Efficacy of intralesional bleomycin sclerotherapy for head and neck vascular malformations

Introduction

Vascular malformations are benign lymphatic, venous, arteriovenous, capillary, or mixed-origin anomalies arising from errors in vasculogenesis during embryonic development (1). Managing these conditions can be challenging, particularly given the morbidity associated with surgical excision. As a result, non-surgical interventions like sclerotherapy have become the preferred treatment approach.

Sclerotherapy is widely recognized as an effective treatment for vascular malformations, either as a standalone intervention or as an adjunct to surgical resection. Among sclerosing agents, bleomycin has emerged as a leading option, particularly for microcystic lesions that are difficult to treat (2-4). Despite increasing use of bleomycin, data on its long-term efficacy and safety in head and neck vascular malformations within New Zealand remains limited.

Bleomycin, an antibiotic derived from Streptomyces, exerts its effects primarily through cytostatic mechanisms. It induces deoxyribonucleic acid (DNA) strand breaks and disrupts endothelial tight junctions, leading to obliteration of vascular channels and subsequent fibrosis. Recent studies reinforce bleomycin’s efficacy in treating microcystic vascular malformations, demonstrating favourable outcomes with minimal systemic toxicity (1,5,6).

This review retrospectively examines a single-centre cohort following the introduction of bleomycin sclerotherapy in 2016. The Auckland Region Interventional Radiology Service, serving over 2.5 million people in the upper North Island of New Zealand, primarily operates out of Auckland City Hospital and Starship Children’s Hospital. The primary aim of this study was to assess the clinical efficacy of intralesional bleomycin sclerotherapy for head and neck vascular malformations. The secondary aim was to evaluate its safety profile and complication rates.

Methods

A retrospective review was performed of patients treated with bleomycin sclerotherapy for head and neck vascular malformations between June 2016 and August 2022. Patients were identified using hospital coding records and radiology procedure logs. Cases involving non-head and neck lesions were excluded.

Clinical outcomes were assessed based on documented follow-ups conducted primarily by interventional radiologists, with occasional assessments by otolaryngologists and ophthalmologists. Treatment response was graded on a four-point scale based on the standard scale used throughout the international literature (4,7,8):

• Grade 0: no response;
• Grade 1: slight improvement;
• Grade 2: moderate improvement with partial lesion regression and functional relief;
• Grade 3: significant improvement with near-total lesion resolution and minimal residual impairment.

Due to the limited correlation between imaging findings and symptomatic improvement, routine post-treatment imaging was not performed. In addition, the need for general anaesthesia in paediatric patients made follow-up imaging logistically challenging and clinically unjustified in most cases (3).

Treatment complications were assessed using the widely accepted Clavien-Dindo Classification system (9).

The study is reported according to the STROBE reporting guidelines (available at https://www.theajo.com/article/view/10.21037/ajo-25-18/rc). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. A retrospective analysis was conducted with approval from the Auckland Health Research Ethics Committee (No. AH24698). Patient confidentiality was maintained by anonymizing data, and individual consent was waived for this retrospective analysis. Means and standard deviations were used for normally distributed continuous variables; medians and interquartile ranges for skewed data. Statistical analyses were performed using SPSS (version 27).

Treatment protocol

All procedures were performed under general anaesthesia (sevoflurane-based inhalational induction with spontaneous ventilation or total intravenous anaesthesia at the anaesthetist’s discretion) in paediatric patients. In adult patients, depending on location, size and patient preference the procedure was either performed under general anaesthetic or with sedation. Lesion morphology and flow characteristics were reviewed on pre-procedural magnetic resonance imaging (MRI) or Doppler ultrasound. After sterile skin preparation and draping, a high-frequency linear ultrasound probe was used to identify lesion margins and plan needle trajectories. Under real-time ultrasound guidance, a 22 G spinal needle was advanced into the deepest portion of the malformation; correct intralesional placement was confirmed by aspiration of blood-tinged fluid and slow injection of 0.5 mL saline to observe cystic expansion. Bleomycin was reconstituted by pharmacy as 5,000 International Units (IU) in 5 mL sterile saline immediately prior to use. Total dose per session did not exceed 0.5 mg/kg (maximum 15 mg), divided into 100–200 IU aliquots injected into separate compartments of the lesion. Superficial macrocystic areas received aliquots under ultrasound only, whereas deeper or high-flow components were treated under combined ultrasound and low-dose fluoroscopic guidance to visualise sclerosant dispersion. Needle withdrawal and redirection were performed to ensure uniform distribution. Each session lasted approximately 30–45 minutes. Patients were observed for 2 hours post-procedure for vital-sign monitoring and discharged with outpatient follow-up scheduled at 4 weeks for clinical and ultrasound assessment. Sessions were repeated at 4-week intervals until maximal response or a maximum of three treatments. Patients not achieving ≥ Grade 1 response after three injections were designated non-responders.

Results

A total of 46 procedures were performed across 27 patients (18 females, 9 males). Ages at diagnosis ranged from 2 to 57 years (mean 8±13 years) and treatment was initiated between ages 2 and 58 years (mean 14±12 years). See Table 1 for patient demographics.

Lesion locations included the tongue (n=9, 33%), lip (n=6, 22%), neck (n=6, 22%), face (n=6, 22%), orbit/eyelids (n=4, 15%), and supraglottis (n=1, 4%). Of the 27 lesions, 18 were lymphatic (67%), 7 venous (26%), and 2 mixed-type (7%). Most patients presented with significant cosmetic concerns and recurrent swelling. Additional symptoms included feeding difficulties, bleeding, airway compromise, speech impairment, and vision obstruction. Of the 27 patients, 18 (67%) had previous sclerotherapy using agents such as doxycycline, ethanol, sodium tetradecyl sulfate (STS), OK432, and bevacizumab. Figure 1 illustrates total cumulative dose of bleomycin. Seven patients (26%) had prior surgical interventions, with one requiring tracheostomy, which was later reversed post-treatment. Sirolimus was introduced for one patient after bleomycin therapy.

