Effıcıency And Clınıcal Results Of Bleomısın Injectıon In The Treatment Of Lymphatıc Malformatıons

doi:10.21203/rs.3.rs-1964054/v1

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Effıcıency And Clınıcal Results Of Bleomısın Injectıon In The Treatment Of Lymphatıc Malformatıons

https://doi.org/10.21203/rs.3.rs-1964054/v1

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INTRODUCTION: Lymphatic malformations (LM) are rare congenital anomalies. The traditional treatment is surgical excision, but intralesional sclerosing agent injection is now preferred because of frequent recurrences after surgery, poor cosmetic results, and a high complication rate. We aimed to evaluate the efficacy of sclerosing agent injection used in the treatment of LMs in children.

MATERIALS AND METHODS: We retrospectively analyzed the age, gender, admission symptoms, physical examination findings, radiological imaging results, treatment methods, complications, length of hospital stay, and outcomes of children treated for LM between January 2011 and January 2022. The lesion sizes of the patients who underwent sclerosant (Bleomycin) injection under general anesthesia were recorded before and after the treatment, and the difference between them was evaluated statistically.

RESULTS: Fifteen patients were retrospectively analyzed. The mean age was 45.2+- 14.1 months (min:3- median:17- max:210). Of these, 10 (66.6%) were male and 5 (33.3%) were female (F/M=1/2). The mean age of male patients was 55 +- 20.1 months (min :3- max:210 months); The mean age of the female patients was 25.8 + - 11.2 (min 3- max: 66 months). Seven patients had a single dose, two had twice and six had three and more. Three patients had LM in different localisations simultaneously. After the sclerosant injection, surgery was performed on 2 patients, and the tissue that became a mass was removed. The average lesion size before the treatment was 55.2+-28.4 mm; after treatment: 23.8+-18.2mm. With the statistical analysis, it was seen that there was a statistically significant difference between the dimensions before and after the treatment (p<0.05) and the sclerosant injection had a great effect on the treatment (R:0.89).

CONCLUSION: Intralesional injection of bleomycin is less effective for microcystic or mixed type LMs, but provides effective reduction for a safe surgical procedure. It is an effective treatment for macrocystic lesions.

lymphatic malformation

sclerotherapy

bleomycin

Vascular anomalies are classified into two types according to the International Society for the Study of Vascular Anomalies (ISSVA) classification; vascular tumors with proliferative changes in endothelial cells and vascular malformations consisting mainly of structural vascular abnormalities[1] Lymphatic malformations (LM) are rare congenital anomalies consisting of thin-walled, vessels lined with lymphatic endothelial cells[2]. LMs can be morphologically classified as macrocystic, microcystic, or combined (mixed). Macrocystis lesions have at least 2 cm3 cystic spaces, microcystic lesions have less than 2 cm3 cystic spaces, and mixed lesions have both macrocystic and microcystic components[3]. Most macrocystic LMs are detected at birth (50-65%), the remainder by 2 years of age. The head and neck are the most common sites, accounting for 75% of these lesions, followed by the axilla. LMs are rarely seen in the tongue, retroperitoneum, mesentery, groin, and pelvis. Very rarely, it can be present in the parotid, arm, chest wall, breast, and substernal regions. The traditional treatment of LMs is surgical excision, but intralesional sclerosing agent injection is now preferred because of the high complication rate, frequent post-surgery recurrences, and poor cosmetic results[4]. Sclerosing agents cause inflammation, fibrosis, and involution by causing damage to the endothelial cells of cystic lymphangiomas[5]. In this study, it was aimed to evaluate the efficacy of sclerosing agent injection used in the treatment of LMs in children.

We retrospectively analyzed the age, gender, admission symptoms, physical examination findings, radiological imaging results, treatment methods, complications, length of hospital stay, and outcomes of children treated for LM between January 2011 and January 2022. The protocol for his study was approved by the Ethics Committee of Selcuk University Faculty of Medicine (15.02.2022-2022/96).

