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Diagnosis and Management of Tracheal Neoplasms
Key Points
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Ninety percent of primary tracheal tumors in adults are malignant.
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Tracheal squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) are the two most common primary tracheal malignancies, and together they account for 75% of all primary tracheal tumors.
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The 5-year survival for patients with resectable SCC is 39% and is influenced by completeness of resection, lymphatic invasion, and invasion of the thyroid gland.
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The 5-year survival for patients with ACC is 52%. The improved survival, compared with that of SCC, may reflect an indolent disease that eventually leads to death, because late recurrences both locally and distally are a common feature of ACC .
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Half of the trachea can be safely resected and anastomosed primarily.
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Unresectable tracheal tumors have a poor prognosis but can be palliated with several different bronchoscopic treatment modalities.
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Overview
Primary tracheal tumors are relatively uncommon, and estimated annual incidence is two cases per 1 million people. Therefore an understanding of these neoplasms is based predominantly on small case series from large referral centers. Tracheal tumors are categorized as either primary or secondary, depending on whether they arise within the trachea or involve the trachea secondarily from metastatic disease or local invasion. Primary tracheal tumors are further subdivided into benign or malignant lesions. In adults, 90% of primary tracheal tumors are malignant, but in children, 80% are benign. Primary tracheal tumors are most often treated with multimodality therapy that includes surgical resection and radiation. Currently, the disease-specific and all-cause mortality for primary malignant tracheal tumors are 73% and 79%, respectively.
Secondary tracheal tumors are, by definition, malignant and involve the trachea either by direct extension or by hematogenous metastases. Direct extension occurs most commonly from cancers that arise in the lungs, esophagus, thyroid, and mediastinum, in decreasing order of frequency. Distant metastases from renal cell carcinoma, sarcoma, breast cancer, colon cancer, and melanoma have been reported. Optimal management for this diverse group of tumors depends on their location, natural history of the primary tumor, and patient comorbidities. Surgical resection offers a chance for cure for patients with lung or thyroid cancers that involve the trachea by direct extension. However, the vast majority of secondary tracheal tumors are treated with palliative intent.
Historic Review
Morgagni described the first primary tracheal neoplasm, a fibroma, in 1761. More than 100 years would pass before experimental attempts at tracheal resection with primary end-to-end reconstruction would be described. Kuester performed the first human tracheal resection and primary reconstruction in 1884. Prior to the 1960s, it was believed that tracheal resection was limited to four tracheal rings, approximately 2 cm, because greater resections would place undue tension on the anastomosis and prevent adequate healing. Because of the presumed limit of resection and primary anastomosis, efforts at prosthetic replacement of the trachea were undertaken. In 1950, Belsey reported his first attempt at tracheal reconstruction after resection of an adenoid cystic carcinoma (ACC) using fascia lata reinforced with stainless steel wire. Pearson and colleagues used heavy Marlex mesh for tracheal replacement and reported excellent function of the airway in three patients for several years. Neville and colleagues reported extensive experience with the use of a solid silicone tube to replace the trachea; however, others have reported unacceptable morbidity and mortality with this nonporous material. Over the past several decades, a variety of other synthetic materials have been used, along with nonviable and autogenous tissue, and various tissue engineering and transplantation techniques have been attempted. One of the first landmark reports published on the use of a tissue-engineered trachea detailed a 36-year-old man with recurrent primary cancer of the distal trachea and main bronchi. He was treated with resection and replacement of the airway with a stem cell–seeded bioartificial nanocomposite and was asymptomatic and tumor free 5 months later. In addition, a 12-year-old boy with long-segment congenital tracheal stenosis underwent airway replacement with a stem cell–seeded cadaveric tracheal scaffold. This graft revascularized within 1 week of surgery, the epithelium was restored at approximately 1 year, and at 2 years postoperatively, the boy had a functional airway and returned to school. A more extensive review of tracheal substitutes will be discussed later in the chapter.
Fortunately, the development of techniques for tracheal mobilization made it possible to undertake extensive tracheal resections that involve 50% of the tracheal length with primary reconstruction. Using these techniques, tracheal replacement is uncommon. For the rare circumstance when primary anastomosis cannot be done and replacement is necessary, tracheal allotransplantation is promising, but long-term immunosuppression requirements limit its potential use.
For secondary tumors that involve the trachea and carina, surgical techniques have been developed to address those with the potential for cure (thyroid and bronchogenic). Advances in therapeutic bronchoscopy offer options for patients who are not candidates for surgical resection. Endoscopic débridement, laser treatment, photodynamic therapy (PDT), cryosurgery, brachytherapy, and tracheal stents can provide palliation for patients with incurable disease.
