NONAMYLOIDOTIC MONOCLONAL IMMUNOGLOBULIN DEPOSITION DISEASE: Light-Chain, Heavy-Chain, and Light- and Heavy-Chain Deposition Diseases

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B-cell proliferative disorders may display their pathogenic effects by increased cell numbers, increased concentrations of the molecules produced by those cells, or both. Immunoglobulins, a major secretory product of terminally differentiated B cells, are the mediators of specific forms of tissue pathology seen in multiple myeloma, occult plasma cell dyscrasias, Waldenström's disease, and chronic lymphocytic leukemia. Intact monoclonal immunoglobulins, by virtue of their properties as antibodies, can have autospecificity with either immune complex or direct tissue damage. They can also self-aggregate to produce syndromes associated with hyperviscosity.

When only light chains are produced, or when the light chains produced are greater than the amount of heavy chain synthesized by the expanded clone, or, less commonly, when some forms of truncated heavy chain are secreted, three forms of tissue damage have been described. All have the kidney as a major target organ.45 In myeloma kidney light chains become insoluble in the renal tubular lumen, forming dense casts (Bence Jones cast nephropathy [BJCN]). Its occurrence is a function of both plasma cell load and the physicochemical properties of the specific light chain, requiring both large amounts of the protein and a tendency to aggregate under the conditions of concentration and pH achievable in the human nephron. The property appears to be independent of light-chain class.

In primary amyloidosis (AL) and heavy-chain amyloidosis (AH) light chains or their fragments (most commonly of the λ class) or truncated heavy chains form fibrillar, Congo red–binding deposits in many tissues which ultimately result in organ compromise.

The more recently recognized form of light-chain deposition, light-chain deposition disease (LCDD), is characterized by deposition of non-Congophilic material which appears amorphous with conventional histologic methods. It is detected by its reactivity with specific anti-immunoglobulin light-chain (usually anti κ) antisera.41 The original definition of immunoglobulin light chains as the precursor of both amyloid and LCDD forms of tissue deposition has been expanded with the recognition that some heavy chains with domain deletions can produce amyloidosis (designated as AH) and that the non-Congophilic tissue deposits may be comprised of immunoglobulin heavy-chain fragments as a major component (light-and-heavy-chain deposition disease [LHCDD]) or as a sole component (heavy-chain deposition disease [HCDD]). To encompass all the identified forms of monoclonal immunoglobulin-related tissue deposition under a single rubric, the designation monoclonal immunoglobulin deposition disease (MIDD) has been suggested,3 with AL, AH, LCDD, LHCDD and HCDD as subtypes, and with the deposits further defined on the basis of the class of immunoglobulin polypeptide involved and its ultrastructure. It has been argued that, if the basic mechanisms governing tissue deposition in amyloid and nonamyloid MIDD (NAMIDD) are different, grouping them together is inappropriate.40 If, however, the two forms of deposits represent different aspects of the same pathogenetic process resulting from the production of the same protein during the course of a monoclonal B-cell expansion, such a classification is appropriate. At present, the issue is unsettled, although the authors believe that current data favor a unimodal process with variations.

Primary amyloidosis and LCDD appear to be more dependent than myeloma kidney on the particular structure of the light chain, because AL and LCDD occur both in the presence and in the absence of clinical myeloma.2 In autopsy and in clinical series of consecutive patients with multiple myeloma, 11% to 20% of patients display tissue amyloid deposition.25, 31, 35 Conversely, data from many centers indicate that only 20% of all AL patients have myeloma at the time of presentation.31 Although there are fewer studies in which the incidence of LCDD in myeloma has been determined, the best estimates indicate that 5% to 10% of myeloma patients have LCDD.25, 35 Review of the first 150 reported cases of well-documented NAMIDD suggests that myeloma was present in 50% to 60% of the cases; however, in many of these cases, the criteria used to establish the diagnosis of myeloma were not clearly stated.4 It is possible that more limited forms of plasma cell dyscrasia, not fulfilling all the requirements for myeloma, were included. For example, studies from French investigators revealed that 20 of 26 patients were diagnosed as having myeloma at the time of presentation or developed the requisite diagnostic features over the 2-year period following recognition of the tissue deposits.6 The latter observation suggests that some of these patients could have been classified as having smoldering myeloma.32

Among the LCDD patients identified by renal biopsy and treated by the authors, 6 of 24 (25%) had a confirmed diagnosis of myeloma with nodular infiltrates in bone marrow biopsies at the time of identifiable tissue deposition. All 6 patients with confirmed myeloma had typical BJCN accompanying the monoclonal light-chain deposition. Fourteen of the remaining 18 individuals had nodular glomerulopathy with less aggressive plasma cell proliferative disease (10% or fewer bone marrow plasma cells) and a clinical and pathologic picture similar to that of AL. A similar distribution is suggested by data from the Mayo Clinic.21 The authors believe that larger numbers of patients with nonamyloid monoclonal immunoglobulin deposition who have undergone complete immunohistologic analysis and clinical evaluation should be studied systematically to determine definitively whether there is a relationship between the pattern of renal involvement and the degree of plasma cell proliferative disease. This may be a significant issue with respect to prognosis and treatment because the authors have found that patients with LCDD, cast nephropathy, and myeloma have a shorter survival time than those with nodular glomerulopathy.

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Address reprint requests to Joel Buxbaum, MD, Research Service, New York Veterans Affairs Medical Center, 423 East 23rd Street, New York, NY 10010, e-mail: [email protected]

Studies from the authors' laboratories were supported by Merit Review Funds from the Department of Veterans Affairs (Dr. Buxbaum). The opinions expressed are those of the authors and not the Department of Veterans Affairs.