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ORIGINAL ARTICLE
Year : 2021  |  Volume : 54  |  Issue : 5  |  Page : 177-182

Comparison of intralesional bleomycin with/without doxycycline in the primary management of pediatric lymphangiomas


Department of Pediatric Surgery, SMS Medical College, Jaipur, Rajsthan, India

Date of Submission24-Dec-2020
Date of Decision12-Mar-2021
Date of Acceptance27-May-2021
Date of Web Publication12-Oct-2021

Correspondence Address:
Naresh M Pawar
B-52 Embassy Park, Flat No-204, 2nd Floor, Yash Path, Tilak Nagar, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_228_20

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  Abstract 


Background: Although surgical excision is the treatment of choice for lymphangiomas, recently many centers are practicing intralesional sclerotherapy as the primary modality. The purpose of this study was to review the efficacy of intralesional Bleomycin, to study the efficacy of a combination of intralesional bleomycin and doxycycline and compare the results.
Materials and Methods: In this clinical observational study, all patients were evaluated clinically and color Doppler ultrasonography. Patients were grouped into Group A, in which intralesional Bleomycin alone and Group B, in which a combination of intralesional Bleomycin and Doxycycline was instilled into the cysts. The clinical response was assessed and compared between the groups.
Results: Out of 52 patients in the study, the most common site of lymphangioma was cervical 28 (53%) and the most common type was macrocystic lesion 44 (84.5%). In Group A, out of 26 patients, the response was excellent in 15 (58%), satisfactory in 8 (30%), and poor in 3 (12%). In Group B, out of 26 patients, the response was excellent in 22 (85%), satisfactory in 2 (7.5%), and poor in 2 (7.5%). The postprocedure complications were observed more in Group A than Group B, of which the most common was pain/tenderness in five patients followed by redness and fever.
Conclusion: Intralesional bleomycin alone and a combination of intralesional bleomycin and Doxycycline injection both can be safe and effective sclerosant formulas for primary nonsurgical management. The use of combination of Bleomycin and Doxycycline required fewer treatment sessions to obtain clinical success compared to Bleomycin alone.

Keywords: Bleomycin, doxycycline, lymphangioma, sclerosant, surgery


How to cite this article:
Pawar NM, Singh AP, Gupta AK, Chaturvedi V, Barolia DK. Comparison of intralesional bleomycin with/without doxycycline in the primary management of pediatric lymphangiomas. Formos J Surg 2021;54:177-82

How to cite this URL:
Pawar NM, Singh AP, Gupta AK, Chaturvedi V, Barolia DK. Comparison of intralesional bleomycin with/without doxycycline in the primary management of pediatric lymphangiomas. Formos J Surg [serial online] 2021 [cited 2021 Nov 28];54:177-82. Available from: https://www.e-fjs.org/text.asp?2021/54/5/177/327885




  Introduction Top


Lymphangiomas are congenital extra-truncular low flow vascular malformations of lymphatic system occurring in 1 in 2000–4000 live births.[1] These anomalies are present at birth and are visible in 50%–60% but may not be apparent until later in life in rest.[1],[2],[3] They arise when the developmental arrest has occurred during the reticular stage of vasculogenesis, during the first 3 weeks of embryogenesis and morphologically result in lymphatic cysts. They do not involve lymphatic trunks or other mature lymphatic vessels.[4] They are further classified into macrocystic lesions, which contain one or more cysts that are at least 2 cc volume; microcystic lesions, which contain cysts that are individually <2 cc volume and mixed cystic lesions, which contains both macrocysts and microcysts.[5],[6]

Surgical excision is the treatment of choice but has complications (12%–23%) and recurrences (15%–53%) due to extensive surgery.[7] To avoid morbidity, the injection of sclerosant agents has long been used. In recent years, many centers are using sclerosant agents such as Bleomycin, Doxycycline, and OK-32 as first-line therapy with satisfactory results. There has been a combination of sclerosant agents studied, for treatment of malignant pleural effusion, in which it was found that the response to the use of a combination of Bleomycin and tetracycline was superior to that achieved by either of these agents used alone.[8]

The aims and objectives of the present study were to review the efficacy of intralesional Bleomycin, to study the efficacy of a combination of intralesional Bleomycin and Doxycycline and compare the results.


  Materials And Methods Top


This is a clinical observational study comprising of 52 patients presented with lymphangioma. Patients for the study were selected from the pediatric surgical unit of a single teaching institute. This study was conducted from October 2018 to May 2020. The study was approved by institute No. 3330/esst/2021/.

