Therapy of lymphatic malformations or isolated lymphatic components in combined slow-flow malformations with bleomycin electrosclerotherapy (BEST)

Abstract

Purpose

The objective of the study was to retrospectively investigate the efficacy, technical feasibility, and patient safety of bleomycin electrosclerotherapy for lymphatic malformations and lymphatic components of combined veno-lymphatic malformations.

Materials and Methods

Between May 2019 and December 2021, this retrospective, single-center study analyzed the safety and feasibility of bleomycin electrosclerotherapy in patients with lymphatic or combined veno-lymphatic malformations. The procedures, performed under imaging guidance, involved intralesional or intravenous bleomycin injection followed by reversible electroporation. Lesion sizes were measured pre- and post-treatment using T2 fatsat magnetic resonance imaging. Previous treatments, clinical symptoms, intervention details, and complications were documented and analyzed.

Results

In 21 interventions, 24 lymphatic malformations of 12 patients (mean age: 14.75 years (range: 10 days-35 years; 5 women, 7 men)) were treated. The average bleomycin dose was 3.65 mg per treatment session (range: 0.5–15 mg). Before the interventions, the mean volume of the treated malformation was 88.76 cm3 (range: 0.38–541.5 cm³) and after treatment it was 36.7 cm³ (range: 0–204.97 cm³), resulting in an average volume reduction of 54.8%. Among the observed side effects, the most frequent were a temporary postinterventional local inflammatory response and temporary skin discoloration at the injection sites. An additional improvement of clinical symptoms was achieved in all patients after a mean follow-up of 8.36 months.

Conclusion

Bleomycin electrosclerotherapy appears to be an effective, technically feasible, and safe treatment option for patients with lymphatic malformations but further studies using a prospective approach and longer post-interventional observation period in a larger study population are required.

Key Points

• BEST is a new therapeutic option for lymphatic malformations.

• Different needle electrodes can be used to specifically treat different types of LMs.

• Typical side effects of BEST appear to be minor, ranging from partly intentional, local inflammation to temporary skin discoloration.

Citation Format

• Loeser JH, Guntau M, Bidakov O et al. Therapy of lymphatic malformations or isolated lymphatic components in combined slow-flow malformations with bleomycin electrosclerotherapy (BEST). Rofo 2025; DOI 10.1055/a-2648-6555

Zusammenfassung

Ziel

Ziel der Studie war die retrospektive Untersuchung der Wirksamkeit, technischen Durchführbarkeit und Patientensicherheit der Bleomycinelektrosklerotherapie bei Patienten mit lymphatischen Malformationen und lymphatischen Anteilen von kombiniert veno-lymphatischen Malformationen.

Materialien und Methoden

Zwischen Mai 2019 und Dezember 2021 untersuchte diese retrospektive, monozentrische Studie die Sicherheit und Durchführbarkeit der Bleomycinelektrosklerotherapie bei Patienten mit lymphatischen oder kombinierten veno-lymphatischen Malformationen. Der Eingriff, der unter angiografischer Kontrolle durchgeführt wurde, umfasste die Gabe von intraläsionalem oder intravenösem Bleomycin, gefolgt von reversiblen Elektroporationen. Die Größe der Läsionen wurde vor und nach der Behandlung mittels Magnetresonanztomografie gemessen. Frühere Behandlungen, klinische Symptome, Einzelheiten des Eingriffes und Komplikationen wurden dokumentiert und analysiert.

