Pulmonary Extranodal Marginal Zone Lymphoma That Presented
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lin Journal of clinical and experimental hematopathology JC Vol. 58 No.3, 141-147, 2018 EH xp ematopathol Case report Pulmonary extranodal marginal zone lymphoma that presented with macroglobulinemia and marked plasmacytic cell proliferation carrying the t(14;18)(q32;q21)/MALT1- immunoglobulin heavy-chain fusion gene in pleural fluid Takashi Akasaka,1) Chiyuki Kishimori,2) Fumiyo Maekawa,2) Kayo Takeoka,2) 2) 3) 3) 1),2) Masahiko Hayashida, Hiroshi Gomyo, Tohru Murayama, and Hitoshi Ohno An 80-year-old man presented with the accumulation of pleural fluid in the right thoracic cavity. Serum electrophoresis revealed an M-component and immunofixation confirmed IgM/λ. The level of IgM was 1,526 mg/dL. Imaging studies showed an infil- trative condition of the ipsilateral lung parenchyma. The fluid contained abundant neoplastic cells with the morphological and immunophenotypic features of plasma cells, which expressed IgM/λ monoclonal immunoglobulins on the cell surface and in the cytoplasm. The karyotype was 48,XY,+3,add(9)(p13),+12,add(14)(q32),del(16)(q22),−18,+mar, and a series of fluores- cence in situ hybridization studies demonstrated that the add(14) chromosome represented der(14)t(14;18)(q32;q21), at which the MALT1-immunoglobulin heavy-chain (IGH) fusion gene was localized. A long-distance polymerase chain reaction ampli- fied the fragment encompassing the two genes, showing that the junction occurred at the J6 segment of IGH and 3.7-kb upstream of the MALT1 breakpoint cluster. We propose that this case represents an extreme form of the plasmacytic differenti- ation of extranodal marginal zone lymphoma that developed in the lung. Keywords: macroglobulinemia, extranodal marginal zone lymphoma, plasmacytic differentiation, t(14;18)(q32;q32)/MALT1- IGH fusion gene distinction between WM/LPL and EMZL/MALT lymphoma INTRODUCTION showing plasmacytic differentiation and associated with the Waldenström macroglobulinemia (WM) is a distinct clin- serum IgM monoclonal protein is not necessarily clear, even icopathological disease entity showing lymphoplasmacytic though >90% cases of the former disease have the MYD88 lymphoma (LPL) in bone marrow and the IgM monoclonal P265P somatic mutation.2,6 protein in serum (i.e., macroglobulinemia) at any concentra- We herein describe a patient who presented with macro- tion.1,2 WM/LPL is characterized by the proliferation of globulinemia and the accumulation of pleural fluid in the uni- small lymphocytes admixed with variable numbers of plasma lateral thoracic cavity. Neoplastic cells in the fluid showed cells and plasmacytoid lymphocytes.2 Patients with WM/ the cytomorphological and immunophenotypic features of LPL present with a number of symptoms attributable to plasma cells, indicating the differential diagnosis between tumor cell proliferation and/or an excess of macroglobulin. WM/LPL and EMZL/MALT lymphoma. Cytogenetic and However, macroglobulinemia is observed not only in WM/ molecular studies demonstrated a translocation and fusion LPL, but also a wide range of B-cell lymphoproliferative dis- gene, which was exclusively associated with the latter orders, including extranodal marginal zone lymphoma disease. (EMZL) of mucosa-associated lymphoid tissue (MALT lym- phoma).3-5 EMZL/MALT lymphoma is composed of mor- phologically heterogeneous small B cells and the plasmacytic differentiation of lymphoma cells is common.4 Thus, the Received: April 8, 2018. Revised: June 15, 2018. Accepted: July 6, 2018. J-STAGE Advance Published: August 8, 2018 DOI:10.3960/jslrt.18013 1)Department of Hematology, Tenri Hospital, Nara Japan, 2)Tenri Institute of Medical Science, Nara Japan, and 3)Hematology Division, Department of Medicine, Hyogo Cancer Center, Hyogo, Japan Corresponding author: Takashi Akasaka, MD, PhD, Department of Hematology, Tenri Hospital, 200 Mishima, Tenri, Nara 632-8552, Japan. E-mail: [email protected] Copyright © 2018 The Japanese Society for Lymphoreticular Tissue Research This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. 141 Akasaka T et al. condition. CASE REPORT Thoracentesis yielded exudative fluid containing abun- dant neoplastic cells with the morphological features of Case presentation plasma cells at a concentration of 6.13 × 103 cells per micro- An 80-year-old man, who had been treated in another liter (Figure 2A). These cells expressed IgM/λ monoclonal hospital for the recurrent accumulation of pleural fluid in the immunoglobulins both on the cell surface and in the cyto- right thoracic cavity for 2 years, was referred to our depart- plasm, and showed a wide range of expression levels of ment because a cytological examination of the fluid sug- CD20, CD22, CD23, CD38, and CD138. CD19 and gested lymphoma cells. On examination, breath sounds CD45RA were positive, and CD5, CD10, CD21, CD24, were decreased in the right hemithorax. There was no sur- CD56, and surface IgD