The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Histopathology of Balloon-Dilation Eustachian Tuboplasty €s, MD, PhD; Wei-Chieh Chao, MD; William Faquin, MD, PhD; Monica Hollowell, MD; Ilkka Kiveka Juha Silvola, MD, PhD; Tali Rasooly, BA; Dennis Poe, MD, PhD Objectives/Hypothesis: Surgical intervention of the Eustachian tube (ET) has become increasingly common in the past decade, and balloon dilation has shown promising results in recent studies. It is unclear how balloon dilation enhances ET function. Our aim was to evaluate histological changes in the ET’s mucosal lumen comparing before balloon dilation, immediately after, and postoperatively. Study Design: Case series. Methods: Thirteen patients with bilateral ET dysfunction were enrolled. Biopsies of the ET mucosa were obtained just before balloon dilation; immediately after; and in three cases, 5 to 12 weeks postoperatively. Specimens were retrospectively examined under light microscopy by two pathologists blinded to the clinical information and whether specimens were pre- or postballoon dilation. Results: Preoperative biopsies were characterized by inflammatory changes within the epithelium and submucosal layer. Immediate response to balloon dilation was thinning of the mucosa, shearing of epithelium and crush injury to the submucosa, especially to lymphocytic infiltrates. Postoperative biopsies demonstrated healthy pseudocolumnar epithelium and replacement of lymphocytic infiltrate with a thinner layer of fibrous tissue. Conclusion: Reduction of inflammatory epithelial changes and submucosal inflammatory infiltrate appeared to be the principal result of balloon dilation. The balloon may shear or crush portions of inflamed epithelium but usually spared the basal layer, allowing for rapid healing. Additionally, it appeared to effectively crush lymphocytes and lymphocytic follicles that may become replaced with thinner fibrous scar. Histopathology of the ET undergoing balloon dilation demonstrated effects that could reduce the overall inflammatory burden and may contribute to clinical improvement in ET function. Key Words: Eustachian tuboplasty, balloon dilation, histopathology, mucosa, inflammation. Level of Evidence: 4. Laryngoscope, 00:000–000, 2014
INTRODUCTION Balloon eustachian tuboplasty (BET) of the cartilaginous Eustachian tube (ET) has been reported to have promising clinical results in the treatment of persistent tubal dilatory dysfunction with otitis media with effusion, negative middle ear pressure/nonadhesive atelectasis, or difficulty with flight or scuba barochallenges.1–5 The mechanism by which balloon dilation might enhance ET function has remained unclear.
From the Department of Otolaryngology (I.K., W-C.C., T.R., D.P.); the Department of Pathology (M.H.), Boston Children’s Hospital; and the Department of Pathology, Massachusetts General Hospital (W.F.), Harvard Medical School, Boston, Massachusetts; the Department of Otorhinolaryngology, Tampere University Hospital and the University of Tampere (I.K.), Tampere, Finland; the Department of Otolaryngology, Chang-Gung Memorial Hospital, Chang-Gung University (W-C.C.), Taoyuan, Taiwan; and the Department of Otorhinolaryngology, Oslo University Hospital, Rikshospitalet (J.S.), Oslo, Norway. Editor’s Note: This Manuscript was accepted for publication July 28, 2014. Financial Disclosure: D.P. received two speaking honoraria from Acclarent, Inc., and is a coprimary investigator in a pending clinical trial, sponsored by Acclarent, Inc. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dennis Poe, MD, PhD, Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital, Department of Otology and Laryngology, 333 Longwood Ave., Lo-367, Boston, MA 02115. E-mail: [email protected] DOI: 10.1002/lary.24894
Laryngoscope 00: Month 2014
Cadaver studies have shown an absence of significant change in the cartilaginous skeleton of the ET either by microscopic or endoscopic dissection,6 or at most, minor tears in the roof of the cartilage have been seen histologically.7 It was proposed that the compressive forces might induce some thinning of the surrounding connective tissue architecture.6 In clinical experience, the lumen has been seen to dilate larger in some but not all cases, and the mucosa usually appears unharmed and intact. There can be small tears in the mucosa with some minor bleeding that have yet to demonstrate any clinical significance.4 In balloon dilation, there is no attempt to dilate the bony portion of the ET because the pathology is most commonly located within the cartilaginous segment, and balloon dilation of the bony portion would create a significant risk to the internal carotid artery that is immediately adjacent. Postoperative observations have been made with endoscopic examinations of the tubal lumen, showing a significant reduction in mucosal inflammation (2.8– 1.4) when using a 4-point rating scale.4 One hypothesis could be that compression of irreversibly injured hypertrophic mucosa and submucosa might permit healing with thinner and healthier layers after balloon dilation. To explain the decreased inflammation, this study was undertaken in the absence of an obvious mechanism.
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
1
Fig. 1. Left Eustachian tube nasopharyngeal orifice preballoon dilation, moderately inflamed with edematous, thickened mucosa. Biopsy site was arrowed (45 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
The present work was undertaken as an observational study to investigate the immediate histological effects of BET.
