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Simultaneous Presentation of Waldenström Macroglobulinemia and Multiple Myeloma: Multidisciplinary Diagnosis, Treatment and 30-Monthfollow-Up

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Simultaneous Presentation of Waldenström Macroglobulinemia and Multiple Myeloma: Multidisciplinary Diagnosis, Treatment and 30-Monthfollow-Up J Clin Exp Hematop Vol. 53, No. 1, June 2013 Case Study Simultaneous Presentation of Waldenström Macroglobulinemia and Multiple Myeloma: Multidisciplinary Diagnosis, Treatment and 30-MonthFollow-up Giovanni Carulli,1) Eugenio M Ciancia,2) Antonio Azzarà,1) Virginia Ottaviano,1) Susanna Grassi,1) Elena Ciabatti,1) Maria I Ferreri,3) Melania Rocco,1) Alessandra Marini,4) and Mario Petrini1) Waldenström macroglobulinemia and multiple myeloma are mature B-cell neoplasms deriving from post-germinal cells at different stages of differentiation. The simultaneous presentation of Waldenström macroglobulinemia and multiple myeloma in the same patient is a very rare phenomenon and, so far, only two cases have been described. We report the case of a 75-year Caucasian female patient, with a silent clinical history, who presented with anemia and two different monoclonal proteins (IgMk and IgGk). The trephine biopsy showed the presence of a dual population, represented by small lymphoplasmacytoid cells and by plasma cells, which infiltrated the bone marrow with a clearly different pattern. Both immunohistochemistry and flow cytometry demonstrated the biclonal origin such neoplastic cells, since lymphoplasmacytoid cells resulted IgMk while plasma cells were IgGk. This biclonal pattern was further confirmed by the demonstration of a different IgH gene rearrangement of the two neoplasms. The patient was treated with bortezomib, dexamethasone and rituximab, achieving partial remission of both Waldenström macroglobulinemia and multiple myeloma. After a 30-month follow-up, she is in stable disease. Multiple myeloma has been described in association with other indolent B-cell neoplasms, mostly chronic lymphocytic leukemia, while Waldenström macroglobulinemia can be followed by diffuse large B-cell lymphoma in some instances, after chemotherapy. The association of Waldenström macroglobulinemia and multiple myeloma seems to be very rare. Our study shows that an integrated diagnostic work-up is very useful in such cases, with an interesting role for flow cytometry. 〔J Clin Exp Hematop 53(1): 29-36, 2013〕 Keywords: flow cytometry, immunohistochemistry, morphology, multiple myeloma, Waldenström macroglobulinemia So far, an association of WM with multiple myeloma INTRODUCTION (MM) has been reported in only two cases,3,4 andinasingle Waldenström macroglobulinemia (WM) is a hematologic case the evolution of WM into an aggressive form of IgM- neoplasm characterized by a monoclonal lymphoplasmacytic positive multiple myeloma has been described.5 expansion, with a variable plasma cell component and accom- On the other hand, MM is a more frequent disease and is panied by a serum monoclonal immunoglobulin M (IgM).1 It characterized by the proliferation of a single clone of plasma is an infrequent disease, accounting for approximately 2% of cells derived from B cells in the bone marrow and, in most all hematologic malignant neoplasms, and shows a 2.8% fre- cases, by the production of a monoclonal protein such as IgG, quency of association with other hematologic diseases. In IgA or light chain only.6 Compared to WM, the association these instances, acute myeloid leukemia and diffuse large B- of MM with another B-cell lymphoproliferative disease has cell lymphoma can occur, always being therapy-related.2 been reported in a higher number of cases. The simultaneous occurrence of MM and chronic lymphocytic leukemia (CLL) Received : October 21, 2012 seems to be the most frequent event. Sometimes, CLL is Revised : December 10, 2012 discovered incidentally in patients with newly-diagnosed Accepted : December 15, 2012 MM,7-9 while in other cases MM develops during the evolu- 1) Division of Hematology, Department of Clinical and Experimental Medicine, 7,9-12 University of Pisa, Italy tion of CLL. In turn, CLL may also occur during the 2)Second Division of Pathology and 3)Laboratory of Cytogenetics, AOUP, Pisa, Italy evolution of MM.13 4)Laboratory of Clinical Pathology, Versilia Hospital, Lido di Camaiore, Italy The coexistence of MM with B-cell diseases other than Corresponding author : Giovanni Carulli, M.D., Division of Hematology, Santa Chiara Hospital, Via Roma 67, 56126 Pisa, Italy. CLL seems to be rarer, and occasional cases of metachronous E-mail : [email protected] or synchronous occurrence of MM with follicular 29 04_12-032.mcd Page 1 v4.21 Carulli G, et al. lymphoma,14 malignant renal lymphoma,15 MALT and fluorescent in situ hybridization (FISH) tests. Smears lymphoma,16 and mantle cell lymphoma17 have been reported. were stained by May-Grünwald-Giemsa and showed conspic- Therefore, because of the rarity of a combined presenta- uous infiltration (70%) by lymphocytes and lymphoplasmacy- tion of WM and MM, we describe a case of a patient who toid cells, and the concomitant presence of plasma cells, presented with severe anemia, two different monoclonal pro- which accounted for 