Volume 170, Issue 4 p. 1091-1098
Original Research
Free Access

Factors Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis

Raymond J. So AB

Raymond J. So AB

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Alexander T. Hillel MD

Alexander T. Hillel MD

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Kevin M. Motz MD

Kevin M. Motz MD

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Lee M. Akst MD

Lee M. Akst MD

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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Simon R. Best MD

Corresponding Author

Simon R. Best MD

Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Corresponding Author: Simon R. Best, MD, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, 601 N. Caroline Street, Baltimore, MD 21287, USA.

Email: [email protected]

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First published: 20 December 2023

Abstract

Objective

To describe iatrogenic laryngeal injury and identify its risk factors in recurrent respiratory papillomatosis (RRP) patients receiving surgical care.

Study Design

Case-control.

Setting

Tertiary care academic hospital in a metropolitan area.

Methods

Charts of patients with RRP seen at our institution from January 2002 to December 2022 were reviewed. Patients were separated into 2 cohorts based upon whether they experienced any form of iatrogenic laryngeal injury—including anterior commissure synechiae, vocal cord scar, reduced vocal fold pliability, vocal fold motion impairment, and glottic and/or subglottic stenosis. Adjusted logistic regressions were performed to identify factors associated with iatrogenic laryngeal injury.

Results

Of 199 RRP patients, 133 (66.8%) had identifiable iatrogenic laryngeal injury. The most common injuries were anterior commissure synechiae (n = 67; 50.4%) and reduced vocal fold pliability (n = 54; 40.6%). On a multivariate logistic regression, patients with diabetes mellitus (adjusted odds ratio [aOR] [95% confidence interval [CI]]: 2.99 [1.02, 8.79]; P = .04) and who received at least 10 surgeries lifetime (aOR [95% CI]: 14.47 [1.70, 123.19]; P = .01) were at increased risk for iatrogenic laryngeal injury, whereas receiving less than 5 surgeries (aOR [95% CI]: 0.21 [0.09, 0.51]; P < .001) was found to be protective. When treating the lifetime number of surgeries as a continuous variable, a greater number of surgeries was a significant risk factor for iatrogenic laryngeal injury (aOR [95% CI]: 1.32 [1.14, 1.53]; P < .001).

Conclusion

These results suggest the importance of strict glucose control for diabetic patients receiving RRP surgical care, and emphasize the clinical need to identify medical therapies to decrease RRP surgical frequency for patients.

Recurrent respiratory papillomatosis (RRP) is a rare, morbid condition caused by human papilloma viruses 6 and 11, and is characterized by recalcitrant growths of benign neoplasms in the aero-digestive tract.1 The clinical symptoms of RRP largely reflect impairment of glottic function, and include chronic dysphonia, dyspnea, cough, and stridor, which frequently synergize to produce profound quality of life impairments for patients.2 RRP follows a trimodal distribution—with peaks at 7, 35, and 64 years of age—but is generally categorized into juvenile-onset (JORRP) and adult-onset (AORRP) depending on the age of symptom presentation.3

As there is presently no curative treatment for RRP, management of the condition revolves around surgical and/or procedural debulking to decrease papilloma burden. Although this effectively offers temporary relief of symptoms, papilloma recurrence is common and often necessitates additional surgical interventions that accumulate into greater health care costs. Indeed, RRP comprises nearly $120,000,000 in annual health care expenditures in the United States,4 with an estimated 25% of RRP patients paying more than 15% of their yearly income towards RRP-related health care.5 Furthermore, repeat surgical interventions present increased risk for iatrogenic complications. In particular, as the larynx is the most commonly involved anatomic subsite for RRP,1 laryngeal sequelae—inclusive of anterior and posterior commissure synechiae, and glottic and subglottic stenosis—following surgery for RRP have been reported in several case reports, with a varying incidence ranging from 2% to 40%.6-11 Laryngeal scar itself may worsen obstructive symptoms and require additional surgical interventions for management.