MATERIALS AND METHODS This study was approved by the institutional review board at Children’s Hospital Boston (IRB-P00010256) and was conducted in accordance with their guidelines. All cases had 2 or more consecutive years of chronic ET dilatory dysfunction, with bilateral persistent otitis media with effusion or significant nonadherent tympanic membrane atelectasis. All patients received a trial of at least 6 weeks of nasal steroid spray, and surgery was undertaken if signs and symptoms persisted. Steroid sprays were continued postoperatively only if the patient was chronically on the medication. Similarly, other chronically
Fig. 2. Balloon catheter, positioned within the lumen of the cartilaginous Eustachian tube, was fully inflated to 12 atm for 2 minutes. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
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Fig. 3. Left Eustachian tube nasopharyngeal orifice immediately postballoon dilation. A widened lumen with slightly excoriated mucosa (45 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
administered medications such as antihistamines, proton pump inhibitors, and so forth were not discontinued for the surgery. Consecutive operations were done under general anesthesia. All operations were performed through trasnasal approaches with endoscopic assistance (45 degree view angle, 4 mm diameter) (Karl Storz, Culver City, CA). A sinuplasty 6 3 16-mm balloon system Relieva Solo Pro, 70 Relieva Flex Sinus Guide Catheter (Acclarent, Inc, Menlo Park, CA) was used in every operation. The balloon catheter was inserted through the lumen slowly and atraumatically. The balloon was inflated once to 12 atm and maintained in position for 2 minutes. On one side, which was chosen arbitrarily, a biopsy was taken before performing the balloon dilation, and a postdilation biopsy was then taken from the second side immediately following the dilation. As depicted in Figures 1–3, biopsies were taken transnasally with pediatric up-biting Blaksley forceps from superiorly on the posterior cushion, just within the lumen. Hemostasis was assured and the procedure was terminated. In three cases, an additional biopsy was taken postoperatively weeks later. Two of these were performed while the patients were under general anesthesia in the operating room for a tympanoplasty for a tympanic membrane perforation and persisted retraction pocket, and one was taken in the office using local topical spray anesthesia (4% oxymetazoline and 4% lidocaine 50:50 solution), which was tolerated very comfortably. These three patients were regularly using medications during the preoperative period and throughout the follow-up period up to the time of the biopsy. The medication histories were: case 1, omeprazole, minocycline, and contraceptives; case 2, antidepressants, atenolol, and fexofenadine; and case 3, montelukast and fluticasone. Specimens were placed in formalin and processed in the usual fashion for paraffin embedding and staining of 5-um sections with hematoxylin and eosin. The smallest specimen diameter was 2 3 1 3 1-mm and all were deemed adequate. They were examined under light microscopy by two pathologists who were blinded to the clinical information and to whether the specimens were pre- or postballoon dilation. The overall quality of the health of the pseudo-columnar ciliated epithelium was rated excellent, good, fair, or poor. The degree to which the epithelium was uniformly or variably
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
TABLE I. Pre- and Postoperative Clinical Findings and Tympanometry Results. Sade’s Grade10 (18 ears)
Preoperative
Postoperative
0 (no retraction)
4
13
I II
6 1
2 1
III
0
0
IV Middle ear effusion
0 7
0 2
A B
3 5
7 0
C
4
5
Tympanometry n 5 12
involved with disease was noted. The epithelium in each specimen was assessed for the presence or absence of cilia, presence of squamous metaplasia, presence of intraepithelial inflammatory changes, and integrity of the epithelial basal layer. The submucosa was evaluated for the presence of lymphocytes (lymphocytic infiltrate), rated from 0 to 31; other inflammatory cells; and the presence of lymphoid follicles. The deeper fibrous layer was assessed for quality (degree of fibrosis) and quantity (thickness and density) of collagen on a scale of 0 to 31; in addition, the presence/health of seromucinous glands were rated as excellent, good, fair, poor, or absent.
RESULTS BET was performed on 41 ETs in 27 patients between December 2011 and March 2014. Pre- and postballoon dilation biopsies were taken in 17 cases, of which 13 had complete information for the study, with a mean age of 46 years (range 18–74 years) and three female patients. Pre- and postoperative clinical findings and tympanometry results are presented in Table I. Three of the 13 cases additionally had biopsies taken at 5, 11, and 12 weeks postoperatively. There were no complications related to any of the biopsies; all sites healed well, leaving a minimal scar. Bleeding from the biopsy sites was limited and did not require any cautery or topical vasoconstrictors to control. A summary of the histopathological results is presented in Table II. There was a statistically significant change (P 5 0.023; nonpaired t tests) in submucosal lymphocytes count between pre- and immediate postoperatively. In other parameters, postoperative changes were not significant (P > 0.05). Generally, preballoon biopsies were characterized by variable degrees of inflammatory changes, most notably lymphocytic infiltrates, and three cases with lymphoid follicles present. Eosinophils were not a component of the inflammatory infiltrate. Eight cases demonstrated significant inflammation with submucosal infiltrates of 21. Five of these eight cases showed variable degrees of diseased epithelium (including one with squamous metaplasia) and loss of cilia, which were severely reduced in one and entirely absent in another. Four of these eight cases had severe inflammatory infiltrates Laryngoscope 00: Month 2014
penetrating through the epithelium, along with some disruption of the basal layer (Fig. 4). Postballoon biopsies demonstrated diffuse crush injury to the mucosa and submucosa in all of the specimens, although relatively minimally in one case in which the preballoon mucosa was also rated as “excellent.” The epithelium was disrupted in eight of the 13 cases and was altogether absent, including the basal
TABLE II. Histological Findings of the Eustachian Tube Mucosa Just Before Balloon Dilation, Immediately After, and in Three Cases, 5–12 Weeks Postoperatively.