Ergebnisse

In 21 Eingriffen wurden 24 lymphatische Malformationen von 12 Patienten (Durchschnittsalter 14,75 Jahre (Umfang 10 Tage-35 Jahre; 5 Frauen, 7 Männer)) behandelt. Die durchschnittlich verabreichte Bleomycindosis betrug 3,65 mg Bleomycin pro Eingriff (Umfang 0,5–15 mg). Vor den Eingriffen betrug das durchschnittliche Volumen der behandelten Malformation 88,76 cm³ (Umfang 0,38–541,5 cm³), nach der Behandlung 36,7 cm³ (Umfang 0–204,97 cm³), was einer durchschnittlichen Volumenreduktion von 54,8% entspricht. Unter den beobachteten Nebenwirkungen waren die häufigsten eine postinterventionelle lokale Entzündungsreaktion während der postinterventionellen Krankenhausphase und vorübergehende Hautverfärbungen an den Einstichstellen der Nadelelektroden. Darüber hinaus wurde bei allen Patienten nach einer durchschnittlichen Nachbeobachtungszeit von 8,36 Monaten Verbesserungen der klinischen Symptome beobachtet.

Schlussfolgerungen

Die Bleomycinelektrosklerotherapie scheint eine wirksame, technisch durchführbare und sichere Behandlungsoption für Patienten mit lymphatischen Malformationen zu sein. Es werden jedoch weitere Studien mit einem prospektiven Ansatz und einer längeren postinterventionellen Beobachtungszeit in einer größeren Studienpopulation benötigt.

Kernaussagen

• Die BEST ist eine neue therapeutische Option für lymphatische Fehlbildungen.

• Verschiedene Nadelelektroden können zur spezifischen Behandlung verschiedener Arten von LMs verwendet werden.

• Die typischen Nebenwirkungen von BEST scheinen gering zu sein und reichen von einer teilweise beabsichtigten, lokalen Entzündung bis hin zu einer vorübergehenden Hautverfärbung.

Keywords

vascular malformation - lymphatic malformation - retrospective study - bleomycin - bleomycin electrosclerotherapy - MR imaging

LIST OF ABBREVIATIONS

BEST: Bleomycin electrosclerotherapy

LM: Lymphatic malformation

VM: Venous malformation

MRI: magnetic resonance imaging

US: Ultrasound

mTOR: mammalian target of rapamycin

VAC: vascular anomalies center

VGD: variable geometry device

Introduction

Lymphatic malformations

Lymphatic malformations (LMs) are rare congenital vascular malformations consisting of multiple large and/or small fluid-filled cysts connected to the normal lymphatic channels [1] [2] [3] [4] [5].

Their occurrence can be isolated or combined with capillary or venous malformations and is often associated with syndromes like Klippel-Trenaunay or CLOVES [1] [6]. Like other types of malformations, LMs typically grow commensurately with the child’s growth [7] [8]. Particularly in LMs, an infection or hemorrhage into the lesion can cause an episodic and rapid increase in size [8]. Symptoms vary based on location and size, ranging from asymptomatic to causing pain, lymphorrhea, or functional impairment [2] [4] [5].

Current treatment approaches

Current treatment approaches for symptomatic LMs include pharmaceutical options such as rapamycin (sirolimus), a mammalian target of rapamycin (mTOR)-inhibitor as well as surgical or interventional methods like conventional sclerotherapy [9] [10]. There is currently no guideline-based standard treatment [9] [10]. The sclerosing agent used, involving pingyangmycin, OK-432 and bleomycin, and others, locally damages the endothelium, causing fibrosis and collapse of the vessel lumen [2] [8] [11] [12]. Recent data confirms the safety and efficacy of sclerotherapy with bleomycin, although multiple therapy sessions are often necessary [13] [14] [15] [16]. Adverse effects are usually mild and dose-dependent, with bleomycin-induced lung fibrosis being exceedingly rare in this indication and, if it occurs, it may be treatable with corticosteroids [4] [13] [14] [17].

Bleomycin electrosclerotherapy

Bleomycin electrosclerotherapy (BEST) augments conventional sclerotherapy with bleomycin by adding multiple reversible electroporations, which enhances the uptake of bleomycin and increases its locally cytotoxic and sclerosing effects [18] [19]. Recent studies regarding BEST have reported its efficacy and benefits in treatment of slow-flow vascular malformations like capillary and venous malformations [10] [16] [20] [21] [22] [23] [24]. Until now no studies have focused directly on the effect of BEST on LM or combined vascular malformations. Recent data suggest that the increased intracellular bleomycin concentration enhances its effect, allowing for a reduced dose while still achieving satisfactory therapeutic outcomes – particularly in terms of malformation shrinkage and reduced side effects [10] [16] [19] [20]. The aim of this study is to investigate the efficacy, technical feasibility, and patient safety of bleomycin electrosclerotherapy (BEST) for LMs and the lymphatic components of combined venous-lymphatic malformations.

