Path. Res. Pract. 164, 41)-422 (1979)
From Institute of Pathology, Liibeck Medical School, Lubeck, West Germany (Head: Prof. A. Gropp)
Senile Pulmonary Amyloidosis W.-P.KUNZE
Summary Lung tissue obtained from 340 necropsies of persons aged 80 years and oyer was investigated for the occurrence of pulmonary amyloid deposits by means of a sensitive fluorescence technique. The incidence of pulmonary amyloidosis was about 2% below the age of 80, nearly 10% in individuals between 80 and 84 years, and more than 20% at and beyond 85 years. Vascular and concomitant alveolar-septal amyloidosis was seen slightly more often than the pure septal form of senile amyloidosis. The two modes of deposition correspond to two different forms of cardiac amyloidosis, vascular and nodular. On the other hand, the two different modes of pulmonary amyloidosis affect different age groups. It is postulated that the disorder is related to age-linked immunological disturbances and to genetically determined factors.
Introduction Pulmonary amyloidosis is classified by Spencer (1977) into four groups: (1) localized amyloidosis of the tracheobronchial walls, (2) diffuse bronchial amyloidosis, (3) nodular parenchymatous amyloidosis, (4) diffuse parenchymal amyloidosis. Some case reports on pulmonary amyloidosis indicate that the nodular and the diffuse parenchymal manifestation of the disorder are rare (Bachmann, 1967; Beck, 1970; Keiser et al., 1974; Poh et al., 1975; Lee and Johnson, 1975). Occasionally diffuse amyloidosis is seen in generalized disease (Toriumi, 1972), and more often it is reported in association with senile amyloidosis of the heart (Buerger and Braunstein, 1960; Pomerance, 1966). In spite of many publications on senile amyloidosis, it is difficult to find exact data on the incidence of pulmonary amyloidosis in persons of advanced age. For that reason tissues collected from autopsies of aged subjects were screened for the occurrence of pulmonary deposits.
4 14 . W.-P. Kunze
Material and Methods Tissues collected from autopsies performed between October 1972 and March 1975 were used in this retrospective study. The material included 340 cases of individuals 80 years of age or older, and a random sample of 251 autopsy cases in younger age groups (see Table I). Paraffin embedded, formalin fixed samples of the left cardiac ventricle, the periphery of the lungs, and in several cases blocks of kidney, liver, and spleen, were screened for amyloid with a simple modification of the highly sensitive fluorescence method of Sajkiewicz and Bausdorf (1968). Routine sections (5-6 urn thick) were brought to distilled water and allowed to dry. Then a few drops of a solution of acridine orange (1 : 10,000) in half-normal hydrochloric acid were placed upon the sections and spread out by mounting a cover slip. After removal of excess solution, the slides were carefully blotted dry and examined by epi-illumination (Zeiss-Universal fluorescence microscope, HBO 200 mercury bulb, KP 500 exciting filter, barrier filters 53 and 47). Under these conditions, amyloid substance fluoresces bright yellow to orange, the tissues are greenish, and fibrin appears amber in color. Color photography may be used to document this staining, but for black and white pictures thioflavin stains are preferable (see Fig. 1-3). The bright fluorescence of acridine organe allows the use of a low power objective (e.g. Neofluar 6,3 X). This fact and the simple staining procedure are ideally suited for fast and precise scanning of many sections. Since the sensitive method is not strictly specific for amyloid, all positive and all doubtful results had to be confirmed by positive green birefringence (Missmahl and Hartwig, 1953) in Congo red stained slides (Puchtler et aI., 1962).
Results The absolute and relative incidence of pulmonary amyloidosis in different age groups and the corresponding chi square tests are shown in Table 2. In all age groups, amyloidosis of the lung was seen nearly as often as it was in the left ventricle of the heart. Pulmonary amyloid was usually found when senile amyloidosis of the heart was present. Isolated amyloid of the left cardiac ventricle occurred in nine cases, but pulmonary amyloidosis without deposits in other organs was found only twice. The
Table
1.
age
List of cases 5°-69
70-79
80-84
85- 89
90-100 ---
total
106
145
206
93
females
46
males
60
57 88
12 4
82
total
---~._---
54
41 20
59 1 3°1
39
21
29°
Senile Pulmonary Amyloidosis . 4 15
amount of pulmonary amyloidosis, however, did not show any relation to the quantity of amyloid in the heart. Men may be affected more often than women (p slightly larger than 0.05 by the chi square test). Two different types of amyloid deposition were found. The more frequent type was represented by combined vascular and alveolar septal deposits. A less frequent type was strictly limited to the alveolar septa, and other structures remained unaffected. Amyloidosis of the bronchial walls was not found, although occasionally vascular amyloidosis occurred in larger bronchi. Tumor-like nodular amyloidosis, observed in a single case, appeared not to be typical for the age groups in this study. Isolated vascular amy-
Table 2.
