Malignant tracheal tumors

INTRODUCTION — The epidemiology, pathology, clinical presentation, treatment, and prognosis of malignant primary tracheal tumors will be reviewed here.

Depending upon histology and location, tracheal tumors may overlap with primary lung cancers or head and neck lesions; these are discussed separately.

●(See "Clinical manifestations of lung cancer".)

●(See "Overview of treatment for head and neck cancer".)

EPIDEMIOLOGY — Primary tracheal tumors are rare. Population-based studies from tumor registries in Finland, Denmark, Netherlands, and England report annual incidence rates of tracheal cancer of approximately 0.1 per 100,000 per year, with tracheal cancers accounting for less than one-half of 1 percent of all malignant tumors [1-4]. The largest reported series comes from a Surveillance, Epidemiology, and End Results (SEER) analysis of 578 cases of primary tracheal carcinoma identified over a 31-year period [5]. In that series, the median age was 63 years, and 56 percent of patients were male. In other series, the mean age at presentation was approximately 60 to 65 years, and 60 to 70 percent of cases occurred in males [1-4].

Primary tracheal tumors are even more rare in children. A 1998 review of the literature identified a total of 38 cases over a 30-year period, of which approximately two-thirds were benign [6].

PATHOLOGY — Rather than being primary tracheal tumors, the majority of tracheal tumors occur via direct invasion of the trachea from carcinoma of the lung, esophagus, larynx, or thyroid gland. Hematogenous tracheal metastases have been described in patients with carcinoma of the breast, colon, and kidney, as well as those with melanoma.

In regards to primary tracheal tumors, most tumors in adult patients are malignant, with approximately one-half to two-thirds being squamous cell carcinomas (SCCs); adenoid cystic carcinomas (ACCs) were the second most common, accounting for approximately 10 to 15 percent of cases [2-5]. Less common primary tracheal tumors include mucoepidermoid carcinoma, nonsquamous cell bronchogenic carcinomas, sarcomas, carcinoid tumors, pleomorphic adenoma, and other even more rare tumors. Benign tracheal lesions include hemangioma, hamartoma, neurogenic tumors, granular cell tumor, and squamous papillomas [7-9]. Features by histologic type are described below:

●SCCs are the most common histopathologic type of tracheal malignancy. Up to 10 percent can be multifocal. Tumors may arise as an intraluminal nodule and progress to include mediastinal extension or lymph node metastases, and may lead to stenosis or tracheoesophageal fistula. They are histologically identical to SCCs of the lung. (See "Pathology of lung malignancies".)

●ACCs, previously called cylindroma, of the tracheobronchial tree are well-differentiated, slow-growing neoplasms. Late tumor recurrence after 10 to 15 years is possible, often as a result of early perineural infiltration. ACCs typically form polypoid lesions in the trachea or main stem bronchi (picture 1), but they may form infiltrative plaques with longitudinal or circumferential extension and often breach the cartilaginous plate. Perineural invasion and extension along vascular structures is very common and accounts for the high rate of positive surgical margins, well beyond the gross limits of the tumor [10,11]. ACCs can have multiple recurrences with late metastases (image 1). They are histologically identical to ACCs of the salivary glands [12,13]. (See "Pathology of head and neck neoplasms", section on 'Adenoid cystic carcinoma'.)

●Mucoepidermoid carcinomas (MECs) are histologically identical to MEC of the salivary gland. MEC is characterized by squamous cells, mucin-secreting cells, and intermediate cells. MECs arise from bronchial glands in the central airways and are more common in the bronchi than in the trachea [14,15]. They are usually well-delineated polypoid tumors. Based upon morphology, MECs are divided into low- and high-grade types [11]. Low-grade tumors seldom (<5 percent) spread to regional lymph nodes, while high-grade tumors frequently spread to regional nodes and metastasize distantly. (See "Pathology of head and neck neoplasms", section on 'Mucoepidermoid carcinoma'.)

●Tracheal carcinoid tumors are relatively unusual; carcinoid tumors occur preferentially in the bronchi [16]. Most are typical carcinoids histologically. Internal calcifications can occur in up to one-third of cases [17]. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts", section on 'Pathology and grading'.)

CLINICAL PRESENTATION — While the most common presenting symptoms of tracheal tumors are due to the presence of a mass within the trachea, these symptoms frequently do not arise until the tumor is large enough to obstruct at least 50 percent of the diameter of the lumen [18]. Symptoms vary based on the location of the tumor as well as the histologic subtype [19]:

●Squamous cell carcinomas often present with hemoptysis, given mucosal irritation and ulceration, and are typically diagnosed within four to six months of symptom onset. Dysphagia and hoarseness may also be present. The peak incidence is in the sixth to seventh decade of life. These tumors are seen primarily in smokers.

●Adenoid cystic carcinoma commonly presents with wheezing or exertional dyspnea, with hemoptysis present in only a minority of cases. Diagnosis is established on average 18 months after symptom presentation. The peak incidence occurs in the fourth and fifth decade of life. It affects males and females equally and usually affects nonsmokers.

●Low-grade tumors such as mucoepidermoid carcinomas or benign tumors may be asymptomatic for years before diagnosis.

Tracheal tumors are likely delayed in diagnosis due to the nonspecific symptoms shared with other benign etiologies. In an analysis from England, the mean time from initial symptoms to diagnosis was 2.5 months, although the diagnosis was substantially delayed in some cases. This may be due in part to the fact that chest radiographs identify the tracheal tumor in only 18 to 28 percent of cases [20].

DIAGNOSIS AND STAGING — The diagnosis of tracheal tumors is often delayed due to similar presenting features with other etiologies including asthma, chronic obstructive pulmonary disease (COPD), and pneumonia. These are discussed in detail separately. (See "Evaluation of wheezing illnesses other than asthma in adults" and "Role of viruses in wheezing and asthma: An overview" and "Chronic obstructive pulmonary disease: Diagnosis and staging" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

While many patients with new-onset respiratory symptoms are evaluated with chest x-ray (CXR), this is an insensitive test for tracheal tumors, showing short-segment tracheal narrowing in only a minority of patients. For a patient who presents with wheezing, the possibility of a tracheal malignancy is usually considered when there is no substantial improvement with bronchodilator therapy or when a CXR suggests the possibility of a tracheal mass. Patients are then typically referred for chest computed tomography (CT) (see "Evaluation of wheezing illnesses other than asthma in adults", section on 'Imaging'). Chest CT is typically ordered for patients with hemoptysis as well. CT with multiplanar reconstructions is the best method of imaging and detecting tracheal or major bronchi lesions (image 2) [20,21]. CT may reveal polypoid lesions, focal stenosis, eccentric narrowing, or circumferential wall thickening.

For patients in whom imaging reveals a tracheal mass or in whom the diagnosis remains unclear after initial imaging, bronchoscopy is the usual means of obtaining tissue for histologic confirmation of the diagnosis. Differentiation between benign etiologies (including benign tumors, infection, or inflammatory process) and malignancy can be made at this time. Malignant processes include direct invasion from other primaries such as lung, thyroid, or esophageal cancer; metastatic spread from other malignancies; or primary tracheal malignancies. Bronchoscopy can also be useful in assessing the resectability of the tumor (picture 1).

Positron emission tomography (PET)/CT may be useful for staging the cancer, but data on tracheal tumors are limited. Preoperative PET/CT scans may help to assess extent of disease and resectability, particularly for squamous cell carcinoma (SCC), similar to its use in squamous cell lung cancer. The magnitude of uptake depends on the degree of differentiation (ie, high-grade malignancies show high and homogeneous uptake of radiotracer). The PET standardized uptake value (SUV) is typically high in SCC and more variable with adenoid cystic carcinoma (ACC) or mucoepidermoid carcinoma (MEC) [21]. ACC and MEC show variable glucose avidity on the fluorodeoxyglucose (FDG)-PET scan [21].

There is no established staging system for tracheal tumors. One staging system that has been used by some investigators is based upon the Tumor, Nodes, Metastases (TNM) system and derived from the Surveillance, Epidemiology, and End Results (SEER) database [22]. The main limitations of this system are the small number of cases and the mixed histologies with insufficient information to allow accurate assessment of its ability to predict survival.