As iatrogenic sequelae following surgery for RRP may often be more morbid and more difficult to treat than papillomas themselves, understanding the extent of this risk and factors that lead to iatrogenic laryngeal injury in RRP is an important clinical need. To date, however, there exist only 2 case-control studies investigating factors associated with iatrogenic sequelae in RRP.6, 11 As was acknowledged by the respective authors, these studies were largely limited by their small sample sizes and focused upon a subpopulation of children with JORRP, which may represent a different disease process from and generally presents with a more aggressive clinical course than AORRP.1 Indeed, the extent of and factors that result in iatrogenic laryngeal injury in AORRP patients have never before been investigated. In this study, we present a large cohort of RRP patients—both JORRP and AORRP—at a single-institution tertiary care academic medical center, and investigate demographic, clinical, and surgical characteristics associated with increased risk for iatrogenic laryngeal injury following surgery for RRP.

Materials and Methods

This study was approved by the Johns Hopkins Institutional Review Board. Informed consent was not required due to the retrospective nature of this study.

Study Design and Detailed Clinical Record Review

We performed a case-control study designed to assess demographic, clinical, and surgical characteristics associated with iatrogenic laryngeal injury following surgery for RRP. Patients with an International Classification of Diseases (ICD) code for benign neoplasm of the larynx (ICD-9: 212.1; ICD-10: D14.1) were identified between January 2002 and December 2022. Medical records for these patients were reviewed, and only those with documented RRP were included for this study. Demographic characteristics, medical comorbidities, and RRP clinical characteristics were noted. Patients with onset of RRP before 12 years of age were classified as JORRP, and patients with onset after 12 years of age were categorized as AORRP. Iatrogenic laryngeal injury was identified using the most recent clinic and operative notes, as well as office stroboscopy and laryngoscopy. Categories of injury were defined prior to chart review, and specifically included vocal scar (assessed operatively), reduced vocal fold pliability (assessed with stroboscopy), vocal fold motion impairment, anterior and posterior commissure synechiae, and glottic and subglottic stenosis. These were not mutually exclusive categories, and many patients had multiple concurrent forms of iatrogenic injury. Anatomic subsites involved by papilloma were confirmed using laryngoscopy and bronchoscopy reports, and computed tomography (CT) imaging findings were used to confirm the presence of pulmonary RRP. Preoperative dysphonia and dyspnea could be attributed to either papilloma or iatrogenic injury, but postoperative symptomatology was only included if symptoms were present despite complete excision of papilloma.

Statistical Analysis

Patients were separated into 2 groups based upon the presence of iatrogenic laryngeal injury. Mean and standard deviations were calculated for continuous data. Frequencies and percentages were calculated for categorical data. All percentages were calculated with respect to the total size of each cohort, unless otherwise specified. Continuous variables were compared using a Student's t-test, and categorical variables were compared with Chi-squared tests. The lifetime number of surgeries was considered both categorically (ie, <5 surgeries, 5-9 surgeries, 10+ surgeries) and continuously in analyses. Relative risk for iatrogenic laryngeal injury stratified by the lifetime number of surgeries received was calculated. Variables that were significant in unadjusted analyses were retained for univariate logistic regressions. Variables that were significant in univariate analyses were further retained for a multivariate logistic regression. Statistical analyses were performed using STATA version 15 (StataCorp.). Statistical significance was defined as P ≤ .05.

Results

Demographic and Clinical Characteristics of RRP Patients

Of the 199 RRP patients identified, 133 (66.8%) had documented iatrogenic laryngeal injury. In the overall cohort, the majority was male (n = 137; 68.8%) and White (n = 119; 59.8%). The average (SD) age at which RRP was diagnosed for the total cohort was 37.0 (21.7) years. The most common comorbidities were hypertension (n = 89; 44.7%), dyslipidemia (n = 65; 32.7%), and diabetes mellitus (n = 36; 18.1%). Compared to those who experienced no iatrogenic sequelae, a greater proportion of patients who experienced iatrogenic laryngeal injury were female (19.7% vs 36.8%; P = .02) and had comorbid diabetes mellitus (9.1% vs 22.6%; P = 0.03) (Table 1).

