- Email: [email protected]
Surgical Excision With Bleomycin Irrigation: A Better Primary Treatment Choice for Pediatric Submandibular Lymphatic Malformations
Accepted Manuscript Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations Lei Jin, MD, Attending, Jiarui Chen, MD, Attending, Xiaoyan Li, MD, Department head PII:
S0278-2391(16)30901-6
DOI:
10.1016/j.joms.2016.09.041
Reference:
YJOMS 57476
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 19 May 2016 Revised Date:
20 September 2016
Accepted Date: 20 September 2016
Please cite this article as: Jin L, Chen J, Li X, Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.09.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page Title: Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations
Department head)
RI PT
Author: Lei Jin (MD, Attending), Jiarui Chen (MD, Attending), Xiaoyan Li (MD,
Children’s Hospital, Shanghai Jiao Tong University
M AN U
Address: 355 Luding Road, Shanghai China, 200062 Corresponding author: Dr. Xiaoyan Li Email: [email protected] Tel: +86 02162474880
AC C
EP
TE D
Fax: +86 02162474880
SC
Affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Shanghai
ACCEPTED MANUSCRIPT Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations Lei Jin, Jiarui Chen, Xiaoyan Li
RI PT
Abstract Purpose: To compare efficacy between surgical excision combined with intralesional bleomycin irrigation and needle aspiration with bleomycin sclerotherapy (IBS) in
SC
pediatric submandibular lymphatic malformations (LMs).
M AN U
Methods: The medical records of thirty-two subjects were analyzed. Clinical response was categorized by improvement in size as determined by imaging studies and calculations of the lesion volume. Excellent response was defined as >90% reduction, satisfactory response was defined as >50% reduction, and poor response was defined
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as <50% reduction in volume. Additionally, we developed a new scale to quantify the treatment outcome. This scoring system is composed of six parts. They are size reduction, aesthetic problem, functional problem (such as breathing, eating, and
EP
speech), post-operative complications, necessity for further intervention and times of
AC C
intervention. We used Pearson’s chi square test and t-tests to compare the treatment outcome between the two groups. Results: The average age at first treatment was 2 years. Twenty-two patients underwent surgical excision with bleomycin irrigation as the primary treatment. Three of the 22 underwent two rounds of cyst aspiration with IBS during follow-up. IBS was performed as the primary treatment in 10 patients. All patients underwent a single surgery, and the number of IBS procedures per patient varied from one to three (mean 1
ACCEPTED MANUSCRIPT 1.8). In the surgical group, 72.7% (16/22) of patients demonstrated excellent response, 18.2% (4/22) demonstrated satisfactory response and 9% (2/22) demonstrated poor response.The surgical excision group had a significantly higher
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rate of excellent response than the sclerotherapy group (P<0.05). According to the new scale, there was a significant difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and surgical excision with bleomycin irrigation had
SC
better efficacy than IBS.
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Conclusion: Surgical excision with bleomycin irrigation is a better primary treatment choice for pediatric submandibular LMs. Cyst aspiration with IBS is a good method with which to address localized recurrence.
Key words: bleomycin; lymphatic malformations; sclerotherapy.
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Introduction
Lymphatic malformations (LMs) are congenital anomalies that occur frequently in the head and neck region of infants and young children. Although they
EP
are benign, large swollen masses in the head and neck can cause cosmetic and
AC C
functional problems or even compression of the airway. Surgical excision has been the standard form of management. However, LMs in the head and neck region are frequently located near important vital structures, and complete excision is sometimes impossible. Therefore, many types of sclerosant agents, including doxycycline, OK432, ethanol, sodium tetradecyl sulfate and bleomycin, have been used since 1933 as an alternative to surgery [1-6]. Adams et al. [7] systematically reviewed head and neck LMs and reported that both surgical excision and sclerotherapy may be effective 2
ACCEPTED MANUSCRIPT for treatment. However, few studies have been conducted to compare efficacy between the various types of treatment. At present, there is no widely accepted management paradigm or guideline for treatment outcomes. Therefore, the aim of this
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study was to compare efficacy between surgical excision combined with intralesional bleomycin irrigation and needle aspiration with bleomycin sclerotherapy in pediatric submandibular lymphatic malformations. To this end, we developed a new scale to
SC
quantify the outcome of treatment.
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Methods
We reviewed the medical records of all children diagnosed with head and neck LMs who were treated in our department from January 2010 to July 2015. The medical records were abstracted for age; mode of presentation (symptoms that were
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present and when the symptoms appeared); location, type and size of the lesion; and treatment procedure. Inclusion criteria of this study included subjects whose lesions were confined to the submandibular region and had been followed for more than six
EP
months after the final intervention. Sixty-four subjects were identified, and 30 cases
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were excluded for the following reasons: 1) the lesion was not located in the submandibular region, or 2) the lesion was so large that it extended to the mouth floor, the parotid region and even the superior mediastinum region. The locations of the LMs are shown in Table 1. Thirty-two of 34 subjects whose lesions were confined to the submandibular region had adequate follow-up data. LM was diagnosed by means of physical examination, and information from imaging studies such as ultrasonography (US), computed tomography and/or magnetic resonance imaging was 3
ACCEPTED MANUSCRIPT used. US assessment was performed on all patients to classify the type of LMs. As described by Ogita [8], type was classified as macrocystic (>1 cm), microcystic (<1 cm) or mixed. CT with contrast was performed to exclude an arterio-venous
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malformation. Cystic volume was calculated using the formula for volume of an ellipsoid.