Incidence of pulmonary amyloidosis according to age
Age:
70-79
80- 84
90-100
total
Lungs, all cases of pulmonary amyloidosis (without nodular type)
3 (2%) ". 1(2010)". 2 (20iO) 'f
total females males
18 (90/0) » 9 (70/0) 'f 9 (IIo/O) x-
20 (22%) I I (200/0) 9 (230/0) "
8 (200/0) 2 (100/0) 6 (29010)
49 23 26
(120/0) 7 (130/0) 4 (100/0)
2 (50/0) 2 (100/0)
27 13 14
9 (roO/o) 4 (70/0) 5 (130/0)
6 (15%) 2 (roO/o) 4 (190/0)
22 10 12
20 (220/0) 8 (150/0) 12 (31%)
9 (220/0) 4 (22%) 5 (24%)
56 28 28
Lungs, mixed vascular and alveolarseptal amyloidosis
3 (20/0) I (2°10) 2 (2%)
total females males
II (50/0)" 5 (40/0) » 6 (70/0)
Lungs, alveolar septal amyloidosis total females males
7 (30/0) x4 (30/0) 'f 3 (4%) ".
II
Lungs, nodular pulmonary amyloidosis female Heart, left ventricle total females males
I (10/0) 3 (20/0) ". I (20/0) 1 (2%) 2 (20/0) ".
23 (IIo/O) 14 (II%) 9 (IIO/o)
The age group from 80 to 89 years of age, which was studied most extensively, is divided into two groups. Significant differences between neighboring columns are marked by an asterisk (").
4 16 .
Fig.
1.
~r._p .
Kunz e
Mixed vascular and alveolar septa l pulmonary amyloidosis. Th ioflavin S; X
15 0 .
Fig. 2 . Alveolar septa l amyloidosis. Note that the vessels are free of amyloid . Th io flavin S; X 220.
Senile Pulm onary Amyloidosis . 417
Fig. 3 a. (top ) Nodular am yloidosis of th e heart in a case of isolated alveolar septal pulmonary amylo idosis. Hydrochloric acridine oran ge inclusion stain. Reproduction of a color slid e using a red filter: X 220. b. (Botto m) Vascular and fine reticular interstitial amyloidosis of the heart in a case of mixed vascular and alveolar septal amyloidosis. Same data as in (a).
418 . W.-P. Kunze
loidosis was not seen. Whenever amyloid occurred in the walls of pulmonary vessels, alveolar septal depositions were also present. Sometimes only traces of concomitant alveolar septal amyloid existed, but usually distinct vascular amyloidosis was linked with marked septal deposition. Patches of amyloid were usually found in the tunica media or in transmural segments of a vessel, but in lungs with more conspicuous changes, involvement of the whole circumference of a vessel was not rare. In general, amyloid was about as frequent in veins as in arteries. Mixed vascular and alveolar-septal amyloidosis of the lung was always linked with vascular amyloidosis of the heart. A few cases showed a delicate interstitial network of amyloid deposits (Fig. 3). The mixed vascular and alveolar-septal type was significantly (Mann and Whitney U-test) more frequent in relatively younger age groups, differing in this respect from the pure septal type, which predominated in higher age groups (85 years and older). In the heart, this latter type was invariably linked with nodular interstitial amyloidosis. In some of the cases studied, amyloid depositions were very scanty. They would have remained undetected but for the aid of the sensitive fluorescence method, although they were subsequently demonstrated by the Congo-red stain. Only in 12 cases out of so were more than 20% of the alveolar septa involved by lesions. Most of such "severe" manifestations were mixed vascular and septal type, and usually occurred in males in the oldest age groups. Owing to the rather small number of cases in this category, no significant differences were found by the chi square test. A careful check of the principal clinical and pathologic diagnoses of all patients with pulmonary amyloidosis reported here revealed the occurrence of some kind of long-standing inflammatory disease - usually mild (in all cases with amyloid. But the same held true for almost all cases in the control group. In 17 cases of pulmonary amyloidosis, carcinomas of various sites and types were present; but in this respect too, the control group was not different. One case of multiple myeloma in an 84 year old woman with marked vascular and septal amyloidosis is included in this material.
Discussion Like cardiac amyloidosis (Hiisselmann, 1955; Pomerance, 1975), pulmonary amyloidosis is rare before the age of 70. However, it becomes a frequent disorder among persons beyond the age of 80 years, and the intensity of manifestation increases with age. These facts and the striking coincidence of pulmonary amyloid with amyloidosis of the left cardiac
Senile Pulmonary Amyloidosis . 4 19
ventricle (Wright and Calkins, 1975) justify the classification of the disorder as a pulmonary manifestation of senile amyloidosis. This probably does not hold true for the one case of nodular, tumorlike amyloidosis in an 80 year old woman (Table 2). In fact, other exceptional pulmonary "amyloid tumors" have been described in aged individuals, but usually they affect patients at approximately the age of 60 years (Kiihl, 1960; Fors and Ryden, 1964; Hayes and Bernhardt, 1969; Fenoglio and Pascal, 1970; Keller et al., 1974; Lee and Johnson, 1975). Thus, it does not seem justified to regard nodular amyloidosis as a manifestation of senile amyloidosis. The cases of age-associated amyloidosis show two different patterns of pulmonary deposition. One type, with predominance in very old individuals, is restricted to the alveolar septa and linked with classical nodular cardiac amyloidosis . The other type of mixed vascular and septal diffuse pulmonary amyloid is somewhat more frequent. Vascular deposits are also common in other organs. In fact, vascular deposition of amyloid represents the basic change of this mixed type of amyloidosis in the lung, since concomitant septal infiltration is also found in nodular pulmonary amyloidosis and in bronchial amyloidosis (Whitwell, 1952; Noring and Paaby, 1952; Attwood et al., 1972). Isolated vascular amyloidosis, on the other hand, has been reported by Toriumi (1972), although it remains possible that more sensitive techniques would have uncovered traces of septal amyloid even in these cases. The reported description of pulmonary changes in cases of presenile primary diffuse pulmonary amyloidosis (Biiriimcekci, 1938; Sappington et al., 1942; Dahlin, 1948 Bachmann, 1967; Beck, 1970; Eshun-Wilson et al., 1976) corresponds mostly to the vascular or mixed vascular and alveolar septal type. We do not know whether or not "severe" cases of this type observed in our series produced an alveolar capillary block, as reported by Zundel and Prior (1971), Crosbie et al. (1972) and Poh et al. (1975). Eshun-Wilson et al. (1976) assumed that amyloid in the basement membranes of alveolar septa causes only minor impairment of pulmonary function. Their opinion was based on scanning and transmission electron microscopy findings in a case of mixed vascular and septal pulmonary amyloidosis in which the deposits consisted of a porous meshwork of interwoven fibrils through which gases were thought to diffuse easily. Thus for it seems that no correlation is established between the amount of amyloid deposited in the alveolar septum and possible impairment of gaseous exchange. Although the nature and origin of senile amyloid are still controversial or even obscure, changes of the immune system and genetic influences
420 .
