Гетерогенная диффузная В-клеточная крупноклеточная лимфома: правильный диагноз как залог успешной терапии

Бабичева Л.Г., Поддубная И.В. Гетерогенная диффузная В-клеточная крупноклеточная лимфома: правильный диагноз как залог успешной терапии. Современная Онкология. 2023;25(2):168–177.
DOI: 10.26442/18151434.2023.2.202237

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Babicheva LG, Poddubnaya IV. Heterogeneous diffuse large B-cell lymphoma: accurate diagnosis as a key to successful therapy. A review. Journal of Modern Oncology. 2023;25(2):168–177.
DOI: 10.26442/18151434.2023.2.202237

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Аннотация

Диффузная В-клеточная крупноклеточная лимфома (ДВККЛ) является наиболее распространенным вариантом неходжкинских лимфом, и на ее долю приходится примерно 1/3 всех неходжкинских лимфом в западных странах и около 40% В-клеточных опухолей во всем мире. Правильный диагноз клинически различающихся подгрупп агрессивных зрелоклеточных В-клеточных лимфом имеет решающее значение для выбора адекватного лечения. В настоящее время идентификация варианта ДВККЛ зависит от сочетания морфологических, иммунофенотипических и цитогенетических/молекулярных особенностей. Классификация охватывает наиболее распространенный, неспецифицированный вариант ДВККЛ, также называемый как «не указано иное» (NOS), и ряд других редких форм. За последние два десятилетия ДВККЛ NOS, на долю которой приходится более 80% всех случаев, стала объектом растущего числа молекулярных исследований, которые позволили идентифицировать прогностические факторы, активно внедряемые в реальную клиническую практику. Только объединение морфологических, иммуногистохимических и молекулярных особенностей ДВККЛ приведет к достижению долгосрочной цели использования персонифицированных методов, способных излечить большинство пациентов, с минимальными токсическими проявлениями или вообще без них.

Ключевые слова: диффузная В-клеточная крупноклеточная лимфома, профилирование экспрессии генов, секвенирование следующего поколения, классификация, диагностика, прогноз

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Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin's lymphoma and accounts for about 1/3 of all non-Hodgkin's lymphomas in Western countries and about 40% of B-cell tumors worldwide. Correct diagnosis of clinically distinct subgroups of aggressive mature B-cell lymphomas is crucial for the choice of adequate treatment. Currently, the identification of DLBCL subtype depends on a combination of morphologic, immunophenotypic, and cytogenetic/molecular features. The classification covers the most common unspecified variant of DLBCL, also referred to as "not otherwise specified" (NOS), and a number of other rare forms. Over the past two decades, DLBCL NOS which accounts for more than 80% of all cases, has been the subject of a growing number of molecular studies that have identified prognostic factors that are being actively introduced into real-world clinical practice. Only the integration of morphological, immunohistochemical and molecular features of DLBCL will lead to the achievement of the long-term goal of curing the majority of patients with minimal or no toxic manifestations with the aid of personalized healthcare.

Keywords: diffuse large B-cell lymphoma, gene expression profiling, next generation sequencing, classification, diagnosis, prognosis

