Acta Oto-Laryngologica. 2015; 135: 277–282

ORIGINAL ARTICLE

Analysis of therapeutic methods for treating vocal process granulomas

LIJING MA, YANG XIAO, JINGYING YE, QINGWEN YANG & JUN WANG Key Laboratory of Otolaryngology Head and Neck Surgery (Ministry of Education of China), Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Abstract Conclusion: The combination of laryngeal microsurgery and local injections of botulinum toxin type A (BTA) can increase the cure rate of patients with vocal process granulomas (VPGs). Objective: To analyze the therapeutic effects of conservative treatments, microsurgical resection with suturing and microsurgery in combination with local injections of BTA for the treatment of VPGs. Methods: A retrospective analysis of 168 cases of VPG was performed. All of the patients initially received a conservative treatment. Some of the patients who did not respond to the conservative treatments were treated using microsurgical resection and microsuturing using an 8-0 absorbable filament. Other patients additionally received a fourpoint injection of BTA into the thyroarytenoid muscle and the arytenoid muscle on the operated side. Results: The lesions of 41.3% (71/168) of the patients who were given the conservative treatments (including acid suppression, vocal rest, and voice therapy) disappeared, and the lesions of 10.7% (18/168) of the patients were reduced. The conservative treatments were unsuccessful for 47% (79/168) of the patients. The cure rate was 78.4% (29/37) for the patients who were treated by microscope resection using a CO2 laser and microsuturing of the surrounding mucosa. Of the eight patients who experienced a recurrence, five of them had lesions that disappeared after 3 months of conservative treatment, whereas the other three patients recovered after a second operation. The cure rate of the 42 patients who were treated using microsurgery combined with local injections of BTA was 95.2% (40/42), with only 2 cases of recurrence at 2 months post-treatment.

Keywords: Microsurgery, botulinum toxin type A, conservative treatment, microsuturing

Introduction Vocal process granuloma (VPG) is a benign lesion affecting the vocal process of the arytenoid cartilage. The pathogenesis of this disease is not understood, but vocal abuse, intubation trauma, and gastroesophageal reflux (GER)/laryngopharyngeal reflux (LPR) have been proven to be the main inducing factors. In 2010, Carroll et al. [1] presented evidence that glottal insufficiency was the possible etiological factor in patients with refractory VPG. Regardless of the etiology, VPGs present similar clinical manifestations. The most common symptom is hoarseness combined with persistent throat clearing, sore throat, and a globus sensation. The optimal treatment regimen for VPG is still controversial. The traditional treatment regimen

consists primarily of voice therapy to reduce the collision forces at the affected site and the administration of anti-acids, such as proton-pump inhibitors (PPIs), to prevent injury from GER. The other conservative treatments include botulinum toxin injection [2] and intralesional steroid injection [3]. In 2009, Wang et al. [4] demonstrated that most VPGs (81%) spontaneously regressed and disappeared within 9 months. Although these treatment regimens achieve desirable outcomes, the long course of treatment, the persistence of the lesions, and the side effects of the drugs made the patients anxious. Surgery is not generally selected as the initial treatment for VPG due to the high recurrence rate of this lesion [5]. Surgery may be indicated to remove obstructive lesions or lesions refractory to other therapies. However, among all of the single treatment

Correspondence: Jun Wang, Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. Tel: +86 10 58269207. Fax: +86 10 65288441. E-mail: [email protected]

(Received 11 September 2014; accepted 6 November 2014) ISSN 0001-6489 print/ISSN 1651-2251 online
2015 Informa Healthcare DOI: 10.3109/00016489.2014.986756