The patient's parents were informed in detail about the study and informed written consent was obtained from all patients' parents included in this study. Once the diagnosis was made, by clinical examination and color Doppler ultrasonography (USG) showing anechoic, at times hyperechoic, multilocular cystic masses with internal septa of varying thickness [Figure 1]. Complete blood count, renal function tests, bleeding time/clotting time, prothrombin time/international normalized ratio, and chest X-ray were done in all patients. For some patients in doubt, computed tomography or magnetic resonance imaging was done. Details were recorded including age, sex, weight, clinical history, site, size, type, and pretreatment color photograph was taken. Patients were grouped into Group A, in which intralesional Bleomycin alone and Group B in which a combination of intralesional Bleomycin and Doxycycline was instilled into the cysts. Patients were selected randomly in two groups, and on the basis of USG color Doppler study, only macrocystic and predominantly macrocystic lymphangioma were managed. All patients received prophylactic antibiotic injection cefotaxime single dose before the procedure.[9] The procedure was performed on a day-care basis under i.v. sedation/under general anesthesia in the operative room. Bleomycin powder (15unit = 15 mg) was reconstituted with 3 ml of normal saline (NS) (dilution 5 mg/ml). The calculated dose was taken from the reconstituted Bleomycin and diluted in 5–10 ml NS in the ratio of 1:1 (1 mg Bleomycin: 1 ml NS).[9] Injection Doxycycline was diluted in distilled water to a concentration of 10 mg/ml. Under USG guidance, using 18G BT needle macrocyst was entered and fluid was aspirated. Keeping the needle in situ, in Group A, Bleomycin 0.5–1 mg/kg was instilled (the total dose not exceeding 15 mg at a time), and in Group B, a combination of Bleomycin (0.5 mg/kg) and Doxycycline 10 mg/kg (maximum dose 300 mg),[10] i.e. Bleomycin followed by Doxycycline was instilled into the macrocysts at a ratio of 1–3:1 (aspirated volume: instilled volume). After the injection, a pressure dressing was applied and was observed till the evening for complications if any and was recorded. If there was no complication, the patient was discharged and recalled after 2–4 weeks for follow-up.
Figure 1: Ultrasonography with color Doppler study of cervical lymphangioma-white arrow showing major neck vessels, red arrow showing anechoic macrocyst and a yellow arrow showing septa

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During follow-up along with clinical assessment, measurement, renal function, chest X-ray was assessed and color photograph was taken.[11],[12] If the lesion was still present, than it was assessed with USG to see the further intralesional injection was feasible. A repeat treatment session was planned, when the size of the cyst was at least 1 cc in size. Follow-up and additional injection was given until the lesion gets completely resolved or intralesional injection was not feasible (cyst <1 cc). The response was graded as excellent (>90% disappearance), satisfactory (showing >50% reduction in size), and poor response (showing <50% reduction or no change in size) and patients were compared into two groups. Patients who showed poor response were offered surgery.

Inclusion criteria

Patients showing macrocystic or predominantly macrocystic lymphangioma on USG color Doppler study were included in the study.

Exclusion criteria

  1. Patients with lesions infiltrating mediastinum
  2. Cervical lymphangioma with strider or breathing difficulty
  3. Patients with intraabdominal lymphangioma
  4. Patients with microcystic or predominantly microcystic lymphangioma
  5. Patients who did not opt for intralesional sclerotherapy.


The statistical analysis was performed using Microsoft Excel (XLSTAT). The mean, range, standard deviation, Chi-square test, and Wilcoxon signed-rank test were analyzed. P <0.05 was considered statistically significant.


  Results Top


In our study, out of 52 patients, 35 were male and 17 were female with a male-to-female ratio of 2:1. The mean age at the presentation was 3½ months, with a range from 3 days to 9 years. Nine patients presented during the neonatal period. The most common location of lymphangioma was cervical 28 (53%) followed by axilla 9 (17%). The most common type was macrocystic lesion 44 (84.5%). The characteristics of pretreatment and posttreatment of cystic lesion of Group A and Group B are shown in [Table 1]. The pretreatment and posttreatment coloured photographs are shown in [Figure 2]. The outcome of the study is shown in [Figure 3].
Table 1: Charecteristic of lymphangioma in Group A and Group B

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Figure 2: (a-c) With yellow arrow showing pretreatment lymphangioma at neck, axilla and mouth at 17 days, 45 days and 6 years respectively. Green arrow showing excellent response with Bleomycin + Doxycycline in a' and c', and b' with Bleomycin alone after 4, 1 and 1 sessions respectively

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Figure 3: Showing clinical response of patients in Group A and Group B

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The Wilcoxon signed-rank test was applied to compare size before the start of the treatment and after the completion of treatment in both Group A and Group B, as shown in [Table 1]. The Wilcoxon signed-rank test was statistically significant if P < 0.05.

