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MONOCLONAL GAMMOPATHIES OF UNDETERMINED SIGNIFICANCE

1999; Elsevier BV; Volume: 13; Issue: 6 Linguagem: Inglês

10.1016/s0889-8588(05)70120-9

1558-1977

Robert A. Kyle, S. Vincent Rajkumar,

Monoclonal and Polyclonal Antibodies Research

Monoclonal gammopathies are disorders characterized by the proliferation of a single clone of plasma cells producing a homogeneous monoclonal protein (M-protein, M-component, paraprotein). Each M-protein consists of two heavy polypeptide chains of the same class and two light polypeptide chains of the same type. The heavy polypeptide chains are gamma (γ) in immunoglobulin G (IgG), alpha (α) in immunoglobulin A (IgA), mu (μ) in immunoglobulin M (IgM), delta (δ) in immunoglobulin D (IgD), and epsilon (ε) in immunoglobulin E (IgE). The two light-chain types are kappa (κ) and lambda (λ). A polyclonal gammopathy is characterized by an increase in one or more heavy chains and in both types of light chain. One must differentiate between a monoclonal and a polyclonal increase in immunoglobulins, because a monoclonal increase is associated with a clonal process that is malignant or potentially malignant, whereas a polyclonal increase of immunoglobulins is caused by a reactive or inflammatory process.A sensitive, rapid, and dependable screening method is needed to detect the presence of an M-protein, and a specific assay is used to identify its heavy-chain type and light-chain class.61 High-resolution agarose gel electrophoresis is the recommended method for detection of an M-protein.54 Immunofixation or immunosubtraction with capillary electrophoresis must be done to confirm the presence and type of M-protein.Serum protein electrophoresis should be done whenever multiple myeloma (MM), Waldenström's macroglobulinemia (WM), primary amyloidosis (AL), or a related disorder is suspected. Serum protein electrophoresis also is indicated for patients with anemia, unexplained back pain, weakness or fatigue, osteolytic lesions or fractures, osteopenia, hypercalcemia, renal insufficiency, presence of Bence Jones proteinuria, or a history of recurrent bacterial infections. Serum protein electrophoresis should be performed for patients with unexplained sensorimotor peripheral neuropathy, carpal tunnel syndrome, nephrotic syndrome or renal insufficiency, cardiomyopathy or refractory congestive heart failure, orthostatic hypotension, or malabsorption, because these conditions are common in AL. Severe weight loss, change in the tongue or voice, paresthesias, numbness, increased bruising, bleeding, and steatorrhea are additional indications for the performance of serum protein electrophoresis. Even when the serum protein electrophoretic pattern is nondiagnostic, immunofixation should be performed whenever MM, WM, AL, or related disorders are suspected.An M-protein usually is visible as a discrete band on the agarose gel electrophoretic strip or as a tall, narrow spike or peak in the γ or β regions, or, rarely, in the α2 area of the densitometer tracing (Fig. 1). A polyclonal increase in immunoglobulins produces a broad band or a broad-based peak and is limited to the γ region (Fig. 2). Two M-proteins (biclonal gammopathy) occur in 3% to 4% of sera containing an M-protein (Fig. 3).63 A small M-protein may be present even when the total protein, α, β, and γ components, and quantitative immunoglobulins are all within normal limits. Such an M-protein may be concealed in the normal β or γ components. Monoclonal κ or λ light chains (Bence Jones proteinemia) usually are present in a concentration too low to be visible as a spike in the agarose gel.The type of M-protein is best determined by immunofixation. Immunofixation should be performed whenever a sharp peak or band is found in the agarose gel or when MM, WM, AL, solitary or extramedullary plasmacytoma, or a related disorder is suspected. Immunofixation is critical for the differentiation of a monoclonal from a polyclonal increase in immunoglobulins. It may be performed with commercial kits, or laboratory personnel can pour their own plates and cut the appropriate troughs. Immunoelectrophoresis also may be used to detect an M-protein, but it is less sensitive than immunofixation and is not recommended.Capillary zone electrophoresis measures protein on-line by absorbance, so protein stains are not necessary and, thus, no point of application is seen. After electrophoresis, immunotyping can be