Tracheobronchopathia Osteochondroplastica

Introduction Abbreviations used in this article: BMP, bone morphogenic protein, CT, computed tomography, ENT, ear, nose and throat, FEV1, forced expiratory volume in 1 second, FVC, forced vital capacity, PFT, pulmonary function tests, TGF, transforming growth factor, TLC, total lung capacity, TO, tracheobronchopathia osteochondroplastica Tracheobronchopathia osteochondroplastica (TO) is a rare disorder of unknown cause affecting the tracheobronchial tree. It is characterized by the presence of multiple osseous and/or cartilaginous submucosal nodules protruding into the lumen of the trachea and large bronchi, typically sparing the posterior wall. Because of its usually benign course, TO was formerly an incidental finding at autopsy. It is presently increasingly discovered at fiberoptic bronchoscopy and/or chest computed tomography (CT) usually performed for other reasons. The first case of TO was described by Wilks (83) in 1857 under the title of “Ossific Deposits on the Larynx, Trachea and Bronchi,” referring to the autopsy findings in a 38-year-old man who died from tuberculosis. In 1863, Virchow (82) considered TO to be an “ecchondrosis and exostosis” arising from the normal tracheal rings. The entity was named “tracheopathia osteoplastica” in 1910 by Aschoff (4), who considered it to be a disorder of the connective tissue, specifically affecting the internal elastic membrane of the trachea and major bronchi. Later, special interest was directed to the association of TO, atrophic rhinitis, and Klebsiella ozaenae(36,49,62,73), the latter being named after its isolation from patients with ozena, the other designation of atrophic rhinitis (1). Hence, most published clinical papers on TO refer to single cases or small series, the only previous large study being a report of 30 cases published in 1977 (32). The present study was undertaken to characterize better the clinical, functional, imaging, and endoscopic features of TO in a large series of cases, to estimate the rate of disease progression, and to determine its morbidity and mortality. Methods Case recruitment This retrospective multicentric study was undertaken by the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P), a French group of pulmonary physicians interested in rare (so called “orphan”) pulmonary diseases, and distributed nationwide, especially in university centers. Cases were recruited through the GERM“O”P’s registry of rare pulmonary diseases. Starting from April 1995, participating physicians were requested to report to the registry all cases of selected rare pulmonary diseases, including TO. Records were nominative for patients who gave written consent, and anonymous otherwise. Data were collected by a coordination center based in Lyon, France. Data collection In March 1998, a detailed questionnaire was sent to all physicians who had reported cases of TO to the registry. Questionnaires were completed by reviewing the medical records. Retrieved items included past medical history, occupation, smoking status, symptoms and signs at presentation, laboratory data including markers of phosphate and calcium metabolism, bacteriologic analysis of bronchial washings, pulmonary function tests, treatment, and outcome. A copy of histopathologic reports was requested. Detailed charts were used to retrieve findings at fiberoptic bronchoscopy, based on reports of the procedure. Physicians were asked to evaluate the localization (anterolateral and/or posterior), elevation (mild, moderate, or important), and size of submucosal nodules, as well as the degree of airway obstruction if present. To estimate the concentration of nodules on the mucosa, lesions were classified as “scattered” (few nodules leaving areas of normal mucosa between them), “diffuse” (numerous nodules covering the entire mucosa without spared areas between them) or “confluent” (numerous nodules to the point that fusion occurs). Chest X-rays were evaluated for tracheobronchial stenosis and calcifications, atelectasis, parenchymal and mediastinal opacities, and possible tuberculous sequelae. Chest CT scans were analyzed for the presence and location of submucosal nodules, submucosal calcifications (distinct from calcifications of cartilaginous tracheal rings), tracheal deformity, mediastinal lymph nodes, bronchiectasis, atelectasis, pneumonia, and opacities consistent with possible tuberculous sequelae. Non-numerical variables were retrieved as binary propositions. Dates of all events were recorded. Data collection ended in May 2000. Numerical data were expressed as mean ± standard deviation, unless stated otherwise. Selection of cases The inclusion criterion used in the present series was the presence of typical endoscopic findings of TO consisting of characteristic multiple hard nodules, arising from the submucosa and projecting into the lumen of the tracheobronchial tree (46), with a beaded (60) to stalactitic cave appearance (81). Histopathologic diagnosis of TO was defined as the presence of either cartilage or bone in the