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C H A P T E R 87

WALDENSTRÖM MACROGLOBULINEMIA/

LYMPHOPLASMACYTIC LYMPHOMA

Steven P. Treon, Jorge J. Castillo, Zachary R. Hunter, and Giampaolo Merlini

Waldenström macroglobulinemia (WM) is a lymphoid neoplasm PATHOGENESIS
resulting from the accumulation, predominantly in the marrow, of a
clonal population of lymphocytes, lymphoplasmacytic cells, and Nature of the WM Clone
1
plasma cells, which secrete a monoclonal immunoglobulin (Ig) M.
WM corresponds to lymphoplasmacytic lymphoma (LPL) as defined Examination of the B-cell clone(s) found in the bone marrow (BM)
in the Revised European-American Lymphoma (REAL) and World of patients with WM reveals a range of differentiation, from small
2,3
Health Organization classification systems. Most cases of LPL are lymphocytes with large focal deposits of surface immunoglobulins,
WM; less than 5% of cases are IgA-secreting, IgG-secreting, or to lymphoplasmacytic cells, to mature plasma cells that contain
14
nonsecreting LPL. intracytoplasmic IgM (Fig. 87.1). Circulating clonal B cells are
In 1944, Jan Waldenström, a Swedish physician-scientist, often detectable in patients with WM, though lymphocytosis is
reported in Acta Medica Scandinavica three cases of a disease he uncommon. 15,16 WM cells express the monoclonal IgM, and some
17
presciently thought was related to myeloma but for the absence of clonal cells also express surface IgD. The characteristic immunophe-
bone involvement and the scarcity of plasma cells in the infiltrate notypic profile of WM lymphoplasmacytic cells includes the expres-
of small lymphocytes. He noted the increase in plasma protein con- sion of the pan–B-cell markers CD19, CD20 (including FMC7),
centration, marked increased serum viscosity, exaggerated bleeding CD22, and CD79. 17,18 Expression of CD5, CD10, and CD23 can
and retinal hemorrhages, and virtually every other feature of the be present in 10% to 20% of cases, and their presence does not
19
disorder in his case descriptions. In collaboration with a colleague, exclude the diagnosis of WM. In addition, multiparameter flow
he showed, using ultracentrifugation and electrophoresis, that the cytometric analysis has also identified CD25 and CD27 as being
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+
dim
abundant abnormal protein had a molecular weight of approximately characteristic of the WM clone, and that a CD22 /CD25 /CD27 /
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1 million and was not an aggregate of smaller proteins. The disease, IgM population can be observed among clonal B lymphocytes in
which he described with such thoroughness, was later named in his patients with IgM monoclonal gammopathy of undetermined signifi-
honor. cance (MGUS) who ultimately progress to WM. 20
Somatic mutations in immunoglobulin genes are present with
increased frequency of nonsynonymous versus silent mutations in
EPIDEMIOLOGY complementarity-determining regions, along with somatic hypermu-
tation, thereby supporting a postgerminal center derivation for the
The age-adjusted incidence rate of WM in the United States is 3.4 WM B-cell clone in most patients. 21,22 A strong preferential use of
per 1 million among males and 1.7 per 1 million among females. It VH3/JH4 gene families without intraclonal variation, and without
4,5
increases in incidence geometrically with age. The incidence rate is evidence for any isotype-switched transcripts, has also been shown. 23,24
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higher among Americans of European descent. Americans of African Taken together, these data support an IgM and/or IgM IgD
descent represent approximately 5% of all patients. memory B-cell origin for most cases of WM.
Genetic factors play a role in the pathogenesis of WM. Approxi- In contrast to myeloma plasma cells, no recurrent translocations
mately 20% of patients with WM are of Ashkenazi Jewish ethnic have been described in WM, which can help to distinguish IgM
6
background. Familial disease has been reported commonly, including myeloma cases that often exhibit t11;14 translocations from WM. 25,26
multigenerational clustering of WM and other B-cell lymphoprolif- Despite the absence of IgH translocations, recurrent chromosomal
erative diseases. 7–10 Approximately 20% of 257 sequential patients abnormalities are present in WM cells. These include deletions in
with WM presenting to a tertiary referral center had a first-degree rela- chromosome 6q21–23 in 40% to 60% of patients with WM, with
9
tive with either WM or another B-cell disorder. Familial clustering of concordant gains in 6p in 41% of patients with 6q deletion. 27–30 In
WM with other immunologic disorders, including hypogammaglobu- a series of 174 untreated patients with WM, 6q deletions, followed
linemia and hypergammaglobulinemia (particularly polyclonal IgM), by trisomy 18, 13q deletions, 17p deletions, trisomy 4, and 11q
30
autoantibody production (particularly to the thyroid), and manifesta- deletions, were observed. Deletion of 6q and trisomy 4 were associ-
tion of hyperactive B cells, has also been reported in relatives without ated with an adverse prognosis in this series. Because 6q deletions
WM. 9,10 Increased expression of the BCL2 gene with enhanced sur- represent the most recurrent cytogenetic finding in WM cases, there
vival has been observed in B cells from familial patients and their has been great interest in identifying the region of minimal deletion
family members. 10 and possible target genes within this region. Two putative gene can-
The role of environmental factors is uncertain; however, but didates within this region include TNFAIP3, a negative regulator of
chronic antigenic stimulation from infections and certain drug or nuclear factor-κB signaling (NFκB), and PRDM1, a master regulator
chemical exposures have been considered but have not reached a level of B-cell differentiation. 29,31 The removal of an NFκB-negative regu-
of scientific certainty. Hepatitis C virus (HCV) infection was impli- lator is of particular interest because the phosphorylation and trans-
cated in WM causality in some series, but no association was found location of NFκB into the nucleus is a crucial event for WM cell
32
in a study of 100 consecutive patients with WM in whom serologic survival. The success of proteasome inhibitor therapy in WM has
and molecular diagnostic studies for HCV infection were been postulated to occur because the degradation of negative regula-
performed. 11–13 tors of NFκB, such as inhibitor of κ B (IκB), is blocked. 33,34
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