Review

Primary tracheal tumours

Prof Paolo Macchiarini MDa, ,

aDepartment of General Thoracic Surgery, Hospital Clinic of Barcelona, University of Barcelona, 170 Villaroel, E-30889 Barcelona

Available online 30 December 2005.

Summary

Primary tumours of the trachea can be benign or malignant and account for fewer than 0·1% of tumours. However, they are a diagnostic and therapeutic challenge. Benign tumours are usually misdiagnosed as asthma or chronic lung disease, and can delay diagnosis for months or years. Because of their rapid growth and onset of haemoptysis, malignant tumours are often diagnosed earlier than benign tumours and patients thus often present with locally advanced disease. Inappropriate treatment is an equally frustrating issue. Modern techniques for tracheal surgery—laryngotracheal, tracheal, or carinal resection—combined with radiotherapy, can be offered curatively with low perioperative risks. Nevertheless, the low numbers of patients undergoing resection and the associated poor survival in epidemiological studies over the past two decades have shown that surgery is rarely considered outside referral centres, with radiotherapy or another form of local treatment (eg, endotracheal stents, debridement, brachytherapy) generally preferred. The liberal use of these other techniques should be avoided because surgery has the potential to cure all patients with benign and low-grade tumours and most patients with malignant primary tracheal tumours, and other techniques are usually palliative at best.

Article Outline

Introduction

Anatomy

Epidemiology

Pathology

Clinical presentation

Diagnosis

Management

Surgery

Radiotherapy

Endotracheal debridement

Endobronchial stents

Chemotherapy

Guidelines for management

Conclusion

Search strategy and selection criteria

Acknowledgements

References

Introduction

Primary tumours of the trachea (figure 1) are rare and are usually malignant in adults and benign in children. Although patients present with signs and symptoms of central-airway obstruction, the definitive diagnosis of these tumours is commonly delayed, and most patients therefore present with advanced disease.1 However surgery should still be considered in all patients with benign tumours and in most with malignant disease, even in advanced disease; only rarely is another local procedure—such as endotracheal stents, debridement, or brachytherapy—appropriate.2 Selection criteria and treatment indications are not consistent and even patients with resectable disease are often managed with palliative treatments. This approach is probably due to lack of awareness of the curative effect of surgery rather than the unavailability of prospective studies that assess and compare treatments, which are almost impossible to do because of the rarity of the tumours. Here, we summarise the evidence available to guide clinicians in treatment of patients with primary tracheal tumours.

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Figure 1. Cross section of tracheal tumour

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Anatomy

The adult trachea is about 12 cm in length, 1·5–2·5 cm wide, and connects the larynx to the carina; the distal two-thirds is located within the thorax. The trachea is composed of c-shaped cartilage rings and is spanned by the trachealis muscle, which provides support anteriorly and laterally and is made up of longitudinal and transverse layers of smooth muscle cells. It also has a posterior membrane and fibrous tissue with a thick layer that covers the outer surface of the cartilaginous ring and a thin layer that covers the inner surface. These layers merge at the upper and lower margins of the cartilaginous rings. A tracheal mucosa is also present, which is applied tightly to the inner surface of the cartilage and posterior muscular membrane and consists of ciliated pseudostratified columnar epithelium that overlie areolar and lymphoid tissue with elastic fibres, blood vessels, nerves, and mucous glands.

The inferior thyroid artery supplies the upper half of the trachea through three branches to either side of the trachea, and joins the superior thyroid artery, which contributes fine branches that run from the thyroid isthmus to the adjacent tracheal wall. The bronchial arteries provide a consistent blood supply to the carina and lowest parts of the trachea. Transverse intercartilaginous arteries from the vessels that reach the trachea extend deeply into the tracheal wall and join those from the opposite side at the midline (figure 2), ultimately branching into the submucosa. Smaller intercartilaginous branches point posteriorly and terminate in the membranous tracheal wall, which is also supplied by secondary small branches from the main oesophageal vessels; longitudinal anastomoses are also present. This fine arterial network is more pronounced in children than in adults.3 The tracheal cartilage receives nourishment from the arterial plexus only.[4], [5] and [6] Pathways of lymph drainage suggest that the draining lymph nodes are similar to those of bronchial carcinomas and that tumour cells usually drain to the nodes nearest to the primary tumour.6

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Figure 2. Fine arterial network of cervical human trachea

T=trachea. BA=brachiocephalic artery. LBV=left brachiocephalic vein.

