset and atypical course of the disease (n=1). Recurrence after surgery happened in one case. One patient had postoperative complication: transient paresis of facial nerve branch. Giant LMs, which occupy several anatomical sites and infiltrate muscles, bones, cellular spaces deserved a particular attention. Bilateral LMs narrowed airway and tracheostomy was evidenced in 5 patients. In this series, decannu- lation was eventually possible in 4 patients after multiple sessions of OK-432 sclerotherapy. One patient with bilateral LMs, mediastinum, retro- pharyngeal space and lung involvement died due to septic complications. Combined treat- ment was performed for 10 (12.3%) children, which consisted of the following procedures: resection of LM, tracheostomy prior to treat- ment, injection of OK-432 into residual cyst ca vity during and/or after surgery (n=5, 6.17%), thoracocentesis, pleural and mediastinal drainage in the patient with purulent medi- astinitis with subsequent sclerotherapy after the elimination of complications (n=1), sclero- therapy and correction of scarring and tissue deformities (n=3), resection of tongue in the patient with pronounced macroglossia, distur- bance of occlusion (n=1), resection of orbital part of LMs due to visual impairment and sub- se quent sclerotherapy (n=1). The most patients (n=68, 83.90%) underwent the OK-432 sclero- therapy as a single method of head and neck LMs. Patients received from 1 to 11 sessions of sclerotherapy, in average 2.44±2.21 sessions per patient. After 1 session of the OK-432 scle- rotherapy, an excellent result was achieved in 24 (29.63%) patients, according to localization and structure, these were unilateral macro cystic LMs of neck. Involvement of the media- stinum and retropharyngeal space was not a contraindication to the sclerotherapy of LMs. I n 1 8 c h i l d r e n w i t h m e d i a s t i n a l a n d retropharyngeal part of LMs an excellent result was evidenced in 5 (27.78%), good in 9 (50.0%), and satisfactory in 2 (11.11%) cases. However, in 1 case, the result was poor and in 1 case the result of the treatment was unsatisfactory. After 198 sessions of the OK-432 sclero- therapy, complications associated with the treatment occurred in 5 (2.52%) cases: signi­ ficant oedema with the need for hospitalization, puncture, and decompression of the cyst (n=4; 2.02%), and skin allergic reaction (n=1; 0.51%). Response data for macro cystic LMs were higher than in other types of LMs with an excel- lent result in 96.97% and good result in 3.03% of patients. In the patients with microcystic LMs, no positive result was evidenced, 33.33% of cases had a good treatment result, 55.56% were satisfactory and 11.11% had no results. In the patients with mixed LM, an excellent result was evidenced in 33.33% of cases, 50.0% of patients had good response to treatment, 11.11% – a satis factory one, and 2.77% of patients had no result. Primary efficacy endpoints were evaluated using Fisher’s exact test. Covariates used in a I. M. benzar 23 Su r g ic a l D iS e a Se S iSSN 2413-6077. iJMMr 2017 Vol. 3 issue 2 univariate analysis included: LM type (macro­ cystic, microcystic, mixed), laterality (unilateral versus bilateral), mediastinal and retropha- ryngeal involvement, prior treatment, age du- ring the first treatment, gender. It was establi­ shed, that the result of treatment was deter- mined primarily by the type of LM and previous intervention: the best results were evidenced in the patients with macrocystic LMs (p<0.005), previous intervention reduced the treatment efficacy (p<0.005). Covariates that proved a significant association with the treatment result were used for logistic regression analysis, the probability of an excellent and good outcome for the patients with macrocystic LM in cases of no prior treatment was 86.6%. Discussion This article presents a relatively large expe- rience of the treatment of cystic LMs in the head and neck region for a relatively short period of time (5.5 years). A peculiarity of this study is that for the first time