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Roger G. Owen - 1, Steven P. Treon2
- 1, Ayad Al-Katib3, Rafael Fonseca - 4, Philip R. Greipp
- 4, Mary L McMaster5, Enrica Morra - 6, Gerasimos A. Pangalis
- 7, Jesus F. San Miguel8, Andrew R. Branagan - 2, Meletios
A. Dimopoulos - 7.
Leeds General Infirmary, Leeds,
UK1; Dana-Farber Cancer Institute and Harvard Medical School,
Boston MA, USA2, Van Elslander Cancer Center, Grosse Point
Woods, MI, USA - 3; Mayo Clinic, Rochester, MN, USA4; National
Cancer Institute, Bethesda, MD, USA - 5; Niguarda Ca¹Granda
Hospital, Milan, ITALY - 6; University of Salamanca, Salamanca,
SPAIN - 8, University of Athens, Athens, Greece - 7.
This manuscript represents consensus
recommendations for the clinicopathological definition of
Waldenström¹s macroglobulinemia (WM), which were prepared
in conjunction with the 2nd International Workshop held
in Athens, Greece during September 2002. WM is an uncommon
lymphoproliferative disorder characterized primarily by
bone marrow infiltration and IgM monoclonal gammopathy.
It should be considered a distinct clinicopathological entity
rather than a clinical syndrome secondary to IgM secretion.
The underlying pathological diagnosis in WM is lymphoplasmacytic
lymphoma as defined by the WHO and REAL classification criteria.
The concentration of monoclonal IgM can vary widely in WM,
and it is not possible to define a concentration, which
reliably distinguishes WM from MGUS and other lymphoproliferative
disorders. A diagnosis of WM can therefore be made irrespective
of IgM concentration if there is evidence on a bone marrow
trephine biopsy of bone marrow infiltration by lymphoplasmacytic
lymphoma with predominantly an intertrabecular pattern and
this is supported by appropriate immunophenotypic studies.
Simple criteria to distinguish patients with symptomatic
WM who require therapy from those with asymptomatic WM and
MGUS were also proposed. Patients with clinical features
attributable to IgM monoclonal gammopathy but no overt evidence
of lymphoma are considered to constitute a distinct clinical
group and the term ³IgM related disorders² is proposed.
There are currently no universally accepted
criteria for the diagnosis of Waldenström¹s macroglobulinemia
(WM), a factor which has hindered our understanding of the
disease. WM is a chronic lymphoproliferative disorder characterized
by bone marrow infiltration and IgM paraproteinemia1-3.
Opinions, however, vary as to the true nature of WM; some
suggest that it is a distinct clinicopathological entity
while others argue that it is a clinical syndrome associated
with monoclonal IgM secretion irrespective of the underlying
pathological diagnosis4-6. The majority of clinical studies
to date have accepted the presence of IgM monoclonal gammopathy
in the context of an apparently indolent lymphoproliferative
disorder as sufficient evidence for the diagnosis of WM.
This is unsatisfactory, and diagnostic criteria incorporating
clinical, morphological, immunophenotypic and ultimately
genotypic parameters are needed for the accurate diagnosis
of WM. A consensus panel of interested investigators was
therefore convened with the aim of resolving these difficulties
and proposing reproducible diagnostic criteria that may
be applied to future clinical trials. These statements are
the result of extensive discussions that were held and subsequently
refined at the 2nd International Workshop on Waldenström¹s
Macroglobulinemia held in Athens, Greece during September
2002. The faculty of the International Workshop proposed
that the consensus panel resolve a number of specific questions
in formulating their proposal for a clinicopathological
definition of WM.
What pathological entities should
be included in the clinicopathological definition of Waldenström¹s
macroglobulinemia (WM)?
Statement 1
WM is an uncommon B-cell lymphoproliferative
disorder characterized primarily by bone marrow infiltration
with a predominately intertrabecular pattern along with
demonstration of an IgM monoclonal gammopathy. WM should
be regarded as a distinct clinicopathological entity and
not a clinical syndrome secondary to IgM secretion irrespective
of the underlying pathological diagnosis. In WM this is
considered to be lymphoplasmacytic lymphoma as defined by
the REAL and WHO criteria7,8.
Should IgG or IgA secreting lymphoplasmacytic
lymphomas be considered in the clinicopathological definition
of WM?