The delicate arterial and lymphatic network could account for the rarity of haematogenous metastasis and the relative frequency of regional-node metastasis at initial presentation.[1], [7] and [8]

Epidemiology

Primary cancer of the upper respiratory tract accounts for more than 1% of malignant diseases, but the frequency of tumours is not consistent throughout the upper respiratory tract. Although the supraglottis is affected in 1·3 per 100 000 people, and the glottis in 2·3 per 100 000 people, fewer than 0·04 per 100 000 population have tumours in the subglottis or trachea.[9] and [10] Primary tracheal tumours account for 0·1–0·4% of malignant diseases, with 2·6 new cases arising per million people every year;[11], [12], [13] and [14] only 8% of these tumours develop in children.[15] and [16] However, squamous-cell carcinoma, the most common primary tumour in the trachea is about 75 times more frequent in the larynx and 140–180 times more frequent in the bronchi.[8] and [13] In the 1960s, this difference was attributed to laminar airflow in the trachea (because of the large diameter) and effective mucociliary clearance (because of evenness and absence of bifurcation)—factors that could prevent accumulation of carcinogens and therefore promote a malignant transformation sequence.17 However, now the difference is attributed to the local mucosa's role in immunosurveillance.18

Pathology

Primary tracheal tumours can arise from the respiratory epithelium, salivary glands, and mesenchymal structures of the trachea (panel).[19] and [20] In adults, 90% of primary tumours are malignant,7 compared with 10–30% in children.[15] and [16] Squamous-cell carcinoma and adenoid cystic carcinoma, which occur in about the same proportions, account for about two-thirds of adult primary tracheal tumours. The remaining third are distributed widely in a heterogeneous group of malignant or benign tumours,[19] and [20] but little information is available on their natural history and management.7 In adults, both sex distribution and incidence vary depending on cell type. Squamous-cell carcinoma develops mainly in men in their sixth and seventh decades, whereas adenoid cystic carcinoma is equally distributed between the sexes and is most common in patients in their fourth and fifth decades. Squamous-cell carcinoma can be either exophytic or ulcerative, is associated with habitual cigarette smoking, and affects 2–4 times more men than women. Squamous-cell carcinoma can be distributed over most of the trachea, and about a third of patients have either mediastinal or pulmonary metastases at diagnosis. Furthermore, metachronous or synchronous lesions are common, because as many as 40% of tumours can develop before, concurrently, or after carcinoma of either the oropharynx, larynx, or lung.[1] and [7] By contrast, adenoid cystic carcinomas are not associated with cigarette smoking, have a propensity to spread along both submucosal and perineural planes, and only 10% of patients have regional lymph-node metastases or remote metastases. Moreover, adenoid cystic carcinoma progresses slowly, often over several years, which is characteristic even of untreated cases. In children, primary tracheal tumours develop mostly at the posterior wall of the cervical trachea, and between the neonate period and 14 years of age.16

Panel. Classification of primary tracheal tumours

Surface epithelium

Benign

Papilloma

Papillomatosis

Malignant

Squamous carcinoma in situ

Squamous-cell carcinoma

Adenocarcinoma

Large-cell undifferentiated carcinoma

Neuroendocrine tumours:

Typical and atypical carcinoids

Large-cell neuroendocrine tumour

Small-cell carcinoma

Salivary glands

Benign

Pleiomorphic adenoma

Mucous-gland adenoma

Myoepithelioma

Oncocytoma

Other

Malignant

Mucoepidermoid carcinoma

Adenoid cystic carcinoma

Carcinoma ex pleiomorphic adenoma

Mesenchyme

Benign

Fibroma

Fibromatosis

Benign fibrous histiocytoma

Haemangioma

Haemangioperycitoma

Paraganglioma (chemodectoma)

Glomus tumour

Leiomyoma

Granular-cell tumour

Schwann-cell tumours

Chondroma

Chondroblastoma

Malignant

Soft-tissue type sarcomas

Chondrosarcoma

Malignant lymphomas

Other

Clinical presentation

Primary tracheal tumours can cause signs and symptoms of upper-airway obstruction (dyspnoea, wheezing, and stridor), mucosal irritation and ulceration (cough and haemoptysis), or direct invasion and involvement of continuous structures (recurrent nerve palsy and dysphagia). Distant metastases develop in fewer than 10% of patients. Diagnosis is often not made until several months after first presentation in adults, possibly because the tracheal lumen has a large functional reserve and tumours do not cause symptoms until they occlude 50–75% of the luminal diameter. Non-specific complaints of cough, positional wheezing, and exertional dyspnoea could lead to a misdiagnosis of asthma, chronic obstructive pulmonary disease, or bronchitis. Exertional dyspnoea will not develop until the trachea has narrowed to less than 8 mm, and once the lumen is less than 5 mm, dyspnoea will also occur at rest.[21] and [22]

Signs and symptoms vary according to the type but not the site of the tumour.23 Haemoptysis is the main symptom in patients with squamous-cell carcinoma and usually leads to an earlier diagnosis at between 4 and 6 months. Hoarseness and dysphagia as early symptoms denote advanced disease but do not preclude resectability. Adenoid cystic carcinomas commonly present with wheezing or stridor as the main symptom, and fewer than 25% of patients have

haemoptysis early in their course, which explains why symptoms can last for about 18 months before a definitive diagnosis is made and why most patients with primary malignant tracheal tumours still present with advanced disease.[1] and [14] Because of their slow growth, most benign or low-grade malignant tumours can have symptoms of obstruction for months or even years without development of life-threatening impairment of the airway. In children, the most common symptoms are wheezing and stridor, which is why asthma is often diagnosed and why many children do not present until more than 50% obstruction of the affected airway at diagnosis.16

Diagnosis

Shortness of breath and wheezing that is unresponsive to bronchodilators should arouse suspicion of a tracheal tumour. Conventional chest radiographs are rarely diagnostic, yet are commonly obtained as the initial radiological test, and tumours can be easily overlooked (figure 3). CT is the most useful method to assess tracheal tumours radiologically, and is regarded as the standard imaging technique for diagnosis and to assess the extent of the tumour and the delineation of the relation of the tumour with adjacent structures (figure 3). However, advances in airway imaging now allow multiplanar and three-dimensional reconstruction with internal (virtual bronchoscopy) and external rendering, and excellent image quality can be obtained with low-dose techniques.24 These new imaging techniques can show whether the lesion is within the lumen, outside the airway, or has features of both. Development of new aerosolised contrast agents or spectroscopic techniques that can discriminate between benign and malignant mucosal tissues might enhance the sensitivity and specificity of virtual bronchoscopy for the detection of preinvasive cancers within the respiratory tract.25 MRI provides no clear advantage over CT in the assessment of tracheal tumours, except for those with adenoid cystic lesions.

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Figure 3. Delineation of trachea

(A) Well-defined small tumour lies a few cartilaginous rings above carina in radiograph (arrow). (B) CT showing locally advanced squamous tumour of trachea, which has infiltrated posterior wall of trachea (T) into anterior of oesophagus (O), with associated invaded lymph nodes (N) between left carotid and subclavial arteries.

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Testing the pulmonary function can detect obstruction in the upper airway, and identify flow-volume loops that have characteristic flattening of both inspiratory and expiratory phases (figure 4), providing further evidence of a fixed upper-airway obstruction. Bronchoscopy (figure 5) is usually used to diagnose and stage tracheal tumours because it allows tissue samples to be obtained from the tumour both proximally and distally, and can assess the location and extent of disease and the relation between the length of the tumour and trachea.26 Endoscopic ultrasound can also establish the amount of tracheal invasion.27

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Figure 4. Flow volume loop in 62-year-old patient before (A) and after (B) surgery

Upper curve is expiratory phase, lower curve is inspiratory phase.

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Figure 5. Locations of tracheal tumours

(A) Bronchoscopic view of a near-occlusive squamous-cell tumour of the intrathoracic trachea. (B) Adenoidcystic tumour located at right cartilaginous pars membranacea groove.

