524470 research-article2014
TAR0010.1177/1753465814524470Therapeutic Advances in Respiratory DiseasePhilip et al.
Therapeutic Advances in Respiratory Disease
Review
Tracheobronchial amyloidosis managed with multimodality therapies Philip Sommer, Gagan Kumar, Randolph J. Lipchik and Jayshil J. Patel
Ther Adv Respir Dis 2014, Vol. 8(2) 48–52 DOI: 10.1177/ 1753465814524470 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract: Amyloidosis is a systemic disease involving abnormal extracellular deposition of amyloid and autologous fibrillar protein material in β-pleated sheets. Accumulation of this abnormal protein leads to organ dysfunction, although respiratory tract involvement is rare. We present two cases of tracheobronchial amyloidosis successfully treated with surgery and radiation.
Keywords: amyloidosis, stridor, tracheobronchial amyloidosis
Introduction Amyloidosis, first described by Virchow in 1854, is extracellular deposition of proteinaceous material comprised of insoluble β-pleated sheets. Accumulation of this abnormal protein leads to organ dysfunction. Amyloidosis can present in many forms and is classified into four subtypes according to the subunit proteins. With primary amyloidosis, there is systemic deposition in multiple organs, although respiratory tract involvement is rare. Since its symptoms of progressive dyspnea, cough and sputum production are nonspecific, the diagnosis of respiratory tract amyloidosis is not usually considered. Furthermore, chest radiographs are usually normal in more than 50% of cases, thus delaying the diagnosis. Tracheobronchial amyloidosis is even rarer. We report two cases that presented with respiratory symptoms and were diagnosed with tracheobronchial amyloidosis. Case 1 A 72-year-old woman with a past medical history of remote colon cancer and diabetes mellitus was scheduled to undergo an elective hernia repair. Pre-operative evaluation revealed progressive dyspnea and a dry cough. She had received two courses of antibiotics for suspected bronchitis without improvement. Review of systems was otherwise unremarkable. Other past medical history included hypertension, dyslipidemia, hypothyroidism, and vocal cord palsy after
thyroidectomy. She had a 30 pack-year tobacco history, quitting 3 years prior, no reported travel, and no occupational exposures. Family history was unremarkable. Medications included aspirin, glipizide, metformin, losartan, hydrochlorothiazide, omeprazole and simvastatin. Physical exam revealed normal vital signs. Pertinent findings include hoarse voice, no lymphadenopathy, no stridor and lungs were clear to auscultation. The remainder of the examination was unremarkable. Chest radiograph was remarkable for 1.5 cm opacity in the right lung base.
Correspondence to: Jayshil J. Patel, MD Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA [email protected] Philip Sommer, Gagan Kumar, MD Randolph J. Lipchik, MD Medical College of Wisconsin, Milwaukee, Wisconsin, USA
A computed tomography (CT) scan of the chest showed diffuse narrowing of the trachea, extending to the left mainstem bronchus (Figure 1). Diagnostic bronchoscopy confirmed tracheal narrowing. Biopsy of tracheal mucosa at the site of narrowing stained positive for Congo red with apple-green birefringence. Evaluation for systemic amyloidosis was negative: absence of serum and urine light chains, normal renal function, no proteinuria, unremarkable bone marrow biopsy and normal echocardiogram. The patient underwent rigid bronchoscopy with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser debridement of endotracheal and left endobronchial lesions (Figure 1). The patient tolerated the procedure well. She subsequently underwent 10 fractions of 20 Gray (Gy) external beam radiation. A repeat chest CT 4 months
48 http://tar.sagepub.com
P Sommer, G Kumar et al.
Figure 1. Endoscopic view of tracheobronchial amyloid showing nodular pattern with whitish nodules.