In the surgical group, after the lesion was completely removed, 20 mL of
SC
bleomycin aqueous solution (15 mg/20 mL) was used to wash the surgical cavity. The
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bleomycin aqueous solution was left in situ for 3 minutes for better penetration into and reaction with the cyst wall, and then the solution was removed. In the sclerotherapy group, the components of the lesion were aspirated using ultrasound guidance. We kept the tip of the aspiration needle within the cyst lumen, and then
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bleomycin aqueous solution (15 mg/20 mL) was injected into the cyst at a maximum volume of 1 mL. When more than one cyst was aspirated, the calculated dose was divided by the number of cysts aspirated, and the divided dose was injected into each
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cyst. A pressure dressing was used postoperatively. Clinical response was categorized
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by improvement in size, which was determined by imaging studies and calculation of the lesion volume. Excellent response was defined as >90% reduction, satisfactory response was defined as >50% reduction, and poor response was defined as <50% reduction in volume observed in follow-up radiological studies or ultrasonographic studies. Because there was no consistent method of assessing and reporting treatment outcomes, we developed a scale to quantify the outcome of treatment. This scoring system is composed of six parts: LM size reduction, aesthetic problem, functional 4
ACCEPTED MANUSCRIPT problem (such as breathing, eating, and speech), post-operative complications, necessity for further intervention and time of intervention (Table 2). Data analysis was performed using SPSS. Pearson’s chi square test and t-tests
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were used, and the significance level was fixed at 5%. Due to the retrospective nature of this study, it was granted an exemption in writing by the IRB of Shanghai Children’s Hospital.
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Results
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The average age at first treatment was 2 years, with a range of 11 days to 12 years, and 56.2%(18/32) of patients were male. Most of the lesions were macrocystic type (n=26), followed by mixed type (n=6); there were no microcystic lesions in this series. The age at diagnosis ranged from prenatal diagnosis to 12 years of age, and
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nearly half of patients (15/32) had symptoms at birth. All the patients in this study had a large swelling in the submandibular and neck region, and five of the 32 patients had slight difficulty in breathing because the lesion extended to the parapharyngeal region
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and the retropharyngeal region and compressed the airway. These five patients
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underwent surgical excision with bleomycin irrigation. The most frequently used diagnostic tool was US, which was used in all patients. CT scan was used in 26 patients (Fig. 1-2), and MRI was used in 6 patients. Twenty-two patients underwent surgical excision with bleomycin irrigation as the initial treatment (Fig. 3-5). Three of 22 patients underwent two rounds of cyst aspiration with intralesional bleomycin sclerotherapy (IBS) during the follow-up period. In 10 patients, IBS was performed as the primary treatment, and one patient underwent surgical excision three months after 5
ACCEPTED MANUSCRIPT the first treatment. All patients underwent a single surgery, and the number of IBS procedures per patient varied from one to three (mean 1.8). The average follow-up period was 28.8±18.1 months (range 6-72 months). One patient had temporary facial
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paralysis after the surgery. Other post-treatment complications included fever (18/32) and swelling (22/32).
In the surgical group, 72.7% (16/22) of patients demonstrated excellent
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response, 18.2% (4/22) demonstrated satisfactory response and 9% (2/22)
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demonstrated poor response. In the sclerotherapy group, 3 demonstrated excellent response, and 6 demonstrated satisfactory response. The one remaining patient had poor response and underwent surgical excision after 3 months of follow-up. The surgical excision group had a significantly higher rate of excellent response than the
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sclerotherapy group (P<0.05), although the total improvement rate was similar in the two groups. Lesion type did affect outcome in both groups (P>0.05). In addition, we compared the treatment outcomes with the new scale. There was a significant
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difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and
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surgical excision with bleomycin irrigation had better efficacy than IBS in submandibular LMs in children. Discussion
It has been reported that LM is typically detected at birth in up to 65% of
cases and presents by the age of two years in 90% of cases [9,10]. In this study, the tumor was detected at birth in more than 50% of the patients, and two patients were diagnosed prenatally. Extensive use of prenatal US has permitted the in utero 6
ACCEPTED MANUSCRIPT diagnosis of cervical lymphangioma. Both CT scans and US are helpful for demonstrating the solid or cystic nature of the lesion. US is usually performed to define the size and extent of the mass; however, US has limited ability to assess
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mediastinal and retropharyngeal structures. CT carries the risk of radiation exposure and the disadvantage of loss of detail, but contrast helps to enhance cyst wall visualization and the relationship with surrounding blood vessels [11]. Pui M et al.
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[12] reported that MRI was the most useful modality for assessing extension. In our
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opinion, ultrasonography is the best choice for initial diagnosis, and CT scanning with contrast should be performed before surgery to determine the relationship between the tumor and the important structures surrounding it. US is also a good choice for follow-up. MRI is not a good choice because it takes longer and thus often requires
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chloral hydrate or another calmative agent in pediatric patients. Moreover, MRI has little advantage in defining the tumor compared to CT scanning with contrast. Adams et al. [7] systematically reviewed head and neck lymphatic
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malformations and reported that both surgery and sclerotherapy may be effective for
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treatment without any clear evidence as to which modality is superior. Bleomycin is an antitumor agent that was discovered in 1965 and can cause non-specific inflammatory reactions leading to fibrosis of cysts. Various studies have produced promising results using bleomycin sclerotherapy [13,14]. Surgical excision is a traditional and effective way to treat LMs, but complete resection of the lesion is challenging for extensive lesions because of potential complications such as facial nerve damage. Inconsistent data presentation limits our ability to make comparisons 7
ACCEPTED MANUSCRIPT across treatment groups, and few publications have discussed the issue of which technique is superior. In addition, we need a consistent assessment system to evaluate treatment outcomes. Therefore, we designed this study to compare the efficacy of
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surgical excision plus intralesional bleomycin irrigation with that of needle aspiration plus bleomycin sclerotherapy in pediatric submandibular LMs. We developed a scale for assessing and reporting treatment outcomes. We designed this evaluation system
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according to recommended documentation guidelines for treatment of lymphatic
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malformation treatment as described in clinical reports by Adams MT et al. [7]. In that review, the degree of size reduction of the malformation, the resolution of functional compromise, treatment complications, need for further treatment and length of hospital stay were recommended as post-treatment assessments. Because a
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large swelling in the head or neck can cause aesthetic problems and can be a psychological burden to the patient and their family, we added aesthetic problem as another evaluating indicator.
