Management of Vocal Process Granuloma: A Systematic Review and Meta-analysis

Bayan O. Besharah; Lina Y. Natto; Lega S. Natto

doi:10.3791/71272

Research Article

Management of Vocal Process Granuloma: A Systematic Review and Meta-analysis

DOI:

10.3791/71272

⸱

July 24th, 2026

Bayan O. Besharah¹ , Lina Y. Natto² , Lega S. Natto²

¹Department of Otolaryngology-Head and Neck Surgery, King Abdullah Medical Complex, ²Department of Otolaryngology-Head and Neck Surgery, King Abdullah Medical City

Corresponding Authors: Bayan O. Besharah <bayan.o.b@gmail.com>

Summary

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This meta-analysis evaluated the effectiveness of conservative and surgical treatments for vocal process granuloma by comparing response and recurrence outcomes across published studies. The study also assessed the relative outcomes of different therapeutic combinations and management strategies.

Abstract

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Vocal process granuloma is a benign laryngeal lesion associated with high recurrence rates, and the optimal management strategy remains uncertain due to heterogeneous treatment approaches and variable outcomes. This systematic review and meta-analysis aimed to evaluate the efficacy of available conservative and surgical modalities, either in isolation or in combination, for the treatment of vocal process granulomas. Following PRISMA guidelines, PubMed, Scopus, Web of Science, Cochrane, and EMBASE databases were searched. Retrieved studies were screened according to predefined eligibility criteria, and two authors independently extracted data from the included studies. A total of 49 studies involving 2,818 patients were included, of which 29 studies reported overall response rates. Among these, 5 studies used surgical intervention and demonstrated a pooled rate ratio (RR) of 0.70, whereas 24 studies used conservative treatment and demonstrated a pooled RR of 0.83. In addition, four studies evaluated the use of botulinum toxin combined with proton pump inhibitors (PPI), showing a complete response rate of 0.756. Recurrence rates were assessed in 22 studies, including 14 on conservative treatment and 8 on surgical treatment, with pooled recurrence rates of 0.09 and 0.59, respectively. Three studies using PPIs combined with voice therapy demonstrated a recurrence rate of 0.009. Overall, conservative treatment was associated with improved symptom outcomes and lower recurrence rates compared with surgery alone, although interpretation is limited by heterogeneity and variability in protocols. Combinations of voice therapy with PPIs or botulinum toxin A injections with PPIs were associated with favorable outcomes in several studies. Surgery remains an important option for large or resistant granulomas; however, adjunctive nonsurgical treatment may help reduce recurrence. Further large, randomized trials are needed to minimize selection bias and strengthen the validity of these findings.

Introduction

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A vocal process granuloma, also known as a laryngeal contact granuloma, is a benign hyperplastic lesion that occurs mostly in the arytenoid cartilage¹. This condition is rare but has a high recurrence rate (between 37%–92%)²^,³^,⁴^,⁵. Vocal process granulomas are more frequently encountered among males and are predominant among individuals in their 40s and 50s⁶^,⁷^,⁸^,⁹^,¹⁰.

Several etiological theories have been proposed to explain vocal process granuloma. However, the exact etiology is not completely understood¹¹. Vocal abuse is considered the most common cause, responsible for 33% of cases, followed by laryngopharyngeal reflux (30%), and endotracheal intubation (23%)⁶^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸. Other contributing factors include chronic cough, smoking, throat infections, postnasal drip, habitual throat clearing, and psychosomatic disorders¹⁹. Typically, several factors interact, leading to a multifactorial granuloma of the vocal process. In some cases, the etiology remains undetermined (idiopathic vocal process granuloma)¹¹^,²⁰^,²¹.

Mechanical injury (e.g., traumatic intubation), repetitive phonotrauma (e.g., vocal abuse), or chemical irritation (e.g., laryngopharyngeal reflux) injures the thin epithelium of the mucoperichondrium that covers the vocal process. The mucoperichondrium responds to this injury by initiating an inflammatory process. Long-term chronic inflammation results in the generation of hyperplastic granulation tissue, which forms a vocal process granuloma. Microscopic histological assessment shows perichondritis with infiltration of inflammatory cells and granulation tissue²²^,²³. Clinical examination revealed a unilateral or bilateral sessile or pedunculated mass on the medial surface of the posterior third of the vocal process, restricted to the arytenoid region, with a round, semicircular, or lobulated shape, and a smooth surface that was reddish, white, or translucent. Patients may present with voice changes, globus sensation, throat pain, odynophagia, and airway obstruction in severe cases¹.