W.-P. Kunze
probably playa role. Reports on presenile diffuse pulmonary amyloidosis allude to the occurrence of multiple myeloma (Bachmann, 1967), plasrnocytosis, and dysproteinemia (Beck, 1970, Keiser et al., 1973). Multiple myeloma was present in one typical case of mixed vascular and alveolar amyloidosis in our series. The more frequent type of senile amyloidosis is morphologically similar to amyloidosis linked with dysproteinaemia and deposition of light chain amyloid (AL) (Cohen, 1965). However, a second type of amyloid, amyloid A (AA), is thought to be important as well, since amyloid A-related serum component (SAA) increases in the average population beyond the age of 70 (Glenner et aI., 1973; Glenner et al., 1974; Anders et al., 1975; Benson et al., 1975). It has been inferred from the occurrence of variant types of age-related amyloidosis in different strains of mice (Thung, 1957b; Ziesche, 1970; Scheinberg et al., 1976) that senile amyloidosis is influenced by genetic factors in this and possibly in other species. Moreover, it has been suggested that not only the well known inheritable amyloid syndromes (Thomas, 1975) but also senile amyloidosis, is determined genetically in man (Walford,19 69)' It is concluded that the two modes of senile pulmonary amyloidosis described in this report correspond to two distinguishable types of ageassociated amyloid disease, characterized by differences in morphology and age profile. Their individuality might depend on a genetically determined susceptibility to the development of chemically distinct amyloid deposits, as suggested by Thung (1957 a).
References 1.
2.
3. 4. 5.
6. 7.
Anders, R. P., Natvig, J. B., Michaelsen, T. E., and Husby, G.: Isolation and characterization of amyloid related serum protein SAA as a low molecular weight protein. Scand. J. Immuno!. 4, 397-401 (1975) Attwood, H. D., Price, c. G., and Riddell, R. J.: Primary diffuse tracheobronchial amyloidosis. Thorax 27, 6-'0-624 (1972) Bachmann, R.: Die diffuse alvcolarseprale Lungenamyloidose. Frankf. Z. Path. 76, I I 1-120 (1967) Beck, O. A.: Diffuse alvcolarseptale Lungcnamy!oidose. Virchows Arch. Abt. A. Path. Anal. 350, 336-352 (1970) Benson, M., Skinner, M., Lian, J., and Cohen, A. S.: "A" protein of amyloidosis. Isolation of a cross-reacting component from serum by affinity chromatography. Arthr, and Rheum. I8, 315-322 (1975) Buerger, 1., and Braunstein, H.: Senile cardiac amyloidosis. Amer. J. Med. 28, 357367 (196o) Biiriimcekci, K.: Mitteilung eines Falles von atypischer Amyloidose. Virchows Arch. Path. Anal. 302,6°7-617 (1938)
Senile Pulmonary Amyloidosis. 421 8. Cohen, A. S.: The constitution and genesis of amyloid. Int. Rev. expo Path. 4, 159243 (1965) • 9. Crosbie, W. A., Lewis, M. c., Ramsay, I. D., and Doyle, D.: Pulmonary amyloidosis with Impaired gas transfer. Thorax 27, 625-630 (1972) 10. Dahlin, D. c.: Primary amyloidosis with report of six cases. Amer. J. Path. 25, 10 5-12 3 (1949) II. Dyke, P. c., Demaray, M. J., Delavan, J. W., and Ramussen, R. A.: Pulmonary amyloidosis. Amer. J. Clin. Path. 61, 301-305 (1974) 12. Eshun-Wilson, K., Frandsen, N. E., and Christensen, H. E.: Pulmonary alveolar septal amyloidosis. Virchows Arch. Abt. A., Path. Anat. 371, 89-99 (1976) 13. Fenoglio, c., and Pascal, R. R.: Nodular Amyloidosis of the lungs. An unusual case associated with chronic lung disease and carcinoma of the bladder. Arch. Path. 90, 577-582 (197 0) 14. Fors, B., and Ryden, L.: Tumoral amyloidosis of the lung. Acta path. microbiol. scand. 61, 1-12 (1964) 15. Franklin, E. c.: Amyloidosis. Bull. Rheum. Dis. 26,832-837 (1975/1976) 16. Glenner, G. G., Terry, W. D., and Isersky, Ch.: Amyloidosis: It's nature and pathogenesis. Sem, Haematol. TO, 65-86 (1973) 17. Glenner, G. G., Eanes, E. D., Bladen, H. A., Linke, R. P., and Termine, J. D.: Beta pleated sheat fibrils. A comparison of native amyloid with synthetic protein fibrils. J. Histochem, Cytochem. 