in Ukraine a new approach to the treatment of LMs of challenging locali- zation in children is presented. Treatment of head and neck LMs is accompanied by significant risks, therefore for children it is necessary to choose the most effective and safe way, until stronger evidence is present, the difference in complication rates is potentially the deciding factor in the choice the treatment options [13]. For decades, resection has been the main- stay for management of LMs. More recently, sclerotherapy has become the first­line treat­ ment for head and neck lesions. Experienced surgeons welcome the ascendancy of sclerosant management. Although some LMs can be successfully resected, complications are ex- pected and results are often disappointing. One of the most safe and effective ways of cystic LMs treatment in children is the OK-432 sclerotherapy [5, 16]. The OK-432 (Chugai Phar- maceuticals, Tokyo, Japan) is a lyophilized powder of Streptococcus pyogenes (group A, type 3, Su strain) incubated with benzylpenicillin. The drug was developed in Japan in the late 1960s as an antitumor agent. Although therapy of OK-432 did not increase the survival of the patients with cancer, its efficacy was proved in pleurodesis in cases of malignant pleural involvement. According to these studies, in the late 1980s, Japanese authors [17] published the first results of using OK-432 as a safe and effective treatment for cystic LMs; in 1994, the authors published the results of treatment of 94 patients with LMs [19]. Since then, the method has become widely used far beyond the borders of the country [20, 21]. The OK-432 is not exactly a sclerosing agent, because it doesn’t destroy vascular endothelium. The OK­ 432 induces apoptosis of lymphatic endothelium and local cellular inflammatory reaction [7, 16]. Recent studies have proved that the pathway of the OK-432 action within lymphangiomas is probably cellular and cytokine-mediated [7, 16]. Complications due to OK-432 management are temporary and predictable [22]. According to the results of the literature analysis, no sys- temic hematological, renal, hepatic or cardiac side effects were detected [23], which was confirmed in our study. The typical side effect of OK­432 sclerotherapy is an inflammatory response that is accompanied by local oedema and may be potentially dangerous in cases of an airway compromised by cervical LMs. In our series, in the patients with impaired mechanics of breathing, tracheostomy was performed prior to treatment. All of those children had signs of respiratory failure, tracheostomy as a preventive procedure was not performed. Unfortunately, none of the suggested methods for cystic LM treatment in children guarantees the complete recovery for all patients [24]; however, the introduction of a minimally invasive treatment of LM significantly reduced the percentage of open surgical inter- ventions and made it possible to differentiate treatment in each individual clinical case. Conclusions The OK-432 sclerotherapy is safe and effective treatment option of head and neck LMs in children. Macrocystic LMs prove the best response to the OK-432 treatment, previous intervention and increasing the part of micro- cystic component reduces the efficacy of treat­ ment. Complications associated with the OK- 432 treatment occurred in 2.52% cases. References 1. Elluru R, Balakrishnan K, Padua H. Lymphatic malformations: Diagnosis and management. Semin Pediatr Surg. 2014;23(4):178–85. doi: 10.1053/j. sempedsurg.2014.07.002. I. M. benzar 24 Su r g ic a l D iS e a Se S iSSN 2413-6077. iJMMr 2017 Vol. 3 issue 2 2. Mulliken JB, Glowacki J. Hemangiomasand vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69(3):412–22. 3. Wassef M, Blei F, Adams D, Alomari A, Ba- selga E, Berenstein A, et al. Vascular Anomalies Classification: Recommendations From the Interna­ tional Society for the Study of Vascular Anomalies. Pediatrics. 2015 Jul;136(1):e203–14. doi: 10.1542/ peds.2014-3673. 