Primary Tracheal Tumors
Primary tumors of the trachea are uncommon, but a variety of benign and malignant tumors have been described ( Table 112.1 ). Primary tumors can originate from any layer of the tracheal wall and are classified histologically as either epithelial or mesenchymal tumors. Although primary tumors can be found anywhere in the trachea, the proximal and distal thirds of the trachea are most frequently affected, as is the membranous wall. Several large surgical series of primary tracheal tumors have been reported ( Table 112.2 ).
TABLE 112.1
Classification of Tracheal Tumors
From McCarthy MJ, Rosado-de-Christenson ML: Tumors of the trachea. J Thorac Imag, 10:180, 1995.
| Epithelial Neoplasms | Mesenchymal Neoplasms |
|---|---|
|
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TABLE 112.2
Summary of Major Surgical Series of Primary Tracheal Tumors
| Malignant Neoplasms | Benign Neoplasms | All | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SCC | ACC | Carcin | ME | Other | Pap | Chon | Leio | GCT | Other | Total | HM (%) | |
| Pearson et al. | 9 | 28 | 0 | 0 | 5 | 0 | 1 | 0 | 0 | 1 | 44 | 12.8 |
| Grillo and Mathisen | 70 | 80 | 11 | 4 | 11 | 5 | 2 | 2 | 2 | 11 | 198 | 5 |
| Perelman et al. | 21 | 66 | 20 | 5 | 13 | 2 | 0 | 1 | 0 | 17 | 145 | 15 |
| Regnard et al. | 94 | 65 | 9 | 5 | 8 | 2 | 5 | 5 | 3 | 12 | 208 | 10.5 |
| Refaely and Weissberg | 5 | 13 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 22 | 4.5 |
| Webb et al. | 34 | 19 | 0 | 1 | 20 | — | — | — | — | — | 74 | 4.1 |
| Ahn et al. | 11 | 9 | 1 | 0 | 2 | 3 | 0 | 1 | 0 | 10 | 37 | — |
| Shadmehr et al. | 6 | 18 | 15 | 1 | 4 | 1 | 1 | 1 | 1 | 3 | 51 | 3.1 |
| Total | 250 | 298 | 58 | 16 | 63 | 13 | 9 | 11 | 6 | 55 | ||
| % Total | 32.1% | 38.3% | 0.07% | 0.02% | 0.08% | 0.02% | 0.01% | 0.01% | 0.01% | 0.07% | ||
ACC, Adenoid cystic carcinoma; Carcin, carcinoid; Chon, chondroma; GCT, granular cell tumor; HM, hospital mortality rate for surgical resection; Leio, leiomyoma; ME , mucoepidermoid tumors (low and high grade); Misc, miscellaneous; Pap, papilloma; SCC , squamous cell carcinoma.
Benign Primary Tracheal Tumors
Uncommon in adults, benign primary tracheal tumors are usually well circumscribed, round, soft, and smaller than 2 cm. On chest computed tomography (CT) scan, these lesions typically are seen as smooth, homogeneous tumors that do not extend through the tracheal wall. The presence of calcium within the lesion suggests a benign histology.
Tracheal Papillomatosis
Tracheal papillomatosis is a benign neoplastic condition characterized by growth of the bronchial epithelium in response to infection with human papillomavirus (HPV). Most cases are associated with HPV-6 and HPV-11. Tracheal papillomatosis is the tracheal manifestation of recurrent respiratory papillomatosis. This condition can be found throughout the respiratory tract; however, 90% to 95% of patients have papillomas isolated to the larynx. Only 1% to 2% of patients have isolated tracheal papillomas, and few patients have been described in the literature. Recurrent respiratory papillomatosis is divided into two types, juvenile onset and adult onset. Juvenile-onset papillomatosis is acquired through exposure to the virus in the birth canal at the time of delivery. Adult-onset papillomatosis is caused by either reactivation of a latent infection, or it is a newly acquired sexually transmitted disease. Despite being a benign tumor, juvenile-onset papillomatosis frequently recurs and requires numerous endoscopic interventions. Fortunately, it usually regresses spontaneously after puberty. The adult-onset type is more responsive to therapy and is less likely to recur.
