REVIEW ARTICLE
The Clinical Respiratory Journal Journal
Tracheobronchopathia osteochondroplastica: a review of the literature Sevinc Sarinc Ulasli1 and Elif Kupeli2 1 Department of Pulmonary Diseases, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey 2 Department of Pulmonary Diseases, Faculty of Medicine, Baskent University, Ankara, Turkey
Abstract Background: Tracheobronchopathia osteochondroplastica (TBPOCP) is an uncommon benign condition affecting the lumen of tracheobronchial tree and characterized by abnormal chondrification and ossification. TBPOCP is more frequent than it has been reported, as it can be asymptomatic or present with non-specific respiratory symptoms. Aims: In this article, we provide a review of the English literature on the condition and discuss its clinical features, general principles, diagnostic approaches and current treatment recommendations for TBPOCP. Methods: We searched for all papers indexed in Science Citation Index and Science Citation Index – Expanded by using Thomson Reuters Web of Knowledge Web of Science software. Results: We reviewed a total of 72 scientific publications. Conclusion: In order to highlight, diagnosis, treatment and treatment outcomes of TBPOCP, further review articles and large case series about this orphan disease are needed.
Please and Kupeli Kupeli E. E. Tracheobronchopathia Tracheobronchopathia Please cite cite this this paper paper as: as: Ulasli Ulasli SS SS and osteochondroplastica: a review of the literature. Clin Respir J 2015; 9: 386–391. osteochondroplastica: a review of the literature. Clin Respir J 2014; ••: ••–••. DOI:10.1111/crj.12166. DOI:10.1111/crj.12166.
Key words rare lung diseases – review – scientific publications – tracheobronchopathia osteochondroplastica Correspondence Sevinc Sarinc Ulasli, MD, Department of Pulmonary Diseases, Faculty of Medicine, Afyon Kocatepe University, I˙zmir Karayolu 7. Km 03200 Afyon, Turkey. Tel: +90 5053073658 Fax: +90 2722463322 email: [email protected] Received: 03 January 2014 Revision requested: 06 May 2014 Accepted: 16 May 2014 DOI:10.1111/crj.12166 Authorship and contributorship S. S. U. designed the review, collected and analyzed data, and prepared the manuscript. E. K. helped in analysis of data and prepared the manuscript. All authors read and approved the final manuscript. Ethics None. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Introduction Tracheobronchopathia osteochondroplastica (TBPOCP) is an uncommon benign condition affecting the lumen of the tracheobronchial tree and characterized by abnormal chondrification and ossification of cartilages, sparing the posterior wall (1). TBPOCP is also referred by its synonyms tracheopathia chondroosteoplastica and tracheopathia osteoplastica.
386 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
TBPOCP was first described in 1857 as ossific deposits in the larynx, trachea and bronchi by Wilks and colleagues (2). Accumulation of calcium phosphate in the submucosa of the large airways, and benign proliferation of bone and cartilage lead to the narrowing of the airways (1). TBPOCP is more frequent than it has been reported, as it can be asymptomatic or present with non-specific respiratory symptoms (3). The common presenting symptoms of TBPOCP are chronic cough and wheezing, which often lead to the
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 1 C 2014 John Wiley & Sons Ltd V
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
misdiagnosis of asthma (4). The aim of this review is to discuss clinical features, diagnostic approaches and current treatment recommendations for the patients with TBPOCP based on the literature.
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
edematous with metaplastic epithelium, suggesting chronic inflammation (12).
Clinical features Review of the literature We searched for all papers indexed in Science Citation Index and Science Citation Index-Expanded by using Thomson Reuters Web of Knowledge Web of Science software (Thomson Reuters Corporation, New York, NY, USA). ‘Tracheobronchopathia osteochondroplastica’ as the key word was entered for the topic section (September 30, 2013). Abstracts of each publication were reviewed. According to the review by AbuHijleh et al. (5), less than 400 reported cases were found in the literature by 2008. We found additional 19 cases in the literature since 2008. We reviewed a total of 72 scientific publications. The following details have been gathered from our literature review.
