Effect analysis of lauromacrogol foam injection under ultrasonic guidance for pediatric superficial lymphatic malformation

doi:10.21203/rs.3.rs-3594164/v1

Download PDF

Research Article

Effect analysis of lauromacrogol foam injection under ultrasonic guidance for pediatric superficial lymphatic malformation

https://doi.org/10.21203/rs.3.rs-3594164/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective To evaluate the efficacy and safety of ultrasound guided lauromacrogol foam sclerotherapy in the treatment of children’s superficial lymphatic malformation.

Methods Retrospectively analyzing 64 pediatric patients (36 male, 28 female), aged 3 months to 14 years, who underwent lauromacrogol foam sclerotherapy with ultrasonic guidance for superficial lymphatic malformation at Hunan Children's Hospital from March 2018 to November 2022, the study grouped patients into 18 macrocystic, 40 microcystic, and 6 mixed types. Pre-sclerotherapy evaluations included local ultrasound, blood routine, liver and kidney function, and coagulation tests. The surface anesthetic lidocaine cream was applied 30 minutes prior, followed by ultrasound-guided lymphatic malformation area localization, cyst fluid extraction, and lauromacrogol foam injection (lauromacrogol: air = 1:3; single dose < 20 ml) to fill the cyst cavity, with retention of the lauromacrogol stock solution (< 2 ml). Assessing drug dispersion in the cyst cavity via ultrasound and confirming high-echo gas filling, the follow-up period ranged from 3 to 12 months, with evaluations on clinical manifestations, imaging data, treatment efficacy, and complications.

Results The children received treatment 2-6 times, with an average of 4 treatments per case. A total of thirty-three cases(51.56%) achieved complete remission, while twenty-eight(43.75%) cases showed significant improvement. Three cases failed to respond and subsequently underwent surgical resection. The overall efficacy rate was determined to be 95.31%. Early edema occurred in five cases, localized skin pigmentation in one case, thrombotic superficial vein inflammation in two cases, and transient cough in one case. None of the children experienced serious complications such as allergic reactions, deep vein thrombosis or pulmonary embolism, skin necrosis or discoloration, chest tightness or other cardiopulmonary issues.

Conclusions The utilization of ultrasound-guided foam sclerotherapy with lauromacrogol represents a secure and efficacious approach for managing lymphatic malformations in pediatric patients.

Pediatric patients

Superficial lymphatic malformation

Lauromacrogol foam

Sclerotherapy

Lymphatic malformation (LM), also known as cystic hydroma or cystic lymphatic malformation, is a prevalent vascular anomaly in pediatric patients. The etiology of LM remains elusive and it is currently postulated to arise from excessive proliferation of lymphatic tissue within the cystic cavity. Recent investigations have identified somatic PIK3CA mutations as potential contributors to LM[1–3]. The incidence of LM ranges from 1:2000 to 1:4000, with no discernible gender or racial predilection, and approximately 80–90% of cases are diagnosed around the age of two [4]. Predominantly affecting the head and neck region, LM exhibits diverse clinical presentations and individual variations. Typically presenting as a painless mass with a soft, sac-like texture, this condition can rapidly enlarge when complicated by infection and hemorrhage, accompanied by local skin warmth elevation, pain, and other associated symptoms [5]. According to the International Society for the Study of Vascular Anomalies (ISSVA) classification system, lymphatic malformations can be categorized into macrocystic, microcystic, or mixed type [6].

At present, the treatments of LM include surgical resection, interventional therapy, local sclerotherapy, oral medication and laser therapy [7]. The local sclerotherapy has emerged as one of the primary treatment modalities for LM due to its minimal complications and low recurrence rate. Common hardeners include Pingyangmycin and lauromacrogol. The application of lauromacrogol is commonly observed in the management of vascular lesions, including varicose veins and venous malformations [8]. The deformations of lymphatic vessels commonly occur in the head and neck region, particularly in close proximity to vital blood vessels and nerves, posing significant challenges for surgical intervention [9]. The utilization of color ultrasound guidance enables more precise localization of diseased tissue, thereby minimizing the risk associated with blind puncture and enhancing the overall safety of surgical procedures [10]. We implemented foam injection of lauromacrogol guided by color ultrasound for the treatment of pediatric superficial lymphatic malformation, resulting in a favorable outcome, as detailed below.

