Resident Short Review
Lymphoplasmacytic Lymphoma
and Waldenström Macroglobulinemia
Nadia Naderi, MD; David T. Yang, MD
 Lymphoplasmacytic lymphoma (LPL) is a low-grade, B-
cell neoplasm composed of small lymphocytes, plasmacy-
toid lymphocytes, and plasma cells that typically involve
the bone marrow, and it is associated with an immuno-
globulin M (IgM) gammopathy. The definition of
Waldenström macroglobulinemia (WM) and its relation-
ship to LPL has been confusing in the past. In addition, the
diagnosis of LPL itself can be challenging because LPL lacks
disease-specific morphologic, immunophenotypic, and
genetic features to differentiate it from other mature B-
cell neoplasms. Accurate diagnosis of LPL/WM rests on
L ymphoplasmacytic lymphoma (LPL) is a chronic, lym-
phoproliferative neoplasm characterized by small B
lymphocytes, plasmacytoid lymphocytes, and plasma cells
typically involving the bone marrow, lymph nodes, and
spleen. The 2008 World Health Organization criteria for
classification of hematologic diseases characterizes Walden-
ström macroglobulinemia (WM) as a subset of LPL that has
a detectable level of monoclonal immunoglobulin (Ig) M
gammopathy, with bone marrow involvement by LPL.1,2
Waldenström macroglobulinemia was originally described
in 1944 by Jan G. Waldenström, MD, DSc, who reported on
2 patients with oronasal bleeding, anemia, lymphadenop-
athy, hypergammaglobulinemia, an elevated sedimentation
rate, hyperviscosity, normal bone survey, cytopenias, and
bone marrow involvement by a predominantly lymphoid
infiltration.3 Although most cases of LPL are WM, there are
exceptions where the diagnosis of WM does not apply.
Examples are rare, primary, lymph node-based presenta-
tions of LPL or lymphoplasmacytic B-cell proliferations in
the bone marrow associated with IgA or IgG gammopa-
thies.
CLINICAL FEATURES
Lymphoplasmacytic lymphoma/WM is a rare disease,
with an annual incidence of 3 to 4 cases per million people,
most commonly affecting older, white men.2,4,5 Infiltration
Accepted for publication May 21, 2012.
From the Department of Pathology and Laboratory Medicine,
University of Wisconsin, Madison.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: David T. Yang, MD, Department of Pathology and
Laboratory Medicine, University of Wisconsin, Madison, K4/446
Clinical Sciences Center, 600 Highland Ave, Madison, WI 53792-
2472 (e-mail: dtyang@wisc.edu).
580 Arch Pathol Lab Med—Vol 137, April 2013
recognition of the differential diagnostic features between
LPL and other diagnostic possibilities and the use of the
recently refined definition of WM and its relationship with
LPL: The presence of an IgM monoclonal gammopathy of
any level in the setting of bone marrow involvement by
LPL. This review summarizes the clinical, laboratory, and
histologic features of LPL/WM, with particular emphasis
on unique aspects of LPL/WM that may aid in accurate
diagnosis.
(Arch Pathol Lab Med. 2013;137:580–585; doi: 10.5858/
arpa.2012-0034-RS)
of the bone marrow and extramedullary sites, such as lymph
nodes, spleen, and liver, by malignant B cells and elevated
IgM levels contribute to symptoms associated with pancy-
topenia, organomegaly, and hyperviscosity. Most patients
are either asymptomatic or present with anemia; presenting
with symptoms of hyperviscosity is uncommon.6 In rare
instances, diffuse lymphoplasmacytic infiltration of the lung,
stomach, or bowel may occur. Associated with rare cases of
WM is a clinical presentation of diffuse urticaria and IgM
paraproteinemia called Schnitzler syndrome. Characteristic
symptoms of hyperviscosity syndrome include mucosal
bleeding, visual disturbance, and headache. More severe
neurologic manifestations include mental confusion, focal
neurologic deficits, and stroke. Hyperviscosity syndrome
occurs in up to 30% of patients, with symptoms of
hyperviscosity usually appearing when the reference range
serum viscosity of 1.4 to 1.8 cP reaches 4 to 5 cP
(corresponding to a serum IgM level of at least 3.0 g/
dL).7,8 The paraprotein may also have autoantibody or
cryoglobulin activity resulting in autoimmune phenomena
or cryoglobulinemia. The deposition of IgM can lead to
peripheral neuropathies and renal impairment. Most cases
of LPL are WM with an IgM paraprotein, however, a few
cases are IgA-secreting, IgG-secreting, or nonsecreting LPL.
