Case Report Localized Amyloidosis of the Lower Respiratory Tract1 ALAN RUBINOW, BARTOLOME R. CELLI, ALAN S. COHEN, BRIAN G. RIGDEN, and JEROME S. BRODY
SUMMARY Amyloidosis limited to the lower respiratory tract is a relatively rare condition. Three new patients are reported, and the pertinent literature is reviewed. The available information is discussed with regard to clinical forms, diagnostic methods, therapy, and clinical course. Tracheobronchial deposition is the most frequent form of localized amyloidosis; it affects relatively younger persons and often gives rise to symptoms of airway obstruction. Bronchoscopy, although carrying a risk of bleeding, is the procedure of choice diagnostically and therapeutically. Single or multiple pulmonary nodules are usually discovered as an incidental roentgenographic finding, and surgical resection (for suspected malignancy) has resulted in cure in all cases. On rare occasions, amyloid may be deposited diffusely in the pulmonary parenchyma, leading to death from respiratory insufficiency.
Introduction Amyloid deposition limited to the lower respiratory tract was first n o t e d by Lesser in 1877 (Received in original form February 27, 1978 and in revised form June 19,1978) 1 From the Thorndike Memorial Laboratory, Pulmonary and Arthritis and Connective Tissue Disease Sections, and the Departments of Medicine, Boston City Hospital and University Hospital, Boston University School of Medicine, Boston, Mass., and Lewes Chest Clinic, University of Sussex, England. 2 These investigations were supported by grants from the U.S. Public Health Service National Institute of Arthritis and Metabolic Diseases (AM-04599 and AM-07014), from the General Clinical Research Centers Branch of the Division of Research Resources, National Institutes of Health (RR-553), and the Massachusetts Chapter of the Arthritis Foundation, from the Arthritis Foundation, and from the John A. Hartford Foundation. 3 Requests for reprints should be addressed to Alan S. Cohen, M.D., Chief of Medicine, Thorndike 314, Boston City Hospital, 818 Harrison Ave., Boston, Mass. 02118.
(1) as an incidental autopsy finding. Since t h e n , it has been considered a r a r e entity a n d has been the subject of case reports a n d small series. I n view of the absence of an organized body of information on this subject, we wish to r e p o r t 3 patients with amyloid localized to the tracheobronchial tree or p u l m o n a r y p a r e n c h y m a a n d to review the p e r t i n e n t literature, emphasizing the clinical, diagnostic, a n d t h e r a p e u t i c features.
Case Reports As part of a long-term study of clinical amyloidosis (2-5), 3 patients with amyloidosis localized to the lower respiratory tract were seen in the Thorndike Memorial Laboratory at Boston City Hospital during the past 15 years. Their case histories are briefly summarized later, and all case descriptions and series in which amyloidosis was reported to be present in a localized form in the lower respiratory tract (trachea, bronchi, pulmonary parenchyma, pleura, and pulmonary lymph nodes) were reviewed. Only cases with histologic proof of diagnosis without evidence of amyloid elsewhere were accepted. In some cases, autopsy reports were available, whereas in others, although no postmortem material was reported, adequate investigation, including urinalysis,
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 118, 1978
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RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
protein electrophoresis, bone marrow examination, and rectal biopsy, failed to reveal generalized amyloidosis. These cases and our 3 cases were grouped according to a classification system that combines that suggested by Briggs (6) and that proposed by Prowse (7). Localized pulmonary amyloidosis was considered to be either tracheobronchial or parenchymal, and if parenchymal, either nodular (single or multiple) or diffuse. Tracheobronchial Amyloidosis A 39-year-old white man was first seen in 1971 because of dyspnea, cough, sputum production, and recurrent episodes of tracheobronchitis with bloodstreaked sputum. These episodes were partially improved by the use of bronchodilators and antimicrobial drugs, but they became more frequent and more severe with time. Expiratory wheezes were noted on physical examination. Repeated chest roentgenograms showed right middle lobe infiltrates (figure 1). Routine laboratory studies including hemograms, blood urea nitrogen, and urinalysis were all normal. Because of persistence of the clinical syndrome, a bronchoscopy was performed, and polypoid masses of abnormal tissue were seen to extend distally from the trachea, involving both major bronchi. A biopsy revealed a hyaline, eosinophilic mass that, after staining with Congo red, showed the typical apple green birefringence of amyloid when viewed under polarized light (figure 2). Blood vessels with thickened amyloid-laden walls were observed dispersed within the tissue. No calcification,
Fig. 1. Posteroanterior chest roentgenogram showing right middle lobe collapse secondary to obstructing tracheobronchial amyloid.
inflammatory infiltrate, or foreign body giant cells were seen. Electron microscopy revealed the characteristic, rigid, nonbranching fibrils characteristic of amyloid (figure 3). Protein electrophoresis and bonemarrow examination were normal. A search for Bence Jones protein in serum and urine was negative. A rectal biopsy was negative for amyloid. During the following 6 years, the patient had intermittent episodes of respiratory distress relieved temporarily by tissue resection performed by bronchoscopy. Severe uncontrollable bleeding after one episode of infection prompted the patient's death in 1976. Nodular Pulmonary Amyloidosis A 63-year-old white man was admitted to the hospital in 1965 because of seizures and a fractured humerus. He had smoked 30 packs of cigarettes per year and had a long history of alcohol consumption. His physical examination and routine laboratory studies were within normal limits. An admission chest roentgenogram showed a left upper lobe mass lesion without evidence of calcification. Sputum cytologic examination was repeatedly negative. Given the likelihood of primary lung cancer, a left upper lobectomy was performed. Pathologic examination revealed a yellow mass with a rubbery consistency that exhibited the apple green birefringence of amyloid when viewed under polarized light after Congo red staining. No calcification, blood vessel involvement, or inflammatory infiltrates were detected. Additional investigations including urinalysis, blood urea nitrogen, creatinine, liver function tests, protein electrophoresis, and a Congo red test were normal or negative. A rectal biopsy was negative for amyloid. The patient was lost to follow-up and died in an automobile accident in 1968. Diffuse Pulmonary Amyloidosis A 53-year-old white woman was in excellent health until June 1977, when she developed a dry, hacking cough followed by progressive dyspnea on exertion during the following 2 months. Physical examination revealed dullness at the base of the right lung and scattered end-inspiratory rales. Laboratory studies including urinalysis, erythrocyte sedimentation rate, blood urea nitrogen, creatinine, and liver function tests were normal. A protein electrophoresis revealed no M-component, and Bence-Jones protein was not detected in serum or urine. A chest roentgenogram showed a small lung volume with a diffuse multinodular pattern and a right pleural effusion. An open-lung biopsy revealed prominent amyloid infiltration of the alveolar septa and blood vessel walls. Biopsies of the rectum, skin, and bone marrow were negative for amyloid. During the subsequent 6 months, her pulmonary status continued to deteriorate.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
I Ul
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Fig. 2. A. Massive submucosal amyloid deposition in major airways. Compressed submucosal glands are evident. B. Polarizing microscopy showing typical green birefringence of amyloid (Congo Red stain; original magnification: X 100).