Table 1. Demographic Characteristics and Comorbidities of Patients with Recurrent Respiratory Papillomatosis
Characteristic Total No injury Injury P value
N 199 66 (33.2) 133 (66.8) --
Sex, N (%)
Male 137 (68.8) 53 (80.3) 84 (63.2) .02
Female 62 (31.2) 13 (19.7) 49 (36.8) .02
Race, N (%)
White 119 (59.8) 35 (53.0) 84 (63.2) .22
Black or African American 24 (12.1) 5 (7.6) 19 (14.3) .26
Asian 2 (1.0) 0 (0.0) 2 (1.5) --
American Indian or Alaska Native 11 (5.5) 6 (9.1) 5 (3.8) .22
Other 2 (1.0) 0 (0.0) 2 (1.5) --
Not reported 41 (20.6) 20 (30.3) 21 (15.8) .03
Age at diagnosis, mean (SD) 37 (21.7) 40 (20.0) 36 (22.4) .24
BMI, mean (SD) 28 (5.9) 27 (5.7) 28 (5.9) .06
Comorbidities, N (%)
Asthma 32 (16.1) 9 (13.6) 23 (17.3) .65
Chronic obstructive pulmonary disease 14 (7.0) 7 (10.6) 7 (5.3) .27
Congestive heart failure 7 (3.5) 2 (3.0) 5 (3.8) .88
Coronary artery disease 21 (10.6) 6 (9.1) 15 (11.3) .82
Peripheral vascular disease 5 (2.5) 2 (3.0) 3 (2.3) .88
Dyslipidemia 65 (32.7) 22 (33.3) 43 (32.3) .99
Chronic kidney disease 12 (6.0) 1 (1.5) 11 (8.3) .12
Hypertension 89 (44.7) 31 (47.0) 58 (43.6) .77
Diabetes mellitus 36 (18.1) 6 (9.1) 30 (22.6) .03
Atrial fibrillation 8 (4.0) 4 (6.1) 4 (3.0) .52
Smoking history 67 (33.7) 25 (37.9) 42 (31.6) .47
  • Note: Bold values indicate statistical significance.
  • Abbreviations: BMI, body mass index; SD, standard deviation.

In the total study cohort, 158 (79.4%) patients were diagnosed with AORRP. No significant difference was observed between the relative rates of injury in the JORRP and AORRP cohorts (respectively, 73.2% vs 65.2%; P = .33). All RRP patients presented with papilloma in the larynx, whereas the trachea (n = 36; 18.1%) and pulmonary parenchyma (n = 10; 5.0%) were less frequently involved. The most common clinical symptoms reported were dysphonia (n = 157; 78.9%), chronic cough (n = 62; 31.2%), and dyspnea (n = 53; 26.6%). A greater proportion of patients who experienced iatrogenic laryngeal injury reported dysphonia compared to those without iatrogenic sequelae (69.7% vs 83.5%; P = .04). No other clinical characteristics were found to be significantly different between the 2 cohorts (Table 2).