22, II41-1I58 (1974) 18. Hayes, W. T., and Bernhardt, H.: Solitary amyloid mass of the lung. Cancer 24, 820-825 (1969) 19. Hiisselmann, H.: Beitrag zum Amyloidproblem auf Grund von Untersuchungen an menschlichen Herzen. Virchows Arch. Path. Anat. 327,607-628 (1955) 20. Keiler, A., Steffen, A., and Syre, G.: Zur Problematik der isolierten tumorformigen Amyloidose. Thoraxchirurgie 22, 86-93 (1974) 21. Keiser, A., Wegemann, W., Lutenegger, H., Baessler, E., and Winzler, A.: Generalisierte Amyloidose mit Paraproteinaemie, diffuser Plasmocytose des Knochenmarks und diffuser alveolarseptaler Lungenamyloidose. Dtsch. med. Wschr. 98, 614-619 (1973) 22. Kiihl, I.: Beitrag zur tumorforrnigen Amyloidose. Z. inn. Med. IS, IODO-I008 (1960) 23. Lee, S. c., and Johnson, H. A.: Multiple nodular pulmonary amyloidosis. Thorax )0, 17 8-185 (1975) 24. Missmahl, H. P., and Hertwig, M.: Polarisarionsoptische Untersuchungen an der Amyloidsubstanz. Virchows Arch. Path. Anat. 324, 489-508 (1953) 25. Noring, 0., and Paaby, H.: Diffuse amyloidosis in the lower air passages. Acta path. microbiol. scand. ]1, 470-475 (1952) 26. Poh, S. c., Tjia, T. S., and Seah, H. Thorax ]0, 186-191 (1975)
c.: Primary diffuse alveolar septal amyloidosis.
27. Pomerance, A.: Amyloidosis. In: Pomerance, A., and Davies, M. J. (Ed.): The Pathology of the Heart, pp. 251-256. Blackwell, Oxford (1975) 28. Puchtler, H., Sweat, F., and Levine, M.: On the binding of congo red by amyloid. J. Histochem. Cytochem, io, 335-364 (1962) 29. Sajkiewicz, K., and Bausdorf, B.: Ein empfindlicher Amyloidnachweis mit einer Acridinorange-Einschlullf1uorochromierung. Z. med. Labortechnik 9, 293-295 (1968) 30. Sappington, S. W., Davie, J. H., and Horneff, J. A.: Primary amyloidosis of the lung. J. Lab. Clin. Med. 27, 882-888 (1942) 28 Path. Res. Pract. Vol. 164
4 2 2 . W.-P. Kunze 31. Scheinberg, M. A., Cathcart, E. S., Eastcott, J. W., Skinner, M., Benson, M., Shirama, T., and Bennet, M.: The SSC-Mouse. A new model for spontaneous age associated amyloidosis I: Morphological and immunochemical aspects. Lab. Invest. 35, 47-54 (1976) 32. Spencer, H.: Amyloidosis of the lung. In: Spencer, H.: Pathology of the lung, pp. 675-680. Pergamon Press, Oxford (1977) 33. Thomas, P. K.: Genetic factors in amyloidosis. J. med. Genet. 12, JI7-326 (1975) 34. Thung, P. J.: The relation between amyloid and ageing in comparative pathology. Gerontologia (Basel) 1,234-254 (1957a) 35· Thung, P. J.: Senile amyloidosis in mice. Gerontologia (Basel) 1, 259-279 (1957b) 36. Toriumi, J.: The lung in generalized amyloidosis. Acta path. Jap. 22, 141-252 (197 2) 37. Walford, R. L.: The immunologic theory of ageing. Munksgaard, Copenhagen (1969) 38. Whitwell, F.: Localized amyloid infiltrations of the lower respiratory tract. Thorax 8,3 09-3 15 (1953) 39. Wright, J. R., and Calkins, E.: Amyloid in the aged heart: Frequency and clinical significance. J. Amer, Geriatr. Soc. 23, 97-103 (1975) 40. Ziesche, W.: Die spontane Amyloidose der Maus, I. Die altersabhangige Amyloidrate verschiedener Inzuchtstamme, Z. Versuchstierk, (lena) 12, 321-329 (1970) 41. Zundel, W. E., and Prior, A. P.: An amyloid lung. Thorax 26, 357-363 (1971)
Received August 14, 1978 . Accepted in revised form November 30, 1978
Key words: Pulmonary amyloidosis - Cardiac amyloidosis - Age distribution - Genetic determination - Fluorescence Dr. Wolf-Peter Kunze, Institut fiir Pathologie der Medizinischen Hochschule Liibeck, Ratzeburger Allee 160, D-2400 Liibeck 1
From Institute of Pathology, Liibeck Medical School, Lubeck, West Germany (Head: Prof. A. Gropp)
Senile Pulmonary Amyloidosis W.-P.KUNZE
Summary Lung tissue obtained from 340 necropsies of persons aged 80 years and oyer was investigated for the occurrence of pulmonary amyloid deposits by means of a sensitive fluorescence technique. The incidence of pulmonary amyloidosis was about 2% below the age of 80, nearly 10% in individuals between 80 and 84 years, and more than 20% at and beyond 85 years. Vascular and concomitant alveolar-septal amyloidosis was seen slightly more often than the pure septal form of senile amyloidosis. The two modes of deposition correspond to two different forms of cardiac amyloidosis, vascular and nodular. On the other hand, the two different modes of pulmonary amyloidosis affect different age groups. It is postulated that the disorder is related to age-linked immunological disturbances and to genetically determined factors.
