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1722 Part XI: Malignant Lymphoid Diseases Chapter 106: Essential Monoclonal Gammopathy 1723

Occasionally, monoclonal gammopathy is the result of exaggerated Some pathologists are still reluctant to give up urinary measurements
production of natural antibody by a B-lymphocyte clone. For exam- because of the uncommon occurrence of urinary monoclonal light
60
ple, patients with cold agglutinins may have monoclonal IgM for years. chains in the absence of evidence of an abnormality of serum mono-
76
A few monoclonal IgM antibodies act as rheumatoid factors and may clonal light chains. Followup of these cases has not shown any clini-
form cryoglobulins through complex formation with IgG molecules. cal consequence of these uncommon false-negative serum light-chain
measurements. Serum protein gel electrophoresis has a limit of detec-
CLINICAL FEATURES tion of approximately 0.03 g/dL, if the monoclonal protein migrates in
the γ-globulin fraction. Small monoclonal proteins that migrate in the
BLOOD CELLS AND MARROW α- or β-globulin fraction are more difficult to identify on electrophore-
Blood counts and the marrow examination are normal. Notably anemia sis. Immunofixation electrophoresis is used to confirm a monoclonal
protein found on gel electrophoresis. Immunofixation electrophoresis
is not present and the proportion of plasma cells in marrow is less than may also detect a monoclonal protein not evident on serum protein gel
10 percent. Although an increased percent of plasma cells is the most electrophoresis, usually because the protein is in too low a concentra-
constant morphologic feature of myeloma, the presence of cytologic tion or is embedded in the normal polyclonal α- or β-globulin peak.
atypia as judged by frequent binucleate plasma cells and large plasma Monoclonal proteins identified by immunofixation electrophoresis may
cell nucleoli are findings more specific for myeloma. Quantitative be transient (approximately 15 to 20 percent) and have a greater like-
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microscopy of the number of marrow microvessels per high-power lihood to progress to a disease if they are of an IgA or IgM isotype.
77
field, using immunohistochemistry, indicates microvessel density on In the future, mass spectroscopy may be a more sensitive and specific
average is threefold greater than in normal persons, but far less than in method to identify monoclonal proteins. 78
patients with myeloma, although some overlap with myeloma occurs. 62 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,
CYTOGENETIC ANALYSIS marrow examination and radiographic examination of the bones have a
Hyperdiploidy, assessed by DNA content, is present in about half the very low diagnostic yield and can be omitted. A presumptive diagnosis
cases and hypodiploidy is present in approximately 10 percent of cases of essential monoclonal gammopathy can be made with reexamination
of monoclonal gammopathy. Use of interphase fluorescence in situ at approximately 6 months and at appropriate intervals, thereafter. 79,80
42
hybridization has uncovered numerical chromosome abnormalities in
the plasma cells of more than 50 percent of subjects. Clones containing FUNCTIONAL IMPAIRMENT FROM A
trisomy or monosomy involving chromosomes 3, 6, 7, 9, 11, 13, 17, and MONOCLONAL PROTEIN
18 have been identified. 38–41,44,45 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 Interaction with Plasma Protein or Blood Cells
subjects. 38–41 Chromosomal changes do not appear to be correlated with Some patients have monoclonal proteins with antibody specific-
progression. ity directed against plasma or cell proteins, resulting in symptomatic
pathophysiologic effects, such as immune hemolytic anemia, acquired
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von Willebrand disease, 82–84 immune neutropenia, 85,86 and other func-
MONOCLONAL PROTEIN tional manifestations 87–92 (Table 106–2).
Characteristically, individuals are detected by the unexpected identifi-
cation of a monoclonal IgG or light chain in the serum in the absence Renal Injury
of symptoms or signs (e.g., anemia, marrow plasmacytosis, lymph node Occasional patients may have severe renal disease associated with
enlargement, plasmacytoma, bone lesions, or amyloid deposits) caused monoclonal gammopathy. 93–100 The renal disease my take the form of
by diseases associated with monoclonal proteins. 6–10,60,63–71 Although a tubular disorder, mimicking Fanconi syndrome (glycosuria, hypouri-
classically a serum Ig or urine monoclonal light chain was the standard cemia, proteinuria, asymptomatic renal insufficiency) 93,96 or a glomer-
for diagnosis, the ability to measure serum free light chains with high ular deposition disorder resulting from the deleterious interaction of
specificity and sensitivity has replaced the necessity to measure urine the monoclonal Ig or a light chain and the renal parenchyma resulting
light chain excretion for diagnosis as the latter is less sensitive than the
former. 72
Monoclonal IgG gammopathy occurs in approximately 70 percent
of persons and IgM and IgA in approximately 20 percent and 10 per- TABLE 106–2. Functional Abnormalities Associated with
cent, respectively. A few percent of persons may have biclonal or tri- Essential Monoclonal Gammopathy
clonal gammopathy (see Table 106–1). 6–10,12,60,63–71 Plasma protein and blood cell disturbances
Most patients with essential monoclonal gammopathy have a 81 82–84
monoclonal protein concentration of less than 30 g/L, but exceptions Antierythrocyte antibodies, acquired von Willebrand disease,
85,86
10
occur. The diagnosis reflects the sum of (1) the monoclonal protein immune neutropenia, cryoglobulinemia, cryofibrinogene- 10
mia, acquired C1 esterase inhibitor deficiency (angioedema),
10
level, (2) the marrow plasma cell concentration (<10 percent), (3) the acquired antithrombin, insulin antibodies, 88,89 antiacetylcho-
87
absence of other features of progressive plasma cell neoplasm (e.g., line receptor antibodies, “antiphospholipid” antibodies,
91
90
hypercalcemia, osteolysis, otherwise unexplained anemia, otherwise dysfibrinogenemia 92
unexplained renal disease), and (4) the absence of progression on peri- Renal disease 93–100
odic long-term followup.
A developing consensus favors measurement of serum pro- Oculopathies 102–106
tein gel electrophoresis and serum free light chain levels (and the κ:λ Neuropathies 107–111
ratio), and serum protein immunofixation electrophoresis without Deep venous thrombosis 136,137
urinary Ig measurements to detect monoclonal gammopathies. 73–75

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