submucosa at laryngotracheobronchial biopsies (2,21,37,59). However, histologic proof of TO was not required for inclusion. Data analysis All questionnaires were carefully reviewed. Ventilatory defects on pulmonary function tests were classified as obstructive ventilatory defects when the forced expiratory volume in 1 second/ forced vital capacity (FEV1/FVC) was <70%; as restrictive ventilatory defects when the total lung capacity (TLC) was <80% predicted or FVC was <80% predicted with FEV1/FVC >70%; or as combined ventilatory defects when the TLC was <80% predicted with FEV1/FVC <70% (See Table 3). Severity of obstructive ventilatory defect was further classified as mild (FEV1 >70% predicted), moderate (50% predicted < FEV1 < 70% predicted), or severe (FEV1 < 50% predicted). Evolution of pulmonary function over time was analyzed if 2 or more tests were available at least 1 year apart. Obstructive deterioration was considered when FEV1/ FVC decreased by more than 15% compared to baseline, and restrictive deterioration when TLC or FVC decreased by more than 15% compared to baseline. This 15% threshold was arbitrarily chosen to take into account both intraindividual and interinstitutional variations. Radiologic follow-up was assessed when 2 or more chest CT scans were available at least 1 year apart. New nodules, recent submucosal calcifications, or recent tracheal stenosis were considered as radiologic progression. In patients who underwent 2 or more fiberoptic bronchoscopies at least 1 year apart, disease progression was assessed by performing systematic site-by-site comparison of bronchoscopy reports, as recorded on data charts. For each patient and at each site of the entire laryngotracheobronchial tree, evolution was defined as stability, progression, or regression, with separate assessment of anterolateral and posterior tracheal walls. Progression was defined as the presence of or in concentration or size of Progression was considered when the were present at only 1 site of the tracheobronchial tree and lesions not previous Progression was considered when lesions or an in nodules size or concentration in more than 1 or in of airway pulmonary function tests in patients with May cases of TO had reported to the registry. detailed questionnaires were and completed for analysis by May 2000. all cases were considered for inclusion in the present of cases published as case reports Cases were between and the after included and The mean at diagnosis was ± patients were or The time between the first medical for symptoms to TO and diagnosis was 2 ± The mean follow-up after diagnosis was ± medical patients had a of or ear, and disease including atrophic rhinitis, or had a of or disease bronchiectasis, or obstructive pulmonary patients had a diagnosis of and had a of patient had TO, and had multiple patients had a past of tuberculosis. patient had pulmonary patient had to and to had of previous and were not not case of TO in In most patients with a of and signs at The symptoms at in Table of patients had or symptoms at the time of and were The of symptoms was in patients and in The mean of symptoms diagnosis was ± The most was present in It was usually with other and was in only patients had as a patients with pneumonia, 2 of had was present at diagnosis in patients patients with in to TO. In was required for in obstructive pulmonary were to severe tracheal and was In the other TO first as for In the other TO was an incidental finding at fiberoptic bronchoscopy performed for atelectasis, and Chest was in cases and/or 1 patient had at Chest was in at in patients with and and were the most features at data the time of diagnosis of TO, patients had a had a rate had a and had phosphate and calcium the normal In from markers of laboratory data not findings at bronchial fiberoptic bronchoscopy in Table or more were in were for in cases, in in and in The most were in of cases, and in patients had symptoms of with 1 or more had were patients with an was in were in data assessment of in patients with function tests patients had pulmonary function tests performed at the time of The of is in Table The mean at were FEV1 ± FVC ± predicted and FEV1/FVC ± of patients had normal and had an obstructive ventilatory defect moderate, and had other cause than TO for obstructive had a diagnosis of obstructive pulmonary disease and 1 had a of patient had a combined The was in were in an expiratory in cases and an in In all nodules were distributed the trachea and at fiberoptic obstruction of large and a 50% obstruction of was present in 1 patient with an expiratory and a obstruction was present in patient with an was in 1 patient with an and in 1 other with an expiratory of lung function was possible in patients who had 2 at least 1 year apart. The mean time between first and study was ± the mean of FEV1, FVC, and FEV1/FVC in this deterioration was not each patient had an of a obstructive defined as a of FEV1/FVC compared to baseline. deterioration was by endoscopic progression of TO in both Chest data were available in