Discussion
Amyloidosis is usually viewed as a generalized disease involving multiple organ systems. Less well recognized is the localized form, in which amyloid deposits may be limited to the skin (8), bladder (9), kidney (10), or the upper respiratory tract (11, 12). Tracheobronchial amyloidosis is the most frequent of the forms of amyloidosis localized to the lower respiratory tract (7, 13-47). Solitary (44, 48-60) or multiple (36, 38, 49, 61-71) pulmonary nodules are less common, and we could find only 3 acceptable cases of diffuse pulmonary amyloidosis (36, 72, 73) in addition to our patient. The clinical, diagnostic, therapeutic, and prognostic features
of each of these forms are summarized in tables 1, 2, and 3. The average age of the 41 reported patients with the tracheobronchial form of amyloidosis was 53 years. Most patients exhibiting the nodular form of localized amyloidosis were older (average age, 65 years). Men and women with this form of the disease were seen with similar frequency, in contrast to the male predominance (2:1) seen in the tracheobronchial form and in systemic amyloidosis (74). Cough, dyspnea, and hemoptysis were the chief complaints of most of the patients with tracheobronchial deposition. On physical examination, wheezes and rhonchi (in many cases
606
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
Fig. 3. Electron micrograph of the tissue shown in figure 2, demonstrating the typical fibrillar structure of amyloid (original magnification: X 25,000).
localized to the affected hemithorax) were observed in 70 per cent of the cases; stridor and hoarseness, in 33 per cent. On the other hand, patients with nodular pulmonary amyloidosis were usually asymptomatic. Although cough was reported in 9 of 26 patients (36 per cent), dyspnea and hemoptysis, as well as abnormal findings on physical examination, were uncommon. All 4 patients with diffuse parenchymal infiltration complained of progressive dyspnea and a dry hacking cough. Bilateral end-inspiratory rales and pleural effusions were also observed, but neither hemoptysis nor signs of obstructive airway disease were seen. Chest roentgenograms were reported in 34 patients with tracheobronchial amyloidosis. Atelectatic changes distal to the site of obstruction were noted in 19 (56 per cent) of cases (3436); in 3 patients (9 per cent) hilar or mediastinal masses were the dominant findings (25, 26). In one case (8), unilateral emphysema was noted, presumably secondary to the ball valve effect of the obstructing amyloid mass (28). An abnormal bronchogram was described in 2 reports (29, 40). Nodules were usually incidentally found on the chest roentgenograms of el-
derly patients being evaluated for other problems. Isolated nodules may be located anywhere in the lung, and multiple nodules may be bilateral (65) or unilateral (67). Calcification (64, 66) or cavitation (65) was observed in 8 (29 per cent) and 3 (11 per cent) of 28 chest roentgenograms, respectively. In 3 cases, an increase in the size of the nodules over time was specifically mentioned (51, 58, 65). A reticulonodular radiographic pattern was seen in the 4 patients with the diffuse form, 2 of whom also demonstrated interstitial infiltration. The first reported cases of tracheobronchial amyloidosis were diagnosed at autopsy or later by thoracotomy (table 2). However, the diagnosis is best established by bronchoscopy (2831), which has been successful in all 25 patients in whom it was reported. A preoperative diagnosis of pulmonary parenchymal nodules is seldom made because of inherent difficulties reaching the lesions. Twenty-four patients were diagnosed at thoracotomy performed for suspected malignant neoplasm. A transthoracic needle biopsy was retrospectively positive in the case described by Dahlgreen and associates (68) and may be a useful procedure in selected cases.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
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Bronchoscopy performed in 11 cases was negative. In 2 of the 4 patients with diffuse pulmonary infiltration, an antemortem diagnosis was established by open lung biopsy. In this widespread form, a transbronchoscopic lung biopsy may have a role as a diagnostic tool. Bronchoscopy and resection of obstructing tracheobronchial amyloid tissue was performed in 18 of 22 patients (81 per cent). Temporary (20-22) and, in some instances, long-lasting improvement (25-30) has been observed. Often the lesion recurs within 6 to 12 months, and repeated resections are required. Severe postresection bleeding, as occurred in our patient, has been the cause of death in 3 patients (43, 45). Pneumonectomy (19), irradiation (30), lobectomy and irradiation (20), and tracheostomy and resection (20) are additional therapeutic procedures performed on rare occasions. From the available data, it is difficult to determine accurately the course of this form of the disease. Twenty-one patients were reported to be well 4 to 6 years after diagnosis. Conversely, 18 patients died. Six patients died from incidental causes; asphyxia (4 patients), respiratory insufficiency (4 patients), bleeding after resection (3 patients), and emphysema (1 patient) accounted for the other deaths. Lobectomy (54-57) was performed in 15 of the 20 pa'tients (75 per cent) with pulmonary nodules. Nodule resection (58) or biopsy alone (69) were other modes of therapy. There were no recurrences when lobar resection was performed, and in these patients, the prognosis is good. Although reports are incomplete, a few patients have died from what appeared to be unrelated causes. The course of patients with diffuse parenchymal pulmonary amyloidosis showed an inexorable progression to respiratory failure and death in 3 patients, and the prognosis in our patient is indeed poor. Corticosteroids administered to 2 patients (36, 73) did not appear to alter the course of the disease. The lung is frequently involved in all types of generalized amyloidosis (2, 6, 75, 76). Approximately 30 per cent of patients with primary amyloidosis complain of dyspnea and cough (6). They may exhibit a reticulonodular pattern or an interstitial infiltrate on chest roentgenogram. In rare instances, pulmonary deposition may result in respiratory insufficiency and death (77). Recently, Celli and co-workers (78) have reported that although 70 per cent of patients with secondary amyloidosis demonstrated amyloid de-
608
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
TABLE 2 LOCALIZED A M Y L O I D O S I S OF T H E LOWER RESPIRATORY T R A C T : DIAGNOSIS Roentgenograph ic Pattern
No. Patients
Type
41
Tracheobronchial
Atelectasis Mass Hilar Mediastinum Bronchogram Normal NR
19 3 2 1
Isolated Nodule Calcification Cavitation Enlarging
14 2
Nodules Calcification Cavitation Enlarging
13 6
16
Single pulmonary nodule
15
Multiple pulmonary nodule
Diffuse pulmonary parenchymal
4
Diagnostic Procedure
Localization
Bronchoscopy Autopsy Thoracotomy Tracheostomy
25 13 2 1
Thoracotomy Autopsy
13 3
LUL, 5 LLL, 3 RUL, 2 RLL, 5 RML, 1
Thoracotomy Autopsy
11 4
Unilateral, 6 Bilateral, 9 Apical, 1
-
2 9 7
1 2
2 1
Reticulonodular Interstitial infiltrate
4 2
Lung biopsy Autopsy
2 2
_
Definitions of abbreviations: NR = not recorded, L U L = left upper lobe, L L L = left lower lobe, R U L = right upper lobe, R L L = right lower lobe, R M L = right middle lobe.
posits in the pulmonary blood vessels and bronchial glands, they observed no infiltration of alveolar septa. Chest roentgenograms were normal, and no pulmonary symptoms were noted in this group of patients.
