REVIEW URRENT C OPINION
Malignant tracheal tumors: a review of current diagnostic and management strategies Khalid Sherani a, Abhay Vakil a,b, Chetan Dodhia c, and Alan Fein a,d
Purpose of review This article reviews the current literature for the purpose of developing a practical approach for the diagnosis and management of primary tracheal tumors. Recent findings Because of nonspecific symptoms, tracheal tumors remain a diagnostic challenge. Currently available management strategies are not being optimally utilized due to lack of physician awareness and knowledge. The use of newer diagnostic modalities has increased diagnostic accuracy resulting in earlier detection in recent years. This review describes currently available diagnostic modalities along with relatively newer ones such as virtual bronchoscopy, anatomic Optical Coherence Tomography, spectroscopic techniques, and endobronchial ultrasonography. We will review and discuss management strategies including surgical options, adjuvant therapies, and interventional pulmonary techniques including their role in palliation. Summary Early detection along with improved surgical and interventional pulmonology techniques has led to a decline in the death rates from tracheal cancer in recent years. However, further studies are required to define the role of chemotherapeutic agents, combination therapies, and novel techniques such as tracheal transplantation, in the management of primary tracheal tumors. More robust evidence-based studies are needed to provide evidence for clinical practice guidelines for the treatment of primary tracheal tumors. Keywords endobronchial ultrasonography, interventional pulmonology, malignant tumors of the trachea, primary tracheal tumors, surgery
INTRODUCTION Primary tracheal tumors are rare, accounting for less than one-half to one percent of all malignant tumors with an annual incidence of 0.1/100 000 [1 ,2 ]. Despite a majority of tracheal tumors being malignant, they represent a small fraction of all lung cancer deaths [3 ]. Squamous cell carcinoma (SCC) is the most common type, accounting for 50–66% of all tracheal tumor cases followed by adenoid cystic carcinoma (ACC) representing 10–15% of cases [4]. Failure to establish early diagnosis and consequent delayed therapy may reduce survival of these patients [5]. Symptoms sometimes are mistaken for those of asthma [6], chronic obstructive pulmonary disease (COPD), or pneumonia, therefore, timely diagnosis remains a major clinical challenge. Approximately, 10% of patients had a diagnostic delay of greater than 6 months from the time they initially presented [1 ] resulting in diagnosis at an advanced stage of disease sometimes beyond the scope of curative treatment [7]. &
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Increasing use of diagnostic modalities such as computed tomographic (CT) and bronchoscopic techniques has led to an earlier diagnosis in the recent years. This along with the use of better surgical and interventional pulmonology techniques has led to a decline in the tracheal cancer deaths [3 ,8]. &&
a
Division of Pulmonary Medicine, Department of internal medicine, Jamaica Hospital Medical Center, New York, bDivision of Critical Care Medicine, Mayo Clinic Rochester, Minnesota, cDepartment of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, New York and dDivision of Pulmonary and Critical Care, Hofstra Northshore -LIJ School of Medicine, New York, USA Correspondence to Khalid Sherani, MD, Department of Pulmonary Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA. E-mail: [email protected] Curr Opin Pulm Med 2015, 21:322–326 DOI:10.1097/MCP.0000000000000181 Volume 21 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Malignant tracheal tumors Sherani et al.
ADVANCES IN DIAGNOSTIC MODALITIES
KEY POINTS Mortality from primary tracheal tumors has declined in recent years. Use of newer diagnostic modalities and improved bronchoscopic techniques has led to earlier detection and more accurate staging. Complete surgical resection supplemented by postoperative adjuvant therapy (in appropriate surgical candidates) is the treatment of choice. Interventional pulmonology techniques have provided a new dimension to the treatment and palliation of patients who are not appropriate surgical candidates.