Vocal process granulomas can be treated conservatively (to reduce inflammation) or surgically (to resolve the mass burden). For conservative treatment, identification of the etiology is essential, as treatment depends primarily on eliminating predisposing factors. Antireflux medications (e.g., proton pump inhibitors) are effective for symptom improvement and lesion regression in treating granulomas caused by laryngopharyngeal reflux²^,¹⁸^,²⁴. In cases of mechanical granuloma resistant to standard treatments, botulinum toxin A injection into the affected vocal fold has demonstrated favorable outcomes²⁵. Granulomas associated with vocal abuse respond well to speech and language therapy and voice re-education¹². Furthermore, corticosteroid administration (inhaled or injected) may reduce the ongoing inflammatory process and improve the condition of patients with vocal process granulomas²⁶^,²⁷. Surgical treatment is generally reserved for long-standing granulomas that are refractory to conservative treatment, as well as for recurrent or large lesions associated with airway obstruction¹^,¹²^,²⁸. Additionally, when a tissue biopsy is required for pathological assessment, surgical excision is performed¹^,¹²^,²⁸. Surgical treatment options include endoscopic excision under local or general anesthesia in addition to low-dose radiotherapy (preferred for refractory granuloma)⁴.

These treatment modalities can be used either alone or in combination. Several conservative approaches may be combined, and in some cases, surgical treatment may complement conservative management. However, outcomes vary significantly due to diverse clinical presentations and multifactorial etiologies. Some patients may show treatment resistance, while others may experience recurrence despite appropriate therapy. In clinical practice, treatment selection is influenced by multiple factors, including underlying etiology, lesion size, symptom severity, disease duration, and recurrence history⁴^,²¹. Although conservative therapy is generally regarded as the preferred initial management approach, the sequencing of medical, behavioral, and surgical interventions remains variable¹^,²⁸. The lack of standardized, evidence–based guidelines contributes to heterogeneity in clinical practice across institutions, which may influence treatment outcomes⁴^,²¹^,²⁸.

This systematic review and meta-analysis aimed to evaluate the efficacy of available conservative and surgical modalities, either in isolation or in combination, for treating vocal process granuloma. Unlike previous reviews, which have largely focused on isolated treatment outcomes or limited comparative synthesis, the present study provides an updated and comprehensive evaluation of the evidence, including both response and recurrence outcomes as well as an assessment of combined treatment strategies.

Protocol

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The study followed the design principles outlined in the Cochrane Handbook for Systematic Reviews of Interventions and adhered to the reporting standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines²⁹^,³⁰. The study protocol was registered using PROSPERO (registration number: CRD42024512257). This systematic review and meta-analysis were based exclusively on data from previously published studies; therefore, ethical approval and informed consent were not required. The completed PRISMA 2020 checklist is provided as Supplementary File 1.

Literature search
We conducted a comprehensive search of five databases: PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE. The search encompassed articles published across all databases from their inception until July 2023. Furthermore, we reviewed all references cited in eligible articles and meta-analyses on the same topic to ensure no relevant citations were overlooked. The search strategy incorporated the following search terms: (“vocal process granuloma” OR “vocal granuloma” OR “contact granuloma” OR “vocal cord granuloma” OR “vocal fold granuloma” OR “laryngeal granuloma” OR “arytenoid granuloma”). Although broader terms were included, the review specifically focused on vocal process granulomas, which represent the most common site of laryngeal granulomas. The complete database-specific search strategies and Boolean operators used for each database are provided in the Supplementary Table 1.

Eligibility criteria
Two reviewers screened the retrieved references based on the eligibility criteria. Our systematic review employed the following criteria for study inclusion: studies involving patients diagnosed with vocal process granuloma, studies involving any surgical or conservative treatment, and studies with at least 5 patients. Studies describing granulomas of other laryngeal subsites (e.g., subglottic or supraglottic), as well as surgical site granuloma/mid-vocal fold granuloma, were also excluded. To ensure accuracy and consistency, any discrepancies during the evaluation process were resolved through discussion among the investigators or by consulting a third assessor.