Epithelium quality
Preballoon
Immediate Postballoon
5–12 Weeks Postoperatively
n 5 13 (%)
n 5 13 (%)
n53
Excellent Good
1 (8) 8 (61)
1 (8) 3 (23)
1 2
Fair
3 (23)
2 (15)
0
1 (8)
7 (54)
0
Poor Epithelial uniformity Uniform
8 (61)
2 (15)
3
Variable Squamous metaplasia
4 (31) 1 (8)
8 (61) 0 (0)
0 0
Absent
0 (0)
3 (23)
0
Cilia quality/quantity Present
11 (85)
4 (31)
3
Fair (fragmented)
1 (8)
3 (23)
0
1 (8)
6 (46)
0
Absent Intraepithelial inflammation Present
3 (23)
0 (100)
0
10 (77)
13 (0)
3
Good
9 (69)
3 (23)
3
Fair Variably present
4 (31) 0 (0)
1 (8) 6 (46)
0 0
0 (0)
3 (23)
0
Absent Basal layer integrity
Absent Submucosal lymphocytes 31
3 (23)
0 (0)
0
21 11
5 (38) 4 (31)
2 (15) 8 (61)
1 2
0
1 (8)
3 (23)
0
3 (23)
0 (0)
0
10 (77)
13 (100)
3
Lymphoid follicles Present Absent Collagen quantity/fibrosis 31
3 (23)
3 (23)
0
21
7 (54)
5 (38)
0
11 0
2 (15) 1 (8)
4 (31) 1 (8)
3 0
4 (31) 5 (38)
3 (23) 4 (31)
2 1
Fair
1 (8)
3 (23)
0
Poor/absent
3 (23)
3 (23)
0
Seromucinous glands quantity/quality Excellent Good
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
3
Fig. 4. Preballoon biopsy. Inflammatory change of the mucosa with lymphocytic infiltrates and lymphoid follicles (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
layer, in three of those cases. Severe loss or absence of cilia increased to nine cases. There was particularly severe injury to the lymphocytes, whose nuclei were prominently thinned and elongated and especially to the lymphoid follicles, which were also severely flattened. Submucosal glands appeared to be untouched and unchanged (Fig. 5). The 5- to 12- week follow-up biopsies generally showed restoration of largely uniformly healthy ciliated pseudo-columnar epithelium. Table II The lymphocytic infiltrate decreased from 31 to 21 in case 1 and from 21 to 11 in case 2. Lymphoid follicles that were present in case 1 and seen to be severely flattened in the immediate postop specimen were replaced with a thin-
Fig. 5. Postballoon biopsy. Diffuse crush injury to the mucosa and submucosa; severe injury to the lymphocytes, whose nuclei were prominently thinned and elongated, and especially to the lymphoid follicles (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
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Fig. 6. Five weeks postballoon biopsy. Restoration of largely and uniformly healthy ciliated pseudo-columnar epithelium is seen. Less lymphocytic infiltrate is noted compared to the preballoon biopsy. Lymphoid follicles are replaced with a thinner layer of fibrous tissue (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
ner layer of fibrous tissue at 5 weeks postoperatively. Submucous glands were irregularly observed and did not appear to have been influenced by the dilation (Figs. 6, 7).
DISCUSSION The predilation histopathology results were consistent with the clinical impression of the presence of inflammatory disease at the tubal orifice and within the lumen. There were variable degrees of mucosal
Fig. 7. Left Eustachian tube nasopharyngeal orifice 1 year postballoon dilation follow-up. Mucosa of the lumen is thinner, and the bulk of the mucosal folds of the posterior cushion is significantly reduced (45 degree 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
disruption, loss of cilia, and inflammatory infiltrate, sometimes even penetrating through to the surface of the epithelium. There was substantial submucosal inflammatory infiltrate in the majority of the cases and even follicle formation in some cases. Lymphoid follicles have been described as the tubal tonsil or the tonsil of Gerlach, a part of Waldeyer’s ring of lymphoid tissue surrounding the oropharynx and nasopharynx.8 They appear grossly as adenoid-like hypertrophied tissue with “cobblestoning” that corresponded with lymphoid hyperplasia in the present study. These follicles have not been previously reported to our knowledge within the tubal lumen. All of the patients in this study had many years of persistent ET dilatory dysfunction and may have been suffering from irreversible injury to the mucosa or submucosa. Alternatively, there could have been ongoing inflammatory etiologies such as allergic rhinitis, chronic rhinosinusitis, local biofilms, and other possible causes. The immediate postdilation histopathology showed a very consistent pattern of crush injury to the epithelium and submucosa, with relative sparing of the deep fibrous layer and submucosal glands. There was a significant shearing off of portions of the epithelium, even down to the basal layer, but in most cases the basal layer was preserved, which likely helped to speed regeneration of the mucosa. This degree of stripping off of the epithelium was not appreciated on clinical examination with the endoscope. On the contrary, the epithelium usually appears grossly largely unharmed, aside from the occasional superficial mucosal tear with minor bleeding. Equally impressive was the degree to which the lymphocytic nuclei—and follicles when present—were crushed and flattened, yet the underlying fibrous layer was largely unharmed. The reduction in lymphocyte counts was statistically significant. There were only three cases in which longer-term follow-up results were obtained, but the epithelium and submucosa appeared well healed in each of these cases. Cases 1 and 2 showed decreases in lymphocytic infiltrate, and case 1 showed resolution of lymphoid follicles being replaced with healthy thinner fibrous tissue. Similar histological results were previously reported in one case with laser Eustachian tuboplasty.9 The exact mechanism of tissue injury with balloon dilation in the ET remains unknown and could be any combination of direct pressure, hypoxia/hypoperfusion, and shearing trauma. The balloon is designed to expand to its full diameter, which in this study was 6 mm, and to become increasingly firm with the addition of pressure. There can be some shearing forces that may occur as the balloon slips in position during insertion—and even during the 2 minutes of inflation time. The shearing injury would be expected to be much less than may have occurred with bougie dilation, which was tried decades ago. Further basic research into the mechanisms of tissue injury and resulting healing effects is needed. All of the parameters currently used for balloon dilation such as size of the balloon (ranges from 3–7 mm in published studies to date), shape, duration of inflation (1–2 mins), method of insertion, pressure, and other factors could all play a potential role and need to be studied. It Laryngoscope 00: Month 2014