Introduction Pulmonary amyloidosis is classified by Spencer (1977) into four groups: (1) localized amyloidosis of the tracheobronchial walls, (2) diffuse bronchial amyloidosis, (3) nodular parenchymatous amyloidosis, (4) diffuse parenchymal amyloidosis. Some case reports on pulmonary amyloidosis indicate that the nodular and the diffuse parenchymal manifestation of the disorder are rare (Bachmann, 1967; Beck, 1970; Keiser et al., 1974; Poh et al., 1975; Lee and Johnson, 1975). Occasionally diffuse amyloidosis is seen in generalized disease (Toriumi, 1972), and more often it is reported in association with senile amyloidosis of the heart (Buerger and Braunstein, 1960; Pomerance, 1966). In spite of many publications on senile amyloidosis, it is difficult to find exact data on the incidence of pulmonary amyloidosis in persons of advanced age. For that reason tissues collected from autopsies of aged subjects were screened for the occurrence of pulmonary deposits.
4 14 . W.-P. Kunze
Material and Methods Tissues collected from autopsies performed between October 1972 and March 1975 were used in this retrospective study. The material included 340 cases of individuals 80 years of age or older, and a random sample of 251 autopsy cases in younger age groups (see Table I). Paraffin embedded, formalin fixed samples of the left cardiac ventricle, the periphery of the lungs, and in several cases blocks of kidney, liver, and spleen, were screened for amyloid with a simple modification of the highly sensitive fluorescence method of Sajkiewicz and Bausdorf (1968). Routine sections (5-6 urn thick) were brought to distilled water and allowed to dry. Then a few drops of a solution of acridine orange (1 : 10,000) in half-normal hydrochloric acid were placed upon the sections and spread out by mounting a cover slip. After removal of excess solution, the slides were carefully blotted dry and examined by epi-illumination (Zeiss-Universal fluorescence microscope, HBO 200 mercury bulb, KP 500 exciting filter, barrier filters 53 and 47). Under these conditions, amyloid substance fluoresces bright yellow to orange, the tissues are greenish, and fibrin appears amber in color. Color photography may be used to document this staining, but for black and white pictures thioflavin stains are preferable (see Fig. 1-3). The bright fluorescence of acridine organe allows the use of a low power objective (e.g. Neofluar 6,3 X). This fact and the simple staining procedure are ideally suited for fast and precise scanning of many sections. Since the sensitive method is not strictly specific for amyloid, all positive and all doubtful results had to be confirmed by positive green birefringence (Missmahl and Hartwig, 1953) in Congo red stained slides (Puchtler et aI., 1962).
Results The absolute and relative incidence of pulmonary amyloidosis in different age groups and the corresponding chi square tests are shown in Table 2. In all age groups, amyloidosis of the lung was seen nearly as often as it was in the left ventricle of the heart. Pulmonary amyloid was usually found when senile amyloidosis of the heart was present. Isolated amyloid of the left cardiac ventricle occurred in nine cases, but pulmonary amyloidosis without deposits in other organs was found only twice. The
Table
1.
age
List of cases 5°-69
70-79
80-84
85- 89
90-100 ---
total
106
145
206
93
females
46
males
60
57 88
12 4
82
total
---~._---
54
41 20
59 1 3°1
39
21
29°
Senile Pulmonary Amyloidosis . 4 15
amount of pulmonary amyloidosis, however, did not show any relation to the quantity of amyloid in the heart. Men may be affected more often than women (p slightly larger than 0.05 by the chi square test). Two different types of amyloid deposition were found. The more frequent type was represented by combined vascular and alveolar septal deposits. A less frequent type was strictly limited to the alveolar septa, and other structures remained unaffected. Amyloidosis of the bronchial walls was not found, although occasionally vascular amyloidosis occurred in larger bronchi. Tumor-like nodular amyloidosis, observed in a single case, appeared not to be typical for the age groups in this study. Isolated vascular amy-
Table 2.