Some studies were excluded for the following reasons: animal studies were not considered; studies not published in English; studies consisting only of abstracts; and unpublished study data.

Data extraction
The data extraction process used a standardized local data extraction sheet, tested on a sample of included studies before formal extraction, to ensure uniformity and accuracy among reviewers. The following information was collected from each study: first author's name, year of publication, details regarding the study arms, study site, study design, participant’s sex, duration of follow-up, granuloma size, granuloma type, inclusion criteria, primary endpoints, and conclusions drawn from each included study.

Additionally, we assessed the following outcomes: overall response rate, defined as any improvement as detected by the investigators in the included study; complete response rate, based on the complete disappearance of granuloma without symptoms; partial response rate, defined as partial improvement or narrowing of the granuloma, but still present with or without symptoms; no response rate, indicating the absence of any improvement; and recurrence rate, defined as the reappearance of granuloma after initial treatment response, as reported by each included study. Because follow-up durations varied among studies, a standardized timeframe for recurrence assessment could not be uniformly applied.

Risk of bias assessment
Two investigators independently assessed the quality of observational studies using the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies, and the NIH quality assessment tool for Case Series studies, developed by the National Heart, Lung, and Blood Institute (NHLBI), NIH. The authors' evaluation was categorized as "good," "fair," or "poor" based on the scores obtained during the assessment process.

Data synthesis
For the purposes of this analysis, botulinum toxin injection was classified as a conservative (non-surgical) treatment because it does not involve tissue excision or lesion removal. This classification was based on procedural invasiveness and was applied consistently throughout the study. Because most included studies did not directly compare conservative and surgical interventions, we performed an indirect comparative meta-analysis based on pooled proportions from single-arm studies. Combined rate ratios (RRs) with 95% confidence intervals (CIs) were used to compare outcomes between treatment groups. This approach enabled comparison between treatment modalities despite the lack of sufficient head-to-head comparative studies. Given the considerable clinical heterogeneity among the pooled studies, we initially adopted a random-effects model for our analysis. We also assessed statistical heterogeneity among studies using the chi-squared test for I² statistics, where p < 0.1 indicated heterogeneity, and an I² value ≥ 50% indicated high heterogeneity. All statistical analyses were performed using Review Manager and Open Meta-Analyst software.

For the single-arm analysis, we evaluated categorical outcomes as pooled proportions with 95% CIs. We used a random-effects model on the DerSimonian-Laird method. To evaluate statistical heterogeneity across studies, we used the chi-squared test for I² statistics; p < 0.1 indicates heterogeneity, and I2 ≥ 50% suggests high heterogeneity.

Results

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Literature search results
We performed a comprehensive literature search across five databases, identifying 1,828 studies. After removing duplicates, 994 studies remained eligible for further assessment. By screening titles and abstracts, we identified 75 articles suitable for a more in-depth evaluation. Of these, 26 articles were excluded, ultimately including 47 articles that met our meta-analysis criteria²^,³^,⁴^,⁵^,⁶^,⁷^,⁸^,¹²^,¹⁹^,²⁰^,²⁵^,²⁷^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,
⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵, with 2 studies included solely for a systematic review⁶⁶^,⁶⁷ (Figure 1).

Study characteristics
We included 49 studies involving 2,818 patients diagnosed with vocal process granuloma. Among them, 19 studies utilized surgical treatment, either alone or in combination with other conservative methods, whereas 43 studies employed various conservative treatments, which could be single or a combination of the following: voice therapy, proton pump inhibitors, antireflux medications, botulinum toxin, steroids, autologous fat injection, anti-inflammatory agents, zinc sulfate, antacids, and mosapride citrate. Most studies were conducted in China, the USA, Japan, or Taiwan. Of the included studies, 42 were cohort studies, and 7 were case series. Characteristics of the included studies are summarized in Table 1.

Risk of bias assessment
When evaluating the case series, NIH tool judgments for the included studies ranged from poor to good quality: specifically, four studies were rated as fair quality, two as poor quality, and one as good quality. Furthermore, in the case of the included cohort studies, 34 studies were rated as fair quality, four as good quality, and five as poor quality. A detailed assessment of each domain of the evaluation tools is presented in Supplementary Table 2 and Supplementary Table 3.