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Список литературы

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12. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-48. DOI:10.1038/s41375-022-01620-2
13. Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94(5):604-16. DOI:10.1002/ajh.25460
14. Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):74-87. DOI:10.1016/j.pathol.2017.09.006
15. Horn H, Staiger AM, Vöhringer M, et al. Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYC-IGH translocations. Am J Surg Pathol. 2015;39(1):61-6. DOI:10.1097/PAS.0000000000000319
16. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood. 2010;116(23):4916-25. DOI:10.1182/blood-2010-03-276766
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18. Kaler AK, Shaila, Ashwini R, et al. Molecular profiling of large B-Cell lymphomas: A retrospective observational pilot study. J Precis Oncol. 2022;2(2):125-32. DOI:10.4103/jpo.jpo_19_22
19. Visco C, Li Y, Xu-Monette ZY, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26(9):2103-13. DOI:10.1038/leu.2012.83
20. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452-9. DOI:10.1200/JCO.2011.41.0985
21. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503‑11. DOI:10.1038/35000501
22. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-47. DOI:10.1056/NEJMoa012914
23. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, et al. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol. 2009;22(8):1094-101. DOI:10.1038/modpathol.2009.73
24. Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA. 2003;100(17):9991-6. DOI:10.1073/pnas.1732008100
25. Choi WWL, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15(17):5494-502. DOI:10.1158/1078-0432.CCR-09-0113
26. de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: Validation of tissue microarray as a prerequisite for broad clinical applications – a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2007;25(7):805-12. DOI:10.1200/JCO.2006.09.4490
27. Gutiérrez-García G, Cardesa-Salzmann T, Climent F, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117(18):4836-43. DOI:10.1182/blood-2010-12-322362
28. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123(8):1214-7. DOI:10.1182/blood-2013-11-536433
29. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-56. DOI:10.1200/JCO.2014.60.2383
30. Jais JP, Molina TJ, Ruminy P, et al. Reliable subtype classification of diffuse large B-cell lymphoma samples from GELA LNH2003 trials using the Lymph2Cx gene expression assay. Haematologica. 2017;102(10):e404-6. DOI:10.3324/haematol.2017.166827
31. Gifford G, Gabrielli S, Gill A, et al. Lymphoma cell-of-origin assignment by gene expression profiling is clinically meaningful across broad laboratory contexts. Br J Haematol. 2018;181(2):272-5. DOI:10.1111/bjh.14556
32. Derenzini E, Mazzara S, Melle F, et al. A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2405-16. DOI:10.3324/haematol.2019.236455
33. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460-7. DOI:10.1200/JCO.2011.41.4342
34. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021-31.
DOI:10.1182/blood-2012-10-460063
35. Rosenwald A, Bens S, Advani R, et al. Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2019;37(35):3359-68. DOI:10.1200/JCO.19.00743
36. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354-61. DOI:10.1182/blood-2014-05-578963
37. Scott DW, King RL, Staiger AM, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018;131(18):2060-4. DOI:10.1182/blood-2017-12-820605
38. Kurz KS, Ott M, Kalmbach S, et al. Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms – Updated Classification and New Concepts. Cancers (Basel). 2023;15(8):2285. DOI:10.3390/cancers15082285
39. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-90. DOI:10.1038/s41591-018-0016-8
40. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-407. DOI:10.1056/NEJMoa1801445
41. Pileri SA, Tripodo C, Melle F, et al. Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas. Cells. 2021;10(3):675.