Symptoms can vary considerably among individual patients,
and many patients are asymptomatic at diagnosis.
LABORATORY FINDINGS
Cell counts in patients with LPL/WM typically demon-
strate mild anemia and thrombocytopenia. Severe throm-
bocytopenia is usually only encountered late in the disease
course. Characterization of the paraprotein is essential in
the laboratory workup of LPL/WM. Serum protein electro-
phoresis, typically represented by a densitometry tracing of
the pattern, should demonstrate a monoclonal immuno-
globulin that is visualized as a peak (M-spike) in the
Waldenström Macroglobulinemia—Naderi & Yang
c-globulin region (Figure 1, A). Immunofixation is recom-
mended to further characterize the type of heavy and light
chain present (Figure 1, B). Densitometry of the M-spike can
be combined with serum nephelometry to monitor IgM
levels. Because of the unique physicochemical characteristics
of paraproteins, different patients with the same IgM levels
can have strikingly divergent viscosities. Most patients with
LPL/WM are symptomatic when serum or whole-blood
viscosity is above 3.0 and 8.0 cP, respectively.7,8 Measuring
whole-blood viscosity is complex because the viscosity is
affected by the hematocrit and does not behave as a
Newtonian fluid, like serum or plasma, where viscosity is
independent of flow rate. Accordingly, measurement of
serum or plasma viscosity is preferred.9
Up to 80% of patients with LPL/WM will have
monoclonal immunoglobulin light chains (Bence-Jones
proteins) in the urine. Laboratory evaluation should include
24-hour urine collection for urine protein electrophoresis.
Because of their correlation with clinical outcomes, levels of
serum free light chains and b2 microglobulin should also be
assessed.10,11
PATHOLOGIC FEATURES
In the peripheral blood, anemia is the most common
finding in symptomatic patients with LPL/WM. The anemia
is probably multifactorial and may be due to the expansion
of clonal cells in the bone marrow, increased plasma
volume, reduced erythropoietin production because of
hyperviscosity, and elevated levels of interleukin 6.12 The
anemia is usually normocytic and normochromic, and
rouleaux formation is often present in WM. Lymphocytosis
may be present, and the circulating neoplastic cells are
primarily small with condensed nuclear chromatin and
inconspicuous nucleoli. A subset of plasmacytoid lympho-
cytes is usually present, characterized by eccentric nuclei
and more-abundant basophilic cytoplasm (Figure 2, A).
In the bone marrow, the pattern of marrow infiltration
may be diffuse, interstitial, or focal nonparatrabecular
(Figure 2, B). A solely paratrabecular pattern of infiltration
is unusual and should raise the possibility of follicular
lymphoma.1 The bone marrow infiltrate of LPL is composed
of small lymphocytes admixed with variable numbers of
plasmacytoid lymphocytes and plasma cells (Figure 2, B and
C). Increased mast cells are often present, and they may
support the growth of LPL.13 Accumulation of cytoplasmic
or pseudonuclear immunoglobulin in the plasma cells,
known as Russell bodies and Dutcher bodies, respectively, are
other typical findings (Figure 2, D).
In the lymph node, the classic pattern is that of a subtle,
paracortical expansion of small lymphocytes associated with
varying numbers of plasma cells, often demonstrating
Dutcher bodies. Most lymphocytes are small with mono-
cytoid, centroblastic, or immunoblastic lymphocytes com-
prising only a small subset of the neoplastic cells. This
pattern does not typically efface the nodal architecture,
leaving the sinuses intact, and is associated with small,
benign B-cell follicles and hemosiderosis. Alternatively,
nodal LPL can be associated with hyperplastic follicles and
vaguely nodular or diffuse effacement of nodal architecture
by the same population of small, mature lymphocytes
associated with plasma cells. Epithelioid histiocytes can be
abundant in this pattern.14 Most LPL cases demonstrate
frank plasmacytic differentiation rather than only lympho-
plasmacytoid cells. That said, other B-cell lymphomas, such
Arch Pathol Lab Med—Vol 137, April 2013
as marginal zone lymphoma (MZL), follicular lymphoma,
small lymphocytic lymphoma/chronic lymphocytic leukemia
(SLL/CLL), and occasionally, mantle cell lymphoma, can
also demonstrate frank plasmacytic differentiation. Overall,
LPL in the bone marrow and lymph node is a diagnostic
challenge, demonstrating a wide spectrum of findings that
can overlap with other B-cell lymphomas with plasmacytic
differentiation, and LPL needs to be approached as a
diagnosis of exclusion. More details regarding diagnostic
strategies are presented in the ‘‘Differential Diagnosis’’
section.
