Amyloid--Ultrastructure

This picture from another case shows the typical ultrastructure of amyloid--randomly-oriented, non-branching fibrils, 7.5-10 nm in diameter, of indeterminate length. Electron microscopy is usually reserved for cases in which the stains at the light microscopic level are non-diagnostic or for cases with minimal deposits, as in the kidney. All amyloids have a similar ultrastructure.

Amyloid Nodules/Amyloidomas

Clinical features: These lesions are usually asymptomatic, but cough, hemoptysis, or dyspnea may occur in 25 to 50% depending on the number of nodules present [1]. Their peak incidence is in the 6th and 7th decades [1-3]. Size averages 3 cm, but may range up to 9 cm [2,3]. Large amyloidomas may cause atelectasis, or localized bronchiectasis by compressing bronchi [4]. Rarely, there is hilar or mediastinal lymph node involvement [5,6]. A few cases have had recurrent nodules (as in the present case), associated tracheobronchial amyloidosis, or systemic amyloidosis [1].

Multinodular disease: The solitary or pauci-nodular disease may be contrasted with the multinodular disease [1]. When the number of nodules exceeds about 10, symptoms--cough, dyspnea, or hemoptysis--occur in about half of patients, and the disease is systemic more frequently than in patients with solitary nodules. Associated diseases include lymphocytic interstitial pneumonia, pulmonary lymphoma [7], chronic lymphocytic leukemia, multiple myeloma, Sjögren's syndrome [8], eosinophilic granuloma, malignant neoplasms (primary in the lung, metastatic to lung, or extra-pulmonary) [1,9,10], or Crohn's disease [11].

Differential diagnosis: The initial clinical and radiographic diagnosis is usually lung cancer, but in the present case of a slowly-growing tumor (>1 year to double in volume), the differential diagnosis would include hamartoma/lipoma, carcinoid tumor, low-grade adenocarcinoma, nodular lymphoid hyperplasia (pseudolymphoma), sclerosing hemangioma, hemangioendothelioma, and hyalinizing granuloma, as well as amyloidoma [4].

Pathology: Grossly, the tumors have a homogeneous, waxy, tan appearance, but large lesions may show cavities, hemorrhage, necrosis, fibrosis, or calcification [4]. Microscopically, most have an associated lymphoplasmacytic infiltrate with multinucleated giant cells. Calcification or ossification is sometimes present [1,3].

Diagnosis: Wedge resection or fine needle aspiration has been used to make a diagnosis. When needle biopsies are used and small amounts of tissue are obtained, there is the possibility that an integral tumor may be present but missed [5,12].

Pathogenesis: Typing of the amyloid is important for understanding the pathogenesis of a particular nodule (see discussion). Most solitary or multiple amyloid nodules are composed of amyloid of immunoglobulin light chain origin (AL) [13]. Less commonly, they are composed of amyloid A (AA) [11], or amyloid E found in metastatic medullary carcinoma of the thyroid [12]. AA was thought to be a possibility in this patient, who had rheumatoid arthritis, but an immunoperoxidase stain for AA was negative, and the nodule is presumed to be the AL type. AA, which, in this country, used to be a common complication of chronic tuberculosis, osteomyelitis, or bronchiectasis, now occurs mainly in patients with rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, or familial Mediterranean fever [14].

AL is the product of a clonal proliferation in myeloma and other lymphoproliferative diseases. Evidence that localized, nodular amyloidomas (AL type) are of clonal origin has been reported. In two cases, rearrangement of the heavy-chain immunoglobulin gene of cells from the central part of the tumor indicated the presence of a monoclonal population of B cells. Polyclonality of the cells at the periphery of the tumor was demonstrated by immunohistochemistry. Given a clonal population and a proliferation of lymphocytes and plasma cells, the authors postulated that amyloidomas may represent low-grade lymphomas of bronchus-associated lymphoid tissue. Such lymphomas typically evolve in areas of chronic inflammation (e.g.,Helicobacter pylori infection in the stomach) or autoimmune inflammation (Sjögren's syndrome). Our patient's rheumatoid arthritis or his mild asbestosis may have predisposed to the amyloidomas. Furthermore, some amyloidomas have more inflammatory cells than others. With time, the accumulation of amyloid may completely replace the cellular component [15].

Treatment: Excision, which is not necessary for small lesions that can be followed, as in the current case, is usually curative.

References

1. Chen K. Amyloidosis presenting in the respiratory tract. Pathol Annu 1989; 24 Pt 1:253-273.

2. Utz J, Swensen S, Gertz M. Pulmonary amyloidosis. The Mayo Clinic experience from 1980 to 1993. Ann Intern Med 1996; 124:407-413.

3. Hui A, Koss M, Hochholzer L, Wehunt W. Amyloidosis presenting in the lower respiratory tract. Clinicopathologic, radiologic, immunohistochemical, and histochemical studies on 48 cases. Arch Pathol Lab Med 1986; 110:212-218.

4. Leu C, Lynch D, Chan E. The case of the torpid thoracic tumor. Chest 1997; 112:535-537.

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

6. Kandel G, Grossman R. Large neck node, silent chest mass. Hospital Practice 1986; 21:79-81.

7. Davis C, Butchart E, Gibbs A. Nodular pulmonary amyloidosis occurring in association with pulmonary lymphoma. Thorax 1991; 46:217-218.

8. Kobayashi H, Matsuoka R, Kitamura S, Tsunoda N, Saito K. Sjögren's syndrome with multiple bullae and pulmonary nodular amyloidosis. Chest 1988; 94:438-440.

9. Benharroch D, Sukenik S, Sacks M. Bronchioloalveolar carcinoma and generalized amyloidosis complicating progressive systemic sclerosis. Hum Pathol 1992; 23:839-841.

10. 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.

11. Beer T, Edwards C. Pulmonary nodules due to reactive systemic amyloidosis (AA) in Crohn's disease. Thorax 1993; 48:1287-1288.

12. Halliday B, Silverman J, Finley J. Fine-needle aspiration cytology of amyloid associated with nonneoplastic and malignant lesions. Diagn Cytopathol 1998; 18:270-275.

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

14. Falk R, Comenzo R, Skinner M. The systemic amyloidoses. N Engl J Med 1997; 337:898-909

15. Ihling C, Weirich G, Gaa A, Schaefer H. Amyloidtumors of the lung--an immunocytoma? Path Res Pract 1996; 192:446-452.

Clinical summary Case 2

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