is possible that some of these parameters may have important effects on inducing temporary or permanent alterations in the tissues. There is a clear need for clinical trials controlling for some of these factors and basic science work to test the effects of these parameters in a model. The limitations of this study were principally related to the relatively small number of cases, especially only three with longer-term follow-up specimens. The histological results cannot be assumed to be representative of the effects that happen throughout the ET, which is a funnel-shaped organ being compressed from within by a largely fixed diameter cylinder. There are also variations in the cartilaginous skeleton of the ET that may affect the compressive forces. Therefore, the histological changes noted in this study should be recognized as providing a limited view of the possible overall changes. The immediate postballoon biopsies were taken within the lumen near the orifice, which is the widest portion of the ET. Therefore, the histological effects taken from deeper sites, which would be subjected to increasingly greater pressure and surface shearing forces, remain unknown. Consequently, surgeons should continue to observe caution and maintain a high respect for safety concerns given the persisting uncertainties regarding the effects of this procedure. Specimens were obtained with cup-biting forceps, which admittedly can obtain tissue samples of variable size and depth. The biopsies were considered to be representative and adequate with epithelium and submucosa present in this study, but an attempt to optimize a technique for standardizing biopsies for a future prospective study would be desirable. The histological factors, although scored, were somewhat subjective, but they appeared reproducible and have been used similarly for other histological studies. The present study did not attempt to correlate the histopathological results with clinical results; those data will be presented in a future article. There was no control group for which to compare normal histological data, but harvesting of normal ET mucosa would create risks to healthy patients and present ethical issues. The effect of the balloon on improvement of tubal function may be on the basis of stripping off irreversibly injured or inflamed epithelium but usually preserving the basal layer, which aids in speeding recovery. The inflammatory infiltrate and lymphoid follicles are crushed and may be replaced by a thinner layer of healthy fibrous tissue, with the net effect being a wider lumen for the ET. The effect could be likened to a mucosal-preserving adenoidectomy within the lumen of the ET, thereby reducing the inflammatory burden and giving the tissues a “fresh start.” Similar to regrowth of adenoid tissue with ongoing inflammatory conditions such as chronic rhinosinusitis or allergic disease, the inflammatory disease could return if the underlying etiologies are not brought under adequate medical control. This work served as an observational study to investigate possible mechanisms, which could be
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
5
associated with a hypothesis that BET may induce a decrease in inflammatory disease within the mucosa or submucosa. The limited evidence generated by this observational study is consistent with the hypothesis. The effects of BET remain uncertain, but it is possible that the immediate effects of dilation may lead to permanent beneficial changes in the mucosal and submucosal lining. There could be other effects such as changes in tubal compliance, muscular effects, or other anatomical and physiological alternations that should be further investigated. Further clinical trials, including prospective long-term postop biopsies, and basic research are needed and justified.
CONCLUSION Histopathology of the ET undergoing balloon dilation has demonstrated some evidence that the balloon may shear or crush portions of the epithelium, however, usually sparing the basal layer and allowing for rapid healing. Additionally, it appears to effectively crush lymphocytes and lymphoid follicles that may become replaced with thinner fibrous scar. These effects reduce
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the overall inflammatory burden and may provide lasting clinical improvement in ET dilation and ventilation.
BIBLIOGRAPHY 1. Schroder S, Reineke U, Lehmann M, Ebmeyer J, Sudhoff H. [Chronic obstructive eustachian tube dysfunction in adults: long-term results of balloon eustachian tuboplasty]. Article in German. HNO 2013;61:142– 151. 2. Tisch M, Maier S, Maier H. [Eustachian tube dilation using the Bielefeld balloon catheter: clinical experience with 320 interventions]. Article in German. HNO 2013;61:483–487. 3. McCoul ED, Anand VK. Eustachian tube balloon dilation surgery. Int Forum Allergy Rhinol 2012;2:191–198. 4. Silvola J, Kivekas I, Poe DS. Balloon dilation of the cartilaginous portion of the eustachian tube. Otolaryngol Head Neck Surg 2014;151:125–130. Epub ahead of print. 5. Poe DS, Silvola J, Pyykko, I. Balloon dilation of the cartilaginous eustachian tube. Otolaryngol Head Neck Surg 2011;144:563–569. 6. Poe DS, Hanna BM. Balloon dilation of the cartilaginous portion of the eustachian tube: initial safety and feasibility analysis in a cadaver model. Am J Otolaryngol 2011;32:115–123. 7. Ockermann T, Reineke U, Upile T, Ebmeyer J, Sudhoff HH. Balloon dilation eustachian tuboplasty: a feasibility study. Otol Neurotol 2010;31: 1100–1103. 8. Emerick KS, Cunningham MJ. Tubal tonsil hypertrophy: a cause of recurrent symptoms after adenoidectomy. Arch Otolaryngol Head Neck Surg 2006;132:153–156. 9. Poe DS, Grimmer JF, Metson R. Laser eustachian tuboplasty: two-year results. Laryngoscope 2007;117:231–237. 10. Sade J, Fuchs C, Luntz M. Shrapnell membrane and mastoid pneumatization. Arch Otolaryngol Head Neck Surg 1997;123:584–588.
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
Rhinological and Otological Society, Inc.