Outcomes
Overall response
Of the 29 studies that reported the overall response rates, 5 employed surgical intervention with a pooled RR with 95% CI of 0.70 [0.54, 0.90], while 24 studies utilized conservative treatment, with a pooled RR of 0.83 [0.78, 0.88]. These results demonstrated a non-significant difference between the two groups (p = 0.18), with a high overall response rate in the conservative group. However, the pooled studies were heterogeneous in both groups, with I²= 57% and p = 0.0003, and I²= 66% and p = 0.02, respectively (Figure 2).

Regarding the conservative and surgical treatment subgroups, four studies evaluating botulinum toxin combined with proton pump inhibitor (PPI) therapy reported an overall response rate of 0.909 (95% CI: 0.886–0.931). Subgroups represented by the three studies demonstrated the following overall response rates: PPI combined with voice therapy (0.873), voice therapy alone (0.757), botulinum toxin alone (0.865), botulinum toxin combined with surgical excision and PPI (0.587), and voice therapy combined with PPI and steroids (0.754). Two studies evaluating PPI combined with steroids reported an overall response rate of 0.755. The single-study subgroups demonstrated the following response rates: PPI combined with another type of anti-reflux therapy and voice therapy (0.905), surgical excision combined with voice therapy (0.923), surgical excision combined with PPI and steroids (0.707), autologous fat injection combined with anti-reflux therapy and voice therapy (0.950), botulinum toxin combined with PPI and steroids (0.826), steroids alone (0.955), and observation (0.815). The overall results were heterogeneous (p < 0.01) (Supplementary Figure 1).

Complete response
A total of 34 studies were included in the analysis to assess complete response outcomes. Of these, 27 underwent conservative treatment, while seven underwent surgical treatment. The pooled RR and 95% CI were 0.75 [0.69, 0.81] and 0.45 [0.33, 0.61], respectively. These results indicate a significant difference between the two groups (p = 0.002), with a notably higher complete response rate observed in the conservative group. However, the pooled studies were heterogeneous in both groups, with I² = 60% (p < 0.00001) and I² = 66% (p = 0.008), respectively (Figure 3).

Within the conservative and surgical treatment subgroups, the most frequently evaluated intervention was PPI combined with voice therapy, assessed in six studies, and associated with a complete response rate of 0.783. Botulinum toxin combined with PPI was evaluated in four studies and demonstrated a complete response rate of 0.756. The subgroups represented by three studies each showed the following complete response rates: voice therapy alone (0.523), steroids alone (0.766), botulinum toxin alone (0.745), and PPI combined with steroids (0.677). Two studies evaluated zinc sulfate (0.964) and surgical excision combined with voice therapy (0.552).

In addition, several subgroups represented by a single study were evaluated, with complete response rates presented alongside each intervention: PPI combined with another type of anti-reflux therapy and voice therapy (0.714), autologous fat injection combined with anti-reflux therapy and voice therapy (0.778), surgical excision combined with radiotherapy (0.969), surgical excision combined with PPI and botulinum toxin (0.423), botulinum toxin combined with PPI and steroids (0.739), PPI combined with mosapride citrate (0.962), and voice therapy combined with antacids and anti-inflammatory treatment (0.786). The overall results showed significant heterogeneity (p < 0.01). For visual representation, please refer to Supplementary Figure 2.

Partial response
Thirteen studies were included in the analysis to assess partial response rates. Twelve studies employed conservative treatment, and the pooled RR and 95% CI were 0.24 [0.20, 0.30]. Notably, the pooled studies demonstrated homogeneity, with an I² value of 23% and p = 0.22. Conversely, only one study used surgical treatment, yielding a mere 0.01 partial response rate. These findings indicated a significant difference between the two groups (p = 0.04), with a low partial response rate in the surgical group (Figure 4).