Statement 2
The clinicopathological definition
of WM should be confined to those patients with lymphoplasmacytic
lymphoma who have demonstrable IgM monoclonal gammopathy.
Discussion
Statement 2 is primarily based on the
unique role that the IgM monoclonal protein sustains in
the clinical presentation of many patients with WM. Individuals
with IgG or IgA monoclonal proteins or indeed non-secretory
lymphoplasmacytic lymphoma undoubtedly exist and they present
similar clinical problems to those seen in WM9-11. However
their relationship to WM is unclear at present and requires
further study.
Is the secretion of IgM sufficient
for inclusion into the clinicopathological diagnosis of
WM? Is there a minimum threshold of IgM required to define
WM?
Statement 3
The demonstration of an IgM monoclonal
protein is not synonymous with a diagnosis of WM as they
are demonstrable in other lymphoproliferative disorders
and MGUS. The concentration of IgM varies widely in WM and
it is not possible to define a concentration which reliably
distinguishes WM from MGUS and other lymphoproliferative
disorders. A diagnosis of WM can therefore be made irrespective
of IgM concentration if there is evidence of bone marrow
infiltration by lymphoplasmacytic lymphoma and this is supported
by immunophenotypic studies.
Discussion
The secretion of monoclonal IgM may be
seen in most forms of B-cell lymphoproliferative disorder
as well as MGUS12-15 and therefore the demonstration of
an IgM monoclonal protein per se is not synonymous with
a diagnosis of WM. IgM concentrations tend to be higher
in WM, but there is considerable overlap. The concentration
of monoclonal protein rarely if ever exceeds 3g/dl in MGUS
and other lymphoproliferative disorders. However the majority
of patients with WM have IgM concentrations of less than
3g/dl, and it is not possible to define an IgM concentration
that consistently distinguishes WM from MGUS and other lymphoproliferative
disorders.15 The panel therefore considered that a diagnosis
of WM could be made irrespective of IgM concentration if
there was evidence of bone marrow infiltration by lymphoplasmacytic
lymphoma and this was supported by immunophenotypic studies
(see below). This statement is further supported by data
from several large studies, which have demonstrated that
the concentration of monoclonal protein has little or no
prognostic relevance in patients with WM16-21. They do not
appear to accurately reflect disease bulk and merely represent
a continuous variable that does not correlate with the extent
of bone marrow infiltration22.
Criteria to distinguish WM from
other IgM secreting B-cell malignancies.
Statement 4
Central to the diagnosis of WM is
the demonstration of bone marrow infiltration by lymphoplasmacytic
lymphoma. This is defined as a tumor of small lymphocytes
showing evidence of plasmacytoid/plasma cell differentiation
without any of the clinical, morphological or immunophenotypic
features of other lymphoproliferative disorders7,8. A trephine
biopsy should be regarded as a mandatory requirement for
the assessment of patients while lymph node biopsies are
encouraged in patients with accessible nodes. Immunophenotypic
studies are strongly recommended for routine clinical practice
and clinical trials.
Discussion
WM is characterized by bone marrow infiltration
in virtually all cases1-3,7,8,19,22-24. It is clear therefore
that the demonstration of bone marrow infiltration by lymphoplasmacytic
lymphoma (as defined by the REAL and WHO criteria) should
be regarded as an absolute requirement in the diagnosis
of WM. WM may very rarely occur in the context of extramedullary
lymphoplasmacytic lymphoma but it is essential in such cases
to satisfactorily exclude other lymphoproliferative disorders
particularly marginal zone lymphoma.
The panel considered that a trephine
biopsy was a mandatory requirement for the assessment of
patients and that the pattern of infiltration was usually
intertrabecular8,19,22,23. A solely paratrabecular pattern
of infiltration is unusual and should raise the possibility
of follicular lymphoma particularly in a patient with lymphadenopathy.
The panel considered that the presence of bone marrow infiltration
should routinely be confirmed by immunophenotypic studies
(flow cytometry and/or immunohistochemistry) and that such
studies should also be encouraged for use in clinical trials.
The combination of cytomorphology, pattern of infiltration
and immunophenotype (see below) should allow a definitive
diagnosis of WM to be made in most instances.
Criteria to distinguish IgM MGUS,
asymptomatic WM and symptomatic WM.