Histopathology of Balloon-Dilation Eustachian Tuboplasty €s, MD, PhD; Wei-Chieh Chao, MD; William Faquin, MD, PhD; Monica Hollowell, MD; Ilkka Kiveka Juha Silvola, MD, PhD; Tali Rasooly, BA; Dennis Poe, MD, PhD Objectives/Hypothesis: Surgical intervention of the Eustachian tube (ET) has become increasingly common in the past decade, and balloon dilation has shown promising results in recent studies. It is unclear how balloon dilation enhances ET function. Our aim was to evaluate histological changes in the ET’s mucosal lumen comparing before balloon dilation, immediately after, and postoperatively. Study Design: Case series. Methods: Thirteen patients with bilateral ET dysfunction were enrolled. Biopsies of the ET mucosa were obtained just before balloon dilation; immediately after; and in three cases, 5 to 12 weeks postoperatively. Specimens were retrospectively examined under light microscopy by two pathologists blinded to the clinical information and whether specimens were pre- or postballoon dilation. Results: Preoperative biopsies were characterized by inflammatory changes within the epithelium and submucosal layer. Immediate response to balloon dilation was thinning of the mucosa, shearing of epithelium and crush injury to the submucosa, especially to lymphocytic infiltrates. Postoperative biopsies demonstrated healthy pseudocolumnar epithelium and replacement of lymphocytic infiltrate with a thinner layer of fibrous tissue. Conclusion: Reduction of inflammatory epithelial changes and submucosal inflammatory infiltrate appeared to be the principal result of balloon dilation. The balloon may shear or crush portions of inflamed epithelium but usually spared the basal layer, allowing for rapid healing. Additionally, it appeared to effectively crush lymphocytes and lymphocytic follicles that may become replaced with thinner fibrous scar. Histopathology of the ET undergoing balloon dilation demonstrated effects that could reduce the overall inflammatory burden and may contribute to clinical improvement in ET function. Key Words: Eustachian tuboplasty, balloon dilation, histopathology, mucosa, inflammation. Level of Evidence: 4. Laryngoscope, 00:000–000, 2014
INTRODUCTION Balloon eustachian tuboplasty (BET) of the cartilaginous Eustachian tube (ET) has been reported to have promising clinical results in the treatment of persistent tubal dilatory dysfunction with otitis media with effusion, negative middle ear pressure/nonadhesive atelectasis, or difficulty with flight or scuba barochallenges.1–5 The mechanism by which balloon dilation might enhance ET function has remained unclear.
From the Department of Otolaryngology (I.K., W-C.C., T.R., D.P.); the Department of Pathology (M.H.), Boston Children’s Hospital; and the Department of Pathology, Massachusetts General Hospital (W.F.), Harvard Medical School, Boston, Massachusetts; the Department of Otorhinolaryngology, Tampere University Hospital and the University of Tampere (I.K.), Tampere, Finland; the Department of Otolaryngology, Chang-Gung Memorial Hospital, Chang-Gung University (W-C.C.), Taoyuan, Taiwan; and the Department of Otorhinolaryngology, Oslo University Hospital, Rikshospitalet (J.S.), Oslo, Norway. Editor’s Note: This Manuscript was accepted for publication July 28, 2014. Financial Disclosure: D.P. received two speaking honoraria from Acclarent, Inc., and is a coprimary investigator in a pending clinical trial, sponsored by Acclarent, Inc. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dennis Poe, MD, PhD, Department of Otolaryngology and Communication Enhancement Boston Children’s Hospital, Department of Otology and Laryngology, 333 Longwood Ave., Lo-367, Boston, MA 02115. E-mail: [email protected] DOI: 10.1002/lary.24894
Laryngoscope 00: Month 2014
Cadaver studies have shown an absence of significant change in the cartilaginous skeleton of the ET either by microscopic or endoscopic dissection,6 or at most, minor tears in the roof of the cartilage have been seen histologically.7 It was proposed that the compressive forces might induce some thinning of the surrounding connective tissue architecture.6 In clinical experience, the lumen has been seen to dilate larger in some but not all cases, and the mucosa usually appears unharmed and intact. There can be small tears in the mucosa with some minor bleeding that have yet to demonstrate any clinical significance.4 In balloon dilation, there is no attempt to dilate the bony portion of the ET because the pathology is most commonly located within the cartilaginous segment, and balloon dilation of the bony portion would create a significant risk to the internal carotid artery that is immediately adjacent. Postoperative observations have been made with endoscopic examinations of the tubal lumen, showing a significant reduction in mucosal inflammation (2.8– 1.4) when using a 4-point rating scale.4 One hypothesis could be that compression of irreversibly injured hypertrophic mucosa and submucosa might permit healing with thinner and healthier layers after balloon dilation. To explain the decreased inflammation, this study was undertaken in the absence of an obvious mechanism.
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
1
Fig. 1. Left Eustachian tube nasopharyngeal orifice preballoon dilation, moderately inflamed with edematous, thickened mucosa. Biopsy site was arrowed (45 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
The present work was undertaken as an observational study to investigate the immediate histological effects of BET.