General information and clinical data

The study protocol was approved by the ethics committee of Hunan Children's Hospital. From July 2018 to December 2022, a total of 64 pediatric patients diagnosed with lymphatic malformation were retrospectively analyzed according to the diagnostic criteria established by ISSVA. Among these patients, there were 36 males and 28 females, aged from 3 months to 14 years (mean age: 6.12 years). The study included 18 cases of single cystic type, 40 cases of polycystic type, and six cases of mixed type. Head and neck regions accounted for thirty-eight cases while limbs and trunk accounted for twenty-six cases in terms of anatomical distribution. Tumor size ranged from approximately dimensions measuring at least about 2.5cm×2.0cm up to those measuring at most around 12.0cm×10.0cm. Preoperative assessments for all children consisted of local B-ultrasound examination as well as blood routine tests evaluating liver function, kidney function, coagulation status among others.

Inclusion criteria

Children under 18 years old and their family members were volunteered to participate in this study. The imaging diagnosis is evident or the pathological findings are conclusive. The cystic cavity of the patient was located superficially, with a maximum puncture depth from the body surface not exceeding 3.0cm. The patient exhibited normal coagulation function, liver and kidney function, blood routine, as well as the absence of autoimmune diseases. Exclusion criteria encompassed children who failed to meet the aforementioned inclusion criteria and those with a documented hypersensitivity to lauromacrogol.

Ethical review

This study was approved by the ethics committee of Hunan Children’s Hospital. The guardians of all children signed the written informed consent of ultrasound-guided percutaneous injection of laurylalcohol for the treatment.

Treatment process

All children underwent percutaneous injection of lauromacrogol foam sclerotherapy guided by color Doppler ultrasound, following the identification of typical ultrasound signs of lymphatic malformation. After determining the precise location and dimensions of the cyst cavity, a direct percutaneous puncture was performed under the guidance of color Doppler ultrasound. The Tessari technique was employed to administer lauromacrogol followed by the application of a foam sclerosing agent. Two 10-ml sterile syringes were used to extract air from the room; one connected to a Millipore self-packaging needle filter, and the other for extracting 1% lauromacrogol injection. The ratio of gas to liquid was 3:1. Make sure that the two syringe ports could be connected to a three-way switch. Rapidly and repeatedly inject the liquid into the two syringes for a minimum of 20 cycles, until the emulsion transforms into a dense foam sclerosing agent, ensuring its readiness for application. Children under the age of 5 received oral administration of chloral hydrate as a sedative prior to surgery, while topical lidocaine cream was applied to the tumor surface 30 minutes before the procedure for local anesthesia. Children aged over 5 years were requested to cooperate, and only compound lidocaine cream was administered for analgesia. Following the marking of the puncture site, local disinfection was performed, and a 5ml syringe was utilized to connect the puncture needle for multi-point puncturing. When the presence of yellow or light red lymph was observed, prompt aspiration of the cyst fluid was performed, and then lauromacrogol foam was slowly injected to fill the cyst cavity (lauromacrogol: air = 1:3; Single dose < 20ml). The foam filling within the cyst cavity was reassessed using Color Doppler ultrasound, followed by a slow injection of 1–2 ml lauromacrogol stock solution into the confirmed filled cavity. After perfusion, compression was applied to the injection site for 10–20 minutes. The children were closely monitored for 24 hours during and after the treatment to assess the occurrence of hypotension, bradycardia, severe cough, skin ulcer necrosis, and other complications.

