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WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 5)

LABORATORY INVESTIGATIONS AND FINDINGS

Hematological abnormalities

Anemia is the most common finding in patients with symptomatic WM and is caused by a combination of factors: mild decrease in red cell survival, impaired erythropoiesis, hemolysis, moderate plasma volume expansion, and blood loss from the gastrointestinal tract. Blood smears are usually normocytic and normochromic, and rouleaux formation is often pronounced. Electronically measured mean corpuscular volume may be elevated spuriously owing to erythrocyte aggregation. In addition, the hemoglobin estimate can be inaccurate, i.e. falsely high, because of interaction between the monoclonal protein and the diluent used in some automated analyzers.93 Leukocyte and platelet counts are usually within the reference range at presentation, although patients may occasionally present with severe thrombocytopenia. As reported above, monoclonal B-lymphocytes expressing surface IgM and late-differentiation B-cell markers are uncommonly detected in blood by flow cytometry. A raised erythrocyte sedimentation rate is almost constantly observed in WM and may be the first clue to the presence of the macroglobulin. The clotting abnormality detected most frequently is prolongation of thrombin time. AL amyloidosis should be suspected in all patients with nephrotic syndrome, cardiomyopathy, hepatomegaly, or peripheral neuropathy. Diagnosis requires the demonstration of green birefringence under polarized light of amyloid deposits stained with Congo red.

Biochemical investigations

High-resolution electrophoresis combined with immuno-fixation of serum and urine are recommended for identification and characterization of the IgM monoclonal protein. The light chain of the monoclonal IgM is k in 75–80% of patients. A few WM patients have more than one M-component. The concentration of the serum monoclonal protein is very variable but in most cases lies within the range of 15–45 g/L. Densitometry should be adopted to determine IgM levels for serial evaluations because nephelometry is unreliable and shows large intralaboratory as well as interlaboratory variation. The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels and, therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis. If present, subsequent serum samples should be analyzed under warm conditions for determination of serum monoclonal IgM level. Although Bence Jones proteinuria is frequently present, it exceeds 1 g/24 hours in only 3% of cases. While IgM levels are elevated in WM patients, IgA and IgG levels are most often depressed and do not demonstrate recovery even after successful treatment suggesting that patients with WM harbor a defect which prevents normal plasma cell development and/or Ig heavy chain rearrangements.94,95

Serum viscosity

Because of its large size (almost 1,000,000 daltons), most IgM molecules are retained within the intravascular compartment and can exert an undue effect on serum viscosity. Therefore, serum viscosity should be measured if the patient has signs or symptoms of hyperviscosity syndrome. Fundoscopy remains an excellent indicator of clinically relevant hyperviscosity. Among the first clinical signs of hyperviscosity, the appearance of peripheral and mid-peripheral dot and blot-like hemorrhages in the retina, which are best appreciated with indirect ophthalmoscopy and scleral depression.45 In more severe cases of hyperviscosity, dot, blot and flame shaped hemorrhages can appear in the macular area along with markedly dilated and tortuous veins with focal constrictions resulting in “venous sausaging”, as well as papilledema.

Bone marrow findings

The bone marrow is always involved in WM. Central to the diagnosis of WM is the demonstration, by trephine biopsy, of bone marrow infiltration by a lymphoplasmacytic cell population constituted by small lymphocytes with evidence of plasmacytoid/plasma cell differentiation (Figure 1). The pattern of bone marrow infiltration may be diffuse, interstitial, or nodular, showing usually an intertrabecular pattern of infiltration. A solely paratrabecular pattern of infiltration is unusual and should raise the possibility of follicular lymphoma.1 The bone marrow infiltration should routinely be confirmed by immunophenotypic studies (flow cytometry and/or immunohistochemistry) showing the following profile: sIgM+CD19+CD20+CD22+CD79+.27-29 Up to 20% of cases may express either CD5, CD10 or CD23.30  In these cases, care should be taken to satisfactorily exclude chronic lymphocytic leukemia and mantle cell lymphoma.1 ‘Intranuclear’ periodic acid-Schiff (PAS)-positive inclusions (Dutcher-Fahey bodies; see Fig. 10)96 consisting of IgM deposits in the perinuclear space, and sometimes in intranuclear vacuoles, may be seen occasionally in lymphoid cells in WM. An increase number of mast cells, usually in association with the lymphoid aggregates is commonly found in WM, and their presence may help in differentiating WM from other B-cell lymphomas.2,3

Other investigations

Magnetic resonance imaging (MRI) of the spine in conjunction with computed tomography (CT) of the abdomen and pelvis are useful in evaluating the disease status in WM.97 Bone marrow involvement can be documented by MRI studies of the spine in over 90% of patients, while CT of the abdomen and pelvis demonstrated enlarged nodes in 43% of WM patients.97 Lymph node biopsy may show preserved architecture or replacement by infiltration of neoplastic cells with lymphoplasmacytoid, lymphoplasmacytic, or polymorphous cytological patterns. The residual disease after high-dose chemotherapy with allogeneic or autologous stem-cell rescue can be monitored by polymerase chain reaction (PCR)-based methods using primers specific for the monoclonal Ig variable regions.

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