Results of Injection Sclerotherapy with Bleomycin in Pediatric Lymphatic Malformations.

AIM: The aim of the study was to evaluate the results of injection sclerotherapy with bleomycin in pediatric patients with lymphatic malformations.
MATERIALS AND METHODS: In this prospective cohort study, all consenting pediatric patients with macrocystic lymphatic malformations were managed with injection bleomycin sclerotherapy (0.5 mg/kg, not exceeding 5 mg at a time) under ultrasound (US) guidance. After aspirating the cyst fluid bleomycin was instilled intralesionally in a ratio of 5:1 (aspirated cyst fluid volume: diluted bleomycin solution volume). Patients were reassessed at three weekly intervals. The response to therapy was assessed clinically as well as by size and volume on ultrasound Doppler study. The response was classified as excellent response, i.e., complete regression, good response >50% regression, and poor response <50% regression.
RESULTS: Sixty patients with lymphatic malformations were enrolled in the study, the mean age was 3.22 years, and the male-to-female was 2.5:1. The most common site of lesion was in the neck (43.3%), followed by the axilla (15%) and flank (8.3%). The responses were excellent, good, and poor in 43 (71.6%), 12 (20%), and five (8.3%) patients, respectively. Two patients underwent surgical excision of the residual lesion. Complications noted were fever in six, local pain in five, and residual lesion in three patients.
CONCLUSION: Sclerotherapy with bleomycin is simple, safe, and effective in the first line of management for macrocystic lymphatic malformations in children. Copyright:

INTRODUCTION

Lymphatic malformations (LMs) are slow-flow vascular anomalies of the lymphatic system, occurring in 1 of 2000–4000 live births.[1] Most of them are evident at birth (65%), while the remainders become evident by the age of 2 years.[2] They occur in nearly all regions of the body but are most frequently seen in the head and neck (75%), axilla (20%), and inguinal areas (2%).[3] The most common mode of presentation is asymptomatic swelling; however, they can cause symptoms due to compression or pressure effects on neighboring structures.

Histologically, LMs are composed of thin-walled irregular lymphatic channels of varying size lined with lymphatic endothelial cells.[45] The cysts are filled with protein-rich fluid containing lymphocytes and macrophages.[6] Based on the diameter of the cyst, they have been characterized into macrocystic (diameter >1 cm), microcystic (diameter <1 cm), or mixed cystic lesions.[7]

The mainstay of therapy is surgical excision, but due to its nature of extending across anatomical regions and infiltration along important anatomical structures (nerves and vessels), total excision is not always feasible. Extensive surgery often leads to disfigurement, damage to vital structures, and ugly scarring. To avoid the morbidity associated with surgical excision, serial aspirations and injection of sclerosing agents have been used with satisfactory results. They act by producing nonspecific inflammatory reaction.[89] Some of the commonly used sclerosants are doxycycline, ethanol, bleomycin, and sodium tetradecyl sulfate; however, there is no proven superiority of one agent over the other. We set up to study the safety and efficacy of injection bleomycin sclerotherapy for the treatment of macrocystic LMs in children.

MATERIALS AND METHODS

This was a prospective observational cohort study conducted in the department of pediatric surgery and the department of radiology of a tertiary care children's hospital between December 2016 and October 2018. All pediatric patients with LMs were enrolled in the study. Patients with microcystic LM and lesions extending into the mediastinum, lesions around the trachea, infected lesions, and deep retroperitoneal lesions were excluded from injection sclerotherapy.

After obtaining ethical clearance and informed parental consent, a standard protocol for bleomycin sclerotherapy was followed. Each vial of bleomycin having 15 units, i.e., equivalent to 15 mg, was diluted with 5 ml of sterile water for injection constituting a solution of 3 mg per ml. This was further diluted as required. The dose of bleomycin injected was 0.5 mg/kg body weight and not exceeding 5 mg at a time. Injections were given under ultrasound (US) guidance in the department of radiology by pediatric surgeons. Puncture and aspiration of all possible cysts was done with a 21 G needle followed by instillation of intralesional bleomycin in each one in a ratio of 5:1 of the constituted solution (aspirated cyst fluid volume: diluted bleomycin solution volume) [Figure 1]. Wherever possible, post-procedure compression was applied. The patients were kept under observation for 3 h post sclerotherapy. Oral paracetamol was prescribed for pain and fever post sclerotherapy. Patients were reviewed after 3 weeks for evaluation of the response and any need for further sclerotherapy. The response was assessed as excellent, i.e., complete regression, good >50% regression, and poor <50% regression. The response was assessed clinically by the reduction in size in comparison to previous records and photographs and on the basis of color Doppler US by the reduction in size as well as volume. Depending on the response, repeat sclerotherapy was given if required at an interval of 3 weeks with a maximum of four sessions. The final evaluation of the response was recorded during the follow-up visit. The post-sclerotherapy residual lesions if any were managed with either surgical intervention or observation depending on the size, site, response, and patient preference.