Statement 5
Clearly defined and reproducible
criteria that distinguish MGUS and WM are required to facilitate
a better understanding of the outcome and natural history
of the IgM gammopathies. Patients with an IgM monoclonal
protein and unequivocal evidence of bone marrow infiltration
by lymphoplasmacytic lymphoma should be considered to have
WM irrespective of the IgM concentration. Patients should
be considered to have MGUS if they have IgM monoclonal gammopathy
but no morphological evidence of bone marrow infiltration
by lymphoma. Patients with WM may be considered symptomatic
if they have features attributable to tumor infiltration
e.g. constitutional symptoms, cytopenia(s) and organomegaly
and/or symptoms attributable to the monoclonal protein e.g.
hyperviscosity syndrome, cryoglobulinemia, amyloidosis or
autoimmune phenomena such as peripheral neuropathy and cold
agglutinin disease. It is also well recognized that some
patients have clinical features attributable to the IgM
monoclonal protein but no overt evidence of lymphoma. It
is considered that these patients constitute a distinct
clinical group and the term ³IgM related disorders² is proposed.
These criteria are summarized in Table 1.
Discussion
The panel considered that it would be
inappropriate to suggest disease definitions based upon
arbitrary values for laboratory parameters such as IgM concentration
and percentage of bone marrow lymphocytes. Patients with
an IgM monoclonal protein and unequivocal evidence of bone
marrow infiltration by lymphoplasmacytic lymphoma should
be considered to have WM irrespective of the IgM concentration.
It is acknowledged that some patients have equivocal evidence
of bone marrow disease. This may manifest in a number of
ways and includes the demonstration of clonal B-cells by
flow cytometry or PCR in the absence of morphologically
detectable disease.24 Similarly patients may have equivocal
bone marrow infiltrates without confirmatory phenotypic
studies. It is proposed that these patients be classified
as MGUS until further data become available.
Considerations
on the need and use of a staging system for WM.
Statement
6
The faculty supported the position
that the development of a prognostic scoring system for
WM was more appropriate than the adoption of a staging system
and deferred considerations to Consensus Panel 2.
Immunophenotypic
definition of WM. Can WM patients express CD5?
Statement
7
Immunophenotyping is of great value in
the differential diagnosis of B-cell lymphoproliferative
disorders and its application in all cases of suspected
WM is strongly recommended. The characteristic immunophenotypic
profile for lymphoplasmacytic cells in WM should include
the expression of the pan B-cell antigens CD19, CD20, CD22,
and CD79 as well as the expression of light chain restricted
surface IgM. The majority of cases do not express CD10 or
CD23. A proportion of patients (5-20%) appear to express
the CD5 antigen, but the significance of this has not been
established and warrants further study.
Discussion
There are relatively few published studies
of immunophenotypic analyses in WM. 19,24-28
It would appear that the pan B-cell antigens
CD19, CD20, CD22 and CD79 are expressed in virtually all
cases while CD10 and CD23 expression is rarely encountered.
CD5 expression is uncommon but this should not preclude
a diagnosis of WM. However care should be taken in CD5+
cases to satisfactorily exclude CLL and mantle cell lymphoma.
Expression of CD25, CD27, FMC7, BCL-2 and CD52 is seen in
the majority of cases but CD103 and CD138 expression is
rarely if ever encountered.27,28
The degree of plasma cell differentiation
can also vary considerably from case to case and may be
extreme in some rare instances. In such circumstances it
is essential to demonstrate that at least a proportion of
cells express surface immunoglobulin and/or B-cell antigens.
Cases consisting entirely of plasma cells (cytoplasmic IgM+,
CD20-, CD138+) do not fulfill the WHO criteria for lymphoplasmacytic
lymphoma and should be considered as part of the spectrum
multiple myeloma. This is also supported by a number of
studies that have demonstrated a high incidence of lytic
bone disease in such patients and the presence of chromosomal
abnormalities more characteristic of multiple myeloma such
as the t(11;14)29-34.
Progress
on characteristic chromosomal abnormalities to define WM.
Statement
8
There are currently no disease defining
cytogenetic abnormalities in WM. Cytogenetic criteria cannot
therefore be included in the clinicopathological definition
of WM at this time.