were negative (Figures 2B and C). face lymphadenopathy or hepatosplenomegaly. Oxygen sat- The DNA index was 1.06 from normal diploid cells. Bone uration was 96% in room air. A chest radiograph showed marrow showed hypercellularity containing CD20-positive prominent pleural effusion (Figure 1A). His hemoglobin plasma cells, and flow cytometry revealed a lymphoplasma- level was 12.5 g/dL, white blood cell count was 6.95 × 103/ cytic population with an identical immunophenotype to that μL, and platelet count was 289 × 103/μL. Total serum pro- of pleural fluid cells. Tests for the MYD88 L265P somatic tein was 6.7 g/dL, albumin 3.2 g/dL, globulin 3.5 g/dL, lac- mutation were negative (Supplementary Figure S1). tate dehydrogenase 307 IU/L, higher than the normal range Cytogenetic studies of 124 to 222 IU/L, creatinine 0.6 mg/dL, and C-reactive pro- tein 2.25 mg/dL. Serum protein electrophoresis revealed an The G-banding of metaphase spreads obtained from a M-component migrating in the γ globulin area and immuno- short-term culture of pleural fluid cells demonstrated numeri- fixation confirmed the IgM/λ M protein. No urinary Bence cal and structural abnormalities, including a 14q+ chromo- Jones protein was detected. The level of IgG was 723 mg/ some and uncharacterized small marker chromosome; the dL, IgA was 83 mg/dL, and IgM was 1,526 mg/dL (normal karyotype according to the ISCN 2016 was 48,XY,+3,add(9) range, 33 to 183 mg/dL). Serum free light-chain κ (FLC-κ) (p13),+12,add(14)(q32),del(16)(q22),−18,+mar (Figure 3A). was 16.1 mg/L, FLC-λ was 20.5 mg/L, and the κ/λ ratio was Fluorescence in situ hybridization (FISH) of interphase 0.79. Soluble interleukin 2 receptor was 3,051 U/mL. nuclei with the MYC, BCL2, and BCL6 dual-color, break- Computed tomography (CT) of the chest revealed the apart probes detected no rearrangement of these 3 genes, accumulation of pleural fluid in the right thoracic cavity in while nuclei carried 3 hybridization signals of BCL2 and association with atelectasis of the middle and lower lobes, BCL6 (Supplementary Figure S2). The hybridization of where the marked accumulation of the tracer was demon- metaphase cells with the BCL2-IGH dual-color dual-fusion strated by 18F-fluorodeoxyglucose-positron emission tomog- probe showed that the add(14) chromosome was marked by raphy (FDG-PET) combined with CT (Figure 1B), suggest- the IGH and BCL2 probes (Figure 3B); however, these ing that the atelectatic lesion contained an infiltrative probes did not generate a fusion signal (Supplementary A B Fig. 1. Imaging studies showing pleural effusion of the right thoracic cavity and an infiltrative condition of the lung parenchyma. (A) Postero-anterior chest X-ray. (B) FDG-PET/CT. The anterior view of a maximum intensity projection image (left) and repre- sentative axial images of the thorax (right) are shown. The maximum standardized uptake value of the pulmonary lesion was 17.89. 142 Pulmonary EMZL with t(14;18)/MALT1-IGH A C B Fig. 2. Cytomorphology and immunophenotype of lymphoma cells. (A) May-Giemsa-stained lymphoma cells in pleural fluid, showing a plasmacytic appearance. A few cells had one or more intranuclear inclusions, i.e., Dutcher bodies (right, arrows). (B and C) Flow cytometry of pleural fluid cells using antibodies against the antigens indicated. In B, cells expressed cell surface and cytoplasmic IgM/κ monoclonal immunoglobulins. In C, cells expressed variable levels of B-cell associated antigens and CD38 and CD138, but lacked myelomatous aberrant expression (e.g. CD56). Figure S2). We then performed hybridization with the and for the Eμ enhancer as well as the Cμ, Cγ, and Cα con- MALT1 dual-color, break-apart probe and found that add(14) stant genes of IGH; the MALT1 probe and IGH probes were was marked by the green-labeled telomeric probe, represent- oriented in the opposite direction (Figures 4A and B, ing 3′ MALT1, while the red-labeled centromeric MALT1 sig- Supplementary Table S1). As shown in Figure 4C, we nal was missing, and, accordingly, interphase nuclei showed obtained LD-PCR products by the MALT1-Eμ and the one green and two yellow signal pattern (Figure 3B). MALT1-Cγ primer combination, indicating Cμ to Cγ class The uncharacterized marker chromosome was marked by switching. Nucleotide sequencing of the MALT1-Eμ product unrearranged BCL2 and MALT1 probes, but not of IGH. revealed that the junction occurred at the J6 segment of IGH These cytogenetic studies indicated that the add(14) chromo- and the nucleotide position −5,399 of adenine of the ATG some represented der(14)t(14;18)(q32;q21), at which the start codon of MALT1 at the position +1, and a fragment of 9 MALT1-IGH fusion gene was localized, while the reciprocal base pairs (bp) in length was inserted at the junction (Figures der(18)t(14;18)(q32;q21) was deleted. 4A and D). As a result of translocation, the MALT1 and IGH Eμ-Cγ segments were aligned in the divergent transcriptional Amplification and sequencing of the t(14;18)(q32;q21)/ orientation.