TREATMENT — The primary treatment modalities for tracheal tumors are surgery and radiation therapy (RT); there are no randomized trials directing the most efficacious treatment approach. The outcome of treatment depends on the stage, as well as the histology of the tracheal tumor. (See 'Prognosis' below.)

Our approach to treatment depends on whether a tumor is amenable to surgical resection, as well as the histologic type.

Resectable tumors — For patients with primary malignant tumors of the trachea, we recommend complete surgical resection when possible. Preoperative positron emission tomography/computed tomography (PET/CT) may help to assess resectability. Additionally, multidetector CT and virtual bronchoscopy can provide crucial information on the extent of disease and aid in deciding on resectability [23]. While rigid bronchoscopy with laser resection and/or stents can be utilized as a bridge to surgery, it should not be considered a definitive treatment for malignancy as the benefits are usually temporary [24-26].

Surgery — Surgical resection is the treatment of choice for malignant tracheal tumors whenever possible [27], given retrospective data suggesting improved disease outcomes and acceptable postoperative morbidity. Because of the lack of suitable replacement material, the suggested maximum resected length of trachea is 5 cm. Decisions on resectability are based on imaging studies and the expertise of the surgical team. Studies have suggested that between 50 and 70 percent of patients have resectable disease at diagnosis [28,29].

The superiority of surgery, with or without radiation, to radiation alone was suggested in a Netherlands database series in which 34 patients underwent surgical resection (24 of whom also received radiation) and 156 patients were treated with RT alone [4]. The five-year survival among patients who underwent surgical resection was 53 percent versus 11 percent among those receiving RT alone. A retrospective analysis of adenoid cystic carcinoma (ACC) of the head and neck similarly noted that radiotherapy combined with surgery resulted in better local control and survival than treatment with radiation alone [30]. A limitation in the interpretation of these retrospective studies is that the group of patients treated nonsurgically included those with unresectable disease and therefore a worse prognosis, which biases the results toward surgical treatment.

Several reports have demonstrated low levels of postoperative morbidity, which have improved over time. For example, the 30-day operative mortality rate ranged from 7 to 11 percent in three large reports, with the study from one large center observing a decreasing operative mortality over the last four decades, to 3 percent in the period from 1992 to 2001 [10,12,31].

Postoperative treatment — Given a lack of data with tracheal tumors, we follow an approach analogous to head and neck cancers and offer postoperative concurrent chemoradiotherapy to patients at the highest risk of recurrence, specifically those with positive surgical margins or extracapsular spread. For such patients who are unable to tolerate concurrent chemoradiation, or for patients with other risk factors, including advanced tumor (T) stage (T3/T4), two or more positive lymph nodes, perineural invasion, or lymphovascular invasion, we use postoperative RT alone. When using chemoradiation, we utilize cisplatin (100 mg/m² every 21 days) concurrently with radiation, similar to the approach used in head and neck cancers, for such patients (see "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Concurrent chemotherapy regimen'). Positive margins occur with a high frequency particularly in ACC, meaning that many of these patients receive postoperative radiation [10,12,29,32].

Although there are no controlled trials for tracheal tumors, available data suggest that postoperative RT improves survival for patients with incompletely resected squamous cell carcinoma (SCC) and ACC, but not for those with completely resected tumors [10,31,33]. For example, in a multicenter French surgical series including 83 resected tracheal cancers, postoperative RT prolonged survival only for those patients with incompletely resected tumors, although the numbers of patients in this subset were small [12]. Among 21 patients with incompletely resected tumors, five-year survival rate with RT was 47 percent versus 0 percent among those not receiving RT.

Furthermore, extrapolating from experience with head and neck cancers, two cooperative oncology group trials of head and neck SCCs have demonstrated superior local control and disease-free survival with adjuvant chemoradiotherapy as compared with adjuvant radiotherapy alone for patients with extracapsular lymph node spread or for positive margins or incomplete resection [34,35]. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Chemoradiation versus radiation therapy alone'.)

Unresectable tumors — Few data guide the approach to treatment of patients with unresectable disease. Rigid bronchoscopy with laser resection and/or stents can be utilized for palliation, although the benefits are usually temporary [24-26].