In most cases, amyloid, an insoluble, eosinophilic, extracellular, fibrillar substance, does not invoke a local inflammatory response (2). Plasma cells, multinucleated giant cells, and occasionally, lymphocytes have been described sur-
TABLE 3 LOCALIZED A M Y L O I D O S I S OF THE LOWER RESPIRATORY T R A C T : T R E A T M E N T AND COURSE No.
Type Tracheobronchial
Patients 41
Treatment Bronchoscopy, resection Pneumonectomy Lobectomy, irradiation Irradiation Tracheostomy, resection None Not recorded
18
10 2
Well
21
Asphyxia
1
Died Incidental
13 5
Respiratory insufficiency 4 Bleeding after resection 3
1 1
N o t recorded
2
Emphysema
Well Died Not recorded
6 2
Incidental
8
Well Died N o t recorded
2 8
16
Lobectomy Nodule resection Not recorded
Multiple pulmonary nodules
15
Lobectomy Biopsy alone Enucleation Not recorded
5 2
Corticosteroids
2
4
4
1
10 9
Single pulmonary nodule
Diffuse pulmonary parenchyma
Cause of Death
Course
4
1 7
Died Progressive respiratory insufficiency No response t o corticosteroids
5
3
1 2
Incidental
Respiratory insufficiency 3
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
r o u n d i n g local amyloid deposits in the l u n g (18, 19, 26). Conceivably, local abnormalities in the i m m u n e or o t h e r cellular systems may be involved in its formation. Biochemical studies from amyloid fibrils isolated from a p a t i e n t with local tracheobronchial amyloidosis revealed an N-terminal a m i n o acid residue identical to the variable regions of the i m m u n o g l o b u l i n light chain (79), similar to t h a t found in primary amyloidosis (80). From o u r review of the literature, as well as from o u r cases, it seems that w h e n amyloidosis is limited to the lower respiratory tract, the clinical course a n d prognosis will d e p e n d on the a n a t o m i c localization of the lesion. Careful a n d detailed prospective investigations in such cases may shed some light o n the pathogenesis of this disease. References 1. Lesser, A.: Ein fall von Enchondroma osteoides mixtum der Lunge mit partieller Amyloidentartung, Virchows Arch, 1877, 69, 404. 2. Cohen, A. S.: Amyloidosis, N Engl J Med, 1967, 277, 522. 3. Brandt, K. D., Cathcart, E. S., and Cohen, A. S.: A clinical analysis of the course and prognosis of forty two patients with amyloidosis, Am J Med, 1968,^,955. 4. Benson, M. D., Cohen, A. S., Brandt, K. D., and Cathcart, E. S.: Neuropathy, M-components and amyloid, Lancet, 1975,7,10. 5. Rubinow, A., and Cohen, A. S.: Skin involvement in generalized amyloidosis, Ann Intern Med, 1978, &?, 781. 6. Briggs, G. W.: Amyloidosis, Ann Intern Med, 1961,55,943. 7. Prowse, C. B.: Amyloidosis of the lower respiratory tract, Thorax, 1958,13, 308. 8. Brownstein, M. H., and Helwig, E. B.: T h e cutaneous amyloidoses. I. Localized forms, Arch Dermatol, 1970,192, 8. 9. Malek, R. S., Greene, L. F., and Farrow, G. M.: Amyloidosis of the urinary bladder, Br J Urol, 1971,43,189. 10. Gardner, K. D., Jr., Castellino, R. A., Kempson, R., Young, B. W., and Stamey, T. A.: Primary amyloidosis of the renal pelvis, N Engl J Med, 1971,2^,1196. 11. New, G. B.: Amyloid tumors of the upper air passages, Laryngoscope, 1919,29, 327. 12. New, G. B., and Erich, J. B.: Benign tumors of the larynx, Arch Otolaryngol, 1938,28, 843. 13. Balser, W.: Tracheo und Bronchostenose mit Amyloid in der wandug der Luftwege, Virchows Arch [Pathol Anat], 1883,91,67. 14. Kraus, F.: Neue Beobachtugen von herdweinsem Amyloid, Z Heick, 1886, 7,245. 15. Ulrich, J. J.: An amyloid tumor of the larynx
609
and lungs, Arch Laryngol Rhinol, 1903, 14, 321. 16. Glockner, A.: Ueber Lokales, tumorformiges amyloid des Larynx der trachea and der grossen Bronchien mit dadurch bedingter Laryngogtracheostenose, Virchows Arch [Pathol Anat], 1900,160, 583. 17. Von Werdt, F.: Lokales Amyloid in gesamten Respiration trakt, Beitr Pathol Anat, 1908, 43, 239. 18. Falconer, B.: Ein fall von amyloid tumor der trachea und der grossen bronchien mit dysproeischen Erscheinungen, Acta Oto-Laryngol, 1938, 26, 353. 19. Weissman, R. E., Clagett, O. T., and McDonald, J. R.: Amyloid disease of the lung treated by pneumonectomy. Report of a case, J Thorac Cardiovasc Surg, 1947,16,269. 20. Hollinger, P. H., Novak, F. J., and Johnston, K. C : Tumors of the trachea, Laryngoscope, 1950, 60,1086. 21. Schottenfeld, A.: Localized amyloid deposition in the lower respiratory tract, Am J Med, 1951, 77,770. 22. Whitnell, F.: Localized amyloid infiltration of lower respiratory tract, Thorax, 1953, 8,309. 23. Bolstad, D. S.: Primary amyloidosis in the lower respiratory tract, Ann Otol, 1954, 63,200. 24. Gordon, W.: Amyloid deposits in the bronchii, Br Med J, 1955,7,825. 25. Schmidt, H. W., McDonald, J. R., and Clagett, O. T.: Amyloid tumors of the lower respiratory tract and mediastinum, Ann Otol, 1953, 62, 880. 26. McGurk, F. M.: Primary bronchial amyloidosis, Br J Radiol, 1968,41, 795. 27. Domm, B. M„ Vasallo, C. L., and Adams, C. L.: Amyloid deposition localized to the lower respiratory tract, Am J Med, 1965,38,151. 28. Dood, A. R., and Mann, J. D.: Primary diffuse amyloidosis of the respiratory tract, Arch Pathol, 1959, 67, 39. 29. Kamberg, S., Loitman, B. S., and Holtz, S.: Amyloidosis of the tracheobronchial tree, N Engl J Med, 1962, 266,587. 30. Shinoi, K., Shirai-Shi, U., and Yahata, J.: Amyloid tumor of the trachea and lung resembling bronchial asthma, Chest, 1962,42,442. 31. Buitendyik, J. H., and Maesen, F.: L'amyloidoise primitive de l'arbre bronchique: A propos d'un cas, Presse Med, 1963, 71,1513. 32. Delarue, J., Pointillart, J., and Garaix, J. P.: Tumerus amyloides localisees de la muqueuse tracheo-bronchique, J Fr Med Chir Thorac, 1957,77,416. 33. Antunes, M. L., and Vieria da Luz, J. M.: Primary diffuse tracheo-bronchial amyloidosis, Thorax, 1969,24, 307. 34. Gregor, W. M., and Lucke, H. H.: Amyloidosis of bronchus resembling carcinoma, Can Med Assoc J,1968,99, 912. 35. O'Malley, E., Neligan, M. C , and Dempsey, J. V.:
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36.
37.
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48.