Figure 1

(a and b) Ultrasound-guided aspiration and sclerotherapy of large lymphatic cyst

Outcome variables studied were total number of sclerotherapy sessions required for the response of the lesion, proportion of patients with complications if any, and proportion of patients requiring post-sclerotherapy surgical management.

The analysis was performed using the Statistical Package for the Social Sciences (IBM SPSS 25.0. Armonk,NY : IBM Corp.). Statistical significance for qualitative data was assessed with “Chi-square test,” while for quantitative data, it was done using Student's t-test.

RESULTS

In this study, 60 pediatric patients with LMs were prospectively enrolled from December 2016 to October 2018. Majority of the patients were <3 years of age (n = 37; 61.7%), followed by 3–9 years of age (n = 19; 31.7%). The mean age was 3.22 ± 3.39 years and male-to-female ratio was 2.5:1. The neck was the most common site of lesions (n = 26; 43.3%), followed by the axilla (n = 9; 15%), flank (n = 5; 8.3%), chest wall (n = 4; 6.7%), suboccipital region (n = 3;5%), and very few on other sites [Table 1].

Table 1

Location of lesions with a response to bleomycin sclerotherapy

Site of lesion	Response			χ2, P
	Excellent (%)	Good (%)	Poor (%)
Neck (26)	19 (73.1)	6 (23.1)	1 (3.8)	41.812, 0.045
Axila (9)	8 (88.9)	1 (11.1)	0
Flank (5)	3 (60.0)	2 (40.0)	0
Chest (4)	2 (50.0)	1 (25.0)	1 (25.0)
Suboccipital (3)	2 (66.7)	0	1 (33.3)
Arm (2)	2 (100.0)	0	0
Hand (2)	2 (100.0)	0	0
Back (2)	0	2 (100.0)	0
Cheek (1)	1 (100.0)	0	0
Post-auricular (1)	1 (100.0)	0	0
Forearm (1)	1 (100.0)	0	0
Forehead (1)	0	0	1 (100.0)
Supra-scapular (1)	0	0	1 (100.0)
Thigh (1)	1 (100.0)	0	0
Thumb (1)	1 (100.0)	0	0
Total	43 (71.6)	12 (20.0)	5 (8.3)

The number of patients receiving one, two, three, and four sessions of sclerotherapy were 60 (100%), 51 (85%), 34 (56.6%), and 19 (31.6%), respectively. The grading of response with sessions of sclerotherapy is shown in Figure 2.

Figure 2

Grading of response with a number of sessions of sclerotherapy

Overall, 55/60 (91.6%) showed satisfactory response to bleomycin sclerotherapy. Complete resolution to sclerotherapy, i.e., excellent response, was observed in 71.6%, (n = 43), good response in 20%, (n = 12), and poor response in 8.3%, (n = 5), respectively [Table 2 and Figure 3]. Twelve patients (20%) had complications in the form of fever (n = 6; 10%), pain (n = 5; 8.3%), and residual lesion (n = 3;5%) [Table 2]. No complication was noted following the first session of sclerotherapy, but some occurred in the subsequent sessions. None of the patients developed enlargement of size, bleeding, skin discoloration, or scarring following the sclerotherapy.

Table 2

Grades of response and complications

Grade of response	Excellent (n=43; 71.6%)	Good (n=12; 20%)	Poor (n=5; 8.3%)
Complications	Fever	6 (10)
	Pain	5 (8.3)
	Residual lesion	3 (5)

Figure 3

(a) Pre- and (b) post bleomycin sclerotherapy response of a lymphatic malformation

Clinically, the size of lesions included in this study ranged from 2 cm to 24 cm; the mean size was 5.89 cm. The US measured size and volume ranged from 1.7 cm and 1.4 cm3 to 20 cm and 38 cm3, mean being 4.74 cm and 5.82 cm3. The mean clinical size (maximal dimension) of lesions that responded to treatment with one to four sessions of sclerotherapy was 2.5 cm, 4.1 cm, 5.4 cm, and 9.44 cm, respectively. The difference between the size of lesions and the number of sessions of sclerotherapy required was statistically significant (P < 0.001). The mean US measured size and volume of lesions that responded with one to four sessions of sclerotherapy was 1.9 cm and 1.7 cm3; 3.1 cm and 3.05 cm3; 4.38 cm and 5.06 cm3, and 7.7 cm and 10.52 cm3, respectively. The difference between the size and volume of the lesions as measured using US, and the number of sessions of sclerotherapy required was statistically significant (P < 0.001). One patient with chest wall lesion had a good response to sclerotherapy; however, he opted for surgery, while other patients with good responses opted for observation. One patient with neck lesion had a poor response to sclerotherapy and underwent surgical excision. Four patients with lesions at the suprascapular, forehead, chest, and suboccipetal regions had a poor response to sclerotherapy but choose for further observation of the residual lesion. There was weak statistical significance noted between different sites of lesion and response to sclerotherapy [P = 0.045, Table 1].

