DIAGNOSIS AND LABORATORY TESTING
The diagnosis in WM is confirmed by the presence of a monoclonal IgM protein in the serum in association with bone marrow infiltration by monoclonal lymphoplasmacytic cells. These diagnostic criteria are the consequence of various consensus meetings to establish standardized diagnostic criteria for WM (see below).22
As mentioned above, the utilization of molecular techniques will likely become essential in the final confirmation of the diagnosis.
The use of the serum monoclonal protein is a cornerstone of disease diagnosis and monitoring, similar to its use in MM. There are multiple laboratory tests that exist for monitoring the serum concentration of the protein. The treating physician needs to be consistent in using the tests that are used for monitored. The serum protein electrophoresis (SPEP) is the preferred method of detecting the monoclonal protein, but quantitative detection of the IgM is also appropriate because the baseline concentration of the normal IgM (polyclonal) is low enough that it does not substantially alter the monoclonal protein concentration. Initially, immunofixation is needed to characterize a new monoclonal protein (in cases where no IgM has been measured) and also to confirm a complete response (CR). In our practice, we measure both the quantitative IgM and the SPEP because discrepancies are sometimes associated with technical aspects of the measurement. The β2
-microglobulin should be determined, in addition to standard laboratory testing, as it is a prognostic factor for the disease (see below).23
At the time of diagnosis, serum viscosity should be determined and repeated as needed. For any given patient, it is usually possible to determine a level at which an IgM protein will result in hyperviscosity.25
Determining viscosity, therefore, at each visit is not really needed (see section “Hyperviscosity, Neurologic and Retinal Complications
”). Urine collections can be performed to measure the monoclonal light chain excreted, but the clinical value of this is not clear. Many series have shown that a significant fraction of patients who have WM can have Bence-Jones proteinuria (i.e., light chains).7
For unknown reasons, WM patients rarely develop intrinsic renal failure despite elevated serum-free light chains (SFLC) in some. Perhaps the large size of the monoclonal IgM prevents most of the intact molecule from reaching kidney tubules, unlike myeloma where the intact immunoglobulin molecule can also be detected in the urine, and possibly contributes to cast formation when large amounts of free light chains are excreted. Studies are not available that address the clinical significance of serum-free light-chain detection; however, it is clear that this assay can be used as a surrogate tumor marker as well.
The use of the serum-free light chain (SFLC) has also been explored in WM.26
Leleu studied 72 patients (15 new diagnosis and 57 previously treated) and found a correlation between the serum concentration of sFLC and negative prognostic indicators.27
Itzykson reported on 42 cases of WM (all at diagnosis) and observed similar associations, with elevated levels predicting shorter times to treatment initiation.28
Larger studies are needed to better quantify these associations and associateds clinical implications.
It is useful to obtain a computed tomographic (CT) scan of the chest, abdomen, and pelvis at baseline to assess the spleen and liver size and the presence or absence of lymphadenopathy. Obtaining a metastatic bone survey for patients with WM has little value because, in most cases of WM, bone disease is not present. Obtaining a bone survey is recommended in cases with bone symptoms or in those where the bone marrow pathology is purely plasmacytic.29
The use of positron emission tomographic scan is not considered routine, but can be useful in determining the extent of disease bulk in selected patients.34
In some cases, discordant results have been observed, however, a global recommendation for its use has not been made. In patients with proven bone lesions, a diagnosis of IgM myeloma rather than WM needs to be considered. Until recently, the entity of IgM myeloma had not been defined at the genetic level, making the distinction between WM and IgM myeloma extremely difficult (see below).
The WHO classification and the Revised European-American Lymphoma classify WM as LPL because of its immunophenotypic and morphologic characteristics.44
Some cases of LPL have no associated monoclonal protein,45
a more aggressive clinical course, and a different set of genetic abnormalities.23
It is now believed that there are several subsets of LPL, of which WM is only one subtype.
Estimation of clonal involvement in the bone marrow is routinely performed at diagnosis with a unilateral trephine aspirate and biopsy. The disease is typically a pleomorphic infiltrate of lymphoplasmacytic cells,46
and variability in cell morphology is common (Fig. 100.1
). The infiltrate can range from purely lymphocytic to one that is predominantly plasmacytic.46
The co-existence of mast cells in association with the lymphomatous infiltrate is a unique feature of WM.46
The role of these mast cells as part of the disease pathogenesis has not been fully elucidated. A complex network of interactions between the WM cells and the bone marrow microenvironment has been suggested in preliminary observations.50
In addition, infiltration by malignant B cells can be seen in lymphoid structures and multiple other organs (giving rise to organomegaly and lymphadenopathy).44
The detection of clonal cells in other organs is not known to have particular prognostic implications; however, clinically evident organomegaly is usually a negative prognostic factor for the disease51
and usually indicates a large tumor burden.
