*From the Department of Radiation Oncology (Drs. Monroe and Zlotecki) and Division of Pulmonary and Critical Care Medicine (Drs. Walia and Jantz), University of Florida College of Medicine, Gainesville, FL.
Correspondence to: Robert A. Zlotecki, MD, PhD, Department of Radiation Oncology, University of Florida Health Science Center, PO Box 100385, Gainesville, FL 32610-0385; e-mail: email@example.com
Tracheobronchial amyloidosis (TBA) refers to the deposition of localized amyloid deposits within the upper airways. Treatments have historically focused on bronchoscopic techniques including debridement, laser ablation, balloon dilation, and stent placement. Local excisions often prove temporarily effective, with multiple local recurrences and progressive compromise pulmonary function occurring frequently. We present a case of TBA managed with definitive external beam radiation therapy. Eighteen months after moderate-dose radiation, the patient demonstrated improvements in functional status, pulmonary function, bronchoscopic visualization, and CT-based luminal diameters. The literature involving the role of radiation therapy in the treatment of TBA is reviewed.
Amyloidosis is a disorder of extracellular protein deposition that encompasses a wide spectrum of related diseases. The underlying pathology involves abnormal protein folding and results in insoluble amyloid fibril proteins accumulating in normal tissues.1–
Various subtypes exist, including primary systemic amyloidosis, reactive systemic amyloidosis associated with chronic inflammatory states, and localized forms of aberrant amyloid deposition. Tracheobronchial amyloidosis (TBA) refers to the deposition of localized amyloid deposits within the upper airways and is typically associated with monoclonal Ig light chains.2
The clinical effects of TBA include dyspnea, cough, hemoptysis, and hoarseness. Pulmonary function abnormalities depend on the location of involvement with proximal deposition typically causing obstructive physiology and mid/distal disease demonstrating normal airflow rates and air trapping.3
TBA has typically been managed by bronchoscopic methods including mechanical debridement, laser ablation, balloon dilation, and stent placement. Local excisions often prove temporarily effective; however, multiple local recurrences with progressive compromise of pulmonary function may occur, often leading to death.3–5
External beam radiation therapy has been successfully utilized in a limited number of case reports.6–7
We present a case of a patient with localized TBA in which symptomatic, radiographic, and bronchoscopic observation demonstrated improvement with localized external beam radiation therapy as the primary treatment modality.
The patient is a 60-year-old white woman with multiple medical comorbidities, including COPD, hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, and an 80-pack-a-year history of cigarette smoking. She presented in June 2001 to an outside institution with a 3-week history of increasing shortness of breath, cough productive of white sputum, and occasional hemoptysis. The patient required 4 L/min of oxygen by nasal cannula at rest to maintain adequate oxygenation. A chest radiograph obtained at hospital admission was significant for collapse of the right lower lobe and a right pleural effusion. A CT scan of the chest demonstrated a central lung mass at the level of the right mainstem bronchus. Flexible bronchoscopy revealed thickening of the distal trachea and obstruction of the right mainstem bronchus by a tumor-like exophytic mass. Pathology from endobronchial biopsies revealed bronchial mucosa with squamous metaplasia. Rigid bronchoscopy was performed and demonstrated the same finding of occlusion of the right mainstem bronchus but was complicated by significant bleeding during the procedure, requiring mechanical ventilation.
The patient was subsequently transferred to our institution. CT of the chest was repeated, revealing significant circumferential thickening with partial calcification of the right mainstem bronchus extending inferiorly to obliterate the right lower lobe bronchus (Fig 1
). A 3 × 3-mm soft-tissue mass with an intraluminal component partially obstructing the right upper lobe bronchus was also identified.
