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Letters to the Editor |
Department of Pathology, Hong Kong Sanatorium and Hospital
aAddress correspondence to this author at: 1/F Li Shu Fan Block, Hong Kong Sanatorium & Hospital, 2 Village Road, Hong Kong. Fax 852-2835-8799; e-mail eskma{at}hksh.com.
To the Editor:
We read with interest the recent paper on the combination of serum protein electrophoresis (SPEP) and serum free light chain (FLC) assay as a potential alternative to SPEP and urine protein electrophoresis (UPEP) screening for paraproteinemia (1), as well as the accompanying editorial on sensitivity and specificity issues of the serum FLC assay (2). This assay, which first became commercially available in 2001, is used to diagnose and monitor light chain myeloma, primary amyloidosis, and related light chain diseases. Despite the usually quoted high clinical sensitivity of serum FLC assay in detecting light chain disease, results within reference intervals can occur with intact immunoglobulin paraproteinemia (3). We describe a patient with IgM paraproteinemia who showed FLC concentrations and 
:
ratio within reference intervals.
A 79-year old Chinese woman presented with blurred vision due to hyperviscosity syndrome and bleeding tendency. Physical examination showed no hepatosplenomegaly or lymphadenopathy. Complete blood counts showed hemoglobin of 78 g/L, 8.3 x 109 leukocytes/L and 110 x 109 platelets/L. The patient’s blood smear showed obvious erythrocyte rouleaux formation in association with 6% circulating plasma cells. The total globulin concentration was markedly increased at 115 g/L, but renal and liver biochemistry tests were unremarkable. No hypercalcemia was apparent, and a skeletal survey showed no osteolytic lesions. Bone marrow examination revealed 46% plasma cells and fair representation of trilineage hematopoiesis. Flow cytometric analysis of a bone marrow sample showed 32% plasma cells that were clonal in nature, with cytoplasmic IgM expression and light chain restriction, as gated by CD38 expression. Few B-cells were demonstrated. Bone biopsy showed interstitial infiltrate of lymphoplasmacytic cells with Dutcher body formation. The abnormal infiltrate was shown by immunohistochemistry to comprise mostly plasma cells that expressed CD79a, CD138, and IgM, with light chain restriction. Very few B cells were present, as demonstrated by the lack of CD20 immunostaining. The overall picture was compatible with IgM multiple myeloma.
Although SPEP (Genio, Interlab Scientific Instruments) in this patient showed an abundant M-protein of 86.7 g/L as determined by densitometry, UPEP showed no evidence of M-protein. Cryoglobulin was negative. Serum immunoglobulin concentrations (Dade Behring, Marburg, GmBH) showed a marked increase in IgM at 99.9 g/L and decreased IgG and IgA concentrations. Serum FLC assay (Binding Site) performed on the Dade Behring BN Pro Spec analyzer showed a concentration of 15.9 mg/L, within the reference interval (RI) of 3.3–19.4 mg/L and a concentration of 14.6 mg/L, also within the RI of 5.7–26.3. The to ratio of 1.09 was also within the reference interval, (RI 0.26–1.65). Dilution study results excluded antigen excess and the presence of a prozone, but a serum total (bound and free) light chains (Dade Behring) showed a marked increase of (20.2 g/L, RI 1.7–3.7 g/L) compared to (1.13 g/L, RI 0.9–2.1 g/L), resulting in a total : ratio of 17.9 (RI 1.35–2.65). Immunofixation (Minifix, Binding Site) confirmed a monoclonal IgM- paraprotein.
IgM paraproteinemia is seen in Waldenström macroglobulinemia, B-cell lymphoma or lymphoproliferative disorders, monoclonal gammopathy of undermined significance (MGUS), µ-heavy chain disease, and IgM myeloma. Our patient was unusual in that the paraprotein most probably consisted of only intact IgM molecules with no excess FLC, thus explaining the normal serum FLC concentration and ratio. The diagnostic performance of serum FLC assay has been evaluated in patients with plasma cell disorders (4) including IgM paraproteins, including macroglobulinemia, IgM lymphoproliferative disorder, and lymphoma, but no detailed breakdown of data was available in this subgroup. In another study, among 37 patients with Waldenström macroglobulinemia, all but one had abnormal FLC concentrations and/or an abnormal : ratio (3). Furthermore, FLC concentrations were reported to be within reference values in 
4% of intact Ig multiple myeloma and in 40% of MGUS at presentation (5). Thus although the serum FLC assay may allow identification of additional monoclonal FLC-producing individuals, the test must be interpreted in conjunction with SPEP with or without immunofixation, especially in the setting of paraprotein screening. This patient serves as a reminder that FLC assays cannot replace SPEP as a screening test but can identify additional patients with light disease that may be missed by a combination of SPEP and UPEP. It would be of interest to extend our case observation to more patients with IgM paraproteinemia to document the frequency and any associated clinical significance of normal : ratios.
References
and free light chain assays in clinical practice. Clin Chem 2005;51:878-881.
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