Methods

Study design

The local ethics committee approved the study. Written informed consent was obtained from the patients or the legal guardians for publication of this study as part of the general treatment agreement and additional voluntary consent for the use of images was also obtained.

This single-center, retrospective cohort study included patients with lymphatic malformation, who were treated with BEST between May 2019 and December 2021 at a tertiary care interdisciplinary vascular anomalies center (VAC).

All included patients had either a lymphatic malformation or a clearly localized lymphatic component within a combined slow-flow malformation and had received at least one BEST. Only patients with suitable pre- and postoperative T2-weighted, fat-saturated magnetic resonance imaging (STIR) were included. MRI (STIR and a radio-frequency-spoiled 3D gradient echo (GRE) sequence) was mainly used to select the clearly localized lymphatic component within a combined slow-flow malformation. Postoperative MRI and clinical examination for the follow-up had to be obtained at least 3 months after the respective intervention. Additionally, only patients whose symptoms were documented before and after each intervention during their outpatient follow-up were included. The diagnosis of a lymphatic malformation was verified based on the patient history, clinical examination, ultrasound (US), MRI and in some cases, histological findings discussed in an interdisciplinary conference at our VAC. In accordance with the standard operating procedure for electrochemotherapy [19], patients with chronic pulmonary dysfunction, with a known allergy to bleomycin, with a previous cumulative bleomycin dose of more than 100 mg, with previous radiotherapy of the chest, with at least one documented epileptic seizure, with primary lymphedema, with a chronic pain syndrome and/or with polyneuropathy grade >2 were not treated with BEST. In addition, pregnant women, breastfeeding mothers, and female patients of childbearing potential not using contraception were not treated. In order to assess any preexisting damage to the lungs, the patient’s history and in particular the cumulative bleomycin dose were taken into account and, if necessary, lung function testing was performed. Corresponding steps were also taken at the time of the follow-up.

Treatment procedure

Under ultrasound guidance, the lymphatic malformation was directly punctured percutaneously. The needle position was verified using fluoroscopy after the injection of iodinated contrast agent through the needle, allowing visualization of the extent, volume, and compartments of the lesion intraoperatively. A potential connection between the targeted lymphatic malformation and other malformation components was assessed. Moreover, the required injection volume of bleomycin was adjusted to the size of the contrasted malformation based on fluoroscopy and MRI. After puncture, lymphatic fluid was aspirated prior to the administration of bleomycin. The bleomycin solution was then injected intralesionally via the previously positioned needles. In the case of a very large or multiple lesions, or when large areas needed to be treated, bleomycin was administered intravenously via a peripheral venous catheter placed remotely from the malformation. After the injection of the bleomycin solution, the lesions were electroporated without delay with short electrical pulses in a standardized fashion. For this purpose, different needle electrodes were selected based on the location (superficial or deep) and size of the malformation . The malformation was repeatedly punctured side-by-side with the electroporation electrodes in all of the area to be treated – but without direct overlap to reduce the risk of skin damage – to apply reversible short electrical pulses. To achieve this, the needle electrodes were connected to the generator output of the electroporation system. This device provides independently controlled and isolated 100 µs outputs of ≤ 3000 V/cm (maximum current, 50 A). To ensure uniform electroporation across the entire lesion, the device automatically adjusted the actual applied voltage between the needle electrodes. The system maintained a nominal voltage-to-distance ratio of 1000 V/cm, depending on the electrical properties of the tissue.