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50.
51. 52. 53.
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
Diffuse tracheo-bronchial amyloidosis, Irish J Med Sci, 1971,140, 343. Gordonson, J. S., Sargent, E. N., Jacobson, G., and Turner, A. F.: Roentgenographic manifestations of pulmonary amyloidosis, J Can Assoc Radiol, 1972,25,269. Gottlieb, L., and Gold, W.: Primary tracheobronchial amyloidosis, Am Rev Respir Dis, 1972,105> 425. Cotton, R. E., and Jackson, J. W.: Localized amyloid "tumors" of the lung simulating malignant neoplasms, Thorax, 1964,19,97. Cood, A. J., Weinstein, M., and Powell, R. D.: Diffuse amyloidosis of the tracheobronchial tree. Bronchographic manifestations, Radiology, 1973, 107, 303. Attwood, H. D., Price, G. C , and Ridell, R. J.: Primary diffuse tracheobronchial amyloidosis, Thorax, 1972, 27,620. Alroy, C. G., Lichty, C , and Kaftori, J. K.: Tracheobronchopathia osteoplastica. End state of primary lung amyloidosis? Chest, 1972, 61, 465. Henrikson, P., and Liljenberg, B.: Bronchial asthma and tumor forming amyloidosis of trachea and bronchi, Acta Allergol (Kbh), 1962, 17, 276. Mainwaring, A. R., Williams, G., and Knight, E. O. W.: Localized amyloidosis of the lower respiratory tract, Thorax, 1969,24,441. Bonfils-Roberts, E., Marx, A. J., and Nealon, T . T., Jr.: Primary amyloidosis of the respiratory tract, Ann Thorac Surg, 1975,19, 313. Shaheen, N. A., Salmon, S. D., and Nassar, V. H.: Fatal bronchopulmonary hemorrhage due to unrecognized amyloidosis, Arch Otol, 1975, 101, 259. Keen, P. E., and Weitzner, S.: Primary localized amyloidosis of trachea, Arch Ophthalmol, 1972, 96, 142. Noring, O., and Paaby, H.: Diffuse amyloidosis in the lower air passages, Acta Pathol Microbiol Scand, 1952,31, 470. Haynes, A. L., Clagett, O. T., and McDonald, J. R.: Tumor forming amyloidosis of the lung, Surgery, 1948,24, 120. Candiani, G.: L'amiloidose atipica del Pulmone (Considerasioni su due casi), Riv Anat Patol Oncol, 1953, 7, 333. Fors, B., and Ryden, L.: Tumoral amyloidosis of the lung, Acta Pathol Microbiol Scand, 1964, 61,1. Craver, W. L.: Solitary amyloid tumor of the lung, J Thorac Cardiovasc Surg, 1965,49,860. Hayes, W. T., and Bernhardt, H.: Solitary amyloid mass of the lung, Cancer, 1969,24,820. Reeder, M. M., Hocholzer, L., and Evans, R. G.: RPC of the month from AFIP, Radiology, 1969, 93, 1369.
54. Chauduri, R. M., and Parker, D.: A solitary amyloid nodule in the lung, Thorax, 1970, 25, 382. 55. Skagset, R., and Norman, T.: Localized amyloid tumor of the lung, Scand J Thorac Cardiovasc Surg, 1970, 4, 135. 56. Saab-Salim, B., Burke, J., Hoperman, A., and Almond, C : Tumor forming amyloidosis, J Thorac Cardiovasc Surg, 1974, 67, 301. 57. Branner, G. J., Albazzaz, F., and Mihm, M. C : Acquired bullous disease of the skin in solitary amyloidoma of the lung, Am J Med, 1974, 57, 978. 58. Dyke, P. C , Demaray, M. J., Delevan, J. W., and Rasmussen, R. A.: Pulmonary amyloidoma, Am J Clin Pathol, 1974,52,301. 59. Klein, G., and Trollman, W.: Localized amyloid tumor of the lung, Prax Pneumol, 1974, 28, 482. 60. Makinen, J., Nickels, J., and Halttunen, P. A. E.: Amyloid tumor of the lung, Acta Pathol Microbiol Scand [A], 1977, 85,907. 61. Meyer, O.: Uber lokales tumorartiges amyloid in den Lungen, Frankf Z Pathol, 1911,8, 304. 62. Gery, M. L.: Amylose locale du poumon, Bull Mem Soc Anat Paris, 1924,94, 328. 63. Bergman, F., and Linder, E.: Tumor-forming amyloidosis of the lung, J Thorac Surg, 1961, 35, 628. 64. Lundin, P., Simonsson, B., and Winberg, T.: Pneumopleural amyloid tumor, Acta Radiol (Stockh), 1961,55, 139. 65. Weiss, L.: Isolated multiple nodular pulmonary amyloidosis, Am J Clin Pathol, 1960,33, 318. 66. Condon, R. E., Pinkham, R. D., and Hames, G. H.: Primary isolated nodular pulmonary amyloidosis. Report of a case, J Thorac Cardiovasc Surg,1964, 48, 498. 67. Firestone, F. N., and Joison, J.: Amyloidosis, a cause of primary tumors of the lung, J Thorac Cardiovasc Surg, 1966, 51, 292. 68. Dahlgreen, S. E., Lewenhaupt, A., and Ovenfors, C. O.: Fine needle biopsy diagnosis in nodular pulmonary amyloidosis, Acta Pathol Microbiol Scand [A], 1970,75,1. 69. Moldow, R. E., Bearman, S., and Edelman, M. H.: Pulmonary amyloidosis simulating tuberculosis, Am Rev Respir Dis, 1972,105,114. 70. Lee, S. C , and Johnson, H. A.: Multiple nodular pulmonary amyloidosis, Thorax, 1975, 30, 178. 71. Teixdor, A.: Multiple amyloid tumors of the lung, Am J Roentgenol Radium Ther Nucl Med, 1971,111,525. 72. Fenoglio, C , and Pascal, R.: Nodular amyloidosis of the lungs: An unusual case associated with chronic lung disease and carcinoma of the bladder, Arch Pathol, 1970,90,577. 73. Zundel, W. E., and Prior, A. P.: An amyloid lung, Thorax, 1971,2(5,357.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
74. Kyle, R. A., and Bayrd, E. D.: Amyloidosis. Review of 236 cases, Medicine (Baltimore), 1975, 54,211. 75. Hallen, J., and Rudin, R.: Peri-collagenous amyloidosis. A study of 51 cases, Acta Med Scand, 1966,179, 483. 76. Toriumi, J.: The lung in generalized amyloidosis, Acta Pathol Jap, 1972,22, 141. 77. Rajau, V. T., and Kikkawa, Y.: Alveolar septal amyloidosis in primary amyloidosis, Arch Pathol,
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1970,59,521. 78. Celli, B., Rubinow, A., Cohen, A. S., and Brody, J. S.: Patterns of pulmonary involvement in systemic amyloidosis, Chest, In press. 79. Page, D. L., Isersky, C , Harada, M., and Glenner, G. G.: Immunoglobulin origin of localized nodular pulmonary amyloidosis, Res Exp Med, 1972, 159, 75. 80. Cohen, A. S.: Studies of amyloidosis, Arthritis Rheum, 1977,20, (Supplement, p. 576).
