Comparison of Treatment Modalities for Contact Granuloma: A Nationwide Multicenter Study

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1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Comparison of Treatment Modalities for Contact Granuloma: A Nationwide Multicenter Study Seung Won Lee, MD, PhD; Hyung Jun Hong, MD; Seung Ho Choi, MD, PhD; Dong IL Sun, MD, PhD; Young Hak Park, MD, PhD; Byung Joo Lee, MD, PhD; Seong Keun Kwon, MD, PhD; IL Seok Park, MD, PhD; Sang Hyuk Lee, MD, PhD; Young-Ik Son, MD, PhD Objectives/Hypothesis: This study evaluated the efficacy of commonly used treatment modalities and determined predictors of treatment outcome for contact granuloma. Study Design: Retrospective study. Methods: Twenty otolaryngologists from 18 university hospitals reviewed the medical records of their own contact granuloma patients for the most recent 4 years. To be enrolled as a valid case, each treatment had to continue for at least 3 months. After excluding intubation granuloma, 590 cases of contact granuloma were analyzed. Treatment outcomes were assessed as complete response (CR), marked response (MR), partial response (PR), and no response. The chi-square test was used to compare the efficacy of each treatment modality and logistic regression to determine the predictors of treatment outcome. Results: The long-term outcomes of good response (GR) (sum of CR and MR) rates after each treatment were 20.5% for observation, 31.6% for steroid inhalation, 44.0% for proton pump inhibitor (PPI), 44.3% for voice therapy, 60.0% for surgical removal, and 74.2% for botulinum toxin injection. Voice therapy, PPI, and botulinum toxin had more good responses than simple observation for the long-term outcome (P < 0.05). Surgical removal had a significantly higher recurrence rate (37.1%) than simple observation (10.3%) (P < 0.05). Conclusions: Voice therapy or PPI are recommended as first-line treatments. Surgical removal should be reserved for selected patients because of the high chance of recurrence. Botulinum toxin injection can be used not only for primary cases but also for refractory cases with an expected high response rate. Key Words: Contact granuloma, treatment guideline, therapeutic. Level of Evidence: 4. Laryngoscope, 124: , 2014 From the Department of Otolaryngology Head and Neck Surgery, Soonchunhyang University (S.W.L.); and Ulsan University (S.H.C.); and Busan University (B.J.L.); and Hallym University (I.S.P.); and Yonsei University (H.J.H.); and Catholic University (D.I.S., Y.H.P.); and Seoul National University, Korea (S.K.K.); and Sungkyunkwan University (S.H.L., Y-I.S.), Seoul, Republic of Korea Editor s Note: This Manuscript was accepted for publication October 10, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Young-Ik Son MD, Department of Otolaryngology Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Il Won Dong, Gang Nam- Gu, Seoul, Republic of Korea, yison@skku.edu DOI: /lary INTRODUCTION A contact granuloma is relatively rare, benign hypertrophic granulation tissue located posterior to the vocal process. 1 Although the lesion is benign, it can recur in 20% to 90% of patients, irrespective of treatment. 2 4 The pathogenesis of contact granulomas is not clear. They are thought to occur as the result of inflammation that produces granulated tissue at the site of the ulcerations. 5 Several etiological factors have been suggested, such as hard glottal attack, vocal abuse, habitual throat clearing, low-pitched voice, laryngopharyngeal reflux (LPR), and psychosomatic disorders. 6 Smoking, postnasal drip, and throat infections can also cause contact granuloma. 1 Several therapeutic approaches have been used to treat contact granuloma. These include voice rest, voice therapy, antibiotics, corticosteroids (injected, inhaled, or parenteral), antireflux therapy, laser treatment, botulinum toxin injection, surgical removal, 2,7,8 and even lowdose radiotherapy for refractory contact granuloma. 