Definition of technical and clinical success

The number and location of the lymphatic malformation(s), individual and cumulative bleomycin dose, type of needle electrodes used in each intervention, number of applied electric pulse series, adverse effects, and technical feasibility during the intervention were evaluated. Clinical signs and symptoms during the postinterventional period and follow-up were documented ([Table 1], [Table 2], [Table 3]). The clinical response was defined as a change in the patient’s symptoms that were documented before the intervention (e.g., pain, swelling, physical functional impairment of the affected area, wounds, skin discoloration). Symptoms were documented before the intervention and at follow-up, at least three months after therapy, in correlation with MRI findings. Clinical response was then categorized as asymptomatic, improved, unchanged, or worsened. Clinical success was defined as a change in clinical response, categorized as either asymptomatic or improved ([Table 3]).

Table 1 Patient data prior to interventions. Legend: LM – lymphatic malformation; VM – venous malformation; CLOVES – Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies; PROS – PIK3CA-related overgrowth spectrum.

Pt. no.	Age, years	Sex	Type of malformation	Location	Previous therapy	Symptoms before treatment
1	2	m	LM	Tongue	–	Pain, swelling (mouth closure not possible)
1	3			Tongue
1	4			Tongue
2	10 days	m	LM	Axilla/thorax wall	–	Swelling, functional impairment of the shoulder, pain, bleeding, skin discoloration
3	16 days	m	LM	Face/neck	–	Swelling, upper airway obstruction, pain, bleeding, skin discoloration
4	33	w	LM	Trunk/groin	–	Pain, swelling, lymphorrhea (chylous ascites)
4	33			Groin/thigh
5	7	w	LM	Temple/orbita	2 sclerotherapies	Swelling, impaired eye opening, nausea, skin discoloration
6	5	m	LM	Face/neck	–	Swelling, pain, bleeding
7	35	m	LM + VM	Groin/foot	–	Lymphorrhea, recurring erysipelas, swelling
8	17	w	CLOVES	Axilla/groin	1 sclerotherapy	Pain, swelling, lymphorrhea, recurring erysipelas, bleeding
8	18			Groin/thigh
9	11	m	CLOVES	Penis root/scrotum	3 sclerotherapies	Pain, swelling, lymphorrhea, Recurring erysipelas, functional impairment
9	13			Penis root/scrotum
10	31	w	LM	Neck/thoracic wall	5 surgeries	Pain, swelling, recurring infections, bleeding, dyspnea, dysesthesia, compression of the venous inflow top right
10	32			Neck/thoracic wall
10	33			Interthoracic
10	33			Neck/thoracic wall
11	6	m	LM	Left arm/thoracic wall	4 sclerotherapies	Pain, swelling, recurring infections
12	30	w	PROS	Axilla/thoracic wall	2 surgeries, 26 laser therapies	Lymphorrhea, pain, swelling, recurring infections
12	32			Left arm/thoracic wall

Table 2 Details on the individual interventions.

Pt. no.	Type of needle electrodes	Single bleomycin doses [mg]	Cumulative bleomycin dose after final intervention [mg]	Number of electroporations	Adverse events
1	F-10-NL Finger electrode	1	5	8	–
1	F-15-NO Finger electrode	2		22	–
1	F-15-NO Finger electrode	2		17	–
2	Triangularly arranged VGD needle electrodes	1.6	1.6	2	–
3	F-15-NO Finger electrode	0.5	0.5	10	Reversible increasing tongue swelling
4	F15-NO Finger electrode	10	25	36	Reversibly enlarged findings of the cystic parts along the left psoas muscle
4	H-40-IN hexagonal adjustable electrode	15		41	–
5	F-15-NO Finger electrode	1.2	1.2	13	Severe swelling with only slightly possible eye opening on the left side
6	Triangularly arranged VGD needle electrodes	3	3	6	–
7	L-30-ST linear adjustable electrode	2.5	2.5	12	–
8	F-15-NO Finger electrode	1.5 (left)	7	24	Reversible functional impairment of the shoulder
	F-15-NO Finger electrode	1.5 (right)		18
8	F-15-NO Finger electrode	4		82	Transient severe pain episodes in the left arm
9	L-30-ST linear adjustable electrode	0.75	2.75	24	–
9	F-15-NO Finger electrode	2		25	–
10	H-40-IN hexagonal adjustable electrode	6	21.66	15	Regressive articular effusion and bone edema in the shoulder
10	F-10-NL Finger electrode	2.66		25	–
10	Triangularly arranged VGD needle electrodes	8		4	Reversible pleural effusion of the right side
10	F-15-NO Finger electrode	5		24	–
11	F-15-NO Finger electrode	1.4	1.4	47	–
12	F-10-NL Finger electrode	1	5	25	–
12	H-40-IN hexagonal adjustable electrode	4		17	–