The typical immunophenotype of LPL demonstrates
expression of CD19, CD20, CD22, FMC7, BCL2, CD38,
and CD79a with monotypic surface light chain. Staining
with CD5, CD10, and CD23 is usually absent.15 However,
up to 20% of cases may express CD5, CD10, or CD23.16
Immunoglobulin light-chain restriction can usually be
demonstrated in both the small lymphocytes and plasma
cells on tissue sections by immunohistochemistry. The
plasma cells in LPL have been reported to have a unique
immunophenotype, when compared with plasma cells
found in marginal-zone lymphoma or plasma cell myeloma,
with coexpression of PAX5 and CD45 with CD19, respec-
tively.17
PATHOGENESIS
The immunophenotypic profile of LPL/WM in combina-
tion with the presence of somatic mutations of genes in the
immunoglobulin heavy-chain variable region without intra-
clonal diversity suggests that the malignant cells originate
from cells at a late stage of differentiation derived from a B
cell arrested after somatic hypermutation in the germinal
center and before terminal differentiation to a plasma cell.18
The causes of LPL/WM are poorly understood; however,
there are emerging data to support a role for immune-
related and genetic factors in the etiology of LPL/WM. A
few studies have reported evidence of frequent somatic
immunoglobulin gene mutations, suggesting chronic anti-
gen stimulation might play an etiologic role.19,20 Population-
based studies from the United States have found autoim-
munity and hepatitis C viral infection to be associated with
an increased risk of developing WM,21,22 although that is not
supported by other studies.23
GENETIC AND MOLECULAR FINDINGS
Like all B-cell neoplasms, the B cells in LPL have clonally
rearranged immunoglobulin genes. Somatic hypermutation
is present in more than 90% of LPL/WM cases, and biased
use of the immunoglobulin heavy-chain variable region has
been documented, suggesting antigenic selection is involved
in the development of this mature B-cell lymphoma.24
Despite plasmacytic differentiation, there is evidence of
deregulated transition of the LPL B cells to plasma cells with
aberrant gene expression patterns and a lack of heavy-chain
class switching in LPL.25 Earlier reports of the association of
LPL/WM with t(9;14)(p13;q32) IGH/PAX5 have not been
supported in more-recent studies.26,27 Recent interest has
focused on the presence of 6q deletions, reported in up to
63% of LPL/WM.28 Although 6q deletion is relatively
nonspecific, it may have an oncogenic role in LPL/WM,
having been found to be associated with features of adverse
prognosis, possibly via inactivation of negative regulators of
the nuclear factor jB (NF-jB) signaling pathway.28,29
Similarly, a set of recent reports suggests that LPL may be
Waldenström Macroglobulinemia—Naderi & Yang 581
Figure 1. Serum protein electrophoresis (SPEP) and immunofixation from a patient with Waldenström macroglobulinemia. A, Densitometric tracing
of SPEP shows an M-spike in the gammaglobulin region. B, Serum immunofixation showing monoclonal bands of immunoglobulin M (M lane) and
light chain (L lane).

582 Arch Pathol Lab Med—Vol 137, April 2013 Waldenström Macroglobulinemia—Naderi & Yang
dependent on constitutive NF-jB signaling, with a large
proportion of LPL cases found to contain a somatic variant
in the MYD88 gene that constitutively activates NF-jB.
Interestingly, although 90% of LPL cases demonstrated that
mutation, it was found in only 6% of MZL cases.30–32 The
genetic abnormalities 13q and trisomy 12, typically
associated with CLL, are uncommon in LPL/WM. Trisomy
4, however, appears to be specific for LPL/WM and has
been reported in 20% of cases.33
DIFFERENTIAL DIAGNOSIS
Accurate diagnosis of LPL/WM can be difficult because of
the absence of specific morphologic, immunophenotypic, or
chromosomal markers, making differentiation from other
small B-cell lymphomas challenging. Additionally, with
current criteria, there is diagnostic overlap among WM,
IgM-monoclonal gammopathy of undetermined signifi-
cance, and smoldering WM.
