CHAPTER 105 ESSENTIAL MONOCLONAL GAMMOPATHY
CHAPTER 105 ESSENTIAL MONOCLONAL GAMMOPATHY
MARSHALL A. LICHTMAN
Definition and History
Etiology and Pathogenesis
Plasma and Urinary Immunoglobulins
Oligoclonal and Monoclonal Immunoglobulins
Lymphocyte and Plasma Cell Phenotypes
Course, Prognosis, and Therapy
Essential monoclonal gammopathy is defined by two key features: the presence of a monoclonal immunoglobulin G, A, or M in the serum or of monoclonal light chains in the urine and the absence of evidence for an overt or progressive malignancy of B lymphocytes or plasma cells (e.g., lymphoma, myeloma, or amyloidosis). Since the latter diseases may be about to emerge at the time the monoclonal immunoglobulin is first detected, follow-up of the patient over several months is required to ascertain if essential monoclonal gammopathy is the appropriate diagnosis. Long-term follow-up at appropriate intervals is prudent to detect conversion from a stable, benign condition to a progressive lymphoma or myeloma, which occurs in about 1 percent of cases per year. Essential monoclonal gammopathy increases in prevalence from about 1 percent in 30-year-old individuals to 10 percent in those 80 years of age or older. The condition has been reported in association with a large variety of disorders, especially nonlymphocytic cancers, but these coincidences are thought to be the chance concurrence of conditions that have a high prevalence in older populations. Some cases of essential monoclonal gammopathy are symptomatic because the immunoglobulin can interact with plasma proteins or neural tissue and cause serious dysfunction. In such cases, disability may be so great that attempts to remove the immunoglobulin by apheresis and to suppress its production using cytotoxic therapy can be warranted. In the absence of such findings, careful periodic follow-up is all that is required.
Acronyms and abbreviations that appear in this chapter include: Ig, immunoglobulin; IL, interleukin.
DEFINITION AND HISTORY
The syndrome of essential monoclonal gammopathy has two important characteristics. The first characteristic is a plasma immunoglobulin or urinary immunoglobulin light chain that has the molecular features of the product of a single clone of B lymphocytes or plasma cells: homogeneous electrophoretic migration and a single light-chain type. The second feature is the absence of evidence of an overt neoplastic disorder of B lymphocytes or plasma cells, such as lymphoma or multiple myeloma.
The observations that Bence Jones proteinuria can precede by many years the clinical signs of multiple myeloma1 and that hyperglobulinemia without evidence of multiple myeloma can occur in some patients2 antedated the concept of monoclonal gammopathy as a syndrome. With the more frequent clinical application of zonal electrophoresis of plasma proteins during the 1950s and 1960s, patients were discovered who had a monoclonal immunoglobulin either without an associated disease or with diseases such as nonlymphoid cancers, infections, and inflammatory disorders, which are not typically associated with a monoclonal proliferation of B lymphocytes.3,4,5,6,7,8,9 and 10 The presence of a monoclonal protein in plasma or urine is referred to as essential monoclonal gammopathy if it is not associated with a disease. Over 30 synonyms for the syndrome have been used, particularly essential monoclonal gammopathy and benign monoclonal gammopathy.6 Monoclonal gammopathy of unknown significance (MGUS) has been proposed as a designation preferable to benign monoclonal gammopathy because about one-third of patients were noted to progress to myeloma, macroglobulinemia, amyloidosis, or a B-cell lymphoma in over 25 years of observation.10 The term essential monoclonal gammopathy seems best, since it neither highlights a benign process nor indicates that the risks of subsequent lymphoma or myeloma are unknown. A classification of monoclonal gammopathies is presented in Table 105-1.
TABLE 105-1 TYPES OF MONOCLONAL IMMUNOGLOBULIN SYNTHESIZED BY ABNORMAL CELL CLONE
Monoclonal gammopathy can occur at any age, but it is unusual before puberty, and its frequency increases with age.11 The frequency of a serum paraprotein using zonal electrophoresis is about 1 percent in persons over age 25 years,4 about 3 percent in those over age 70 years,4,9 and about 10 percent in those over age 80 years.3 A much higher prevalence of monoclonal gammopathy has been reported using more sensitive screening methods, such as isoelectric focusing or immunoblotting.12,13 The prevalence rate among Americans of African descent is significantly greater than among those of European descent in each age group over 50 years.14,15 Familial occurrence also has been described.16,17 An increased incidence of monoclonal gammopathy has been associated with several occupation groups, including farmers and industrial workers.18
ETIOLOGY AND PATHOGENESIS
Monoclonal gammopathy can be compared with any benign tumor, such as a colonic polyp, that can stay the same size indefinitely or undergo malignant transformation at an unpredictable future time.