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In this study, the surgical excision group had a significantly higher rate of
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excellent response than the sclerotherapy group (72.7 vs. 30%). There was a significant difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and surgical excision with bleomycin irrigation had better efficacy than IBS in submandibular LMs in children. Olímpio et al. [15] reported a cross-sectional study, and the proportion of patients considered cured after the first therapeutic approach was 44% in the surgery group and 29% in the bleomycin group. Although the favorable rate was higher in the surgical group, they encountered two serious 8
ACCEPTED MANUSCRIPT intraoperative complications and suggested that surgical excision be reserved either for the resection of remaining fibrotic tissue after sclerotherapy or as a first-line therapy for LMs localized outside the cervicofacial region, where the risk of injuring
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nervous structures is smaller. In our research, there were no serious complications in the surgical group. We agree that complete excision is not always possible because the cyst wall is very thin, and the lesion is often infiltrative and involves critical
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neurovascular structures. However, we were still able to carefully perform the
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procedure, and we tried to open up every “cell” of the lesion and remove the fluid inside. We attempted to remove as much cyst wall as we could, but when it adhered to critical structures, we could perform marsupialization only. After surgical excision, we used 20 mL bleomycin aqueous solution (15 mg/20 mL) to wash the surgical
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cavity to induce a non-specific inflammatory reaction, and a pressure dressing was necessary to promote adhesion of cyst walls and fibrosis of the lesion. This is a retrospective study, and by its nature, it has inherent bias. However,
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the size of the lesion does not affect our choice of treatment. In our opinion, the
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treatment modality should be designed according to the location and type of lesion but not by its size. For example, one patient with a lymphatic malformation located in the parotid region and another patient with a lesion located in the submandibular and neck region should be treated according to different protocols. In this study, we enrolled patients treated in our department between 2010 and 2015. Over these five years, we treated more than sixty children with lymphatic malformations of the head and neck region. Until recently, we had an additional 18 patients completing follow-up. We 9
ACCEPTED MANUSCRIPT continued to think about the best treatment and summarized our experience. Initially, we chose needle aspiration with bleomycin sclerotherapy as the primary treatment choice because it was recommended by many institutions and because it seems safer.
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However, after follow-up of several cases and the accumulation of surgical experience, we gradually formed our treatment protocols for LMs of different locations. Surgical excision with bleomycin irrigation is a better primary treatment
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choice for pediatric submandibular LMs. Regardless of lesion size, as long as it is
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confined to the submandibular and neck region, we are still able to perform surgical excision and open up every “cell” of the lesion and remove the fluid inside. Jeffrey Cheng [16] agreed in his review that patient selection is probably the most important factor in choosing an optimal treatment strategy and limiting morbidity.
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For sclerotherapy of LMs, previous authors have suggested a dose of less than 1 mg/kg with a total dose of 5 mg/kg [13,15,17,18]. Olímpio [15] reported bleomycin (2 mg/mL solution administered at dose of 0.5 mg/kg) being injected into the lesion.
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Erikçi V et al. [13] reported 1 mg/kg body weight of aqueous bleomycin (1 mg/mL)
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being injected after aspiration, with the maximum volume for replacement being 20 ml regardless of the volume of aspirated fluid. In this study, bleomycin aqueous solution (15 mg/20 ml) was injected into the cyst after aspiration, and the maximum volume for injection was 1 ml. The total amount of bleomycin injected was much less than that reported in other studies. There has been no uniformity in the dose of this drug in the reported series. In our opinion, 1 mL (0.75 mg/mL) of bleomycin is adequate to induce intralesional fibrosis, and a lower dose is safer for pediatric 10
ACCEPTED MANUSCRIPT patients. In addition, as much as 20 mL of bleomycin aqueous injection does not improve the aesthetic problem of LMs. In this study, most of the lesions were of the macrocystic type (n=26),
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followed by the mixed type (n=6), and there were no microcystic lesions in this series. It is reported that in cases of microcystic disease, sclerotherapy is often less effective, as there are no dominant cysts to target with image-guided sclerotherapy delivery
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[15,16]. Although there is emerging experience showing favorable results with the use
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of bleomycin for microcystic head and neck lymphatic malformations in children [19], we recommend surgical excision because theoretically, bleomycin will not induce adhesion of the cyst wall in this type of lesion. Conclusion
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Surgical excision with bleomycin irrigation is a better primary treatment choice for pediatric submandibular LMs, and cyst aspiration with IBS is a good way to address localized recurrence. The scoring system in this study is thought to be a
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useful tool, although it requires improvement.
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Conflict of interests None.
