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* From the Division of General Internal Medicine (Dr. Neben-Wittich), the Department of Radiation Oncology (Dr. Foote), and the Division of Pulmonary and Critical Care Medicine (Dr. Kalra), Mayo Clinic College of Medicine, Rochester, MN.
Correspondence to: Robert L. Foote, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: foote.robert{at}mayo.edu
Abstract
Background: Tracheobronchial amyloidosis is a rare form of primary amyloidosis. There have been no regimens for treatment of this disease that have proven to be effective. There have been case reports of external beam radiation therapy (EBRT) providing marked improvement in symptoms and the appearance of lesions. We report a series of seven consecutive patients who were treated with EBRT.
Methods: All patients with tracheobronchial amyloidosis were identified who had received EBRT at Mayo Clinic, Rochester, MN. A retrospective chart review was performed. Data were collected including symptoms, method of diagnosis, treatments, result of treatments, and side effects.
Results: All patients received 20 Gy of radiation in 10 fractions. All patients had a favorable response to treatment ranging from symptom relief to a decrease in the frequency of pulmonary infections and objective improvement in pulmonary function. The time to subjective improvement ranged from 1 month to 1 year from the completion of EBRT. Grade 1 esophagitis developed in four patients, and grade 2 esophagitis developed in one patient. Grade 2 pneumonitis that resolved after 10 days of treatment with antibiotics and corticosteroids developed in one patient. FEV1 was the most consistently used method of objective follow-up, and three of seven patients showed improvement. Follow-up ranged from 10 to 69 months (median, 40 months). The recurrence of asymptomatic endobronchial narrowing requiring no additional treatment was noted on bronchoscopy in one patient after 17 months.
Conclusions: Tracheobronchial amyloidosis has been difficult to treat due to the limitations of treatment, recurrence, and complications. EBRT appears to be safe and can provide symptomatic as well as objective improvement.
Key Words: radiation therapy • tracheobronchial amyloidosis
Amyloidosis is a disease that is characterized by the deposition of insoluble protein fibers in organs and tissues, leading to organ dysfunction. There are several forms of amyloidosis, including primary amyloidosis, hereditary amyloidosis, senile amyloidosis, reactive amyloidosis in the setting of systemic disease, and dialysis-related amyloidosis. Primary amyloidosis is usually a systemic disease that is characterized by widespread protein deposition in multiple organs, most commonly the kidneys, heart, peripheral nervous system, and GI tract. In contrast to the systemic forms of amyloidosis, which can involve any organ except the brain, there are some rare forms of localized primary amyloidosis that occur without systemic involvement.
Pulmonary amyloidosis can occur with systemic disease or, more commonly, isolated to the respiratory system.1 These isolated forms of amyloidosis, which are rare manifestations of an already rare disease, can manifest as parenchymal nodules, diffuse alveolar septal disease, or tracheobronchial disease.1 Typically, amyloidosis restricted to the lung affects only one of the areas mentioned above.2
Tracheobronchial amyloidosis is an isolated form of primary amyloidosis. The largest series have reported 17 patients2 and 14 patients.3 The manifestations described are related to the airway involvement and include symptoms ranging from mild dyspnea, cough, hoarseness, and hemoptysis, to lobar collapse and airway occlusion.2345 For symptomatic patients who require treatment, many different therapies have been utilized.2345 The most common approach has been bronchoscopic intervention with mechanical debulking by forceps resection or laser therapy.678 This has been effective in relieving airway obstruction but has the disadvantage of bleeding due to the friable nature of the amyloid deposits,23456789 the recurrence of lesions, and the inaccessibility of some lesions to bronchoscopic intervention.2 Systemic medications such as colchicine, melphalan, and corticosteroids have been tried with little or no benefit.210 More recently, successful treatment with external beam radiation therapy (EBRT) has been described. There have been four case reports2111213 of patients who either did not respond to other therapies or were not able to pursue other therapies, who showed symptomatic, bronchoscopic, and functional improvement after treatment with EBRT (Table 1 ). This study reports on seven patients with tracheobronchial amyloidosis who were treated with EBRT at the Mayo Clinic between 1999 and 2004. We describe the dose, results, side effects, and complications of EBRT in the treatment of tracheobronchial amyloidosis.