Etiology The theories regarding the formation of these nodules include chronic airway inflammation, ecchondrosis and exostosis arising from the cartilaginous tracheal rings and metaplasia of submucosal elastic and connective tissue. The etiology of TBPOCP remains unknown. Numerous cases of TBPOCP have been reported in association with different diseases including allergic rhinitis. Although Klebsiella ozaenea is frequently isolated in the latter coexistence, no association between these two conditions has been confirmed (1, 5–7). In a recent case report, a TBPOCP was found in association with immunoglobulin A deficiency as well (8). Prakash et al. (9) reported a familial occurrence of TBPOCP. Tajima et al. (10) suggested a possible role of a bone morphogenetic protein 2 in formation of new bone and cartilage and synergistic action with transforming growth factor beta-1. However, further studies are needed to explore this relationship.
Pathogenesis In TBPOCP, abnormalities and metaplasia in elastic tissue undergo ossification and nodular excrescences, which represent exostoses and ecchondroses from the cartiliginous trachea (11). These nodules are located along the airway cartilage sparing the posterior membranous wall of the trachea. The mucosa over the cartiliginous nodule may be thinned or could be
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The condition presents itself between the fourth and the seventh decades of life without any gender predominance (1, 6, 13). However, reports of TBPOCP in 12-, 9- and 5-year-old patients are also present in the literature (13–15). Most patients with TBPOCP are asymptomatic. No pathognomonic symptom for TBPOCP exists (16). Symptoms usually correlate with the site and degree of airway obstruction. Cough, sputum production, dyspnea, recurrent respiratory tract infections and hemoptysis due to an acute infection, bronchiectasis or ulceration of a nodule are common. In a case series with 15 patients, the most common symptoms were cough (66%), hemoptysis (60%), dyspnea on exertion (53%) and wheeze (30%) while 13% of the patients were asymptomatic (17). In a case series by Jabbardarjani et al. involving 10 of patients chronic dyspnea on exertion was found as the most frequent presentation (n = 9) while other symptoms included chronic cough (n = 7), sputum production (n = 4), hemoptysis (n = 2), chest pain (n = 2), and constitutional symptoms of fever and chills (n = 2) (18). Physical examination may be unremarkable. Stridor and ronchi may be present if severe airway obstruction exits (6).
Diagnosis Chest X-ray is not useful for detecting the nodules and usually normal in TBPOCP patients as demonstrated in the report by Jabbardarjani et al. (18). Computed tomography (CT) of the chest reveals the protrusion of calcified cartiliginous nodules through the lumen of trachea (Fig. 1). Multiple sessile submucosal nodules with or without calcifications with sparing membranous posterior wall and deformed tracheal cartilage rings without external compression or submucosal calcification are the pathognomonic CT findings of TBPOCP (18, 19). However, such findings are not universally present. Nienhuis et al. (17) reported that only four of 15 patients with TBPOCP had characteristic lesions on the CT. The variable size of the lesions and variable degree of calcification can cause difficulty in determining the TBPOCP lesions on the CT scan. Locations of the lesions and degree of airway obstruction effect the pulmonary function tests. A 387 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
Figure 1. Thorax computed tomography: calcified cartiliginous nodules on anterior and laterall walls of trachea (from the archive of Dr. Elif Kupeli).
normal spirometry can be present in mild cases while obstructive pattern or fixed upper airway obstruction may be observed in symptomatic patients with extensive disease (20). If the tracheal involvement is prominent, flow volume loops can be helpful in suspecting the condition and for the follow up. The bronchscopic view of bony or cartilaginous nodules on tracheal walls is diagnostic of TBPOCP (Fig. 2) (6). Multiple isolated or converging nodules measured between 1 and 10 mm protruding into the airway lumen are seen at bronchoscopy. These lesions are more commonly found in the distal 2/3 of trachea.
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
Figure 3. Submucosal bone formation as a histopathologic finding of tracheobronchopathia osteochondroplastica (TBPOCP) (from the archive of Dr. Elif Kupeli).
Proximal trachea, subglottic region and larynx involvement have also been demonstrated (17, 21–23). When larynx and upper airway are affected, laryngoscopy may be sufficient to establish the diagnosis. However, bronchoscopy confirms the diagnosis and provides information on the extent of disease. It is considered as a gold standard for the diagnosis of TBPOCP. Need for histopathologic examination of TBPOCP diagnosis is controversial. Some authors believe that histopathologic confirmation is not needed for the diagnosis because of the benign nature and typical bronchoscopic appearance of TBPOCP (6). However, others believe that histopathologic examination is needed to confirm the diagnosis, to evaluate for associated conditions and especially in symptomatic cases where endobronchial interventions are required (18, 24). Limited experience of the bronchoscopists for this rare disorder also leads to invasive diagnostic procedures (5). Epithelial squamous metaplasia, submucosal cartilage (continuous with or distinctive from the large airway cartilage rings), submucosal ossification (bone formation), calcification and hematopoietic bone marrow within the ossified areas are the histopathologic findings of TBPOCP (Fig. 3) (19, 25).