performed by an immunosubtraction procedure in which the serum sample is incubated with sepharose beads coupled with anti-γ, anti-α, anti-μ, anti-κ, and anti-λ antisera. After incubation, the supernatants are reanalyzed to determine which reagents removed the electrophoretic abnormality.45 This procedure is technically less demanding, is automated, and is a useful procedure for immunotyping M-proteins.The use of a rate nephelometer is best for the quantitation of immunoglobulins. This method is not affected by molecular size, so it measures monomers, polymers, and aggregates of the M-protein. The levels of IgM may be 1000 to 2000 mg/dL more than the size of the M-spike in the densitometer tracing. Immunoglobulin G and IgA may also be spuriously increased.93 Obviously, the clinician must use the same technique to measure the M-protein on subsequent visits.Electrophoresis and immunofixation of an aliquot from a 24-hour urine specimen should be done initially in all patients with MM, WM, or AL. The amount of M-protein is best measured by multiplying the percentage of the M-spike in the densitometer tracing by the total protein in the 24-hour specimen. The amount of M-protein in the urine provides an index of the patient's tumor mass. It is useful for monitoring the disease.84The differential diagnosis of monoclonal gammopathies is outlined in the following box. Classification of Monoclonal Gammopathies IMonoclonal gammopathy of undetermined significance (MGUS) ABenign (IgG, IgA, IgM, IgD)BAssociated with neoplasms of cell types not known to produce monoclonal proteinsCIdiopathic Bence Jones proteinuriaDBiclonal gammopathiesETriclonal gammopathiesII AMalignant monoclonal gammopathies 1Symptomatic multiple myeloma2Smoldering multiple myeloma3Plasma cell leukemia4Nonsecretory myeloma5Osteosclerotic myeloma (POEMS)* BPlasmacytoma 1Solitary plasmacytoma of bone2Extramedullary plasmacytomaIIIWaldenström's macroglobulinemiaIVHeavy-chain diseases (HCD) Aγ-HCDBα-HCDCμ-HCDVPrimary amyloidosis (AL)During 1998, 1149 newly recognized cases of monoclonal gammopathy were identified at Mayo Clinic, Rochester, Minnesota (Fig. 4). The term monoclonal gammopathy of undetermined significance denotes the presence of an M-protein in persons without evidence of MM, WM, AL, lymphoproliferative disorders, plasmacytoma, or related conditions. The previously used term benign monoclonal gammopathy is misleading, because a proportion of patients will develop MM or related disorders during long-term follow-up. It is impossible to tell at the time of diagnosis whether the process producing an M-protein will remain stable and benign or will progress to a serious disease.Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum M-protein value less than 3 g/dL, less than 5% plasma cells in the bone marrow, no or only small amounts of Bence Jones protein in the urine, absence of lytic bone lesions, and no related anemia, hypercalcemia, or renal failure. The proliferative rate of the plasma cells (plasma cell labeling index) is low. The finding of MGUS is an unexpected event in the laboratory tests of an apparently normal person or during the evaluation of an unrelated disorder.Monoclonal gammopathy of undetermined significance has been found in approximately 3% of persons older than 70 years in Sweden,5 the United States,57 and France.97 In 6995 persons older than 25 years from Sweden, an M-protein was found in 1%.5 In a cluster of cases of MM in a small Minnesota community,57 M-protein was detected in 15 of 1200 persons 50 years or older (1.25%), and in France, 303 of 17,968 persons 50 years or older (1.7%) had an M-protein.97 The incidence of MGUS is higher in older patients. Crawford et al21 reported that 10% of 111 persons older than 80 years had an M-protein. In another report, 23% of 439 persons aged 75 to 84 years had an M-protein.68 Cohen et al20 found that 3.6% of 816 persons 70 years or older had an M-protein.As in MM, the incidence of M-proteins is higher in African-Americans than in whites.98 In a recent study, the prevalence of an M-protein was 8.4% in 916 African-Americans.20 In contrast, the incidence of monoclonal gammopathies was less (4 of 146 [2.7%]) in elderly Japanese patients.14Because the prevalence of MGUS is relatively high, and patients are seen by physicians in different fields of clinical practice, it is important to know whether the disorder is benign or whether MM, WM, AL, or a related disorder will develop.