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This study was approved by the Mayo Foundation Institutional Review Board. In accordance with Minnesota state law, only patients who authorized a review of their medical records were included in the study. A computer search of the Department of Radiation Oncology tumor registry using "amyloid/amyloidosis" and "radiation therapy" as search words was performed for patients who had been seen at the Mayo Clinic between 1975 and 2004. Seven patients fitting that description were identified who had been treated with EBRT for amyloidosis confined to the tracheobronchial tree. No patients were treated with EBRT prior to 1999. We performed a retrospective chart review to ascertain the dose delivered, clinical results, side effects, and complications of EBRT. We also examined diagnostic data, including the method of diagnosis as well as investigation for systemic amyloidosis. In addition, we reviewed the findings of chest x-rays, CT scans, bronchoscopic images, and pulmonary function tests, where they were available, for objective measures of improvement. The toxicity associated with radiation therapy was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. One patient in this study has been reported on previously.12
Results
The patient demographics and clinical information are summarized in Table 2 . There were four male patients and three female patients. The median age at diagnosis was 58 years (range, 32 to 61 years). All patients had a history of tobacco use. Disease was diagnosed in all patients by bronchoscopic biopsy, and all patients were symptomatic at diagnosis (Table 2). Investigations for systemic amyloidosis were negative in all cases. Three patients were treated with either systemic corticosteroid/colchicine therapy or bronchoscopic therapy prior to EBRT. Table 2 details all treatments that were administered prior to EBRT.
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Table 3 also summarizes the side effects and complications of EBRT in these patients. Acute esophagitis developed in five of the seven patients (grade 1, four patients; grade 2, one patient). This resolved in all patients. One patient had what was thought to be consistent with grade 2 pneumonitis 3 weeks after receiving treatment. This resolved with 10 days of antibiotic and corticosteroid treatment.
Discussion
Tracheobronchial amyloidosis is a rare disorder that is characterized by the deposition of amyloid proteins in the airways. Respiratory symptoms result from progressive airway narrowing. Like primary systemic amyloidosis, tracheobronchial amyloidosis appears to involve the deposition of monoclonal Ig light chains.141516 However, there is no associated population of monoclonal plasma cells identified either within the deposits or systemically,1416 unlike primary systemic amyloidosis. It is not understood why the disease process is so localized to the tracheobronchial tree, but it has been proposed that the light chains are deposited by plasma cells that are present locally in the tracheobronchial tree.
The mechanism by which EBRT exerts its effects on the amyloid deposits in this disease is unclear. Radiation therapy has been used to treat conjunctival amyloidosis.17 In addition, there has been one case report18 of EBRT causing an amyloidoma in the lung to regress. There have been several proposed mechanisms by which radiation exerts its effect on the amyloid deposits. One theory is that radiation therapy has an effect on local plasma cells, as has been shown in patients with multiple myeloma and plasmacytomas.192021 It has been postulated that amyloid deposits in patients with tracheobronchial amyloidosis are a result of light chain deposition by local plasma cells. However, the amyloid deposits in tracheobronchial amyloidosis themselves contain scarce plasma cells, and a radiation effect on plasma cell function or turnover is unlikely to be the only mechanism of action. Other possibilities could include a radiation effect on local vasculature or the induction of immune responses against the deposits by causing local inflammation. In addition, there may be other blood, tissue, or pH factors in the local milieu that mediate the response.
There has previously been no effective treatment for this disorder. Systemic therapies similar to those used in patients with primary systemic amyloidosis have been generally ineffective. Bronchoscopic debulking with forceps or a YAG laser can be effective but does not affect the underlying disease process at all. It is also limited by the accessibility of lesions, bleeding, and the near-inevitability of recurrence. In our series, patients treated with EBRT achieved a symptomatic response as well as an objective improvement (ie, in FEV1, CT scan findings, and bronchoscopic appearance). Therapy was well tolerated, and the doses used did not preclude retreatment if needed. However, no patient in this series received a second course of EBRT.
Based on this series, it appears that radiation therapy may change the progressive course of tracheobronchial amyloidosis. Therefore, we now recommend radiation therapy as a first-line treatment in patients with bulky or distal disease that is not amenable to bronchoscopic recanalization, especially if there is evidence of symptomatic or functional decline. This is based on the treatment being well tolerated and the patient showing a significant durable symptomatic response lasting for > 5 years in our earliest treated patients.
Further follow-up may be helpful in determining the ideal dosing, the best way of monitoring the response and in determining how sustained the observed benefit is likely to be. In our series, FEV1 was the most commonly used objective measure of improvement, but was limited by comorbidities (all patients had smoked) and did not always correlate with symptoms. Flow-volume loops were not helpful in diagnosis or follow-up. Importantly, objective evidence of improvement was often delayed, and the FEV1 response especially usually lagged behind the symptomatic benefit by several months. Bronchoscopic visualization remains the most reliable marker of disease but is more invasive and subject to interobserver bias. CT scanning likely has a role, but the confounding effect of radiation-induced changes on the lung parenchyma should be given due consideration.
Footnotes
Abbreviation: EBRT = external beam radiation therapy
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication December 29, 2006. Accepted for publication March 31, 2007.
References
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