European Journal of Cardiovascular Medicine

Venous and lymphatic malformations (VMs and LMs) are congenital vascular anomalies classified as slow-flow or low-flow vascular malformations that arise from developmental abnormalities during embryogenesis.¹ These benign lesions represent some of the most common vascular malformations encountered in clinical practice, with VMs occurring in approximately 1 in 10,000 births and LMs affecting roughly 1 in 16,000 births.² The head and neck region is particularly susceptible to these malformations, with approximately 40-75% of all vascular malformations occurring in this anatomical location.^3,4

The clinical presentation of head and neck VMs and LMs varies considerably depending on their size, location, and morphological characteristics. These lesions can cause significant functional impairment, cosmetic disfigurement and quality of life deterioration. Patients may experience pain, swelling, bleeding and in severe cases involving the upper aerodigestive tract, potentially life-threatening complications such as dysphagia, dysphonia, or airway obstruction.⁵ The infiltrative nature of these malformations, particularly in the head and neck region, often makes complete surgical excision challenging and associated with high morbidity and recurrence rates.⁶

Traditional surgical management of head and neck vascular malformations has been associated with significant complications, including nerve injury, functional deficits, cosmetic deformity and high recurrence rates due to incomplete resection.⁷ These limitations have led to the evolution of percutaneous sclerotherapy as a first-line treatment modality for slow-flow vascular malformations. Sclerotherapy involves the direct injection of sclerosing agents into the malformation, causing endothelial damage, thrombosis, and subsequent fibrosis, ultimately leading to lesion obliteration.⁸

Among the various sclerosing agents available, bleomycin has emerged as one of the most widely used and effective agents for treating head and neck VMs and LMs. Originally developed as an antineoplastic antibiotic derived from Streptomyces verticillus, Bleomycin's sclerosing properties were first recognized by Yura and colleagues in 1977 when they successfully used it to treat cystic lymphangiomas.⁹ The mechanism of action involves DNA strand breaks and inhibition of DNA synthesis, leading to endothelial cell death and subsequent vessel sclerosis. Unlike ethanol-based sclerosants, bleomycin produces minimal post-injection swelling, making it particularly suitable for treatment of lesions in critical anatomical locations such as the periorbital region and upper aerodigestive tract.⁶

Recent systematic reviews and meta-analyses have demonstrated the efficacy and safety of bleomycin sclerotherapy in treating head and neck vascular malformations. Finitsis and colleagues conducted a comprehensive systematic review of 32 studies involving 1,121 patients with veno-lymphatic malformations of the head and neck, reporting lesion reduction in 93.7% of patients treated with various sclerosing agents, with bleomycin being used in 562 patients.¹ The study revealed a mean of 3.4 sclerotherapy sessions per patient, with minor complications occurring in 16.2% of cases and major complications in only 1.1% of patients. Similarly, a recent meta-analysis by Kumar and colleagues analyzing 21 studies with 428 patients treated with bleomycin sclerotherapy for lymphatic malformations reported an overall effective rate of 84.0%.¹⁰

The clinical outcomes of bleomycin sclerotherapy have been particularly encouraging for head and neck applications. Spence and colleagues reported their experience with facial venous malformations, demonstrating marked improvement (≥50% size reduction) in 71% of lesions and minor improvement in an additional 19% of cases.⁸ More recent studies have shown similar success rates, with Wohlgemuth and colleagues demonstrating significant lesion reduction and clinical effectiveness in patients with therapy-resistant venous malformations using bleomycin electrosclerotherapy.⁹ These results highlight the reproducible efficacy of bleomycin across different anatomical subsites within the head and neck region.

This retrospective observational study was conducted in the division of Interventional radiology at a tertiary care hospital in Northen India, over a period of 2 years. The study aimed to evaluate the efficacy and safety of bleomycin sclerotherapy in patients diagnosed with slow-flow vascular malformations and lymphatic malformations involving the head and neck region. All patients who underwent bleomycin sclerotherapy during the study period were included in the analysis, providing a comprehensive assessment of treatment outcomes in a real-world clinical setting.

The diagnosis of slow-flow vascular malformations was established based on clinical presentation, physical examination findings, and comprehensive imaging evaluation including ultrasound or magnetic resonance imaging (MRI). Patients were considered eligible for bleomycin sclerotherapy based on the presence of symptomatic lesions, cosmetic concerns, functional impairment, or progressive growth of the malformation.