CLINICAL MANIFESTATIONS AND PRESENTATION Delayed diagnosis of tracheal tumors may be ascribed to shared symptomatology with benign conditions such as asthma, COPD, and pneumonia. Clinical manifestations arising from tracheal tumors may be due to upper airway obstruction (depending on the location and size of the tumor) as well as from involvement of surrounding structures (Table 1). Distant metastasis is less commonly encountered and develops in less than 10% of patients [9]. Symptoms rarely develop until the tumor grows large enough to obstruct at least 50% of the tracheal diameter [10 ]. Relative reductions in airway diameter may be more important than absolute reductions in determining onset of symptoms. Tracheal diameters less than 8 mm will produce exertional dyspnea, whereas dyspnea at rest occurs when the airway falls below 5 mm [11]. Signs and symptoms may also vary according to the histopathological type and size of the tumor (Table 2) [5,9,12]. &
Table 1. Clinical manifestation of tracheal tumors Mechanism for cause of symptoms
Clinical manifestations
Upper-airway obstruction
Wheezing Dyspnea (exertional or positional) Stridor
Mucosal irritation and ulceration
Cough Hemoptysis
Direct invasion of surrounding structures
Dysphagia Hoarseness of voice
Imaging studies Chest radiography was found to identify 18–28% of tracheal tumors [13]. Chest radiographs may prove useful to exclude confounding pathologies. CT of the chest is used not only to assess size and extent of the tracheal tumor, but also provides useful information on the extent of local and metastases and precise volumetric analysis [14]. However, conventional CT techniques may underestimate tracheal wall involvement. Shadmehr et al. [5] described a prospective study in which 9% of the tumors estimated by CT imaging to be resectable were ultimately determined to be unresectable at surgical exploration. Recent advances in CT imaging techniques have allowed three-dimensional reconstructions and virtual bronchoscopic imaging to identify intraluminal and extraluminal components, pedunculated and broad-based lesions and the extent of the lesion over multiple cartilaginous rings [15]. Three-dimensional reconstruction techniques provide a useful alternative to bronchoscopy as a screening tool for aftertreatment recurrence [14]. Han et al. [16] has described the use of anatomic Optical Coherence Tomography to determine the interventional/surgical techniques that can be used for the treatment of tracheal tumors [17]. The use of new aerosolized contrast agent allows differentiation between benign and malignant mucosal lesions [18 ]. MRI has limited utility for the evaluation of tracheal tumors but can be used in some instances to better evaluate extension into tissue planes and vascular structures. PET also has limited utility in evaluation of tracheal tumors. However, PET may be helpful in the detection of distant metastases, and offers the advantage of obviating unnecessary surgical treatment. Park et al. [19] have described that SCC usually has a high fludeoxyglucose (FDG) uptake, compared with ACC wherein variable FDG uptake on PET imaging. &
Bronchoscopic techniques Tracheobronchoscopy facilitates direct visualization of the airway, gives anatomical considerations, and allows for tissue diagnosis. Rigid bronchoscopy, by securing the airway, is preferred when there is a near complete airway obstruction: flexible bronchoscopy may exacerbate obstruction by inducing bleeding, cough, and edema. The use of spectroscopic technique during bronchoscopy allows for differentiating between benign and malignant mucosal lesions [17]. Endobronchial ultrasonography (EBUS), improves sensitivity of bronchoscopy in the evaluation of the extent of airway wall involvement with
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Neoplasms of the lung Table 2. Unique features of different histopathological variants of tracheal tumors Histopathological type
Unique features
Squamous cell carcinoma
Usually presents with symptoms of mucosal irritation and ulceration (bleeding) Diagnosed earlier (4–6 months within symptom onset) as compared with other histologic variants [12] Dysphagia and hoarseness are markers of locally advanced disease but do not preclude respectability
Adenoid cystic carcinoma
Commonly presents with symptoms of upper airway obstruction Average time for establishing diagnosis from symptom onset is 18 months [5,9] Less than 25% patients present with hemoptysis early in the course [12] Most patients will be diagnosed with advanced disease
Benign or low-grade malignant tumors
Slowly growing Can remain asymptomatic for months or years before diagnosis
malignancy (95%) [20]. Para tracheal tumors invading the tracheal wall can be easily identified using EBUS [21], thereby determining the potential of surgical intervention. When tracheal carcinomas extend to adjacent mediastinal structures including the esophagus, esophageal endoscopic ultrasound may be used to further characterize the extent of such spread.
ADVANCES IN MANAGEMENT Surgical techniques The best opportunity for achieving long-term cure is still complete surgical resection of the tumor supplemented by postoperative adjuvant therapy [22 ]. However, Honings et al. [13] reported epidemiological data indicated that significantly more patients could have received curative surgical therapy than were actually treated (about 2.3 times). The goal of surgical resection with a curative intent is to achieve complete resection without cancer cells seen microscopically at the margins [23,24]. Because of the indolent nature of ACC, incomplete resection margins are commonly seen [25]. Surgical resection has been shown to improve survival in the patients with ACC who have distant metastases. The role of other bronchoscopic modalities for the treatment of ACC is under study. In centers that have expertise with tracheal tumors, resection rates of up to 70% and perioperative mortality rates as low as 3% have been reported [26]. Five-year survival rate has been reported to be greater than 50% for patients undergoing surgery, whereas it is only 10% for the patients who are determined to be nonsurgical candidates [25]. For tumors extending greater than 50% of the tracheal length, surgical resection and tracheal reconstruction have been associated with high mortality [22 ]. Therefore, surgery is not recommended in these &&
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patients. Surgery is also contraindicated in patients with involvement of heart or aorta, distant metastases, involvement of multiple lymph nodes on PET scan, and in those with prior mediastinal surgeries or irradiation with a dose greater than 60 Gy.
Radiotherapy Radiotherapy is indicated as adjuvant therapy following surgical resection for almost all patients. Improved survival has been reported in SCC, even in cases with negative postsurgical resection margins [27]. ACCs are typically less radiosensitive as compared with SCC. However, adjuvant radiotherapy has been known to reduce recurrence rates in the patients with ACC [27]. Radiation therapy is the first-line treatment for nonsurgical candidates [28] and can also be used for palliation in advanced disease. Neoadjuvant radiotherapy prior to surgery in surgical candidates does not appear to improve survival. Intraluminal brachytherapy is an additive therapy following external-beam radiation therapy, which increases local tumor control [29].