10% of cellularity (Fig. 2). teins (IgMk and IgGk) and evidence of simultaneous occur- Flow cytometric immunophenotyping of bone marrow rence of IgGk MM and WM. Diagnosis was made by combi- samples was performed using a FacsCanto II cytometer nation of morphology with immunohistochemistry, flow (Becton Dickinson) equipped with three lasers (405, 488 and cytometry and IgH gene rearrangement analysis. In the 633 nm). Samples (50 mL) were stained with fluorochrome- present paper we present the diagnostic work-up, results of conjugated monoclonal antibodies (MoAbs) specific for the therapy, a 30-month follow-up. following antigens: CD5, CD8, CD10, CD11c, CD16, CD19, CD20, CD22, CD23, CD25, CD27, CD38, CD45, CD56, CD81, CD103, CD117, CD138, (purchased from CASE REPORT Becton Dickinson), rabbit F(ab’)2 polyclonal antibodies di- A Caucasian 75-year-olf female, with a silent clinical rected to g and m immunoglobulin heavy chains and k and l history, presented with anemia-related symptoms (fatigue and immunoglobulin light chains (purchased from Dako). A mul- effort dyspnea). A complete blood count showed: Hb 9.3 tiparametric method with either seven or eight fluorescences g/dL; white blood cell 5,71 × 109/L (differential: neutrophil was used for each tube, associating MoAbs conjugated with 55%, lymphocyte 35%, monocyte 7%, eosinophil 2.5%, and FITC, PE, PerCP-Cy5.5, PE-Cy.7, APC, APC-Cy.7, Am- basophil 0.5%); platelets 271 × 109/L. Chemistries showed: Cyan and Pacific Blue. Lymphocytes were gated using CD45 plasmatic protein 9.6 g/dL, b2-microglobulin 8.5 mg/L (nor- expression and right angle scatter, and at least 100,000 events/ mal range < 2), IgG 3,250 mg/dL, IgA 55 mg/dL, and IgM tube were acquired. A second gate included CD19+ events 1,380 mg/dL. Serum protein electrophoresis showed g- and was used to analyze the expression of the other markers. globulins 46.3% and an altered g-globulin area morphology, Plasma cells were identified by the CD38/CD138 combina- with the apparent presence of two spikes (Fig. 1). Calcium tion, acquiring 500,000 events/tube. A second gate was set to concentrations were normal as well as creatinine concentra- analyze events with homogeneous forward scatter and side tions. Serum immunofixation demonstrated the presence of scatter (SSC) properties, and was used to analyzed the expres- two monoclonal proteins, one identified as IgGk, the other as sion of the other markers eventually associated with plasma IgMk. Urinary immunofixation was negative for monoclonal cells (CD10, CD20, CD27, CD56, CD81, and CD117).18,19 proteins. X-ray skeletal survey showed a few lytic areas Immunophenotyping showed infiltration by two neoplas- involving femurs. No involvement of lymph nodes nor tic clones. The former was predominant (60%) and consisted hepato-splenomegaly were found by whole body computed tomography and ultrasound sonography. The patient underwent bone marrow evaluation by mye- loaspirate and trephine biopsy. Samples from myeloaspirate were subjected to light microscope observation, flow cytome- try, molecular tests for IgH gene rearrangement, karyotype Fig. 2. Myeloaspirate at diagnosis showing infiltration by lym- phocytes, plasmacytoid lymphocytes and plasma cells (×1,000). Some plasma cells (the longest arrows), plasmacytoid lympho- Fig. 1. Altered morphology of serum protein electrophoresis. cytes (intermediate arrows) and lymphocytes (the shortest arrows) The gamma region shows two different spikes. are shown. 30 04_12-032.mcd Page 2 v4.21 Waldenström disease and myeloma of B lymphocytes (CD19+ and CD20+) with restriction for m heavy chains and cytoplasmic k light chains (Fig. 4A-4E). As heavy chains and k light chains, and without CD27 expression a final result, neoplastic lymphocytes and MM plasma cells (Fig. 3). The latter was represented by atypical plasma cells were found in different areas of CD45/SSC dot-plot (Fig. 4F). (CD38+,CD138+,CD19-, and CD45-), which accounted for In our samples plasma cells belonging to the neoplastic clone 10% of cellularity and were negative for CD10, CD20, CD27, of WM were not found, since the entire CD38+/CD138+ cell CD56, CD81, and CD117, with restriction for cytoplasmic g population displayed features consisting with the MM pheno- Fig. 3. Immunophenotyping of bone marrow lymphocytes after CD19 gating. B-cells show bright expression of CD20, negativity for CD27 (3A), and restriction for m heavy chain and k light chain (3B). Fig. 4. Immunophenotyping of bone marrow plasma cells. (4A) CD38/CD138 gat- ing. (4B) forward scatter/side scattergating. (4C-4E) Abnormal phenotype (negative for CD19, CD27, and CD81) and restriction for g heavy chain and k light chain. (4F) multiple myeloma plasma cells (long arrow, red dots) and Waldenström macroglobu- linemia lymphocytes (short arrow, blue dots) occupy different areas of CD45/side scatter dot-plot. 31 04_12-032.mcd Page 3 v4.21 Carulli G, et al. type. tion of the equivalence point of PCR products with 10-4-10-5 Bone marrow trephines were fixed in Myelodec® reagent sensitivity of molecular assays. The samples were also ana- A (Bio-Optica) for 2 hr, decalcified, embedded in paraffin, lysed for FR1 region to confirm the specific rearrangements. and cut into 3-5 µm sections.
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