Patient data were retrieved from medical records, imaging archives, and procedural databases maintained by the Department of Radiodiagnosis. Comprehensive demographic information was collected including age, gender, and clinical presentation. Detailed lesion characteristics were documented including anatomical location, size, morphological type (macrocystic, microcystic, or mixed), and associated symptoms. Pre-procedural imaging findings, number of treatment sessions required, dose of bleomycin administered per session, and technical details of the sclerotherapy procedure were systematically recorded for each patient.

All bleomycin sclerotherapy procedures were performed by experienced interventional radiologists under imaging guidance, typically ultrasound or fluoroscopy, depending on lesion characteristics and anatomical location. The procedures were conducted using standard sterile techniques with appropriate patient monitoring and sedation. Bleomycin dosage was calculated based on patient weight and lesion volume, with careful attention to maximum recommended dosing guidelines to minimize systemic toxicity. Lesion was accessed using 22G needle and diluted contrast injected into the malformation. The sclerosant was administered directly into the vascular malformation using 22G needle till the washout of contrast form veno-lymphatic malformation.

Patient follow-up was conducted at regular intervals following sclerotherapy to assess treatment response and monitor for complications. The primary outcome measure was lesion size reduction, evaluated through clinical examination and follow-up imaging. Percentage reduction in lesion volume or dimensions was calculated by comparing pre- and post-treatment measurements. Secondary outcome measures included symptomatic improvement, improved cosmesis, functional status and patient satisfaction. Complications were systematically documented and classified as minor (requiring no specific treatment or simple management) or major (requiring additional intervention or hospitalization).

Treatment efficacy was assessed based on the degree of lesion size reduction achieved following bleomycin sclerotherapy. Response categories were defined as complete response (>90% size reduction), marked response (50-90% reduction), partial response (25-49% reduction), or minimal/no response (<25% reduction). The relationship between various patient factors, lesion characteristics, and treatment outcomes were analysed to identify potential predictors of successful intervention. Safety assessment included documentation of all adverse events, their severity and management required. Long-term follow-up data were analysed to evaluate the durability of treatment response and identify any delayed complications or recurrence patterns.

In our study, the age distribution shows a predominance of younger patients, with 55% falling in the 11-20 years age group and 25% in the 21-30 years range. Only 10% were children under 10 years old, while patients over 30 years comprised just 10% of the cohort. The gender distribution favoured females, representing 65% of patients compared to 35% males. Regarding anatomical locations, the facial region was most commonly affected at 35%, followed by periorbital region (20%) and then equal distributions of 15% each for oral cavity, scalp, and salivary glands. The clinical presentation was evenly split between cosmetic concerns and swelling-related symptoms, each affecting 40% of patients, while functional impairments involving vision or swallowing were reported in 20%. Most patients (70%) had no previous treatment history, though 20% had undergone prior surgery and 10% had received previous sclerotherapy.

Table 1: Patient Demographics and Clinical Characteristics

This table 2 details the treatment protocols administered and their corresponding outcomes. The majority of patients received 2-3 treatment cycles, with 40% receiving 2 cycles and 35% receiving 3 cycles. Fewer patients required 4 cycles (20%) or 5 cycles (5%), with the mean number of cycles per patient being 2.9. At one-month follow-up, size reduction responses were predominantly in the partial to good range, with 45% achieving partial response (25-50% reduction) and 45% achieving good response (50-75% reduction). Only 5% showed minimal response, while 5% achieved excellent response. The overall treatment success rate was high, with 95% of patients achieving partial response (≥25% reduction) and 50% achieving substantial response (≥50% reduction). Patient satisfaction levels showed 35% rating treatment as excellent, 25% as good, and 40% as fair, with no patients reporting poor satisfaction. When categorized broadly, 60% of patients were satisfied with their treatment outcomes.