Chemotherapy In the absence of prospective randomized control trials, the role of systemic chemotherapy as a primary treatment or as an adjunctive therapy remains unclear [30]. However, there have been recent case reports demonstrating successful outcomes with a combination of chemotherapy with radiation therapy in nonsurgical candidates. Combination therapy might be a suitable option for patients with unresectable tumors or who are not surgical candidates [30]. Some of the commonly used chemotherapeutic regimens include Carboplatin and Paclitaxel containing regimens, Cisplatin, 5-fluorouracil, and Etoposide containing regimens, Volume 21 Number 4 July 2015
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Malignant tracheal tumors Sherani et al. Table 3. Advantages and disadvantages of various pulmonary interventional techniques Interventional pulmonology techniques
Advantages and disadvantages
Laser therapy
Suitable for use in emergency cases for acute airway obstruction [33] Use with supplemental oxygen is dangerous Risk of hemorrhage or perforation of irradiated area
Argon plasma coagulation
More effective for broad-based lesion Can be safely used with supplemental oxygen Less risk for localized hemorrhage or perforation [33] Choice of treating hemoptysis from visible lesions on bronchoscopy Can be used for superficial tissues only Difficult to apply to acute angles, such as lesions at bifurcations
High frequency snares
Does not denature or lyse the tissue, thereby; preserving it for histological diagnosis Little risk for hemorrhage or perforation
Dehydrated ethanol injection
Excellent hemostatic effect Does not need expensive specialized equipment for delivery [33] Induces cough, that may be intense Injection is difficult with friable tissue
Airway stents
Maintain airway patency Protect against collapse from edema [33,34] Can be performed to compress endotracheal lesions, thereby avoiding debulking [34] May allow for stabilization while a reconstructive effort heals
and Cisplatin and Vinorelbine containing regimens. However, the use and timing of various regimens remains under study. [31]. There is a lack of sufficient data to recommend general use of combined high-precision radiotherapy techniques such as image-guided radiation therapy, intensity-modulated radiation therapy, or volumetric intensity-modulated arc therapy combined with platinum-based chemotherapy for the treatment of locally advanced tracheal tumors. These techniques might offer better disease control and constitute opportunities for potential research.
Interventional pulmonology techniques It has been shown that interventional techniques, when combined with adjuvant therapy, provide definitive treatment in selected cases. Additionally, these techniques serve as emergency therapy in patients presenting with complete or significant central airway obstruction prior to definitive treatment [32]. However, studies have recommended against stent placement in patients who are surgical candidates. Interventional techniques have a greater role in palliation for patients in which surgery is not possible. When combined with radiation therapy, patients undergoing interventional techniques for palliation have a median survival of less than 12 months [1 ]. &
Available interventional options include the use of laser therapy, cryotherapy, electrocautery, photodynamic therapy, brachytherapy, and argon plasma coagulation, with or without stents. These techniques allow for intraluminal debulking of the tumor. Each technique has its unique advantages and disadvantages (Table 3) [33,34].
Alternative strategies Alternative strategies such as tracheal transplantation or those that aim at replacing the trachea with other viable or nonviable substitutes such as foreign materials, tissue engineering, and autogenous tissues have not yet developed sufficiently to enter routine clinical practice. Despite advances in surgical techniques, attempts at tracheal transplantation in such patients have been limited [35].
CONCLUSION Due to their rarity, slow growth and nonspecific symptoms primary malignant tracheal tumors pose a diagnostic challenge. Lack of physician knowledge and awareness has led to significant delay as well as suboptimal use of appropriate therapy. The use of diagnostic modalities like EBUS and virtual bronchoscopy has significantly increased diagnostic accuracy. Newer surgical and interventional pulmonology techniques offer additional options for cure
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Neoplasms of the lung
and palliation. Further studies are needed to establish a definitive role of adjuvant therapies and to develop guidelines for the management of primary tracheal tumors. Acknowledgements We would like to thank Dr Shah for his assistance with the review. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nouraei SM, Middleton SE, Nouraei SA, et al. Management and prognosis of & primary tracheal cancer: a national analysis. Laryngoscope 2014; 124:145– 150. This article highlights the outcomes of various management modalities used for the treatment of tracheal tumors in Europe. 2. Junker K. Pathology of tracheal tumors. Thorac Surg Clin 2014; 24:7–11. &&
This article describes all the histopathological variants of the tracheal tumors with their staging and prognosis. 3. Thompson AD, Talavari Y, Mehari A, Gillum R. Tracheal cancer mortality && trends in the United States. Internet J Oncol 2014; 10:1–2. This is the first report describing national mortality patterns and trends for tracheal tumors in the United States from 1979 to 2010. 4. Urdaneta AI, Yu JB, Wilson LD. Population based cancer registry analysis of primary tracheal carcinoma. Am J Clin Oncol 2011; 34:32–37. 5. Shadmehr MB, Farzanegan R, Graili P, et al. Primary major airway tumors; management and results. Eur J Cardiothorac Surg 2011; 39:749–754. 6. Wang HL, Xu L, Li FJ. Subglottic adenoid cystic carcinoma mistaken for asthma. J Zhejiang Univ Sci B 2009; 10:707–710. 7. Bhattacharyya N. Contemporary staging and prognosis for primary tracheal malignancies: a population-based analysis. Otolaryngol Head Neck Surg 2004; 131:639–642. 8. Yasumatsu R, Fukushima J, Nakashima T, et al. Surgical management of malignant tumors of the trachea: report of two cases and review of the literature. Case Rep Oncol 2012; 5:302–307. 9. Macchiarini P. Primary tracheal tumors. Lancet Oncol 2006; 7:83–91. 10. Brand-Saberi B, Scha¨fer T. Trachea. Thorac Surg Clin 2014; 24:1–5. &
This article describes the anatomy and physiology of normal adult trachea and helps us to understand the physiological basis of symptoms caused by tracheal tumors.