SUMMARY Amyloidosis limited to the lower respiratory tract is a relatively rare condition. Three new patients are reported, and the pertinent literature is reviewed. The available information is discussed with regard to clinical forms, diagnostic methods, therapy, and clinical course. Tracheobronchial deposition is the most frequent form of localized amyloidosis; it affects relatively younger persons and often gives rise to symptoms of airway obstruction. Bronchoscopy, although carrying a risk of bleeding, is the procedure of choice diagnostically and therapeutically. Single or multiple pulmonary nodules are usually discovered as an incidental roentgenographic finding, and surgical resection (for suspected malignancy) has resulted in cure in all cases. On rare occasions, amyloid may be deposited diffusely in the pulmonary parenchyma, leading to death from respiratory insufficiency.
Introduction Amyloid deposition limited to the lower respiratory tract was first n o t e d by Lesser in 1877 (Received in original form February 27, 1978 and in revised form June 19,1978) 1 From the Thorndike Memorial Laboratory, Pulmonary and Arthritis and Connective Tissue Disease Sections, and the Departments of Medicine, Boston City Hospital and University Hospital, Boston University School of Medicine, Boston, Mass., and Lewes Chest Clinic, University of Sussex, England. 2 These investigations were supported by grants from the U.S. Public Health Service National Institute of Arthritis and Metabolic Diseases (AM-04599 and AM-07014), from the General Clinical Research Centers Branch of the Division of Research Resources, National Institutes of Health (RR-553), and the Massachusetts Chapter of the Arthritis Foundation, from the Arthritis Foundation, and from the John A. Hartford Foundation. 3 Requests for reprints should be addressed to Alan S. Cohen, M.D., Chief of Medicine, Thorndike 314, Boston City Hospital, 818 Harrison Ave., Boston, Mass. 02118.
(1) as an incidental autopsy finding. Since t h e n , it has been considered a r a r e entity a n d has been the subject of case reports a n d small series. I n view of the absence of an organized body of information on this subject, we wish to r e p o r t 3 patients with amyloid localized to the tracheobronchial tree or p u l m o n a r y p a r e n c h y m a a n d to review the p e r t i n e n t literature, emphasizing the clinical, diagnostic, a n d t h e r a p e u t i c features.
Case Reports As part of a long-term study of clinical amyloidosis (2-5), 3 patients with amyloidosis localized to the lower respiratory tract were seen in the Thorndike Memorial Laboratory at Boston City Hospital during the past 15 years. Their case histories are briefly summarized later, and all case descriptions and series in which amyloidosis was reported to be present in a localized form in the lower respiratory tract (trachea, bronchi, pulmonary parenchyma, pleura, and pulmonary lymph nodes) were reviewed. Only cases with histologic proof of diagnosis without evidence of amyloid elsewhere were accepted. In some cases, autopsy reports were available, whereas in others, although no postmortem material was reported, adequate investigation, including urinalysis,
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 118, 1978
603
604
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
protein electrophoresis, bone marrow examination, and rectal biopsy, failed to reveal generalized amyloidosis. These cases and our 3 cases were grouped according to a classification system that combines that suggested by Briggs (6) and that proposed by Prowse (7). Localized pulmonary amyloidosis was considered to be either tracheobronchial or parenchymal, and if parenchymal, either nodular (single or multiple) or diffuse. Tracheobronchial Amyloidosis A 39-year-old white man was first seen in 1971 because of dyspnea, cough, sputum production, and recurrent episodes of tracheobronchitis with bloodstreaked sputum. These episodes were partially improved by the use of bronchodilators and antimicrobial drugs, but they became more frequent and more severe with time. Expiratory wheezes were noted on physical examination. Repeated chest roentgenograms showed right middle lobe infiltrates (figure 1). Routine laboratory studies including hemograms, blood urea nitrogen, and urinalysis were all normal. Because of persistence of the clinical syndrome, a bronchoscopy was performed, and polypoid masses of abnormal tissue were seen to extend distally from the trachea, involving both major bronchi. A biopsy revealed a hyaline, eosinophilic mass that, after staining with Congo red, showed the typical apple green birefringence of amyloid when viewed under polarized light (figure 2). Blood vessels with thickened amyloid-laden walls were observed dispersed within the tissue. No calcification,
Fig. 1. Posteroanterior chest roentgenogram showing right middle lobe collapse secondary to obstructing tracheobronchial amyloid.
inflammatory infiltrate, or foreign body giant cells were seen. Electron microscopy revealed the characteristic, rigid, nonbranching fibrils characteristic of amyloid (figure 3). Protein electrophoresis and bonemarrow examination were normal. A search for Bence Jones protein in serum and urine was negative. A rectal biopsy was negative for amyloid. During the following 6 years, the patient had intermittent episodes of respiratory distress relieved temporarily by tissue resection performed by bronchoscopy. Severe uncontrollable bleeding after one episode of infection prompted the patient's death in 1976. Nodular Pulmonary Amyloidosis A 63-year-old white man was admitted to the hospital in 1965 because of seizures and a fractured humerus. He had smoked 30 packs of cigarettes per year and had a long history of alcohol consumption. His physical examination and routine laboratory studies were within normal limits. An admission chest roentgenogram showed a left upper lobe mass lesion without evidence of calcification. Sputum cytologic examination was repeatedly negative. Given the likelihood of primary lung cancer, a left upper lobectomy was performed. Pathologic examination revealed a yellow mass with a rubbery consistency that exhibited the apple green birefringence of amyloid when viewed under polarized light after Congo red staining. No calcification, blood vessel involvement, or inflammatory infiltrates were detected. Additional investigations including urinalysis, blood urea nitrogen, creatinine, liver function tests, protein electrophoresis, and a Congo red test were normal or negative. A rectal biopsy was negative for amyloid. The patient was lost to follow-up and died in an automobile accident in 1968. Diffuse Pulmonary Amyloidosis A 53-year-old white woman was in excellent health until June 1977, when she developed a dry, hacking cough followed by progressive dyspnea on exertion during the following 2 months. Physical examination revealed dullness at the base of the right lung and scattered end-inspiratory rales. Laboratory studies including urinalysis, erythrocyte sedimentation rate, blood urea nitrogen, creatinine, and liver function tests were normal. A protein electrophoresis revealed no M-component, and Bence-Jones protein was not detected in serum or urine. A chest roentgenogram showed a small lung volume with a diffuse multinodular pattern and a right pleural effusion. An open-lung biopsy revealed prominent amyloid infiltration of the alveolar septa and blood vessel walls. Biopsies of the rectum, skin, and bone marrow were negative for amyloid. During the subsequent 6 months, her pulmonary status continued to deteriorate.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
I Ul
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Fig. 2. A. Massive submucosal amyloid deposition in major airways. Compressed submucosal glands are evident. B. Polarizing microscopy showing typical green birefringence of amyloid (Congo Red stain; original magnification: X 100).