Table 2: Treatment Protocol and Efficacy Outcomes

This table 3 demonstrates the safety profile of the treatment approach. The majority of patients (60%) experienced no complications, while 40% developed some form of complication. Among those who experienced complications, swelling was the most common at 20%, followed by hyperpigmentation at 10%, and thrombophlebitis at 5%. Importantly, all complications were classified as minor, with no major complications reported. When analysed by anatomical location, periorbital region showed the highest complication rate at 50%, compared to 42.9% for facial regions and 33.3% for other locations. The number of treatment cycles did not significantly impact complication rates, with similar frequencies observed between patients receiving 2 cycles (37.5%) and those receiving 3-5 cycles (41.7%). Most complications were self-resolving (35% of total patients), with only one patient (5%) requiring active intervention. The table emphasizes that no major systemic complications or permanent adverse effects were observed throughout the study.

Table 3: Complications and Safety Profile

Note: All complications were minor and manageable. No major systemic complications or permanent adverse effects were observed.

This comprehensive analysis table 4 reveals the relationship between the number of treatment cycles and various outcome measures. The data shows statistically significant associations between cycle number and both size reduction and patient satisfaction. Patients receiving 3 cycles demonstrated optimal efficacy with 100% achieving ≥50% size reduction, while those receiving 2 cycles showed more moderate efficacy at 37.5% but achieved 100% patient satisfaction. In contrast, patients requiring 4 or 5 cycles showed poor outcomes with 0% achieving substantial size reduction and 0% reporting good or excellent satisfaction. The complication rates showed no statistically significant association with cycle number. The statistical analysis revealed highly significant p-values for size reduction (p<0.001) and significant p-values for patient satisfaction (p=0.034), while complications showed no significant correlation (p=0.493). The key clinical findings suggest that 3 cycles provide optimal efficacy with the lowest complication rate, while 2 cycles offer the best patient satisfaction with lowest treatment burden, leading to a clinical recommendation that 2-3 cycles represent the optimal treatment approach for balancing efficacy, safety, and patient satisfaction.

Table 4: Treatment Cycles vs Outcomes

*p<0.05 (significant), ***p<0.001 (highly significant), NS = not significant.

The present study demonstrates the efficacy and safety of bleomycin sclerotherapy for slow-flow venous and lymphatic malformations in the head and neck region, with 95% of patients achieving size reduction (≥25% reduction) and an overall complication rate of 40%, all of which were minor and manageable. These findings are consistent with the broader literature, which supports bleomycin as a highly effective first-line treatment for veno-lymphatic malformations in this anatomical region.

Our study achieved a substantial response rate (≥50% reduction) in 50% of patients, which aligns favourably with published literature. Mathur et al.¹¹ reported that in 10 paediatric patients with head and neck lymphatic and vascular malformations, the size of swelling reduced by 50% or more in seven patients (70%), with three showing complete or near complete response, and no major deleterious side effects occurred. A recent meta-analysis by Liu et al.¹² of 21 studies involving 428 patients found that bleomycin achieved a combined effective rate of 84.0% (95% CI 0.81‒0.87) for lymphatic malformations, ranging from 39% to 94%. Nevesny et al.¹³ demonstrated significant volume reductions of 45% in venous malformations and 76% in lymphatic malformations in their 26-patient study, with overall improvement reported by 69% and 82% of patients in the VM and LM groups, respectively. Our findings of 95% overall response rate and 50% substantial response rate fall within the range of these established studies, confirming bleomycin's therapeutic efficacy in this patient population.

A unique contribution of our study is the identification of optimal treatment cycles for balancing efficacy, safety, and patient satisfaction. We found that 3 cycles achieved 100% success rate (≥50% reduction) with the lowest complication rate (14.3%), while 2 cycles showed 100% patient satisfaction despite moderate efficacy (37.5% with ≥50% reduction). This finding is supported by previous literature showing that multiple treatment sessions are often required. Berenguer et al.¹⁴ in their study of 40 patients with craniofacial venous malformations found that 76% achieved marked improvement or cure, with logistic regression analysis revealing that number of sclerotherapeutic procedures was a significant multivariate predictor of outcome. Mack et al.¹⁵ reported that 90% of patients surveyed were satisfied to very satisfied with bleomycin sclerotherapy results, though they noted that about 24% experienced transient nausea, vomiting and/or local hyperpigmentation. Our mean of 2.9 cycles per patient aligns with literature reports, though our data suggests that exceeding 3 cycles may result in diminishing returns and increased patient dissatisfaction.