Squamous cell carcinoma — For patients with unresectable, nonmetastatic SCC, we treat with concurrent chemoradiotherapy with a platinum-based regimen, extrapolating from multiple trials of patients with head and neck SCCs demonstrating superior survival with chemoradiotherapy versus radiotherapy alone. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

For patients with metastatic SCC, we offer systemic therapy following the treatment approach for lung or head and neck SCCs, recognizing that the data to support any strategy are lacking. Subsequent therapies are also not well defined, although immunotherapy may be offered, as in the case of lung or head and neck SCC. (See "Overview of the initial treatment of advanced non-small cell lung cancer" and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease" and "Treatment of metastatic and recurrent head and neck cancer", section on 'General approach'.)

Additionally, palliative radiation may be offered for airway obstruction or other symptoms, as in the management of advanced non-small cell lung cancer. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Symptom palliation'.)

Adenoid cystic carcinoma — For patients with unresectable, nonmetastatic ACC of the trachea, there are few data to guide treatment. Either RT or combined chemoradiotherapy with a platinum-based regimen is an option based on experience from ACC of the head and neck. For example, two cases of ACC of the larynx were treated with weekly paclitaxel and carboplatin and daily radiotherapy. With follow-up of 112 and 60 months, local control was maintained and the larynx had been preserved [36]. (See "Salivary gland tumors: Treatment of locoregional disease", section on 'Definitive treatment'.)

For patients with metastatic ACC, there is no evidence that chemotherapy alters the natural history of ACC [37]. In the absence of symptoms, we typically observe these patients. If symptoms are present, either palliative RT or chemotherapy may be attempted. (See "Overview of the initial treatment of advanced non-small cell lung cancer" and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)

PROGNOSIS — Histology has a significant impact on prognosis, with patients with squamous cell carcinoma (SCC) generally having a worsened prognosis relative to other subtypes. In a study of the Surveillance, Epidemiology, and End Results (SEER) database, patients with SCC did significantly worse than those with adenoid cystic carcinoma (ACC; five-year survival rate 13 versus 74 percent), even among those with localized disease (five-year survival 25 versus 91 percent) [5,31]. The better prognosis for patients with ACC relative to SCCs may reflect slower growth and a more prolonged natural history, as has been described for patients with ACC arising in salivary glands [38]. (See "Pathology of head and neck neoplasms", section on 'Adenoid cystic carcinoma'.)

Among tumors of a given histology, resectability is the strongest prognostic feature. Data regarding prognosis among patients with specific histologic subtypes of tumors include:

●Squamous cell carcinoma – Among patients with SCC of the trachea, prognosis depends upon whether the disease was resectable or not. In a hospital-based series of 135 cases, 90 patients (67 percent) underwent resection, and 41 of these (46 percent) received postoperative radiation therapy (RT) [31]. The 5- and 10-year survival rates in patients undergoing resection were 39 and 18 percent, respectively, compared with 7 and 5 percent for patients with unresectable disease.

Smaller series report similar survival rates. A multicenter French surgical series included 83 resected tracheal cancers, most of which were SCCs, and 59 percent of which received adjuvant RT [12]. The observed 5- and 10-year survival rates were 47 and 36 percent, respectively. By contrast, in a Netherlands population database study in which only 12 percent of patients had resected disease, the overall five-year survival was only 12 percent [4].

●Adenoid cystic carcinoma – There have been several surgical series that included significant numbers of patients with ACC, together demonstrating a five-year survival ranging between approximately 50 and 80 percent in patients with resectable disease, and 30 percent for those with unresectable disease [5,10,12,29,39]. For those with resectable disease, many patients achieve longer-term survival. Ten-year survival rates range from approximately 30 to 60 percent for this subset of patients [12,29]. In one study of 108 patients with resectable tracheal ACC, the median overall and disease-free survival were 17.7 and 10.2 years, respectively [32]. RT is a component of treatment for many patients with ACC. (See 'Postoperative treatment' above.)

●Mucoepidermoid carcinoma – Experience in patients with mucoepidermoid carcinoma (MEC) is limited, but in general suggests more favorable outcomes than for SCC, particularly for those with low-grade disease [14,15,40].

