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BLOOD CELLS AND MARROW
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Blood counts and the marrow examination are normal. Notably anemia is not present and the proportion of plasma cells in marrow is less than 10 percent. Although an increased percent of plasma cells is the most constant morphologic feature of myeloma, the presence of cytologic atypia as judged by frequent binucleate plasma cells and large plasma cell nucleoli are findings more specific for myeloma.61 Quantitative microscopy of the number of marrow microvessels per high-power field, using immunohistochemistry, indicates microvessel density on average is threefold greater than in normal persons, but far less than in patients with myeloma, although some overlap with myeloma occurs.62
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Hyperdiploidy, assessed by DNA content, is present in about half the cases and hypodiploidy is present in approximately 10 percent of cases of monoclonal gammopathy.42 Use of interphase fluorescence in situ hybridization has uncovered numerical chromosome abnormalities in the plasma cells of more than 50 percent of subjects. Clones containing trisomy or monosomy involving chromosomes 3, 6, 7, 9, 11, 13, 17, and 18 have been identified.38,39,40,41,44,45 Deletions of 13q14 are present in about one-quarter of patients and abnormalities involving 14q32, the site of the Ig heavy-chain genes, are present in approximately 60 percent of subjects.38,39,40,41 Chromosomal changes do not appear to be correlated with progression.
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Characteristically, individuals are detected by the unexpected identification of a monoclonal IgG or light chain in the serum in the absence of symptoms or signs (e.g., anemia, marrow plasmacytosis, lymph node enlargement, plasmacytoma, bone lesions, or amyloid deposits) caused by diseases associated with monoclonal proteins.6,7,8,9,10,60,63–71 Although classically a serum Ig or urine monoclonal light chain was the standard for diagnosis, the ability to measure serum free light chains with high specificity and sensitivity has replaced the necessity to measure urine light chain excretion for diagnosis as the latter is less sensitive than the former.72
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Monoclonal IgG gammopathy occurs in approximately 70 percent of persons and IgM and IgA in approximately 20 percent and 10 percent, respectively. A few percent of persons may have biclonal or triclonal gammopathy (see Table 106–1).6,7,8,9,10,12,60,63–71
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Most patients with essential monoclonal gammopathy have a monoclonal protein concentration of less than 30 g/L, but exceptions occur. The diagnosis reflects the sum of (1) the monoclonal protein level, (2) the marrow plasma cell concentration (<10 percent), (3) the absence of other features of progressive plasma cell neoplasm (e.g., hypercalcemia, osteolysis, otherwise unexplained anemia, otherwise unexplained renal disease), and (4) the absence of progression on periodic long-term followup.
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A developing consensus favors measurement of serum protein gel electrophoresis and serum free light chain levels (and the κ:λ ratio), and serum protein immunofixation electrophoresis without urinary Ig measurements to detect monoclonal gammopathies.73,74,75 Some pathologists are still reluctant to give up urinary measurements because of the uncommon occurrence of urinary monoclonal light chains in the absence of evidence of an abnormality of serum monoclonal light chains.76 Followup of these cases has not shown any clinical consequence of these uncommon false-negative serum light-chain measurements. Serum protein gel electrophoresis has a limit of detection of approximately 0.03 g/dL, if the monoclonal protein migrates in the γ-globulin fraction. Small monoclonal proteins that migrate in the α- or β-globulin fraction are more difficult to identify on electrophoresis. Immunofixation electrophoresis is used to confirm a monoclonal protein found on gel electrophoresis. Immunofixation electrophoresis may also detect a monoclonal protein not evident on serum protein gel electrophoresis, usually because the protein is in too low a concentration or is embedded in the normal polyclonal α- or β-globulin peak. Monoclonal proteins identified by immunofixation electrophoresis may be transient (approximately 15 to 20 percent) and have a greater likelihood to progress to a disease if they are of an IgA or IgM isotype.77 In the future, mass spectroscopy may be a more sensitive and specific method to identify monoclonal proteins.78
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In individuals with a serum monoclonal IgG of less than 1.5 g/dL, especially if of an older age and with no overt end-organ abnormality, marrow examination and radiographic examination of the bones have a very low diagnostic yield and can be omitted. A presumptive diagnosis of essential monoclonal gammopathy can be made with reexamination at approximately 6 months and at appropriate intervals, thereafter.79,80
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FUNCTIONAL IMPAIRMENT FROM A MONOCLONAL PROTEIN
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Interaction with Plasma Protein or Blood Cells
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Some patients have monoclonal proteins with antibody specificity directed against plasma or cell proteins, resulting in symptomatic pathophysiologic effects, such as immune hemolytic anemia,81 acquired von Willebrand disease,82,83,84 immune neutropenia,85,86 and other functional manifestations87,88,89,90,91,92 (Table 106–2).
