YaK Mangasarova, YuV Sidorova, AU Magomedova, BV Biderman, EE Nikulina, AB Sudarikov, AM Kovrigina, SK Kravchenko
National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
For correspondence: Yana Konstantinovna Mangasarova, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(926)395-82-52; e-mail: email@example.com
For citation: Mangasarova YaK, Sidorova YuV, Magomedova AU. Rearrangement of Immunoglobulin Genes in Tumor Cells of Patients with Primary Mediastinal (Thymic) Large B-Cell Lymphoma. Clinical oncohematology. 2019;12(3):271–7 (In Russ).
Background. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a malignant tumor with large atypical lymphoid cells expressing post-germinal differentiation markers. Rearrangements of immunoglobulin genes in PMBCL are revealed in 30–65 % of cases. Immunoglobulin molecules, however, are expressed neither on the surface, nor in cytoplasm of tumor cells.
Aim. To assess cell clonality rate on the basis of rearrangements of immunoglobulin heavy/light chain genes; to determine rearrangement stability at the time of relapse development; to study the range of rearrangements and clonal relationship with primary tumor in metachronous development of mediastinal gray zone lymphoma.
Materials & Methods. The assessment of rearrangements of immunoglobulin heavy/light chain genes was based on molecular analysis of 29 primary tumor biopsies and 4 tissue samples with histologically and immunohistochemically verified relapses or metachronous lymphoma development.
Results. In 16 (55.2 %) out of 29 cases a rearrangement of immunoglobulin heavy chain genes was reported, in 7 (24.1 %) cases a rearrangement of light chain genes was identified, in 6 (20.7 %) cases no rearrangements of immunoglobulin heavy/light chain genes were found. On the basis of immunoglobulin gene analysis in 2 patients with early relapse a tumor clone was detected that was identical with the one identified at the onset of the disease. In 2 patients with complete remission a metachronous development of mediastinal gray zone lymphoma was reported, whereas molecular genetic analysis revealed a change/disappearance of initial clonal rearrangements of immunoglobulin genes.
Conclusion. Total detection rate of B-cell clonality in PMBCL was 79.3 %. Molecular genetic analysis confirmed that initial clonal rearrangements of immunoglobulin genes were preserved in early relapses, and invalidated tumor clonal relationship in a metachronous development of mediastinal gray zone lymphoma.
Keywords: primary mediastinal (thymic) large B-cell lymphoma, rearrangement of immunoglobulin heavy/light chain genes, polymerase chain reaction, metachronous development of lymphoma.
Received: November 2, 2018
Accepted: May 29, 2019
Evans PA, Pott Ch, Groenen PJ, et al. Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia. 2007;21(2):207–14. doi: 10.1038/sj.leu.2404479.
Мангасарова Я.К., Магомедова А.У., Ковригина А.М. и др. Первичная медиастинальная (тимическая) В-крупноклеточная лимфома: диагностика отдаленных экстрамедиастинальных поражений и возможности лечения. Клиническая онкогематология. 2018;11(3):220–6. doi: 21320/2500-2139-2018-11-3-220-226.
[Mangasarova YaK, Magomedova AU, Kovrigina AM, et al. Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Diagnostics of Extramediastinal Lesions and Treatment Opportunities. Clinical oncohematology. 2018;11(3):220–6. doi: 10.21320/2500-2139-2018-11-3-220-226. (In Russ)]
Harris NL; The International Lymphoma Study Group. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Curr Diagn Pathol. 1995;2(1):58–9. doi: 10.1016/S0968-6053(00)80051-4.
Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62. doi: 10.1084/jem.20031074.
Pileri SA, Zinzani PL, Gaidano G, et al. Pathobiology of primary mediastinal B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl 3):S21–6. doi: 10.1080/10428190310001623810.
Loddenkemper C, Anagnostopoulos I, Hummel M, et al. Differential Emu enhancer activity and expression of BOB.1/OBF.1, Oct2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas. J Pathol. 2004;202(1):60–9. doi: 10.1002/path.1485.
De Leval L, Ferry JA, Falini B, et al. Expression of bcl-6 and CD10 in primary Mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Pathol. 2001;25(10):1277–82. doi: 10.1097/00000478-200110000-00008.
Rosenquist R, Lindstrom A, Holmberg D, et al. V(H) gene family utilization in different B-cell lymphoma subgroups. Eur J Haematol. 1999;62(2):123–8. doi: 10.1111/j.1600-0609.1999.tb01732.x.
Zhong DR, Ling Q, Shi XH, et al. Comparative study between primary mediastinal B-cell lymphoma and non-mediastinal diffuse large B-cell lymphoma by immunoglobulin gene rearrangement and Epstein-Barr virus infection detection. J Hematop. 2009;2(1):45–9. doi: 1007/s12308-009-0022-3.
Leithauser F, Bauerle M, Quang Huynh M, et al. Isotype-switched immunoglobulin genes with a high load of somatic hypermutation and lack of ongoing mutational activity are prevalent in mediastinal B-cell lymphoma. 2001;98(9):2762–70; doi: 10.1182/blood.v98.9.2762.
Burack WR, Laughlin TS, Friedberg JW, et al. PCR assays detect B-lymphocyte clonality in formalin-fixed, paraffin-embedded specimens of classical Hodgkin lymphoma without microdissection. Am J Clin Pathol. 2010;134(1):104–11. doi: 10.1309/AJCPK6SBE0XOODHB.
Evens AM, Kanakry JA, Sehn LH, et al. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol. 2015;90(9):778–83. doi: 10.1002/ajh.24082.
Eberle FC, Salaverria I, Steidl C, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24(12):1586–97. doi: 10.1038/modpathol.2011.116.
Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17(12):2257–317. doi: 10.1038/sj.leu.2403202.