Monoclonal gammopathy is caused by the proliferation of a single B lymphocyte, a plasma cell progenitor, leading to a clonal population that reaches a steady state at or below about 1 × 1011 cells. At this cell population density, marrow plasma cell prevalence is indistinguishable from that of normal marrow. The expanded clone secretes monoclonal immunoglobulin at a rate per cell sufficient to be detected by standard tests. The clonal expansion, however, does not cause osteolysis, inhibit hematopoietic proliferation and maturation, or impair differentiation of polyclonal B lymphocytes to plasma cells. As such, immunoglobulin synthesis is normal, and patients do not necessarily incur an increased risk of infection. The cells in the benign clone do not accumulate further and do not elaborate significant amounts of osteoclast-activating factors [i.e., interleukin (IL)-1 b, IL-6, soluble IL-6 receptor a, and macrophage colony stimulating factor (M-CSF)] that are responsible for bone destruction. Remarkably, despite these significant differences from myeloma in the behavior of the neoplastic B cells, cytogenetic abnormalities akin to those seen in myeloma involving chromosomes 3, 7, 11, and 18 are present in plasma cells derived from the clone.19,20 and 21
The C57BL mouse provides a model of benign monoclonal gammopathy. The frequency of monoclonal gammopathy increases with mouse age.22 The disease can be transferred to either irradiated or nonirradiated mice by marrow or spleen cells.23 The transfer can only be accomplished during the first four consecutive transplantations, and there is no effect on the survival of the recipient compared with that of appropriate control subjects. In contrast, if mouse B-cell lymphoma or myeloma cells are transplanted into normal mice, the engraftment frequency is higher than that of B cells from mice with benign gammopathy, and passage from the original recipient to a new recipient is unlimited; progressive disease develops, and survival of recipients is decreased. Thus, there is an intrinsic difference in the growth potential (degree of malignancy) of these two B-cell clones.23 The frequency of monoclonal gammopathy increases with age, but the progression to multiple myeloma in the C57BL mouse is a rare event.24 Studies in transgenic mice and their litter mates replicate the increased incidence of B-cell clones and gammopathy with aging.25
Occasionally, monoclonal gammopathy may occur from the exaggerated production of natural antibody by a B-lymphocyte clone.26 For example, patients with cold agglutinins may have monoclonal IgM for years. A few monoclonal IgMs act as rheumatoid factors and may form cryoglobulins through complex formation with IgG molecules.
Characteristically, individuals are detected by the unexpected identification of a monoclonal protein in plasma or urine in the absence of symptoms or signs caused by diseases associated with monoclonal proteins (e.g., anemia, marrow plasmacytosis, lymph node enlargement, plasmacytoma, bone lesions, or amyloid deposits).6,7,8,9 and 10,26,27,28,29,30,31,32,33 and 34
Some patients may have monoclonal proteins with antibody specificity directed against plasma or cell proteins, resulting in symptomatic pathophysiologic effects, such as immune hemolytic anemia,35 acquired von Willebrand disease,36,37 immune neutropenia,38 or other functional manifestations listed in Table 105-2.
TABLE 105-2 FUNCTIONAL ABNORMALITIES ASSOCIATED WITH ESSENTIAL MONOCLONAL GAMMOPATHY
Rare patients with essential urinary light-chain excretion and renal disease have been described.43,44 and 45
There is a significant association between the occurrence of neuropathies and essential monoclonal gammopathy.46,47,48,49,50,51,52,53,54,55 and 56 About 10 percent of patients with idiopathic neuropathy have a monoclonal immunoglobulin, a frequency about eight times that of healthy comparison groups.46,47,50 Monoclonal antibodies can react with peripheral nerve myelin, specifically with myelin-associated glycoprotein, glycolipids, or sulfitides.48,52,56,57,58 and 59 Neuropathy in the absence of such reactivity implies that other mechanisms also may operate to cause nerve damage.49,52
Patients with essential IgM 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.56,57,58,59 and 60 In contrast, patients with essential IgG or IgA gammopathy usually have a chronic axonal sensorimotor neuropathy, sometimes with limb paralysis and occasionally with a remitting-relapsing course.61,62,63 and 64 Essential IgA gammopathy has been associated with dysautonomia.49 The presence or absence of antibody to myelin-associated glycoprotein may have an effect on the specific nature of the neuropathic manifestations.52,56,57,58,59 and 60
Demyelinization is reflected in a marked decrease in conduction velocity. Axonal loss is reflected in decreased sensory potentials.50,52,55,56,61,62,63 and 64 Electromyography shows denervation of muscles.50,52,65,66 and 67 Immunofluorescence studies of sural nerve or of skin biopsies may uncover immunoglobulin binding to nerve.52,56,58
Four treatment approaches may result in improvement in the neuropathies: (1) intravenous gamma globulin administration, (2) immunoadsorption of perfused blood with staphylococcal protein A, (3) plasmapheresis, or (4) immunosuppressive chemotherapy, such as cyclophosphamide or chlorambucil with or without glucocorticoids.52,55,59,60,65,67,68,69 and 70 In some cases use of plasmapheresis has been followed by cytotoxic therapy in an effort to produce a sustained effect. Response rates to each form of therapy are low and duration of response is variable,52,60,65,66,67,68,69 and 70 but some patients appear to obtain significant improvement for prolonged periods.