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Occasional patients may have severe renal disease associated with monoclonal gammopathy.93,94,95,96,97,98,99,100 The renal disease my take the form of a tubular disorder, mimicking Fanconi syndrome (glycosuria, hypouricemia, proteinuria, asymptomatic renal insufficiency)93,96 or a glomerular deposition disorder resulting from the deleterious interaction of the monoclonal Ig or a light chain and the renal parenchyma resulting in renal insufficiency.94,95,97,100 The term “dangerous small B-cell clone” has been applied to a monoclonal gammopathy that can produce disease, often quite serious, without lymphoproliferation and progression of the neoplastic cell population. The principal approach to therapy is to attempt to suppress the small B-cell clone and, thereby, its monoclonal protein secretion with chemotherapy. Cyclophosphamide, thalidomide, bortezomib, or bendamustine are favored because they have much less renal toxicity than congeners such as melphalan or lenalidomide. A glucocorticoid and rituximab can, also, be useful.100,101 One should also consider the possibility that the monoclonal protein may be secreted by a solitary plasmacytoma, which would be amenable to local radiation therapy. Thus, in the face of significant renal impairment a careful evaluation, including positron emission tomography, should be considered to exclude a solitary lesion. In exceptional cases, ablative therapy with an autologous hematopoietic stem cell transplant may be considered.101
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Corneal deposits of crystalline Ig102,103 and a monoclonal copper binding Ig resulting in copper deposits in the eye,104,105 each associated with classical monoclonal gammopathy, have led to loss of visual acuity. Remarkably, despite very high serum copper levels in the latter cases, no other organ damage ensued. Iritis, vitritus, and maculopathy with loss of visual acuity have also been described in association with a monoclonal gammopathy.106
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Frequency of Occurrence
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A significant association exists between the incidence of neuropathies and essential monoclonal gammopathy.107,108,109,110,111,112,113,114 Approximately 10 percent of patients with idiopathic neuropathy have a monoclonal Ig, a frequency about eight times that of age-adjusted healthy comparison groups.107,108,109,110,111 The frequency of neuropathy among patients with monoclonal gammopathy varies depending on the distribution of Ig classes, but is in the range of 3 to 5 percent. IgM monoclonal gammopathy has a significantly higher frequency of neuropathy than does IgG or IgA monoclonal gammopathy.107,108
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Mechanisms of Nerve Damage
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Monoclonal antibodies, especially IgM, can react with peripheral nerve myelin, specifically with myelin-associated glycoprotein, glycolipids, or sulfatides.112,113,114,115,116,117 Although various antinerve antibodies are present in approximately 40 percent of patients with neuropathy and IgG monoclonal gammopathy, a similar frequency has been found in such patients without neuropathy.118 Neuropathy in the absence of reactivity of the monoclonal protein with nerve antigens implies other mechanisms also operate to cause nerve damage.107,109,116 Deposition of monoclonal protein in the epineurium has been proposed as an alternative mechanism of nerve injury.119 Also, in one report, four of 16 patients with IgG monoclonal gammopathy and neuropathy had polyclonal, not monoclonal, antibodies against neurofilament protein.116 In addition, a proportion of patients develop a detectable monoclonal protein after the onset of the neuropathy, sometimes years later.118
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Patients with essential IgM monoclonal gammopathy and neuropathy can have dysesthesia of the hands and feet, loss of vibration and position sense, atrophy of distal muscles, ataxia, and intention tremor.114,115,117 The monoclonal antibodies reactive with nerve antigens usually are of the IgM type. Serum often contains antibodies to myelin-associated glycoprotein.107,108 In contrast, patients with IgG or IgA monoclonal gammopathy usually have chronic inflammatory demyelinating polyneuropathy; a minority have sensory axonal or mixed neuropathy.108,118,120,121,122 The neuropathy may be (1) mild with minor motor and/or sensory signs with or without mild functional impairment, (2) moderately disabling but with full range of activities, or (3) severely disabling, interfering with walking, dressing, and eating.118 The course may be relapsing and remitting or progressive. IgA gammopathy is associated with dysautonomia.123 The presence or absence of antibody to myelin-associated glycoprotein may have an effect on the specific nature of the neuropathic manifestations.108,109,114,115,116,117