Pulmonary function testing revealed FEV1 of 1.25 L (54% of predicted), FVC of 1.75 L (55% of predicted), FEV1/FVC ratio of 72%, total lung capacity of 3.12 L (59% of predicted), and diffusing capacity of 8.16 mL/min/mm Hg (37% of predicted). A repeat fiberoptic bronchoscopy revealed thickening of the mucosa over the distal trachea and carina and 75% occlusion of the right mainstem bronchus by an exophytic mass (Fig 2
). The right upper lobe could not be visualized. The bronchus intermedius, right middle, and right lower lobe bronchi also had significant abnormal thickening of the mucosa causing significant narrowing. Biopsy specimen of the endobronchial mass demonstrated green birefringence with Congo red staining and was immunoreactive for κ and λ light chains. Serum protein electrophoresis, urine protein electrophoresis, and echocardiography failed to demonstrate evidence of systemic amyloidosis.
The patient was thought not to be a candidate for laser resection or stent placement given the diffuse involvement of the airways and the extent of the disease into the distal airways. Due to the lack of therapeutic options, it was elected to provide a trial of external beam radiotherapy. Beginning in July 2001, the patient received localized external beam radiation therapy via parallel-opposed anteroposterior-posteroanterior fields. CT simulation was used to plan treatment fields that covered the radiographically defined target with a 2.5- to 3-cm margin. The dose of 24 Gy was delivered in 12 daily fractions using 6-megavolt (MV) photons. In addition, the patient was started on colchicine, 0.6 mg bid.
By August 30, 2001, the patient’s functional status had improved significantly and she was using oxygen only with exertion as opposed to continuous use before radiation therapy. A chest radiograph demonstrated residual atelectasis at the right lung base with significantly improved aeration. Repeat pulmonary function testing at that time revealed an FEV1 of 1.27 L (55% of predicted), FVC of 2.07 L (66% of predicted), FEV1/FVC ratio of 61%, total lung capacity of 4.04 L (77% of predicted), and diffusing capacity of 10.0 mL/min/mm Hg (45% of predicted).
Bronchoscopy was repeated in March 2002. A significant improvement in the appearance of the distal trachea and carina was noted with almost normal restoration of the normal mucosa. The right mainstem bronchus was now open, and there was no endobronchial mass seen (Fig 3
). The right upper lobe bronchus was visualized but was narrowed by approximately 80%. The bronchoscope could not be advanced into the right upper lobe segments. The bronchus intermedius demonstrated mucosal thickening with a stenosis of approximately 70%. The bronchus intermedius was partially dilated with a balloon catheter. The right middle and lower lobes continued to show an abnormally thickened mucosa.
In October 2001 and July 2002, CT scans of the chest demonstrated progressive resolution of thickening in the right mainstem bronchus and marked improvement in right lower lobe airspace disease/atelectasis. The most recent CT scan of the chest obtained in November 2002 revealed a continued improvement in the thickening of the right mainstem bronchus and near-complete resolution of right lower lobe atelectasis (Fig 4
). The most recent pulmonary function tests were performed in December 2002 and demonstrated an FEV1 of 1.57 L (69% of predicted), FVC of 2.37 L (72% of predicted), FEV1/FVC ratio of 68%, and diffusing capacity of 13.23 mL/min/mm Hg (60% of predicted).
The patient currently has minimal respiratory symptoms and has not required supplemental oxygen for the previous 7 months. The colchicine has been continued at a dose of 0.6 mg bid since diagnosis.
TBA is a relatively rare disorder characterized by submucosal amyloid deposition in the airways ranging from the larynx to the distal airways. Commonly associated symptoms include dyspnea, nonproductive cough, hemoptysis, and hoarseness. Diagnosis is frequently delayed by up to 17 months,3
and is verified by green birefringence of Congo red-stained areas when viewed with polarized light.
TBA along with nodular and diffuse alveolar septal parenchymal involvement represent the three primary patterns of localized respiratory involvement.1
Within the subgroup of tracheobronchial amyloidosis, three primary distribution patterns exist: proximal, mid, and distal airway involvement. Localized TBA is thought to not be usually associated with systemic amyloidosis.1
Our patient demonstrated mid and distal airway involvement and has had no clinical or laboratory evidence of systemic amyloidosis.