DISCUSSION

LMs are frequently seen in children. The most common location reported is the head-and-neck region, similar to our finding (43.3%).[3] Treatment options can vary from observation to sclerotherapy to surgical excision. However, no clear treatment algorithm is currently available. Optimal treatment is to restore function and cosmesis. In the absence of any strong evidence in the literature, the choice of treatment depends on the treating team, the type and site of the lesion, and preference of the family. Although surgical excision is a definitive treatment for LMs, it may be difficult at times because of the infiltrative nature of the lesions. These thin-walled lesions often do not respect tissue planes leading to a high incidence of complications (12%–23%) like vital organ injuries, nerve injuries, bleeding, infection scar formation, and recurrences ranging from 15-53%.[1011] In a retrospective cohort study comparing primary surgery versus primary sclerotherapy in LMs, Balakrishnan et al. found no statistically significant difference in effectiveness after the first intervention or at 1 year.[12] Sclerotherapy is a simpler alternative to tedious surgical excision treatment and avoids the complications related to the surgery.[13] Various sclerosants are available for the treatment of LMs. The results seen with most of the agents are comparable.[14] The reported success rates with injection bleomycin, doxycycline, picibanil (OK 432), and sodium tetradecyl sulfate are between 84% and 90%.[1516] Picibanil is currently not Food and Drug Administration approved, sodium tetradecyl sulfate has a higher risk of infections, and doxycycline causes tooth discoloration and mainly works on macrocystic lesions. We have been using bleomycin as it is reported to be effective in macrocystic and some microcystic LMs; it is easily available with satisfactory response rate and has minimal side effects.[17] Complications of bleomycin include mild flu-like symptoms, erythema, edema, and pigmentation which are minor in nature. It is important to keep the dose of bleomycin at 0.5 mg/kg and not exceeding 5 mg at a time to avoid any dose-related toxicity. The systemic complication of pulmonary fibrosis does not occur with the above dose of injection sclerotherapy recommended for the treatment of LMs, as shown in a systematic review and meta-analysis.[18]

The mean age of patients in our study was 3.22 ± 3.39 years, youngest being 11 days and the oldest being 15 years similar to most of the reports.[1920] Post sclerotherapy, no major injection-related event or complication occurred. Oral paracetamol was found to be effective for control of pain and fever. The procedure under sedation is preferred for accurate drug delivery, although we avoided intravenous sedation and managed them on an outpatient basis.[1920] Patients were reviewed after 3 weeks for assessment of response and repeat sclerotherapy was given if deemed necessary for a maximum of four sessions.

The response was graded as excellent, good, and poor as per the report of Rozman et al.[19] The overall satisfactory response rate of 91.6% in this study fared better than most of the reported series[21222324] [Table 3]. Size and volume of the lesions correlated with the number of injection sessions required, as larger lesions required more sessions of sclerotherapy.

Table 3

Comparison of results of bleomycin injection sclerotherpy for lymphatic malformations

Study	Excellent response (%)	Good response (%)	Poor response (%)
Tanigawa et al.[21]	39.4	82	18
Okada et al.[10]	55	86	14
Orford et al.[22]	44	88	12
Zulfiqar et al.[23]	36	82	18
Mahajan et al.[24]	53.3	86.7	13.3
Rozman et al.[19]	63	84	16
Present study	71.6	20	8.3

The probable reason of our higher success rate can be attributed to selective inclusion of macrocystic lesion and exclusion of mediastinal lesions, lesions around the trachea with respiratory distress, infected lesions, and deep retroperitoneal lesions as they generally respond poorly to injection sclerotherapy. Furthermore, ultrasound-guided aspiration and sclerosant therapy used by us resulted in accurate drug delivery leading to a good response. Lesions showing poor response were located in the forehead, neck, chest, suprascapular, and suboccipital regions. Complications observed in our study in the form of fever (10%), tenderness (8.3%), and residual fibrosis (5%) are comparable to similar studies.[2526] Residual lesions post sclerotherapy can be effectively managed by surgery if deemed necessary.[27] Sirolimus has recently been found to be effective in the management of complex LMs due to their anti-lymphangiogenetic properties.[28] A lacuna of our study is the lack of comparison with other modes of therapy. A randomized control trial including various agents used for sclerotherapy in LMs would be more appropriate to validate the role of each one; however, it would require a large number of patients with longer duration of the study.

CONCLUSION

LMs in children require careful selection of procedure from less invasive sclerotherapy to surgical excision or combinations of therapy as definitive treatment. The results of our study reveal that sclerotherapy with injection bleomycin as the first line of treatment in the macrocystic variety has a very good response rate with minimal complications.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.