Incidence of pulmonary amyloidosis according to age
Age:
70-79
80- 84
90-100
total
Lungs, all cases of pulmonary amyloidosis (without nodular type)
3 (2%) ". 1(2010)". 2 (20iO) 'f
total females males
18 (90/0) » 9 (70/0) 'f 9 (IIo/O) x-
20 (22%) I I (200/0) 9 (230/0) "
8 (200/0) 2 (100/0) 6 (29010)
49 23 26
(120/0) 7 (130/0) 4 (100/0)
2 (50/0) 2 (100/0)
27 13 14
9 (roO/o) 4 (70/0) 5 (130/0)
6 (15%) 2 (roO/o) 4 (190/0)
22 10 12
20 (220/0) 8 (150/0) 12 (31%)
9 (220/0) 4 (22%) 5 (24%)
56 28 28
Lungs, mixed vascular and alveolarseptal amyloidosis
3 (20/0) I (2°10) 2 (2%)
total females males
II (50/0)" 5 (40/0) » 6 (70/0)
Lungs, alveolar septal amyloidosis total females males
7 (30/0) x4 (30/0) 'f 3 (4%) ".
II
Lungs, nodular pulmonary amyloidosis female Heart, left ventricle total females males
I (10/0) 3 (20/0) ". I (20/0) 1 (2%) 2 (20/0) ".
23 (IIo/O) 14 (II%) 9 (IIO/o)
The age group from 80 to 89 years of age, which was studied most extensively, is divided into two groups. Significant differences between neighboring columns are marked by an asterisk (").
4 16 .
Fig.
1.
~r._p .
Kunz e
Mixed vascular and alveolar septa l pulmonary amyloidosis. Th ioflavin S; X
15 0 .
Fig. 2 . Alveolar septa l amyloidosis. Note that the vessels are free of amyloid . Th io flavin S; X 220.
Senile Pulm onary Amyloidosis . 417
Fig. 3 a. (top ) Nodular am yloidosis of th e heart in a case of isolated alveolar septal pulmonary amylo idosis. Hydrochloric acridine oran ge inclusion stain. Reproduction of a color slid e using a red filter: X 220. b. (Botto m) Vascular and fine reticular interstitial amyloidosis of the heart in a case of mixed vascular and alveolar septal amyloidosis. Same data as in (a).
418 . W.-P. Kunze
loidosis was not seen. Whenever amyloid occurred in the walls of pulmonary vessels, alveolar septal depositions were also present. Sometimes only traces of concomitant alveolar septal amyloid existed, but usually distinct vascular amyloidosis was linked with marked septal deposition. Patches of amyloid were usually found in the tunica media or in transmural segments of a vessel, but in lungs with more conspicuous changes, involvement of the whole circumference of a vessel was not rare. In general, amyloid was about as frequent in veins as in arteries. Mixed vascular and alveolar-septal amyloidosis of the lung was always linked with vascular amyloidosis of the heart. A few cases showed a delicate interstitial network of amyloid deposits (Fig. 3). The mixed vascular and alveolar-septal type was significantly (Mann and Whitney U-test) more frequent in relatively younger age groups, differing in this respect from the pure septal type, which predominated in higher age groups (85 years and older). In the heart, this latter type was invariably linked with nodular interstitial amyloidosis. In some of the cases studied, amyloid depositions were very scanty. They would have remained undetected but for the aid of the sensitive fluorescence method, although they were subsequently demonstrated by the Congo-red stain. Only in 12 cases out of so were more than 20% of the alveolar septa involved by lesions. Most of such "severe" manifestations were mixed vascular and septal type, and usually occurred in males in the oldest age groups. Owing to the rather small number of cases in this category, no significant differences were found by the chi square test. A careful check of the principal clinical and pathologic diagnoses of all patients with pulmonary amyloidosis reported here revealed the occurrence of some kind of long-standing inflammatory disease - usually mild (in all cases with amyloid. But the same held true for almost all cases in the control group. In 17 cases of pulmonary amyloidosis, carcinomas of various sites and types were present; but in this respect too, the control group was not different. One case of multiple myeloma in an 84 year old woman with marked vascular and septal amyloidosis is included in this material.
Discussion Like cardiac amyloidosis (Hiisselmann, 1955; Pomerance, 1975), pulmonary amyloidosis is rare before the age of 70. However, it becomes a frequent disorder among persons beyond the age of 80 years, and the intensity of manifestation increases with age. These facts and the striking coincidence of pulmonary amyloid with amyloidosis of the left cardiac
Senile Pulmonary Amyloidosis . 4 19
ventricle (Wright and Calkins, 1975) justify the classification of the disorder as a pulmonary manifestation of senile amyloidosis. This probably does not hold true for the one case of nodular, tumorlike amyloidosis in an 80 year old woman (Table 2). In fact, other exceptional pulmonary "amyloid tumors" have been described in aged individuals, but usually they affect patients at approximately the age of 60 years (Kiihl, 1960; Fors and Ryden, 1964; Hayes and Bernhardt, 1969; Fenoglio and Pascal, 1970; Keller et al., 1974; Lee and Johnson, 1975). Thus, it does not seem justified to regard nodular amyloidosis as a manifestation of senile amyloidosis. The cases of age-associated amyloidosis show two different patterns of pulmonary deposition. One type, with predominance in very old individuals, is restricted to the alveolar septa and linked with classical nodular cardiac amyloidosis . The other type of mixed vascular and septal diffuse pulmonary amyloid is somewhat more frequent. Vascular deposits are also common in other organs. In fact, vascular deposition of amyloid represents the basic change of this mixed type of amyloidosis in the lung, since concomitant septal infiltration is also found in nodular pulmonary amyloidosis and in bronchial amyloidosis (Whitwell, 1952; Noring and Paaby, 1952; Attwood et al., 1972). Isolated vascular amyloidosis, on the other hand, has been reported by Toriumi (1972), although it remains possible that more sensitive techniques would have uncovered traces of septal amyloid even in these cases. The reported description of pulmonary changes in cases of presenile primary diffuse pulmonary amyloidosis (Biiriimcekci, 1938; Sappington et al., 1942; Dahlin, 1948 Bachmann, 1967; Beck, 1970; Eshun-Wilson et al., 1976) corresponds mostly to the vascular or mixed vascular and alveolar septal type. We do not know whether or not "severe" cases of this type observed in our series produced an alveolar capillary block, as reported by Zundel and Prior (1971), Crosbie et al. (1972) and Poh et al. (1975). Eshun-Wilson et al. (1976) assumed that amyloid in the basement membranes of alveolar septa causes only minor impairment of pulmonary function. Their opinion was based on scanning and transmission electron microscopy findings in a case of mixed vascular and septal pulmonary amyloidosis in which the deposits consisted of a porous meshwork of interwoven fibrils through which gases were thought to diffuse easily. Thus for it seems that no correlation is established between the amount of amyloid deposited in the alveolar septum and possible impairment of gaseous exchange. Although the nature and origin of senile amyloid are still controversial or even obscure, changes of the immune system and genetic influences
420 .