References
[1] Cordes BM1, Seidel FG, Sulek M, Giannoni CM, Friedman EM: Doxycycline sclerotherapy as the primary treatmentfor head and neck lymphatic malformations. Otolaryngol Head Neck Surg137(6):962–4,2007. 11
ACCEPTED MANUSCRIPT [2] Shiels WE 2nd, Kang DR, Murakami JW, Hogan MJ, Wiet GJ. Percutaneous treatment of lymphaticmal formations. Otolaryngol Head Neck Surg 141(2):219– 24,2009.
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[3] Smith MC1, Zimmerman MB, Burke DK, Bauman NM, Sato Y, Smith RJ. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope 119(1):107–15,2009.
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[4] Alomari AI, Karian VE, Lord DJ, Padua HM, Burrows PE. Percutaneous
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sclerotherapy for lymphatic malformations: a retrospective analysis of patientevaluated improvement. J VascInterv Radiol 17(10):1639–48,2006. [5] Bloom DC, Perkins JA, Manning SC. Management of lymphatic malformations. Curr Opin Otolaryngol Head Neck Surg 12(6):500–4,2004.
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[6] Balakrishnan K, Perkins J. Management of head and neck lymphatic malformations. Facial Plast Surg 28(6):596–602,2012. [7] Adams MT, Saltzman B, Perkins JA. Head and neck lymphatic malformation
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treatment: a systematic review. Otolaryngol Head Neck Surg 147:627-639,2012.
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[8] Ogita S, Tsuto T, Deguchi E, Tokiwa K, Nagashima M, Iwai N. OK-432 therapy for unresectable lymphangiomas in children. J Pediatr Surg 26:263-268,1991. [9] Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for lymphangiomas: a systematic review. Otolaryngol Head Neck Surg 138:418-424,2008. [10] Sanlialp I, Karnak I, Tanyel FC, Senocak ME, Büyükpamukçu N. Sclerotherapy for lymphangioma in children. Int J Pediatr Otorhinolaryngol 67:795-800,2003.
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ACCEPTED MANUSCRIPT [11] Mosca RC, Pereira GA, Mantesso A. Cystic hygroma: characterization by computerized tomography. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105(5):65-9,2008.
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[12] Pui M,Li Z, Chen W, Chen JH. Lymphangioma: Imaging diagnosis. Austrialia Radiol 41:324-328,1997.
[13] Erikçi V, Hoşgör M, Yıldız M, Örnek Y, Aksoy N, Okur Ö, Demircan Y, Genişol
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İ. Intralesional bleomycin sclerotherapy in childhood lymphangioma. Turk J Pediatr
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55(4):396-400,2013.
[14] Rozman Z, Thambidorai RR, Zaleha AM, Zakaria Z, Zulfiqar MA. Lymphangioma: Is intralesional bleomycin sclerotherapy effective? Biomed Imaging Interv J 7(3):e18,2011.
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[15] Olímpio Hde O, Bustorff-Silva J, Oliveira Filho AG, Araujo KC. Cross-sectional study comparing different therapeutic modalities for cystic lymphangiomas in children. Clinics (Sao Paulo) 69(8):505-8,2014.
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[16] Cheng J. Doxycycline sclerotherapy in children with head and neck lymphatic
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malformations. J Pediatr Surg 50(12):2143-6,2015. [17] Kim KH, Sung MW, Roh JL, Han MH. Sclerotherapy for congenital lesions in the head and neck. Otolaryngol Head Neck Surg 131(3):307-16,2004. [18] Zhou Q, Zheng JW, Mai HM, Luo QF, Fan XD, Su LX, Wang YA, Qin ZP. Treatment guidelines of lymphatic malformations of the head and neck. Oral Oncol 47(12):1105-9,2011.
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ACCEPTED MANUSCRIPT [19] Chaudry G, Guevara CJ, Rialon KL, Kerr C, Mulliken JB, Greene AK, Fishman SJ, Boyer D, Alomari AI. Safety and efficacy of bleomycin sclerotherapy for microcystic lymphatic malformation. Cardiovasc Intervent Radiol 37(6):1476-
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81,2014.
Table 1. Sites of involvement
n
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Site
Parotid region Axillary and thoracic wall Temporal region Shoulder
34
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Submandibular and neck region
10 4 1 2 2
Tongue
2
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Floor of Mouth
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Supraclavicular and superior mediastinum region
7
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Huge mass extending to multiple regions
2
14
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ACCEPTED MANUSCRIPT
Table 2. Quantitative scoring system for the treatment of lymphangioma score 3
2
1
Size reduction
>90%
50-90%
10-50%
<10%
Aesthetic problem
no
a little
some disturbance
annoyed
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Functional problem
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Items
no
much
minor
improvement
improvement
0
no improvement
Post-operative no
Necessity of further
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complications
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serious infections,
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no
fever, swelling
hematoma,
permanent facial
temporal facial
paralysis and other
paralysis, Horner
nerve injuries
syndrome... another another intervention
maybe
intervention within
intervention
Times of intervention
one time
within 2 weeks 6 months two times
15
three times
>three times
ACCEPTED MANUSCRIPT
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Figure legends
right submandibular lymphangioma. Fig. 2. Coronal CT with contrast of this patient.
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Fig. 1. Axial CT with contrast of a one-month-old patient with a macrocystic type
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Fig. 3-4. Two weeks after surgical excision plus intralesional bleomycin irrigation. Complete regression.
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Fig. 5. Three months after the primary treatment. There is no sign of recurrence.