Differential diagnosis
Figure 2. The fiberoptic bronchscopic view of cartilaginous nodules on tracheal walls and carina (from the archive of Dr. Elif Kupeli).
388 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Tracheobronchial amyloidosis present as multifocal submucosal amyloid plaques obstructing the lumen of trachea. Posterior membranous wall is usually involved in amyloidosis in contrast to TBPOCP. Histopathologic examination with Congo red staining The Clinical Respiratory Journal (2015) • ISSN 1752-6981 3 C 2014 John Wiley & Sons Ltd V
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
of amyloid tissue is also helpful in the differential diagnosis (26). Interestingly, an unusual coexistence of amyloidosis and TBPOCP has been reported in the literature (27). Leske et al. (19) reported that in 16 biopsy specimens that were specifically examined for amyloidosis, only two (13%) were compatible with both TBPOCP and amyloidosis. Thus, if amyloidosis is suspected, pathologic examination should be performed to determine its coexistence with other airway conditions or sole presence. TBPOCP and lung cancer association has been reported in the literature. Karlikaya et al. (28) reported a coexistence of TBPOCP with pulmonary nonHodgkin lymphoma and trichylemmal cyst. However Leske et al. (19) have found no evidence of the development of malignancy occurred during follow up in their patients. Association with malignancy has been probably coincidental (5, 28). Endobronchial sarcoidosis can also present with nodular lesions of the trachea. Posterior wall involvement of trachea increases the suspicion for polychondritis, sarcoidosis, amyloidosis and papillomatosis (29, 30). Diffuse calcification of trachea can also be seen in elderly patients or patients with tuberculosis, chondrosarcoma, Wegener’s granulomatosis and fibroma (5, 31).All of these conditions should be kept in mind while making the diagnosis of TBPOCP. Asthma is the most common misdiagnosis of TBPOCP (4, 6).
Table 1. Distribution of scientific publications about tracheobronchopathia osteochondroplastica (TBPOCP) from all countries in the world (top 10 countries)
Treatment
The distribution of 72 scientific publications according to countries is outlined in Table 1. Only five records were from Turkey. When we reviewed these publications, we determined that the total number of cases from our country was eight (27, 28, 35–37). Distribution of these papers according to research areas is demonstrated in Table 2. Multiple diciplinary
There is no specific treatment for TBPOCP. Recurrent infections and atelectasis are seen as complications during the disease course and are treated in conventional fashion. Intubations, if required, may be difficult because of the calcified rings of trachea (32, 33). Occasionally, tracheostomy is required. Surgical treatment options should be considered when conservative measures have been failed (5, 6). Resection of the affected tracheal segment, anterior laryngo fissure, partial laryngectomy, removal of lesion with bronchoscopy and rigid bronchoscopic dilatation are the reported surgical options as it is difficult to remove bony lesions with a rigid bronchoscope. In a recent case series, all symptomatic patients (n = 10) underwent removal of endobronchial calcified nodules with the use of a neodymium-doped yttrium aluminium garnet (Nd : YAG) laser (18). Five patients with confluent disease underwent coring of the lesions using the tip of the rigid bronchoscope in addition to laser photoresection. In one patient, 6 years of palliative treatment with laser ablation and coring through the rigid bronchoscope
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Countries
Publication count (n = 72) (%)
United States England Japan France Germany Turkey India Italy Belgium Brazil
18 (25) 6 (8.3) 6 (8.3) 5 (6.9) 5 (6.9) 5 (6.9) 3 (4.1) 3 (4.1) 2 (2.7) 2 (2.7)
resulted in significant tracheal narrowing, and a stent placement was eventually required (18). Prognosis is favorable but usually depends upon the extension and location of the nodular lesions. Leske et al. reported that over 55% of the patients do not show any disease progression following the diagnosis (19). In a recent case report, Branden (34) presented a 20 year follow up of a stable female patient with TBPOCP.
Scientific publications regarding TBPOCP: review of literature
Table 2. Distribution of scientific publications according to research areas Research areas
n (%)
Respiratory system General internal medicine Radiology and nuclear medicine and medical imaging Cardiovascular system and cardiology Surgery Otorhinolaryngology Anesthesiology Pathology Pediatrics Veterinary sciences
31 (43.05) 19 (26.3) 12 (16.6) 8 (11.1) 7 (9.7) 5 (6.9) 4 (5.5) 3 (4.1) 3 (4.1) 2 (2.7)
389 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
Figure 4. Distribution of publications according to years.
research areas other than respiratory system were pointed out as general internal medicine, radiology and nuclear medicine and medical imaging, surgery, pathology, etc., reflecting multidisciplinary interest and approach to this disease. Distribution of publications according to years is demonstrated in Fig. 4. After 2000, number of publications was increased. In years 2001 and 2010, number of publications was the highest (Fig. 4). The number of publications about this orphan disease will probably increase in the future as a result of improved complex diagnostic radiographic techniques, performed bronchoscopies for different medical problems and increased number of experienced bronchoscopists and radiologists in TBPOCP. The types of articles being published are depicted in Table 3. It is interesting to see the presence of only three review articles about TBPOCP. In order to highlight diagnosis, treatment and treatment outcomes of TBPOCP, further review articles and large case series about this orphan disease are needed. We believe that this analysis and contribution of physicians to the literature are essential in developing and improving future of our patients with TBPOCP.
Table 3. Article types of publications about tracheobronchopathia osteochondroplastica (TBPOCP) Document types
n (%)
Article Editorial material Review Letter
52 (72.2) 12 (16.6) 3 (4.1) 2 (2.7)
390 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
References 1. Lazor R, Cordier JF. Tracheobronchopathia osteochondroplastica. Orphanet Encyclopedia. 2004; 1–4. Available at: http://www.orpha.net/data/patho/ GB/UK-TO.pdf (accessed June 2004). 2. Wilks S. Ossific deposits on larynx, trachea, and bronchi. Rans Pathol Soc London. 1857;8: 88. 3. Jindal S, Nath A, Neyaz Z, Jaiswal S. Tracheobronchopathia osteochondroplastica – a rare or an overlooked entity? J Radiol Case Rep. 2013;7(3): 16–25. 4. Hayes DJ. Tracheopathia osteochondroplastica misdiagnosed as asthma. J Asthma. 2007;44: 253–5. 5. Abu-Hijleh M, Lee D, Braman SS. Tracheobronchopathia osteochondroplastica: a rare large airway disorder. Lung. 2008;186: 353–9. 6. Prakash UB. Tracheobronchopathia osteochondroplastica. Semin Respir Crit Care Med. 2002;23(2): 167–75. 7. Ferguson JL, McCaffrey TV, Kern EB, Martin WJ 2nd. Effect of Klebsiella ozaenae on ciliary activity in vitro: implications in the pathogenesis of atrophic rhinitis. Otolaryngol Head Neck Surg. 1990;102(3): 207–11. 8. Dincer HE, Dunitz JM. Tracheobronchopathia osteochondroplastica and selective IgA deficiency. J Bronchology Interv Pulmonol. 2012;19(1): 54–6. doi: 10.1097/LBR.0b013e3182446949. 9. Prakash U, McCullough A, Edell E, Nienhuis D. Tracheobronchopathia osteoplastica. Familial occurance. Mayo Clin Proc. 1989;64: 1091–6. 10. Tajima K, Yamakawa M, Katagiri T, Sasaki H. Immunohistochemical detection of bone morphogenetic protein-2 and transforming growth factor beta-1 in tracheopathia osteochondroplastica. Virchows Archiv. 1997;431: 359–63. 11. Way S. Tracheopathia osteoplastica. J Clin Pathol. 1967;20: 814–20. 12. Mariotta S, Paalone G, Pedicelli G, Bisetti A. Spiral CT and endoscopic findings in a case of tracheopathia
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25. Pounder DJ, Pieterse AS. Tracheopathia osteoplastica: a study of the minimal lesion. J Pathol. 1982;138: 235–9. 26. Toyoda M, Ebihara Y, Kato H, Kita S. Tracheobronchial AL amyloidosis: histologic, immunohistochemical, ultrastructural, and immunoelectron microscopic observations. Hum Pathol. 1993;24(9): 970–6. 27. Kirbas¸ G, Dag˘li CE, Tanrikulu AC, Yildiz F, Bükte Y, Senyig˘it A, Kiyan E. Unusual combination of tracheobronchopathia osteochondroplastica and AA amyloidosis. Yonsei Med J. 2009;50(5): 721–4. 28. Karlikaya C, Yüksel M, Kiliçli S, Candan L. Tracheobronchopathia osteochondroplastica. Respirology. 2000;5(4): 377–80. 29. White BD, Kong A, Khoo E, Southcott AM. Computed tomography diagnosis of tracheobronchopathia osteochondroplastica. Australas Radiol. 2005;49: 319–21. 30. Marom EM, Goodman PC, McAdams HP. Diffuse abnormalities of the trachea and main bronchi. AJR Am J Roentgenol. 2001;176: 713–17. 31. Lloyd DC, Taylor PM. Calcification of the intrathoracic trachea demonstrated by computed tomography. Br J Radiol. 1990;63: 31–2. 32. Smith DC, Pillai R, Gillbe CE. Tracheopathia osteochondroplastica: a cause of unexpected difficulty in tracheal intubation. Anaesthesia. 1987;42: 536–8. 33. Gurunathan U. Tracheobronchopathia osteochondroplastica: a rare cause of difficult intubation. Br J Anaesth. 2010;104(6): 787–8. doi: 10.1093/bja/aeq107. 34. Brandén E. A 20-year follow-up of a case with tracheobronchopathia osteochondroplastica. J Bronchology Interv Pulmonol. 2013;20(1): 84–6. doi: 10.1097/LBR.0b013e31827d13bc. 35. Simsek PO, Ozcelik U, Demirkazik F, Unal OF, Orhan D, Aslan AT, Dogru D. Tracheolbronchopathia osteochondroplastica in a 9-year-old girl. Ped Pulmon. 2006;41: 95–7. 36. Tatar D, Senol G, Demir A, Polat G. Tracheobronchopathia osteochondroplastica: four cases. Chinese Med J. 2012;125: 2942–4. 37. Oztuna F, Yilmaz I, Gulsoy A, Ozsu S, Bulbul Y, Ozlu T. Tracheobronchopathia osteoplastica with Behçet’s disease: case report. Turkiye Klin Tip Bilimleri Dergisi. 2012;32: 1109–13.
391 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
The Clinical Respiratory Journal Journal
Tracheobronchopathia osteochondroplastica: a review of the literature Sevinc Sarinc Ulasli1 and Elif Kupeli2 1 Department of Pulmonary Diseases, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey 2 Department of Pulmonary Diseases, Faculty of Medicine, Baskent University, Ankara, Turkey
Abstract Background: Tracheobronchopathia osteochondroplastica (TBPOCP) is an uncommon benign condition affecting the lumen of tracheobronchial tree and characterized by abnormal chondrification and ossification. TBPOCP is more frequent than it has been reported, as it can be asymptomatic or present with non-specific respiratory symptoms. Aims: In this article, we provide a review of the English literature on the condition and discuss its clinical features, general principles, diagnostic approaches and current treatment recommendations for TBPOCP. Methods: We searched for all papers indexed in Science Citation Index and Science Citation Index – Expanded by using Thomson Reuters Web of Knowledge Web of Science software. Results: We reviewed a total of 72 scientific publications. Conclusion: In order to highlight, diagnosis, treatment and treatment outcomes of TBPOCP, further review articles and large case series about this orphan disease are needed.
Please and Kupeli Kupeli E. E. Tracheobronchopathia Tracheobronchopathia Please cite cite this this paper paper as: as: Ulasli Ulasli SS SS and osteochondroplastica: a review of the literature. Clin Respir J 2015; 9: 386–391. osteochondroplastica: a review of the literature. Clin Respir J 2014; ••: ••–••. DOI:10.1111/crj.12166. DOI:10.1111/crj.12166.
Key words rare lung diseases – review – scientific publications – tracheobronchopathia osteochondroplastica Correspondence Sevinc Sarinc Ulasli, MD, Department of Pulmonary Diseases, Faculty of Medicine, Afyon Kocatepe University, I˙zmir Karayolu 7. Km 03200 Afyon, Turkey. Tel: +90 5053073658 Fax: +90 2722463322 email: [email protected] Received: 03 January 2014 Revision requested: 06 May 2014 Accepted: 16 May 2014 DOI:10.1111/crj.12166 Authorship and contributorship S. S. U. designed the review, collected and analyzed data, and prepared the manuscript. E. K. helped in analysis of data and prepared the manuscript. All authors read and approved the final manuscript. Ethics None. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Introduction Tracheobronchopathia osteochondroplastica (TBPOCP) is an uncommon benign condition affecting the lumen of the tracheobronchial tree and characterized by abnormal chondrification and ossification of cartilages, sparing the posterior wall (1). TBPOCP is also referred by its synonyms tracheopathia chondroosteoplastica and tracheopathia osteoplastica.
386 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
TBPOCP was first described in 1857 as ossific deposits in the larynx, trachea and bronchi by Wilks and colleagues (2). Accumulation of calcium phosphate in the submucosa of the large airways, and benign proliferation of bone and cartilage lead to the narrowing of the airways (1). TBPOCP is more frequent than it has been reported, as it can be asymptomatic or present with non-specific respiratory symptoms (3). The common presenting symptoms of TBPOCP are chronic cough and wheezing, which often lead to the
The Clinical Respiratory Journal (2015) • ISSN 1752-6981 1 C 2014 John Wiley & Sons Ltd V
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
misdiagnosis of asthma (4). The aim of this review is to discuss clinical features, diagnostic approaches and current treatment recommendations for the patients with TBPOCP based on the literature.
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
edematous with metaplastic epithelium, suggesting chronic inflammation (12).
Clinical features Review of the literature We searched for all papers indexed in Science Citation Index and Science Citation Index-Expanded by using Thomson Reuters Web of Knowledge Web of Science software (Thomson Reuters Corporation, New York, NY, USA). ‘Tracheobronchopathia osteochondroplastica’ as the key word was entered for the topic section (September 30, 2013). Abstracts of each publication were reviewed. According to the review by AbuHijleh et al. (5), less than 400 reported cases were found in the literature by 2008. We found additional 19 cases in the literature since 2008. We reviewed a total of 72 scientific publications. The following details have been gathered from our literature review.
Etiology The theories regarding the formation of these nodules include chronic airway inflammation, ecchondrosis and exostosis arising from the cartilaginous tracheal rings and metaplasia of submucosal elastic and connective tissue. The etiology of TBPOCP remains unknown. Numerous cases of TBPOCP have been reported in association with different diseases including allergic rhinitis. Although Klebsiella ozaenea is frequently isolated in the latter coexistence, no association between these two conditions has been confirmed (1, 5–7). In a recent case report, a TBPOCP was found in association with immunoglobulin A deficiency as well (8). Prakash et al. (9) reported a familial occurrence of TBPOCP. Tajima et al. (10) suggested a possible role of a bone morphogenetic protein 2 in formation of new bone and cartilage and synergistic action with transforming growth factor beta-1. However, further studies are needed to explore this relationship.
Pathogenesis In TBPOCP, abnormalities and metaplasia in elastic tissue undergo ossification and nodular excrescences, which represent exostoses and ecchondroses from the cartiliginous trachea (11). These nodules are located along the airway cartilage sparing the posterior membranous wall of the trachea. The mucosa over the cartiliginous nodule may be thinned or could be
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The condition presents itself between the fourth and the seventh decades of life without any gender predominance (1, 6, 13). However, reports of TBPOCP in 12-, 9- and 5-year-old patients are also present in the literature (13–15). Most patients with TBPOCP are asymptomatic. No pathognomonic symptom for TBPOCP exists (16). Symptoms usually correlate with the site and degree of airway obstruction. Cough, sputum production, dyspnea, recurrent respiratory tract infections and hemoptysis due to an acute infection, bronchiectasis or ulceration of a nodule are common. In a case series with 15 patients, the most common symptoms were cough (66%), hemoptysis (60%), dyspnea on exertion (53%) and wheeze (30%) while 13% of the patients were asymptomatic (17). In a case series by Jabbardarjani et al. involving 10 of patients chronic dyspnea on exertion was found as the most frequent presentation (n = 9) while other symptoms included chronic cough (n = 7), sputum production (n = 4), hemoptysis (n = 2), chest pain (n = 2), and constitutional symptoms of fever and chills (n = 2) (18). Physical examination may be unremarkable. Stridor and ronchi may be present if severe airway obstruction exits (6).
Diagnosis Chest X-ray is not useful for detecting the nodules and usually normal in TBPOCP patients as demonstrated in the report by Jabbardarjani et al. (18). Computed tomography (CT) of the chest reveals the protrusion of calcified cartiliginous nodules through the lumen of trachea (Fig. 1). Multiple sessile submucosal nodules with or without calcifications with sparing membranous posterior wall and deformed tracheal cartilage rings without external compression or submucosal calcification are the pathognomonic CT findings of TBPOCP (18, 19). However, such findings are not universally present. Nienhuis et al. (17) reported that only four of 15 patients with TBPOCP had characteristic lesions on the CT. The variable size of the lesions and variable degree of calcification can cause difficulty in determining the TBPOCP lesions on the CT scan. Locations of the lesions and degree of airway obstruction effect the pulmonary function tests. A 387 The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Tracheobronchopathia osteochondroplastica Ulasli and Kupeli
Figure 1. Thorax computed tomography: calcified cartiliginous nodules on anterior and laterall walls of trachea (from the archive of Dr. Elif Kupeli).
normal spirometry can be present in mild cases while obstructive pattern or fixed upper airway obstruction may be observed in symptomatic patients with extensive disease (20). If the tracheal involvement is prominent, flow volume loops can be helpful in suspecting the condition and for the follow up. The bronchscopic view of bony or cartilaginous nodules on tracheal walls is diagnostic of TBPOCP (Fig. 2) (6). Multiple isolated or converging nodules measured between 1 and 10 mm protruding into the airway lumen are seen at bronchoscopy. These lesions are more commonly found in the distal 2/3 of trachea.
Ulasli and Kupeli Tracheobronchopathia osteochondroplastica
Figure 3. Submucosal bone formation as a histopathologic finding of tracheobronchopathia osteochondroplastica (TBPOCP) (from the archive of Dr. Elif Kupeli).
Proximal trachea, subglottic region and larynx involvement have also been demonstrated (17, 21–23). When larynx and upper airway are affected, laryngoscopy may be sufficient to establish the diagnosis. However, bronchoscopy confirms the diagnosis and provides information on the extent of disease. It is considered as a gold standard for the diagnosis of TBPOCP. Need for histopathologic examination of TBPOCP diagnosis is controversial. Some authors believe that histopathologic confirmation is not needed for the diagnosis because of the benign nature and typical bronchoscopic appearance of TBPOCP (6). However, others believe that histopathologic examination is needed to confirm the diagnosis, to evaluate for associated conditions and especially in symptomatic cases where endobronchial interventions are required (18, 24). Limited experience of the bronchoscopists for this rare disorder also leads to invasive diagnostic procedures (5). Epithelial squamous metaplasia, submucosal cartilage (continuous with or distinctive from the large airway cartilage rings), submucosal ossification (bone formation), calcification and hematopoietic bone marrow within the ossified areas are the histopathologic findings of TBPOCP (Fig. 3) (19, 25).
Differential diagnosis
Figure 2. The fiberoptic bronchscopic view of cartilaginous nodules on tracheal walls and carina (from the archive of Dr. Elif Kupeli).
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Tracheobronchial amyloidosis present as multifocal submucosal amyloid plaques obstructing the lumen of trachea. Posterior membranous wall is usually involved in amyloidosis in contrast to TBPOCP. Histopathologic examination with Congo red staining The Clinical Respiratory Journal (2015) • ISSN 1752-6981 3 C 2014 John Wiley & Sons Ltd V
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of amyloid tissue is also helpful in the differential diagnosis (26). Interestingly, an unusual coexistence of amyloidosis and TBPOCP has been reported in the literature (27). Leske et al. (19) reported that in 16 biopsy specimens that were specifically examined for amyloidosis, only two (13%) were compatible with both TBPOCP and amyloidosis. Thus, if amyloidosis is suspected, pathologic examination should be performed to determine its coexistence with other airway conditions or sole presence. TBPOCP and lung cancer association has been reported in the literature. Karlikaya et al. (28) reported a coexistence of TBPOCP with pulmonary nonHodgkin lymphoma and trichylemmal cyst. However Leske et al. (19) have found no evidence of the development of malignancy occurred during follow up in their patients. Association with malignancy has been probably coincidental (5, 28). Endobronchial sarcoidosis can also present with nodular lesions of the trachea. Posterior wall involvement of trachea increases the suspicion for polychondritis, sarcoidosis, amyloidosis and papillomatosis (29, 30). Diffuse calcification of trachea can also be seen in elderly patients or patients with tuberculosis, chondrosarcoma, Wegener’s granulomatosis and fibroma (5, 31).All of these conditions should be kept in mind while making the diagnosis of TBPOCP. Asthma is the most common misdiagnosis of TBPOCP (4, 6).
