Targeted Bevacizumab Therapy for Recurrent Vocal Fold Hemorrhage: First Case Report

Abstract

This case report describes the use of targeted intracordal bevacizumab therapy for recurrent vocal fold hemorrhage refractory to conventional treatment. The intervention was associated with resolution of hemorrhagic episodes and sustained clinical improvement over follow‐up. These findings suggest a potential role for antiangiogenic therapy in selected cases.

1. Introduction

Vocal fold hemorrhage (VFH) is an acute phonotraumatic lesion secondary to the rupture of a blood vessel in the superficial layer of the vocal fold lamina propria, causing sudden dysphonia due to mucosal wave disruption [1, 2]. It usually resolves with conservative management, primarily voice rest, without resulting in permanent vocal sequelae [1]. However, in some patients, bleeding may recur, constituting recurrent vocal fold hemorrhage (RVFH), defined by more than one documented episode [1].

Vocal fold varices and vascular ectasias constitute the main anatomical risk factor for RVFH, conferring up to a tenfold increased risk of VFH compared to their absence [2]. These lesions are explained by a process of neoangiogenesis, in which mechanical stress and hypoxia induced by phonotrauma promote the formation of abnormal, fragile, and unstable vasculature [3].

In patients with varices or vascular ectasias who have experienced one or more hemorrhagic episodes, phonosurgical intervention is recommended to eliminate the anatomical source of bleeding and reduce the risk of recurrence [2]. Nevertheless, the management of RVFH can be challenging in persistent cases.

We present a case of chronic RVFH associated with persistent vascular ectasias, refractory to conventional phonosurgical management, successfully treated with intracordal Bevacizumab as rescue therapy.

2. Case Presentation

A 47‐year‐old woman with a history of overweight and insulin resistance on pharmacological treatment. She denied smoking and reported social alcohol consumption. She held a managerial position in the banking sector, with sustained high vocal demand. She occasionally experienced gastroesophageal reflux symptoms, treated with lansoprazole. Her medical history included uterine fibroid surgery and use of combined oral contraceptives.

She consulted in February 2009 for dysphonia of one‐month duration. Laryngeal endoscopy revealed a hypervascular polypoid lesion of the left vocal fold. In August of the same year, phonosurgery was performed via medial cordotomy with subepithelial resection of an extensive fibrovascular lesion, sparing the vocal ligament (Figure 1).

FIGURE 1.

(A) Intraoperative image prior to medial cordotomy, showing an extensive fibrovascular lesion of the left vocal fold. (B) Intraoperative image at the end of surgery, following medial cordotomy with complete subepithelial resection of the fibrovascular lesion, sparing the vocal ligament.

In June 2011, the patient again presented with dysphonia, at which time the first episode of VFH was documented. It was managed conservatively with strict voice rest, speech therapy, and optimization of treatment for laryngopharyngeal reflux. Semestral nasofibroscopic controls documented three episodes of RVFH associated with progressive superficial cord edema, consistent with localized Reinke's edema of the left vocal fold while conservative management was maintained.

Due to persistence and refractoriness of the condition, a new phonosurgery was performed in April 2013, consisting of organized edge edema resection and vascular ectasia ablation using CO₂ laser (Figure 2). Nevertheless, semestral endoscopic controls during 2014 documented VFH episodes at each evaluation (Figure 3).

FIGURE 2.

Intraoperative images of the left vocal fold, 2013. (A) Preoperative view showing organized edge edema and visible vascular ectasias. (B) Immediate postoperative result following subepithelial edema resection and CO₂ laser ablation of vascular ectasias.

FIGURE 3.

Videolaryngostroboscopy, August 2014, demonstrating an episode of left VFH.

In May 2015, another surgical intervention with CO₂ laser was performed; however, in September of the same year, another left vocal fold hemorrhage was documented, followed by four additional VFH episodes during 2016 (Figure 4). Up to that point, since 2011, the patient reported persistent dysphonia of variable intensity at every follow‐up, without achieving full recovery of baseline vocal quality. Vocal assessment was always based on subjective self‐report.

FIGURE 4.

Videolaryngostroboscopy, May 2016, demonstrating left vocal fold hemorrhage.