In Group A, out of 26 patients, the response was excellent in 15 (58%), satisfactory in 8 (30%), and poor in 3 (12%). In Group B, out of 26 patients, the response was excellent in 22 (85%), satisfactory in 2 (7.5%), and poor in 2 (7.5%). When compared to the overall response of patients in Group A and Group B by the Chi-square test, it was statistically not significant (P > 0.05). However, the number of treatment sessions required for patients in Group A as compared to Group B was statistically significant (P < 0.05), i.e. the number of sessions required for patients in Group B was less compared to patients in Group A. The postprocedure complications were observed more in Group A than Group B, of which the most common was pain/tenderness in five patients followed by redness and fever, as shown in [Table 1]. Out of five patients who had a poor response (all mixed lesions) after four treatment sessions, three underwent surgical excisions which were located at the left flank, left axilla, and left cervical region. The other two patients are in follow-up.


  Discussion Top


In this clinical observational study of 52 patients with lymphangiomas, the mean age of presentation was 3.5 months with a range (3 days–9 years) as in other studies.[6],[13],[14],[15] There was male predominance with a male-to-female ratio of 2:1 as found in other studies.[11],[16] They can be found in all tissues or organ systems, most commonly in the cervical and axillary locations with the exception of the central nervous system. They most commonly appear as ballottable masses with the normal overlying skin, although a blue hue may result if large underlying cysts are present.[12] The cervical region was the most common site followed by the axilla and chest wall as 53%, 17%, and 7.5%, respectively, similar was observed in other studies.[15],[17] The most common type was macrocystic 44 (84.5%) as observed in other studies.[6],[13],[14],[15],[16],[17],[18],[19],[20]

Conventionally, complete surgical excision has been the modality of choice for lymphangioma. However, the presence of important neurovascular structures in the vicinity of the lymphangioma and infiltration into the surrounding tissue planes makes dissection difficult, and complete excision may require multiple operations. Moreover, complete excision may not be possible without damage to adjacent important structures in complex lymphangiomas and also there is a high rate of complications and recurrence.[2],[3],[11] The first reported case of lymphangioma treated by sodium morrhuate sclerosant was in 1933 by Harrower.[18] In the last two decades, there has been the use of percutaneous sclerotherapy as a primary treatment modality in many centers with promising results by using mainly Bleomycin, Doxycycline, and OK-32.[2],[3],[6],[13],[14],[16],[17],[18],[19],[20] The surgery can be reserved for poor responders or who is with complications.[15]

Bleomycin is an antibiotic chemotherapeutic agent discovered by Umezawa in 1962.[21] It is administered parenterally in the treatment of squamous cell carcinoma, head and neck tumors, non-Hodgkin's lymphoma, and testicular teratomas. It has been also used in haemangioma and congenital vascular malformations intralesionally.[22] In cystic lymphangioma, its sclerosant action is the result of direct action on endothelial linings, which leads to aseptic nonspecific inflammation, fibrosis, and involution of cystic cavity.[11],[14],[15],[19]

Bleomycin was first trialled with successful results for unresectable eight cases of lymphangiomas by Yura et al. in 1977.[22] It was originally prepared in an oil emulsion for intralesional injection of lymphangioma and the success rate (excellent and good results) was about 80%.[19] Okada et al. and Niramis et al. prepared Bleomycin in NS instead of oil emulsion and observed the same satisfactory results of about 88% and 83%, respectively.[2],[15] In the present study, Group A (Bleomycin alone) patients showed an 88.5% success rate (excellent and satisfactory results), when it was prepared in NS (aqueous preparation).