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Management

Primary benign and malignant tumours are usually treated with surgery, endoscopic resection by various techniques, and radiotherapy. However, only surgery can cure all benign and low-grade malignant tumours, achieve long-term survival in tracheal carcinomas, provide pathological confirmation of complete tumour removal, and relieve airway obstruction permanently.[7] and [28] The decision to resect or irradiate a tracheal tumour will depend on many factors, including the health of the patient, tumour histology and location, and amount of airway that would remain after resection. However, resectability should be established before any other treatment, local or systemic, is started. If the patient presents with a life-threatening airway obstruction, rigid bronchoscopic resection can be used to delay surgery and to allow further assessment.29 However, management with stents or neoadjuvant radiotherapy is not recommended unless resection cannot be done.[7] and [28]

Surgery

Various surgical techniques can cure primary tumours of the upper airway—eg, laryngectomy with resection of the upper trachea, larynx and trachea, trachea, carina, or carina and lungs. In children, endoscopic resection or laser or electrocautery fulguration of benign lesions is usually used. Although the importance of one positive pretracheal or paratracheal lymph node is questionable, absolute contraindications to surgery include the presence of many positive lymph nodes, involvement of more than 50% of the trachea, mediastinal invasion of unresectable organs, a mediastinum that has received the maximum radiation dose of more than 60 Gy or has been operated on, and distant metastases of squamous-cell carcinoma.[1], [7] and [28] The various surgical procedures have been described previously,[30], [31], [32], [33], [34], [35] and [36] but a few principles should be emphasised. Anaesthesia needs to be managed carefully and in various ways—for instance, intravenous anaesthesia can be used to target immediate postoperative extubation. Neck-collar incision (figure 6), usually with a manubriotomy, is used for tumours of the cervical and uppermost portion of the intrathoracic trachea, and median sternotomy or right posterolateral thoracotomy is used for tumours of the lower part of the trachea. The blood supply to the lateral segment should be preserved and all encountered tissues handled gently and anastomosis done meticulously. The need for oncological radicality needs to be balanced against anastomotic tension, and some acceptance of tumour-bearing margins is needed in adenoid cystic carcinomas because postoperative radiotherapy can treat these efficiently. Furthermore, laryngotracheal resection should be used in preference to laryngectomy for subglottic tumours—anatomical mobilisation can allow about half of the trachea to be resected in adults, with primary reconstruction on a dependable and predictable basis, and about a third of the trachea in children. Lymph nodes should not be dissected extensively because the technique jeopardises the blood supply to the remaining trachea; however, no consensus has been made on this issue.

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Figure 6. Surgical techniques in trachea

(A) U-shaped cervical incision that can eventually be extended to manubrium. (B) Lateral intraoperative view showing preservation of delicate arterial blood supply (arrow) above section of cervical trachea for a primary intrathoracic tracheal tumour. (C) Median sternotomy showing how incision can best approach middle and distal part of intrathoracic trachea after mobilising ascending aorta (AO) and sectioning brachiocephalic artery (BA) and vein (BV). (D) Determination of total length of tracheal tumour and of trachea itself, and distance of tumour from vocal cord and main carina.

Radiotherapy

Radiotherapy is indicated as an adjuvant after resection, for tumours that are unresectable or medically inoperable, and for palliation of severe symptoms.37 Few data are available for this modality. Resection can be converted from incomplete to complete by administration of 60 Gy photon radiotherapy postoperatively, given as five 2-Gy fractions per week over 6 weeks, or a biologically equivalent dose of neutron radiation. This treatment kills residual microscopic carcinoma in the tumour bed and regional lymph nodes in both squamous-cell carcinoma and adenoid cystic carcinoma. For gross residual carcinoma, the dose needs to be increased to 68–70 Gy given as five 2-Gy fractions over 6·8–7 weeks. Although sparse, data for the relation between dose and tumour suggest that a dose of higher than 60 Gy given as 30 fractions over 6 weeks, and preferably in the order of 70 Gy given as 35 fractions over 7 weeks, is needed for local tumour control in most patients with unresectable or medically inoperable squamous-cell carcinomas[38], [39], [40], [41], [42], [43], [44], [45] and [46] and in adenoid cystic carcinomas.[47], [48] and [49]

Endotracheal brachytherapy could be a reasonable approach for tracheal carcinomas, and has been shown to improve local tumour control when used after 60–68 Gy external-beam radiotherapy at a dose of 8–15 Gy.[50], [51] and [52] Further studies are needed to establish the maximum and optimum dose of endotracheal brachytherapy after external-beam radiotherapy.