The 2008 World Health Organization criteria for classifi-
cation of hematologic diseases characterizes WM as a subset
of LPL that has a detectable level of monoclonal IgM
gammopathy with bone marrow involvement by LPL.1,2
That definition overlaps with the diagnosis of IgM-
monoclonal gammopathy of undetermined significance,
which is characterized by a serum IgM paraprotein of less
than 3 g/dL, less than 10% lymphoplasmacytic marrow
infiltration, and an absence of the constitutional symptoms,
anemia, hyperviscosity, lymphadenopathy, and hepato-
splenomegaly.34 Cases with an IgM paraprotein of more
than 3 g/dL and/or more than 10% marrow infiltration, but
still without constitutional symptoms, symptomatic anemia,
and hyperviscosity have been classified as smoldering WM.34
If patients are divided into symptomatic WM and asymp-
tomatic WM, those with IgM-monoclonal gammopathy of
undetermined significance have a 262-fold increased risk for
the development of symptomatic WM, and patients with
smoldering WM have a 55% risk of progression to
symptomatic WM at 5 years.3,21,34
Lymphoplasmacytic lymphoma is a diagnosis of exclu-
sion. The differential diagnosis includes mantle cell lym-
phoma, CLL/SLL, MZL, and plasma cell myeloma.
Differentiating LPL from MZL can be especially difficult
because both are low-grade B-cell lymphomas that share
the nonspecific CD5/CD10 immunophenotype and lack
disease-defining molecular-genetic markers. However, this
may be changing with the recent discoveries of the MYD88
mutation in LPL and the finding that, unlike the plasma
cells in MZL, some plasma cells in LPL aberrantly express
PAX5.17 Marginal zone lymphoma is divided into 3
categories: (1) extranodal MZL of mucosa-associated
lymphoid tissue (MALT lymphoma), (2) splenic MZL, and
(3) nodal MZL. Of the 3, differentiating LPL/WM from
MALT lymphoma is probably the most straightforward.
Typically, MALT lymphoma is not associated with a
monoclonal gammopathy, and, conversely, extranodal
involvement by LPL/WM, especially at sites such as the
gastrointestinal tract and salivary gland favored by MALT
Figure 2. Morphologic features of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. A, Wright-Giemsa–stained peripheral blood
test shows a plasmacytoid lymphocyte and a prominent rouleaux formation (inset). B, A core biopsy shows hematoxylin-eosin–stained bone marrow,
with hypercellular bone marrow and marked infiltration by a spectrum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. CD20
immunohistochemical staining highlights most lymphocytes (inset, 320 original magnification). C, CD138 immunohistochemical stain highlights
clusters of plasma cells. D, Arrow points to a plasma cell with a pseudointranuclear immunoglobulin inclusion, Dutcher body (original magnification
31000 [A] and 340 [inset]; original magnification 320 [B]; original magnification 320 [C]; hematoxylin-eosin, original magnification 31000 [D]).
Arch Pathol Lab Med—Vol 137, April 2013
lymphoma, is uncommon in LPL/WM. Histologically,
distinguishing features of MALT lymphomas are lympho-
epithelial lesions and ‘‘monocytoid’’ B cells.
Distinguishing LPL/WM from splenic MZL can be very
challenging. Like LPL/WM, splenic MZL consistently
involves the bone marrow and is often associated with an
IgM paraprotein. To further complicate matters, splenic
MZL frequently exhibits plasma cell differentiation. Accord-
ingly, distinguishing LPL/WM from splenic MZL on a bone
marrow biopsy alone can be virtually impossible, and
histologic evaluation of the spleen may be necessary to
confirm the diagnosis. The identification of circulating,
villous lymphocytes, although frequently nonspecific, may
add support for the diagnosis of splenic MZL.