Discussion
Amyloidosis is usually viewed as a generalized disease involving multiple organ systems. Less well recognized is the localized form, in which amyloid deposits may be limited to the skin (8), bladder (9), kidney (10), or the upper respiratory tract (11, 12). Tracheobronchial amyloidosis is the most frequent of the forms of amyloidosis localized to the lower respiratory tract (7, 13-47). Solitary (44, 48-60) or multiple (36, 38, 49, 61-71) pulmonary nodules are less common, and we could find only 3 acceptable cases of diffuse pulmonary amyloidosis (36, 72, 73) in addition to our patient. The clinical, diagnostic, therapeutic, and prognostic features
of each of these forms are summarized in tables 1, 2, and 3. The average age of the 41 reported patients with the tracheobronchial form of amyloidosis was 53 years. Most patients exhibiting the nodular form of localized amyloidosis were older (average age, 65 years). Men and women with this form of the disease were seen with similar frequency, in contrast to the male predominance (2:1) seen in the tracheobronchial form and in systemic amyloidosis (74). Cough, dyspnea, and hemoptysis were the chief complaints of most of the patients with tracheobronchial deposition. On physical examination, wheezes and rhonchi (in many cases
606
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
Fig. 3. Electron micrograph of the tissue shown in figure 2, demonstrating the typical fibrillar structure of amyloid (original magnification: X 25,000).
localized to the affected hemithorax) were observed in 70 per cent of the cases; stridor and hoarseness, in 33 per cent. On the other hand, patients with nodular pulmonary amyloidosis were usually asymptomatic. Although cough was reported in 9 of 26 patients (36 per cent), dyspnea and hemoptysis, as well as abnormal findings on physical examination, were uncommon. All 4 patients with diffuse parenchymal infiltration complained of progressive dyspnea and a dry hacking cough. Bilateral end-inspiratory rales and pleural effusions were also observed, but neither hemoptysis nor signs of obstructive airway disease were seen. Chest roentgenograms were reported in 34 patients with tracheobronchial amyloidosis. Atelectatic changes distal to the site of obstruction were noted in 19 (56 per cent) of cases (3436); in 3 patients (9 per cent) hilar or mediastinal masses were the dominant findings (25, 26). In one case (8), unilateral emphysema was noted, presumably secondary to the ball valve effect of the obstructing amyloid mass (28). An abnormal bronchogram was described in 2 reports (29, 40). Nodules were usually incidentally found on the chest roentgenograms of el-
derly patients being evaluated for other problems. Isolated nodules may be located anywhere in the lung, and multiple nodules may be bilateral (65) or unilateral (67). Calcification (64, 66) or cavitation (65) was observed in 8 (29 per cent) and 3 (11 per cent) of 28 chest roentgenograms, respectively. In 3 cases, an increase in the size of the nodules over time was specifically mentioned (51, 58, 65). A reticulonodular radiographic pattern was seen in the 4 patients with the diffuse form, 2 of whom also demonstrated interstitial infiltration. The first reported cases of tracheobronchial amyloidosis were diagnosed at autopsy or later by thoracotomy (table 2). However, the diagnosis is best established by bronchoscopy (2831), which has been successful in all 25 patients in whom it was reported. A preoperative diagnosis of pulmonary parenchymal nodules is seldom made because of inherent difficulties reaching the lesions. Twenty-four patients were diagnosed at thoracotomy performed for suspected malignant neoplasm. A transthoracic needle biopsy was retrospectively positive in the case described by Dahlgreen and associates (68) and may be a useful procedure in selected cases.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
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Bronchoscopy performed in 11 cases was negative. In 2 of the 4 patients with diffuse pulmonary infiltration, an antemortem diagnosis was established by open lung biopsy. In this widespread form, a transbronchoscopic lung biopsy may have a role as a diagnostic tool. Bronchoscopy and resection of obstructing tracheobronchial amyloid tissue was performed in 18 of 22 patients (81 per cent). Temporary (20-22) and, in some instances, long-lasting improvement (25-30) has been observed. Often the lesion recurs within 6 to 12 months, and repeated resections are required. Severe postresection bleeding, as occurred in our patient, has been the cause of death in 3 patients (43, 45). Pneumonectomy (19), irradiation (30), lobectomy and irradiation (20), and tracheostomy and resection (20) are additional therapeutic procedures performed on rare occasions. From the available data, it is difficult to determine accurately the course of this form of the disease. Twenty-one patients were reported to be well 4 to 6 years after diagnosis. Conversely, 18 patients died. Six patients died from incidental causes; asphyxia (4 patients), respiratory insufficiency (4 patients), bleeding after resection (3 patients), and emphysema (1 patient) accounted for the other deaths. Lobectomy (54-57) was performed in 15 of the 20 pa'tients (75 per cent) with pulmonary nodules. Nodule resection (58) or biopsy alone (69) were other modes of therapy. There were no recurrences when lobar resection was performed, and in these patients, the prognosis is good. Although reports are incomplete, a few patients have died from what appeared to be unrelated causes. The course of patients with diffuse parenchymal pulmonary amyloidosis showed an inexorable progression to respiratory failure and death in 3 patients, and the prognosis in our patient is indeed poor. Corticosteroids administered to 2 patients (36, 73) did not appear to alter the course of the disease. The lung is frequently involved in all types of generalized amyloidosis (2, 6, 75, 76). Approximately 30 per cent of patients with primary amyloidosis complain of dyspnea and cough (6). They may exhibit a reticulonodular pattern or an interstitial infiltrate on chest roentgenogram. In rare instances, pulmonary deposition may result in respiratory insufficiency and death (77). Recently, Celli and co-workers (78) have reported that although 70 per cent of patients with secondary amyloidosis demonstrated amyloid de-
608
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
TABLE 2 LOCALIZED A M Y L O I D O S I S OF T H E LOWER RESPIRATORY T R A C T : DIAGNOSIS Roentgenograph ic Pattern
No. Patients
Type
41
Tracheobronchial
Atelectasis Mass Hilar Mediastinum Bronchogram Normal NR
19 3 2 1
Isolated Nodule Calcification Cavitation Enlarging
14 2
Nodules Calcification Cavitation Enlarging
13 6
16
Single pulmonary nodule
15
Multiple pulmonary nodule
Diffuse pulmonary parenchymal
4
Diagnostic Procedure
Localization
Bronchoscopy Autopsy Thoracotomy Tracheostomy
25 13 2 1
Thoracotomy Autopsy
13 3
LUL, 5 LLL, 3 RUL, 2 RLL, 5 RML, 1
Thoracotomy Autopsy
11 4
Unilateral, 6 Bilateral, 9 Apical, 1
-
2 9 7
1 2
2 1
Reticulonodular Interstitial infiltrate
4 2
Lung biopsy Autopsy
2 2
_
Definitions of abbreviations: NR = not recorded, L U L = left upper lobe, L L L = left lower lobe, R U L = right upper lobe, R L L = right lower lobe, R M L = right middle lobe.
posits in the pulmonary blood vessels and bronchial glands, they observed no infiltration of alveolar septa. Chest roentgenograms were normal, and no pulmonary symptoms were noted in this group of patients.
In most cases, amyloid, an insoluble, eosinophilic, extracellular, fibrillar substance, does not invoke a local inflammatory response (2). Plasma cells, multinucleated giant cells, and occasionally, lymphocytes have been described sur-
TABLE 3 LOCALIZED A M Y L O I D O S I S OF THE LOWER RESPIRATORY T R A C T : T R E A T M E N T AND COURSE No.