Medical therapies include intralesional injection of cidofovir, interferon-α, acyclovir, methotrexate, celecoxib, and consumption of vegetables rich in indole 3-carbinol. The surgical approach entails papilloma excision to rule out malignant degeneration into squamous cell carcinoma (SCC). This usually occurs in association with a history of smoking or exposure to radiation. Malignant degeneration is more commonly seen with HPV-11, and it occurs with an incidence of 1.6% to 4%. The most commonly used endoscopic treatment is the carbon dioxide laser. Other endoscopic modalities include PDT, cryotherapy, radiofrequency ablation, and neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser. Endobronchial stenting with a silicone stent is reserved for cases of recurrent respiratory papillomatosis that are refractory to medical and endoscopic therapy. Recent data have suggested that the HPV vaccine (which promotes antibody formation against HPV-6 and HPV-11) may decrease the need for surgical intervention in patients with recurrent respiratory papillomatosis. There have been promising new data that have shown that HPV vaccine administration in patients with recurrent respiratory papillomatosis may be associated with the reduced need for surgical intervention. In one small prospective pilot study, Goon and colleagues administered the HPV vaccine to 12 patients with recurrent respiratory papillomatosis. The authors measured the incidence rate of surgical interventions required before and after vaccination over a 2-year minimum follow-up period. They found that the incidence rate of surgeries before vaccination was 47.44/1000 patient-months, and after intervention the incidence rate dropped to 6.71/1000 patient-months. This study has potential bias issues due to lack of risk adjustment and small sample size but suggests future promise of vaccination in patients with this troubling disease process.
Granular Cell Tumor
Granular cell tumors are rare tumors of neurogenic origin that arise from Schwann cells. The majority of tumors occur in the head and neck region, and tumors of the respiratory tract are rare. The glottis is the most common site for granular cell tumors in the respiratory tract, followed by subglottis, supraglottis, bronchi, and trachea, in that order. Multiple tumors occur in approximately 10% of patients; however, tracheal lesions are multiple 20% of the time. Two-thirds of tracheal tumors are found in the cervical trachea, and the rest are intrathoracic. In addition, 73% of tracheal granular cell tumors are intraluminal. Less than 40 tracheal granular cell tumors have been reported, and less than 10 of those were in the pediatric age group. Granular cell tumors are more common in women, and most occur between the ages of 20 and 50 years with a peak incidence around the fourth decade of life.
The diagnosis of granular cell tumor is made via bronchoscopy with biopsy, and CT or magnetic resonance imaging (MRI) is usually done to assess extraluminal spread. Upper endoscopy should be done to rule out esophageal invasion. Pseudoepitheliomatous hyperplasia of the overlying epithelium may occur in 10% of cases and may lead to misdiagnosis of SCC, but the finding of an underlying granular tumor is evidence against a malignant lesion. In terms of tumor biology, 98% of these tumors are benign and 2% are malignant. Malignant granular cell tumors are histologically similar to benign granular cell tumors except for nuclear pleomorphism and mitotic activity. Malignant tumors are usually larger than 4 cm at presentation and grow rapidly.
Surgery is the treatment of choice, and there is no role for chemotherapy or radiation therapy (RT). Treatment consists of bronchoscopic excision for tumors less than 1 cm and wide local excision for tumors greater than 1 cm. Granular cell tumors may be difficult to completely excise, and incomplete excision with a positive margin is not necessarily associated with clinical persistence or an increased recurrence rate. Completely excised tumors have a recurrence rate of approximately 10%.
Chondroma
Although they are extremely rare tumors, chondromas are the most common benign mesenchymal tracheal tumors and originate from the cartilaginous rings. They occur most often in older men. These tumors are hard and broad based, and they grow within the submucosal space with an intact mucosal covering. Calcification is seen on imaging in 75% of tumors. The most common site of origin is the internal aspect of the posterior cricoid, but otherwise, they are evenly distributed throughout the length of the trachea. Chondromas are predominantly intraluminal, whereas their malignant counterpart, chondrosarcomas, are more likely to cause thickening of the tracheal wall with extraluminal extension. Radical resection of the trachea is recommended for all cartilaginous tumors of the trachea given the likelihood of recurrence after incomplete resection and the risk of malignant transformation.
Leiomyoma
Tracheal leiomyomas originate from the smooth muscle cells of the tracheal wall and most commonly arise from the membranous portion of the lower third of the trachea. They account for 1% of all tracheal tumors, and fewer than 30 cases have been reported to date. These tumors occur most commonly in the fourth decade of life and are more common in men. Most tumors appear as a homogeneous nodule on unenhanced CT scan and enhance with intravenous (IV) contrast. Tracheal leiomyomas are either pedunculated or have a broad base. For tumors that are exclusively endoluminal and polypoid, complete removal is possible via bronchoscopic techniques that include electrocautery, snare excision, YAG laser, and cryotherapy. However, for tumors with a broad base, surgical resection is indicated. The incidence of recurrence following treatment has not been established given the small number of cases; however, two recurrences have been described: one after tracheal resection and one after bronchoscopic removal and laser ablation.
Hemangioma
Hemangiomas of the airway are extremely rare in adults; they are more common in children. These congenital vascular tumors can be found anywhere in the tracheobronchial tree but are most commonly found in the subglottis. More than half of children with subglottic hemangiomas also have cutaneous hemangiomas. Airway hemangiomas usually come to medical attention within the first 6 months with progressive stridor that prompts further evaluation with bronchoscopy. These lesions exhibit a proliferative phase in infancy followed by an involution phase after the first few years of life.