Figure 2. CT scan of chest in 2006, pre-operative and 2 months after surgery and 20 Gy radiation therapy. CT, computerized tomography.
post-radiation showed improved patency of the trachea and left mainstem bronchus (Figure 2). At 2-year follow up, the patient had no further dyspnea or cough. Case 2 A 58-year-old man presented to the emergency department in December 2011 with a 2-week history of progressively worsening dyspnea and productive sputum. A chest radiograph was unremarkable. He was diagnosed with community-acquired pneumonia, and was given both an antibiotic and an inhaler. Two weeks later, the patient’s dyspnea persisted. He had no significant past medical history. Family history was unremarkable. Social history was positive for 25 packyear tobacco use, quitting 5 years prior. There was
no travel exposure.
and
no
significant
occupational
Physical exam revealed blood pressure 184/92 mmHg, temperature 102.9, heart rate of 151 beats per minute, respiratory rate of 28 per minute, and oxygen saturation of 91% on room air. The patient was in respiratory distress using accessory muscles with diffuse rhonchi and crackles in the right lung base. There was no stridor. Remainder of the exam was unremarkable. A chest CT showed proximal tracheobronchial and right and left bronchial thickening with new right lower lobe infiltrate. Bronchoscopy revealed that the posterior wall of the carina was thickened with narrowing of the left and right mainstem bronchi. Direct laryngoscopy revealed a
http://tar.sagepub.com 49
Therapeutic Advances in Respiratory Disease 8(2)
Figure 3. Chest CT: pre-operative, immediate post-operative and 4 months post-operative. CT, computerized tomography.
nasopharyngeal mass that was excised. Biopsies of both the mass and tracheal mucosa were both positive for amyloid staining positive for Congo red with identification of amyloid A protein. An evaluation for systemic amyloidosis was negative. Between December 2011 and January 2012, rigid bronchoscopy with Nd:YAG laser debridement was successfully performed. This was followed by 10 fractions of 20 Gy external beam radiation. Repeat CT chest revealed improvement in the tracheal and proximal bronchial stenosis (Figure 3). At 9-month follow up, the patient reported intermittent, but improved, bouts of dyspnea. Discussion Amyloidosis is a systemic disease involving abnormal extracellular deposition of amyloid and autologous fibrillar protein material in β-pleated sheets. It is classified into four subtypes according to the subunit proteins – amyloid light chain (AL) disease (has monoclonal immunoglobulin), amyloid protein A (AA) disease (has serum amyloid A protein), amyloid transthyretin (ATTR) disease (has variant transthyretin) and amyloid β2-microglobulin (β2M) disease (has β2-microglobulin) [Berk et al. 2002]. These represent the most common forms of amyloidosis. The incidence of β2M disease is on decline due improvements in composition of dialysis filters [Traut et al. 2007]. Respiratory amyloidosis was first described by Lesser in 1877 [Lesser, 1877] and presents in three forms: focal/diffuse tracheobronchial pattern, nodular parenchymal pattern and diffuse parenchymal pattern. Nodular opacities are calcified in 30% and about 10% are cavitary. In one series, two-thirds of patients had multiple nodules [Hui et al. 1986]. They are present in the subpleural region of the mid-lung zones. There is no
associated lymphadenopathy [Berk et al. 2002]. The diffuse parenchymal pattern is usually seen with systemic amyloidosis and suggests primary AL disease [Berk et al. 2002]. Selective involvement of tracheobronchial tree is rare and is a potentially serious problem due to progressive airway compromise. The deposition of amyloid is submucosal and presents either as plaques or polyps. The deposits are either nodular or diffuse. In either case, these are mostly composed of immunoglobulin light chains produced by small number of plasma cells surrounding the involved airway. In a series of 15 patients, none expressed monoclonal protein, clonal plasma cell expansion, or