Type Tracheobronchial
Patients 41
Treatment Bronchoscopy, resection Pneumonectomy Lobectomy, irradiation Irradiation Tracheostomy, resection None Not recorded
18
10 2
Well
21
Asphyxia
1
Died Incidental
13 5
Respiratory insufficiency 4 Bleeding after resection 3
1 1
N o t recorded
2
Emphysema
Well Died Not recorded
6 2
Incidental
8
Well Died N o t recorded
2 8
16
Lobectomy Nodule resection Not recorded
Multiple pulmonary nodules
15
Lobectomy Biopsy alone Enucleation Not recorded
5 2
Corticosteroids
2
4
4
1
10 9
Single pulmonary nodule
Diffuse pulmonary parenchyma
Cause of Death
Course
4
1 7
Died Progressive respiratory insufficiency No response t o corticosteroids
5
3
1 2
Incidental
Respiratory insufficiency 3
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
r o u n d i n g local amyloid deposits in the l u n g (18, 19, 26). Conceivably, local abnormalities in the i m m u n e or o t h e r cellular systems may be involved in its formation. Biochemical studies from amyloid fibrils isolated from a p a t i e n t with local tracheobronchial amyloidosis revealed an N-terminal a m i n o acid residue identical to the variable regions of the i m m u n o g l o b u l i n light chain (79), similar to t h a t found in primary amyloidosis (80). From o u r review of the literature, as well as from o u r cases, it seems that w h e n amyloidosis is limited to the lower respiratory tract, the clinical course a n d prognosis will d e p e n d on the a n a t o m i c localization of the lesion. Careful a n d detailed prospective investigations in such cases may shed some light o n the pathogenesis of this disease. References 1. Lesser, A.: Ein fall von Enchondroma osteoides mixtum der Lunge mit partieller Amyloidentartung, Virchows Arch, 1877, 69, 404. 2. Cohen, A. S.: Amyloidosis, N Engl J Med, 1967, 277, 522. 3. Brandt, K. D., Cathcart, E. S., and Cohen, A. S.: A clinical analysis of the course and prognosis of forty two patients with amyloidosis, Am J Med, 1968,^,955. 4. Benson, M. D., Cohen, A. S., Brandt, K. D., and Cathcart, E. S.: Neuropathy, M-components and amyloid, Lancet, 1975,7,10. 5. Rubinow, A., and Cohen, A. S.: Skin involvement in generalized amyloidosis, Ann Intern Med, 1978, &?, 781. 6. Briggs, G. W.: Amyloidosis, Ann Intern Med, 1961,55,943. 7. Prowse, C. B.: Amyloidosis of the lower respiratory tract, Thorax, 1958,13, 308. 8. Brownstein, M. H., and Helwig, E. B.: T h e cutaneous amyloidoses. I. Localized forms, Arch Dermatol, 1970,192, 8. 9. Malek, R. S., Greene, L. F., and Farrow, G. M.: Amyloidosis of the urinary bladder, Br J Urol, 1971,43,189. 10. Gardner, K. D., Jr., Castellino, R. A., Kempson, R., Young, B. W., and Stamey, T. A.: Primary amyloidosis of the renal pelvis, N Engl J Med, 1971,2^,1196. 11. New, G. B.: Amyloid tumors of the upper air passages, Laryngoscope, 1919,29, 327. 12. New, G. B., and Erich, J. B.: Benign tumors of the larynx, Arch Otolaryngol, 1938,28, 843. 13. Balser, W.: Tracheo und Bronchostenose mit Amyloid in der wandug der Luftwege, Virchows Arch [Pathol Anat], 1883,91,67. 14. Kraus, F.: Neue Beobachtugen von herdweinsem Amyloid, Z Heick, 1886, 7,245. 15. Ulrich, J. J.: An amyloid tumor of the larynx
609
and lungs, Arch Laryngol Rhinol, 1903, 14, 321. 16. Glockner, A.: Ueber Lokales, tumorformiges amyloid des Larynx der trachea and der grossen Bronchien mit dadurch bedingter Laryngogtracheostenose, Virchows Arch [Pathol Anat], 1900,160, 583. 17. Von Werdt, F.: Lokales Amyloid in gesamten Respiration trakt, Beitr Pathol Anat, 1908, 43, 239. 18. Falconer, B.: Ein fall von amyloid tumor der trachea und der grossen bronchien mit dysproeischen Erscheinungen, Acta Oto-Laryngol, 1938, 26, 353. 19. Weissman, R. E., Clagett, O. T., and McDonald, J. R.: Amyloid disease of the lung treated by pneumonectomy. Report of a case, J Thorac Cardiovasc Surg, 1947,16,269. 20. Hollinger, P. H., Novak, F. J., and Johnston, K. C : Tumors of the trachea, Laryngoscope, 1950, 60,1086. 21. Schottenfeld, A.: Localized amyloid deposition in the lower respiratory tract, Am J Med, 1951, 77,770. 22. Whitnell, F.: Localized amyloid infiltration of lower respiratory tract, Thorax, 1953, 8,309. 23. Bolstad, D. S.: Primary amyloidosis in the lower respiratory tract, Ann Otol, 1954, 63,200. 24. Gordon, W.: Amyloid deposits in the bronchii, Br Med J, 1955,7,825. 25. Schmidt, H. W., McDonald, J. R., and Clagett, O. T.: Amyloid tumors of the lower respiratory tract and mediastinum, Ann Otol, 1953, 62, 880. 26. McGurk, F. M.: Primary bronchial amyloidosis, Br J Radiol, 1968,41, 795. 27. Domm, B. M„ Vasallo, C. L., and Adams, C. L.: Amyloid deposition localized to the lower respiratory tract, Am J Med, 1965,38,151. 28. Dood, A. R., and Mann, J. D.: Primary diffuse amyloidosis of the respiratory tract, Arch Pathol, 1959, 67, 39. 29. Kamberg, S., Loitman, B. S., and Holtz, S.: Amyloidosis of the tracheobronchial tree, N Engl J Med, 1962, 266,587. 30. Shinoi, K., Shirai-Shi, U., and Yahata, J.: Amyloid tumor of the trachea and lung resembling bronchial asthma, Chest, 1962,42,442. 31. Buitendyik, J. H., and Maesen, F.: L'amyloidoise primitive de l'arbre bronchique: A propos d'un cas, Presse Med, 1963, 71,1513. 32. Delarue, J., Pointillart, J., and Garaix, J. P.: Tumerus amyloides localisees de la muqueuse tracheo-bronchique, J Fr Med Chir Thorac, 1957,77,416. 33. Antunes, M. L., and Vieria da Luz, J. M.: Primary diffuse tracheo-bronchial amyloidosis, Thorax, 1969,24, 307. 34. Gregor, W. M., and Lucke, H. H.: Amyloidosis of bronchus resembling carcinoma, Can Med Assoc J,1968,99, 912. 35. O'Malley, E., Neligan, M. C , and Dempsey, J. V.:
610
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51. 52. 53.