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strategies, surgical resection is the most rapid method of eliminating granulomas. Considering the multifactorial etiology of VPGs and the advantages and disadvantages of different treatments, some otolaryngologists have begun to search for a combined therapy for VPG. Song et al. [6] used surgical resection plus low-dose X-ray radiation to treat refractory VPG. When Hong-Gang et al. [7] used surgery and the administration of PPIs to treat VPG, the recurrence rate was 38.7%. In particular, there was no recurrence among the patients who had a recent history of intubation. In this report, we describe the results obtained when different VPG treatments were applied to determine which treatment was most efficacious. Material and methods For this study, 168 patients with VPG who were treated in the Otolaryngology Head and Neck Surgery Center of the affiliated Beijing Tongren Hospital of Capital Medical University between January 2005 and January 2013 were enrolled. The diagnosis was reached using rigid video-strobolaryngoscopy on an outpatient basis. The medical records were reviewed and data were collected, including the age, gender, occupation, intubation history, history of GER or LPR, symptoms or signs, previous treatment methods applied, course of the treatments, and whether a recurrence had presented. The granulomas were graded using Farwell’s grading system according to the laryngoscopic findings [8]. All the patients were given a conservative treatment of omeprazole or esomeprazole (20 mg bid) administration for 3 months. The patients were told to control their speaking, improve bad speaking habits, and avoid unconsciously clearing the throat and coughing during this period. The patients for whom the conservative treatment failed were treated with surgery. The patients treated before 2009 were subjected to microsurgical resection and microsuturing. These patients were subjected to tracheal intubation under general anesthesia, using 1-2 gauze tracheal tubes that were smaller than those used for general anesthesia. A self-retaining laryngoscope was usedto expose the lesion in the posterior of the vocal cords (Figure 1A). Under a microscope, a radical resection of the lesion and the surrounding neoplastic tissue was conducted using micro-scissors and a 1.0 W CO2 laser (Figure 1B). The cartilaginous membrane surrounding the vocal process and the normal mucosa surrounding the neoplasm were protected. The incision was closed using 8-0 absorbable suture material (Vicryl), using the interrupted apposition suturing method to apply two to three stitches (Figure 1C).

A

B

C

D

Figure 1. Female, 48 years. (A) Image of the granulation-like neoplasm on the vocal process of the right arytenoid, before the resection was performed (arrow); (B) image of the same site after the resection (arrow); (C) image of the incision site after closure using an 8-0 absorbable suture filament (arrow); (D) diagram of the sites of injection of botulinum toxin type A (red dots).

Since 2009, the VGA patients have been treated using microsurgery combined with local injections of botulinum toxin type A (BTA). After the granuloma was removed, injections of BTA were given. The BTA was diluted to 10 U/ml using a sterile saline solution. A total of 8–15 U of BTA was injected into four points of the thyroarytenoid and arytenoid muscles near the arytenoid cartilage of the affected side. The BTA injection sites are shown in Figure 1D (red dots). For the thyroarytenoid injections, the injection needle was aimed toward the side of the vocal ligament of the mid-membranous vocal fold at the floor of the laryngeal ventricle. If lesions were found on both sides, the left thyroarytenoid muscle was injected. A budesonide inhalant was administered for 2 weeks after the surgery and omeprazole or esomeprazole was administered for 3 consecutive months after the surgery. The patients who were injected with BTA underwent stroboscopic laryngoscopy to observe the movements of the arytenoid before surgery and at 3 days, 1 month, 2 months, and 3 months after surgery. A voice assessment was conducted, which consisted of a perceptual evaluation of HRB (the grade of hoarseness, roughness, and breathiness) and determination of the maximum phonation time (MPT). The perceptual evaluation was performed using a four-point assessment scale, as follows: 0, normal; 1, mild; 2, moderate; and 3, severe. The voice assessment was performed at 3 days, 1 month, and 3 months after surgery. The mean follow-up period was 28 months, with a range of 12–58 months. The other patients underwent stroboscopic laryngoscopy at 1 month and 3 months after treatment.