Table 3 Follow-up data collection.

Pt. no.	Follow-up period, months	Symptoms after final treatment	Clinical change	Volume before treatment [cm3]	Volume after treatment [cm3]	Volume reduction [%]	Complications	Additional medication (Sirolimus)
1	14	No more pain, reduced swelling	Improvement	27.02	21.02	22.18	–	+
1	13		Improvement	39.73	32.85	17.31	–	+
1	8		Improvement	49.03	36.66	25.23	–	+
2	6	Reduced swelling, significantly fewer functional limitations, less pain, no bleeding	Improvement	541.5	204.97	62.15	–	–
3	5	Breathing difficulties only in left lateral position, little to nonacute symptoms, no bleeding, no more discoloration	Improvement	50.03	39.24	21.45	–	–
4	4	Reduced swelling, no more lymphorrhea	Improvement	65.55	19.21	70.69	–	–
4	6		Improvement	19.21	5.72	70.24	–	–
				13.42	4.99	62.82
5	5	Reduced swelling, increased eye opening possible, only aesthetic problems remaining	Improvement	23.6	2.89	87.76	Temporary skin discoloration at the injection sites	–
6	10	Reduced swelling, no more pain	Improvement	223.66	9.24	95.87	–	–
7	20	Reduced lymphorrhea, no recurring erysipelas	Improvement	13.9	21.62	– 55.6	Temporary skin discoloration at the injection sites	–
				34.74	27.19	21.73
8	3	No more pain, reduced swelling, rarely lymphorrhea, less erysipelas, still bleeding	Improvement	8.3	0	100	–	+
				32.60	16.73	48.68
8	8		Improvement	20.44	13.92	31.89	Irregular hypesthesia in the left arm	+
				12.02	5.93	50.69
9	18	Reduced swelling, still recurring infections, still vesicles with lymphorrhea	Improvement	0.81	0.38	52.57	–	+
9	10		Improvement	0.38	0	100	–	+
10	4	No more pain, slight swelling, no more recurring infections, no dyspnea, no dysesthesia, no more compression of the venous inflow	Improvement	33.78	9.03	73.26	Skin discoloration at the injection sites	–
				17.73	6.30	64.44
				79.71	37.65	52.76
10	14		Improvement	43.07	47.63	-10.85	–	–
10	4		Improvement	269.56	129.43	51.99	–	–
10	8		Improvement	13.31	5.49	58.77	–	–
				5.9	2.09	64.55
				104.49	37.05	64.54
11	7	No more pain, reduced swelling, fewer recurring infections	Improvement	4.27	1.29	69.89	Skin discoloration at the injection sites	–
				28.09	10.9	61.2
				7.8	4.03	48.35
				7.78	2.07	73.36
12	3	No more lymphorrhea, less pain reduced swelling, no more recurring infections	Improvement	4.73	0	100	–	+
				15.07	7.26	51.8
12			Improvement	38.38	0.86	97.77	–	–
				14.46	7.02	54.47

Definition of adverse events

All adverse events that occurred during the intervention and follow-up were analyzed according to the classification system of the Cardiovascular and Interventional Radiology Society of Europe (CIRSE) [25]. Particular attention was given to skin changes (e.g., pigmentation, blisters, fistulas, wounds, necrosis), peripheral nerve injuries, and pulmonary adverse events – especially bleomycin-induced pneumonitis.