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11. Hollingsworth HM. Wheezing and stridor. Clin Chest Med 1987; 8:231– 240. 12. Gaissert HA. Primary tracheal tumors. Chest Surg Clin N Am 2003; 13:247– 256. 13. Honings J, Gaissert H, Verhagen A, et al. Undertreatment of tracheal carcinoma: multidisciplinary audit of epidemiologic data. Ann Surg Oncol 2009; 16:246–253. 14. Javidan-Nejad C. MDCT of trachea and main bronchi. Radiol Clin North Am 2010; 48:157–176. 15. Seemann M, Schaefer JM, Englmeier KH. Virtual positron emission tomography/computed tomography-bronchoscopy: possibilities, advantages and limitations of clinical application. Eur Radiol 2007; 17:709–715. 16. Han S, El-Abbadi N, Hanna N, et al. Evaluation of tracheal imaging by optical coherence tomography. Respiration 2005; 72:537–541. 17. Williamson JP, Mclaughlin RA, Phillips MJ, et al. Using optical coherence tomography to improve diagnostic and therapeutic bronchoscopy. Chest 2009; 136:272–276. 18. Wu CC, Shepard JO. Tracheal and airway neoplasms. Semin Roentgenol & 2013; 48:354–364. This article reviews the role of different imaging modalities in the diagnosis and management of tracheal tumors. 19. Park CM, Goo JM, Lee HJ, et al. Tumors in the tracheobronchial tree: CT and FDG PET features. Radiographics 2009; 29:55–71. 20. Haas AR, Vachani A, Sterman DH. Advances in diagnostic bronchoscopy. Am J Respir Crit Care Med 2010; 182:589–597. 21. Tanaka F. Evaluation of tracheo-bronchial wall invasion using transbronchial ultrasonography (TBUS). Eur J Cardiothoracic Surg 2000; 17:570–574. 22. Behringer D, Ko¨nemann S, Hecker E. Treatment approaches to primary && tracheal cancer. Thorac Surg Clin 2014; 24:73–76. This article describes the role of different treatment approaches in the management of tracheal tumors. 23. Gaissert HA, Grillo HC, Shadmehr MB, et al. Uncommon primary tracheal tumors. Ann Thorac Surg 2006; 82:268–273. 24. Shadmehr MB, Farzanegan R, Graili P, et al. Primary major airway tumors; management and results. Eur J Cardiothorac Surg 2011; 39:749–754. 25. Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell carcinoma of the trachea and carina. Ann Thorac Surg 2004; 78:1889–1896. 26. Honings J, Gaissert H, Henricus F, et al. Clinical aspects and treatment of primary tracheal malignancies. Acta Oto-laryngologica 2010; 130:763–772. 27. Xie L, Fan M, Sheets NC, et al. The use of radiation therapy appears to improve outcome in patients with malignant primary tracheal tumors: A SEER-based analysis. Int J Radiat Oncol 2012; 84:464–470. 28. Webb BD, Walsh GL, Roberts DB, Sturgis EM. Primary tracheal malignant neoplasms: the university of texas md anderson cancer center experience. J Am Coll Surg 2006; 202:237–246. 29. Chang CY, Cheng SL, Chang SC. Adenoid cystic carcinoma of trachea treated with tumor curettage and adjuvant intensity modulated radiation therapy. South Med J 2011; 104:68–70. 30. Kunhiparambath H, Das P, Kumar R, et al. Unresectable basaloid squamous cell carcinoma of the trachea treated with concurrent chemoradiotherapy: a case report with review of literature. J Cancer Res Ther 2010; 6:321–322. 31. Allen AM, Rabin MS, Reilly JJ, Mentzer SJ. Unresectable adenoid cystic carcinoma of the trachea treated with chemoradiation. J Clin Oncol 2007; 25:5521–5523. 32. Wood DE. Management of malignant tracheobronchial obstruction. Surg Clin North Am 2002; 82:621–642. 33. Kajiwara N, Kakihana M, Usuda J, et al. Interventional management for benign airway tumors in relation to location, size, character and morphology. J Thorac Dis 2011; 3:221–230. 34. Makris D, Marquette CH. Tracheobronchial stenting and central airway replacement. Curr Opin Pulm Med 2007; 13:278–283. 35. Delaere PR. Tracheal transplantation. Curr Opin Pulm Med 2012; 18:313– 320.