Curative effect and Followup

The children had monthly follow-up visits after being discharged, where changes in tumor characteristics (size, color, and photographic documentation) were assessed. Tumor evaluation was done using color Doppler ultrasound, while patient observation focused on identifying potential complications.

Efficacy evaluation

Ineffective: The ultrasound examination revealed no discernible change or tumor growth following a 2-month infusion of the treatment. Effective: The treatment yielded a significant reduction of over 50% in tumor size. Cure: Complete eradication of the tumor. The overall response rate is calculated by dividing the sum of cure and remission cases by the total number of cases, multiplied by 100%.

A retrospective analysis was conducted on a cohort of 64 pediatric patients diagnosed with lymphatic malformations (LM). The age distribution of the study population is depicted in Fig. 1.The group of children underwent treatment (2–6) times per case, with an average frequency of 4 times per case. Among the pediatric patients, the surgical procedure lasted for 37.59 ± 1.38 (36 to 40) minutes, and the follow-up duration was 9.93 ± 8.43(3–12)months (Table 1).Thirty-three cases achieved complete remission and twenty-eight cases showed partial response. Three cases experienced treatment failure and subsequently underwent surgical resection (Table 2).The total effective rate was 95.31%. The 33 cured children showed resolution of clinical symptoms, absence of LM body upon physical examination, and were followed up for over 6 months.The corresponding B-ultrasound showed that LM body basically subsided (Fig. 2a-b and Fig. 3a-b), and 28 cases were relieved. Clinical symptoms disappeared or significantly improved, and LM body subsided by more than 50% (Fig. 2c-d and Fig. 3c-d).

Table 1

General data of patients
Gender		Age (Years)	Operation time (Minutes)	Treatment times (N)	Fellow-up time(Months)
Male	Female
36	28	6.12 ± 4.13	37.59 ± 1.38	4.35 ± 1.83	9.93 ± 8.43

Table 2

The therapeutic effect and results of treatments
Gender		Cured (N)	Relieved (N)	Noneffective (N)
Male	Female
36	28	33	28	3

Five patients with early swelling (ES) were relieved spontaneously without special treatment. Two patients with thrombotic superficial vein inflammation (TSVI) were relieved spontaneously without special treatment in a few days, and one patient with transient cough (TC) was relieved spontaneously. One child had residual local skin pigmentation (LSP) after surgery. The other 58 children had no special discomfort. None of the children had serious complications such as allergic reactions, deep vein thrombosis and pulmonary embolism, pigmentation, skin necrosis, chest tightness, or other cardiopulmonary.

Table 3

The statistics of complications
Gender		ES (N)	LSP (N)	TSVI (N)	TC (N)	None (N)
Male	Female
36	28	5	1	2	1	58

Lymphatic malformation (LM) is a low-flow vascular anomaly, the pathogenesis of which remains obscure. Empirical evidence indicates that LM is associated with the abnormal development of the early embryonic lymphatic system [11]. The etiology of lymphatic malformations may stem from the aberrant proliferation of lymphatic mesenchyme, exacerbated by the local microenvironment and the density and composition of surrounding tissues, which can facilitate tumor growth. Furthermore, certain theories postulate a potential link with the PIK3/AKT/mTOR signaling pathway [12].The pathological manifestations of LM feature lymphatic endothelial cells with thin walls, irregular morphology, and dilated vessels filled with lymph fluid. Lesions are surrounded by fibroblasts, adipocytes, and neutrophils. There was no aberrant proliferation of lymphatic endothelial cells, and their morphology and function remained unaltered; however, the lumen diameter exhibited abnormal enlargement [13]. Furthermore, a majority of the lesions were disconnected from the normal lymphatic system within the body, with only a few lesions demonstrating unidirectional flow towards the upper lymphatic vessels [14].