Treatment methods for vocal process granulomas Statistical analysis The paired-samples t test and the Wilcoxon signedrank test were performed to assess whether there were significant differences in the MPTs and the HRB grades before and at the last follow-up following surgery. A value of p < 0.05 was considered to be significant. Results There were 143 (85.1%) male and 25 (14.9%) female patients with refractory VPG enrolled in this study. Their ages ranged from 25 to 81 years, with an average of 49 years. In 100 (59.5%) of the patients, the granuloma originated on the left vocal process, whereas 55 (32.8%) of the patients had a right-sided granuloma. The other 13 (7.7%) patients had bilateral VPG. According to Farwell’s grading system, there were 12 (7.2%) cases of grade I granuloma, in which a sessile, non-ulcerative granuloma was limited to the vocal process; 36 (21.4%) cases of grade II granuloma, in which a pedunculated or ulcerated granuloma was limited to the vocal process; and 104 (61.9%) cases of grade III granuloma, in which the granuloma extended past the vocal process but did not cross the midline of the airway when the process was in the fully abducted position. The other 16 (9.5%) patients were diagnosed with grade IV granulomas, which extended past the vocal process and past the midline of the airway when the process was in the fully abducted position. There were 57 (33.9%) patients with a history of GER, 41 (24.4%) patients with a history of laryngeal intubation for general anesthesia, 39 (23.2%) patients who had used their voices excessively, 33 (19.6%) patients with a history of smoking, and 19 (11.3%) patients with no obvious etiology. Among the patients with a history of laryngeal intubation for general anesthesia, there were 23 (16.1%) males and 18 (72%) females. A total of 148 (88.1%) of the patients had different degrees of hoarseness, 111 (66.1%) patients had the sensation of having a foreign body in the throat and a cough, 29 (17.3%) patients had throat pain, and 16 (9.5%) patients had mild to moderate apnea. Only five (3%) patients, who had no obvious symptoms, had VPG that was found upon physical examination. The symptoms of patients had lasted from 1 to 108 months (average of 12 months). The diagnoses of the patients were confirmed by pathology of specimens taken during the operations. The lesions of 41.3% (71/168) of the patients who were given the conservative treatment (including acid

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suppression, vocal rest, and vocal therapy) disappeared and the lesions of 10.7% (18/168) of the patients were reduced. The conservative treatment was unsuccessful for 47% (79/168) of the patients. The cure rate was 78.4% (29/37) in the patients who were treated by microscope resection using a CO2 laser and microsuturing of the surrounding mucosa. In the eight patients who experienced a recurrence, five of the lesions disappeared after 3 months of conservative treatment and another three patients recovered after a second operation. The cure rate of the other 42 patients who were treated using the microsurgical operation combined with local injections of BTA was 95.2% (40/42). The two patients who had a recurrence 2 months after the operation refused a repeat surgery. At 1 year of follow-up, their lesions were still present (Farwell class I) and the patients did not have obvious symptoms. The patients who were treated using BTA injections experienced hoarseness and breathiness for 2–3 days after the surgery. Using an electronic laryngoscope, we observed that the movements of the arytenoid on the injected side were weaker than those on the contralateral side. At 1 month after surgery, the arytenoid on the injected side was fixed and the vocal cord was arched. Therefore, there was a gap when the glottis was closed (Figure 2). The arytenoid on the injected side could move in 34 (80.95%) of the patients at 2 months after the surgery, but the movements were weaker than those on the opposite side. The activity of the arytenoid was normal in eight (19.05%) of the patients at this point. At 3 months after surgery, the activity of the arytenoid on the injected side was normal in all of the patients. Compared with the preoperative values, the mean MPT at 1 month after operation was significantly decreased (p < 0.0001), by an average of 3.9 s, but at 3 months after the operation, the mean MPT was increased by 5.3 s. Compared with the value at 1 month after operation, the mean MPT at 3 months after operation was increased by 9.2 s (Table I). There was no significant difference in the roughness of the voice at 1 month after operation and preoperatively, but there was a significant difference between the other scores at these points. In general, the postoperative HRB scores were better than the preoperative scores (Table II). Discussion In 1935, Jackson and Jackson first described vocal process contact granulomas, which are nontumorous granulation-like, proliferative tissue, chronic inflammatory lesions located over the tip of the cartilaginous region of the vocal processes

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A1

B1

C1

A2

B2

C2

Figure 2. Female, 48 years, with a granulation-like neoplasm on the vocal process of the right arytenoid. (A1, A2) Images showing the movement of the bilateral arytenoid before the resection was performed; (B1, B2) images taken 3 days after the operation, showing that the right vocal cord was arched and in a fixed position; (C1, C2) images taken 3 months after the operation, showing that the bilateral movements of the arytenoid were normal.