Doxycycline is a derivative of tetracycline and it is easily an available less expensive broad-spectrum antibiotic. With minimal side effects, it was used as a sclerosant in the pleurodesis of malignant pleural effusion.[23] For this reason, its usefulness in lymphangioma was evaluated and Molitch et al. discovered it as an efficient therapy for the first time in 1995.[24] Although it has been used as a sclerosant for almost two decades, its exact mechanism is unknown. However, it is speculated that it initiates an inflammatory process that results in fibrosis and involution of the cyst. Doxycycline therapy seems to be associated with an inhibition of matrix metalloproteinase (MMP), which may be a cause of its effectiveness. Moreover, it suppresses the vascular endothelial growth factor (VEGF) induced angiogenesis and lymphangiogenesis.[20]

In 1996 Emad et al. conducted a trial for pleurodesis of malignant pleural effusion using a combination of Bleomycin and tetracycline and Bleomycin or tetracycline alone. The study concluded that a combination of Bleomycin and tetracycline was superior to that achieved by either of these agents used alone. In the present study, we analyzed the efficacy of the combination of Bleomycin and Doxycycline in cystic lymphangiomas. In Group B (combination of Bleomycin and Doxycycline), out of 26 patients, the response was excellent in 22 (85%), satisfactory in 2 (7.5%), and poor in 2 (7.5%). On comparing overall response of patients in Group A and Group B, both had equal effectiveness. However, the number of sessions required for patients in Group B was significantly less as compared to patients in Group A. The reason may be the additive or synergetic local action of two sclerosant agents on lymphangioma. The postprocedure complications were observed more in Group A than Group B, of which the most common was pain/tenderness followed by redness and fever as observed in other studies.[13],[14],[15],[16],[19],[20],[22],[23],[24] The reason for fewer complications observed in Group B may be local action of Doxycycline, i.e. inhibition of MMP, suppression of VEGF-induced angiogenesis, and lymphangiogenesis.[20] Surgery was done in poor responders as in other studies.[14],[17]

Pulmonary toxicity/fibrosis is a potential side effect of Bleomycin therapy. This risk is related to the dose, and increasing incidence being associated with the total dose of more than 400 units or a single dose exceeding 30 mg. The pulmonary fibrosis of intralesional Bleomycin therapy is not reported so far because of its low dose.[13],[14],[15],[16] In the present study also, none developed pulmonary complication.

Tooth discoloration is well-known long-term complication of Doxycycline in children below 8 years when used either enteral or parenterally,[25] but not observed when used intralesional in many studies.[14],[16] Similarly, in the present study, none has developed tooth discoloration till now and will be in follow-up to monitor.

The limitation of the study was small sample size; it needs further studies with large sample size by making three groups as combination of Bleomycin and Doxycycline and Bleomycin or Doxycycline alone to compare the efficacy as independent and in combination.


  Conclusion Top


The experience from the present study suggests that Intralesional Bleomycin alone and a combination of intralesional Bleomycin and Doxycycline injection both can be safe and effective sclerosant formulas for primary nonsurgical management of macrocystic and predominantly macrocystic lymphangiomas. Both Bleomycin and Doxycycline are easily available and relatively less expensive. The use of a combination of Bleomycin and Doxycycline required fewer treatment sessions to obtain clinical success compared to Bleomycin alone in our experience. There was no grave complication observed in the study. The long-term risk of tooth discoloration from Doxycycline use remains to be investigated, particularly in children under 2 years. The exact local action of combination of Bleomycin and Doxycycline, additive or synergetic action needs to be investigated in further studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Okada A, Kubota A, Fukuzawa M, Imura K, Kamata S. Injection of bleomycin as a primary therapy of cystic lymphangioma. J Pediatr Surg 1992;27:440-3.  Back to cited text no. 2
    
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Emad A, Rezaian GR. Treatment of malignant pleural effusions with a combination of bleomycin and tetracycline. A comparison of bleomycin or tetracycline alone versus a combination of bleomycin and tetracycline. Cancer 1996;78:2498-501.  Back to cited text no. 8
    
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Sanlialp I, Karnak I, Tanyel FC, Senocak ME, Büyükpamukçu N. Sclerotherapy for lymphangioma in children. Int J Pediatr Otorhinolaryngol 2003;67:795-800.  Back to cited text no. 14
    
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[PUBMED]  [Full text]  
18.
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19.
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22.
Yura J, Hashimoto T, Tsuruga N, Shibata K. Bleomycin treatment for cystic hygroma in children. Nihon Geka Hokan 1977;46:607-14.  Back to cited text no. 22
    
23.
Månsson T. Treatment of malignant pleural effusion with doxycycline. Scand J Infect Dis Suppl 1988;53:29-34.  Back to cited text no. 23
    
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