Thorax (1975), 30, 178.

Multiple nodular pulmonary amyloidosisA case report and comparison with

diffuse alveolar-septal pulmonary amyloidosisSIONG-CHUAN LEE and HORTON A. JOHNSON

Department of Pathology, Indiana University School of Medicine, 1100 W. Michigan Street,Indianapolis, Indiana 46202, USA

Lee, S-C. and Johnson, H. A. (1975). Thorax, 30, 178-185. Multiple nodular pulmonaryamyloidosis. A case of multiple nodular pulmonary amyloidosis in a 54-year-oldCaucasian man is presented. Discrete symptomless radiodensities had developed in thispatient's lungs within a period of three years, leading to a suspicion of a neoplasticprocess. The amyloid nature of these nodules was demonstrated by biopsy. In this case,

as in others previously reported, there was no evidence of systemic disease, and immuno-globulins were normal. Local factors probably play an important part in the patho-genesis of this disease.

This entity is to be distinguished from the diffuse type of pulmonary amyloidosis,which has a far graver prognosis. Diffuse alveolar septal amyloidosis is usually associatedwith primary systemic amyloidosis or multiple myeloma and leads rapidly to respiratorydistress.

Amyloidosis, either generalized or localized, canaffect the upper or lower respiratory tract.Amyloidosis of the larynx, trachea, and bronchiis well known and has been the subject of manyreports (Whitwell, 1953; Prowse, 1958; Heiner,1968; McGurk, 1968; Spencer, 1968; Attwood,Price, and Riddell, 1972). Amyloidosis of the lungparenchyma occurs in two different forms, thenodular type and the diffuse alveolar septal type.Although postmortem examinations frequentlyreveal small foci of amyloid in lung parenchymawhich are of no clinical significance, amyloidosiscan occasionally form single or multiple nodulesor a diffuse pulmonary infiltrate that will drawspecial attention and will require medical man-agement. Thus far, about 30 to 40 cases ofisolated multiple or solitary nodular pulmonaryamyloidosis (Whitwell, 1953; Prowse, 1958; Duke,1959; Condon, Pinkham, and Hames, 1964;Cotton and Jackson, 1964; Fors and Ryden, 1964;Firestone and Joison, 1966; Hayes and Bernhardt,1969; Zundel and Prior, 1971; Dyke et al., 1974)and less than 15 cases of diffuse alveolar septalamyloidosis (Larsen, 1930; Sappington, Davie,and Horneff, 1942; Bruno and Ober, 1968;Thomsen, 1968; Gonzalez-Cueto et al., 1970;Crosbie et al., 1972) have been reported in the

literature. The following is a report of a case ofisolated multinodular pulmonary amyloidosiswhich was investigated at Indiana UniversityMedical Center following discovery by routinechest radiography. This case is reported not onlybecause of the rarity of the condition, but alsobecause of its striking difference from the diffusealveolar septal type of pulmonary amyloidosis inits clinical aspects, prognosis, and histopathologi-cal picture.

CASE REPORT

CLINICAL FINDINGS A 54-year-old Caucasian manwas admitted to Indiana University MedicalCenter because of a chest radiograph whichshowed multiple nodular lesions in both lungfields strongly suggestive of neoplasm (Figs 3 and4). The patient had been in good health exceptfor mild gout, hypertension, and chronic inter-mittent diarrhoea. Review of previous chest filmsshowed the nodules to have been present, al-though of smaller size, on 15 October 1971 (Fig.2), but entirely absent from a chest film takenon 3 October 1969 (Fig. 1). Physical examinationwas within normal limits, showing no evidenceof respiratory distress, hepatosplenomegaly, or

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FIG. 1. Chest radiograph in 1969 showing no evidence of nodular lesions.

..4. 5S #

FIG. 2. Chest radiograph in 1971 showing multiple nodular lesions in both lung fields.

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FIG. 3. Chest radiograph in 1973 before exploratory thoracotomy showing increase in sizeand density of the nodular lesion in both lung fields.

FIG. 4. Lateral view showing nodular lesions distri-buted in the anterior and posterior parts of the lungs.

macroglossia. Diagnostic tests, includingcreatinine clearance, liver function tests, pul-monary function tests, intravenous pyelography,and liver and spleen scans, were also withinnormal limits. The bone marrow examinationshowed no evidence of multiple myeloma or otherneoplastic disease. No Bence-Jones protein waspresent in the urine. Serum electrophoresis andimmunodiffusion studies showed normal immuno-globulins with no evidence of a monoclonalgammopathy. An exploratory thoracotomy wascarried out, and multiple discrete nodules werefound in the subpleural areas. A representativewedge biopsy was taken.