deposits outside of the airways [Berk et al. 2002]. Once amyloidosis is diagnosed, it is imperative to evaluate other organ system involvement. Tracheobronchial amyloidosis affects females earlier, more often, and more extensively than males, and the typical age group affected is fifth or sixth decade, though it has been described in ages 16 through 85 [Diaz-Jimenez et al. 1999; Capizzi et al. 2000; O’Regan et al. 2000]. Presentation is usually subacute, with patients presenting with progressive dyspnea, wheezing, cough, recurrent pneumonia and hemoptysis. The symptoms of the disease can depend on location of the lesions. In those with proximal airway involvement, the symptoms are prominently obstructive. Those with mid-airway involvement present with lobar collapse and recurrent infections, while the distal airway involvement presents with recurrent pneumonia, cough, and bronchiectasis [Berk et al. 2002; Gibbaoui et al. 2004]. Bronchoscopy remains a cornerstone in establishing the diagnosis. Chest radiograph is normal in more than 50% of cases. CT scan of the chest is more accurate in identifying the circumferential
50 http://tar.sagepub.com
P Sommer, G Kumar et al. wall thickening with calcifications [Ding et al. 2010]. Other findings include features associated with bronchial narrowing such as atelectasis, bronchiectasis and lobar collapse [Ding et al. 2010]. Pleural effusion has also been reported with pulmonary amyloidosis [Kavuru et al. 1990; Berk et al. 2002; Rafii et al. 2011]. The differential diagnoses include tracheobronchial tuberculosis, relapsing polychondritis, and tracheobronchopathia with osteochondroplastica. Histopathological examination is thus crucial for a definitive diagnosis. The gold standard for the diagnosis of primary tracheobronchial amyloidosis is tissue with positive Congo red staining that produces green birefringence under crossed polarized light. There is no established treatment for tracheobronchial amyloidosis [Ding et al. 2010]. Therapeutic options include (1) bronchoscopic recanalization, (2) pharmacologic treatments and (3) external beam radiation therapy (EBRT) [Ding et al. 2010]. Bronchoscopic recanalization therapy options include laser resection, bronchoscopic dilatation and stenting, and cryosurgery. This may be useful for proximal or mid-airway lesions [Berk et al. 2002]. Surgical literature shows good control of symptoms with repeated bronchoscopic resection for as long as 11 years [Flemming et al. 1980; O’Regan et al. 2000; Maiwand et al. 2001]. The surgery is usually complicated by bleeding due to the friable nature of the amyloid affected mucosa [Capizzi et al. 2000]. Carbon dioxide (CO2) and Nd:YAG laser surgery and cryosurgery have good results with reduced bleeding [Herman et al. 1985; Maiwand and Homasson, 1995; O’Regan et al. 2000; Alloubi et al. 2012]. Medical therapies with corticosteroids, melphalan, colchicine and an iodinated isoform of doxorubicin have a limited role [Berk et al. 2002]. Since plasma cells are radiosensitive, low-dose radiation therapy remains the mainstay of treatment for tracheobronchial amyloidosis. The mechanism by which EBRT exerts its effects on the amyloid deposits in this disease is unclear. It has been proposed that amyloid deposition in the airway is a result of light chain deposition by local plasma cells and EBRT has an effect on these plasma cells [Neben-Wittch et al 2007]. Another theory suggests that EBRT has an effect on local vasculature with induction of an immune response against the deposits [Neben-Wittch et al 2007]. Kurrus and colleagues described regression in tracheobronchial amyloidosis after 20 Gy of radiation in 10 fractions [Kurrus et al. 1998]. Truong