In the conservative and surgical treatment subgroups, two studies evaluated each of the following interventions with corresponding partial response rates: voice therapy alone (0.272), PPI combined with voice therapy (0.225), botulinum toxin combined with surgical excision and PPI (0.214), and botulinum toxin combined with PPI (0.359). The single-study subgroups demonstrated the following partial response rates: PPI combined with another type of anti-reflux therapy and voice therapy (0.190), surgical excision combined with voice therapy (0.154), autologous fat injection combined with anti-reflux therapy and voice therapy (0.222), botulinum toxin combined with PPI and steroids (0.087), surgical excision alone (0.014), PPI combined with steroids (0.228), and steroids alone (0.400). The overall results were heterogeneous (p < 0.01) (Supplementary Figure 3).

No response
Nineteen studies reported this outcome, with 15 employing conservative treatment and four utilizing surgical treatment. The pooled RR and 95% CI were 0.16 [0.12–0.23] and 0.14 [0.05–0.36], respectively. No significant differences were observed between the two groups (p = 0.72). However, the pooled studies were heterogeneous in the conservative treatment group, with an I² value of 44% and p = 0.03 (Figure 5).

Regarding the conservative and surgical treatment subgroups, two studies evaluated each of the following interventions with corresponding response rates: PPI combined with voice therapy (0.168), surgical excision combined with botulinum toxin and PPI (0.469), and botulinum toxin combined with PPI (0.076). All other subgroups were represented by a single study and demonstrated the following response rates: surgical excision combined with voice therapy (0.077), PPI combined with another type of anti-reflux therapy and voice therapy (0.095), autologous fat injection combined with another type of anti-reflux therapy and voice therapy (0.050), voice therapy alone (0.059), botulinum toxin combined with PPI and steroids (0.174), botulinum toxin alone (0.227), steroids alone (0.071), PPI combined with steroids (0.088), voice therapy combined with PPI and steroids (0.062), observation (0.185), and zinc sulfate (0.083); the overall results were heterogeneous (p < 0.01) (Supplementary Figure 4).

Recurrence rate
The recurrence rate was assessed in 22 studies, with 14 employing conservative treatment and eight using surgical treatment. The pooled RR and 95% CI for the two groups were 0.09 [0.05, 0.16] and 0.59 [0.44 and 0.78] respectively. These results indicated a significant difference between the two groups (p < 0.00001), with a higher rate of recurrence observed in the surgical group. However, the pooled studies were heterogeneous in both groups, with I² = 82% and p < 0.00001 for the conservative group and I² = 74% and p = 0.0003 for the surgical group (Figure 6).

Within the conservative and surgical treatment subgroups, three studies evaluated PPI combined with voice therapy and demonstrated a recurrence rate of 0.009. Two studies evaluated the following interventions with corresponding recurrence rates: surgical excision combined with PPI and steroids (0.214), voice therapy combined with antacids and anti-inflammatory treatment (0.110), botulinum toxin alone (0.372), and botulinum toxin combined with PPI (0.180). Single-study subgroups demonstrated the following recurrence rates: surgical excision combined with voice therapy (0.462), PPI combined with another type of anti-reflux therapy and voice therapy (0.023), surgical excision combined with radiotherapy (0.031), autologous fat injection combined with anti-reflux therapy and voice therapy (0.050), surgical excision combined with cryotherapy (0.944), surgical excision combined with steroids (0.556), PPI combined with steroids (0.053), PPI combined with mosapride citrate (0.038), surgical excision combined with botulinum toxin and PPI (0.048), zinc sulfate (0.083), voice therapy combined with PPI and steroids (0.057), and steroids alone (0.024) (Supplementary Figure 5). Overall, the findings of this meta-analysis demonstrated that conservative treatment modalities were associated with higher complete response rates and lower recurrence rates compared with surgical interventions alone. Combination therapies involving proton pump inhibitors, voice therapy, or botulinum toxin generally yielded the most favorable outcomes. Although surgical treatment remains important for refractory or large granulomas, adjunctive conservative therapy appears to reduce recurrence and improve overall treatment success.

DATA AVAILABILITY:
This systematic review and meta-analysis were conducted using previously published data extracted from the included studies. The extracted study-level dataset and the outcome variables used for the analyses are provided in Supplementary Table 4 and Supplementary Table 5, respectively.

Systematic review process flowchart; databases, screening, inclusion; research study selection.
Figure 1. PRISMA Flow diagram. Flow diagram illustrating the study selection process, including database searching, duplicate removal, screening, eligibility assessment, and final inclusion of studies in the systematic review and meta-analysis according to PRISMA 2020 guidelines. Please click here to view a larger version of this figure.