LM can occur in all parts of the lymphatic network, especially in the head and neck, followed by axilla, mediastinum and limbs. LM grows slowly and generally does not resolve spontaneously without conscious symptoms. However, it can exhibit rapid growth following trauma, infection, intracapsular hemorrhage, and inappropriate treatment, accompanied by localized pain and elevated skin temperature [15]. Specifically, lesions situated in the facial region, neck, and extremities can potentially lead to disfigurement, deformity, or symptoms of compression. The presence of LM in critical locations such as the respiratory tract and joints can lead to respiratory obstruction or impaired motor function, thereby exerting a profound impact on patients' well-being and even posing life-threatening risks. The current treatment options encompass surgical intervention, interventional therapy, pharmacotherapy, and sclerotherapy among others [16–18]. Oral medications such as rapamycin exhibit a gradual onset of response, rendering them suitable for children in specific locations or with limited response to sclerotherapy. Local tissue biopsy and genetic testing can be conducted to confirm the presence of somatic PIK3CA mutation. Sclerotherapy has been established as the primary treatment modality for superficial lymphatic malformations (LM) [19, 20].

At present, commonly used sclerosing agents include lauromacrogol, pingyangmycin, absolute alcohol, etc. [21]. Pingyangmycin is an anti-tumor drug, which has dose-dependent pulmonary toxicity and can cause pulmonary fibrosis when the involved dose is more than 160mg [22, 23]. Absolute alcohol is highly corrosive to endothelial cells, causing tissue necrosis and severe pain [8]. Multiple treatments under general anesthesia are necessary, increasing the associated risks. Lauromacrogol, also known as polyoxyethylene lauryl ether, rapidly precipitates cellular proteins when injected into the capsule. This disrupts the cell wall bilayer and damages the endothelial cells of the capsule wall, leading to aseptic inflammation that results in necrosis and fibrosis of skin cells on the capsule wall [24]. Ultimately, this permanent blockage of the capsule cavity achieves therapeutic goals. The initial application of lauromacrogol was as an anesthetic drug, followed by its utilization in the treatment of various vascular malformations, which has been clinically proven to be both safe and effective [25]. In this study, the administration of lauromacrogol foam was employed for the treatment of surface LM under the guidance of color ultrasound. Firstly, complete extraction of the capsule fluid was performed under the guidance of color ultrasound to maximize removal. Subsequently, a foam was generated using a lauromacrogol stock solution (air = 1:3; single dose < 20ml) to ensure optimal contact with the cyst wall. Lauromacrogol possesses the ability to disrupt lymphatic endothelial cell membranes, induce endothelial cell lysis, and promote fibrosis [26]. Simultaneously, we administered 1-2ml of a 1% lauromacrogol [27] stock solution into the cystic cavity, as recent studies have demonstrated that this concentration induces optimal cellular damage, prolongs its therapeutic effect, and promotes occlusion and atrophy of the cystic cavity. Previous studies have demonstrated the safety of a single dose of lauromacrogol foam below 40ml. The young age of children in this study, optimal outcomes can be achieved with a dosage of lauromacrogol foam below 20ml. The color ultrasound-guided puncture technique [28] is a minimally invasive treatment, offering the advantages of minimal tissue damage, rapid recovery, ease of operation, and repeatability. At the same time, ultrasound helps to locate the diseased tissue and avoid the damage of peripheral blood vessels and nerves caused by blind puncture. During the perfusion treatment procedure, drug dispersion within the cystic cavity becomes apparent, allowing for more precise dosage administration. To reduce pain during puncture and minimize risks associated with multiple general anesthesia in a short timeframe due to potential repeated treatments, topical lidocaine cream is applied for surface anesthesia. Additionally, lauromacrogol itself has anesthetic properties that alleviate discomfort in children during therapy, enhancing compliance and cooperation among both children and their parents.

In conclusion, ultrasound-guided lauromacrogol sclerotherapy demonstrates efficacy in the treatment of cutaneous LM in pediatric patients. This technique offers the advantages of being minimally invasive, easy to perform, and associated with a lower incidence of complications, thus warranting its clinical application and widespread adoption.