The safety profile observed in our study, with 40% minor complications and no major complications, requires careful interpretation in the context of published literature. Nevesny et al.³ reported no major complications during a mean follow-up of 51 ± 34 months in the VM group and 29 ± 18 months in the LM group, with a recurrence rate of 23% within 2 years. However, Horbach et al.¹⁶ in their systematic review found that complications occurred more frequently after ethanol sclerotherapy (18%) compared to other sclerosing agents (0–6%), with bleomycin showing superior safety characteristics. Similarly, Wiegand et al.¹⁷ noted that while ethanol is highly effective, it carries significant risks of skin necrosis and nerve injury, particularly in head and neck locations. Our complication rate, while higher than some reports, included only minor and self-resolving complications such as swelling (20%), hyperpigmentation (10%), and thrombophlebitis (5%), which aligns with the known safety profile of bleomycin.

When compared to other sclerosing agents, bleomycin demonstrates superior safety characteristics, particularly in sensitive head and neck locations. Berenguer et al.¹⁴ using ethanol and sodium tetradecyl sulfate reported that 75% of patients were rated as having marked improvement or cure, but with higher complication rates associated with ethanol use. Qiu et al.¹⁸ in their systematic review found that skin damage (10.0%) was the most common minor complication across all sclerosants, with more severe complications including renal damage (3.9%) and nerve damage (1.85%) being rare but present. A recent study by Ni et al.¹⁹ using bleomycin polidocanol foam reported a notable average reduction in lesion volume by 78.50% ± 15.71%, with 70.3% of patients experiencing effective relief after a single treatment. Our study's exclusive reporting of minor complications supports the literature consensus that bleomycin offers an excellent safety profile compared to ethanol-based sclerotherapy.

Our study population showed a predominance of younger patients (55% aged 11-20 years), which is consistent with literature indicating that veno-lymphatic malformations often present in childhood and young adulthood. Horbach et al.²⁰ in their patient-reported outcomes study of 77 patients found that approximately half (49.3%) indicated improvement in overall health status following bleomycin sclerotherapy, with most improvement seen in pain (54.5%) and overall severity of symptoms (57.1%). The facial region was most commonly affected (35%) in our series, which aligns with literature reports that the majority of venous malformations occur in the head and neck region. The higher complication rate observed in the periorbital region (50%) compared to other locations in our study is consistent with the anatomically sensitive nature of periorbital structures, as noted by various authors who emphasize the need for careful technique in these areas.

Our findings support the current consensus that bleomycin sclerotherapy should be considered the first-line treatment for head and neck veno-lymphatic malformations before surgical intervention. The identification of 2-3 cycles as optimal represents a clinically valuable finding that can guide treatment protocols and patient counselling. The excellent safety profile, combined with high efficacy rates and patient satisfaction, reinforces bleomycin's position as the preferred sclerosant for head and neck applications. Future research should focus on developing standardized protocols for cycle number determination and investigating combination approaches for complex or treatment-resistant lesions.

This comprehensive study demonstrates that bleomycin sclerotherapy represents a highly effective and safe first-line treatment modality for slow-flow venous and lymphatic malformations in the head and neck region, achieving significant response rates in 95% of patients with an excellent safety profile characterized by only minor, self-resolving complications. The identification of 2-3 treatment cycles as the optimal therapeutic approach provides clinically valuable guidance, with three cycles offering superior efficacy (100% achieving ≥50% reduction) and the lowest complication rate (14.3%), while two cycles demonstrate exceptional patient satisfaction (100%) despite moderate efficacy, suggesting that treatment individualization based on patient priorities and lesion characteristics may optimize outcomes. The absence of major complications, combined with high patient satisfaction rates (60% satisfied to excellent) and reproducible efficacy across diverse anatomical locations within the head and neck region, reinforces bleomycin's position as the preferred sclerosant over more aggressive agents like ethanol, particularly in anatomically sensitive areas where cosmetic outcomes are paramount. These findings support the current paradigm shift toward minimally invasive interventional approaches over traditional surgical management, while the statistically significant relationship between treatment cycles and outcomes (p<0.001 for efficacy, p=0.034 for satisfaction) provides evidence-based foundation for developing standardized treatment protocols that can guide clinical decision-making and patient counselling in routine practice.

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