Volume 21 Number 4 July 2015
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Malignant tracheal tumors: a review of current diagnostic and management strategies Khalid Sherani a, Abhay Vakil a,b, Chetan Dodhia c, and Alan Fein a,d
Purpose of review This article reviews the current literature for the purpose of developing a practical approach for the diagnosis and management of primary tracheal tumors. Recent findings Because of nonspecific symptoms, tracheal tumors remain a diagnostic challenge. Currently available management strategies are not being optimally utilized due to lack of physician awareness and knowledge. The use of newer diagnostic modalities has increased diagnostic accuracy resulting in earlier detection in recent years. This review describes currently available diagnostic modalities along with relatively newer ones such as virtual bronchoscopy, anatomic Optical Coherence Tomography, spectroscopic techniques, and endobronchial ultrasonography. We will review and discuss management strategies including surgical options, adjuvant therapies, and interventional pulmonary techniques including their role in palliation. Summary Early detection along with improved surgical and interventional pulmonology techniques has led to a decline in the death rates from tracheal cancer in recent years. However, further studies are required to define the role of chemotherapeutic agents, combination therapies, and novel techniques such as tracheal transplantation, in the management of primary tracheal tumors. More robust evidence-based studies are needed to provide evidence for clinical practice guidelines for the treatment of primary tracheal tumors. Keywords endobronchial ultrasonography, interventional pulmonology, malignant tumors of the trachea, primary tracheal tumors, surgery
INTRODUCTION Primary tracheal tumors are rare, accounting for less than one-half to one percent of all malignant tumors with an annual incidence of 0.1/100 000 [1 ,2 ]. Despite a majority of tracheal tumors being malignant, they represent a small fraction of all lung cancer deaths [3 ]. Squamous cell carcinoma (SCC) is the most common type, accounting for 50–66% of all tracheal tumor cases followed by adenoid cystic carcinoma (ACC) representing 10–15% of cases [4]. Failure to establish early diagnosis and consequent delayed therapy may reduce survival of these patients [5]. Symptoms sometimes are mistaken for those of asthma [6], chronic obstructive pulmonary disease (COPD), or pneumonia, therefore, timely diagnosis remains a major clinical challenge. Approximately, 10% of patients had a diagnostic delay of greater than 6 months from the time they initially presented [1 ] resulting in diagnosis at an advanced stage of disease sometimes beyond the scope of curative treatment [7]. &
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Increasing use of diagnostic modalities such as computed tomographic (CT) and bronchoscopic techniques has led to an earlier diagnosis in the recent years. This along with the use of better surgical and interventional pulmonology techniques has led to a decline in the tracheal cancer deaths [3 ,8]. &&
a
Division of Pulmonary Medicine, Department of internal medicine, Jamaica Hospital Medical Center, New York, bDivision of Critical Care Medicine, Mayo Clinic Rochester, Minnesota, cDepartment of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, New York and dDivision of Pulmonary and Critical Care, Hofstra Northshore -LIJ School of Medicine, New York, USA Correspondence to Khalid Sherani, MD, Department of Pulmonary Medicine, Jamaica Hospital Medical Center, 8900 Van Wyck Expressway, Jamaica, NY 11418, USA. E-mail: [email protected] Curr Opin Pulm Med 2015, 21:322–326 DOI:10.1097/MCP.0000000000000181 Volume 21 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Malignant tracheal tumors Sherani et al.
ADVANCES IN DIAGNOSTIC MODALITIES
KEY POINTS Mortality from primary tracheal tumors has declined in recent years. Use of newer diagnostic modalities and improved bronchoscopic techniques has led to earlier detection and more accurate staging. Complete surgical resection supplemented by postoperative adjuvant therapy (in appropriate surgical candidates) is the treatment of choice. Interventional pulmonology techniques have provided a new dimension to the treatment and palliation of patients who are not appropriate surgical candidates.