and colleagues recently reported 80% local control in 10 patients after median follow up of 6.7 years [Truong et al. 2011]. Radiation esophagitis was the most common complication [NebenWittich et al. 2007; Truong et al. 2011]. Treatment with low dose radiation therapy has been reported with similar efficacy by others in the literature [Monroe et al. 2004; Neben-Wittich et al. 2007; Neuner et al. 2010]. Reports of multimodal therapy are scarce. In the case series reported by Truong and colleagues, 10 patients underwent initial external beam radiation at doses ranging from 18–20 Gy [Truong et al. 2011]. Of these, three patients underwent local control with laser surgical debulking, one underwent three surgical procedures and one underwent bronchodilatation with stent placement [Truong et al. 2011]. In this series, eight out of 10 patients achieved local control of airway amyloid at 6.7-year follow up [Truong et al. 2011]. It is unclear from this series if the patients receiving local surgical control followed by radiation had a longer duration of improvement. Ding and colleagues reported a total of 64 cases in China between the years 1970 and 2009 [Ding et al. 2010]. Of these, 36 cases reported therapeutic strategies. A total of 17 of the 36 were treated with Nd:YAG laser therapy with poor long-term response. One patient underwent EBRT. It was unclear from this study which patients, if any, underwent multimodality therapy. Neben-Wittich and colleagues reported a case series of seven patients who underwent successful EBRT with improvement in symptoms as early as 1 month of therapy and with symptom relief lasting >5 years [Neben-Wittich et al. 2007]. Two of the seven patients underwent prior local control surgical therapies. One underwent tracheal dilatation and one underwent repeated YAG laser. While all seven patients had improvement in symptoms with EBRT, it is unclear from the report if the two patients who had prior surgery had a sustained improvement. Prognosis is poorer for those with proximal airway involvement and those with diffuse disease [O’Regan et al. 2000; Berk et al. 2002]. Based on data from a cohort of 64 patients in China from years 1970–2009, estimated 5-year survival has ranged from 30% to 50% in diffuse disease [Ding et al. 2010]. A case series of patients treated with EBRT, with and without prior surgical therapies,
http://tar.sagepub.com 51
Therapeutic Advances in Respiratory Disease 8(2) shows disease recurrence with symptoms to be in the range 6–80 months [Truong et al. 2011]. Though the most common form of amyloid deposition is the AL type, it is not clear from the literature if the form of amyloidosis has any bearing on overall prognosis. Our case reports add to the literature the success of multimodal therapy in the management of tracheobronchial amyloidosis. Surgical debulking followed by radiation therapy in both patients has produced sustained improvement in symptoms at 8-month follow up. Further studies are warranted to determine if radiation alone versus debulking therapy plus radiation affects outcomes of symptom relief, disease recurrence and mortality. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement The authors declare no conflicts of interest in preparing this article.
References Alloubi, I., Thumerel, M., Begueret, H., Baste, J., Velly, J. and Jougon, J. (2012) Outcomes after bronchoscopic procedures for primary tracheobronchial amyloidosis: retrospective study of 6 cases. Pulm Med 2012: 352719. Berk, J., O’Regan, A. and Skinner, M. (2002) Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 23: 155–165. Capizzi, S., Betancourt, E. and Prakash, U. (2000) Tracheobronchial amyloidosis. Mayo Clin Proc 75: 1148–1152. Diaz-Jimenez, J., Rodriguez, A., Ballarin, J., Castro, M., Argemi, T. and Manresa, F. (1999) Diffuse tracheobronchial amyloidosis. J Bronchol 6: 13–17. Ding, L., Li, W., Wang, K., Chen, Y., Xu, H., Wang, H. et al. (2010) Primary tracheobronchial amyloidosis in China: analysis of 64 cases and a review of literature. J Huazhong Univ Sci Technolog Med Sci 30: 599–603. Flemming, A., Fairfax, A., Arnold, A. and Lane, D. (1980) Treatment of endobronchial amyloidosis by intermittent bronchoscopic resection. Br J Dis Chest 74: 183–188. Visit SAGE journals online http://tar.sagepub.com
SAGE journals
Gibbaoui, H., Abouchacra, S. and Yaman, M. (2004) A case of primary diffuse tracheobronchial amyloidosis. Ann Thorac Surg 77: 1832–1834.