Meta-analysis forest plot; rate ratio CI for conservative vs surgical treatments; statistical summary.
Figure 2. Forest plot of overall response rate (Indirect comparison). Forest plot comparing pooled overall response rates between conservative and surgical treatment modalities for vocal process granuloma using indirect comparative meta-analysis. Effect estimates are presented as pooled rate ratios (RRs) with 95% confidence intervals using a random-effects model. Abbreviations: RR, rate ratio; CI, confidence interval. Please click here to view a larger version of this figure.

Forest plot showing meta-analysis of rate ratios with confidence intervals for treatment efficacy.
Figure 3. Forest plot of complete response rate (Indirect comparison). Forest plot comparing pooled complete response rates between conservative and surgical treatment modalities for vocal process granuloma using indirect comparative meta-analysis. Effect estimates are presented as pooled rate ratios (RRs) with 95% confidence intervals using a random-effects model. Abbreviations: RR, rate ratio; CI, confidence interval. Please click here to view a larger version of this figure.

Meta-analysis forest plot, rate ratios, subgroup comparison, conservative vs surgical treatments.
Figure 4. Forest plot of partial response rate (Indirect comparison). Forest plot comparing pooled partial response rates between conservative and surgical treatment modalities for vocal process granuloma using indirect comparative meta-analysis. Effect estimates are presented as pooled rate ratios (RRs) with 95% confidence intervals using a random-effects model. Abbreviations: RR, rate ratio; CI, confidence interval. Please click here to view a larger version of this figure.

Meta-analysis forest plot showing rate ratios in conservative vs. surgical methods, includes CI.
Figure 5. Forest plot of no response rate (Indirect comparison). Forest plot comparing pooled no-response rates between conservative and surgical treatment modalities for vocal process granuloma using indirect comparative meta-analysis. Effect estimates are presented as pooled rate ratios (RRs) with 95% confidence intervals using a random-effects model. Abbreviations: RR, rate ratio; CI, confidence interval. Please click here to view a larger version of this figure.

Forest plot comparing conservative vs surgical subgroup outcomes; statistical analysis diagram.
Figure 6. Forest plot of recurrence rate (Indirect comparison). Forest plot comparing the pooled recurrence rate between conservative and surgical treatment modalities for vocal process granuloma using indirect comparative meta-analysis. Effect estimates are presented as pooled rate ratios (RRs) with 95% confidence intervals using a random-effects model. Abbreviations: RR, rate ratio; CI, confidence interval. Please click here to view a larger version of this figure.

Table 1. Summary and Baseline characteristics of the included studies. Table summarizing study design, patient characteristics, treatment modalities, granuloma characteristics, follow-up duration, and primary outcomes of the included studies. Please click here to download this Table.

Supplementary Figure 1. Forest plot of overall response rate (Single arm subgroup analysis). Forest plot demonstrating pooled overall response rates across different treatment subgroups for vocal process granuloma using single-arm meta-analysis with a random-effects model. Abbreviations: CI, confidence interval. Please click here to download this file.

Supplementary Figure 2. Forest plot of complete response rate (Single arm subgroup analysis). Forest plot demonstrating pooled complete response rates across different treatment subgroups for vocal process granuloma using single-arm meta-analysis with a random-effects model. Abbreviations: CI, confidence interval. Please click here to download this file.

Supplementary Figure 3. Forest plot of partial response rate (Single arm subgroup analysis) Forest plot demonstrating pooled partial response rates across different treatment subgroups for vocal process granuloma using single-arm meta-analysis with a random-effects model. Abbreviations: CI, confidence interval. Please click here to download this file.

Supplementary Figure 4: Forest plot of no response rate (Single arm subgroup analysis). Forest plot demonstrating pooled no-response rates across different treatment subgroups for vocal process granuloma using single-arm meta-analysis with a random-effects model. Abbreviations: CI, confidence interval. Please click here to download this file.

Supplementary Figure 5. Forest plot of recurrence rate (Single arm subgroup analysis). Forest plot demonstrating pooled recurrence rate across different treatment subgroups for vocal process granuloma using single-arm meta-analysis with a random-effects model. Abbreviations: CI, confidence interval. Please click here to download this file.