Endotracheal debridement

Endotracheal tumours can be cleared endoscopically to palliate otherwise inoperable patients (eg, patients with T4N3 or higher-stage tumours) or as a way to keep the airway open until subsequent definitive resection can be done. Tumours can be removed with biopsy forceps and suction, electrocoagulation,52 cryotherapy,53 laser,54 photodynamic therapy,55 or argon-beam coagulation.55 However, these measures should never be attempted with curative intent, because they rarely offer long-term survival.[54] and [56]

Endobronchial stents

In patients with unresectable or medically inoperable lesions, reliable and durable palliation can be achieved in 80–90% of properly-selected patients through use of silicone or expandable stents.57 Stents have different shapes and styles to suit the location of the stricture,58 but the benefits and risks of airway stenting should be weighed up against other options of airway palliation.[1] and [7]

Chemotherapy

Cisplatin-based chemotherapy has been used successfully in one patient with an unresectable tumour and in association with radiation.59 However, this form of treatment has not yet been assessed prospectively in primary tracheal tumours.

Guidelines for management

Epidemiological studies in Europe,12 the USA,14 and Japan,8 have shown that most patients with primary malignant tracheal tumours present with advanced local disease, have squamous-cell tumours, and are treated non-surgically. The low rates of resection in these studies are consistent with those reported by Gelder and Hetzel, UK.13 Furthermore, 5-year survival was 39% in patients with squamous-cell tumours who received resection, but only 7% in those who did not. In patients with adenoid cystic tumours, those who had resection had a 5-year survival of 52%, compared with 33% in patients who did not have resection.12

The improved survival in patients who had resection suggests that surgery should be regarded as the only curative treatment option. Furthermore, patients should be referred to centres where the rate of resection is more than 70%[2] and [3] and where operative mortality, (which is substantially affected by the length and type of procedure, the need for laryngeal release, and the histology60) ranges between 5 and 10%.[1], [31], [60], [61], [62], [63], [64], [65] and [66]

Table 1 shows long-term survival in patients with resectable tumours. Disease-free survival after resection is limited by distant metastasis and regional disease but not by local recurrence. The leading centre[1] and [65] reported that disease-free survival was longer in patients who had had complete resection than in those whose resection was incomplete (p<0·05), in those with negative airway margins than in those who had positive airway margins (p<0·05), and in patients with adenoid cystic histology compared with patients with squamous histology (p<0·001). Tumour depth or length, and nodal status were not predictive of survival, but the lack of significance could have been because of the rarity of the tumour and the lack of reported lymphadenectomy and data to formulate a precise staging system. Licht and colleagues12 and Bhattacharyya14 have shown a significant correlation between prognosis and staging. However, neither of the staging systems used in these studies define the anatomical regions or location of node metastasis for the different primary tumours, which have been identified on a retrospective basis.[12] and [14] Therefore, assembling the previously-proposed staging systems with the lessons learned from other intrathoracic solid tumours,67 we propose a staging system for primary tracheal carcinomas (tables 2 and 3). However, the effectiveness of this system needs to be investigated prospectively.

Table 1. 5-year and 10-year survival after resection for malignant primary tracheal tumours

n

Follow-up (years)

Survival

Ref

5-year

10-year

Adenoid cystic tumours 101 41 52%

29%

1

Adenoid cystic tumours 65 23 73%

51%

60

Adenoid cystic tumours 32 32 79%

51%

64

Adenoid cystic tumours and squamous-cell carcinoma 21/66

29 36%

27%

62

Squamous-cell carcinoma 90 41 39%

18%

1

Squamous-cell carcinoma 94 23 47%

36%

60

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Table 2. Proposed TNM classification for primary tracheal carcinoma

Definition

Tumour stage

Tx Cannot be assessed

Tis Any tumour without invasion

T1a <3 cm limited to mucosa

Definition

T1b 3 cm limited to mucosa

T2* Any tumour that invades cartilage or adventitia

T3 Any tumour that invades trachea or larynx

T4a Any tumour that invades carina or main

Definition

bronchus

T4b Any tumour that invades neighbouring structures

Nodal stage

Definition

Nx Regional lymph nodes cannot be assessed

N0 No evidence of node metastasis

N1 Local nodes positive (N1a <3 cm; N1b 3 cm)