Herman, D., Colchen, A., Milleron, B., BentataPessayre, M., Personne, C. and Akoun, G. (1985) [The treatment of tracheobronchial amyloidosis Using a bronchial laser. Apropos of a series of 13 cases]. Rev Mal Respir 2: 19–23. Hui, A., Koss, M., Hochholzer, L. and Wehunt, W. (1986) Amyloidosis presenting in the lower respiratory tract. Clinicopathologic, radiologic, immunohistochemical, and histochemical studies on 48 cases. Arch Pathol Lab Med 110: 212–218. Kavuru, M., Adamo, J., Ahmad, M., Mehta, A. and Gephardt, G. (1990) Amyloidosis and pleural disease. Chest 98: 20–23. Kurrus, J., Hayes, J., Hoidal, J., Menendez, M. and Elstad, M. (1998) Radiation therapy for tracheobronchial amyloidosis. Chest 114: 1489–1492. Lesser, A. (1877) Ein fall von enchondroma osteiodes mixtum der lunge mit partieller amyloid entortung. Virchows Arch (Path Anat) 69: 404–408. Maiwand, M., Omar, N. and Kamath, B. (2001) Cryosurgery in the treatment of tracheobronchial amyloidosis. J Bronchol 8: 95–97. Maiwand, M. and Homasson, J. (1995) Cryotherapy for tracheobronchial disorders. Clin Chest Med 16: 427–443. Monroe, A., Walia, R., Zlotecki, R. and Jantz, M. (2004) Tracheobronchial amyloidosis: a case report of successful treatment with external beam radiation therapy. Chest 125: 784–789. Neben-Wittich, M., Foote, R. and Kalra, S. (2007) External beam radiation therapy for tracheobronchial amyloidosis. Chest 132: 262–267. Neuner, G., Badros, A., Meyer, T., Nanaji, N. and Regine, W. (2010) Complete resolution of laryngeal amyloidosis with radiation treatment. Head Neck 34: 748–752. O'Regan, A., Fenlon, H., Beamis, J., Jr, Steele, M., Skinner, M. and Berk, J. (2000) Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999. Medicine 79: 69–79. Rafii, R., Leslie, K., Heo, J. and Chan, A. (2011) A 71-year-old woman with an unusual cause for pleural effusions. Chest 139: 1237–1241. Traut, M., Haufe, C., Eismann, U., Deppisch, R., Stein, G. and Wolf, G. (2007) Increased binding of beta-2-microglobulin to blood cells in dialysis patients treated with high-flux sialyzers compared with low-flux membranes contributed to reduced beta-2microglobulin concentrations. Results of a cross-over study. Blood Purif 25: 432–440. Truong, M., Kachnic, L., Grillone, G., Bohrs, H., Lee, R., Sakai, O. et al. (2011) Long-term results of conformal radiotherapy for progressive airway amyloidosis. Int J Radiat Oncol Biol Phys 83: 734–739.
52 http://tar.sagepub.com
TAR0010.1177/1753465814524470Therapeutic Advances in Respiratory DiseasePhilip et al.
Therapeutic Advances in Respiratory Disease
Review
Tracheobronchial amyloidosis managed with multimodality therapies Philip Sommer, Gagan Kumar, Randolph J. Lipchik and Jayshil J. Patel
Ther Adv Respir Dis 2014, Vol. 8(2) 48–52 DOI: 10.1177/ 1753465814524470 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract: Amyloidosis is a systemic disease involving abnormal extracellular deposition of amyloid and autologous fibrillar protein material in β-pleated sheets. Accumulation of this abnormal protein leads to organ dysfunction, although respiratory tract involvement is rare. We present two cases of tracheobronchial amyloidosis successfully treated with surgery and radiation.
Keywords: amyloidosis, stridor, tracheobronchial amyloidosis
Introduction Amyloidosis, first described by Virchow in 1854, is extracellular deposition of proteinaceous material comprised of insoluble β-pleated sheets. Accumulation of this abnormal protein leads to organ dysfunction. Amyloidosis can present in many forms and is classified into four subtypes according to the subunit proteins. With primary amyloidosis, there is systemic deposition in multiple organs, although respiratory tract involvement is rare. Since its symptoms of progressive dyspnea, cough and sputum production are nonspecific, the diagnosis of respiratory tract amyloidosis is not usually considered. Furthermore, chest radiographs are usually normal in more than 50% of cases, thus delaying the diagnosis. Tracheobronchial amyloidosis is even rarer. We report two cases that presented with respiratory symptoms and were diagnosed with tracheobronchial amyloidosis. Case 1 A 72-year-old woman with a past medical history of remote colon cancer and diabetes mellitus was scheduled to undergo an elective hernia repair. Pre-operative evaluation revealed progressive dyspnea and a dry cough. She had received two courses of antibiotics for suspected bronchitis without improvement. Review of systems was otherwise unremarkable. Other past medical history included hypertension, dyslipidemia, hypothyroidism, and vocal cord palsy after
thyroidectomy. She had a 30 pack-year tobacco history, quitting 3 years prior, no reported travel, and no occupational exposures. Family history was unremarkable. Medications included aspirin, glipizide, metformin, losartan, hydrochlorothiazide, omeprazole and simvastatin. Physical exam revealed normal vital signs. Pertinent findings include hoarse voice, no lymphadenopathy, no stridor and lungs were clear to auscultation. The remainder of the examination was unremarkable. Chest radiograph was remarkable for 1.5 cm opacity in the right lung base.