4. Perkins J, Manning S, Tempero R, Cunning- ham M, Edmonds J, Hoffer F, et al. Lymphatic mal- formations: Current cellular and clinical investi ga­ tions. Otolaryngol Head Neck Surg. 2010;142(6):789– 94. doi: 10.1016/j.otohns.2010.02.025. 5. Churchill P, Otal D, Pemberton J, Ali A, Flageo- le H, Walton JM. Sclerotherapy for lymphatic mal- formations in children: a scoping review. J Pediatr Surg. 2011;46(5):912–22. doi: 10.1016/j.jped­ surg.2011.02.027. 6. Chen E, Hostikka S, Oliaei S, Duke W, Schwartz S. Perkins J. Similar Histologic Features and Immuno- histochemical Staining in Microcystic and Macrocystic Lymphatic Malformations. Lymphat Res Biol. 2009; 7(2):75–80. doi: 10.1089/lrb.2009.0003. 7. Ardıclı B, Karnak I, Ciftci AO, Tanyel FC, Seno­ cak ME. Sclerotherapy with bleomycin versus surgical excision for extracervical cystic lymphatic malfor- mations in children. Surg Today. 2016;46(1):97–101. 10.1007/s00595-015-1128-0. 8. Weitz-Tuoretmaa A, Rautio R, Valkila J, Keski- Säntti H, Keski­Nisula L, Laranne J. Efficacy of OK­432 sclerotherapy in treatment of lymphatic malfor- mations: long­term follow­up results. Eur Arch Otor­ hinolaryngol. 2014;271(2):385–90. doi: 10.1007/ s00405-013-2542-9. 9. Adams MT, Saltzman B, Perkins JA. Head and Neck Lymphatic Malformation Treatment. Oto- laryngol Head Neck Surg. 2012;147(4):627–39. 10. Love Z. Hsu D. Low­flow vascular malfor­ mations of the head and neck: clinicopathology and image guided therapy. J Neurointerv Surg. 2012; 4(6):414­25. doi: 10.1136/neurintsurg­2011­010126. 11. Malic CC, Guilfoyle R, Courtemanche RJM, Arneja JS, Heran MKS, Courtemanche DJ. Lymphatic Mal formation Architecture. J Craniofac Surg. 2017; 28(7):1721–1724. doi: 10.1097/SCS.0000000000003789. 12. Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for lymphangiomas: A systematic review. Otolaryngol Head Neck Surg. 2008;138(4):418–24. doi: 10.1016/j.otohns.2007.11.018. 13. Horbach SE, Lokhorst MM, Saeed P, de Goüyon Matignon de Pontouraude CM, Rothová A, van der Horst CM. A. Sclerotherapy for low­flow vascular malformations of the head and neck: A systematic review of sclerosing agents. J Plast Reconstr Aesthet Surg. 2016;69(3):295–304. doi: 10.1016/j.bjps.2015.10.045. 14. Wiegand S, Eivazi B, Sel S, Renz H, Werner JA, Folz BJ. Analysis of Cytokine Levels in Human Lymphangiomas. In Vivo. 2008;22(2):253–6. 15. Ogita S, Tsuto T, Deguchi E, Tokiwa K, Nagashima M, Iwai N. OK 432 therapy for unresectable lymphangiomas in children. J Pediatr Surg. 1991; 26(3):263–8. 16. Ghaffarpour N, Petrini B, Svensson LA, Bo- man K, Wester T, Claesson G. Patients with lymphatic malformations who receive the immunostimulant OK-432 experience excellent long-term outcomes. Acta Paediatr. 2015;104(11):1169–73. doi: 10.1111/ apa.13086. 17. Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK­432: a new sclerosing the­ rapy for cystic hygroma in children. Br J Surg. 1987; 74(8):690–1. 18. Benzar I. Treatment of Lymphatic malfor- mations with OK­432: the First Experience of a Single Hospital. Internat J of Biomed. 2014;4(4):237–41. 19. Ogita S, Tsuto T, Nakamura K, Deguchi E, Iwai N. OK-432 therapy in 64 patients with lymphangioma. J Pediatr Surg. 1994;29(6):784–5. 20. Poldervaart MT, Breugem CC, Speleman L, Pasmans S. Treatment of Lymphatic Malformations With OK-432 (Picibanil). J Craniofac Surg. 2009; 20(4):1159–62. doi: 10.1097/SCS.0b013e3181abb249. 21. Tu JH, Do HM, Patel V, Yeom KW, Teng JMC. Sclerotherapy for lymphatic malformations of the head and neck in the pediatric population. J Neuro- interv Surg. 2017;9(10):1023–1026. doi: 10.1136/ neurintsurg-2016-012660. 22. Smith MC, Zimmerman MB, Burke DK, Bauman NM, Sato Y, Smith RJ. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope. 2009;119(1):107–15. doi: 10.1002/ lary.20041. 23. Kim DW. OK-432 sclerotherapy of lymphatic malformation in the head and neck: factors related to outcome. Pediatr Radiol. 2014;44(7):857–62. doi: 10.1007/s00247-014-2889-0. 24. Trenor CC 3rd, Chaudry G. Complex lymphatic anomalies. Semin Pediatr Surg. 2014;23(4):186–90. doi: 10.1053/j.sempedsurg.2014.07.006. Received: 2017-10-13 I. M. benzar