CLINICAL MANIFESTATIONS AND PRESENTATION Delayed diagnosis of tracheal tumors may be ascribed to shared symptomatology with benign conditions such as asthma, COPD, and pneumonia. Clinical manifestations arising from tracheal tumors may be due to upper airway obstruction (depending on the location and size of the tumor) as well as from involvement of surrounding structures (Table 1). Distant metastasis is less commonly encountered and develops in less than 10% of patients [9]. Symptoms rarely develop until the tumor grows large enough to obstruct at least 50% of the tracheal diameter [10 ]. Relative reductions in airway diameter may be more important than absolute reductions in determining onset of symptoms. Tracheal diameters less than 8 mm will produce exertional dyspnea, whereas dyspnea at rest occurs when the airway falls below 5 mm [11]. Signs and symptoms may also vary according to the histopathological type and size of the tumor (Table 2) [5,9,12]. &
Table 1. Clinical manifestation of tracheal tumors Mechanism for cause of symptoms
Clinical manifestations
Upper-airway obstruction
Wheezing Dyspnea (exertional or positional) Stridor
Mucosal irritation and ulceration
Cough Hemoptysis
Direct invasion of surrounding structures
Dysphagia Hoarseness of voice
Imaging studies Chest radiography was found to identify 18–28% of tracheal tumors [13]. Chest radiographs may prove useful to exclude confounding pathologies. CT of the chest is used not only to assess size and extent of the tracheal tumor, but also provides useful information on the extent of local and metastases and precise volumetric analysis [14]. However, conventional CT techniques may underestimate tracheal wall involvement. Shadmehr et al. [5] described a prospective study in which 9% of the tumors estimated by CT imaging to be resectable were ultimately determined to be unresectable at surgical exploration. Recent advances in CT imaging techniques have allowed three-dimensional reconstructions and virtual bronchoscopic imaging to identify intraluminal and extraluminal components, pedunculated and broad-based lesions and the extent of the lesion over multiple cartilaginous rings [15]. Three-dimensional reconstruction techniques provide a useful alternative to bronchoscopy as a screening tool for aftertreatment recurrence [14]. Han et al. [16] has described the use of anatomic Optical Coherence Tomography to determine the interventional/surgical techniques that can be used for the treatment of tracheal tumors [17]. The use of new aerosolized contrast agent allows differentiation between benign and malignant mucosal lesions [18 ]. MRI has limited utility for the evaluation of tracheal tumors but can be used in some instances to better evaluate extension into tissue planes and vascular structures. PET also has limited utility in evaluation of tracheal tumors. However, PET may be helpful in the detection of distant metastases, and offers the advantage of obviating unnecessary surgical treatment. Park et al. [19] have described that SCC usually has a high fludeoxyglucose (FDG) uptake, compared with ACC wherein variable FDG uptake on PET imaging. &
Bronchoscopic techniques Tracheobronchoscopy facilitates direct visualization of the airway, gives anatomical considerations, and allows for tissue diagnosis. Rigid bronchoscopy, by securing the airway, is preferred when there is a near complete airway obstruction: flexible bronchoscopy may exacerbate obstruction by inducing bleeding, cough, and edema. The use of spectroscopic technique during bronchoscopy allows for differentiating between benign and malignant mucosal lesions [17]. Endobronchial ultrasonography (EBUS), improves sensitivity of bronchoscopy in the evaluation of the extent of airway wall involvement with
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323
Neoplasms of the lung Table 2. Unique features of different histopathological variants of tracheal tumors Histopathological type
Unique features
Squamous cell carcinoma
Usually presents with symptoms of mucosal irritation and ulceration (bleeding) Diagnosed earlier (4–6 months within symptom onset) as compared with other histologic variants [12] Dysphagia and hoarseness are markers of locally advanced disease but do not preclude respectability
Adenoid cystic carcinoma
Commonly presents with symptoms of upper airway obstruction Average time for establishing diagnosis from symptom onset is 18 months [5,9] Less than 25% patients present with hemoptysis early in the course [12] Most patients will be diagnosed with advanced disease
Benign or low-grade malignant tumors
Slowly growing Can remain asymptomatic for months or years before diagnosis
malignancy (95%) [20]. Para tracheal tumors invading the tracheal wall can be easily identified using EBUS [21], thereby determining the potential of surgical intervention. When tracheal carcinomas extend to adjacent mediastinal structures including the esophagus, esophageal endoscopic ultrasound may be used to further characterize the extent of such spread.
ADVANCES IN MANAGEMENT Surgical techniques The best opportunity for achieving long-term cure is still complete surgical resection of the tumor supplemented by postoperative adjuvant therapy [22 ]. However, Honings et al. [13] reported epidemiological data indicated that significantly more patients could have received curative surgical therapy than were actually treated (about 2.3 times). The goal of surgical resection with a curative intent is to achieve complete resection without cancer cells seen microscopically at the margins [23,24]. Because of the indolent nature of ACC, incomplete resection margins are commonly seen [25]. Surgical resection has been shown to improve survival in the patients with ACC who have distant metastases. The role of other bronchoscopic modalities for the treatment of ACC is under study. In centers that have expertise with tracheal tumors, resection rates of up to 70% and perioperative mortality rates as low as 3% have been reported [26]. Five-year survival rate has been reported to be greater than 50% for patients undergoing surgery, whereas it is only 10% for the patients who are determined to be nonsurgical candidates [25]. For tumors extending greater than 50% of the tracheal length, surgical resection and tracheal reconstruction have been associated with high mortality [22 ]. Therefore, surgery is not recommended in these &&
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patients. Surgery is also contraindicated in patients with involvement of heart or aorta, distant metastases, involvement of multiple lymph nodes on PET scan, and in those with prior mediastinal surgeries or irradiation with a dose greater than 60 Gy.
Radiotherapy Radiotherapy is indicated as adjuvant therapy following surgical resection for almost all patients. Improved survival has been reported in SCC, even in cases with negative postsurgical resection margins [27]. ACCs are typically less radiosensitive as compared with SCC. However, adjuvant radiotherapy has been known to reduce recurrence rates in the patients with ACC [27]. Radiation therapy is the first-line treatment for nonsurgical candidates [28] and can also be used for palliation in advanced disease. Neoadjuvant radiotherapy prior to surgery in surgical candidates does not appear to improve survival. Intraluminal brachytherapy is an additive therapy following external-beam radiation therapy, which increases local tumor control [29].