After the adequate radiologic evaluation (Magnetic Resonance (MR) / Color Doppler ultrasonography (US)), complete blood count and blood biochemistry tests were performed. Sclerosing agent injection was applied under general anesthesia. An aqueous solution of bleomycin (Bleocin®) was used as a sclerosant. The maximum dose was 0.1-0.5 mg/kg per session. Under general anesthesia, the area was first cleaned with povidone-iodine solution (Batticon®) and covered with a sterile drape. After the cyst was punctured with an 18G needle, all the fluid was aspirated and diluted bleomycin was administered into the cyst in an equal volume with the aspirated fluid, not exceeding 20 ml. The patient was hospitalized for 24 hours postoperatively. All patients had ampicillin 10 mg/kg/ day per oral. The response was assessed 4-12 weeks after sclerosant injection. Response to treatment was 'excellent' in patients with full recovery after treatment; 'good' response to treatment in patients with >50% reduction in lesion size; Response to treatment was evaluated as 'poor' in patients with less than 50% reduction in lesion size or recurrence. Relapse was defined as the regrowth of lesions after treatment. The interval between sclerosant injection treatments was 10-12 weeks. Follow-up periods ranged from 6 months to 10 years.

Data were analyzed with SPSS 21.0 software. Descriptive data were expressed as mean ± SD, median, and minimum and maximum values. All treated patients were evaluated for the presence or absence of significant improvement after treatment. The lesion sizes of the patients before and after treatment were compared using the Wilcoxon Signed-Ranks test. P values less than 0.05 were considered statistically significant.

Fifteen patients were reviewed retrospectively. LM was present in 18 localizations. The mean age was 45.2+- 14.1 months (min:3- median:17- max:210). Of these, 10 (66.6%) were male and 5 (33.3%) were female (F/M = 1/2). The mean age of male patients was 55 +- 20.1 months (min :3- max:210 months); The mean age of the female patients was 25.8 + − 11.2 (min 3- max: 66 months). Seven patients had a single dose, two had twice and six had three and more. Three patients had LM in different localizations at the same time. After the sclerosant injection in 2 patients, the tissue that became a mass was removed by surgery. One patient had been operated on twice by plastic surgery before applying to our department. Recurrence was observed in 1 patient 2 years after the treatment. Based on the measurements made in post-treatment ultrasound or MR examinations; response to treatment was perfect in 8, well in 3, and worst in 4 patients. Response rates to treatment are schematized in graph 1. Localization with lesions; the dimensions, injection numbers, and complications before and after treatment are demonstrated in Table 1. There was a statistically significant difference between the dimensions before and after the treatment (p < 0.05) and the sclerosant injection had a great effect on the treatment (R:0.89).

LMs are rare and benign diseases. It is believed that LMs arise from sequestrations of lymphatic tissues/vessels that fail to connect with normal drainage vessels during the embryonic period[6]. Sclerotherapy is an alternative to surgery. The lesion may disappear completely or be reduced to a size that will allow for surgical removal. Bleomycin is used in the treatment of various cancers such as lymphomas, testicular cancer, and other germ cell tumors. It is also applied locally into the pleural space for malignant pleural effusions and intravesically for bladder tumors[7].

75% of LMs are seen in the head and neck region, and the second most common site is the axilla. Tongue, retroperitoneum, mesentery, groin, and pelvis are rare sites. It can very rarely be found in the parotid, arm, chest wall, breast, and substernal regions.

LMs are less common in the tongue. Treatment is indicated only in symptomatic patients or for cosmetic reasons. Complete surgical excision is difficult and the recurrence rate is very high. For these reasons, more conservative procedures such as sclerotherapy are applied[8].In our study,3 patients underwent sclerosant injection to the facial region. In 2 of these patients, an injection was made around the tongue root. In one patient, an injection was made into the upper lip. The patient who had an injection on his upper lip had been operated on twice by the plastic surgery and reconstruction clinic before he applied to our clinic. One of the 2 patients who underwent sclerosant injection around the tongue root was a 10-year-old male patient. He complained of difficulty in speaking and eating. As a result of imaging examinations, it was observed that there were LMs at the base of the tongue that spread to the cervical region. After repeated bleomycin injections, his complaints regressed. Significant regression in lesion dimensions was confirmed by imaging studies (figures − 1–2). The other patient was a 7-month-old infant. He had a macroscopically visible LM on both sides of his tongue and neck. The patient underwent tracheostomy due to respiratory difficulty and gastrostomy due to dysphagia. Due to repeated sclerosant injection, the tongue size decreased and settled in the mouth. His neck lesions regressed.