Given this evolution, in November 2016, a surgical approach consisting of cordotomy, CO₂ laser, and intracordal Bevacizumab injection was decided. Since then, no new VFH episodes have been documented.

Additional doses of bevacizumab were administered in January 2017 and subsequently repeated on an annual basis in January 2018, 2019, and 2020, due to the persistence of some vascular ectasias observed on nasofibroscopic follow‐up, without evidence of active bleeding (Figure 5). All injections were performed in the operating room under general anesthesia. The initial dose was administered in this setting due to its concurrence with a cordotomy and CO₂ laser ablation. Although office‐based infiltration under local anesthesia was offered for subsequent treatments, the patient consistently preferred operating‐room administration. Bevacizumab was used at a concentration of 25 mg/mL (2.5 mg/0.1 mL), with 0.1–0.3 mL injected depending on the extent of vocal fold involvement.

FIGURE 5.

Nasofibroscopic control, January 2020, demonstrating residual vascular ectasias with no evidence of active bleeding.

At the most recent follow‐up visit in 2020, the patient had accumulated 3 years without clinically evident episodes of vocal fold hemorrhage and, from a clinical standpoint, reported being asymptomatic.

It is worth noting that, starting in 2011, the patient was followed with endoscopic evaluations every 3–6 months during the initial years of follow‐up; subsequently, from 2019 onward, follow‐up was conducted on an annual basis. The total duration of follow‐up was 11 years, including 3 years after the initiation of antiangiogenic therapy.

3. Discussion

To our knowledge, there are no previous reports describing the use of targeted antiangiogenic therapy with Bevacizumab for the treatment of vascular ectasias associated with RVFH, making this case novel and clinically relevant.

Available evidence suggests that phonotrauma weakens the vasculature of the vocal fold, and over‐vibration, particularly in inflammatory contexts, can reduce blood perfusion and increase vascular permeability, promoting edema formation and hypervascular lesions [2, 3]. Vocal fold varices and ectasias correspond to abnormally dilated and fragile vascular segments, with excessive phonatory vibration due to voice use or abuse being the main predisposing factor [2, 3]. These alterations are a well‐recognized anatomical risk factor for vocal fold hemorrhage [1, 2].

Initial management of acute VFH is conservative; however, in recurrent cases or in the presence of varices, phonosurgical intervention is recommended to eliminate the bleeding source [1, 2]. The most commonly used techniques include angiolytic or CO₂ laser ablation and cold knife excision, depending on lesion location [2]. In this case, repeated failure of these interventions prompted exploration of a therapy based on pathophysiological reasoning.

Bevacizumab, a monoclonal antibody inhibitor of vascular endothelial growth factor (VEGF), has demonstrated a favorable safety profile in laryngeal conditions characterized by high angiogenic activity, such as recurrent respiratory papillomatosis [4]. Nevertheless, its targeted use for the treatment of refractory RVFH has not been previously reported. From a pathophysiological perspective, its inhibitory effect on pathological neoangiogenesis is consistent with evidence linking angiogenesis to vascular fragility of the lamina propria [5]. On this basis, the treating team elected to use bevacizumab in a targeted manner for the management of RVFH. Notably, experimental studies have not demonstrated evidence of fibrosis or histological alterations following intracordal administration [1, 4].

The sustained therapeutic effect observed despite prolonged intervals between injections suggests that bevacizumab may induce enduring modifications in the vascular architecture of the superficial lamina propria. Although this phenomenon has not been characterized in the larynx, evidence from ophthalmology demonstrates durable anti‐angiogenic effects. In a prospective study, Zhang et al. reported that intravitreal bevacizumab achieved stable anatomic resolution of idiopathic subfoveal choroidal neovascularization with a limited number of injections and no recurrences over 12 months. On average, two injections per eye were required, and in 40% of cases complete resolution of subretinal fluid and macular edema was achieved after a single dose [6]. Further studies are required to confirm the reproducibility of these findings in laryngeal tissue and to define the optimal dosing parameters and duration of effect of locally administered bevacizumab.

4. Conclusion

This case suggests that targeted antiangiogenic therapy with intracordal bevacizumab may represent a therapeutic alternative in selected patients with recurrent vocal fold hemorrhage associated with vascular ectasias refractory to conventional phonosurgical management. However, further studies are required to define its role and indications in this clinical context.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Research data are not shared.