Chemotherapy In the absence of prospective randomized control trials, the role of systemic chemotherapy as a primary treatment or as an adjunctive therapy remains unclear [30]. However, there have been recent case reports demonstrating successful outcomes with a combination of chemotherapy with radiation therapy in nonsurgical candidates. Combination therapy might be a suitable option for patients with unresectable tumors or who are not surgical candidates [30]. Some of the commonly used chemotherapeutic regimens include Carboplatin and Paclitaxel containing regimens, Cisplatin, 5-fluorouracil, and Etoposide containing regimens, Volume 21 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Malignant tracheal tumors Sherani et al. Table 3. Advantages and disadvantages of various pulmonary interventional techniques Interventional pulmonology techniques
Advantages and disadvantages
Laser therapy
Suitable for use in emergency cases for acute airway obstruction [33] Use with supplemental oxygen is dangerous Risk of hemorrhage or perforation of irradiated area
Argon plasma coagulation
More effective for broad-based lesion Can be safely used with supplemental oxygen Less risk for localized hemorrhage or perforation [33] Choice of treating hemoptysis from visible lesions on bronchoscopy Can be used for superficial tissues only Difficult to apply to acute angles, such as lesions at bifurcations
High frequency snares
Does not denature or lyse the tissue, thereby; preserving it for histological diagnosis Little risk for hemorrhage or perforation
Dehydrated ethanol injection
Excellent hemostatic effect Does not need expensive specialized equipment for delivery [33] Induces cough, that may be intense Injection is difficult with friable tissue
Airway stents
Maintain airway patency Protect against collapse from edema [33,34] Can be performed to compress endotracheal lesions, thereby avoiding debulking [34] May allow for stabilization while a reconstructive effort heals
and Cisplatin and Vinorelbine containing regimens. However, the use and timing of various regimens remains under study. [31]. There is a lack of sufficient data to recommend general use of combined high-precision radiotherapy techniques such as image-guided radiation therapy, intensity-modulated radiation therapy, or volumetric intensity-modulated arc therapy combined with platinum-based chemotherapy for the treatment of locally advanced tracheal tumors. These techniques might offer better disease control and constitute opportunities for potential research.
Interventional pulmonology techniques It has been shown that interventional techniques, when combined with adjuvant therapy, provide definitive treatment in selected cases. Additionally, these techniques serve as emergency therapy in patients presenting with complete or significant central airway obstruction prior to definitive treatment [32]. However, studies have recommended against stent placement in patients who are surgical candidates. Interventional techniques have a greater role in palliation for patients in which surgery is not possible. When combined with radiation therapy, patients undergoing interventional techniques for palliation have a median survival of less than 12 months [1 ]. &
Available interventional options include the use of laser therapy, cryotherapy, electrocautery, photodynamic therapy, brachytherapy, and argon plasma coagulation, with or without stents. These techniques allow for intraluminal debulking of the tumor. Each technique has its unique advantages and disadvantages (Table 3) [33,34].
Alternative strategies Alternative strategies such as tracheal transplantation or those that aim at replacing the trachea with other viable or nonviable substitutes such as foreign materials, tissue engineering, and autogenous tissues have not yet developed sufficiently to enter routine clinical practice. Despite advances in surgical techniques, attempts at tracheal transplantation in such patients have been limited [35].
CONCLUSION Due to their rarity, slow growth and nonspecific symptoms primary malignant tracheal tumors pose a diagnostic challenge. Lack of physician knowledge and awareness has led to significant delay as well as suboptimal use of appropriate therapy. The use of diagnostic modalities like EBUS and virtual bronchoscopy has significantly increased diagnostic accuracy. Newer surgical and interventional pulmonology techniques offer additional options for cure
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and palliation. Further studies are needed to establish a definitive role of adjuvant therapies and to develop guidelines for the management of primary tracheal tumors. Acknowledgements We would like to thank Dr Shah for his assistance with the review. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nouraei SM, Middleton SE, Nouraei SA, et al. Management and prognosis of & primary tracheal cancer: a national analysis. Laryngoscope 2014; 124:145– 150. This article highlights the outcomes of various management modalities used for the treatment of tracheal tumors in Europe. 2. Junker K. Pathology of tracheal tumors. Thorac Surg Clin 2014; 24:7–11. &&
This article describes all the histopathological variants of the tracheal tumors with their staging and prognosis. 3. Thompson AD, Talavari Y, Mehari A, Gillum R. Tracheal cancer mortality && trends in the United States. Internet J Oncol 2014; 10:1–2. This is the first report describing national mortality patterns and trends for tracheal tumors in the United States from 1979 to 2010. 4. Urdaneta AI, Yu JB, Wilson LD. Population based cancer registry analysis of primary tracheal carcinoma. Am J Clin Oncol 2011; 34:32–37. 5. Shadmehr MB, Farzanegan R, Graili P, et al. Primary major airway tumors; management and results. Eur J Cardiothorac Surg 2011; 39:749–754. 6. Wang HL, Xu L, Li FJ. Subglottic adenoid cystic carcinoma mistaken for asthma. J Zhejiang Univ Sci B 2009; 10:707–710. 7. Bhattacharyya N. Contemporary staging and prognosis for primary tracheal malignancies: a population-based analysis. Otolaryngol Head Neck Surg 2004; 131:639–642. 8. Yasumatsu R, Fukushima J, Nakashima T, et al. Surgical management of malignant tumors of the trachea: report of two cases and review of the literature. Case Rep Oncol 2012; 5:302–307. 9. Macchiarini P. Primary tracheal tumors. Lancet Oncol 2006; 7:83–91. 10. Brand-Saberi B, Scha¨fer T. Trachea. Thorac Surg Clin 2014; 24:1–5. &
This article describes the anatomy and physiology of normal adult trachea and helps us to understand the physiological basis of symptoms caused by tracheal tumors.