W.-P. Kunze
probably playa role. Reports on presenile diffuse pulmonary amyloidosis allude to the occurrence of multiple myeloma (Bachmann, 1967), plasrnocytosis, and dysproteinemia (Beck, 1970, Keiser et al., 1973). Multiple myeloma was present in one typical case of mixed vascular and alveolar amyloidosis in our series. The more frequent type of senile amyloidosis is morphologically similar to amyloidosis linked with dysproteinaemia and deposition of light chain amyloid (AL) (Cohen, 1965). However, a second type of amyloid, amyloid A (AA), is thought to be important as well, since amyloid A-related serum component (SAA) increases in the average population beyond the age of 70 (Glenner et aI., 1973; Glenner et al., 1974; Anders et al., 1975; Benson et al., 1975). It has been inferred from the occurrence of variant types of age-related amyloidosis in different strains of mice (Thung, 1957b; Ziesche, 1970; Scheinberg et al., 1976) that senile amyloidosis is influenced by genetic factors in this and possibly in other species. Moreover, it has been suggested that not only the well known inheritable amyloid syndromes (Thomas, 1975) but also senile amyloidosis, is determined genetically in man (Walford,19 69)' It is concluded that the two modes of senile pulmonary amyloidosis described in this report correspond to two distinguishable types of ageassociated amyloid disease, characterized by differences in morphology and age profile. Their individuality might depend on a genetically determined susceptibility to the development of chemically distinct amyloid deposits, as suggested by Thung (1957 a).
References 1.
2.
3. 4. 5.
6. 7.
Anders, R. P., Natvig, J. B., Michaelsen, T. E., and Husby, G.: Isolation and characterization of amyloid related serum protein SAA as a low molecular weight protein. Scand. J. Immuno!. 4, 397-401 (1975) Attwood, H. D., Price, c. G., and Riddell, R. J.: Primary diffuse tracheobronchial amyloidosis. Thorax 27, 6-'0-624 (1972) Bachmann, R.: Die diffuse alvcolarseprale Lungenamyloidose. Frankf. Z. Path. 76, I I 1-120 (1967) Beck, O. A.: Diffuse alvcolarseptale Lungcnamy!oidose. Virchows Arch. Abt. A. Path. Anal. 350, 336-352 (1970) Benson, M., Skinner, M., Lian, J., and Cohen, A. S.: "A" protein of amyloidosis. Isolation of a cross-reacting component from serum by affinity chromatography. Arthr, and Rheum. I8, 315-322 (1975) Buerger, 1., and Braunstein, H.: Senile cardiac amyloidosis. Amer. J. Med. 28, 357367 (196o) Biiriimcekci, K.: Mitteilung eines Falles von atypischer Amyloidose. Virchows Arch. Path. Anal. 302,6°7-617 (1938)
Senile Pulmonary Amyloidosis. 421 8. Cohen, A. S.: The constitution and genesis of amyloid. Int. Rev. expo Path. 4, 159243 (1965) • 9. Crosbie, W. A., Lewis, M. c., Ramsay, I. D., and Doyle, D.: Pulmonary amyloidosis with Impaired gas transfer. Thorax 27, 625-630 (1972) 10. Dahlin, D. c.: Primary amyloidosis with report of six cases. Amer. J. Path. 25, 10 5-12 3 (1949) II. Dyke, P. c., Demaray, M. J., Delavan, J. W., and Ramussen, R. A.: Pulmonary amyloidosis. Amer. J. Clin. Path. 61, 301-305 (1974) 12. Eshun-Wilson, K., Frandsen, N. E., and Christensen, H. E.: Pulmonary alveolar septal amyloidosis. Virchows Arch. Abt. A., Path. Anat. 371, 89-99 (1976) 13. Fenoglio, c., and Pascal, R. R.: Nodular Amyloidosis of the lungs. An unusual case associated with chronic lung disease and carcinoma of the bladder. Arch. Path. 90, 577-582 (197 0) 14. Fors, B., and Ryden, L.: Tumoral amyloidosis of the lung. Acta path. microbiol. scand. 