MATERIALS AND METHODS This study was approved by the institutional review board at Children’s Hospital Boston (IRB-P00010256) and was conducted in accordance with their guidelines. All cases had 2 or more consecutive years of chronic ET dilatory dysfunction, with bilateral persistent otitis media with effusion or significant nonadherent tympanic membrane atelectasis. All patients received a trial of at least 6 weeks of nasal steroid spray, and surgery was undertaken if signs and symptoms persisted. Steroid sprays were continued postoperatively only if the patient was chronically on the medication. Similarly, other chronically
Fig. 2. Balloon catheter, positioned within the lumen of the cartilaginous Eustachian tube, was fully inflated to 12 atm for 2 minutes. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
Laryngoscope 00: Month 2014
2
Fig. 3. Left Eustachian tube nasopharyngeal orifice immediately postballoon dilation. A widened lumen with slightly excoriated mucosa (45 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
administered medications such as antihistamines, proton pump inhibitors, and so forth were not discontinued for the surgery. Consecutive operations were done under general anesthesia. All operations were performed through trasnasal approaches with endoscopic assistance (45 degree view angle, 4 mm diameter) (Karl Storz, Culver City, CA). A sinuplasty 6 3 16-mm balloon system Relieva Solo Pro, 70 Relieva Flex Sinus Guide Catheter (Acclarent, Inc, Menlo Park, CA) was used in every operation. The balloon catheter was inserted through the lumen slowly and atraumatically. The balloon was inflated once to 12 atm and maintained in position for 2 minutes. On one side, which was chosen arbitrarily, a biopsy was taken before performing the balloon dilation, and a postdilation biopsy was then taken from the second side immediately following the dilation. As depicted in Figures 1–3, biopsies were taken transnasally with pediatric up-biting Blaksley forceps from superiorly on the posterior cushion, just within the lumen. Hemostasis was assured and the procedure was terminated. In three cases, an additional biopsy was taken postoperatively weeks later. Two of these were performed while the patients were under general anesthesia in the operating room for a tympanoplasty for a tympanic membrane perforation and persisted retraction pocket, and one was taken in the office using local topical spray anesthesia (4% oxymetazoline and 4% lidocaine 50:50 solution), which was tolerated very comfortably. These three patients were regularly using medications during the preoperative period and throughout the follow-up period up to the time of the biopsy. The medication histories were: case 1, omeprazole, minocycline, and contraceptives; case 2, antidepressants, atenolol, and fexofenadine; and case 3, montelukast and fluticasone. Specimens were placed in formalin and processed in the usual fashion for paraffin embedding and staining of 5-um sections with hematoxylin and eosin. The smallest specimen diameter was 2 3 1 3 1-mm and all were deemed adequate. They were examined under light microscopy by two pathologists who were blinded to the clinical information and to whether the specimens were pre- or postballoon dilation. The overall quality of the health of the pseudo-columnar ciliated epithelium was rated excellent, good, fair, or poor. The degree to which the epithelium was uniformly or variably
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
TABLE I. Pre- and Postoperative Clinical Findings and Tympanometry Results. Sade’s Grade10 (18 ears)
Preoperative
Postoperative
0 (no retraction)
4
13
I II
6 1
2 1
III
0
0
IV Middle ear effusion
0 7
0 2
A B
3 5
7 0
C
4
5
Tympanometry n 5 12
involved with disease was noted. The epithelium in each specimen was assessed for the presence or absence of cilia, presence of squamous metaplasia, presence of intraepithelial inflammatory changes, and integrity of the epithelial basal layer. The submucosa was evaluated for the presence of lymphocytes (lymphocytic infiltrate), rated from 0 to 31; other inflammatory cells; and the presence of lymphoid follicles. The deeper fibrous layer was assessed for quality (degree of fibrosis) and quantity (thickness and density) of collagen on a scale of 0 to 31; in addition, the presence/health of seromucinous glands were rated as excellent, good, fair, poor, or absent.
RESULTS BET was performed on 41 ETs in 27 patients between December 2011 and March 2014. Pre- and postballoon dilation biopsies were taken in 17 cases, of which 13 had complete information for the study, with a mean age of 46 years (range 18–74 years) and three female patients. Pre- and postoperative clinical findings and tympanometry results are presented in Table I. Three of the 13 cases additionally had biopsies taken at 5, 11, and 12 weeks postoperatively. There were no complications related to any of the biopsies; all sites healed well, leaving a minimal scar. Bleeding from the biopsy sites was limited and did not require any cautery or topical vasoconstrictors to control. A summary of the histopathological results is presented in Table II. There was a statistically significant change (P 5 0.023; nonpaired t tests) in submucosal lymphocytes count between pre- and immediate postoperatively. In other parameters, postoperative changes were not significant (P > 0.05). Generally, preballoon biopsies were characterized by variable degrees of inflammatory changes, most notably lymphocytic infiltrates, and three cases with lymphoid follicles present. Eosinophils were not a component of the inflammatory infiltrate. Eight cases demonstrated significant inflammation with submucosal infiltrates of 21. Five of these eight cases showed variable degrees of diseased epithelium (including one with squamous metaplasia) and loss of cilia, which were severely reduced in one and entirely absent in another. Four of these eight cases had severe inflammatory infiltrates Laryngoscope 00: Month 2014
penetrating through the epithelium, along with some disruption of the basal layer (Fig. 4). Postballoon biopsies demonstrated diffuse crush injury to the mucosa and submucosa in all of the specimens, although relatively minimally in one case in which the preballoon mucosa was also rated as “excellent.” The epithelium was disrupted in eight of the 13 cases and was altogether absent, including the basal
TABLE II. Histological Findings of the Eustachian Tube Mucosa Just Before Balloon Dilation, Immediately After, and in Three Cases, 5–12 Weeks Postoperatively.