Retrospective studies of MECs arising from the lung and trachea have suggested that most tumors are resectable, with good long-term outcomes [14,15,40]. For example, in a series of 69 MECs of the lung, three of which were located in the trachea and five in the mainstem bronchi, the survival at 5 and 10 years was approximately 85 and 80 percent, respectively [40]. Individual data on outcomes for tumors arising from the trachea versus elsewhere in the lung were not provided. In another series of 18 patients with MEC, in eight of whom the tumor originated in the trachea and mainstem bronchi, surgery was possible in 95 percent of cases (79 percent lobectomy or sleeve resection; 16 percent tracheal resection) [15]. Survival at both 5 and 10 years was 87 percent [15].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer" and "Society guideline links: Head and neck cancer".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – The majority of tracheal tumors occur via direct invasion of the trachea from carcinoma of the lung, esophagus, larynx, or thyroid gland, rather than occurring as primary tracheal tumors. Primary tracheal tumors are rare, with annual incidence rates of approximately 0.1 per 100,000 per year, accounting for less than one-half of 1 percent of all malignant tumors. (See 'Introduction' above and 'Epidemiology' above.)

●Pathology – Most primary tracheal tumors are malignant, with approximately one-half to two-thirds being squamous cell carcinomas (SCCs). Adenoid cystic carcinomas (ACCs) are the second most common, accounting for approximately 10 to 15 percent of cases. Less common primary tracheal tumors include mucoepidermoid carcinoma, nonsquamous cell bronchogenic carcinomas, sarcomas, carcinoid tumors, pleomorphic adenoma, and other even more rare tumors. Benign tracheal lesions include hemangioma, hamartoma, neurogenic tumors, granular cell tumor, and squamous papillomas. (See 'Pathology' above.)

●Clinical presentation – The most common presenting symptoms of tracheal tumors are due to the presence of a mass within the trachea and vary based on the location of the tumor as well as the histologic subtype. For example, SCCs often present with hemoptysis, given mucosal irritation and ulceration. By contrast, ACC commonly presents with wheezing or exertional dyspnea, with hemoptysis present in only a minority of cases. (See 'Clinical presentation' above.)

●Diagnosis and staging – For patients in whom imaging reveals a tracheal mass or in whom the diagnosis remains unclear after chest x-ray (CXR) and computed tomography (CT), bronchoscopy is the usual means of obtaining tissue for histologic confirmation of the diagnosis. (See 'Diagnosis and staging' above.)

Preoperative positron emission tomography (PET)/CT scans may help to assess extent of disease and resectability, particularly for SCC, similar to its use in squamous cell lung cancer. (See 'Diagnosis and staging' above.)

●Surgery – Surgical resection is the treatment of choice for malignant tracheal tumors whenever possible, given retrospective data suggesting improved disease outcomes and acceptable postoperative morbidity. Because of the lack of suitable replacement material, the suggested maximum resected length of trachea is 5 cm. (See 'Surgery' above.)

●Postoperative treatment – Given a lack of data with tracheal tumors, we follow an approach analogous to head and neck cancers and offer postoperative concurrent chemoradiotherapy to patients with positive surgical margins or extracapsular spread. For such patients who are unable to tolerate concurrent chemoradiation, or for patients with other risk factors, including advanced tumor (T) stage (T3/T4), two or more positive lymph nodes, perineural invasion, or lymphovascular invasion, we use postoperative RT alone. (See 'Postoperative treatment' above.)

●Unresectable tumors

•For patients with unresectable, nonmetastatic SCC or ACC, concurrent chemoradiotherapy with a platinum-based regimen may be attempted, though data are limited. For those with ACC histology, RT only is also an acceptable strategy. (See 'Unresectable tumors' above.)

•For patients with metastatic SCC, we offer systemic therapy, following the treatment approach for lung or head and neck SCCs, recognizing that the data to support any strategy are lacking. (See "Overview of the initial treatment of advanced non-small cell lung cancer" and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease" and "Treatment of metastatic and recurrent head and neck cancer", section on 'General approach'.)

•For patients with metastatic ACC, there is no evidence that chemotherapy alters the natural history of ACC. In the absence of symptoms, we suggest observation of these patients. If symptoms are present, either palliative RT or chemotherapy may be attempted. (See 'Adenoid cystic carcinoma' above.)

ACKNOWLEDGMENT — The authors and editors would like to recognize Dr. James R. Jett, MD, who contributed to previous versions of this topic review.