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CHAPTER 106 clinical signs of multiple myeloma by many years and that hyper-
The observations that Bence Jones proteinuria could precede the
1
ESSENTIAL MONOCLONAL globulinemia without evidence of multiple myeloma could occur in
some patients antedated the concept of monoclonal gammopathy as
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GAMMOPATHY a syndrome. With the more frequent clinical application of zonal elec-
trophoresis of plasma proteins during the 1950s and 1960s, patients
were discovered who had a monoclonal Ig, either without an associ-
ated disease or with diseases such as nonlymphoid cancers, infec-
Marshall A. Lichtman tions, and inflammatory disorders, which typically are not associated
with a monoclonal proliferation of B lymphocytes. 3–10 The presence of
a monoclonal Ig or monoclonal free light chain in serum, if it is not
associated with an overt neoplastic disease of lymphocytes, is referred
SUMMARY to as essential monoclonal gammopathy. Several synonyms for the syn-
drome have been used, particularly monoclonal gammopathy and benign
Essential monoclonal gammopathy is defined by two key features: (1) the monoclonal gammopathy. Monoclonal gammopathy of unknown signif-
6
presence of a monoclonal immunoglobulin or a monoclonal immunoglob- icance (MGUS) has become fashionable as a designation preferable to
ulin light chain in the serum and (2) the absence of evidence for an overt benign monoclonal gammopathy because approximately one quarter of
malignancy of B lymphocytes or plasma cells (e.g., lymphoma, myeloma, or patients eventually progress to myeloma, macroglobulinemia, amyloi-
amyloidosis). The prevalence of essential monoclonal gammopathy depends dosis, or a B-cell lymphoma over decades of observation. 10–12 The suf-
on the demographic features in the population under study. In Americans of fix “of unknown significance” was justified, it was argued, because one
European descent, the prevalence increases from approximately 2 percent in did not know in whom or when the progression might occur. Now the
individuals 50 years of age to approximately 7 percent in octogenarians. It is term “monoclonal gammopathy of renal significance” has been coined,
arguing that in this case the monoclonal gammopathy is of significance.
two to three times as prevalent in persons of African descent. The condition has However, other organs (e.g., nerves, eyes, bones), plasma proteins, and
been reported in association with a large variety of disorders, especially non- blood cells, as well as kidneys, may be injured or inactivated by a mono-
lymphocytic cancers. These coincidences are thought, in most cases, to be the clonal protein (see “Functional Impairment from a Monoclonal Pro-
chance concurrence of conditions that have a high prevalence in older persons. tein” below) and we will have to have (an unnecessary) proliferation of
Some cases of essential monoclonal gammopathy are symptomatic because such designations. The term essential monoclonal gammopathy seems
in those cases the immunoglobulin can interact with plasma proteins, blood best, because it neither highlights a benign process nor indicates that
cells, kidney, ocular structures, or neural tissue and cause serious dysfunction, the risks of subsequent lymphoma or myeloma are unknown; that risk
for example, an acquired bleeding disorder, renal insufficiency, or an incapac- is universally appreciated. It is unnecessary to assign the postscript “of
itating neuropathy. In such cases, disability may be so great that attempts to unknown significance” to the numerous well-defined benign neoplasms
remove the immunoglobulin by plasmapheresis and to suppress its production at risk of clonal evolution and progression, such as colonic adenoma-
using immune or cytotoxic therapy can be warranted. Because myeloma or tous polyps, other adenomas, uterine leiomyomas, monoclonal B-cell
lymphocytosis, and clonal sideroblastic anemia. Biologically, essential
lymphoma may emerge at the time the monoclonal immunoglobulin is first monoclonal gammopathy is one of many such well-defined examples
detected, periodic evaluation of the patient is required to ascertain if essential of a stable (“benign”) neoplasm with the potential to evolve through
monoclonal gammopathy is the appropriate diagnosis. Long-term followup at the acquisition of additional somatic mutations to a progressive neo-
appropriate intervals is prudent to detect conversion from a stable, asymptom- plasm. More is known about its significance and pathobiology than
atic condition to a progressive lymphoma or myeloma, which occurs in approx- perhaps any other benign neoplasm with a risk of clonal evolution to a
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imately 0.5 to 1.0 percent of cases per year. In the absence of a symptomatic malignant state. As in all diseases, the physician should understand its
gammopathy or evolution to a progressive clonal gammopathy, periodic fol- pathobiology and act accordingly.
lowup is all that is required. Table 106–1 presents an immunologic classification of essential
monoclonal gammopathy.

EPIDEMIOLOGY
DEFINITION AND HISTORY
Monoclonal gammopathy can occur at any age, but it is unusual before
The syndrome of essential monoclonal gammopathy has two important puberty, and its frequency increases with age. 14,15 The frequency of a
characteristics. The first feature is a plasma immunoglobulin (Ig) or serum paraprotein using zonal electrophoresis is approximately 1 per-
4
Ig light chain that has the molecular features of the product of a sin- cent in persons older than age 25 years, approximately 3 percent in
gle clone of B lymphocytes or plasma cells: homogeneous electropho- those older than age 70 years, and approximately 10 percent in those
4,9
retic migration and a single light-chain type. The second feature is the older than age 80 years. A much higher prevalence of monoclonal gam-
3
absence of evidence of an overt neoplastic disorder of B lymphocytes mopathy has been reported using more sensitive screening methods,
or plasma cells, such as lymphoma, myeloma, macroglobulinemia, or such as isoelectric focusing or immunoblotting. 16,17 Prevalence rates
amyloidosis. differ in different geographic areas and have been somewhat lower in
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the United States (Minnesota), Iceland, and the Netherlands. The
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frequency of monoclonal gammopathy is less in Japanese 20,21 and Chi-
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nese. The prevalence rate among Africans and Americans of African
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Acronyms and Abbreviations: CD, cluster of differentiation; HLA, human leuko- descent 15,24–27 is significantly greater than the rate among those of Euro-
cyte antigen; Ig, immunoglobulin; IL, interleukin. pean descent in each comparative age group. Males are more frequently
affected than females. Familial occurrence also has been described. 28–31

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