It was reported that sclerosant injection is highly effective in the treatment of cervical LMs. Sclerotherapy is very effective for macrocystic disease. It should be the first-line treatment for pure macrocystic lesions and mixed lesions with macrocystic components[9, 10]. ]. In our study, there were 8 patients who underwent sclerosant injection to the cervical region. Sclerosant injection was applied to the right cervical region in 3 patients, to the left cervical region in 3 patients, and to the bilateral neck region in 2 patients. All 3 patients had simultaneous LMs extending to the axilla or face. After repeated (3 or more) injections, it was observed that there was a significant reduction in the size of the lesion. In 1 patient, the tissue that became a mass was surgically removed completely. In 1 patient, recurrence was observed in the left cervical region approximately 1 year after the treatment, and he was followed up again. No permanent side effects related to bleomycin injection were observed during the treatment period.

LMs are rarely seen in the axillary region. They often occur simultaneously with neck LMs. Depending on the size of the lesion in the axillary region, shoulder joint abnormalities may also be seen. Surgical excisions may be required after lesion size is reduced by repeated injections of sclerosing agents[11, 12]. The present study, we had a patient with a massive LM in the left axilla and he also had a lesion on the left neck. After repeated injections, the lesion on the neck regressed almost completely. The axillary lesion became a hard mass and shrunk quite well, and it was almost completely removed with surgical treatment. (Fig. 3-4-5-6)

There are cases of aspirated milk-like liquid on the anterior chest wall[4]. We had a patient with a lesion on the anterior chest wall. During the sclerosant injection into the lesion under the left breast, aspiration was first performed and a milk-like liquid was observed. Diluted bleomycin solution was injected into the lesion at an approximate ratio to the aspirated fluid, and the lesion regressed almost completely.

Injection of sclerosing agents is more effective in macrocystic lesions[4, 13, 14]. We had a patient with macrocystic LM in the anterior abdominal wall. Ultrasonographic imaging revealed that the lesion extended into the abdomen between the anterior abdominal wall muscles. During the procedure, a single port entrance was made and the intra-abdominal evaluation was performed by laparoscopy, and it was observed that the lesion was not associated with the abdomen and remained on the peritoneum, and the lesion regressed completely after 1 session of sclerosing substance ejection. We had a patient with a lesion in the right lumbar region extending to the back. Almost complete regression was observed after a single injection. The lesion was not visible macroscopically.

There were 3 patients with LM in the gluteal region, which is a very rare locality. One of these patients applied with the complaint of recurrent perianal and gluteal abscess and cellulitis. With the imaging studies, it was confirmed that there was a fistula tract extending into the rectum associated with the LM and therefore recurrent abscess-cellulitis. Reduction in LM size with the repetitive injection of sclerosing agents after appropriate antibiotic therapy; Along with the improvement in physical appearance, there was a decrease in abscess-cellulite complaints. It was thought that the fistula tract causing cellulitis was also obliterated, along with the LM shrinking with fibrosis and inflammation. (Figure − 7–8) The other two patients had lesions, the majority of which were macrocysts, and almost complete regression in lesion size was observed with sclerosant injection.

Bleomycin is one of the sclerosing agents that can be used safely in sclerotherapy. Except for local temperature increase and skin changes at the injection site, no significant side effects are observed due to bleomycin[4, 6, 13, 15]. We did not have any patients with systemic side effects in the study. Especially in macrocystic LMs, a significant reduction in lesion size was achieved with bleomycin injection. Significant reduction in lesion size was also observed in microcystic or mixed type LMs. We saw that preoperative injection of belomycin facilitated complete removal of the lesion in our patients.

Studies are demonstrating that invasive procedures related to postpartum airway obstruction can be prevented by injecting the appropriate dosage immediately after delivery to patients with antenatally diagnosed LM that compresses the airway or esophagus[16]. The time of application of sclerotherapy to patients diagnosed in the neonatal period is important in terms of localization and location of the LM.

Intralesional bleomycin sclerotherapy is a safe treatment for macrocystic LM in children and should be the first choice of treatment options. Macrocystic LMs can be treated in a single session. Although not as effective as the treatment of macrocystic LMs, it also effectively reduces lesion sizes in the treatment of microcystic and mixed type LMs. It facilitates the surgical operation and reduces the post-surgical complication rates. Of course, larger case series are needed to see its effectiveness on microcyst and mixed type LMs.