Table 2. Clinical Characteristics of Patients with Recurrent Respiratory Papillomatosis
Characteristic Total No injury Injury P value
Diagnosis, N (%)
JORRP 41 (20.6) 11 (16.7) 30 (22.6) .43
AORRP 158 (79.4) 55 (83.3) 103 (77.4) .43
RRP subsite, N (%)
Laryngeal 199 (100.0) 66 (100.0) 133 (100.0) --
Tracheal 36 (18.1) 12 (18.2) 24 (18.0) .86
Pulmonary 10 (5.0) 3 (4.5) 7 (5.3) .90
Symptoms, N (%)
Dysphonia 157 (78.9) 46 (69.7) 111 (83.5) .04
Dyspnea 53 (26.6) 12 (18.2) 41 (30.8) .08
Stridor 23 (11.6) 4 (6.1) 19 (14.3) .14
Cough 62 (31.2) 16 (24.2) 46 (34.6) .19
Dysphagia 31 (15.6) 8 (12.1) 23 (17.3) .46
Treatment characteristics
Last surgery before documented complication, N (%)
Laser 66 (33.2) 26 (39.4) 40 (30.1) .19
Microdebrider/cold steel 133 (66.8) 40 (61.6) 93 (69.9) .19
Year
Before 2010 94 (47.2) 22 (33.3) 72 (54.1) .01
After 2010 105 (52.8) 44 (66.7) 61 (45.9) .01
Adjuvant treatments, N (%)
Local or systemic Bevacizumab 43 (21.6) 8 (12.1) 35 (26.3) .02
  • Note: Bold values indicate statistical significance.
  • Abbreviations: AORRP, adult-onset recurrent respiratory papillomatosis; JORRP, juvenile-onset recurrent respiratory papillomatosis; RRP, recurrent respiratory papillomatosis.

Types of Iatrogenic Laryngeal Injury and the Lifetime Number of Surgeries in RRP Patients

Of the 133 patients who experienced iatrogenic laryngeal sequelae, the most common injuries identified were anterior commissure synechiae (n = 67; 50.4%), reduced vocal fold pliability (n = 54; 40.6%), and vocal scar (n = 41; 30.8%) (Table 3). In the total cohort, 99 (49.7%) patients received less than 5 surgeries, 40 (20.1%) received between 5 and 9 surgeries, and 60 (30.2%) received at least 10 surgeries in their lifetime. Patients who received less than 5 surgeries in their lifetime were at half the risk for iatrogenic laryngeal injury compared to those who received at least 5 surgeries. Receiving at least 10 surgeries lifetime resulted in nearly 80% increased risk for iatrogenic laryngeal injury (Table 4).

Table 3. Types of Iatrogenic Laryngeal Injury Following Surgical Treatment of Recurrent Respiratory Papillomatosis
Complication N (%)
Anterior commissure synechiae 67 (50.4)
Reduced vocal fold pliability 54 (40.6)
Vocal scar 41 (30.8)
Posterior glottic stenosis 5 (3.8)
Subglottic stenosis 5 (3.8)
Vocal fold motion impairment 5 (2.5)
Table 4. Lifetime Number of Surgeries Stratified by the Presence of Iatrogenic Laryngeal Injury
Cohort <5 Surgeries 5-9 Surgeries 10+ Surgeries
No injury, N (%) 55 (55.6) 9 (22.5) 2 (3.3)
Injury, N (%) 44 (44.4) 31 (77.5) 58 (96.7)
Preliminary comparison
Relative risk 0.50 1.21 1.79

Logistic Regressions Assessing Factors Associated with Iatrogenic Laryngeal Injury

On a univariate logistic regression, male patients were more than 50% less likely to experience iatrogenic laryngeal injury following surgery for RRP (OR [95% CI]: 0.42 [0.21, 0.85]; P = .02). In contrast, the presence of iatrogenic laryngeal injury was significantly associated with comorbid diabetes mellitus (OR [95% CI]: 2.91 [1.15, 7.40]; P = .02) and dysphonia (OR [95% CI]: 2.19 [1.09, 4.40]; P = .03). Whereas patients who received less than 5 surgeries in their lifetime were less likely to experience iatrogenic laryngeal injury (OR [95% CI]: 0.10 [0.05, 0.21]; P < .001), receiving at least 10 surgeries was strongly predictive of iatrogenic sequelae (OR [95% CI]: 24.75 [5.81, 105.34]; P < .001). The use of adjuvant bevacizumab treatment, whether local or systemic, was additionally associated with iatrogenic laryngeal injury (OR [95% CI]: 2.59 [1.12, 5.96]; P = .03). Finally, the use of microdebriders/cold steel at the last surgery prior to the documented complication (OR [95% CI]: 1.94 [1.05, 3.57]; P = .03) and if the surgery occurred prior to 2010 (OR [95% CI]: 2.36 [1.28, 4.37]; P = .01) were both significantly associated with greater risk for laryngeal injury (Table 5).

