Case 3--Special Studies

Further tests

The next two images show immunoperoxidase stains for light chains in a cellular area of the infiltrate.

Kappa chains: Compare this immunoperoxidase stain for kappa chains with the stain for lambda chains in a similar area below. The positive cells have a brown cytoplasm.

Lambda chains: The normal ratio of kappa- to lambda-stained cells is 2 to 1. What is the ratio in this case? Answer

Clinical summary Case 4

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Answer: The ratio is around 8 to 1, indicating a clonal population of plasma cells. The light chain deposits were not differentially stained with the antibodies in paraffin sections. Frozen sections are preferable for staining the deposits.

Further, A PCR study for immunoglobulin heavy chain gene rearrangement was consistent with the presence of a clonal B-cell population.

Finally, electron microscopy was performed on the homogeneous pink tissue.

A. Low-power view of a vessel wall. L = lumen

B. High-power view

Electron microscopy: At low power (A), the deposits resembling amyloid with H&E stain show an electron dense material that replaces the normal wall structures. At high-power (B), the dense deposit is granular and has interspersed pale collagen fibrils cut in cross section. This pattern excludes amyloid.

Subsequently, a PAS-D stain on a paraffin section showed a positive reaction.

What is the diagnosis? Answer

Clinical summary Case 4

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Diagnosis: Clonal B-cell lymphoplasmacytic proliferation with light chain deposition disease (LCDD) (kappa). Cystic changes in lung parenchyma.

Comment: The rearrangement of the heavy chain gene demonstrated by PCR and the kappa restriction shown by the immunoperoxidase staining support a clonal B-cell proliferation. The absence of a paraprotein in the serum and urine suggests the possibility of a localized pulmonary B-cell neoplasm--a low-grade lymphoma of bronchus-associated lymphoid tissue (BALT)--and a local synthesis of light chains. Alternatively, the process may represent systemic LCDD not yet diagnosed. More sensitive studies would include examination of the bone marrow for light chain restriction of plasma cells and an immunofixation test (see discussion) on serum and urine for diagnosis of a paraprotein. Chronic inflammation and autoimmune diseases have been linked to low-grade lymphomas of the mucosa, and it is possible that this patient's idiopathic thrombocytopenic purpura is in some way linked to her B-cell neoplasm and LCDD. The cystic lesions, noted radiographically and histologically, as destruction of alveolar walls around nodules, are discussed below.

Non-amyloid Monoclonal Immunoglobulin Deposition Diseases (MIDD):
Light Chain Deposition Disease (LCDD)

Introduction: LCDD is similar to amyloidosis in having deposits of immunoglobulin light chains in tissues. However, in contrast to AL, the deposits are in a nonfibrillar (non-amyloid) form. In both diseases, the deposits increase the morbidity of the underlying cellular proliferation. LCDD is less common (or at least, less diagnosed) than AL. (The so-called "para-amyloid" found in some lymphomas may be light chain deposits.) In about 70% of cases of LCDD, patients have myeloma or, less frequently, a lymphoplasmacytic neoplasm. About 15% of cases have only a paraprotein, and 15% have no detectable paraprotein. Rarely, heavy chains or entire immunoglobulin molecules comprise the deposits, hence the designation MIDD [1-3]. Diagnosis is by biopsy of the affected organ. There are no data on the sensitivity of aspiration of abdominal fat for diagnosis [2]. Structural data on the light chains are limited. In about 1/2 of reported cases, the light chains were normal-sized and in the other 1/2 they were short or enlarged by glycosylation [3]. Like amyloid, amino acid sequencing of the light chains has shown unusual substitutions possibly responsible for their deposition [3,4]. Also like amyloid, basement membrane components are increased in light chain deposits (see discussion) [3].

Clinical features: The disease affects adults, aged 35-76 (mean 56) years, with a male to female ratio of 2.5:1. Most patients have renal disease with nephrotic syndrome or renal failure, but about 1/2 of the reported cases have had extra renal disease. Liver and heart followed kidney in frequency of deposits. Pulmonary involvement was rare. Of seven reported cases of pulmonary LCDD (all kappa type) with histologic confirmation, 4 had minimal vascular and interstitial involvement, whereas multiple small nodules were scattered throughout the parenchyma in three cases [5]. As in amyloidosis, therapy is directed against the clonal cell population. In a retrospective report on the response of 19 patients with LCDD to intermittent administration of melphalan and prednisone, it was found that treatment stabilized or improved renal function in patients with a serum creatinine concentration less than 4 mg/dl. Patient survival was 70% at 5 years, and 37% did not have end-stage renal disease at that time [6]. As pulmonary involvement is rare, details of several cases are described below.