RUBINOW, CELLI, COHEN, RIGDEN, AND BRODY
Diffuse tracheo-bronchial amyloidosis, Irish J Med Sci, 1971,140, 343. Gordonson, J. S., Sargent, E. N., Jacobson, G., and Turner, A. F.: Roentgenographic manifestations of pulmonary amyloidosis, J Can Assoc Radiol, 1972,25,269. Gottlieb, L., and Gold, W.: Primary tracheobronchial amyloidosis, Am Rev Respir Dis, 1972,105> 425. Cotton, R. E., and Jackson, J. W.: Localized amyloid "tumors" of the lung simulating malignant neoplasms, Thorax, 1964,19,97. Cood, A. J., Weinstein, M., and Powell, R. D.: Diffuse amyloidosis of the tracheobronchial tree. Bronchographic manifestations, Radiology, 1973, 107, 303. Attwood, H. D., Price, G. C , and Ridell, R. J.: Primary diffuse tracheobronchial amyloidosis, Thorax, 1972, 27,620. Alroy, C. G., Lichty, C , and Kaftori, J. K.: Tracheobronchopathia osteoplastica. End state of primary lung amyloidosis? Chest, 1972, 61, 465. Henrikson, P., and Liljenberg, B.: Bronchial asthma and tumor forming amyloidosis of trachea and bronchi, Acta Allergol (Kbh), 1962, 17, 276. Mainwaring, A. R., Williams, G., and Knight, E. O. W.: Localized amyloidosis of the lower respiratory tract, Thorax, 1969,24,441. Bonfils-Roberts, E., Marx, A. J., and Nealon, T . T., Jr.: Primary amyloidosis of the respiratory tract, Ann Thorac Surg, 1975,19, 313. Shaheen, N. A., Salmon, S. D., and Nassar, V. H.: Fatal bronchopulmonary hemorrhage due to unrecognized amyloidosis, Arch Otol, 1975, 101, 259. Keen, P. E., and Weitzner, S.: Primary localized amyloidosis of trachea, Arch Ophthalmol, 1972, 96, 142. Noring, O., and Paaby, H.: Diffuse amyloidosis in the lower air passages, Acta Pathol Microbiol Scand, 1952,31, 470. Haynes, A. L., Clagett, O. T., and McDonald, J. R.: Tumor forming amyloidosis of the lung, Surgery, 1948,24, 120. Candiani, G.: L'amiloidose atipica del Pulmone (Considerasioni su due casi), Riv Anat Patol Oncol, 1953, 7, 333. Fors, B., and Ryden, L.: Tumoral amyloidosis of the lung, Acta Pathol Microbiol Scand, 1964, 61,1. Craver, W. L.: Solitary amyloid tumor of the lung, J Thorac Cardiovasc Surg, 1965,49,860. Hayes, W. T., and Bernhardt, H.: Solitary amyloid mass of the lung, Cancer, 1969,24,820. Reeder, M. M., Hocholzer, L., and Evans, R. G.: RPC of the month from AFIP, Radiology, 1969, 93, 1369.
54. Chauduri, R. M., and Parker, D.: A solitary amyloid nodule in the lung, Thorax, 1970, 25, 382. 55. Skagset, R., and Norman, T.: Localized amyloid tumor of the lung, Scand J Thorac Cardiovasc Surg, 1970, 4, 135. 56. Saab-Salim, B., Burke, J., Hoperman, A., and Almond, C : Tumor forming amyloidosis, J Thorac Cardiovasc Surg, 1974, 67, 301. 57. Branner, G. J., Albazzaz, F., and Mihm, M. C : Acquired bullous disease of the skin in solitary amyloidoma of the lung, Am J Med, 1974, 57, 978. 58. Dyke, P. C , Demaray, M. J., Delevan, J. W., and Rasmussen, R. A.: Pulmonary amyloidoma, Am J Clin Pathol, 1974,52,301. 59. Klein, G., and Trollman, W.: Localized amyloid tumor of the lung, Prax Pneumol, 1974, 28, 482. 60. Makinen, J., Nickels, J., and Halttunen, P. A. E.: Amyloid tumor of the lung, Acta Pathol Microbiol Scand [A], 1977, 85,907. 61. Meyer, O.: Uber lokales tumorartiges amyloid in den Lungen, Frankf Z Pathol, 1911,8, 304. 62. Gery, M. L.: Amylose locale du poumon, Bull Mem Soc Anat Paris, 1924,94, 328. 63. Bergman, F., and Linder, E.: Tumor-forming amyloidosis of the lung, J Thorac Surg, 1961, 35, 628. 64. Lundin, P., Simonsson, B., and Winberg, T.: Pneumopleural amyloid tumor, Acta Radiol (Stockh), 1961,55, 139. 65. Weiss, L.: Isolated multiple nodular pulmonary amyloidosis, Am J Clin Pathol, 1960,33, 318. 66. Condon, R. E., Pinkham, R. D., and Hames, G. H.: Primary isolated nodular pulmonary amyloidosis. Report of a case, J Thorac Cardiovasc Surg,1964, 48, 498. 67. Firestone, F. N., and Joison, J.: Amyloidosis, a cause of primary tumors of the lung, J Thorac Cardiovasc Surg, 1966, 51, 292. 68. Dahlgreen, S. E., Lewenhaupt, A., and Ovenfors, C. O.: Fine needle biopsy diagnosis in nodular pulmonary amyloidosis, Acta Pathol Microbiol Scand [A], 1970,75,1. 69. Moldow, R. E., Bearman, S., and Edelman, M. H.: Pulmonary amyloidosis simulating tuberculosis, Am Rev Respir Dis, 1972,105,114. 70. Lee, S. C , and Johnson, H. A.: Multiple nodular pulmonary amyloidosis, Thorax, 1975, 30, 178. 71. Teixdor, A.: Multiple amyloid tumors of the lung, Am J Roentgenol Radium Ther Nucl Med, 1971,111,525. 72. Fenoglio, C , and Pascal, R.: Nodular amyloidosis of the lungs: An unusual case associated with chronic lung disease and carcinoma of the bladder, Arch Pathol, 1970,90,577. 73. Zundel, W. E., and Prior, A. P.: An amyloid lung, Thorax, 1971,2(5,357.
AMYLOIDOSIS OF THE LOWER RESPIRATORY TRACT
74. Kyle, R. A., and Bayrd, E. D.: Amyloidosis. Review of 236 cases, Medicine (Baltimore), 1975, 54,211. 75. Hallen, J., and Rudin, R.: Peri-collagenous amyloidosis. A study of 51 cases, Acta Med Scand, 1966,179, 483. 76. Toriumi, J.: The lung in generalized amyloidosis, Acta Pathol Jap, 1972,22, 141. 77. Rajau, V. T., and Kikkawa, Y.: Alveolar septal amyloidosis in primary amyloidosis, Arch Pathol,
611
1970,59,521. 78. Celli, B., Rubinow, A., Cohen, A. S., and Brody, J. S.: Patterns of pulmonary involvement in systemic amyloidosis, Chest, In press. 79. Page, D. L., Isersky, C , Harada, M., and Glenner, G. G.: Immunoglobulin origin of localized nodular pulmonary amyloidosis, Res Exp Med, 1972, 159, 75. 80. Cohen, A. S.: Studies of amyloidosis, Arthritis Rheum, 1977,20, (Supplement, p. 576).
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