Discussion
There have been a number of published
series of cytogenetic analyses in WM35-39. It is evident
that many patients appear to be karyotypically normal which
reflects in part the low proliferative activity of the clonal
cells in WM. When clonal karyotypic changes are detected,
the karyotypes of individual patients may be complex. Indeed
a plethora of numerical and structural abnormalities have
thus far been described but to date no disease defining
abnormalities exist. Translocations into the immunoglobulin
heavy chain (IgH) locus at 14q32 are a defining feature
of many B-cell lymphomas and multiple myeloma and might
therefore be an important oncogenic event in WM. Indeed
initial reports suggested that ³lymphoplasmacytoid² lymphoma
was associated with the presence of a t(9;14) that deregulates
the PAX-5 gene40,41. However, none of the cases included
in these analyses had demonstrable monoclonal proteins,
and they could not therefore be defined as WM. In a more
recent analysis Schop et al were unable to demonstrate (by
FISH) the t(9;14) in 48 patients with WM. Intriguingly none
of these cases had additional 14q32 signals indicating the
absence of alternative IgH translocations in WM39. This
observation has been confirmed in two subsequent studies,28,34
and it seems likely that the absence of immunoglobulin translocations
is a characteristic feature of WM. Further analysis, however,
is required to identify ³positive² genetic markers that
may ultimately be used in the routine diagnostic setting.
CONCLUSIONS
WM is a distinct entity characterized
by bone marrow infiltration by lymphoplasmacytic lymphoma
and IgM monoclonal gammopathy. It can be confidently diagnosed
through a combination of clinical features, cytomorphology,
pattern of bone marrow infiltration and immunophenotype.
It is to be hoped that the proposed diagnostic criteria
(summarized in Table 2) will be incorporated into future
clinical trials and that they will be refined as more phenotypic
and genotypic data become available.
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| |
IgM monoclonal
proteina - a |
BM infiltrationb-
b |
Symptoms attributable
to IgM |
Symptoms attributable
to tumor infiltrationd-d |
| WM Symptomatic |
+ |
+
|
+
|
+ |
| WM Symptomatic |
+
|
+
|
-
|
- |
| WM Symptomatic |
+
|
-(b)
|
+
|
- |
| MGUS |
+ |
-(b) |
- |
_ |
 |
|
|
|
|
Table 1. Classification
of Waldenström¹s macroglobulinemia and related disorders.
a - The panel considered
it to be inappropriate to define an IgM concentration to
distinguish MGUS from WM. However it is important to note
that the IgM concentration rarely if ever exceeds 3g/dl
in MGUS.
b - Patients with unequivocal
bone marrow infiltration by lymphoplasmacytic lymphoma will
be considered to have WM while patients without evidence
of infiltration will be considered to have MGUS. However
it is acknowledged that in some patients equivocal evidence
of bone marrow infiltration is demonstrable. This may be
manifest in a number of ways and includes the detection
of clonal B-cells by flow cytometry or PCR in the absence
of morphological evidence of bone marrow infiltration. Alternatively
patients may have equivocal bone marrow infiltrates without
confirmatory phenotypic studies. It is considered that these
patients should be classified as MGUS until further data
become available.
c- It is well recognized
that a population of patients exist who have symptoms attributable
to the IgM monoclonal protein but no overt evidence of lymphoma.
Such patients may present with symptomatic cryoglobulinemia,
amyloidosis or autoimmune phenomena such as peripheral neuropathy
and cold agglutinin disease. It is appropriate to consider
these patients as a clinically distinct group and the term
"IgM related disorders" is proposed.
d- Symptoms attributable
to tumor infiltration will include any of the following
manifestations: constitutional symptoms, cytopenia(s) and
organomegaly.
Table 2. Waldenström¹s
Macroglobulinemia: Proposed Diagnostic Criteria.
•
IgM monoclonal gammopathy of any concentration
•
Bone marrow infiltration by small lymphocytes showing plasmacytoid
/ plasma cell differentiation
• Intertrabecular pattern
of bone marrow infiltration
• Surface IgM+ CD5+
CD10- CD19+ CD20+ CD22+ CD23- CD25+ CD27+ FMC7+ CD103- CD138-
immunophenotype - 1
1
- Variations from this immunophenotypic profile can occur.
In these instances however care should be taken to satisfactorily
exclude other lymphoproliferative disorders. This is most
relevant in CD5+ cases when chronic lymphocytic leukemia
and mantle cell lymphoma require specific exclusion before
a diagnosis of WM can be made.
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