Case 2--Histologic Changes

This low-power view shows a mixture of amyloid and collagen in interlobular septa and around bronchovascular bundles. Intervening alveoli are normal.

Focally, the pleura was markedly thickened by amyloid and fibrosis.

Here, in an early nodule, amyloid replaces the vessel (V) wall and has infiltrated and expanded the surrounding interstitium. A sparse lymphoid infiltrate remains within the deposits. Type II cell hyperplasia is present in some areas.

Larger nodules are composed of amyloid (A), cartilage surrounded by bone (C), bone (B), and marrow (M). Note the blending of the pink amyloid with the darker pink bone with faint, dark osteocytes.

A patchy interstitial pneumonia (left panel) is present adjacent to some nodules. These areas show widened alveolar walls, interstitial lymphocytes and plasma cells, type II cell hyperplasia, and hemosiderin-filled macrophages within the septum, as well as in the alveolar spaces.

The amyloid itself (right panel) has collections of lymphocytes and plasma cells embedded within it. Immunoperoxidase stains of these cells for lambda and kappa light chains showed a preponderance of lambda + cells over kappa + cells of about 3 to 1, indicating a clonal population of cells that corresponds to his IgG lambda serum paraprotein. The normal kappa to lambda ratio is 2 to 1.

Follow-up: Seven months after transplantation, gradual dyspnea on exertion and wheeze developed. A flow-volume loop showed fixed intrathoracic airway obstruction, which on bronchoscopy involved the left mainstem bronchus proximal to the anastomotic site. A CT showed lymph nodes compressing the bronchus. Transbronchial needle biopsy of a node showed amyloid.

A mediastinal window again shows calcified, confluent parenchymal nodules. Note the enlarged right paratracheal and aortico-pulmonary window lymph nodes (arrows). Similar nodes were responsible for the bronchial stenosis on the left.

Placement of a Palmaz stent produced improvement in air flow. Two other subsequent stenosing episodes were treated by extending the stented region. The patient is alive with good exercise tolerance 5 years after transplantation. Surveillance biopsies of the lung have shown no amyloid deposition, and there is no evidence of systemic amyloidosis. The paraprotein dropped from 2.6 g/dl before transplantation to 0.95 g/dl 9 months after transplantation [1,2].

Diagnoses: Primary amyloidosis (AL) involving lung, and hilar and mediastinal lymph nodes. Patchy, clonal (lambda +) lymphoplasmacytic infiltrates. Monoclonal gammopathy, IgG lambda. Left lung transplant, 5 years ago.

Comment: As was postulated for the solitary amyloid nodule, the cellular proliferation in diffuse amyloid disease may also represent a low-grade lymphoma, based on the evidence of clonality in the lung and progressive lymph nodal involvement. The main form of treatment is directed toward eradicating the clonal cellular population, but as with other low-grade lymphomas with a long course, it is not very effective.

Diffuse Pulmonary Multinodular and Interstitial Amyloidosis

Clinical aspects: Diffuse nodular and interstitial amyloidosis involving all lobes is less frequent than solitary or multinodular types. In a study of 48 patients with pulmonary amyloidosis presumed to be localized to the lung, only 6 showed a diffuse interstitial pattern [3] (4 of 126 in another series [4]). Because complete autopsies were not done, isolated diffuse lung disease may be even less frequent. Most cases are considered to be manifestations of primary systemic amyloidosis (AL type) on the basis of analysis of the protein [5] or association with a paraprotein. Patients with diffuse parenchymal disease present with dyspnea, hypoxemia, and decreased DLCO [6], but disease outside the lung should always be anticipated. Diffuse amyloidosis that involves the lung may be associated with radiographic enlargement of the hilar and mediastinal lymph nodes (6 of 12 in one study [7], 2 of 12 in another [8]). Still, the absence of other organ involvement in our patient is unusual, especially since the amyloid lymphadenopathy is progressive, as indicated by the recurring need for bronchial stenting.