9 However, no treatment modality has been uniformly successful. Furthermore, no treatment consensus or guidelines based on randomized trials or large cohort studies are available. Therefore, it is imperative to establish treatment guidelines for contact granuloma. This study evaluated various treatment modalities to determine their relative efficacies and to identify predictors of treatment outcomes, with the aim of establishing treatment guidelines for contact granuloma. This multicenter study was conducted between November 2010 and April 2012 with the support and assistance of the Korean Society of Laryngology Phoniatrics and Logopedics (KSLPL). MATERIALS AND METHODS Patients This study involved patients from multiple centers across South Korea and was headed by 20 laryngologists from 18 universities. 1187

2 Characteristic TABLE I. Patient Demographics (n 5 590). Primary Cases n (%) (64.7%) Refractory Cases n (%) (35.6%) Overall Age (years) (12 87) Sex Male 327 (85.6) 174 (83.7) 501 (84.9) Female 55 (14.4) 34 (16.3) 89 (15.1) Size Small 149 (39.0) 83 (40.1) 232 (39.4) Medium 167 (43.7) 89 (43.0) 256 (43.5) Large 66 (17.3) 35 (16.9) 101 (17.1) Characteristics Fibrotic 37 (9.7) 36 (17.3) 73 (12.4) Typical 314 (82.2) 154 (74.0) 468 (79.3) Cystic 18 (4.7) 7 (3.4) 25 (4.2) Ulcerative 8 (2.1) 9 (4.3) 17 (2.9) Others 5 (1.3) 2 (1.0) 7 (1.2) Treatment Antireflux Tx 224 (58.6) 124(59.6) 348(59.0) Botulinum toxin 4 (1.0) 27 (13.0) 31(5.3) Surgery 23 (5.8) 12(5.8) 35(5.9) Voice Tx 47 (12.3) 14 (6.7) 61(10.3) Steroid inhalation 65 (17.0) 11(5.3) 76(12.9) Observation 19 (9.6) 20 (9.6) 39(6.6) Values represent number (%), except for age (years). Botox 5 botulinum toxin injection into the thyroarytenoid and lateral cricoarytenoid muscles; Antireflux Tx 5 antireflux treatment using the PPI; surgery 5 surgical removal under general anesthesia; Tx 5 treatment. Prior to the study onset, each participating institute obtained approval from its institutional review board. Patient medical records and endoscopic images obtained between January 2008 and December 2011 were retrospectively analyzed. Pretreatment and posttreatment endoscopic images were available for all enrolled cases. Each single treatment modality that patients were given had to continue for at least 3 months. Cases with intubation granuloma were excluded because, although the lesion appears similar to contact granuloma, the etiology and disease progression are different. 7,10 Finally, 590 cases of contact granuloma were enrolled in this study. Table I shows the patient demographic characteristics. The subjects were divided into two groups according to whether they had received treatment prior to enrollment in the study. The primary group (n 5 382, 64.7%) had received no prior treatment, and the refractory group (n 5 208, 35.6%) had received prior treatment, such as voice therapy, antireflux treatment, and steroid inhalation. The fibrotic type of contact granuloma was more common in the refractory group (17.3%) than in the primary group (9.7%) (P < 0.05). Patients in the primary group received voice therapy (12.3%) and steroid inhalation (17.0%) more often than patients in the refractory group (6.7% and 5.3%, respectively), whereas botulinum toxin injection was more frequently applied in the refractory group (13.0%) than in the primary group (1.0%) (P < 0.05). Treatment Modality The treatment modalities that were evaluated were simple observation, voice therapy, antireflux therapy using a proton pump inhibitor (PPI) (lansoprazole 30 mg Qd, rabeprazole 20 mg Qd), steroid inhalation (Pulmicort Turbuhaler; budesonide inhalation powder 200 mcg), botulinum toxin (botulinum toxin type A, Botox, Allergan Inc, Irvine, CA) injection to adductor muscles (2 units into the ipsilateral thyroid arytenoid muscle, 3 units into the lateral cricoarytenoid muscle, or 2.5 units into the bilateral thyroarytenoid muscles), and surgical removal under general anesthesia. Treatment Outcome Measurement Granuloma size was defined as small (less than the width of the normal vocal fold), medium (one to two times the width of the normal vocal fold), and large (larger than two times the width of the normal vocal fold). The granuloma type was characterized as typical, fibrotic, cystic, or ulcerative. Endoscopic images taken and interpreted