Table I. Maximum phonation times (x ± s) of the patients (n = 42) who were given botulinum toxin type A injections at different time points. Before operation

1 month after operation

3 months after operation

17.3 ± 6.3

13.5 ± 5.4*

22.6 ± 5.2*

*p < 0.01, paired-sample t test.

Table II. HRB grades of the patients who were given botulinum toxin type A injections before the operation and 1 month and 3 months after the operation. Before the operation (%)

1 month after operation (%)

3 months after operation (%)

0

9 (21.4)*

2 (4.8)*

34 (80.95)*

1

16 (38.1)*

6 (14.3)*

8 (19.05)*

2

11 (26.2)*

18 (42.9)*

3

6 (14.3)*

16 (38.0)*

0

18 (42.9)*

15 (35.7)

35 (83.3)*

1

18 (42.9)*

24 (57.1)

7 (16.7)*

2

5 (11.9)*

3 (7.1)

3

1 (2.3)*

Factor Hoarseness

Roughness

Breathiness 0

16 (38.1)*

1 (2.3)*

39 (92.9)*

1

23 (54.8)*

6 (14.3)*

3 (7.1)*

2

3 (7.1)*

18 (42.9)*

3

17 (40.5)*

HRB, grade of hoarseness, roughness, and breathiness. *p < 0.01, Wilcoxon signed-rank test.

[9]. In subsequent studies, the clinical manifestations and syndromes of VPG were found to be similar. The main related syndromes are hoarseness, a sore throat, and the sensation that a foreign body is present. Men have a relatively higher incidence of this lesion than women [10]; however, VPG caused by endotracheal intubation occurs more often in women. In the present study, 148 (88.1%) patients experienced various degrees of hoarseness, 111 (66.1%) patients had the sensation of having a foreign body in the throat and coughed, 29 (17.3%) patients experienced throat pain, and 16 (9.5%) patients had mild to moderate apnea. Only five (3%) of the patients with VPG exhibited no obvious symptoms upon physical examination. There were 23 (16.1%) males and 18 (72%) females among the patients who had a history of laryngeal intubation for general anesthesia, which was consistent with the results of previous reports. The hypothesis of McFerran et al. was that because women have a relatively narrow laryngeal cavity and thin mucosa compared with those of men, women are more vulnerable to intubationrelated injuries, which leads to the formation of a vocal process ulcer that develops into granuloma [11,12]. Most studies have shown that phonation-based injuries, injuries caused by laryngeal intubation, and GER are the primary causes of VPG [13,14]. In the present study, 6 patients had a history of laryngeal intubation, 8 patients had definitive GER confirmed by 24 h pH monitoring or gastroscopy, 4 patients had used their voices excessively, and 10 patients had no obvious etiology. The incidence rate of VPG is low, and the three specific causes mentioned above are responsible for most of the reported cases, which indicates that the main

Treatment methods for vocal process granulomas mechanisms underlying the pathogenesis of VPG are still not clear. In addition, these three causes fail to account for the formation of idiopathic and recalcitrant granulomas. The treatments offered to patients with VPG are driven by the etiology of the lesions. Because the pathogenic mechanisms are unclear, the results of treatments – particularly single therapies – are not ideal. Conservative therapies, including correcting bad phonation habits, voice rest, precautions against reflux and/or medication using an H2-blocker, and medication using a proton-pump inhibitor (PPI), are the first-line treatments for VPG. The results of these therapies are not satisfactory because the long-term nature of the treatment and the occurrence of complications and adverse reactions typically cause noncompliance. Hanson et al. [15] reported 12 cases of laryngeal granulomas treated with omeprazole, with an average treatment time of 5 months. Wani and Woodson [16] used omeprazole or ranitidine to treat 18 patients, among whom 14 cases had complete remission after drug administration for 1–20 months, with an average time of 10.4 months. In this study, the efficiency of 3 months conservative treatment was 53%, which is lower than found in other studies. This outcome may be due to our short observation time, which was because the patients were eager to improve their symptoms as soon as possible. Surgery is always controversial. Physicians argue that surgery should be used only in the patients for whom conservative treatments have failed or in patients with a large granuloma in the airway. The reason for surgical excision being unacceptable is the high recurrence rate; some studies have reported a recurrence rate of up to 90%. The diagnosis of VPG is performed using video laryngoscopy, but not biopsy. Some of the patients who saw the mass in a video recording were afraid of surgery, regardless of what diagnosis we gave them. However, because the symptoms of VGA, such as hoarseness and a globus sensation, are persistent, the patients are eager to eliminate them by whatever means possible. Among the single therapies, surgery is the most rapid method for removing the granuloma and eliminating the hoarseness and the sensation of the presence of a pharyngeal foreign body. Physicians have been searching for options that would lower the high recurrence rate of surgery. Hirano et al. [17] proposed fiberoptic laryngeal surgery as a procedure that facilitated repeated surgical removal of these lesions. We applied a CO2 laser to resect the lesion and closed the incision using 8-0 absorbable suture filaments and the interrupted apposition method, along the mucosal edge in 23 patients with VPG, among whom the recurrence rate was 21.6%. There was no recurrence