Monoclonal gammopathy of unknown significance (MGUS) and amyloidosis: In long-term follow-up of patients with MGUS, 20% developed multiple myeloma, a lymphoproliferative disease, or amyloidosis (AL) after 10 years, and 24% developed one of these diseases by 22 years [9]. In a study of patients with MGUS, most (13/16) had circulating clonal cells that could be identified by PCR, and the authors concluded that the disease involves lymphoid compartments other than the marrow [9]. Furthermore, by combining the use of immunofluorescence stains for light chains on marrow aspirates with the use of immunoperoxidase stains on biopsies, the sensitivity for detecting clonality was 100% in cases with 5 to 10% marrow plasma cells and 75% in those with less than 5% plasma cells [10]. Given the neoplastic basis for many cases of monoclonal gammopathy, the clonality of cells in the blood and marrow in cases without overt neoplasia, and the clonality of lymphoid cells in tissues with associated amyloidosis (as in the present case), it seems reasonable to propose that primary amyloidosis represents a low-grade lymphoma.

Complications of diffuse nodular amyloidosis: Complications other than respiratory failure are apparently rare. Hemoptysis occurred in one patient with diffuse alveolar septal disease as a result of medial dissection of muscular arteries infiltrated with amyloid [11]. In another patient, the disease was complicated by pulmonary hypertension caused by arterial narrowing by the amyloid [12]. When the pleura is involved in the absence of heart failure, effusion can occur [13].

Treatment and outcome: Most patients with diffuse nodular and interstitial amyloidosis die within two years of onset [8], but several long-term survivors have been reported at 5 [14], 7 [8], and 10 years [15]. In general, immunosuppressive therapy has been disappointing in controlling the disease, only doubling the overall survival from 8.5 months to 17 or 18 months. However, survival is considerably longer in patients without cardiac involvement [16].

References

1. Ware L, Keith F, Gordon R, Ries C, Seitz R, Gold W, Golden J. Lung transplantation for pulmonary amyloidosis: a case report. J Heart Lung Transplant 1998; 17:1129-1132.

2. Graham C, Stern E, Finkbeiner W, Webb W. High-resolution CT appearance of diffuse alveolar septal amyloidosis. AJR 1992; 158:265-267.

3. Hui A, Koss M, Hochholzer L, Wehunt W. Amyloidosis presenting in the lower respiratory tract. Arch Pathol Lab Med 1986; 110:212-218.

4. Thompson P, Citron K. Amyloid and the lower respiratory tract. Thorax 1983; 38:84-87.

5. Page D, Isersky C, Harada M, Glenner G. Immunglobulin origin of localized nodular pulmonary amyloidosis. Res Exp Med 1972; 159:75-86.

6. Cordier J, Loire R, Brune J. Amyloidosis of the lower respiratory tract. Clinical and pathologic features in a series of 21 patients. Chest 1986; 90:827-831.

7. Pickford H, Swensen S, Utz J. Thoracic cross-sectional imaging of amyloidosis. AJR 1997; 168:351-355.

8. Kanada D, Sharma O. Long-term survival with diffuse interstitial pulmonary amyloidosis. Am J Med 1979; 67:879-882.

9. Billadeau D, Van Ness B, Kimlinger T, Kyle R, Therneau T, Greipp P, Witzig T. Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma. Blood 1996; 88:289-296.

10. Menke D, Greipp P, Colon-Otero G, Solberg Jr L, Cockerill K, Hook C, Witzig T. Bone marrow aspirate immunofluorescent and bone marrow biopsy immunoperoxidase staining of plasma cells in histologically occult plasma cell proliferative marrow disorders. Arch Pathol Lab Med 1994; 118:811-814.

11. Road J, Jacques J, Sparling J. Diffuse alveolar septal amyloidosis presenting with recurrent hemoptysis and medial dissection of pulmonary arteries. Am Rev Respir Dis 1985; 132:1368-1370.

12. Shiue S-T, McNally D. Pulmonary hypertension from prominent vascular involvement in diffuse amyloidosis. Arch Intern Med 1988; 148:687-689.

13. Knapp M, Roggli V, Kim J, Moore J, Shelburne J. Pleural amyloidosis. Arch Pathol Lab Med 1988; 112:57-60.

14. Fenoglio C, Pascal R. Nodular amyloidosis of the lungs. An unusual case associated with chronic lung disease and carcinoma of the bladder. Arch Pathol 1970; 90:577-582.

15. Takashi S, Koizumi T, Yamazaki Y, Hayasaka M, Kubo K, Sekiguchi M, Honda T. Diffuse pulmonary amyloidosis with monoclonal IgG-kappa gammopathy. Intern Med 1997; 36:357-359.

16. Kyle R, Gertz M, Greipp P, Witzig T, Lust J, Lacy M, Therneau T. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 1997; 336:1202-1207.

Clinical summary Case 3

Table of Contents