________________________________________________

1. Sarkozy C, Coiffier B. Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties. Clin Cancer Res. 2013;19(7):1660-9. DOI:1158/1078-0432.CCR-12-2837
2. National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. Available at: https://seer.cancer.gov/ Accessed: 18.01.2021.
3. López-Guillermo A, Colomo L, Jiménez M, et al. Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin. J Clin Oncol. 2005;23(12):2797-804. DOI:10.1200/JCO.2005.07.155
4. Riedell PA, Smith SM. Double hit and double expressors in lymphoma: Definition and treatment. Cancer. 2018;124(24):4622-32. DOI:10.1002/cncr.31646
5. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. International Agency for Research on Cancer. Lyon, France, 2017; p. 2.
6. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer. Lyon, France, 2008.
7. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-92. DOI:10.1182/blood.V84.5.1361.1361
8. Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press. Lyon, France, 2001.
9. Tumyan GS. New Prospects for Treatment of Diffuse Large B-Cell Lymphoma. Clinical Oncohematology. 2022;15(3):213-31 (in Russian).
10. Poddubnaya IV, Parovichnikova EN, Kaprin AD, Kovrigina AM. Rossiiskie klinicheskie rekomendatsii "Agressivnye nefollikuliarnye limfomy – diffuznaia krupnokletochnaia V-kletochnaia limfoma, pervichnaia mediastinal'naia V-kletochnaia limfoma, limfoma Berkitta" 2022 (in Russian).
11. Falini B, Martino G, Lazzi S. A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas. Leukemia. 2023;37:18-34. DOI:10.1038/s41375-022-01764-1
12. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-48. DOI:10.1038/s41375-022-01620-2
13. Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94(5):604-16. DOI:10.1002/ajh.25460
14. Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):74-87. DOI:10.1016/j.pathol.2017.09.006
15. Horn H, Staiger AM, Vöhringer M, et al. Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYC-IGH translocations. Am J Surg Pathol. 2015;39(1):61-6. DOI:10.1097/PAS.0000000000000319
16. Ott G, Ziepert M, Klapper W, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood. 2010;116(23):4916-25. DOI:10.1182/blood-2010-03-276766
17. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-82. DOI:10.1182/blood-2003-05-1545
18. Kaler AK, Shaila, Ashwini R, et al. Molecular profiling of large B-Cell lymphomas: A retrospective observational pilot study. J Precis Oncol. 2022;2(2):125-32. DOI:10.4103/jpo.jpo_19_22
19. Visco C, Li Y, Xu-Monette ZY, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26(9):2103-13. DOI:10.1038/leu.2012.83
20. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452-9. DOI:10.1200/JCO.2011.41.0985
21. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503‑11. DOI:10.1038/35000501
22. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-47. DOI:10.1056/NEJMoa012914
23. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, et al. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol. 2009;22(8):1094-101. DOI:10.1038/modpathol.2009.73
24. Wright G, Tan B, Rosenwald A, et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci USA. 2003;100(17):9991-6. DOI:10.1073/pnas.1732008100
25. Choi WWL, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15(17):5494-502. DOI:10.1158/1078-0432.CCR-09-0113
26. de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: Validation of tissue microarray as a prerequisite for broad clinical applications – a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2007;25(7):805-12. DOI:10.1200/JCO.2006.09.4490
27. Gutiérrez-García G, Cardesa-Salzmann T, Climent F, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117(18):4836-43. DOI:10.1182/blood-2010-12-322362
28. Scott DW, Wright GW, Williams PM, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123(8):1214-7. DOI:10.1182/blood-2013-11-536433
29. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-56. DOI:10.1200/JCO.2014.60.2383
30. Jais JP, Molina TJ, Ruminy P, et al. Reliable subtype classification of diffuse large B-cell lymphoma samples from GELA LNH2003 trials using the Lymph2Cx gene expression assay. Haematologica. 2017;102(10):e404-6. DOI:10.3324/haematol.2017.166827
31. Gifford G, Gabrielli S, Gill A, et al. Lymphoma cell-of-origin assignment by gene expression profiling is clinically meaningful across broad laboratory contexts. Br J Haematol. 2018;181(2):272-5. DOI:10.1111/bjh.14556
32. Derenzini E, Mazzara S, Melle F, et al. A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma. Haematologica. 2021;106(9):2405-16. DOI:10.3324/haematol.2019.236455
33. Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460-7. DOI:10.1200/JCO.2011.41.4342
34. Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021-31.
DOI:10.1182/blood-2012-10-460063
35. Rosenwald A, Bens S, Advani R, et al. Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma: a study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol. 2019;37(35):3359-68. DOI:10.1200/JCO.19.00743
36. Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354-61. DOI:10.1182/blood-2014-05-578963
37. Scott DW, King RL, Staiger AM, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018;131(18):2060-4. DOI:10.1182/blood-2017-12-820605
38. Kurz KS, Ott M, Kalmbach S, et al. Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms – Updated Classification and New Concepts. Cancers (Basel). 2023;15(8):2285. DOI:10.3390/cancers15082285
39. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679-90. DOI:10.1038/s41591-018-0016-8
40. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396-407. DOI:10.1056/NEJMoa1801445
41. Pileri SA, Tripodo C, Melle F, et al. Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas. Cells. 2021;10(3):675.

Авторы

Л.Г. Бабичева*, И.В. Поддубная

ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*lalibabicheva@mail.ru

________________________________________________

Lali G. Babicheva*, Irina V. Poddubnaya

Russian Medical Academy of Continuous Professional Education, Moscow, Russia
*lalibabicheva@mail.ru

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