Nodal MZL is more aggressive than MALT lymphoma
and splenic MZL. Patients frequently have a disseminated
presentation with multifocal adenopathy, bone marrow
involvement, and an IgM gammopathy in up to one-third of
cases but, by definition, lack extranodal or splenic involve-
ment. Histologically, the findings of a marginal-zone
growth pattern, follicular colonization, scattered germinal
center remnants, and disrupted follicular dendritic-cell
meshworks, highlighted by immunohistochemical staining
for CD21, are helpful features to suggest a diagnosis of
nodal MZL rather than LPL.35 The presence of monocytoid
B cells in the lymph node may not be especially helpful as a
distinguishing feature of nodal MZL because monocytoid
cells have been described in LPL/WM. The problem with
distinguishing nodal MZL with plasmacytic differentiation
from LPL/WM is well recognized, especially in non-WM
cases where there is no bone marrow involvement and/or
IgM gammopathy to help support the diagnosis of LPL. In
those cases, rather than making an arbitrary decision, the
diagnosis of small B-cell lymphoma with plasmacytic differen-
tiation should be rendered.
Both mantle cell lymphoma and SLL/CLL typically
express CD5 and usually pose less of a diagnostic dilemma.
Mantle cell lymphoma can also be distinguished by the
expression of cyclin D1. The distinctive immunophenotype
of SLL/CLL, including expression of CD23 without FMC7,
can be combined with morphologic identification of the
proliferation centers to aid in differentiation from LPL.
Plasma cell myeloma expressing IgM is extremely rare.
Differentiating LPL/WM from plasma cell myeloma hinges
on identification of a pure plasma cell population, without
lymphoid marrow infiltration, which is associated with
osteolytic lesions and hypercalcemia. At the cytogenetic
level, the IGH translocations frequently found in plasma cell
myeloma are extremely rare in LPL.31,36
Rare cases of LPL that present primarily with extramed-
ullary disease and are not WM remain poorly characterized,
which is likely related to the reproducibility of the diagnosis
of LPL being highest in the setting of IgM gammopathy
with bone marrow involvement (WM), and, conversely,
diagnosis of extramedullary LPL lacks sufficient criteria for
adequate reproducibility and is frequently indistinguishable
from cases of MZL.37
Waldenström Macroglobulinemia—Naderi & Yang 583
 PROGNOSIS AND MANAGEMENT
Like many other mature, small B-cell lymphomas, LPL/
WM is an indolent, incurable disease with a median survival
of 5 to 10 years.2 The most frequent causes of death related
to LPL/WM are progressive disease, transformation to a
higher-grade lymphoma, and infection. Poor prognostic
factors include advanced age, low hemoglobin, low serum
albumin, and high b2-microglobulin levels. Quantitative
serum IgM levels, leukopenia, thrombocytopenia, and
organomegaly have also been associated with adverse
outcome.38–40 Deletion of chromosome arm 6q has been
associated with features of adverse prognosis.28
As an incurable, indolent B-cell lymphoma, treatment of
LPL/WM is generally expectant in asymptomatic patients.
Symptomatic patients with modest hematologic abnormal-
ities, IgM-related neuropathy, hemolytic anemia, or glo-
merulonephritis can be treated with single-agent rituximab
therapy without maintenance. Patients with advanced
disease consisting of bulky disease, profound cytopenias,
constitutional symptoms, and hyperviscosity syndrome are
typically treated with a regimen of rituximab, cyclophos-
phamide, and dexamethasone.38 Symptoms of hyperviscos-
ity can be dramatically improved by plasmapheresis,
although that does not affect tumor burden. Novel agents
that target deregulated signaling pathways, such as protea-
some and PI3K/Akt/mTOR inhibitors, are currently being
evaluated in patients with LPL/WM.41
SUMMARY
Lymphoplasmacytic lymphoma is a B-cell neoplasm
composed of small lymphocytes, plasmacytoid lymphocytes,
and plasma cells, which typically affects older adults. Most
cases of LPL are WM, which is defined as bone marrow
involvement with LPL and a detectable monoclonal IgM
serum paraprotein. Patients with LPL/WM can present with
distinctive symptoms associated with hyperviscosity syn-
drome, including visual disturbance and neurologic com-
promise. Diagnosis of LPL/WM can be challenging because
LPL lacks disease-specific morphologic, immunophenotyp-
ic, and genetic features that readily differentiate it from
other small B-cell lymphomas, all of which are capable of
plasma cell differentiation. Using 2008 World Health
Organization diagnostic criteria for WM, there is diagnostic
overlap among WM, IgM monoclonal gammopathy of
undetermined significance, and smoldering WM. Manage-
ment of LPL/WM is expectant. Systemic chemotherapy is
typically reserved for patients with advanced disease, and
plasmapheresis is used to treat patients with hyperviscosity
syndrome.
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