PATHOLOGICAL FINDINGS The surgical specimenmeasured 5 X 5 X 1-0 cm. The pleural surfacewas smooth but elevated by underlying nodules.There were several discrete, well-circumscribed,but unencapsulated nodules measuring 0-5 to1-0 cm in diameter immediately beneath thepleura. The cut surface of these nodules had atranslucent, homogeneous, gray, waxy appear-ance. The surrounding lung parenchyma wasslightly compressed. On examination by light

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microscopy the nodules were well demarcatedfrom the lung parenchyma (Fig. 5). Each masswas composed of amorphous, homogenous,eosinophilic material, which stained red to pinkwith Congo Red and metachromatically withCrystal Violet. Within the nodules foci of calcifi-cation and dystrophic bone formation were seen(Fig. 6). At the periphery of each nodule therewere variable numbers of lymphocytes, plasmacells, histiocytes, and a few multinucleated giantcells (Fig. 7).

HOSPITAL COURSE The postoperative course wasuneventful, and the patient was discharged ingood condition without specific treatment. He hasremained free of symptoms since that time.

DISCUSSION

Although isolated nodular pulmonary amyloidosisis a very rare type of localized amyloidosis, thisentity was reported as early as 1877 by Lesser.Since then some 30 to 40 cases have appeared inthe literature. Most of these cases have beentabulated and reviewed by Condon et al. (1964),Firestone and Joison (1966), Weiss (1960), andFors and Ryden (1964), and so a further reviewof these cases is not necessary here. In brief, thedisease tends to affect patients in an older age

group. The average age of the 30 well-documentedcases was 68 years. Two-thirds of those patientswere over 60, one-third were older than 70, andthe overall age range was 38 to 95. No sexpredilection has been noted. The majority ofpatients were free of symptoms, and pulmonaryfunction tests have shown no evidence of impair-ment of gas transfer. These patients were gener-ally discovered by routine chest radiographswhich were interpreted as either metastatic neo-plasm or miliary tuberculosis. The histopathologyhas been presented in detail by Weiss (1960). Themost prominent features are the presence ofamyloid, calcification, dystrophic bone formationwith plasma cells, histiocytes, lymphocytes, andmultinucleated giant cells. The intimate relation-ship between amyloid and plasma cells is wellknown, and it is thought that plasma cells play arole in the production and perhaps also in thedegradation of immunoglobulins (Glenner, 1973).The role of the multinucleated giant cells, whichare also present in the diffuse alveolar septal typeof amyloidosis and in amyloid tumours of thelarynx, is not clear, but they may represent ahost reaction to abnormal protein. The commonfinding of calcification and ossification of thesenodules indicates their long duration. In the caseson which necropsies have been carried out, nonehas shown amyloidosis of other visceral organs.

IIV; , . ,,iW Rt7 'w'i*~~~~~~~v

FIG. 5. Low magnification showing discrete well-demarcated amyloid nodule(H and E X10).

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.--

................

.. ^: > .

4*~~~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~~~4

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FIG. 7. Magnification showing close relationship of plasma cells and giant cell to theamyloid (H and E X400).

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In the present case, intensive investigation showedno evidence of extrapulmonary amyloidosis.The isolated nodular type of amyloidosis is an

entity quite distinct from the diffuse alveolarseptal type of pulmonary amyloidosis. The latteris usually associated with overt multiple myeloma(Crosbie et al., 1972) or primary amyloidosis(Larsen, 1930; Sappington et al., 1942; Brunoand Ober, 1968; Thomsen, 1968), although aprimary form without concurrent disease has alsobeen reported by Zundel and Prior (1971) andGonzalez-Cueto et al. (1970). The histologicalpattern of diffuse alveolar septal amyloidosis isentirely different from that of the isolated nodulartype. The amyloid infiltration is diffuse, involvingalmost every alveolar septum. The amyloid isdeposited around capillaries and within the inter-stitial tissue, ultimately obliterating alveolar capil-laries. Grossly, the lungs are free of nodules butare bulky, rubbery, and heavy. There is apt to bea prominent inflammatory infiltrate similar to thatfound in the isolated nodular type. Patientsusually die of respiratory insufficiency secondaryto the extensive diffuse interstitial amyloidinfiltrate.The tinctorial characteristics of the amyloid

are identical in both types of pulmonaryamyloidosis, but the anatomical distribution ofthe amyloid leads to different clinical courses. Theisolated nodular type is usually discovered inci-dentally and is nearly always misinterpreted asmetastatic neoplasm or miliary tuberculosis,whereas the diffuse alveolar septal type is usuallythought to be an inflammatory infiltrate or pul-monary oedema. In the present case, as inpreviously recorded cases, the amyloid infiltrateproduced no signs or symptoms, whereas typicallythe patient with diffuse alveolar septal amyloidosisexperiences severe respiratory difficulty withdisturbed gas transfer. Isolated nodular amy-loidosis, although untreated, has not led to deathin any of the reported cases. On the other hand,patients with the diffuse type, as reported bySappington et al. (1942), Crosbie et al. (1972) andGonzalez-Cueto et al. (1970), all died of respira-tory failure. Thus involvement of the lung bydiffuse amyloidosis should always be suspected ina patient with multiple myeloma or primarygeneralized amyloidosis who develops respiratoryinsufficiency. The clinical differences between theisolated nodular pulmonary amyloidosis and thediffuse alveolar septal type are summarized in theTable.The pathogenesis of amyloidosis is not well

understood. The intimate relation between the

Bence-Jones protein and M-protein and amy-loidosis has been emphasized by Osserman,Takatsuki, and Tatal (1964), Isobe and Osserman(1974), Glenner (1972, 1973), and Glenner, Ein,and Terry (1972), and the frequency ofgeneralized amyloidosis in multiple myeloma hasbeen reported to be as high as 20%. Althoughamyloidosis in myeloma patients usually involvesmany visceral organs, the lung is nearly alwaysspared. Twenty-seven well-documented cases withplasma-cell dyscrasia have been studied by Osser-man et al. (1964), and none of the cases showeddeposition of amyloid in the pulmonary paren-chyma. However, once the lung is involved inmultiple myeloma or primary amyloidosis, theclinical course is rapid and the patient dies ofrespiratory failure within a few months.The general resistance of the lung to amy-

loidosis remains unexplained but may be due inpart to the fact that the lung has considerablecapacity for protein resorption, as evidenced bythe rapid resorption of protein-rich oedema fluid.Since the presence of high levels of Bence-Jonesprotein or M-protein alone does not usually resultin pulmonary amyloidosis, the occasional occur-rence of pulmonary amyloidosis in multiple mye-loma must depend also upon local factors in thelung, such as break-down of capillary integrity or

TABLE

Isolated Nodular Diffuse(Multiple or Alveolar-Septal

Solitary) Pulmonary PulmonaryAmyloidosis Amyloidosis

Associated diseases None Multiple myelomaPrimary generalizedamyloidosis

Chest radiograph Solitary or multiple Diffuse pulmonarynodular lesions infiltrate resemblingsimulating pulmonary oedemametastatic or or inflammatoryprimary neoplasm infiltratein lung or miliarytuberculosis

Lung function Normal Severely impaired

Impaired gas Absent Presenttransfer

Bence-Jones protein Undetectable Always presentor M-proteinHistopathology Multiple or solitary Diffuse infiltration

discrete nodules of amyloid aroundthe capillaries andwithin alveolarsepta

Gross Slight increase in Bulky, rubbery, andweight or normal marked increase in

weight

Course Slow RapidPrognosis Excellent Poor

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failure of adsorptive mechanisms. An out-pouringof abnormal proteins into the interstitial space,together with failure of resorption, may result inprotein degradation and conversion to amyloid.Once amyloid is formed it cannot be reabsorbed.

It is possible that the production of isolatednodular amyloidosis of the lung may occur as aresult of the same two factors, i.e., the presenceof circulating amyloidogenic protein plus localfactors, but that deposition occurs at a muchlower rate because of the lower concentration ofabnormal protein in the plasma. In fact, Glenner(1972) has isolated a portion of light chain pro-tein from a case of nodular pulmonary amy-loidosis, indicating that its pathogenesis isprobably related to a primary disorder of thereticuloendothelial system.At least one case of isolated nodular pulmonary

amyloidosis has been associated with the macro-globulinaemia of Waldens'trom (Spencer, 1968).Although neither the present case nor previouslyreported cases have shown the presence of M-protein or Bence-Jones protein, it is possible thatthe amount of abnormal protein in plasma is toosmall to be detected. It may also be the case thatthe amyloidogenic protein in these patients hasbeen rapidly deposited in the lung so that theconcentration in blood remains low. Thus it maybe that both types of pulmonary amyloidosis havea similar pathogenesis and that the difference inclinical course and in anatomical distribution ofamyloid depends chiefly upon the rate of de-position of amyloid which is in turn dependentupon the concentration of abnormal protein oramyloidogenic protein present in the blood streamof the affected patients.

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Brigg, G. W. (1961). Amyloidosis. Annals of InternalMedicine, 55, 943.

Bruno, M. S. and Ober, W. B. (1968). Pleural effusion,dyspnea, and progressive liver enlargement.Clinicopathologic Conference of BeekmanDowntown Hospital. New York State Journal ofMedicine, 68, 1404.

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McGurk, F. M. (1968). Case reports. Primarybronchial amyloidosis. British Journal ofRadiology, 41, 795.

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Osserman, E. F., Takatsuki, K., and Tatal, N.(1964). Multiple myeloma. I. The pathogenesisof amyloidosis. Seminars of Hematology, 1, 3.

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Requests for reprints to: Dr. Siong-Chuan Lee,Department of Pathology, Indiana University Schoolof Medicine, 1100 W. Michigan Street, Indianapolis,Indiana 46202, USA.

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