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, shown in Table 105-3.71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,
91,92,93,94,95,96,97,98,99,100 and 101 Although they are grouped under the designation monoclonal gammopathy with an associated disease, few such reports have examined whether the coincidence is greater than would be expected in a control group matched for age and ethnicity, the two variables that have the greatest impact on incidence of monoclonal gammopathy. Non-B-cell malignancies, including solid tumors,3,5,6,102,103 and 104 myeloproliferative disorders,105,106,107,108,109,110 and 111 and non-B-cell lymphomas,112,113,114 and 115 have been associated with paraproteinemia. These relationships could be the result of (1) patients with an M component having an increased risk of developing cancer, (2) the M component being an antibody against some antigen associated with the cancer, (3) the globulin being the product of cancer cells, or (4) coincidence. The last possibility is favored by one epidemiologic study that found the same frequency of monoclonal gammopathy in a matched control group as in cancer patients.9 Furthermore, where the monoclonal immunoglobulin is associated with a cancer, it usually persists after surgical excision of the tumor.
TABLE 105-3 DISORDERS REPORTED IN COINCIDENCE WITH MONOCLONAL GAMMOPATHY
Chemotherapy, radiotherapy, and organ or marrow transplantation have been associated with a transient or persistent monoclonal immunoglobulin,116,117,118,119,120 and 121 as have other miscellaneous disorders (Table 105-3).5,7,10,15,16,78,79
The high prevalence of monoclonal proteins and associated diseases, especially after age 50 years, indicates that some of these associations may be coincidental. Thus, although surgical correction of hyperparathyroidism has been associated with disappearance of the plasma monoclonal protein,88 statistical studies of this disorder suggest a coincidental relationship in most patients.89 In hematopoietic stem cell diseases, some observers have proposed that the paraprotein reflects subtle B-cell lineage involvement. In inflammatory, autoimmune, and infectious diseases, the association has been viewed as an unusual expansion of a restricted population of B lymphocytes. Following marrow transplantation, the presence of oligoclonal blood B-lymphocyte populations may reflect the effect of a reconstitution of the B-cell population.
PLASMA AND URINARY IMMUNOGLOBULINS
The monoclonal protein is usually IgG; however, IgM, IgA, IgD, and IgE urinary light chains, double gammopathy involving IgA and IgG or IgM and IgA, and triple gammopathy can occur (Table 105-1).103,104,105,106 and 107,129 By definition, no findings other than a plasma or urinary M component are present that would permit a diagnosis of a B-lymphocyte or plasma cell malignancy.