16
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S0278-2391(16)30901-6
DOI:
10.1016/j.joms.2016.09.041
Reference:
YJOMS 57476
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 19 May 2016 Revised Date:
20 September 2016
Accepted Date: 20 September 2016
Please cite this article as: Jin L, Chen J, Li X, Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.09.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title page Title: Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations
Department head)
RI PT
Author: Lei Jin (MD, Attending), Jiarui Chen (MD, Attending), Xiaoyan Li (MD,
Children’s Hospital, Shanghai Jiao Tong University
M AN U
Address: 355 Luding Road, Shanghai China, 200062 Corresponding author: Dr. Xiaoyan Li Email: [email protected] Tel: +86 02162474880
AC C
EP
TE D
Fax: +86 02162474880
SC
Affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Shanghai
ACCEPTED MANUSCRIPT Surgical excision with bleomycin irrigation: A better primary treatment choice for pediatric submandibular lymphatic malformations Lei Jin, Jiarui Chen, Xiaoyan Li
RI PT
Abstract Purpose: To compare efficacy between surgical excision combined with intralesional bleomycin irrigation and needle aspiration with bleomycin sclerotherapy (IBS) in
SC
pediatric submandibular lymphatic malformations (LMs).
M AN U
Methods: The medical records of thirty-two subjects were analyzed. Clinical response was categorized by improvement in size as determined by imaging studies and calculations of the lesion volume. Excellent response was defined as >90% reduction, satisfactory response was defined as >50% reduction, and poor response was defined
TE D
as <50% reduction in volume. Additionally, we developed a new scale to quantify the treatment outcome. This scoring system is composed of six parts. They are size reduction, aesthetic problem, functional problem (such as breathing, eating, and
EP
speech), post-operative complications, necessity for further intervention and times of
AC C
intervention. We used Pearson’s chi square test and t-tests to compare the treatment outcome between the two groups. Results: The average age at first treatment was 2 years. Twenty-two patients underwent surgical excision with bleomycin irrigation as the primary treatment. Three of the 22 underwent two rounds of cyst aspiration with IBS during follow-up. IBS was performed as the primary treatment in 10 patients. All patients underwent a single surgery, and the number of IBS procedures per patient varied from one to three (mean 1
ACCEPTED MANUSCRIPT 1.8). In the surgical group, 72.7% (16/22) of patients demonstrated excellent response, 18.2% (4/22) demonstrated satisfactory response and 9% (2/22) demonstrated poor response.The surgical excision group had a significantly higher
RI PT
rate of excellent response than the sclerotherapy group (P<0.05). According to the new scale, there was a significant difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and surgical excision with bleomycin irrigation had
SC
better efficacy than IBS.
M AN U
Conclusion: Surgical excision with bleomycin irrigation is a better primary treatment choice for pediatric submandibular LMs. Cyst aspiration with IBS is a good method with which to address localized recurrence.
Key words: bleomycin; lymphatic malformations; sclerotherapy.
TE D
Introduction
Lymphatic malformations (LMs) are congenital anomalies that occur frequently in the head and neck region of infants and young children. Although they
EP
are benign, large swollen masses in the head and neck can cause cosmetic and
AC C
functional problems or even compression of the airway. Surgical excision has been the standard form of management. However, LMs in the head and neck region are frequently located near important vital structures, and complete excision is sometimes impossible. Therefore, many types of sclerosant agents, including doxycycline, OK432, ethanol, sodium tetradecyl sulfate and bleomycin, have been used since 1933 as an alternative to surgery [1-6]. Adams et al. [7] systematically reviewed head and neck LMs and reported that both surgical excision and sclerotherapy may be effective 2
ACCEPTED MANUSCRIPT for treatment. However, few studies have been conducted to compare efficacy between the various types of treatment. At present, there is no widely accepted management paradigm or guideline for treatment outcomes. Therefore, the aim of this
RI PT
study was to compare efficacy between surgical excision combined with intralesional bleomycin irrigation and needle aspiration with bleomycin sclerotherapy in pediatric submandibular lymphatic malformations. To this end, we developed a new scale to
SC
quantify the outcome of treatment.
M AN U
Methods
We reviewed the medical records of all children diagnosed with head and neck LMs who were treated in our department from January 2010 to July 2015. The medical records were abstracted for age; mode of presentation (symptoms that were
TE D
present and when the symptoms appeared); location, type and size of the lesion; and treatment procedure. Inclusion criteria of this study included subjects whose lesions were confined to the submandibular region and had been followed for more than six
EP
months after the final intervention. Sixty-four subjects were identified, and 30 cases
AC C
were excluded for the following reasons: 1) the lesion was not located in the submandibular region, or 2) the lesion was so large that it extended to the mouth floor, the parotid region and even the superior mediastinum region. The locations of the LMs are shown in Table 1. Thirty-two of 34 subjects whose lesions were confined to the submandibular region had adequate follow-up data. LM was diagnosed by means of physical examination, and information from imaging studies such as ultrasonography (US), computed tomography and/or magnetic resonance imaging was 3
ACCEPTED MANUSCRIPT used. US assessment was performed on all patients to classify the type of LMs. As described by Ogita [8], type was classified as macrocystic (>1 cm), microcystic (<1 cm) or mixed. CT with contrast was performed to exclude an arterio-venous
RI PT
malformation. Cystic volume was calculated using the formula for volume of an ellipsoid.