61, 1-12 (1964) 15. Franklin, E. c.: Amyloidosis. Bull. Rheum. Dis. 26,832-837 (1975/1976) 16. Glenner, G. G., Terry, W. D., and Isersky, Ch.: Amyloidosis: It's nature and pathogenesis. Sem, Haematol. TO, 65-86 (1973) 17. Glenner, G. G., Eanes, E. D., Bladen, H. A., Linke, R. P., and Termine, J. D.: Beta pleated sheat fibrils. A comparison of native amyloid with synthetic protein fibrils. J. Histochem, Cytochem. 22, II41-1I58 (1974) 18. Hayes, W. T., and Bernhardt, H.: Solitary amyloid mass of the lung. Cancer 24, 820-825 (1969) 19. Hiisselmann, H.: Beitrag zum Amyloidproblem auf Grund von Untersuchungen an menschlichen Herzen. Virchows Arch. Path. Anat. 327,607-628 (1955) 20. Keiler, A., Steffen, A., and Syre, G.: Zur Problematik der isolierten tumorformigen Amyloidose. Thoraxchirurgie 22, 86-93 (1974) 21. Keiser, A., Wegemann, W., Lutenegger, H., Baessler, E., and Winzler, A.: Generalisierte Amyloidose mit Paraproteinaemie, diffuser Plasmocytose des Knochenmarks und diffuser alveolarseptaler Lungenamyloidose. Dtsch. med. Wschr. 98, 614-619 (1973) 22. Kiihl, I.: Beitrag zur tumorforrnigen Amyloidose. Z. inn. Med. IS, IODO-I008 (1960) 23. Lee, S. c., and Johnson, H. A.: Multiple nodular pulmonary amyloidosis. Thorax )0, 17 8-185 (1975) 24. Missmahl, H. P., and Hertwig, M.: Polarisarionsoptische Untersuchungen an der Amyloidsubstanz. Virchows Arch. Path. Anat. 324, 489-508 (1953) 25. Noring, 0., and Paaby, H.: Diffuse amyloidosis in the lower air passages. Acta path. microbiol. scand. ]1, 470-475 (1952) 26. Poh, S. c., Tjia, T. S., and Seah, H. Thorax ]0, 186-191 (1975)
c.: Primary diffuse alveolar septal amyloidosis.
27. Pomerance, A.: Amyloidosis. In: Pomerance, A., and Davies, M. J. (Ed.): The Pathology of the Heart, pp. 251-256. Blackwell, Oxford (1975) 28. Puchtler, H., Sweat, F., and Levine, M.: On the binding of congo red by amyloid. J. Histochem. Cytochem, io, 335-364 (1962) 29. Sajkiewicz, K., and Bausdorf, B.: Ein empfindlicher Amyloidnachweis mit einer Acridinorange-Einschlullf1uorochromierung. Z. med. Labortechnik 9, 293-295 (1968) 30. Sappington, S. W., Davie, J. H., and Horneff, J. A.: Primary amyloidosis of the lung. J. Lab. Clin. Med. 27, 882-888 (1942) 28 Path. Res. Pract. Vol. 164
4 2 2 . W.-P. Kunze 31. Scheinberg, M. A., Cathcart, E. S., Eastcott, J. W., Skinner, M., Benson, M., Shirama, T., and Bennet, M.: The SSC-Mouse. A new model for spontaneous age associated amyloidosis I: Morphological and immunochemical aspects. Lab. Invest. 35, 47-54 (1976) 32. Spencer, H.: Amyloidosis of the lung. In: Spencer, H.: Pathology of the lung, pp. 675-680. Pergamon Press, Oxford (1977) 33. Thomas, P. K.: Genetic factors in amyloidosis. J. med. Genet. 12, JI7-326 (1975) 34. Thung, P. J.: The relation between amyloid and ageing in comparative pathology. Gerontologia (Basel) 1,234-254 (1957a) 35· Thung, P. J.: Senile amyloidosis in mice. Gerontologia (Basel) 1, 259-279 (1957b) 36. Toriumi, J.: The lung in generalized amyloidosis. Acta path. Jap. 22, 141-252 (197 2) 37. Walford, R. L.: The immunologic theory of ageing. Munksgaard, Copenhagen (1969) 38. Whitwell, F.: Localized amyloid infiltrations of the lower respiratory tract. Thorax 8,3 09-3 15 (1953) 39. Wright, J. R., and Calkins, E.: Amyloid in the aged heart: Frequency and clinical significance. J. Amer, Geriatr. Soc. 23, 97-103 (1975) 40. Ziesche, W.: Die spontane Amyloidose der Maus, I. Die altersabhangige Amyloidrate verschiedener Inzuchtstamme, Z. Versuchstierk, (lena) 12, 321-329 (1970) 41. Zundel, W. E., and Prior, A. P.: An amyloid lung. Thorax 26, 357-363 (1971)
Received August 14, 1978 . Accepted in revised form November 30, 1978
Key words: Pulmonary amyloidosis - Cardiac amyloidosis - Age distribution - Genetic determination - Fluorescence Dr. Wolf-Peter Kunze, Institut fiir Pathologie der Medizinischen Hochschule Liibeck, Ratzeburger Allee 160, D-2400 Liibeck 1