by participating laryngologists after at least 3 months of treatment were used to determine the short-term treatment outcome. Treatment responses were categorized as complete (CR; 90% 100% decrease in granuloma size), marked (MR; 75% 89% decrease), moderate (50% 74% decrease), stable (25% 49% decrease), or progression (no change or aggravation during treatment). Recurrence was defined as a positive response following initial treatment, with regrowth of the granuloma during the followup period. The CR and MR outcome subgroups were categorized as the good response (GR) group; and the moderate response, stable response, and disease progression subgroups were categorized as the partial response (PR) group. Endoscopic images taken at the last follow-up visit were used to determine the long-term treatment outcome. The mean follow-up period at the time of analysis was months. The endoscopic findings were used to compare treatment outcomes between the GR and PR groups. Statistical Analysis Several independent variables, including age, sex, granuloma size, granuloma bilaterality, granuloma type, previous treatment, and treatment modality were examined using the chi-square test and logistic regression analysis to identify significant predictors of treatment outcome (SPSS 14.0 for Windows; SPSS Inc., Chicago, IL). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Values of P <0.05 were considered to indicate statistical significance. RESULTS Treatment Outcomes Univariate analysis. The univariate analysis using the chi-square test revealed that granuloma type (P ) and treatment modality (P ) were significantly related to treatment outcome. The other factors examined (sex, age, size of granuloma, bilaterality, and subjective symptoms) were not significantly related to treatment outcome (Table II). Multivariate analysis. The rate of long-term good response (sum of CR 1 MR) after each treatment was 20.5% for observation, 31.6% for steroid inhalation, 44.0% for PPI, 44.3% for voice therapy, 60.0% for surgical removal, and 74.2% for botulinum toxin injection. Table III shows the multivariate analysis results for treatment outcome according to contact granuloma type. Logistic regression analysis revealed that treatment outcomes were significantly better for typical and ulcerative 1188

3 TABLE II. Univariate Analysis for Predictive Factor of Contact Granuloma. TABLE IV. Short-Term Outcome According to Treatment Modality. Parameter P Value for Treatment Outcome Treatment Modality P Value Exp(B) Odds Ratio 95% CI Sex Age Size of granuloma Bilaterality Characteristics* Previous Tx Treatment modalities * *statistically significant parameters. Tx 5 treatment. granulomas than for fibrotic granulomas (P < 0.05). Based on the odds ratios, the likelihoods of a GR for typical and ulcerative granulomas were 2.11 and 3.90 times, respectively, that for fibrotic granulomas. Logistic regression analysis revealed that PPI antireflux treatment, botulinum toxin, and surgical removal had significantly better short-term outcome compared with simple observation (Table IV, P < 0.05). The odds ratios showed that the likelihoods of a GR to PPI antireflux treatment, botulinum toxin, and surgical removal were 2.69, 12.03, and 6.38 times, respectively, the likelihood of a GR to simple observation (Table IV). In an analysis of the long-term outcome, a GR to voice therapy, PPI antireflux treatment, and botulinum toxin was more likely than a GR to simple observation (P < 0.05). However, the long-term outcome of surgical removal was not better than that for simple observation (Table V, VI). On comparing the treatment outcome between the primary and refractory groups, a short-term GR treatment outcome was more common in the refractory group (GR, 61.7%) than in the primary group (GR, 47%; P < 0.05), although the long-term treatment outcome had similar GR rates for both groups (primary 41.1% vs. refractory 47.6%; P > 0.05; Table VII). Recurrence Rates The recurrence rate was similar between the primary and refractory groups (8.40% vs. 10.6%, respectively; P > 0.05; Table VII). TABLE III. Multivariate Analysis According to Contact