Acknowledgements

The author would like to thank the Scientific Research Project of Hunan Provincial Health Commission. Author contribution

L.T. Z. and Z.W designed the study; K.Y. L., Z.W. and J.Q. L. made the data collection and analysis together; K.Y. L. wrote the paper. W.Y. H., Y.Q. L. and B.Z. revised the manuscript. All authors participated in the injection of polyvinyl lauromacrogol foam and contributed to and approved the manuscript.

Funding

This project was supported by the Scientific Research Project of Hunan Provincial Health Commission (Grant No.20200341). All the research procedures involving human subjects met the ethical standards of the Ethics Committee of Hunan Children's Hospital, Changsha, China.

Conflict of interest

The authors declare no competing interests.

Mäkinen T, Boon LM, Vikkula M, Alitalo K (2021) Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies. Circul Res 129(1):136–154
Wiegand S, Wichmann G, Dietz A, Werner JA (2023) Association between malformation type, location and functional deficits in lymphatic malformations of the head and neck in children, European archives of oto-rhino-laryngology: official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology -. Head and Neck Surgery 280(5):2535–2540
Francois M, Oszmiana A, Harvey NL (2021) When form meets function: the cells and signals that shape the lymphatic vasculature during development, Development 148(11)
Janardhan HP, Saheera S, Jung R, Trivedi CM (2021) Vascular and Lymphatic Malformations: Perspectives From Human and Vertebrate Studies. Circul Res 129(1):131–135
Geisel D, Walter-Rittel TC (2023) Pelvic Microcystic Lymphatic Malformation Radiology 308(1):e230364
Kunimoto K, Yamamoto Y, Jinnin M (2022) ISSVA Classification of Vascular Anomalies and Molecular Biology, Int J Mol Sci 23(4)
Kulungowski AM, Patel M (2020) Lymphatic malformations. Semin Pediatr Surg 29(5):150971
Cao J, Liu J, Zhang X, Wang Z (2023) A systematic review and network meta-analysis of the effectiveness of sclerotherapy for venous malformation. J vascular Surg Venous lymphatic disorders 11(1):210–218e3
Plettendorff L, Werner JA, Wiegand S (2023) Vascular Malformations of the Head and Neck in Children. In vivo (Athens Greece) 37(1):366–370
Li K, Jiang Y, Wei Z, Chang J, Jinqiao L, Yongqi L, Zhou B, Sheng X (2023) Lauromacrogol foam injection under ultrasonic guidance for pediatric lip venous malformations. Pediatr Surg Int 39(1):93
McCuaig CC (2017) Update on classification and diagnosis of vascular malformations. Curr Opin Pediatr 29(4):448–454
Shaheen MF, Tse JY, Sokol ES, Masterson M, Bansal P, Rabinowitz I, Tarleton CA, Dobroff AS, Smith TL, Bocklage TJ, Mannakee BK, Gutenkunst RN, Bischoff J, Ness SA, Riedlinger GM, Groisberg R, Pasqualini R, Ganesan S, Arap W et al (2022) Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical triLife 11
Oliver G, Kipnis J, Randolph GJ, Harvey NL (2020) The Lymphatic Vasculature in the 21(st) Century: Novel Functional Roles in Homeostasis and Disease. Cell 182(2):270–296
Petrova TV, Koh GY (2020) Biological functions of lymphatic vessels, Sci (New York N Y) 369(6500)
Petrova TV, Koh GY (2018) Organ-specific lymphatic vasculature: From development to pathophysiology. J Exp Med 215(1):35–49
Méndez-Echevarría A, Fernandez-Prieto A, de la Serna O, Lopez-Gutierrez JC, Parron M, Marin-Aguilera B, Calvo C (2018) Acute Lung Toxicity After Intralesional Bleomycin Sclerotherapy Pediatrics 141(1)