Supplementary File 1. PRISMA 2020 reporting checklist showing the location of each reporting item within the manuscript, together with the corresponding page numbers, to facilitate assessment of adherence to the PRISMA 2020 reporting recommendations for systematic reviews and meta-analyses. Please click here to download this file.

Supplementary Table 1. Detailed Search Strategy used across electronic databases. Table presenting the complete database-specific search strategies, Boolean operators, and search syntax used for PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE to identify studies related to vocal process granuloma. Please click here to download this file.

Supplementary Table 2. NIH Quality Assessment Tool for Observational Case Series Studies. Table summarizing the methodological quality assessment of the included case series studies using the National Institutes of Health (NIH) Quality Assessment Tool for Case Series Studies. Studies were classified as good, fair, or poor quality according to predefined criteria. Please click here to download this file.

Supplementary Table 3. NIH Quality Assessment Tool for Observational Cohort Studies. Table summarizing the methodological quality assessment of the included cohort studies using the National Institutes of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Studies were classified as good, fair, or poor quality according to predefined criteria. Please click here to download this file.

Supplementary Table 4. Study-Level dataset used for direct meta-analysis. Summary of the study-level data and outcome variables used in direct meta-analysis. Outcomes were classified as complete response, overall response, partial response, no response, and recurrence rate. Please click here to download this file.

Supplementary Table 5. Study-Level dataset used for indirect meta-analysis. Summary of the study-level data and outcome variables used in indirect meta-analysis. Outcomes were classified as complete response, overall response, partial response, no response, and recurrence rate. Please click here to download this file.

Discussion

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A diverse range of treatment modalities is available for vocal process granulomas. However, no consensus has been reached on the ideal treatment modality. We conducted a systematic review and meta-analysis to evaluate the efficacy of conservative and surgical treatment options, both in isolation and in combination, for vocal process granuloma. Our evaluation depended on both the treatment response and recurrence rates. Our analysis included data from 49 studies, comprising 42 cohort studies and 7 case series, with a total of 2,818 patients. Conservative treatments were investigated in 43 studies, either alone or in combination, whereas surgical treatments were evaluated in 19 studies, either alone or in combination.

The results suggested improved outcomes with conservative treatment modalities compared with surgical approaches in terms of complete response, partial response, and recurrence rates. In subgroup analyses, the combination of botulinum toxin and PPI demonstrated the highest overall response rate, followed by voice therapy combined with PPI and botulinum toxin monotherapy. Regarding complete response rates, the most favorable outcomes were observed with voice therapy combined with PPI, followed by local steroid therapy and botulinum toxin combined with PPI. Botulinum toxin combined with PPI also demonstrated favorable partial response and recurrence outcomes.

Our study builds upon the previous meta-analysis conducted by Tsai et al.⁶⁸. We updated their findings with the inclusion of 31 additional studies and an increased sample size. Our results are consistent with those of Tsai et al. in terms of symptom improvement and recurrence. However, we found a statistically significant advantage of conservative modalities over surgical modalities, which was not evident in their analysis. Furthermore, our study is the first to conduct subgroup analyses for all treatment modalities used in the included studies, whether in isolation or in combination. This approach allowed us to explore the efficacy of these subgroups, which has not been previously investigated in published meta-analyses.

Voice therapy and botulinum toxin A injections appear to act via similar functional mechanisms in the management of vocal process granulomas. Localized botulinum toxin A injection into the interarytenoid or thyroarytenoid muscle, whether unilateral or bilateral, induces temporary paresis for approximately three months³⁸^,³⁹^,⁴²^,⁵⁴^,⁵⁵. This paresis reduces forceful and abrupt adduction of the vocal processes during phonation, minimizes epithelial injury, and allows the granuloma to heal. Similarly, voice therapy trains patients to phonate with an altered vocal fold contact pattern, thereby decreasing forceful closure of the vocal processes¹²^,⁴⁸. Laryngopharyngeal reflux is recognized as one of several contributing factors to the development of vocal process granulomas. Accordingly, PPI therapy is often included as part of management in patients with suspected or confirmed reflux, although its efficacy may vary depending on the underlying etiology²^,⁵⁵. Our review supports these observations, with combination therapies incorporating voice therapy or botulinum toxin A injection alongside PPIs demonstrating favorable outcomes.