Granuloma Type. Granuloma Type P Value Exp(B) Odds Ratio 95% CI Fibrotic References Typical Cystic Ulcerative Others CI 5 confidence interval; fibrotic references 5 fibrotic type contact granuloma was used as the references treatment modalities for the comparison with good and partial response. Observation References Voice Tx Antireflux Tx Steroid inhalation Botulinum toxin Surgical removal observation references 5 simple observation was used as the references treatment modalities for the comparison with good and partial response. Short-term outcome was based on endoscopic images followed at least 3 months of treatment with each modality. Antireflux Tx 5 antireflux treatment using a PPI; Tx 5 treatment. The recurrence rate for voice therapy (4.9%), PPI antireflux treatment (6.9%), steroid inhalation (10.5%), and botulinum toxin (6.5%) did not differ significantly from that for simple observation (10.3%). Although surgical removal had a good short-term outcome, long-term follow-up revealed a 37.1% recurrence rate, which was significantly higher than that for simple observation. The odds of recurrence following surgical removal of a contact granuloma were 5.17 times more frequent than that of simple observation (P < 0.05), (Table VIII). DISCUSSION Contact granuloma is a rare disease and has a wide variety of treatment options, including simple observation, voice therapy, PPI antireflux treatment, steroid inhalation, botulinum toxin injection, surgical removal, and even radiotherapy. However, no randomized trials or large cohort studies have been performed to prove the efficacy of each treatment modality. The largest previous contact granuloma series included about 100 cases. 11 The Korean Society of Laryngology Phoniatrics and Logopedics (KSLPL) recognized the importance of establishing treatment guidelines for contact granulomas; thus, a multicenter study was undertaken to evaluate the efficacy of various treatment modalities. TABLE V. Long-Term Outcome According to Treatment Modality. Treatment Modality P Value Exp(B) Odds Ratio 95% CI Observation References Voice Tx Antireflux Tx Steroid inhalation Botulinum toxin Surgical removal Long-term outcome was based on the endoscopic images at the last follow-up visit. Antireflux Tx 5 antireflux treatment using a PPI; Tx 5 treatment. Antireflux Tx 5 antireflux treatment using the PPI. 1189

4 TABLE VI. Long-Term Outcome and Recurrence Rate According to Treatment Modality. Long-Term Outcome Treatment Modality GR PR Recurrence Overall Observation 8 (20.5) 27 (69.2) 4 (10.3) 39 (100.0) Voice Tx 27 (44.3) 31 (50.8) 3 (4.9) 61 (100.0) Antireflux Tx 153 (44.0) 171 (49.1) 24 (6.9) 348 (100.0) Steroid inhalation 24 (31.6) 44 (57.9) 8 (10.5) 76 (100.0) Botulinum toxin 23 (74.2) 6 (19.4) 2 (6.5) 31 (100.0) Surgical removal 21 (60.0) 1 (2.9) 13 (37.1) 35 (100.0) Overall 256 (43.4) 280 (47.5) 54 (9.2) 590 (100.0) GR 5 good response (combination of complete and marked responses following treatment); PPI 5 proton pump inhibitor; PR 5 partial response (combination of moderate, stable responses, and disease progression following treatment); Antireflux Tx 5 antireflux treatment using a PPI; Tx 5 treatment. Based on the long-term outcome in the present study, treatment modality was the single most important factor for prognosis. Botulinum toxin, PPI antireflux treatment, and voice therapy were more effective than simple observation, whereas steroid inhalation and surgical removal were not significantly different from simple observation in terms of the long-term outcome (Tables V, VI). The long-term outcome was not related to age, sex, granuloma size, granuloma laterality, or previous treatment (primary vs. refractory group). The GR rate following botulinum toxin was 74.2%, and the likelihood of a GR to botulinum toxin was 58.6 times the likelihood of a GR to simple observation. PPI antireflux treatment had a GR rate of 44.0% and an odds ratio of 5.4, and voice therapy had a GR rate of 44.3% and an odds ratio of 6.6, compared with simple observation. The type of the granuloma was associated with treatment outcome based on the multivariate analysis. TABLE