Epithelium quality
Preballoon
Immediate Postballoon
5–12 Weeks Postoperatively
n 5 13 (%)
n 5 13 (%)
n53
Excellent Good
1 (8) 8 (61)
1 (8) 3 (23)
1 2
Fair
3 (23)
2 (15)
0
1 (8)
7 (54)
0
Poor Epithelial uniformity Uniform
8 (61)
2 (15)
3
Variable Squamous metaplasia
4 (31) 1 (8)
8 (61) 0 (0)
0 0
Absent
0 (0)
3 (23)
0
Cilia quality/quantity Present
11 (85)
4 (31)
3
Fair (fragmented)
1 (8)
3 (23)
0
1 (8)
6 (46)
0
Absent Intraepithelial inflammation Present
3 (23)
0 (100)
0
10 (77)
13 (0)
3
Good
9 (69)
3 (23)
3
Fair Variably present
4 (31) 0 (0)
1 (8) 6 (46)
0 0
0 (0)
3 (23)
0
Absent Basal layer integrity
Absent Submucosal lymphocytes 31
3 (23)
0 (0)
0
21 11
5 (38) 4 (31)
2 (15) 8 (61)
1 2
0
1 (8)
3 (23)
0
3 (23)
0 (0)
0
10 (77)
13 (100)
3
Lymphoid follicles Present Absent Collagen quantity/fibrosis 31
3 (23)
3 (23)
0
21
7 (54)
5 (38)
0
11 0
2 (15) 1 (8)
4 (31) 1 (8)
3 0
4 (31) 5 (38)
3 (23) 4 (31)
2 1
Fair
1 (8)
3 (23)
0
Poor/absent
3 (23)
3 (23)
0
Seromucinous glands quantity/quality Excellent Good
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
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Fig. 4. Preballoon biopsy. Inflammatory change of the mucosa with lymphocytic infiltrates and lymphoid follicles (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
layer, in three of those cases. Severe loss or absence of cilia increased to nine cases. There was particularly severe injury to the lymphocytes, whose nuclei were prominently thinned and elongated and especially to the lymphoid follicles, which were also severely flattened. Submucosal glands appeared to be untouched and unchanged (Fig. 5). The 5- to 12- week follow-up biopsies generally showed restoration of largely uniformly healthy ciliated pseudo-columnar epithelium. Table II The lymphocytic infiltrate decreased from 31 to 21 in case 1 and from 21 to 11 in case 2. Lymphoid follicles that were present in case 1 and seen to be severely flattened in the immediate postop specimen were replaced with a thin-
Fig. 5. Postballoon biopsy. Diffuse crush injury to the mucosa and submucosa; severe injury to the lymphocytes, whose nuclei were prominently thinned and elongated, and especially to the lymphoid follicles (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.]
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Fig. 6. Five weeks postballoon biopsy. Restoration of largely and uniformly healthy ciliated pseudo-columnar epithelium is seen. Less lymphocytic infiltrate is noted compared to the preballoon biopsy. Lymphoid follicles are replaced with a thinner layer of fibrous tissue (203 power filed hematoxylin and eosin stain). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
ner layer of fibrous tissue at 5 weeks postoperatively. Submucous glands were irregularly observed and did not appear to have been influenced by the dilation (Figs. 6, 7).
DISCUSSION The predilation histopathology results were consistent with the clinical impression of the presence of inflammatory disease at the tubal orifice and within the lumen. There were variable degrees of mucosal
Fig. 7. Left Eustachian tube nasopharyngeal orifice 1 year postballoon dilation follow-up. Mucosa of the lumen is thinner, and the bulk of the mucosal folds of the posterior cushion is significantly reduced (45 degree 4-mm endoscope view). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
disruption, loss of cilia, and inflammatory infiltrate, sometimes even penetrating through to the surface of the epithelium. There was substantial submucosal inflammatory infiltrate in the majority of the cases and even follicle formation in some cases. Lymphoid follicles have been described as the tubal tonsil or the tonsil of Gerlach, a part of Waldeyer’s ring of lymphoid tissue surrounding the oropharynx and nasopharynx.8 They appear grossly as adenoid-like hypertrophied tissue with “cobblestoning” that corresponded with lymphoid hyperplasia in the present study. These follicles have not been previously reported to our knowledge within the tubal lumen. All of the patients in this study had many years of persistent ET dilatory dysfunction and may have been suffering from irreversible injury to the mucosa or submucosa. Alternatively, there could have been ongoing inflammatory etiologies such as allergic rhinitis, chronic rhinosinusitis, local biofilms, and other possible causes. The immediate postdilation histopathology showed a very consistent pattern of crush injury to the epithelium and submucosa, with relative sparing of the deep fibrous layer and submucosal glands. There was a significant shearing off of portions of the epithelium, even down to the basal layer, but in most cases the basal layer was preserved, which likely helped to speed regeneration of the mucosa. This degree of stripping off of the epithelium was not appreciated on clinical examination with the endoscope. On the contrary, the epithelium usually appears grossly largely unharmed, aside from the occasional superficial mucosal tear with minor bleeding. Equally impressive was the degree to which the lymphocytic nuclei—and follicles when present—were crushed and flattened, yet the underlying fibrous layer was largely unharmed. The reduction in lymphocyte counts was statistically significant. There were only three cases in which longer-term follow-up results were obtained, but the epithelium and submucosa appeared well healed in each of these cases. Cases 1 and 2 showed decreases in lymphocytic infiltrate, and case 1 showed resolution of lymphoid follicles being replaced with healthy thinner fibrous tissue. Similar histological results were previously reported in one case with laser Eustachian tuboplasty.9 The exact mechanism of tissue injury with balloon dilation in the ET remains unknown and could be any combination of direct pressure, hypoxia/hypoperfusion, and shearing trauma. The balloon is designed to expand to its full diameter, which in this study was 6 mm, and to become increasingly firm with the addition of pressure. There can be some shearing forces that may occur as the balloon slips in position during insertion—and even during the 2 minutes of inflation time. The shearing injury would be expected to be much less than may have occurred with bougie dilation, which was tried decades ago. Further basic research into the mechanisms of tissue injury and resulting healing effects is needed. All of the parameters currently used for balloon dilation such as size of the balloon (ranges from 3–7 mm in published studies to date), shape, duration of inflation (1–2 mins), method of insertion, pressure, and other factors could all play a potential role and need to be studied. It Laryngoscope 00: Month 2014