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Demyelinization is reflected in decreased nerve conduction velocity. Axonal loss is reflected in decreased sensory potentials.109,113,114,120,121,122,123,124 Electromyography may show denervation of muscles.109,113 Immunofluorescence studies of sural nerve or of skin biopsies may uncover Ig binding to nerve.109,114 Morphologic studies of nerve biopsies may show decreased or absent myelinated fibers or axonal degeneration. A rare case of crystal formation in the epineurium has been described.125
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At least seven treatment approaches have been used to ameliorate the neuropathies: (1) intravenous Ig administration; (2) glucocorticoids alone; (3) immunoadsorption of perfused blood with staphylococcal protein A; (4) plasma exchange or plasmapheresis; (5) immunosuppressive cytotoxic chemotherapy, such as cyclophosphamide, chlorambucil, or fludarabine with or without added glucocorticoids; (6) rituximab (anti–cluster of differentiation [CD]20 antibody) to deplete B cells; and (7) high-dose cytotoxic therapy with autologous hematopoietic stem cell rescue.107,108,109,117,118,124,126–135 In some cases, use of plasmapheresis has been followed by cytotoxic therapy in an effort to produce a sustained effect. Plasma exchange has shown benefit in a small clinical trial. The other modalities of treatment await such studies.107 Response rates to each form of therapy are low and duration of response is variable,109,118,126,127,128,129,130,131 but some patients obtain coincidental significant improvement for prolonged periods. A recommendation has been made to start therapy with intravenous Ig, especially in essential monoclonal IgM-associated neuropathy, because of the relative safety of this approach.107 Mild symptoms and signs may not be an indication for treatment because of the low response rate and the potential noxious effects of therapy.107
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Monoclonal gammopathy unrelated to a clinically evident proliferation of B lymphocytes or plasma cells has been observed in association with a wide variety of conditions (Table 106–3).136–201 Although they are grouped under the designation monoclonal gammopathy with a coincidental disease, few such reports have examined whether the coincidence is greater than expected in a control group matched for age and ethnicity, the two variables having the greatest impact on the incidence of monoclonal gammopathy. Non–B-cell malignancies, including solid tumors,3,5,6,18,178,179,180,181 myeloproliferative disorders,182,183,184,185,186,187,188,189 and Hodgkin and T-cell lymphomas,190,191,192,193 are associated with monoclonal Ig. These relationships could result from various factors: (1) patients with a monoclonal Ig have an increased risk of developing cancer; (2) the monoclonal Ig is an antibody against some antigen associated with the cancer; (3) the monoclonal Ig is the product of cancer cells; or (4) coincidence. The last possibility is favored by two epidemiologic studies that found the same frequency of monoclonal gammopathy in a matched control group as in cancer patients.9,18 Furthermore, when the monoclonal Ig is associated with a cancer, it usually persists after successful resection of the tumor. A convincing case for an association of acute myelogenous leukemia and myelodysplasia with monoclonal gammopathy was made by one group of scientists183,184 but a large longitudinal study did not find this association.12 Some observers propose that in clonal myeloid diseases the monoclonal protein reflects B-cell lineage involvement.
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Chemotherapy, radiotherapy, organ or marrow transplantation,194,195,196,197,198,199 and other miscellaneous disorders5,7,10,24,25,26,147,148,200,201,202 are associated with a transient or persistent monoclonal Ig (see Table 106–3). The high prevalence of monoclonal proteins and associated diseases, especially after age 50 years, indicates some of these associations are coincidental. Thus, although surgical correction of hyperparathyroidism is associated with disappearance of the plasma monoclonal protein,158 statistical studies of this disorder suggest a coincidental relationship in most patients.159 Gaucher disease type I has a higher-than-expected frequency of polyclonal (approximately 40 percent) and monoclonal (approximately 20 percent) gammopathy, and, probably, of myeloma.160,161,162 Elaboration of proinflammatory cytokines, growth factors, and chemokines, several involved in B-cell function, is disturbed in type I Gaucher disease. An increase of interleukin (IL)-10 and pulmonary and activation-regulated chemokine is notable. A high frequency of B-cell clonality and IgH gene rearrangements have also been described.162 The administration of recombinant glucocerebrosidase therapy may decrease the occurrence and progression of gammopathies.161
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In inflammatory, autoimmune, and infectious diseases, the association is viewed as an unusual expansion of a restricted population of B lymphocytes. Following marrow transplantation, the presence of oligoclonal blood B-lymphocyte populations often reflects the process of reconstitution of the B-cell population.