VII. Treatment Outcome According to the Primary Versus Refractory Group. Primary (%) Refractory (%) P Value Short-term outcome PR GR Long-term outcome Recurrence PR GR Recurrence No Yes Short-term outcome was based on endoscopic images followed at least 3 months of treatment with each modality. Long-term outcome was based on the endoscopic images at the last follow-up visit. GR 5 good response (combination of complete and marked responses following treatment); PR 5 partial response (combination of moderate, stable responses, and disease progression following treatment). TABLE VIII. Recurrence Rate According to Treatment Modality. Treatment Modality P Value Exp(B) Odds Ratio 95% CI of EXP(B) Observation Reference Voice Tx Antireflux Tx Steroid inhalation Botulinum toxin Surgical removal observation references 5 simple observation was used as the references treatment modalities for the comparison with good and partial response. Antireflux Tx 5 antireflux treatment using a PPI; Tx 5 treatment. The typical and ulcerative granuloma types had GR rates of 54.4% and 68.8%, respectively, compared with 38.4% for fibrotic granulomas, and odds ratios of 2.1 and 3.9 compared with fibrotic granulomas (Table III). For the short-term outcome, the GR rate was higher in the refractory group than in the primary group (P <0.05). This finding might have been influenced by numbers of botulinum toxin injection in the refractory group who received more botulinum toxin injections than the primary group (1.0% vs. 13%, primary vs. refractory group) because botulinum toxin could lead to the early resolution of contact granuloma when primary treatment fails. 12 The recurrence rate was slightly higher, but not significantly, in the refractory group (10.6%) than the primary group (8.4%) (Table VII). Surgical removal had a high GR rate and odds ratio compared with simple observation in the short-term outcome analysis; however, the long-term outcome of surgical removal were not significantly better than that of simple observation. Surgical removal had a significantly higher recurrence rate (37.1%) compared with simple observation (10.3%), and an odds ratio of 5.17 for recurrence compared with simple observation. These findings demonstrate that surgical removal could lead to immediate improvement but not lead to long-term improvement. Given the high rate of recurrence, we do not recommend surgical removal for treatment modality of contact granuloma. PPI and botulinum toxin were the only effective treatments for better short-term and long-term outcome (Tables IV, V). Although voice therapy was not significantly more effective than simple observation in the short term (P ), it provided significant long-term improvement compared with observation (P ). This is probably, the voice therapy requires considerable times to reduce the size of the granuloma. Therefore, voice therapy could be a possible first-line treatment for contact granuloma. Regarding the limitations of this study, although we have a very large number of patients, the data are disparate with fewer patients having botulinum toxin injection or surgical removal. And the uneven distribution among treatment modality was due to the retrospective study design. However, the numbers of each treatment 1190

5 CONCLUSION Based on these results of Korea nation-wide multicenter study, voice therapy and PPI antireflux treatment are recommended as the first-line treatment for contact granuloma. Given the high recurrence rate, surgical removal should be reserved for special circumstances. Botulinum toxin injection has a high response rate in primary and refractory cases. Fig. 1. Suggested treatment algorithm for contact granuloma. CR 5 complete response. modality were sufficient enough for the statistical analysis to infer appropriate conclusions. For the botulinum toxin, the total numbers are relatively small (n 5 31) and it is also comprised of heterogenous dosages and injection sites. Some of the patients received a unilateral 5 units into the thyroarytenoid and lateral cricoarytenoid muscle complex and some received 2.5 units injection into thyroarytenoid muscle bilaterally. In the past, the dosages of botulinum toxin has been used for unilateral thyroarytenoid muscle complex range from 7 to 15 units, but then gradually decreased to avoid postinjection breathy voice and aspiration, and to optimize the treatment efficacy. 