Table 5. Univariate Logistic Regressions Assessing Characteristics Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis
Variable Odds Ratio [95% CI] P value
Male 0.42 [0.21, 0.85] .02
Diabetes mellitus 2.91 [1.15, 7.40] .02
Dysphonia 2.19 [1.09, 4.40] .03
<5 Surgeries 0.10 [0.05, 0.21] <.001
5-9 Surgeries 1.92 [0.86, 4.33] .11
10+ Surgeries 24.75 [5.81, 105.34] <.001
Adjuvant bevacizumab treatment 2.59 [1.12, 5.96] .03
Last surgery before documented complication
Microdebrider/cold Steel 1.94 [1.05, 3.57] .03
Surgery before 2010 2.36 [1.28, 4.37] .01
  • Note: Bold values indicate statistical significance.
  • Abbreviation: CI, confidence interval.

Variables significant in univariate analyses were further retained for a multivariate logistic regression. In this adjusted model, when considering the lifetime number of surgeries categorically, diabetes mellitus (aOR [95% CI]: 2.99 [1.02, 8.79]; P = .04) and receiving at least 10 surgeries lifetime (aOR [95% CI]: 14.47 [1.70, 123.19]; P = .01) were significantly associated with greater risk for iatrogenic laryngeal injury, whereas receiving less than 5 surgeries lifetime (aOR [95% CI]: 0.21 [0.09, 0.51]; P < .001) was a significantly protective factor. Similarly, when treating the lifetime number of surgeries continuously, diabetes mellitus (aOR [95% CI]: 2.94 [1.01, 8.57]; P = .04) and a greater number of surgeries (aOR [95% CI]: 1.32 [1.14, 1.53]; P < .001) were significantly associated with increased risk for iatrogenic laryngeal injury (Table 6). Surgical technique and the year of the surgery were no longer significantly associated with iatrogenic laryngeal injury on multivariate analyses. To further assess the effect of diabetes mellitus on risk for iatrogenic laryngeal injury, a multivariate logistic regression subsetted on the AORRP cohort was performed. In these sub-analyses, a greater effect of diabetes mellitus was observed (aOR [95% CI]: 3.28 [1.02, 10.52]; P = .02).

Table 6. Multivariate Logistic Regression Assessing Characteristics Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis
Covariate Odds Ratio [95% CI] P value
Number of surgeries treated categorically
Male 0.59 [0.25, 1.39] .22
Diabetes mellitus 2.99 [1.02, 8.77] .05
Dysphonia 2.02 [0.82, 4.99] .13
<5 Surgeries 0.19 [0.07, 0.51] <.001
10+ Surgeries 16.59 [1.90, 144.49] .01
Adjuvant bevacizumab treatment 0.53 [0.16, 1.76] .30
Last surgery before documented complication
Microdebrider/cold Steel 1.04 [0.44, 2.50] .92
Surgery before 2010 1.52 [0.61, 3.77] .37
Number of surgeries treated continuously
Male 0.56 [0.23, 1.32] .18
Diabetes mellitus 2.60 [0.89, 7.60] .08
Dysphonia 2.02 [0.80, 5.11] .14
Total number of surgeries 1.40 [1.17, 1.67] <.001
Adjuvant bevacizumab treatment 0.53 [0.16, 1.76] .30
Last surgery before documented complication
Microdebrider/cold steel 1.04 [0.43, 2.47] .94
Surgery before 2010 1.54 [0.62, 3.85] .36
  • Abbreviation: CI, confidence interval.