In the surgical group, after the lesion was completely removed, 20 mL of
SC
bleomycin aqueous solution (15 mg/20 mL) was used to wash the surgical cavity. The
M AN U
bleomycin aqueous solution was left in situ for 3 minutes for better penetration into and reaction with the cyst wall, and then the solution was removed. In the sclerotherapy group, the components of the lesion were aspirated using ultrasound guidance. We kept the tip of the aspiration needle within the cyst lumen, and then
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bleomycin aqueous solution (15 mg/20 mL) was injected into the cyst at a maximum volume of 1 mL. When more than one cyst was aspirated, the calculated dose was divided by the number of cysts aspirated, and the divided dose was injected into each
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cyst. A pressure dressing was used postoperatively. Clinical response was categorized
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by improvement in size, which was determined by imaging studies and calculation of the lesion volume. Excellent response was defined as >90% reduction, satisfactory response was defined as >50% reduction, and poor response was defined as <50% reduction in volume observed in follow-up radiological studies or ultrasonographic studies. Because there was no consistent method of assessing and reporting treatment outcomes, we developed a scale to quantify the outcome of treatment. This scoring system is composed of six parts: LM size reduction, aesthetic problem, functional 4
ACCEPTED MANUSCRIPT problem (such as breathing, eating, and speech), post-operative complications, necessity for further intervention and time of intervention (Table 2). Data analysis was performed using SPSS. Pearson’s chi square test and t-tests
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were used, and the significance level was fixed at 5%. Due to the retrospective nature of this study, it was granted an exemption in writing by the IRB of Shanghai Children’s Hospital.
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Results
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The average age at first treatment was 2 years, with a range of 11 days to 12 years, and 56.2%(18/32) of patients were male. Most of the lesions were macrocystic type (n=26), followed by mixed type (n=6); there were no microcystic lesions in this series. The age at diagnosis ranged from prenatal diagnosis to 12 years of age, and
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nearly half of patients (15/32) had symptoms at birth. All the patients in this study had a large swelling in the submandibular and neck region, and five of the 32 patients had slight difficulty in breathing because the lesion extended to the parapharyngeal region
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and the retropharyngeal region and compressed the airway. These five patients
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underwent surgical excision with bleomycin irrigation. The most frequently used diagnostic tool was US, which was used in all patients. CT scan was used in 26 patients (Fig. 1-2), and MRI was used in 6 patients. Twenty-two patients underwent surgical excision with bleomycin irrigation as the initial treatment (Fig. 3-5). Three of 22 patients underwent two rounds of cyst aspiration with intralesional bleomycin sclerotherapy (IBS) during the follow-up period. In 10 patients, IBS was performed as the primary treatment, and one patient underwent surgical excision three months after 5
ACCEPTED MANUSCRIPT the first treatment. All patients underwent a single surgery, and the number of IBS procedures per patient varied from one to three (mean 1.8). The average follow-up period was 28.8±18.1 months (range 6-72 months). One patient had temporary facial
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paralysis after the surgery. Other post-treatment complications included fever (18/32) and swelling (22/32).
In the surgical group, 72.7% (16/22) of patients demonstrated excellent
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response, 18.2% (4/22) demonstrated satisfactory response and 9% (2/22)
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demonstrated poor response. In the sclerotherapy group, 3 demonstrated excellent response, and 6 demonstrated satisfactory response. The one remaining patient had poor response and underwent surgical excision after 3 months of follow-up. The surgical excision group had a significantly higher rate of excellent response than the
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sclerotherapy group (P<0.05), although the total improvement rate was similar in the two groups. Lesion type did affect outcome in both groups (P>0.05). In addition, we compared the treatment outcomes with the new scale. There was a significant
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difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and
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surgical excision with bleomycin irrigation had better efficacy than IBS in submandibular LMs in children. Discussion
It has been reported that LM is typically detected at birth in up to 65% of
cases and presents by the age of two years in 90% of cases [9,10]. In this study, the tumor was detected at birth in more than 50% of the patients, and two patients were diagnosed prenatally. Extensive use of prenatal US has permitted the in utero 6
ACCEPTED MANUSCRIPT diagnosis of cervical lymphangioma. Both CT scans and US are helpful for demonstrating the solid or cystic nature of the lesion. US is usually performed to define the size and extent of the mass; however, US has limited ability to assess
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mediastinal and retropharyngeal structures. CT carries the risk of radiation exposure and the disadvantage of loss of detail, but contrast helps to enhance cyst wall visualization and the relationship with surrounding blood vessels [11]. Pui M et al.
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[12] reported that MRI was the most useful modality for assessing extension. In our
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opinion, ultrasonography is the best choice for initial diagnosis, and CT scanning with contrast should be performed before surgery to determine the relationship between the tumor and the important structures surrounding it. US is also a good choice for follow-up. MRI is not a good choice because it takes longer and thus often requires
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chloral hydrate or another calmative agent in pediatric patients. Moreover, MRI has little advantage in defining the tumor compared to CT scanning with contrast. Adams et al. [7] systematically reviewed head and neck lymphatic
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malformations and reported that both surgery and sclerotherapy may be effective for
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treatment without any clear evidence as to which modality is superior. Bleomycin is an antitumor agent that was discovered in 1965 and can cause non-specific inflammatory reactions leading to fibrosis of cysts. Various studies have produced promising results using bleomycin sclerotherapy [13,14]. Surgical excision is a traditional and effective way to treat LMs, but complete resection of the lesion is challenging for extensive lesions because of potential complications such as facial nerve damage. Inconsistent data presentation limits our ability to make comparisons 7
ACCEPTED MANUSCRIPT across treatment groups, and few publications have discussed the issue of which technique is superior. In addition, we need a consistent assessment system to evaluate treatment outcomes. Therefore, we designed this study to compare the efficacy of
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surgical excision plus intralesional bleomycin irrigation with that of needle aspiration plus bleomycin sclerotherapy in pediatric submandibular LMs. We developed a scale for assessing and reporting treatment outcomes. We designed this evaluation system
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according to recommended documentation guidelines for treatment of lymphatic
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malformation treatment as described in clinical reports by Adams MT et al. [7]. In that review, the degree of size reduction of the malformation, the resolution of functional compromise, treatment complications, need for further treatment and length of hospital stay were recommended as post-treatment assessments. Because a
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large swelling in the head or neck can cause aesthetic problems and can be a psychological burden to the patient and their family, we added aesthetic problem as another evaluating indicator.
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In this study, the surgical excision group had a significantly higher rate of
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excellent response than the sclerotherapy group (72.7 vs. 30%). There was a significant difference between the mean value of the two groups (14.2±2.1 vs. 9.8±1.8), and surgical excision with bleomycin irrigation had better efficacy than IBS in submandibular LMs in children. Olímpio et al. [15] reported a cross-sectional study, and the proportion of patients considered cured after the first therapeutic approach was 44% in the surgery group and 29% in the bleomycin group. Although the favorable rate was higher in the surgical group, they encountered two serious 8
ACCEPTED MANUSCRIPT intraoperative complications and suggested that surgical excision be reserved either for the resection of remaining fibrotic tissue after sclerotherapy or as a first-line therapy for LMs localized outside the cervicofacial region, where the risk of injuring
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nervous structures is smaller. In our research, there were no serious complications in the surgical group. We agree that complete excision is not always possible because the cyst wall is very thin, and the lesion is often infiltrative and involves critical
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neurovascular structures. However, we were still able to carefully perform the
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procedure, and we tried to open up every “cell” of the lesion and remove the fluid inside. We attempted to remove as much cyst wall as we could, but when it adhered to critical structures, we could perform marsupialization only. After surgical excision, we used 20 mL bleomycin aqueous solution (15 mg/20 mL) to wash the surgical
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cavity to induce a non-specific inflammatory reaction, and a pressure dressing was necessary to promote adhesion of cyst walls and fibrosis of the lesion. This is a retrospective study, and by its nature, it has inherent bias. However,
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the size of the lesion does not affect our choice of treatment. In our opinion, the
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treatment modality should be designed according to the location and type of lesion but not by its size. For example, one patient with a lymphatic malformation located in the parotid region and another patient with a lesion located in the submandibular and neck region should be treated according to different protocols. In this study, we enrolled patients treated in our department between 2010 and 2015. Over these five years, we treated more than sixty children with lymphatic malformations of the head and neck region. Until recently, we had an additional 18 patients completing follow-up. We 9
ACCEPTED MANUSCRIPT continued to think about the best treatment and summarized our experience. Initially, we chose needle aspiration with bleomycin sclerotherapy as the primary treatment choice because it was recommended by many institutions and because it seems safer.
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However, after follow-up of several cases and the accumulation of surgical experience, we gradually formed our treatment protocols for LMs of different locations. Surgical excision with bleomycin irrigation is a better primary treatment
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choice for pediatric submandibular LMs. Regardless of lesion size, as long as it is
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confined to the submandibular and neck region, we are still able to perform surgical excision and open up every “cell” of the lesion and remove the fluid inside. Jeffrey Cheng [16] agreed in his review that patient selection is probably the most important factor in choosing an optimal treatment strategy and limiting morbidity.
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For sclerotherapy of LMs, previous authors have suggested a dose of less than 1 mg/kg with a total dose of 5 mg/kg [13,15,17,18]. Olímpio [15] reported bleomycin (2 mg/mL solution administered at dose of 0.5 mg/kg) being injected into the lesion.
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Erikçi V et al. [13] reported 1 mg/kg body weight of aqueous bleomycin (1 mg/mL)
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being injected after aspiration, with the maximum volume for replacement being 20 ml regardless of the volume of aspirated fluid. In this study, bleomycin aqueous solution (15 mg/20 ml) was injected into the cyst after aspiration, and the maximum volume for injection was 1 ml. The total amount of bleomycin injected was much less than that reported in other studies. There has been no uniformity in the dose of this drug in the reported series. In our opinion, 1 mL (0.75 mg/mL) of bleomycin is adequate to induce intralesional fibrosis, and a lower dose is safer for pediatric 10
ACCEPTED MANUSCRIPT patients. In addition, as much as 20 mL of bleomycin aqueous injection does not improve the aesthetic problem of LMs. In this study, most of the lesions were of the macrocystic type (n=26),
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followed by the mixed type (n=6), and there were no microcystic lesions in this series. It is reported that in cases of microcystic disease, sclerotherapy is often less effective, as there are no dominant cysts to target with image-guided sclerotherapy delivery
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[15,16]. Although there is emerging experience showing favorable results with the use
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of bleomycin for microcystic head and neck lymphatic malformations in children [19], we recommend surgical excision because theoretically, bleomycin will not induce adhesion of the cyst wall in this type of lesion. Conclusion
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Surgical excision with bleomycin irrigation is a better primary treatment choice for pediatric submandibular LMs, and cyst aspiration with IBS is a good way to address localized recurrence. The scoring system in this study is thought to be a
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useful tool, although it requires improvement.
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Conflict of interests None.
References
[1] Cordes BM1, Seidel FG, Sulek M, Giannoni CM, Friedman EM: Doxycycline sclerotherapy as the primary treatmentfor head and neck lymphatic malformations. Otolaryngol Head Neck Surg137(6):962–4,2007. 11
ACCEPTED MANUSCRIPT [2] Shiels WE 2nd, Kang DR, Murakami JW, Hogan MJ, Wiet GJ. Percutaneous treatment of lymphaticmal formations. Otolaryngol Head Neck Surg 141(2):219– 24,2009.
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[3] Smith MC1, Zimmerman MB, Burke DK, Bauman NM, Sato Y, Smith RJ. Efficacy and safety of OK-432 immunotherapy of lymphatic malformations. Laryngoscope 119(1):107–15,2009.
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[4] Alomari AI, Karian VE, Lord DJ, Padua HM, Burrows PE. Percutaneous
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sclerotherapy for lymphatic malformations: a retrospective analysis of patientevaluated improvement. J VascInterv Radiol 17(10):1639–48,2006. [5] Bloom DC, Perkins JA, Manning SC. Management of lymphatic malformations. Curr Opin Otolaryngol Head Neck Surg 12(6):500–4,2004.
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[6] Balakrishnan K, Perkins J. Management of head and neck lymphatic malformations. Facial Plast Surg 28(6):596–602,2012. [7] Adams MT, Saltzman B, Perkins JA. Head and neck lymphatic malformation
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treatment: a systematic review. Otolaryngol Head Neck Surg 147:627-639,2012.
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[8] Ogita S, Tsuto T, Deguchi E, Tokiwa K, Nagashima M, Iwai N. OK-432 therapy for unresectable lymphangiomas in children. J Pediatr Surg 26:263-268,1991. [9] Acevedo JL, Shah RK, Brietzke SE. Nonsurgical therapies for lymphangiomas: a systematic review. Otolaryngol Head Neck Surg 138:418-424,2008. [10] Sanlialp I, Karnak I, Tanyel FC, Senocak ME, Büyükpamukçu N. Sclerotherapy for lymphangioma in children. Int J Pediatr Otorhinolaryngol 67:795-800,2003.
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ACCEPTED MANUSCRIPT [11] Mosca RC, Pereira GA, Mantesso A. Cystic hygroma: characterization by computerized tomography. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105(5):65-9,2008.
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[12] Pui M,Li Z, Chen W, Chen JH. Lymphangioma: Imaging diagnosis. Austrialia Radiol 41:324-328,1997.
[13] Erikçi V, Hoşgör M, Yıldız M, Örnek Y, Aksoy N, Okur Ö, Demircan Y, Genişol
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İ. Intralesional bleomycin sclerotherapy in childhood lymphangioma. Turk J Pediatr
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55(4):396-400,2013.
[14] Rozman Z, Thambidorai RR, Zaleha AM, Zakaria Z, Zulfiqar MA. Lymphangioma: Is intralesional bleomycin sclerotherapy effective? Biomed Imaging Interv J 7(3):e18,2011.
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[15] Olímpio Hde O, Bustorff-Silva J, Oliveira Filho AG, Araujo KC. Cross-sectional study comparing different therapeutic modalities for cystic lymphangiomas in children. Clinics (Sao Paulo) 69(8):505-8,2014.
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[16] Cheng J. Doxycycline sclerotherapy in children with head and neck lymphatic
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malformations. J Pediatr Surg 50(12):2143-6,2015. [17] Kim KH, Sung MW, Roh JL, Han MH. Sclerotherapy for congenital lesions in the head and neck. Otolaryngol Head Neck Surg 131(3):307-16,2004. [18] Zhou Q, Zheng JW, Mai HM, Luo QF, Fan XD, Su LX, Wang YA, Qin ZP. Treatment guidelines of lymphatic malformations of the head and neck. Oral Oncol 47(12):1105-9,2011.
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ACCEPTED MANUSCRIPT [19] Chaudry G, Guevara CJ, Rialon KL, Kerr C, Mulliken JB, Greene AK, Fishman SJ, Boyer D, Alomari AI. Safety and efficacy of bleomycin sclerotherapy for microcystic lymphatic malformation. Cardiovasc Intervent Radiol 37(6):1476-
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81,2014.
Table 1. Sites of involvement
n
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Site
Parotid region Axillary and thoracic wall Temporal region Shoulder
34
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Submandibular and neck region
10 4 1 2 2
Tongue
2
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Floor of Mouth
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Supraclavicular and superior mediastinum region
7
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Huge mass extending to multiple regions
2
14
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Table 2. Quantitative scoring system for the treatment of lymphangioma score 3
2
1
Size reduction
>90%
50-90%
10-50%
<10%
Aesthetic problem
no
a little
some disturbance
annoyed
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Functional problem
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Items
no
much
minor
improvement
improvement
0
no improvement
Post-operative no
Necessity of further
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complications
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serious infections,
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no
fever, swelling
hematoma,
permanent facial
temporal facial
paralysis and other
paralysis, Horner
nerve injuries
syndrome... another another intervention
maybe
intervention within
intervention
Times of intervention
one time
within 2 weeks 6 months two times
15
three times
>three times
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Figure legends
right submandibular lymphangioma. Fig. 2. Coronal CT with contrast of this patient.
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Fig. 1. Axial CT with contrast of a one-month-old patient with a macrocystic type
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Fig. 3-4. Two weeks after surgical excision plus intralesional bleomycin irrigation. Complete regression.
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Fig. 5. Three months after the primary treatment. There is no sign of recurrence.
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