Figure 1 Total cumulative bleomycin dose administered per patient. This figure illustrates the variation in cumulative bleomycin dosage received across the study cohort. Each bar represents an individual patient, reflecting total dose in International Units (IU) administered over one or more treatment sessions. Variation reflects lesion complexity, anatomical location, and response to therapy. No patient exceeded the maximum cumulative dose threshold of 18,100 IU or the per-session dosing limit of 0.5 mg/kg.

Clinical outcomes

Treatment response was graded on a four-point scale (4,7,8). All five patients with airway involvement showed improvement, including successful tracheostomy decannulation. Two patients (7.4%) were classified as non-responders, having failed to achieve even slight lesion regression after three injections.

Grade 0 (no response) was seen in 7.4% (n=2) of patients; Grade 1 (slight improvement) in 18.5% (n=5); Grade 2 (moderate improvement, with partial lesion regression and functional relief) in 26% (n=7); and Grade 3 (significant improvement) in 44.4% (n=12).

This a can be seen in table format below (Table 2).

Safety and complications

Complications were assessed using the Clavien-Dindo classification (9). Of the 27 patients, 8 (30%) experienced minor complications. There were 11 classified complications as some patients received more than one complication. In total there were 3 Grade I complications noted, and 8 Grade II complications.

• Grade I: mild, self-limiting side effects (minor superficial pigmentation changes and mild swelling).
• Grade II: reactions requiring pharmacological treatment (transient swelling/haematoma/bleeding or ulceration necessitating overnight observation, infection in one and a single event of corneal abrasion in another which settled with emollient).

These were the only observed complications.

No cases of bleomycin-induced pulmonary fibrosis were reported. Follow-up durations ranged from 6 months to 6 years.

Discussion

This retrospective study supports the efficacy and safety of intralesional bleomycin sclerotherapy for head and neck vascular malformations. Of the 27 patients treated, 70% (n=19) achieved moderate to significant lesion regression, including near-complete resolution in 44% (n=12). All five patients with airway involvement showed clinical improvement, including one who underwent successful tracheostomy decannulation. Minor complications occurred in 30% (n=8) of cases, and importantly, no cases of bleomycin-induced pulmonary fibrosis were observed, reinforcing its safety at the dosages used (10,11).

These findings are consistent with previous reports demonstrating favourable outcomes for low-flow vascular malformations treated with intralesional bleomycin (10). Use of image-guided, compartmentalised injection has been shown to enhance response while minimising complications, a strategy also employed in the current study (12). Skin hyperpigmentation, a recognised side effect, was mitigated in our cohort by implementing protective skin protocols following earlier cases (12).

High response rates for lymphatic malformations treated with bleomycin have been reported in large paediatric cohorts, particularly for lesions with microcystic morphology (13). Although detailed subclassification was not consistently available in our dataset, the predominance of lymphatic lesions suggests a substantial proportion were microcystic in nature. Consistent with prior studies, patients previously treated with other sclerosants or surgical interventions still benefited from bleomycin. The use of low cumulative doses and per-session limits aligns with established safety thresholds designed to prevent pulmonary toxicity (11,14,15).

Several limitations must be acknowledged. This study was retrospective and relied on clinical grading of response rather than validated scoring tools or objective imaging metrics. Routine post-treatment imaging was not performed due to the need for general anaesthesia in paediatric patients and the limited correlation between radiographic findings and symptom resolution (12). The sample size was modest, and lesion heterogeneity (lymphatic, venous, mixed) limits extrapolation of findings. Furthermore, accurate subclassification into microcystic versus macrocystic lesions was not feasible in all cases due to inconsistent documentation.

Future research should include prospective, multicentre trials incorporating standardised outcome measures and long-term follow-up. Integration of sclerotherapy with systemic therapies, such as mammalian target of rapamycin (mTOR) inhibitors, is a promising direction, particularly for lesions associated with genetic mutations such as PIK3CA. Combined treatment regimens have shown potential in improving lesion control and symptom relief (16).

An emerging adjunctive technique is Bleomycin ElectroScleroTherapy (BEST), which uses electroporation to enhance bleomycin uptake and efficacy. Although not applied in our series, recent data suggest that BEST may reduce the number of sessions required and lower total drug exposure while achieving comparable outcomes (13). Further studies are needed to define its role in managing therapy-resistant vascular malformations.

Conclusions

Bleomycin sclerotherapy is a safe and effective intervention for head and neck vascular malformations, particularly microcystic lesions. Our data contribute to the growing international literature, reinforcing bleomycin’s role in contemporary vascular anomaly management. Further studies with larger cohorts and long-term follow-up will enhance understanding of optimal treatment strategies and patient selection criteria.

Acknowledgments

We would like to acknowledge the Passe Williams Foundation for the ongoing support of Dr. Johnston as an Academic Surgeon Scientist Fellow.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-25-18/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-25-18/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-25-18/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-25-18/coif). J.J. serves as an unpaid editorial board member of Australian Journal of Otolaryngology from July 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. A retrospective analysis was conducted with approval from the Auckland Health Research Ethics Committee (No. AH24698). Patient confidentiality was maintained by anonymizing data, and individual consent was waived for this retrospective analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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