Discussion

As the current standard of treatment for RRP is repeat surgical interventions to decrease papilloma burden, iatrogenic laryngeal injury is a clinical concern for this patient population. Factors associated with iatrogenic laryngeal injury following surgery for RRP, however, are not well-described in the literature. In this study, we present a large cohort of JORRP and AORRP patients seen at a single-institution tertiary care academic medical center, and investigate variables associated with the development of iatrogenic laryngeal injury. We show that comorbid diabetes mellitus and a greater lifetime number of surgeries are significantly predictive of iatrogenic laryngeal injury in this patient population.

As a chronic condition of airway obstruction, RRP often presents refractorily with the symptoms of dyspnea, dysphonia, and chronic cough. In our cohort, dysphonia was present in a majority (n = 157; 78.9%) of patients, and dyspnea (n = 53; 26.6%) and chronic cough (n = 62; 31.2%) were additionally experienced by a non-trivial proportion. It is this combination of symptoms involving breathing and speaking processes that often produces extensive communication handicaps and significant quality of life impairments for patients.2 Indeed, in one study, nearly all RRP patients reported skipping participation in career and social activities due to their concerns of voice quality and breathing, and nearly 90% admitted experiencing social anxiety related to their condition.5 Further, in a 2017 study by San Giorgi et al, patients diagnosed with RRP were found to have worse depression and voice-related quality of life scores compared to non-RRP controls.12 Taken together, these results are especially concerning given that a minority of RRP patients report accessing mental health services despite experiencing profound psychosocial impairments.5

Although surgical treatment may offer temporary relief of clinical symptoms, the repeat surgical interventions often necessitated for lifetime management of RRP may produce iatrogenic sequelae that in and of themselves may further contribute to and worsen symptoms. As our study suggests, iatrogenic laryngeal injury is common in RRP, with nearly 70% of our cohort experiencing some form of laryngeal sequelae. The most common laryngeal injuries observed in this study were anterior commissure synechiae (n = 67; 50.4%), reduced vocal fold pliability (n = 54; 40.6%), and subglottic (n = 5; 3.8%) and posterior glottic stenosis (n = 5; 3.8%), with rates similar to those found in prior case reports in the literature.6-11 Anterior commissure synechiae, subglottic stenosis, and posterior glottic stenosis all decrease patency of the upper airway, and may thereby exacerbate the symptoms of airway obstruction experienced by patients with RRP. Management of anterior commissure synechiae involves surgical and/or laser dissection of the web and is challenging to address,13-16 often presenting with consequences such as loss of normal tissue architecture and vibration. Treatment for subglottic and posterior glottic stenosis is more involved, and may include posterior cricoid split, posterior cordotomy, endoscopic dilation, and/or surgical resection of scar tissue,17-22 all of which may disrupt normal airway function. Reduced vocal fold pliability, on the other hand, is a clinical entity without any medical or surgical treatment, and is largely managed via vocal therapy,23, 24 which may be frustrating for patients seeking more immediate outcomes.

Understanding factors that are associated with the development of iatrogenic laryngeal injury may help inform potentially modifiable characteristics to decrease the incidence of laryngeal sequelae. On a multivariate logistic regression, we found that the presence of comorbid diabetes mellitus was a significant risk factor for iatrogenic laryngeal injury. This finding is consistent with the dysfunctional wound healing and altered tissue responses commonly found in diabetic patients,25-28 and emphasizes the importance of strict glucose control for patients undergoing treatment for RRP. We additionally found that whether treated as a categorical or continuous variable, a greater lifetime number of surgeries received was significantly associated with increased risk for iatrogenic laryngeal injury, which is an intuitive result. We stress, however, that even among patients who have had less than 5 surgeries, which proved to be a protective factor on multivariate analyses, 44% of these patients still incurred permanent iatrogenic injury. The risk for iatrogenic laryngeal injury, therefore, may be best conceptualized via a cumulative geometric distribution in probability theory. That is, the cumulative risk for injury increases with every surgery, but ultimately it only takes 1 surgical misadventure to permanently damage the larynx.