Although our results favor conservative treatment modalities, certain situations may require surgical intervention. Surgical excision is generally considered when the granuloma is large, causes severe symptoms or airway obstruction, or is refractory to conservative management⁶^,⁷^,¹⁰^,¹¹^,⁵⁵. Surgical intervention provides faster resolution, whereas conservative treatment may take several months to achieve granuloma resolution²^,¹²^,⁴⁸. In refractory cases, adjunctive botulinum toxin injection into the interarytenoid or thyroarytenoid muscle has been shown to improve outcomes³⁸^,³⁹^,⁴²^,⁵⁴^,⁵⁵. However, it is essential to consider the associated risks of anesthesia, local scarring, and potential recurrence⁷. Conservative treatment following surgical excision may help reduce the risk of granuloma recurrence²^,¹²^,⁴⁸^,⁵⁵.

Heterogeneity was encountered in our meta-analysis, which is thought to be caused by the wide variety of granuloma etiologies, applied treatment modalities, and study designs. Most included studies were of fair quality. However, the poorer treatment outcomes of surgical modalities might be attributed to bias in the characteristics of the granuloma selected for surgical treatment. This selection bias is further compounded in the included studies by the lack of standardized criteria guiding treatment allocation and provider decision-making. In most studies, the rationale for selecting conservative management, botulinum toxin injection, or surgical intervention was not clearly defined and was likely influenced by granuloma size, symptom severity, clinician preference, and other patient-specific factors⁴^,²¹^,²⁸. Consequently, patients undergoing surgical treatment may have represented more severe or refractory cases, limiting direct comparability between treatment groups. Therefore, comparative interpretations of treatment outcomes should be made with caution. Surgical treatment is usually indicated for large refractory granulomas, which are difficult to treat and have high recurrence rates. A limitation of this study was selection bias, which should be avoided in future randomized controlled trials. Moreover, a limitation of this systematic review and meta-analysis is the variability in follow-up duration across the included studies. The follow-up periods ranged widely, with some studies assessing outcomes within a few months and others extending over a year. Shorter follow-up periods may have led to an underestimation of recurrence rates, particularly for treatments that require longer periods to show their full effect, or for granulomas that tend to recur over time. Additionally, long-term outcomes have not been consistently evaluated, which limits our ability to fully assess the sustainability of the treatment effects and the potential for delayed recurrence. Furthermore, the sample size of the included studies was small because of the rarity of vocal process granuloma.

Further large-scale studies are required to improve the generalizability of our findings. In addition, studies should aim to standardize the follow-up duration, with a minimum of 12 months of post-treatment observation, to better evaluate the long-term efficacy and recurrence rates of different treatment modalities. This would provide a more comprehensive understanding of treatment durability and recurrence patterns. Long-term follow-up is essential to distinguish between short-term symptom relief and sustained therapeutic benefits, particularly in conservatively treated patients.

Several therapeutic modalities, either in isolation or in combination, have been used to treat patients with vocal process granulomas. Our systematic review and meta-analysis suggested a potential advantage of conservative treatment over surgical modalities in improving symptoms and reducing recurrence rates. Nevertheless, surgical modalities are required to treat large refractory granulomas owing to their rapid effects. Therefore, adjunctive conservative treatment following surgery may help reduce recurrence. Further large-scale randomized controlled trials are required to eliminate selection bias and enhance the generalizability of these findings.

Disclosures

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The authors declare that there is no conflict of interest.

Acknowledgements

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The authors are grateful to Anas Zakarya for assistance in the design and conduct of this study. The authors also acknowledge Editage (www.editage.com) for English language editing support. This research received no specific funding from any funding agency in the public, commercial, or not-for-profit sectors.

Materials

List of materials used in this article
Name	Company	Catalog Number	Comments
Open Meta-Analyst	Center for Evidence Synthesis in Health, Brown University, Providence, RI, USA	—	Single-arm meta-analysis
Review Manager (RevMan)	The Cochrane Collaboration, London, UK	version 5.4	Indirect comparative meta-analysis

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Management of Vocal Process Granuloma: A Systematic Review and Meta-analysis

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