The nature of the clonal B-cell populations is remarkable.53
Sahota has identified the normal counterpart of WM cells as mature B cells that have undergone somatic hypermutation, but that have not yet completed isotype class switching.55
In that particular study, they did not find evidence of intraclonal heterogeneity. It is notable that in many cases of WM, one can observe co-existent populations of monoclonal B cells and plasma cells. Recently, Zehentner and colleagues demonstrated that only in 40% of cases are the clonal B-cell and plasma cell populations related.56
Conversely, in 60% of cases, they represent two separate and independent clones. By performing sequencing of the immunoglobulin genes, and in some cases using fluorescence
in situ hybridization (FISH) analysis, they conclusively show the separate nature of these clones in 60% of cases.
FIGURE 100.1. Lymphoplasmacytic morphology of the clonal cells of Waldenström macroglobulinemia. As shown in the graph, the cells have variable morphology but most show transition between mature lymphocytes and plasma cell morphology. The cells have been called in the past “plymphs.” The morphology can be variable with some cases showing more extreme plasma cell morphology, whereas others have more lymphocytic predominance.
Flow cytometry is usually indicated as part of the pathologic work-up to make the diagnosis of WM. Flow cytometry is helpful in differentiating WM from other morphologically similar neoplasms, such as mantle cell lymphoma, marginal zone lymphomas, and B-cell chronic lymphocytic leukemia (CLL).49
WM cells are characterized by the surface expression of CD19, CD20, CD22,49
are light chain restricted, and commonly express CD79a. They are also typically CD10 and CD23 negative, in contrast to follicular lymphoma and B-cell CLL, respectively. The associated plasma cells are monoclonal and express CD138.49
CD5 is not expressed on the malignant cells (in contrast to mantle cell lymphoma and B-cell CLL) in the majority of cases; however, some cases can be positive.49
Cell proliferation markers are usually indicative of the indolent nature of the disease. The fraction of cells incorporating 5-bromo-2′-deoxyuridine (BrdU),62
indicating cell replication, is usually minimal, and frequently no such fraction is detected at all. The evolution of WM to a more aggressive lymphoproliferative disorder has been previously reported,63
and the presence of a highly proliferative fraction may suggest transformed disease. The role of karyotype analysis in the clinical management of patients is not felt to be necessary and, in most patients, the metaphases will be normal.65
Therefore, this analysis should be reserved for patients suspected of having treatment-associated myelodysplasia.68
WM variants have been described where patients have a similar pathology to WM, but present with IgG monoclonal proteins.69
These patients appear to be clinically different from WM and tend to have a lymphocytosis present in the peripheral blood. It is not clear if these diseases have a similar pathogenesis, as only one series of patients with this variant tumor has been reported. Also, some patients have been described as having WM with associated bone lesions.29
This makes distinguishing WM from IgM myeloma very difficult. Given the availability of molecular testing that can identify MYD88 mutations and also chromosome abnormalities seen in IgM MM, this distinction should now be possible. If some cases of true WM indeed have bone lesions, it is likely that these will be due to the same mechanisms operative for myeloma.70
In a recent study of patients with IgM myeloma, it was found that the t(11;14)(q13;q32) was nearly universally present.71
Another recent study did not find it as universal, but still common in IgM myeloma patients (38%).72
Also, the t(14;16) (q32;q23) has been reported in one case of IgM myeloma.73
In addition, we have found that translocations of the IGH
locus seen in IgM myeloma are not typically observed in patients with WM, and when present, they are secondary genetic events, seen only in cell subsets.67
This, along with the new-found mutation of MYD88
, clearly separates WM and IgM myeloma as separate disease entities.
It is best to differentiate the clinical symptoms of this disease based on their causes: those signs and symptoms secondary to the effects of the monoclonal protein and other paraneoplastic phenomena, and those related to the clonal proliferation in the bone marrow and other lymphoid organs.3
It should be noted that most patients with WM have a limited symptom complex at the time of diagnosis, consisting of a monoclonal IgM and various degrees of anemia.24
This anemia is often secondary to the clonal expansion of cells in the bone marrow, but may also be due to hyperviscosity (by reducing erythropoietin production) or the increased plasma volume.111
In many cases, anemia can be a consequence of treatment. Recent data suggest that some patients may have an anemia secondary to elevated levels of IL-6 emanating from the clonal cells, and will present with a picture reminiscent of the anemia of inflammation.100
Given the high level of expression of IL-6 and IL-6 receptors in at least half of WM, it is not surprising that elevated levels of hepcidin have been postulated as key mediators in the anemia of WM.102
In cases with significant involvement of the bone marrow by the WM clonal cells, thrombocytopenia may also be observed.24
In 20% of cases, the clonal cells of WM can infiltrate other organs and result in hepatomegaly and splenomegaly in 15% of patients.23
Splenomegaly can result in hypersplenism, with worsening pancytopenia. Although patients may have liver involvement, this is usually asymptomatic. Lymphadenopathy can be seen in 15% to 20% of patients,23
and involvement of other organs, such as the lung, can be seen in WM, although this is present in only a minority of cases.113