MRI volumetric analysis

T2-weighted, fat-saturated short-tau inversion recovery (T2w-STIR) MRI scans were used to evaluate the changes in volume of the LM before and after treatment. As LMs often have an irregular shape, an idealized ellipsoid was fitted to the lesion for volume calculation. This method approximates the true extent of the malformation and allows for a faster volume estimation compared to manual slice-by-slice segmentation. The volume was calculated using the standard formula for ellipsoids

where d_a is the frontal diameter, d_b is the sagittal diameter, and d_c is the transverse diameter. The percentage change in volume was calculated by comparing the pre-interventional and follow-up MRI scans.

Results

12 out of 21 patients with a lymphatic malformation treated with BEST could be analyzed according to the previously defined inclusion and exclusion criteria, including 7 men and 5 women. The mean age was 14.75 years (range: 10 days to 35 years). The most common symptoms prior to intervention ([Table 1]) were swelling (12/12), pain (10/12), and reduced physical functioning (3/12). Additionally, patients reported lymphorrhea (5/12) and recurrent infections especially erysipelas (6/12). Four of twelve patients were receiving sirolimus regularly at the time of the intervention. However, Patient 12 discontinued the drug after three weeks due to side effects. In addition, no other drugs with known effects on LMs were prescribed to patients during the period between intervention and follow-up. None of the patients had pulmonary disease or any other condition that could have influenced the LM at the time of intervention. Patients had previously undergone an average of 3.58 previous invasive treatments (range: 0–28), most commonly sclerotherapy (e.g., alcohol, sodium tetradecyl sulfate, polidocanol) and surgical resection.

Of the patients treated with BEST, eight had LMs and four had a combined veno-lymphatic malformation, in which only the lymphatic component was treated. The individual locations of the lymphatic malformations are shown in [Table 1].

A total of 21 individual BEST procedures were performed. Despite the high number of previous treatments, a single intervention was sufficient in many cases. Six patients received only one BEST session, four patients underwent two sessions, one patient had three sessions, and one patient required four sessions. All interventions were performed with the patient under general anesthesia. During each intervention, a mean bleomycin dose of 3.65 mg (range: 0.5–15 mg) was administered. The mean bleomycin dose per kg BW was 0.12 mg/kg BW (range: 0.01–0.67 mg/kg BW) for intralesional administration and 0.21 mg/kg BW (range: 0.17–0.25 mg/kg BW) for intravenous administration. The median cumulative dose used was 6.38 mg (range: 0.5–25 mg). The exact dose of injected bleomycin per individual is shown in [Table 2]. For small, superficial malformations, mainly finger electrodes of the NFD series were used. For deeper lesions, mainly freely positionable electrodes of the VGD-type were used. On average, 23.66 (range: 2–82) electroporation pulse series were applied per intervention. The exact number of electroporations is detailed in [Table 2]. All procedures were performed without periprocedural complications.

In six treatments of the 24 lesions, a postinterventional local inflammatory response with pain occurred during the clinical stay. These events were managed with medication when necessary (CIRSE grade 2). Patient #9 had a recurrence of erysipelas after the second BEST session, requiring antibiotic treatment. However, the patient had a history of recurrent erysipelas for several years prior to the first intervention. Two patients (Patients #8 and #10) developed reversible functional impairment of the shoulder (CIRSE grade 2). These events resolved spontaneously without the need for additional treatment. Patient #10 developed a pleural effusion after the third BEST session, which caused typical symptoms but was self-limiting and required only conservative treatment. This was likely related to the treatment location, as this intervention involved an intrathoracic part of the LM. In four of the 21 interventions, temporary, brownish skin discoloration was observed at the injection sites. In patient # 5, these were no longer visible after 21 months and in patient # 7 after 20 months. In patients #10 and #11, they were almost completely faded at follow-up with very few puncture sites, taking into account that one knew where punctures had been made. No necrosis or local wounds were observed. After one intervention, new neurological symptoms were detected. This occurred in patient #12 during follow-up, six weeks after the second intervention, following a locally applied bleomycin dose of 2 mg. At the same time, the patient was newly diagnosed with multiple sclerosis. As all punctures and electroporations in the treated area were performed at superficial levels only, a causal relationship between the neurological symptoms and the BEST procedure is considered unlikely. The symptoms were attributed to the newly diagnosed multiple sclerosis.

