Prozone effect of serum IgE levels in a case of plasma cell leukemia
© Talamo et al; licensee BioMed Central Ltd. 2010
Received: 19 June 2010
Accepted: 10 September 2010
Published: 10 September 2010
We describe a case of multiple myeloma (MM) and secondary plasma cell leukemia (PCL) secreting IgE-kappa immunoglobulin. To our knowledge, only 2 cases of IgE-producing secondary PCL have been reported in the medical literature. In our patient, the only tumor marker available for monitoring the therapeutic response to chemotherapy and allogeneic stem cell transplantation was the quantitative M component at serum protein electrophoresis (SPEP), because serum free light chains were in the normal range, Bence-Jones proteinuria was absent, and quantitative serum IgE levels provided inaccurate and erratic results, due to the prozone effect. This is a laboratory phenomenon that occurs when antigen excess interferes with antibody-based methods requiring immune complex formation for detection. It is important to recognize the presence of a prozone effect, because it can produce falsely normal results, and therefore it could lead clinicians to incorrect assessment of the response to therapy.
IgE myeloma is a very rare subtype of MM, and it represents < 0.01% of all plasma cell dyscrasias . Since the first case was described in 1967 , approximately 47 cases of IgE MM have been reported in the literature [3–6]. IgE antibodies are named from the ragweed E antigen, which was used for their isolation, and they are involved in allergic responses, atopic conditions, helminthic and respiratory infections, and chronic inflammatory diseases . It is important to note that commonly available serum immunofixation (IFE) testing screens only for monoclonal IgG, IgM, and IgA chains. Therefore, IFE specific for IgD and IgE should be requested when these rare subtypes are suspected (e.g., when a monoclonal protein has been detected by SPEP, but routine IFE is negative). The clinical manifestations of IgE MM are similar to those seen in other MM subtypes, but some experts consider IgE MM an aggressive disease, associated with a significantly higher rate of plasma cell leukemia [8, 9]. Other data do not support the aggressive nature of this subtype of MM. A review of the first 19 reported cases of IgE MM showed no difference in the incidence of extramedullary plasma cell infiltration compared with other subtypes of the disease .
We describe a case of IgE-kappa MM and secondary PCL with falsely normal serum levels of IgE due to the prozone effect.
Erratic serum levels of IgE during the response of MM/PCL after allogeneic stem cell transplantation.
PCL is distinguished in "primary PCL", which occurs as a de novo presentation of the leukemia, and "secondary PCL", which is the leukemic transformation of a previously diagnosed MM. Our patient had the secondary form, because it developed 28 months after the initial diagnosis of MM. To our knowledge, 8 other cases of IgE-producing PCL have been reported in the medical literature, and only 2 of them were secondary PCL [12, 13]. The incidence of high-risk chromosomal abnormalities, such as complex karyotype and monosomy 13, is high in patients with secondary PCL . However, in our patient, malignant plasma cells both in peripheral blood and BM displayed the same cytogenetic abnormalities observed at baseline, i.e., only the translocation t(11;14)(q13;q32) at FISH, and no other chromosomal aberrations. Of note, the t(11;14) translocation is considered a hallmark of IgE, IgM, and nonsecretory MM, all rare subtypes of MM . Interestingly, a recent publication described a case of IgE MM associated with very high serum levels of serum CA125 (1292.3 U/mL) , a tumor marker expressed in various cancers, including ovarian carcinoma and hematologic malignancies . We did not confirm this association in our patient, because his serum CA125 level before induction therapy was 17.9 U/mL, within normal limits (0-34 U/mL).
An important aspect of our case was the unreliability of quantitative IgE levels in the assessment of disease response, due to the prozone effect. Response to therapy in our case was best monitored with the quantification of the M component at SPEP. The recent introduction of the quantitative serum free light chains (FLC) assay has offered another useful tumor marker for monitoring response to therapy in MM . Due to the rarity of IgE MM, no sufficient data of the use of FLC in this subtype of MM are available. In our patient, the serum FLC assay had no role in assessing response to therapy, because the serum free kappa level was always within normal limits.
The prozone effect is a laboratory phenomenon that occurs when antigen excess interferes with antibody-based methods requiring immune complex formation for detection. For immunometric immunoassays, detection of the analyte (in this case, serum IgE) requires that each molecule binds to two separate reagent antibodies in an antibody-analyte-antibody complex: one antibody that "captures" the antigen and the second that provides a detection signal. With excessive amounts of analyte, each reagent antibody binds to separate analyte molecules, not forming the complex essential for detection. The presence of this "high-dose hook" effect should be suspected when the result on a diluted sample is higher than in the undiluted sample. The prozone effect is a well know phenomenon that may complicate the interpretation of various quantitative assays, including those for IgG and IgA [19, 20], and laboratory protocols to avoid it have been proposed . The elevations that produce such results are so high that significant manual dilutions are required to bring the concentration into the reporting range of the instrument, and dilution errors are common. For this patient, a 1:10,000 or 1:100,000 dilution was required to obtain a reading, a difficult task even for experienced bench personnel. The variability in serum IgE levels shown in Table 1 may be explained by the challenge of diluting each sample a minimum of 10,000 fold, when standard medical laboratory techniques rarely require a dilution greater 1:100. It is important to recognize the presence of a prozone effect, because it can produce falsely normal results. Due to this effect, the use of only IgE levels for monitoring the response to therapy in our patient could have led the clinicians to inappropriate interpretations of the results and possible therapeutic mismanagement.
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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