stenosis was in tracheobronchial calcifications in in in and tuberculous in Chest CT was available for The findings in Table submucosal nodules, present in of cases, were on the anterolateral tracheal in all for 1 case with both anterolateral and posterior nodules and calcifications were in of cases, and tracheal stenosis in The mean of tracheal in was ± Chest CT findings at diagnosis in patients with Chest CT anterolateral nodules protruding into the tracheal Chest CT of the the multiple anterolateral nodules sparing the posterior patients had a chest CT In 2 progression was by the presence of nodules, with submucosal calcifications in 1 stenosis was on the in all a mild tracheal stenosis was in 1 patient on the All patients underwent fiberoptic bronchoscopy, a typical of TO. were most distributed the tracheobronchial tree, especially in the and in and of cases, The trachea was in of cases, and the in had lesions the The and were and of cases, and were and of cases, The was in only patient had were to the anterolateral in patients who had posterior In the the concentration of lesions was most evaluated as and or In in the bronchi, concentration was most evaluated as and elevation in the trachea was usually moderate or mild and and obstruction was in the in 1 in the trachea in in the in and in the in 2 A 50% of airway was at the tracheal in only with bronchial stenosis in 1 of and stenosis in anterolateral of nodules in the typical appearance of tracheobronchopathia The posterior is anterolateral nodules in the the protruding at the the airway a stalactitic of the nodules was reported in and of the on the lesions was in trachea was in and expiratory tracheal in The tracheal mucosa was in and in were in or in patients were evaluated at least 1 year ± was of patients were and disease progression in It was in patients and in In 1 nodules to the trachea with a lumen obstruction had the entire tracheobronchial tree, with in size and a obstruction of the tracheal lumen at the bronchoscopy performed In the disease in the trachea and bronchi, and was in more The posterior was spared in most The most was of the tracheobronchial tree, obstruction was progression over time was usually or severe progression in biopsies were performed in was considered in patients In cases histologic diagnosis was at first in the other cases the not histopathologic were in of cases to in 1 and histopathologic diagnosis in more The histopathologic findings in Table The most findings were the characteristic presence of bone in the bronchial submucosa of and of the tracheal biopsies specifically for after only both TO and of patients with posterior tracheal had TO, with for in of and in only patient had a of the and of the of the lesions of TO were to the and the 2 were considered In case with TO, was in a site from TO be for were and was further for or other as of patients with for at bronchial had histologic of TO. The patient not histologic had typical tracheal and bronchial nodules characteristic of TO at Histopathologic findings from tracheobronchial biopsies in patients with patients directed to with TO, as obstructive pulmonary bronchiectasis, or of in in in in and in 2 patients to or tracheal of had and was on of severe tracheal patient in or was in of patients were of were at The other patients had or including and patient died of of pulmonary in the of with severe with severe tracheal stenosis to TO patients died of This series of patients with TO to the reported and a of and endoscopic of TO, with of the clinical In study the mean at diagnosis was in with 2 previous series et reported a mean at diagnosis of in a series of 30 patients with atrophic rhinitis who were for TO. In the of disease symptoms were usually present ± in series, and to ± in the series of and at in the patient was a TO reported in an patient (32). This at diagnosis of the in a was reported in 2 previous series, with and of cases (32). In the latter series, the from the recruitment that patients with atrophic rhinitis, is more reported in A of TO reported in only 1 of a and at the of of TO in of patients were in with previous medical A of was in of rhinitis was in of patients rhinitis, called ozena, is a disease characterized by and of the of and a The of atrophic rhinitis and TO was first described by and and a was that the of the and tracheal had in of of of submucosal elastic into elastic cartilage by and et reported cases of TO, of had a of atrophic reported in patients with TO. et reported that of patients with TO had a of atrophic rhinitis and were specifically for TO in this The rate of atrophic rhinitis in patients compared with the latter series from of an was the of recruitment for et (32). and signs at In this series, of patients had 1 or more symptoms at be to TO in most cases, fiberoptic bronchoscopy was performed in of or with TO being an incidental finding in all of patients were at was the in of cases, and was to TO in all 1 patient who had et reported 2 cases with a of diagnosis of TO. was the in the case of TO In a small series, 2 