The lack of literature on this subject speaks more to the historical lack of options for RRP, rather than a novel understanding about the disease process, as the results of this study are both intuitive and obvious to those that treat this disease. In the past, it did little to highlight the significant damage that accumulates from surgery if surgery was the only feasible option. In our cohort, the long surgical history of these patients and changes in surgical techniques over the years make it difficult for us to comment if one technique was more likely than another to cause injury. Our rough approximation to answer this question shows that surgery prior to 2010 and microdebrider/cold steel were associated with iatrogenic laryngeal injury, but we stress that this was not significant on multivariate analysis and that assembling this data retrospectively depends on accurate clinical documentation at the exact onset of injury. But now, there are emerging options that could potentially reduce the lifetime number of surgeries, regardless of technique, and our result demonstrates the crucial importance of identifying nonsurgical therapies to avoid this iatrogenic damage. Systemic bevacizumab has demonstrated ability to nonsurgically manage even the most severe cases of RRP, although therapy must be continued indefinitely.29-32 Interestingly, we found in this study that the use of adjuvant bevacizumab, whether local or systemic, was associated with greater risk for iatrogenic laryngeal injury on univariate analyses but not in multivariate analyses. This reflects a selection bias as adjuvant bevacizumab is typically reserved for the most refractory cases of RRP and thus for patients with the highest surgical burden. Our results support earlier induction of these adjuvant treatments that may decrease surgical frequency in this patient population. Future treatments with immunologic strategies to eliminate HPV-infected cells may be the next step in finally developing a non-surgical treatment for this disease.33 Until then, prevention of RRP is critical. The HPV vaccine is an effective preventative measure, and efforts to increase the presently suboptimal rates of vaccination uptake should be prioritized by all clinicians to reduce HPV-related morbidity and rates of associated diseases.34

Limitations

As this was a retrospective study, analysis was limited to the data elements readily accessible from the electronic medical records and archival imaging systems. We acknowledge that as our study was single-institutional, these results may not be broadly generalizable, although given the long-history of many RRP patients and their transfer of care over the years, many different institutions and surgeons are represented in our large cohort. Many previous RRP studies leverage the anatomic Derkay score to define disease severity, but we elected not to investigate this variable in our study. As the anatomic Derkay score is calculated based upon findings at a single point in time, it is a poor measure of the long-term disease and surgical burden of RRP, especially given the long chronicity and variable clinical course of the illness. Additionally, as the diagnosis of diabetes mellitus covers a wide variety of clinical phenotypes, HbA1c at the time of surgery may be a more precise marker of glucose control and its effects on complication rates, and should be the focus of future studies.

Conclusion

Iatrogenic laryngeal injury is extraordinarily common in RRP, and is due to the repeat surgical interventions needed to manage this disease. The most common injuries reported are anterior commissure synechiae and reduced vocal fold pliability. Patients with comorbid diabetes mellitus are at nearly 3 times increased risk for iatrogenic laryngeal injury, which suggests the importance of strict glucose control for diabetic patients receiving RRP surgical care. Likewise, a greater lifetime number of surgeries received was a significant risk factor for iatrogenic laryngeal injury, which highlights the importance of medical therapies to help decrease RRP surgical frequency.

Author Contributions

Raymond J. So, AB, study design, data curation, formal analysis, writing—original draft, writing—review and editing; Alexander T. Hillel, MD, writing—review and editing; Kevin M. Motz, MD, writing—review and editing; Lee M. Akst, MD, writing—review and editing; Simon R. Best, MD, study design, writing—review and editing.

Disclosures

Competing interests

Dr. Simon R. Best is a consultant for Inovio Pharmaceuticals.

Funding source

None.