In Patient #3, the lymphatic malformation was located in the lateral cervical region without direct involvement of the upper airway. Given the clinical history of airway-related symptoms, the intervention was performed under protective endotracheal intubation, followed by overnight monitoring in the pediatric intensive care unit. Extubation was achieved without complications the next day. No pulmonary complications occurred periinterventionally or during the observation period.

Follow-up was performed at least three months after the last procedure with a mean interval of 8.38 months (range: 3–20). During the follow-up period, symptoms improved in all 12 patients. However, no patient became completely asymptomatic, likely due to other untreated parts of malformation and the systemic nature of symptom assessment. No patients’ symptoms remained unchanged, and none experienced worsening of symptoms. Before treatment, the LMs had a mean volume of 88.76 cm³ (range: 0.38–541.5 cm³). After treatment, the mean volume was 36.7 cm³ (range: 0–204.97 cm³) ([Table 3]). The average relative volume reduction was 54.8% (range: 55.6–100%). In 20 treatments, the malformation decreased in size, and in three treatments, it disappeared completely, corresponding to a 100% volume reduction on MRI. In two cases, the malformation showed an increase in size during follow-up. However, in both cases, the follow-up intervals were particularly long (14 and 20 months ) due to the COVID-19 pandemic. Therefore, a potential initial volume reduction may not have been captured by MRI, and the malformation may have increased in size again during this extended period, due to the known progressive nature caused by the pathophysiology of LMs.

Discussion

Despite multiple interventions in individual patients, the cumulative bleomycin dose remained far below the described threshold for systemic bleomycin-induced adverse effects. No pulmonary complications occurred at any time.

Despite an average of 3.58 previous unsuccessful treatments, clinical improvement of symptoms was achieved in all patients, with a mean volume reduction of 54.8%. This effect was comparable, though slightly less pronounced than the effect observed in venous malformations ([Fig. 2], [Fig. 3]) [16].

Fig. 2 Picture of patient (no. 6 – face/neck) before intervention. Clear swelling can be seen around the lower left cheek, which is caused by a lymphatic malformation.

Fig. 3 Picture of patient (no. 6 – face/neck) 10 months after intervention. The previously swollen area of the lower left cheek is noticeably reduced after BEST at the time of follow-up.

Overall, only a few interventions (usually one or two) were necessary per patient to achieve a volume reduction of the malformations and, in particular, a significant improvement in symptoms. Even if this study does not represent a direct comparison to conventional sclerotherapy, the effectiveness of BEST as a new method for the treatment of LMs could also be a possible alternative to conventional procedures. However, if the use of conventional sclerotherapy for the treatment of LMs is also scientifically proven to be successful, BEST may offer the potential for interventional treatment of LMs that have been difficult to treat and inaccessible so far. The present results also suggest that, similar to the case of venous malformations, BEST could also be suitable for the treatment of previously therapy-resistant LMs. If previously established procedures, such as surgical procedures, are unsuccessful, BEST may provide a further approach to help symptomatic patients.

BEST also appears to have a beneficial outcome in terms of adverse events and complications [24]. Most side effects were minor and only temporary. However, local hyperpigmentation seems to occur repeatedly, also in consideration of the current literature. Severe adverse events also appear to be rare, similar to current published studies, although most of them can be treated. Nevertheless, these should never be underestimated regardless of the current outcomes.