of patients had and in series patients had with TO was discovered in of a of described in 2 reports as in of reported Histopathologic findings in 1 case of normal The of this report that from including by of the of the and to the of normal TO was in patients who underwent for of to after It is that of cases had a of and with at TO described and be included in the diagnosis of large The diagnosis of TO was by or or in with the usually to the disease at the time when it was an incidental finding at autopsy data for a all laboratory including markers of phosphate and calcium metabolism, were normal in and calcium was reported to be normal in patients with TO, 2 of had growth in 1 1 case of TO with was reported in the an incidental it that TO from a single of or growth this not and more to from the and the normal lung is by as the of in the tracheobronchial tree of In TO, of the and of normal airway to especially Hence, bronchial were in of to other pulmonary TO to presence of in the The most in TO was in of of had a of atrophic The most was in patients of had obstructive pulmonary a was in of cases with a rate to that in of In the the most and This was to the findings of study with the of usually not described in was the most in et in the tracheal of cases of A case of TO with to and bronchial for both this and reported patient with TO and a past of atrophic rhinitis to with (81). to et a in as to of this of with between the This was and and required a between the and The that the of to the of be an in the of atrophic rhinitis that tracheobronchial by a in the of TO. This to and in TO this is the other in the tracheobronchial mucosa to TO the of Klebsiella and other to bronchial as a of TO than its In data the of in TO, that between 2 were in of cases had TO, or submucosal and calcifications from first patient had by stenosis of the with atelectasis, at bronchial and for tuberculosis. However, had typical endoscopic features of TO, with multiple hard submucosal nodules in the trachea and bronchi, sparing the posterior wall. of the TO lesions not be The patient for performed 1 and 2 findings in the trachea and bronchi, of bronchial stenosis and of the features of described In the the features and bronchial mucosa with multiple lesions 2 of a bronchial and present. that lesions from and typical TO be and that in patient at the time of with of under of TO. of TO and reported this or case had TO with an association published as a case report features were typical for TO, and bone was at bronchial was on bronchial The patient was not a chest CT small and of the lesions in described in as well as in present as or multiple with a and features be with typical TO, and that patient had TO and The latter by with published as a case report had TO discovered after for biopsies typical features of TO with and A single of was on 1 at a bronchoscopy performed after the diagnosis of TO, and was not considered In that patients had TO and or function tests In this series, patients had an obstructive ventilatory assessed in patients a mean follow-up of obstructive deterioration in only 2 In 1 series of patients with TO lung function follow-up obstructive ventilatory defect in 2 cases, and 1 obstruction to deterioration in patients a mean follow-up of series an obstructive defect in cases deterioration of lung and follow-up reported in only 1 case of TO with in expiratory was in was at in of This finding is in in the of cartilage was in 2 et published an case of TO with normal and an with decreased to severe of the posterior and reported in a patient with TO and symptoms is usually by The normal of the posterior an anterolateral tracheal the decreased in severe cases of TO. The typical chest appearance of TO described as multiple the and tracheal calcifications Chest CT scans an and more of TO. The presence of multiple submucosal nodules with sparing of the posterior at chest CT considered by In this series, of evaluated patients were to nodules in the of large were on the anterolateral of the trachea in all 1 patient who had posterior lesions as into the airway lumen in and submucosal calcifications were in The to be considered at and tracheobronchial trachea is a tracheal consisting of and is with obstructive pulmonary disease nodules with calcifications, when to the cartilaginous and sparing the trachea with TO reported with this of patients had deformity, of had obstructive pulmonary is a rare characterized by cartilage and of and nose and of the tracheobronchial tree CT scans a and of the cartilaginous of the tracheobronchial tree sparing the posterior submucosal nodules present as without airway in an or as submucosal the airway It that TO be a of tracheobronchial In to TO, tracheobronchial typically not the posterior In the rare cases of TO the posterior be by the in of the typical under of TO at and usually a more airway in a than TO In the of calcifications, and be The latter usually and opacities into the lumen of on chest CT the lesions from the submucosal nodules of TO. bronchoscopy, as or lesions be