is possible that some of these parameters may have important effects on inducing temporary or permanent alterations in the tissues. There is a clear need for clinical trials controlling for some of these factors and basic science work to test the effects of these parameters in a model. The limitations of this study were principally related to the relatively small number of cases, especially only three with longer-term follow-up specimens. The histological results cannot be assumed to be representative of the effects that happen throughout the ET, which is a funnel-shaped organ being compressed from within by a largely fixed diameter cylinder. There are also variations in the cartilaginous skeleton of the ET that may affect the compressive forces. Therefore, the histological changes noted in this study should be recognized as providing a limited view of the possible overall changes. The immediate postballoon biopsies were taken within the lumen near the orifice, which is the widest portion of the ET. Therefore, the histological effects taken from deeper sites, which would be subjected to increasingly greater pressure and surface shearing forces, remain unknown. Consequently, surgeons should continue to observe caution and maintain a high respect for safety concerns given the persisting uncertainties regarding the effects of this procedure. Specimens were obtained with cup-biting forceps, which admittedly can obtain tissue samples of variable size and depth. The biopsies were considered to be representative and adequate with epithelium and submucosa present in this study, but an attempt to optimize a technique for standardizing biopsies for a future prospective study would be desirable. The histological factors, although scored, were somewhat subjective, but they appeared reproducible and have been used similarly for other histological studies. The present study did not attempt to correlate the histopathological results with clinical results; those data will be presented in a future article. There was no control group for which to compare normal histological data, but harvesting of normal ET mucosa would create risks to healthy patients and present ethical issues. The effect of the balloon on improvement of tubal function may be on the basis of stripping off irreversibly injured or inflamed epithelium but usually preserving the basal layer, which aids in speeding recovery. The inflammatory infiltrate and lymphoid follicles are crushed and may be replaced by a thinner layer of healthy fibrous tissue, with the net effect being a wider lumen for the ET. The effect could be likened to a mucosal-preserving adenoidectomy within the lumen of the ET, thereby reducing the inflammatory burden and giving the tissues a “fresh start.” Similar to regrowth of adenoid tissue with ongoing inflammatory conditions such as chronic rhinosinusitis or allergic disease, the inflammatory disease could return if the underlying etiologies are not brought under adequate medical control. This work served as an observational study to investigate possible mechanisms, which could be
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
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associated with a hypothesis that BET may induce a decrease in inflammatory disease within the mucosa or submucosa. The limited evidence generated by this observational study is consistent with the hypothesis. The effects of BET remain uncertain, but it is possible that the immediate effects of dilation may lead to permanent beneficial changes in the mucosal and submucosal lining. There could be other effects such as changes in tubal compliance, muscular effects, or other anatomical and physiological alternations that should be further investigated. Further clinical trials, including prospective long-term postop biopsies, and basic research are needed and justified.
CONCLUSION Histopathology of the ET undergoing balloon dilation has demonstrated some evidence that the balloon may shear or crush portions of the epithelium, however, usually sparing the basal layer and allowing for rapid healing. Additionally, it appears to effectively crush lymphocytes and lymphoid follicles that may become replaced with thinner fibrous scar. These effects reduce
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the overall inflammatory burden and may provide lasting clinical improvement in ET dilation and ventilation.
BIBLIOGRAPHY 1. Schroder S, Reineke U, Lehmann M, Ebmeyer J, Sudhoff H. [Chronic obstructive eustachian tube dysfunction in adults: long-term results of balloon eustachian tuboplasty]. Article in German. HNO 2013;61:142– 151. 2. Tisch M, Maier S, Maier H. [Eustachian tube dilation using the Bielefeld balloon catheter: clinical experience with 320 interventions]. Article in German. HNO 2013;61:483–487. 3. McCoul ED, Anand VK. Eustachian tube balloon dilation surgery. Int Forum Allergy Rhinol 2012;2:191–198. 4. Silvola J, Kivekas I, Poe DS. Balloon dilation of the cartilaginous portion of the eustachian tube. Otolaryngol Head Neck Surg 2014;151:125–130. Epub ahead of print. 5. Poe DS, Silvola J, Pyykko, I. Balloon dilation of the cartilaginous eustachian tube. Otolaryngol Head Neck Surg 2011;144:563–569. 6. Poe DS, Hanna BM. Balloon dilation of the cartilaginous portion of the eustachian tube: initial safety and feasibility analysis in a cadaver model. Am J Otolaryngol 2011;32:115–123. 7. Ockermann T, Reineke U, Upile T, Ebmeyer J, Sudhoff HH. Balloon dilation eustachian tuboplasty: a feasibility study. Otol Neurotol 2010;31: 1100–1103. 8. Emerick KS, Cunningham MJ. Tubal tonsil hypertrophy: a cause of recurrent symptoms after adenoidectomy. Arch Otolaryngol Head Neck Surg 2006;132:153–156. 9. Poe DS, Grimmer JF, Metson R. Laser eustachian tuboplasty: two-year results. Laryngoscope 2007;117:231–237. 10. Sade J, Fuchs C, Luntz M. Shrapnell membrane and mastoid pneumatization. Arch Otolaryngol Head Neck Surg 1997;123:584–588.
€s et al.: Histopathology of Balloon-Dilation Eustachian Tuboplasty Kiveka