In terms of total dosage and dosage per body weight, there were large differences in the applied bleomycin dose. However, this indirectly reflects the heterogeneity and variability of LMs, particularly with regard to extent, size, and time of onset. For both intravenous and intralesional application, the dose was far below the threshold for described systemic complications, particularly pulmonary toxicity. This supports previous results on the safety of BEST, suggesting that systemic bleomycin-associated adverse events are not to be regularly assumed for the time being. Nevertheless, due to the current status of the studies and the primarily retrospective data, it is still important to ensure patient safety in clinical practice.

The availability of different types of needle electrodes enabled the treatment of LMs in various anatomical locations. For example, in patient #12, superficial components of an LM in the axilla were treated successfully using finger needle electrodes of the NFD series (F-10-NL finger electrode) ([Fig. 4], [Fig. 5]). In another patient, a deep intrathoracic part was treated using triangle-arranged long VGD needle electrodes.

Fig. 4 MRI (T2 STIR) of patient (no. 6 – face/neck) before intervention with a large mainly macrocystic lymphatic malformation.

Fig. 5 MRI (T2 STIR) of patient (No. 6 – Face/Neck) after intervention with noticeable volume reduction of the lymphatic malformations and accompanying effects of sclerotherapy.

This study has several limitations, including its retrospective design, the absence of a control group, and a single-center selection bias. In addition, the number of included patients was relatively small (n=12), which reflects the rarity of LMs [26]. Nonetheless, we believe that these initial retrospective results focused on LMs are an important step toward future treatment of LMs using BEST and may assist attending physicians in treatment planning.

Another limitation is the timing of the follow-up, which occurred as early as 3 months and as late as 20 months after treatment, resulting in highly heterogeneous intervals. This was mainly due to the COVID-19 pandemic, which frequently delayed the scheduling and execution of the routine follow-up appointments. Consequently, the measured volumes on follow-up imaging may have limited correlation with therapeutic outcome especially in pediatric patients who were still growing at that time. Since LMs tend to increase in size during growth spurts, areas of the malformation reduced by BEST may subsequently enlarge again during mid-term follow-up, particularly in growing children, thereby altering the expected volume change on follow-up imaging [3] [8]. Some patients, particularly children, with delayed follow-up, reported that the malformation had initially decreased in size after treatment but subsequently regained volume as part of the normal growth. Therefore, the actual postinterventional volume reduction may be greater than reported here. However, the heterogeneous follow-up intervals also allowed for the detection of potential late adverse events – none of which were observed.

An important confounder in the observed volume changes in four patients was the concurrent indicated therapy with sirolimus, which inhibits the regeneration and invasion of lymphatic vessels [27] [28]. Among the reported side effects, localized brown skin discoloration frequently occurred around the needle puncture sites. This is a well-known side effect of bleomycin, particularly from its use in dermatological or oncological therapy [19]. These discolorations can be temporary and can be minimized or prevented by carefully avoiding skin trauma (e.g. when removing adhesive tape) [19]. Typical postinterventional symptoms, such as pain and a local inflammatory reaction, are already known from treatment with conventional bleomycin injection alone and were managed with medication and local cooling [13] [24] [30]. No other intraoperative complications occurred during any intervention.

Conclusion

In conclusion, BEST appears to be an effective and generally easy to perform new therapeutic option for treating patients with LMs, with mainly mild adverse events. However, further prospective studies are required.

Clinical relevance

1. BEST is a new therapeutic option for lymphatic malformations.

2. Typical side effects of BEST appear to be minor, ranging from partly intentional, local inflammation to temporary skin discoloration.

3. BEST can be a suitable addition to conventional sclerotherapy, particularly in the case of previously therapy-resistant lymphatic malformations.

Conflict of Interest

JHL: Honorarium for a speech at a conference organized by Terumo Neuro, but without any association with the present study.

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Publication History

Received: 12 March 2025

Accepted after revision: 02 July 2025

Article published online:
29 September 2025