2,13 At present in South Korea, 3 units of ipsilateral lateral cricoarytenoid muscle and 2 units of thyroarytenoid muscle injection, or 2.5 units for bilateral thyroarytenoid muscle, are the most commonly used dosages. But these are based on surgeon s experiences without objective evidences. 14 Therefore, well-designed prospective study is mandatory for optimizing the dosages and injection sites to establish the consensus for contact granuloma. Based on these results of our nation-wide multicenter study, we suggest the following treatment algorithm for contact granuloma (Fig. 1). Voice therapy or antireflux treatment using a PPI is recommended as the primary treatment modality for contact granuloma. Botulinum toxin should be reserved as a second-line treatment for cases in which the first treatment was not effective, but also could be used as a first-line treatment depending on the patient s and institution s situation. Surgical removal has a high recurrence rate and is not recommended as a treatment modality. Acknowledgements This nation-wide multicenter study was performed with the support and assistance of Korean Society of Laryngology Phoniatrics and Logopedics (KSLPL) Sung Min Jung: President of KSLPL, Ewah Women s Mok Dong University Hospital, Ewha Women s University; Hong Sik Choi: Gangnam Severance University Hospital, Yonsei University; Phil Sang Chung: Dankook University Hospital, Dankook University; Sung Min Jin: Kangbuk Samsung Medical Center, Sunkyunkwan University; DongTan; Se Young Lee: ChungAng University Hospital, ChungAng University; Byung Kon Park: Konyang University Hospital, Konyang University; Seung Hoon Woo: GyeongSang University Hospital, GyeongSang University; Joo Hyun Woo: Gil University Hospital, Gachon University; Yong Man Lee: Soon Chung Hyang CheonAn University Hospital, Soon Chung Hyang University; Soon Yeol Nam: Asan Medical Center, Ulsan University. BIBLIOGRAPHY 1. Hoffman HT, Overholt E, Karnell M, McCulloch TM. Vocal process granuloma. Head Neck 2001;23: Orloff LA, Goldman SN. Vocal fold granuloma: successful treatment with botulinum toxin. Otolaryngol Head Neck Surg 1999;121: Havas TE, Priestley J, Lowinger DS. A management strategy for vocal process granulomas. Laryngoscope 1999;109: Ylitalo R, Lindestad PA. Laryngeal findings in patients with contact granuloma: a long-term follow-up study. Acta Otolaryngol 2000;120: Emami AJ, Morrison M, Rammage L, Bosch D. Treatment of laryngeal contact ulcers and granulomas: a 12-year retrospective analysis. J Voice 1999;13: Carroll TL, Gartner-Schmidt J, Statham MM, Rosen CA. Vocal process granuloma and glottal insufficiency: an overlooked etiology? Laryngoscope 2010;120: doi: /lary Roh HJ, Goh EK, Chon KM, Wang SG. Topical inhalant steroid (budesonide, Pulmicort nasal) therapy in intubation granuloma. J Laryngol Otol 1999;113: Clyne SB, Halum SL, Koufman JA, Postma GN. Pulsed dye laser treatment of laryngeal granulomas. Ann Otol Rhinol Laryngol 2005;114: Mitchell G, Pearson CR, Henk JM, Rhys-Evans P. Excision and low-dose radiotherapy for refractory laryngeal granuloma. J Laryngol Otol 1998; 112: Hillel AT, Lin LM, Samlan R, Starmer H, Leahy K, Flint PW. Inhaled triamcinolone with proton pump inhibitor for treatment of vocal process granulomas: a series of 67 granulomas. Ann Otol Rhinol Laryngol;119: Ylitalo R, Lindestad PA. A retrospective study of contact granuloma. Laryngoscope 1999;109: Pham J, Yin S, Morgan M, Stucker F, Nathan CO. Botulinum toxin: helpful adjunct to early resolution of laryngeal granulomas. J Laryngol Otol 2004;118: Damrose EJ, Damrose JF. Botulinum toxin as adjunctive therapy in refractory laryngeal granuloma. J Laryngol Otol 2008;122: Yilmaz T, Suslu N, Atay G, Ozer S, Gunaydin RO, Bajin MD. Recurrent contact granuloma: experience with excision and botulinum toxin injection. JAMA Otolaryngol Head Neck Surg 2013;139: doi: /jamaoto