Upper

Highest mediastinal nodes; upper paratracheal

Definition

third nodes, prevascular and retrotracheal

Middle third

Upper paratracheal nodes; prevascular and retrotracheal; lower paratracheal nodes; paraaortic nodes (ascending aorta or phrenic)

Lowe Upper paratracheal nodes; prevascular and

Definition

r third

retrotracheal; subaortic nodes (aorto-pulmonalis window)

N1A 1–3 positive nodes in upper third

N1B >3 positive nodes in upper third

Definition

N2 Regional nodes positive

Upper third

Lower paratracheal nodes; subaortic nodes (aortopulmonalis window)

Midd Highest mediastinal nodes; subaortic nodes

Definition

le third

(aortopulmonalis window)

Lower third

Upper paratracheal nodes; pulmonary ligament

Definition

Metastasis

Mx Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Metastasis to nodes other than N1 and N2

Definition

M2 Distant metastasis (eg, lung)

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* Tumour involvement of pars membranacea always classified at least as T2, irrespective of infiltration depth.

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Table 3. Proposed staging for malignant tracheal carcinoma

Stage

T N M

0 Tis N0 M0

Ia T1a N0 M0

Ib T1b–2

N0 M0

IIa T1b–2

N1 M0

IIb T1b–2

N2 M0

IIIa T3 N0 M0

IIIb T3 N1–2

M0

IVa Any N1–2

M1

IVb Any N1–2

M2

T=tumour stage. N=nodal stage. M=metastasis stage.

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Some investigators have recommended primary treatment with radiotherapy alone for early-stage lesions.43 However, no consensus about this unique observation has been made because median survivals of less than 12 months are consistently reported, especially for tracheal squamous-cell carcinomas treated with radiotherapy alone.[37], [39], [41], [45] and [46] Few studies have been done to assess the effectiveness of chemoradiation.

Conclusion

Primary tracheal tumours are the least common neoplastic lesions of the airway, and this subsite specificity could be related directly to the local mucosal capacity for immunoediting, with immunosurveillance being higher in the subglottis and trachea than in the glottis and bronchi.18 Most patients with primary tracheal benign and malignant tumours present with limited locoregional disease once symptoms occur. Although non-specific symptoms commonly delay diagnosis, resection with primary reconstruction yields better long-term results than any other treatment and should be regarded as the preferred initial treatment in almost all patients with benign lesions, tumours of intermediate aggressiveness, and malignant tumours. Absolute surgical contraindications include the presence of many positive lymph nodes, involvement of more than 50% of tracheal length in adults and 30% in children, mediastinal invasion of unresectable organs, a mediastinum that has received the maximum radiation dose of more than 60 Gy, and distant metastases in squamous-cell carcinoma. Radiotherapy is indicated as an adjuvant after tracheal resection, for unresectable and medically inoperable lesions, and for palliation of severe symptoms. Since disease-free survival of resected tumours depends on systemic metastasis and regional disease but not local recurrence, an exact staging system incorporating tumour, nodal status, and metastasis is warranted to identify subgroups of patients in which this tumour profile can be better targeted.

Surgical management is delayed for most patients because diagnosis has not been timely, because of a lack of appreciation of the availability and effectiveness of surgical techniques and radiotherapy, or because a laser has been used repetitively without any clear rationale for its use in continuing management.7

Search strategy and selection criteria

Data for this review were identified by searches of Medline, Current Contents, PubMed, and references from relevant articles using, the search terms “primary tracheal tumours”, including all subheadings. Abstracts and reports from meetings were not included. I also reviewed the references of all relevant papers identified, review articles and textbooks. Only papers published in English between June, 1950 and Aug, 2005 were included.

Conflict of interest

I declare no conflicts of interest.

Acknowledgment

I thank Helmut Ostertag (Department of Pathology, Hannover Medical School, Hannover, Germany) for his pathological expertise, and credit part of the proposed tumour, nodal, and metastasis staging to him, Ingeborg Wildfang (Radiation Oncology Clinic, Hannover Medical School, Hannover, Germany) for her radiotherapy advice, and Susanne Czichos (Hannover Medical School, Hannover, Germany) for her photographic assistance.

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Correspondence to: Prof Paolo Macchiarini

Volume 7, Issue 1, January 2006, Pages 83-91