Traditional management of airway hemangiomas involved tracheostomy with expected decannulation between 1 and 2 years of age. Several other bronchoscopic therapies, including carbon dioxide and potassium titanyl-phosphate laser ablation and microdebrider resection, and medical therapies that include steroids, vincristine, and interferon have all been used. However, most recently, the efficacy of propranolol for the treatment of laryngotracheal hemangioma was first described in 2008; since then, many children have been treated with rapid, excellent results. The mechanism of action is not entirely clear; however, β-blockers appear to act by inhibiting the secretion of proangiogenic factors that stimulate the endothelial growth that leads to hemangioma. Children are admitted to the hospital for initiation and titration of therapy; the propranolol dose is gradually increased to 2 to 3 mg/kg/day in three divided doses while monitoring for side effects. Most experts recommend treatment until at least 1 year of age, and β-blockers are now indicated as first-line treatment for hemangiomas in children. The only exceptions are those with contraindications to β-blockers and patients with small, minimally active subglottic hemangiomas, in which the benefit of a single endoscopic procedure must be weighed against the risk of propranolol therapy for several months. Relative contraindications include sinus bradycardia, cardiogenic shock, hypotension, second- or third-degree heart block, or hypersensitivity/drug allergy. Potential adverse effects include bradycardia, hypotension, bronchospasm, and hypoglycemia, making close monitoring after administration important.
Miscellaneous Benign Primary Tumors
A variety of other benign tracheal tumors have been reported (see Table 112.1 ). All combined, these tumors represent less than 10% of all primary tracheal tumors. Treatment for these diverse tumors is generally surgical excision, although some may be successfully managed with endoscopic resection.
Malignant Primary Tracheal Neoplasms
In adults, 90% of primary tracheal tumors are malignant. The incidence of primary tracheal cancer is approximately 0.1 in every 100,000 persons per year, and these tumors account for 0.2% of all tumors of the respiratory tract. Carcinomas of the larynx and bronchi occur 40 and 400 times more frequently than carcinoma of the trachea, respectively. Because the incidence of these tumors is low, so is the index of suspicion; therefore diagnosis and definitive treatment are often delayed. In most series, approximately 75% of all primary malignant tracheal neoplasms are either SCC or ACC.
A population-based study using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database analyzed 578 cases of primary tracheal carcinomas from 1973 through 2004. The cohort consisted of 322 men (55.7%) and 256 women (44.3%), and most of the patients were white (84.1%). The most common tumor type was SCC (44.8%), followed by ACC (16.3%) and neuroendocrine tumors (9.7%). At the time of diagnosis, approximately one-third of patients had locally advanced disease, defined as extension into adjacent tissues. Only 24.2% of patients came to medical attention with carcinoma localized to the trachea, and 18.7% had distant disease. A multivariable analysis demonstrated improved prognosis with localized disease and with adenoid cystic histology.
Squamous Cell Carcinoma
SCC is the most common primary malignancy of the trachea, constituting 50% to 60% of clinical cases. Men are two to four times as likely to develop this cancer than are women, most commonly in the sixth and seventh decades of life. A history of cigarette smoking is present in 90% of patients, and synchronous or metachronous respiratory tract malignancies occur in 30% of these patients. These tumors demonstrate either exophytic or ulcerative growth. The lateral tracheal wall is often involved by these tumors, although when an SCC that involves the membranous tracheal wall is found, invasion from a primary esophageal tumor should always be considered.
Squamous cell cancers of the trachea are biologically aggressive tumors that grow rapidly and metastasize early. In a large series from Massachusetts General Hospital of 270 patients with primary tracheal carcinoma, 135 patients had SCC, and the other 135 had ACC. At the initial visit, one-third of the patients with SCC had unresectable tumors, and the most common contraindication to resection was advanced locoregional disease. However, this percentage declined over the past four decades. Mean survival was 38 months for patients with resectable SCC but only 8.8 months for patients with unresectable tumors. The 5-year survival rates for these two groups were 39.1% and 7.3%, respectively. Of those with resected squamous cell tumors who also underwent selective lymph node sampling, 35% had positive lymph nodes. The 5-year survival for patients with negative mediastinal lymph nodes was 48% compared with 12.5% of patients with positive lymph nodes. The presence of invasive carcinoma at the resection margin was an independent predictor of both 5- and 10-year survival. Patients with a positive margin had a 5-year survival of 26.7%; in those with a negative margin, 5-year survival was 43.1%. Among those with a positive margin, none survived 10 years. Hospital mortality for the entire cohort averaged 7% over four decades, but it improved to 3% in the past decade. In a follow-up study to analyze the pathologic features of the 59 most recent SCCs in this series, completeness of resection, lymphatic invasion, and invasion of the thyroid gland had the most important prognostic value.
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