Van Damme A, Seront E, Dekeuleneer V, Boon LM, Vikkula M (2020) New and Emerging Targeted Therapies for Vascular Malformations. Am J Clin Dermatol 21(5):657–668
Kronfli AP, McLaughlin CJ, Moroco AE, Grant CN (2021) Lymphatic malformations: a 20-year single institution experience. Pediatr Surg Int 37(6):783–790
De Maria L, De Sanctis P, Balakrishnan K, Tollefson M, Brinjikji W (2020) Sclerotherapy for lymphatic malformations of head and neck: Systematic review and meta-analysis. J vascular Surg Venous lymphatic disorders 8(1):154–164
Markovic JN, Nag U, Shortell CK (2020) Safety and efficacy of foam sclerotherapy for treatment of low-flow vascular malformations in children. J vascular Surg Venous lymphatic disorders 8(6):1074–1082
Fernandes S, Yeung P, Heran M, Courtemanche D, Chadha N, Baird R (2022) Sclerosing agents in the management of lymphatic malformations in children: A systematic review. J Pediatr Surg 57(5):888–896
Jia R, Xu S, Huang X, Song X, Pan H, Zhang L, He F, Lin M, Ge S, Fan X (2014) Pingyangmycin as first-line treatment for low-flow orbital or periorbital venous malformations: evaluation of 33 consecutive patients. JAMA Ophthalmol 132(8):942–948
Luo QF, Gan YH (2013) Pingyangmycin with triamcinolone acetonide effective for treatment of lymphatic malformations in the oral and maxillofacial region, Journal of cranio-maxillo-facial surgery: official publication of the European Association for Cranio-Maxillo. -Facial Surg 41(4):345–349
Nguyen QD, Stender C, Bur D, Silapunt S, Polidocanol et al (2022) A Review of Off-Label Dermatologic Uses, Dermatologic surgery: official publication for American Society for Dermatologic Surgery [. 48(9):961–966
Gloviczki P, Lawrence PF, Wasan SM, Meissner MH, Almeida J, Brown KR, Bush RL, Di Iorio M, Fish J, Fukaya E, Gloviczki ML, Hingorani A, Jayaraj A, Kolluri R, Murad MH, Obi AT, Ozsvath KJ, Singh MJ, Vayuvegula S, Welch HJ (2023) The 2022 Society for Vascular Surgery, American Venous Forum, and American Vein and Lymphatic Society clinical practice guidelines for the management of varicose veins of the lower extremities. Part I. Duplex Scanning and Treatment of Superficial Truncal Reflux: Endorsed by the Society for Vascular Medicine and the International Union of Phlebology, Journal of vascular surgery. Venous and lymphatic disorders 11(2) 231–261.e6
Yang C, Li M, Li X, Zhu J, Shu C et al (2023) Foam Sclerotherapy in the Treatment of Hemangiomas and Venous Malformations, Dermatologic surgery: official publication for American Society for Dermatologic Surgery [. 49(9):855–861
Hoss E, Kollipara R, Boen M, Alhaddad M, Goldman MP et al (2020) Comparison of the Safety and Efficacy of Foam Sclerotherapy With 1: 2 Polidocanol to Air Ratio Versus 1: 4 Ratio for the Treatment of Reticular Veins of the Lower Extremities, Dermatologic surgery: official publication for American Society for Dermatologic Surgery [. 46(12):1715–1720
Hanna C, Montague S, Hanna NM (2022) The power of Doppler in ultrasound-guided paracentesis. Cjem 24(4):447–449

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Effect analysis of lauromacrogol foam injection under ultrasonic guidance for pediatric superficial lymphatic malformation

Status:

Version 1

Abstract

Figures

Introduction

Methods

General information and clinical data

Ethical review

Treatment process

Curative effect and Followup

Efficacy evaluation

Results

Discussion

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1