Correspondence to: Jayshil J. Patel, MD Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA [email protected] Philip Sommer, Gagan Kumar, MD Randolph J. Lipchik, MD Medical College of Wisconsin, Milwaukee, Wisconsin, USA
A computed tomography (CT) scan of the chest showed diffuse narrowing of the trachea, extending to the left mainstem bronchus (Figure 1). Diagnostic bronchoscopy confirmed tracheal narrowing. Biopsy of tracheal mucosa at the site of narrowing stained positive for Congo red with apple-green birefringence. Evaluation for systemic amyloidosis was negative: absence of serum and urine light chains, normal renal function, no proteinuria, unremarkable bone marrow biopsy and normal echocardiogram. The patient underwent rigid bronchoscopy with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser debridement of endotracheal and left endobronchial lesions (Figure 1). The patient tolerated the procedure well. She subsequently underwent 10 fractions of 20 Gray (Gy) external beam radiation. A repeat chest CT 4 months
48 http://tar.sagepub.com
P Sommer, G Kumar et al.
Figure 1. Endoscopic view of tracheobronchial amyloid showing nodular pattern with whitish nodules.
Figure 2. CT scan of chest in 2006, pre-operative and 2 months after surgery and 20 Gy radiation therapy. CT, computerized tomography.
post-radiation showed improved patency of the trachea and left mainstem bronchus (Figure 2). At 2-year follow up, the patient had no further dyspnea or cough. Case 2 A 58-year-old man presented to the emergency department in December 2011 with a 2-week history of progressively worsening dyspnea and productive sputum. A chest radiograph was unremarkable. He was diagnosed with community-acquired pneumonia, and was given both an antibiotic and an inhaler. Two weeks later, the patient’s dyspnea persisted. He had no significant past medical history. Family history was unremarkable. Social history was positive for 25 packyear tobacco use, quitting 5 years prior. There was
no travel exposure.
and
no
significant
occupational
Physical exam revealed blood pressure 184/92 mmHg, temperature 102.9, heart rate of 151 beats per minute, respiratory rate of 28 per minute, and oxygen saturation of 91% on room air. The patient was in respiratory distress using accessory muscles with diffuse rhonchi and crackles in the right lung base. There was no stridor. Remainder of the exam was unremarkable. A chest CT showed proximal tracheobronchial and right and left bronchial thickening with new right lower lobe infiltrate. Bronchoscopy revealed that the posterior wall of the carina was thickened with narrowing of the left and right mainstem bronchi. Direct laryngoscopy revealed a
http://tar.sagepub.com 49
Therapeutic Advances in Respiratory Disease 8(2)
Figure 3. Chest CT: pre-operative, immediate post-operative and 4 months post-operative. CT, computerized tomography.