Examples of Pulmonary LCDD:

Cystic lesions similar to those seen in our patient have been described in patients with amyloidosis. Small, thin-walled cysts and bullae were described in 2 patients with diffuse pulmonary amyloidosis. Both were women in their 50's.

The authors of these reports speculated that the cysts were caused by bronchiolar narrowing and subsequent air trapping with cyst formation [10] or by ischemic fragility of alveolar walls caused by the amyloid deposits [11].

Histology in the lung: With H&E staining, the deposits have an appearance similar to that of amyloid. Whereas in some cases the deposits are confined to the vessels, nodules also occur, as in our case. Perivascular deposits destroy normal muscle and elastic tissue. Multinucleated giant cells, focal calcification, and ossification may be present in the deposits, which stimulate a fibrotic reaction [5]. Deposits differ from amyloid in that they are PAS positive, do not stain with Congo red or show green birefringence, and have an electron dense, granular, but not fibrillar, appearance by electron microscopy. Paraproteins of kappa types predominate over lambda types 4:1 [1].

Similarities and differences of amyloid and LCDD: Signs and symptoms in both diseases depend on the organ involved and extent of involvement and not the type of deposit. Both recur in transplants. Melphalan and prednisone sometimes lead to shrinkage of deposits and improvement in renal function [1,6]. Although both diseases may be systemic, both may be local. It has been suggested that primary pulmonary amyloid deposits are caused by low-grade lymphoplasmacytic lymphomas of BALT, which may evolve from chronic or autoimmune inflammation [12]. Primary LCDD may have a similar cause. Contrasting features are listed in the table below.

Table: Differences between LCDD and Amyloidosis (AL) [2]

LCDD

Amyloidosis (AL)

Kappa types outnumber lambda types

Lambda types outnumber kappa types

Noncongophilic

Congophilic

Granular by electron microscopy

Fibrillar by electron microscopy

Amyloid P component absent (see discussion)

Amyloid P component present

References

1. Feiner H. Pathology of dysproteinemia: light chain amyloidosis, non-amyloid immunoglobulin deposition disease, cryoglobulinemia syndromes, and macroglobulinemia of Waldenström. Hum Pathol 1988; 19:1255-1272.

2. Buxbaum J. Mechanisms of disease: monoclonal immunoglobulin deposition. Amyloidosis, light chain deposition disease, and light and heavy chain deposition disease. Hematol/Oncol Clin N Am 1992; 6:323-346.

3. Preud'homme J-L, Aucouturier P, Touchard G, Striker L, Khamlichi A, Rocca A, Denoroy L, et al. Monoclonal immunoglobulin deposition disease (Randall type). Relationship with structural abnormalities of immunoglobulin chains. Kidney Int 1994; 46:965-972.

4. Decourt C, Touchard G, Preud'homme J-L, Vidal R, Beaufils H, Diemert M-C, Cogné M. Complete primary sequences of two lambda immunoglobulin light chains in myelomas with nonamyloid (Randall-type) light chain deposition disease. Am J Pathol 1998; 153:313-318.

5. Kijner C, Yousem S. Systemic light chain deposition disease presenting as multiple pulmonary nodules. A case report and review of the literature. Am J Surg Pathol 1988; 12:405-413.

6. Heilman R, Velosa J, Holley K, Offord K, Kyle R. Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis 1992; 20:34-41.

7. Stokes M, Jagirdar J, Burchstin O, Kornacki S, Kumar A, Gallo G. Nodular pulmonary immunoglobulin light chain deposits with coexistent amyloid and nonamyloid features in an HIV-infected patient. Mod Pathol 1997; 10:1059-1065.

8. Kaplan B, Vidal R, Kumar A, Ghiso J, Frangione B, Gallo G. Amino-terminal identity of co-existent amyloid and non-amyloid immunoglobulin kappa light chain deposits. A human disease to study alterations of protein conformation. Clin Exp Immunol 1997; 110:472-478.

9. Morinaga S, Watanabe H, Gemma A, Mukai K, Nakajima T, Shimosato Y, Goya T, et al. Plasmacytoma of the lung associated with nodular deposits of immunoglobulin. Am J Surg Pathol 1987; 11:989-995.

10. 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.

11. Ohdama S, Akagawa S, Matsubara O, Yoshizawa Y. Primary diffuse alveolar septal amyloidosis with multiple cysts and calcification. Eur Respir J 1996; 9:1569-1571.

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

Clinical summary Case 4

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