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www.co-pulmonarymedicine.com
11. Hollingsworth HM. Wheezing and stridor. Clin Chest Med 1987; 8:231– 240. 12. Gaissert HA. Primary tracheal tumors. Chest Surg Clin N Am 2003; 13:247– 256. 13. Honings J, Gaissert H, Verhagen A, et al. Undertreatment of tracheal carcinoma: multidisciplinary audit of epidemiologic data. Ann Surg Oncol 2009; 16:246–253. 14. Javidan-Nejad C. MDCT of trachea and main bronchi. Radiol Clin North Am 2010; 48:157–176. 15. Seemann M, Schaefer JM, Englmeier KH. Virtual positron emission tomography/computed tomography-bronchoscopy: possibilities, advantages and limitations of clinical application. Eur Radiol 2007; 17:709–715. 16. Han S, El-Abbadi N, Hanna N, et al. Evaluation of tracheal imaging by optical coherence tomography. Respiration 2005; 72:537–541. 17. Williamson JP, Mclaughlin RA, Phillips MJ, et al. Using optical coherence tomography to improve diagnostic and therapeutic bronchoscopy. Chest 2009; 136:272–276. 18. Wu CC, Shepard JO. Tracheal and airway neoplasms. Semin Roentgenol & 2013; 48:354–364. This article reviews the role of different imaging modalities in the diagnosis and management of tracheal tumors. 19. Park CM, Goo JM, Lee HJ, et al. Tumors in the tracheobronchial tree: CT and FDG PET features. Radiographics 2009; 29:55–71. 20. Haas AR, Vachani A, Sterman DH. Advances in diagnostic bronchoscopy. Am J Respir Crit Care Med 2010; 182:589–597. 21. Tanaka F. Evaluation of tracheo-bronchial wall invasion using transbronchial ultrasonography (TBUS). Eur J Cardiothoracic Surg 2000; 17:570–574. 22. Behringer D, Ko¨nemann S, Hecker E. Treatment approaches to primary && tracheal cancer. Thorac Surg Clin 2014; 24:73–76. This article describes the role of different treatment approaches in the management of tracheal tumors. 23. Gaissert HA, Grillo HC, Shadmehr MB, et al. Uncommon primary tracheal tumors. Ann Thorac Surg 2006; 82:268–273. 24. Shadmehr MB, Farzanegan R, Graili P, et al. Primary major airway tumors; management and results. Eur J Cardiothorac Surg 2011; 39:749–754. 25. Gaissert HA, Grillo HC, Shadmehr MB, et al. Long-term survival after resection of primary adenoid cystic and squamous cell carcinoma of the trachea and carina. Ann Thorac Surg 2004; 78:1889–1896. 26. Honings J, Gaissert H, Henricus F, et al. Clinical aspects and treatment of primary tracheal malignancies. Acta Oto-laryngologica 2010; 130:763–772. 27. Xie L, Fan M, Sheets NC, et al. The use of radiation therapy appears to improve outcome in patients with malignant primary tracheal tumors: A SEER-based analysis. Int J Radiat Oncol 2012; 84:464–470. 28. Webb BD, Walsh GL, Roberts DB, Sturgis EM. Primary tracheal malignant neoplasms: the university of texas md anderson cancer center experience. J Am Coll Surg 2006; 202:237–246. 29. Chang CY, Cheng SL, Chang SC. Adenoid cystic carcinoma of trachea treated with tumor curettage and adjuvant intensity modulated radiation therapy. South Med J 2011; 104:68–70. 30. Kunhiparambath H, Das P, Kumar R, et al. Unresectable basaloid squamous cell carcinoma of the trachea treated with concurrent chemoradiotherapy: a case report with review of literature. J Cancer Res Ther 2010; 6:321–322. 31. Allen AM, Rabin MS, Reilly JJ, Mentzer SJ. Unresectable adenoid cystic carcinoma of the trachea treated with chemoradiation. J Clin Oncol 2007; 25:5521–5523. 32. Wood DE. Management of malignant tracheobronchial obstruction. Surg Clin North Am 2002; 82:621–642. 33. Kajiwara N, Kakihana M, Usuda J, et al. Interventional management for benign airway tumors in relation to location, size, character and morphology. J Thorac Dis 2011; 3:221–230. 34. Makris D, Marquette CH. Tracheobronchial stenting and central airway replacement. Curr Opin Pulm Med 2007; 13:278–283. 35. Delaere PR. Tracheal transplantation. Curr Opin Pulm Med 2012; 18:313– 320.
Volume 21 Number 4 July 2015
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