Kunimoto, K., Y. Yamamoto, and M. Jinnin, ISSVA Classification of Vascular Anomalies and Molecular Biology. International Journal of Molecular Sciences, 2022. 23(4): p. 2358.
Bawazir, O.A., et al., Efficacy and Clinical Outcomes of Bleomycin in the Treatment of Lymphangiomas: A Multicenter Experience. Dermatol Surg, 2021. 47(7): p. 948–952.
Ardıçlı, B., et al., Sclerotherapy with bleomycin versus surgical excision for extracervical cystic lymphatic malformations in children. Surg Today, 2016. 46(1): p. 97–101.
Bhatnagar, A., et al., Management of macrocystic lymphatic malformation at uncommon site with aqueous bleomycin sclerotherapy. Natl J Maxillofac Surg, 2020. 11(2): p. 193–198.
Muhammad Khuzaemah Saalim Hashmi, S.A., et al., Efficacy Of Intralesional Bleomycin Injection Sclerotherapy In Macrocystic Lymphangioma In Paediatric Patients. J Ayub Med Coll Abbottabad, 2020. 32(1): p. 42–45.
Li, W., et al., The Management of Giant Cerviofacial Lymphatic Malformations in Children. J Craniofac Surg, 2019. 30(6): p. e553-e555.
Baskin, D., B. Tander, and M. Bankaoğlu, Local bleomycin injection in the treatment of lymphangioma. Eur J Pediatr Surg, 2005. 15(6): p. 383–6.
Kataria, P., J.C. Passey, and A.K. Agarwal, Lymphangioma circumscriptum of the tongue: successful treatment using intralesional bleomycin. J Laryngol Otol, 2009. 123(12): p. 1390–2.
Zobel, M.J., et al., Management of cervicofacial lymphatic malformations requires a multidisciplinary approach. J Pediatr Surg, 2021. 56(5): p. 1062–1067.
Lerat, J., et al., Head and neck lymphatic malformation and treatment: Clinical study of 23 cases. Eur Ann Otorhinolaryngol Head Neck Dis, 2016. 133(6): p. 393–396.
Hutchison, D.M., et al., Massive unilateral fetal axillary lymphangioma: A case report. Case Rep Womens Health, 2021. 31: p. e00319.
Ho, F.-C., H.-L. Chen, and H.-W. Chung, Axillary Cystic Hygroma. The Journal of Pediatrics, 2021. 234: p. 273–274.
Sonmez, K., R. Karabulut, and Z. Turkyilmaz, Macrocystic Lymphangioma in Children Treated by Sclerotherapy With Bleomycin. J Craniofac Surg, 2020. 31(3): p. e250-e251.
Upadhyaya, V.D., et al., Is multiple session of intralesional bleomycin mandatory for complete resolution of macrocystic lymphatic malformation? Indian J Plast Surg, 2018. 51(1): p. 60–65.
Usui, H., et al., Lymphatic malformations compromising the upper airway in children: ultrasound-guided intralesional focal sclerotherapy with bleomycin targeting culprit lesions. Pediatr Surg Int, 2020. 36(9): p. 1047–1054.
Jiao-Ling, L., et al., Treatment and prognosis of fetal lymphangioma. Eur J Obstet Gynecol Reprod Biol, 2018. 231: p. 274–279. EFFICIENCY AND CLINICAL RESULTS OF BLEOMYCIN INJECTION IN THE TREATMENT OF LYMPHANGIOMAS

Table-1: Localization of the lesions; dimensions, number of injections, and complications before and after treatment

Parameters		Number of The Lesions (%)
Localization	Face	3 (2 tongue-1 upper lip)(16,6)
	Neck	8 (3 left-3 right-2 bilateral ) (44,4)
	Axilla	1 (5,5)
	Chest wall	1 (breast) (5,5)
	Abdomen	1 (5,5)
	Back	1 (5,5)
	Glutea	3 (16,6)

Type of cystic lymphangioma	Macrocystis	10 (55,5)
	Microcystic	0 (0)
	Mixed	8 (44,4)
Sclerotherapy		15 (83,3)
Scleroterapy+ Surgery		2 (16,6)
Pre procedure Size (mm) (mean±SD)		55,2+-28,4
Number of treatments	1	8 (44,4)
	2	3 (16.6)
	3	3 (16,6)
	>3	4 (22,2)
Post procedure size (mm) (mean±SD)		23,8+-18,2
Complications of procedure	Fever	0
	Local tenderness	3
	Injection site infection	0
	Skin changes	3
	Increase in swelling size	1( 1 year after treatment)
Post-procedure swelling	Present	11
Post-procedure swelling	Absent	7

No competing interests reported.

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Effıcıency And Clınıcal Results Of Bleomısın Injectıon In The Treatment Of Lymphatıc Malformatıons

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