Management has primarily consisted of debulking procedures and laser ablation. Unfortunately, such methods may be ineffective and repeated procedures may be required. Capizzi et al5
reported 17 patients with TBA who were treated with laser or forceps resection, systemic therapy, radiation, or observation. Of 13 patients with follow-up data, 6 patients were alive with recurrence, and 5 patients had died (recurrent respiratory compromise secondary to amyloid [n = 2] and multiple myeloma [n = 1]). Two patients remained alive with stable disease. Hui et al4
reported on 14 patients with tracheobronchial amyloidosis. Of the seven patients with an average follow-up of 4.8 years, three patients died of recurrent disease. Similarly, of the 10 patients recently reported by O’Regan et al3
at Boston University, 3 patients died of respiratory failure after numerous excisions, 2 patients have progressive disease after 11 years and 6 years of follow-up, respectively, and 1 patient requires mechanical ventilation. A review of the literature by Rubinow et al8
revealed that 11 of 39 patients (28%) died of respiratory causes.
Radiation therapy has a limited and variable history in the treatment of localized amyloid lesions. Pecora et al9–
reported on the successful use of superficial radiation therapy to treat amyloidosis of the eyelid and conjunctiva. The earliest reported pulmonary cases included two patients treated for presumed primary bronchogenic carcinomas.10–11
Shinoi et al11–
treated a presumed primary bronchogenic carcinoma to a dose of 60 Gy using 60Co. The lesion decreased in size and was found to be amyloid at resection 3 months after radiotherapy. Additional use of external beam radiation therapy is briefly mentioned in reports by Rajan et al12
and Thompson and Citron,13
but no details of technique, dose, or response were given.
Kurrus et al6
reported one of the first intentional uses of external beam radiation therapy for TBA. The patient was initially observed until the development of life-threatening, progressive obstruction. External beam radiation therapy was then delivered to the distal trachea and right mainstem bronchus using a dose of 20 Gy in 10 fractions with improvement. Six months later, the patient underwent external beam radiation therapy to the right lower lobe bronchi because of disease progression in this area. As in our case, there was evidence of bronchoscopic and radiographic improvement in the radiated fields several months after treatment.
Capizzi et al5
reported one patient with near-complete tracheal occlusion who had received a diagnosis of multiple myeloma 3 years before. He underwent airway debridement followed by external beam radiation therapy to an unspecified dose. The patient died of multiple myeloma 6 months after radiotherapy. O’Regan et al3
described “airway-directed” external beam radiation therapy in one patient. Improvement in airway edema was noted after a single treatment, but at a 1-year follow-up the patient was noted to have required a tracheostomy and mechanical ventilation.
Most recently, Kalra et al7
described a case of a 59-year-old woman with airway obstruction because of diffuse deposition of amyloid throughout her tracheobronchial tree. She was treated with external beam radiation therapy, 20 Gy in 10 fractions, using a combination of 6-MV and 10-MV photons delivered to the entire tracheobronchial tree, and also with colchicine, 0.6 mg bid. Over time, improvement in symptoms, bronchoscopic appearance, and spirometry was observed. Improvement was not noted at the 1-month follow-up but was seen 6 months and 21 months after radiotherapy.
Our experience with external beam radiation therapy for TBA is similar to that of Kurrus et al6–
and Kalra et al.7
Our treatment plan and prescription dose of 24 Gy was based on the association of monoclonal plasma cells Ig light-chain deposition in both multiple myeloma and amyloidosis. Low radiation doses have proven successful in treating localized multiple myeloma, presumably by inactivating monoclonal plasma cells.14
In the case presented here, 24 Gy was well tolerated and resulted in significant improvements in both patient function and measurable disease. In all probability, recurrent disease could be treated with a repeat course of radiation therapy within the constraints of normal tissue tolerances.
A case of external beam radiation therapy for amyloidosis localized to the tracheobronchial tree is presented. We report improvements in functional status, pulmonary function, bronchoscopic visualization, and CT-based luminal diameters after moderate-dose radiation therapy. External beam radiation therapy may prove more definitive than current management techniques and warrants further investigation.
Abbreviations: MV = megavolt; TBA = tracheobronchial amyloidosis
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