nasopharyngeal mass that was excised. Biopsies of both the mass and tracheal mucosa were both positive for amyloid staining positive for Congo red with identification of amyloid A protein. An evaluation for systemic amyloidosis was negative. Between December 2011 and January 2012, rigid bronchoscopy with Nd:YAG laser debridement was successfully performed. This was followed by 10 fractions of 20 Gy external beam radiation. Repeat CT chest revealed improvement in the tracheal and proximal bronchial stenosis (Figure 3). At 9-month follow up, the patient reported intermittent, but improved, bouts of dyspnea. Discussion Amyloidosis is a systemic disease involving abnormal extracellular deposition of amyloid and autologous fibrillar protein material in β-pleated sheets. It is classified into four subtypes according to the subunit proteins – amyloid light chain (AL) disease (has monoclonal immunoglobulin), amyloid protein A (AA) disease (has serum amyloid A protein), amyloid transthyretin (ATTR) disease (has variant transthyretin) and amyloid β2-microglobulin (β2M) disease (has β2-microglobulin) [Berk et al. 2002]. These represent the most common forms of amyloidosis. The incidence of β2M disease is on decline due improvements in composition of dialysis filters [Traut et al. 2007]. Respiratory amyloidosis was first described by Lesser in 1877 [Lesser, 1877] and presents in three forms: focal/diffuse tracheobronchial pattern, nodular parenchymal pattern and diffuse parenchymal pattern. Nodular opacities are calcified in 30% and about 10% are cavitary. In one series, two-thirds of patients had multiple nodules [Hui et al. 1986]. They are present in the subpleural region of the mid-lung zones. There is no
associated lymphadenopathy [Berk et al. 2002]. The diffuse parenchymal pattern is usually seen with systemic amyloidosis and suggests primary AL disease [Berk et al. 2002]. Selective involvement of tracheobronchial tree is rare and is a potentially serious problem due to progressive airway compromise. The deposition of amyloid is submucosal and presents either as plaques or polyps. The deposits are either nodular or diffuse. In either case, these are mostly composed of immunoglobulin light chains produced by small number of plasma cells surrounding the involved airway. In a series of 15 patients, none expressed monoclonal protein, clonal plasma cell expansion, or deposits outside of the airways [Berk et al. 2002]. Once amyloidosis is diagnosed, it is imperative to evaluate other organ system involvement. Tracheobronchial amyloidosis affects females earlier, more often, and more extensively than males, and the typical age group affected is fifth or sixth decade, though it has been described in ages 16 through 85 [Diaz-Jimenez et al. 1999; Capizzi et al. 2000; O’Regan et al. 2000]. Presentation is usually subacute, with patients presenting with progressive dyspnea, wheezing, cough, recurrent pneumonia and hemoptysis. The symptoms of the disease can depend on location of the lesions. In those with proximal airway involvement, the symptoms are prominently obstructive. Those with mid-airway involvement present with lobar collapse and recurrent infections, while the distal airway involvement presents with recurrent pneumonia, cough, and bronchiectasis [Berk et al. 2002; Gibbaoui et al. 2004]. Bronchoscopy remains a cornerstone in establishing the diagnosis. Chest radiograph is normal in more than 50% of cases. CT scan of the chest is more accurate in identifying the circumferential
50 http://tar.sagepub.com
P Sommer, G Kumar et al. wall thickening with calcifications [Ding et al. 2010]. Other findings include features associated with bronchial narrowing such as atelectasis, bronchiectasis and lobar collapse [Ding et al. 2010]. Pleural effusion has also been reported with pulmonary amyloidosis [Kavuru et al. 1990; Berk et al. 2002; Rafii et al. 2011]. The differential diagnoses include tracheobronchial tuberculosis, relapsing polychondritis, and tracheobronchopathia with osteochondroplastica. Histopathological examination is thus crucial for a definitive diagnosis. The gold standard for the diagnosis of primary tracheobronchial amyloidosis is tissue with positive Congo red staining that produces green birefringence under crossed polarized light. There is no established treatment for tracheobronchial amyloidosis [Ding et al. 2010]. Therapeutic options include (1) bronchoscopic recanalization, (2) pharmacologic treatments and (3) external beam radiation therapy (EBRT) [Ding et al. 2010]. Bronchoscopic recanalization therapy options include laser resection, bronchoscopic dilatation and stenting, and cryosurgery. This may be useful for proximal or mid-airway lesions [Berk et al. 2002]. Surgical literature shows good control of symptoms with repeated bronchoscopic resection for as long as 11 years [Flemming et al. 1980; O’Regan et al. 2000; Maiwand et al. 2001]. The surgery is usually complicated by bleeding due to the friable nature of the amyloid affected mucosa [Capizzi et al. 2000]. Carbon dioxide (CO2) and Nd:YAG laser surgery and cryosurgery have good results with reduced bleeding [Herman et al. 1985; Maiwand and Homasson, 1995; O’Regan et al. 2000; Alloubi et al. 2012]. Medical therapies with corticosteroids, melphalan, colchicine and an iodinated isoform of doxorubicin have a limited role [Berk et al. 2002]. Since plasma cells are radiosensitive, low-dose radiation therapy remains the mainstay of treatment for tracheobronchial amyloidosis. The mechanism by which EBRT exerts its effects on the amyloid deposits in this disease is unclear. It has been proposed that amyloid deposition in the airway is a result of light chain deposition by local plasma cells and EBRT has an effect on these plasma cells [Neben-Wittch et al 2007]. Another theory suggests that EBRT has an effect on local vasculature with induction of an immune response against the deposits [Neben-Wittch et al 2007]. Kurrus and colleagues described regression in tracheobronchial amyloidosis after 20 Gy of radiation in 10 fractions [Kurrus et al. 1998]. Truong
and colleagues recently reported 80% local control in 10 patients after median follow up of 6.7 years [Truong et al. 2011]. Radiation esophagitis was the most common complication [NebenWittich et al. 2007; Truong et al. 2011]. Treatment with low dose radiation therapy has been reported with similar efficacy by others in the literature [Monroe et al. 2004; Neben-Wittich et al. 2007; Neuner et al. 2010]. Reports of multimodal therapy are scarce. In the case series reported by Truong and colleagues, 10 patients underwent initial external beam radiation at doses ranging from 18–20 Gy [Truong et al. 2011]. Of these, three patients underwent local control with laser surgical debulking, one underwent three surgical procedures and one underwent bronchodilatation with stent placement [Truong et al. 2011]. In this series, eight out of 10 patients achieved local control of airway amyloid at 6.7-year follow up [Truong et al. 2011]. It is unclear from this series if the patients receiving local surgical control followed by radiation had a longer duration of improvement. Ding and colleagues reported a total of 64 cases in China between the years 1970 and 2009 [Ding et al. 2010]. Of these, 36 cases reported therapeutic strategies. A total of 17 of the 36 were treated with Nd:YAG laser therapy with poor long-term response. One patient underwent EBRT. It was unclear from this study which patients, if any, underwent multimodality therapy. Neben-Wittich and colleagues reported a case series of seven patients who underwent successful EBRT with improvement in symptoms as early as 1 month of therapy and with symptom relief lasting >5 years [Neben-Wittich et al. 2007]. Two of the seven patients underwent prior local control surgical therapies. One underwent tracheal dilatation and one underwent repeated YAG laser. While all seven patients had improvement in symptoms with EBRT, it is unclear from the report if the two patients who had prior surgery had a sustained improvement. Prognosis is poorer for those with proximal airway involvement and those with diffuse disease [O’Regan et al. 2000; Berk et al. 2002]. Based on data from a cohort of 64 patients in China from years 1970–2009, estimated 5-year survival has ranged from 30% to 50% in diffuse disease [Ding et al. 2010]. A case series of patients treated with EBRT, with and without prior surgical therapies,
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Therapeutic Advances in Respiratory Disease 8(2) shows disease recurrence with symptoms to be in the range 6–80 months [Truong et al. 2011]. Though the most common form of amyloid deposition is the AL type, it is not clear from the literature if the form of amyloidosis has any bearing on overall prognosis. Our case reports add to the literature the success of multimodal therapy in the management of tracheobronchial amyloidosis. Surgical debulking followed by radiation therapy in both patients has produced sustained improvement in symptoms at 8-month follow up. Further studies are warranted to determine if radiation alone versus debulking therapy plus radiation affects outcomes of symptom relief, disease recurrence and mortality. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement The authors declare no conflicts of interest in preparing this article.
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