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among the patients who had a recent history of intubation. Microsurgical scissors and a CO2 laser were used to perform a radical resection of the lesions under a microscope. An 8-0 absorbable suture filament was used to suture the mucosal edge of the incision. Then, a four-point injection of 8–15 U of BTA into the thyroarytenoid muscle of the affected side was conducted. In the present study, we applied a microsurgical suturing method using an 8-0 absorbable suture filament to close the wound, promote healing, and reduce the probability of recurrence. We also injected BTA into the concave side of the muscle to limit the movement of the arytenoid. As a chemical denervation agent, BTA was first used to treat spasmodic dysphonia [18]. In 1995, Nasri et al. [2] were the first group to report treating VPG by injecting BTA into the thyroarytenoid muscle (LTA) and obtained a desirable level of efficacy. The success of this therapy was confirmed by the subsequent serial studies. Treatment through BTA injection was the basis of the theory of the hammer and the anvil as a cause of VGA [19]. Due to the force of the collision of the bilateral arytenoid cartilage, the mucosa of the vocal process is damaged, resulting in the formation of a granuloma. Therefore, inhibiting the movement of the arytenoid cartilage can facilitate the repair of the mucosal injury and reduce the rate of recurrence of VGA. BTA causes temporary paresis of the vocal folds, allowing the mucosa of the vocal process to regenerate. The total doses used ranged from 5 U to 20 U. In the present study, the total dose of BTA used was 8–15 U, which was divided into four doses that were injected into the thyroidarytenoid muscle. Our results showed that the activity of the arytenoid on the injected side was limited for 2–3 days after the injections were performed. The activity of the arytenoid was generally normal at 2 months after the injections were performed. The main side effect of the BTA injections was a breathy voice. Voice assessment revealed that the chemical denervation of the ipsilateral thyroarytenoid muscle was apparent 12–72 h after the injection was performed, inhibiting the adduction movement of the arytenoid muscle and reducing the strength of the collision of the bilateral vocal process. This state could persist for approximately 3 months, after which the denervated neuromuscular junction was fully recovered. First, we removed the granuloma and closed the incision through the surface of the arytenoid cartilage using microsurgery. Then, we took advantage of the denervating effect of BTA to inhibit the movement of the arytenoid cartilage to reduce the force of collision. Moreover, anti-acid medication was given to eliminate the pathogenic factors of VPG.

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The treatment regimen for VPG should be targeted and comprehensive due to the complexity and diversity of the inducing factors. Only a comprehensive treatment approach can shorten the treatment period, improve the response rate, and reduce the rate of complications and adverse reactions. Combined therapy is considered to be the preferred choice for treating refractory VPG. Although VPG is a benign lesion, it affects patients’ quality of life due to its persistence and the long-term nature of its treatment. An otolaryngologist should be concerned about how to shorten the treatment process and reduce the relapse rate. Surgical removal is a rapid treatment method with a high recurrence rate. Surgical resection combined with the use of other conservative treatment methods may provide a bright future for patients with this disease.

Acknowledgment This study was supported by a grant from the National Natural Science Foundation of China (no. 81170900). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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