Table 1. Distribution of scientific publications about tracheobronchopathia osteochondroplastica (TBPOCP) from all countries in the world (top 10 countries)
Treatment
The distribution of 72 scientific publications according to countries is outlined in Table 1. Only five records were from Turkey. When we reviewed these publications, we determined that the total number of cases from our country was eight (27, 28, 35–37). Distribution of these papers according to research areas is demonstrated in Table 2. Multiple diciplinary
There is no specific treatment for TBPOCP. Recurrent infections and atelectasis are seen as complications during the disease course and are treated in conventional fashion. Intubations, if required, may be difficult because of the calcified rings of trachea (32, 33). Occasionally, tracheostomy is required. Surgical treatment options should be considered when conservative measures have been failed (5, 6). Resection of the affected tracheal segment, anterior laryngo fissure, partial laryngectomy, removal of lesion with bronchoscopy and rigid bronchoscopic dilatation are the reported surgical options as it is difficult to remove bony lesions with a rigid bronchoscope. In a recent case series, all symptomatic patients (n = 10) underwent removal of endobronchial calcified nodules with the use of a neodymium-doped yttrium aluminium garnet (Nd : YAG) laser (18). Five patients with confluent disease underwent coring of the lesions using the tip of the rigid bronchoscope in addition to laser photoresection. In one patient, 6 years of palliative treatment with laser ablation and coring through the rigid bronchoscope
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Countries
Publication count (n = 72) (%)
United States England Japan France Germany Turkey India Italy Belgium Brazil
18 (25) 6 (8.3) 6 (8.3) 5 (6.9) 5 (6.9) 5 (6.9) 3 (4.1) 3 (4.1) 2 (2.7) 2 (2.7)
resulted in significant tracheal narrowing, and a stent placement was eventually required (18). Prognosis is favorable but usually depends upon the extension and location of the nodular lesions. Leske et al. reported that over 55% of the patients do not show any disease progression following the diagnosis (19). In a recent case report, Branden (34) presented a 20 year follow up of a stable female patient with TBPOCP.
Scientific publications regarding TBPOCP: review of literature
Table 2. Distribution of scientific publications according to research areas Research areas
n (%)
Respiratory system General internal medicine Radiology and nuclear medicine and medical imaging Cardiovascular system and cardiology Surgery Otorhinolaryngology Anesthesiology Pathology Pediatrics Veterinary sciences
31 (43.05) 19 (26.3) 12 (16.6) 8 (11.1) 7 (9.7) 5 (6.9) 4 (5.5) 3 (4.1) 3 (4.1) 2 (2.7)
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Figure 4. Distribution of publications according to years.
research areas other than respiratory system were pointed out as general internal medicine, radiology and nuclear medicine and medical imaging, surgery, pathology, etc., reflecting multidisciplinary interest and approach to this disease. Distribution of publications according to years is demonstrated in Fig. 4. After 2000, number of publications was increased. In years 2001 and 2010, number of publications was the highest (Fig. 4). The number of publications about this orphan disease will probably increase in the future as a result of improved complex diagnostic radiographic techniques, performed bronchoscopies for different medical problems and increased number of experienced bronchoscopists and radiologists in TBPOCP. The types of articles being published are depicted in Table 3. It is interesting to see the presence of only three review articles about TBPOCP. In order to highlight diagnosis, treatment and treatment outcomes of TBPOCP, further review articles and large case series about this orphan disease are needed. We believe that this analysis and contribution of physicians to the literature are essential in developing and improving future of our patients with TBPOCP.
Table 3. Article types of publications about tracheobronchopathia osteochondroplastica (TBPOCP) Document types
n (%)
Article Editorial material Review Letter
52 (72.2) 12 (16.6) 3 (4.1) 2 (2.7)
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