with TO. radiologic findings as and as first of TO The presence of or cartilaginous nodules of the tracheal is the endoscopic of TO on the size of the the trachea present a beaded (60) or stalactitic cave of the the hard nodules is characteristic and was present in of The airway and the hard of lesions it to the were of hard at in of This the is to the presence of submucosal bone and cartilage in TO, with other that endoscopic appearance as tracheobronchial in lesions not hard and at to the capacity of the with were in a series of patients with tracheobronchial in were not in after was present in all cases, and was reported in a single case In this series, lesions were distributed the including the reported that the of the trachea most A posterior tracheal was in a finding only described tracheobronchial to be in cases with an was present in only 1 patient with posterior tracheal The that TO a of was based on the finding of both on histopathologic as in 2 of cases, is of a between the 2 of patients in this series had of TO, and of had at of TO with of described in only cases endoscopic follow-up over a mean of ± progression of lesions in of was in of cases in TO is usually a benign not a progression in severe tracheal stenosis reported is rare as by the present The characteristic histopathologic appearance of TO when analyzed at autopsy in cases and cartilaginous nodules in the tracheal with be in the bone nodules of the nodules between the TO lesions and the of the tracheal in not all cases The criterion used in series to TO was the presence of either or calcifications in the submucosa at tracheal (2,21,37,59). It is not presently possible to from biopsies in the used at the nodules a hard and at and the usually The criterion used in 70% of In the rare cases of TO the posterior be by the in of the typical under In tracheobronchial was by the tracheobronchial be in the other the of on histologic of the with the of of the and of at and the endoscopic diagnosis of TO. of the tracheobronchial was present in of that in TO, be the first of a by cartilaginous and bone from the submucosal of the of follow-up in of TO for TO. Virchow considered the as and arising from the cartilaginous tracheal was by Aschoff the of of the elastic (4), by who that elastic cartilage by a of of the elastic and connective and and in other without in normal cartilage and and in TO that of multiple growth and et the presence of bone morphogenic and transforming growth by in 2 cases of TO at autopsy. de bone and through of into by and of is in the normal lung In the study by was distributed in normal tracheal was TO nodules in cartilage and This that in TO and of into and in of cartilage and bone in the tracheal In the was in and in submucosal TO nodules is expressed in the bronchial its presence in normal bronchial submucosa is In the location of this TO nodules that it is to the in airway as and and is to bone and and and each other through of bone a in TO and with to nodules data for It is that the findings by both and TO lesions were both in with the of tracheal cartilage and in the submucosa for TO is to tracheal stenosis in severe cases, published is 1 of patients a in the of with only moderate of tracheal In the 1 patient with severe tracheal stenosis after endoscopic of nodules, previous had of the nodules in patient with not in of the atelectasis, a 50% bronchial was of a in a patient reported is to into account that an of patients had bronchial for that of is when This is the first series the clinical of TO. or symptoms were present in of patients patient died of of pulmonary to both and TO. patient a and is under for severe tracheal with other published cases the rare possible severe of TO. In a small series, patients died of severe with TO Tracheobronchopathia osteochondroplastica (TO) is a rare disorder of unknown cause characterized by the presence of multiple submucosal osseous and/or cartilaginous nodules protruding into the lumen of the trachea and large bronchi. In this retrospective to characterize better the clinical, functional, and endoscopic features of TO, estimate its rate of progression, and determine the and morbidity of the The study of were and with a mean at diagnosis of ± patients had or disease rhinitis, or and had or disease bronchiectasis, or obstructive pulmonary patients were at the time of of and patients with pneumonia, and 2 with function tests in patients an obstructive defect in a restrictive defect in and normal in A deterioration of lung function over time in Chest CT scans submucosal nodules in bronchoscopy usually a of tracheobronchial nodules, typically with sparing of the posterior wall. of the posterior tracheal was in cases patients had degree of airway stenosis at follow-up in patients in progression in and progression in Histopathologic diagnosis of TO was in cases an in cases and Klebsiella a of TO, was in patient a and had to severe tracheal was to TO. that TO with or findings at Chest CT be a or disease progression over time is the and tracheobronchial stenosis for of the