In monoclonal gammopathy of the IgG type, the concentration of monoclonal immunoglobulin is usually less than 3.0 g/dl, and in the IgA or IgM type, it is usually below 2.5 g/dl.10,129 However, there are dramatic exceptions to this rule, with occasional patients with essential monoclonal gammopathy having concentrations as high as 6.0 g/dl. Some patients have Bence Jones proteinuria as the sole manifestation of monoclonal gammopathy.1,10 The amount of urinary light chains excreted may occasionally be large (>1.0 g/day), and renal dysfunction can develop.43
Most patients with myeloma or macroglobulinemia have a significant depression in the nonmonoclonal immunoglobulin levels. For example, patients with IgG myeloma usually have very low IgA and IgM concentrations as well as a reduction in polyclonal IgG level. Patients with monoclonal gammopathy usually have normal polyclonal immunoglobulin levels, and depression of their polyclonal immunoglobulin levels, when it occurs, is usually not as severe as in myeloma.10,129,130
OLIGOCLONAL AND MONOCLONAL IMMUNOGLOBULINS
Oligoclonal or monoclonal serum immunoglobulins have been detected with high-resolution agarose gel electrophoresis in hospitalized patients with acute phase reactions or polyclonal hyperglobulinemia.127 Oligoclonal immunoglobulin bands are frequently seen in the cerebrospinal fluid and serum of patients with a variety of neurological conditions, especially in patients with multiple sclerosis when the fluids are analyzed by isoelectric focusing.131 Patients with acquired immunodeficiency syndrome (AIDS) have B-cell activation and aberrancies of B-cell regulation. High-resolution electrophoresis has indicated that most AIDS patients with advanced disease have monoclonal or oligoclonal serum immunoglobulin bands. Subjects with AIDS, lymphadenopathy syndrome, or antibody to the human immunodeficiency virus also have oligoclonal or monoclonal immunoglobulin bands by standard zonal electrophoresis.94,96 These monoclonal proteins are IgG.
LYMPHOCYTE AND PLASMA CELL PHENOTYPES
The concentration of plasma cells in the marrow is less than 5 percent, and the incorporation of tritiated thymidine into marrow plasma cells is negligible (<1 percent) in essential monoclonal gammopathy. Blood T-lymphocyte subset levels are normal in monoclonal gammopathy, whereas CD4+ T cell levels are lower and CD8+ T cell levels higher in myeloma and macroglobulinemia.132,133,134 and 135 Blood B-cell concentration is normal in monoclonal gammopathy but is often decreased in myeloma patients. Clonally restricted, idiotype-positive blood B cells are characteristic of myeloma but not of monoclonal gammopathy.136
b2 microglobulin is the light chain of cell surface HLA molecules, and normally it is present at low concentrations in serum. Its concentration in serum frequently is elevated in myeloma, and the magnitude of the elevation is positively correlated with tumor mass. b2 microglobulin concentration is not elevated in essential monoclonal gammopathy.137,138
The distinction between stable essential monoclonal gammopathy and emerging (so-called larval myeloma) with a very low tumor burden is blurred at the margins. This has not kept investigators from looking for a distinguishing test. Over 20 variables have been studied as an index for discriminating benignity from malignancy (Table 105-4). No single test is sufficiently sensitive and specific to be useful in an individual patient. Periodic examination of the patient is the best method of detecting the emergence of myeloma or a related disease. Measurement of the concentration of the serum monoclonal protein, urinary light chains, serum b2-microglobulin, and hemoglobin concentration at appropriate intervals is required. Practical methods of measuring serum IL-6 and bone density may become additional useful measures of stability or progression.
TABLE 105-4 VARIABLES THAT HAVE BEEN USED IN AN ATTEMPT TO DISTINGUISH ESSENTIAL MONOCLONAL GAMMOPATHY FROM MYELOMA
COURSE, PROGNOSIS, AND THERAPY
Longitudinal studies have reported three major patterns of outcome for patients with essential monoclonal gammopathy.10,129,130,139,170,171 and 172 About 25 percent of patients do not progress. In this group, occasional patients may experience increases in monoclonal protein concentration of up to 50 percent of their initial diagnostic value. However, these patients restabilize and do not develop signs of myeloma, macroglobulinemia, amyloidosis, or lymphoproliferative disease. About one-half of patients die of an unrelated cause. The remaining one-quarter of the patients develop myeloma, amyloidosis, macroglobulinemia, or lymphoma over two decades of observation. The latter group of patients continues to increase slowly without reaching a plateau, and evolution to myeloma has been observed more than 20 years after the diagnosis of monoclonal gammopathy. The actuarial risk of progressing to lymphoma or myeloma is about 1percent per year.139,141,170,171,172 and 173 In rare patients, the monoclonal protein may appear transiently in relation to a disease (e.g., infection)125,126 and 127 or may disappear spontaneously even when not associated with a disease.3
Generally, the diagnosis of essential monoclonal gammopathy cannot be made with certainty at the time of the initial evaluation. Periodic reexamination is required to document a stable clinical course. Therapy usually is not required unless there is a confirmed diagnosis of myeloma, macroglobulinemia, amyloidosis, or lymphoma with evidence of progressive disease. Therapy may also be indicated in the uncommon circumstance that the monoclonal protein interferes with the vital function of a normal plasma or tissue constituent.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn