Comment: The four cases presented here have in common a low-grade clonal proliferation of cells that show lymphocyte and plasmacytic differentiation, and secrete a light chain product that deposits in the parenchyma as amyloid, a granular material, or crystals. The extent of the deposits, not the clonal cells, is the source of morbidity. These proliferations have the potential to cause systemic disease, and perhaps should be considered to represent low-grade lymphoma. The initiating event may be a chronic nonspecific or autoimmune inflammation. The cellular population is resistant to eradication by present chemotherapy, and new therapy, at least for the non-crystalline forms, might be directed to prevention of deposits, perhaps by interfering with the interaction of precursor protein with basement membrane components that are a part of the deposits.

Pulmonary Amyloidosis

Introduction: Amyloidosis refers to a heterogeneous group of disorders that are accompanied by the deposition in tissues of one of several types of amyloid. In H&E-stained sections, all amyloids appear as an extracellular, homogeneous, pink deposit in the parenchyma. Electron microscopy shows a fibrillar ultrastructure, which is imparted by a beta-pleated sheet structure. All amyloids react with Congo red to give a light green birefringence when viewed with polarized light. Amyloidosis is rare: an estimate of the incidence of one type of amyloidosis--amyloid of light chain origin (AL)--is 1275 to 3200 new cases a year in the U.S. [1].

Classification of amyloids: Amyloids are classified on the basis of the chemical composition of the protein component. Some of these proteins are listed in Table 1 along with the situations in which they are found.

Table 1. Classification of Amyloidosis [1-4]

Amyloidosis of the Respiratory Tract: Most of the amyloids deposited in the lung are of one of 3 types: AL, ATTR, or AA. Of these, AL, which occurs with multiple myeloma or primary amyloidosis, as well as in amyloidosis localized to the lung, is most frequent and most likely to cause symptoms. ATTR of either wild or mutant type may be deposited in the lung but other organs--heart, kidneys, peripheral nervous system--bear the brunt of this disease, and respiratory symptoms are rare. AA is caused by an acute phase protein produced by the liver in chronic inflammatory conditions and infrequently causes pulmonary symptoms.

Clinical features of respiratory amyloidosis: Symptomatic respiratory amyloidosis is usually localized to the larynx, tracheobronchial tree, lung parenchyma, or any combination [8]. Clinical features with different types of deposition are indicated below. Laryngeal, tracheobronchial, and nodular parenchymal types are far more frequent than confluent nodular/interstitial disease [9,10].

Laryngeal amyloidosis accounts for 1/2 of cases of respiratory amyloidosis. It occurs in patients from 9 to 90 years old (average 48 years). Men and women are equally affected, and additional sites of respiratory involvement occur in 12 to 40%. Hoarseness is the presenting symptom. In one case, a localized, monoclonal infiltrate of lambda-positive plasma cells was found to be associated with the amyloid [8].

Tracheobronchial amyloidosis occurs in persons from ages 16 to 76 years (average 53 years). Men and women are equally affected, and additional sites of involvement of the respiratory tree occur in 14%. The ratio of diffuse or multifocal to solitary nodular disease is 5:2. Symptoms include wheeze, dyspnea, cough, hoarseness, hemoptysis, or evidence of post-obstructive atelectasis or pneumonia. Endoscopically, it appears as extensive smooth ridges, plaques, or localized pale or reddish nodules. Treatment consists of endoscopic removal to open the airway [8]. Laser irradiation has been used [11,12]. Bleeding is an occasional complication of the procedure, and recurrence has been noted. The disease is fatal in 19% due to bleeding, infection, or respiratory failure [8].

Parenchymal amyloidosis occurs in persons from ages 37 to 94 years (mean, 7th decade), males slightly more than females [8]. It may be divided into a solitary or pauci-nodular type (up to about 10 nodules), a multinodular type (>10 nodules), a confluent nodular/interstitial type recognized radiographically, and a diffuse alveolar septal type recognized only at autopsy. There may be overlap of types.

Subgroups of Parenchymal Amyloidosis

Radiographic abnormalities: A study of thoracic CT manifestations of amyloidosis found three patterns. The tracheobronchial type narrows the trachea and/or mainstem bronchi diffusely or focally and may be accompanied by atelectasis. The nodular type consists of solitary or rarely, multiple (up to 10), homogeneous nodules with smooth or lobulated contours. They are frequently peripheral or subpleural. Calcification may sometimes be seen, but cavitation is rare. Spiculated nodules, which resemble cancer, have also been described. The tracheobronchial and localized nodular forms are not usually associated with systemic disease. Diffuse lung disease is characterized by multiple small nodules, diffuse irregular lines or interlobular septal thickening, and adenopathy. Punctate calcification in this setting increases the likelihood of amyloidosis. Underlying diseases include primary amyloidosis, and rarely familial Mediteranean fever, and familial amyloidosis [13].

Summary of findings in 8 patients with diffuse nodular/interstitial pulmonary amyloidosis [13]

Radiographic differential diagnosis of diffuse lung disease [13]

Imaging: Uptake of radiolabeled serum amyloid P component, which binds specifically to amyloid, can show progression or regression of disease, but is expensive and not widely available. Radiolabeled aprotinin may be more sensitive than technetium Tc 99m pyrophosphate, which has a low degree of sensitivity [1].

Diagnosis of amyloidosis: Endobronchial biopsy, transbronchial biopsy, pleural biopsy, and needle aspiration of nodules have been employed to make a diagnosis [14-16]. Reported complications of biopsy are rare. In one patient with a 10-year history of diffuse nodular disease, transbronchial biopsy was followed by pulmonary hemorrhage and then, during resuscitation, by air embolism, apparently due to inability of vascular walls stiffened by amyloid to contract [17]. Hemorrhage has followed biopsy in other organ sites also [17]. Other biopsy sites include kidney, heart, abdominal fat pad, rectum, stomach, or nodular masses. Examination of aspirated subcutaneous abdominal fat yields a positive diagnosis of amyloidosis in about 95% of cases of AL, 66% of AA, and 86% of ATTR [18].

Typing of amyloid: After a diagnosis of amyloidosis has been made by identifying by polarized light the green birefringence of the Congo red-stained tissue, the type of amyloid should be determined. Antibodies for immunohistochemical tests that are commercially available include those against AA, AL, transthyretin, and beta2-microglobulin. For AL type, stains for kappa and lambda light chains are more reliable on fresh frozen, than on paraffin-embedded, tissue sections.

Diagnosing the cause: If AL is diagnosed, further tests to identify an underlying lymphoplasmacytic dyscrasia include examination of serum and urine for monoclonal immunoglobulins, and bone marrow for plasma cell percentage and kappa:lambda ratio by immunofluorescent and immunoperoxidase staining [19]. Immunofixation electrophoresis is more sensitive than the usual serum or urinary protein electrophoresis [1]. (An example of immunofixation can be seen in the link indicated below. The serum protein electrophoresis (left) can be compared to other similarly-prepared slides that are stained for immunoglobulin heavy and light chains to identify a specific paraprotein. Scroll to Pathology, Specimen #2 (click to enlarge).) Immunoperoxidase stains of normal plasma cells show that kappa-positive cells outnumber lambda-positive cells (kappa:lambda, 2:1). Similarly, among all myeloma proteins, kappa types outnumber lambda types. In contrast, in primary systemic amyloidosis, the lambda-positive plasma cell types outnumber the kappa-positive ones (kappa:lambda, 1:3), suggesting an abnormal plasma cell proliferation [18]. Finally, amyloid may occur as an integral part of neoplasms including bronchogenic carcinoma and carcinoid tumors, and a small biopsy showing amyloid may not be representative of the lesion [9,20].

Gross appearances: Amyloid is a substance that imparts a firm, waxy appearance to a tissue or organ. The tissue or organ can be stained directly with Lugol's iodine solution to give a mahogany brown color that resists decolorization by 1% sulfuric acid.

Microscopic features: By light microscopy, amyloid is a homogeneous, acellular, pink, extracellular material that infiltrates tissues and interferes with function by causing compression atrophy. It has an apple green birefringence with polarized light after staining with Congo red. This reaction sometimes requires thick sections (10-15 µm rather than the usual 5 µm), bright polarized light, and good dark adaptation. Amyloid also reacts with metachromatic stains such as crystal violet or toluidine blue to give a violet, rather than a blue, color, but this reaction is not specific for amyloid. Ultrastructurally, amyloid deposits show randomly-oriented, non-branching fibrils with a width of 7.5-10 nm and an indeterminate length.

Differential diagnosis of homogeneous pink substances in tissue: Amyloid must be distinguished from hyaline membranes or fibrinous exudates that line or coat eroded surfaces, and from hyalinized collagen that usually appears more fibrous and has a few spindled fibroblasts within it. Fibrinoid necrosis in angiitis usually has some karyorrhectic, inflammatory cell debris with it. Cautery-damaged tissue often looks like amyloid.

Summary of steps in the pathogenesis of amyloid deposition


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Clinical summary


Table of Contents

Last revised 12/12/99

Copyright 1999 by Martha L. Warnock. All rights reserved.