Современные аспекты дифференциальной диагностики и лечения В-крупноклеточных лимфом с поражением средостения у детей и подростков
Современные аспекты дифференциальной диагностики и лечения В-крупноклеточных лимфом с поражением средостения у детей и подростков
Левашов А.С., Ковригина А.М., Строганова А.М. и др. Современные аспекты дифференциальной диагностики и лечения В-крупноклеточных лимфом с поражением средостения у детей и подростков. Современная Онкология. 2015; 17 (5): 22–32.
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Levashov A.S., Kovrigina A.M., Stroganova A.M. et al. Modern aspects of differential diagnosis and treatment of large B-cell lymphomas with mediastinum involvement in children and adolescents. Journal of Modern Oncology. 2015; 17 (5): 22–32.
Современные аспекты дифференциальной диагностики и лечения В-крупноклеточных лимфом с поражением средостения у детей и подростков
Левашов А.С., Ковригина А.М., Строганова А.М. и др. Современные аспекты дифференциальной диагностики и лечения В-крупноклеточных лимфом с поражением средостения у детей и подростков. Современная Онкология. 2015; 17 (5): 22–32.
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Levashov A.S., Kovrigina A.M., Stroganova A.M. et al. Modern aspects of differential diagnosis and treatment of large B-cell lymphomas with mediastinum involvement in children and adolescents. Journal of Modern Oncology. 2015; 17 (5): 22–32.
Введение. В настоящее время опубликованы результаты лечения детей с В-крупноклеточными лимфомами (ВККЛ) с поражением средостения (первичной медиастинальной (тимической) ВККЛ и диффузной ВККЛ – ДВККЛ) по разным программам терапии (FAB/LMB96 ± ритуксимаб, B-NHL-BFM90/95, B-NHL-2004m). Но прогностическая и диагностическая значимость маркеров, таких как экспрессия C-MYC, STAT3, pSTAT3, TRAF1, TNFAIP2, наличие реаранжировки, амплификации гена C-MYC, остается неизвестной. В данной статье представлены результаты лечения по протоколам IDM-NHL-BFM90, B-NHL-BFM95 ± ритуксимаб c учетом морфоиммунологических особенностей опухоли. Материалы и методы. С 1994 по 2015 г. 22 пациента с ВККЛ с поражением средостения были включены в исследования IDM-NHL-BFM90, B-NHL-BFM95 ± ритуксимаб. Соотношение мальчиков и девочек составило 1/2. Средний возраст 12,2±0,6 года (от 5 до 18 лет). Медиана возраста 13,5 года. Все пациенты с III или IV стадией заболевания, R3 или R4 группой риска. GCB/non-GCB-субтипы ДВККЛ оценивались с помощью иммуногистохимических алгоритмов Hans и Visco-Young. C-MYC-позитивный вариант ВККЛ определялся при уровне экспрессии более 40%; BCL2 – более 70%, STAT3 – более 20%; pSTAT3, TRAF1, TNFAIP2 – при уровне экспрессии более 50%. Реаранжировка, амплификация гена C-MYC определялись методом FISH с использованием локус-специфических проб. Результаты. В результате данного исследования выявлены характерные особенности «молекулярного портрета» первичной медиастинальной ВККЛ (ПМВККЛ) у детей и подростков: экспрессия CD20 у всех пациентов, высокая частота экспрессии CD23, CD30, C-MYC, PAX5, TRAF1, TNFAIP2 и STAT3, отсутствие экспрессии CD10, pSTAT3tyr705, низкая частота экспрессии иммуноглобулина M, отсутствие реаранжировки и/или амплификации гена C-MYC при уровне экспрессии C-MYC>70%, высокая активность JAK2-JMJD2C эпигенетической регуляции pSTAT3tyr705 независимой экспрессии C-MYC.
Отмечается тенденция к формированию «молекулярного портрета» ДВККЛ с поражением средостения с учетом результатов данного исследования и международного опыта: экспрессия CD20 у всех пациентов, низкая частота экспрессии CD30, non-GCB-вариант, C-MYC-позитивный вариант, BCL2/C-MYC-позитивный вариант, реаранжировка гена C-MYC, отсутствие экспрессии CD23, TRAF1, TNFAIP2.
При проведении программы B-NHL-BFM95 + ритуксимаб удалось добиться высоких показателей безрецидивной выживаемости как у пациентов с ПМВККЛ, так и при ДВККЛ с поражением средостения.
Статистически достоверного значения морфоиммунологических характеристик опухоли (CD23, CD30, C-MYC, BCL2/C-MYC, STAT3) для показателей общей выживаемости, бессобытийной выживаемости, безрецидивной выживаемости не выявлено. Заключение. Число пациентов в данном исследовании недостаточно, чтобы оценить достоверную прогностическую значимость данных маркеров, но высокоинтенсивная программа терапии B-NHL-BFM95 + ритуксимаб показала хороший терапевтический эффект у наших пациентов. Исследование будет продолжено.
Background. At the present time results of some pediatric protocols (FAB/LMB96 with and without rituximab, B-NHL-BFM90/95, B-NHL-2004m) were published but prognostic and diagnostic significance of markers, such as: C-MYC, STAT3, pSTAT3, TRAF1 expression, C-MYC gene rearrangement and amplification in childhood large B-cell lymphomas with mediastinum involvement is unknown. In this article there were presented results of treatment childhood large B-cell lymphomas with mediastinum involvement according to protocols IDM-NHL-BFM90, B-NHL-BFM 95 ± rituximab in view of morpho-immunological tumor’s features. Design/Methods. From 1994 to 2015 twenty two pediatric patients with large B-cell lymphomas with mediastinum involvement were included in trials IDM-NHL-BFM90, B-NHL-BFM 95 ± rituximab. Male/female ratio was 1/2. Median age – 12.2±0.6 years (range from 5 till 18). Median of age was 13.5 years. Stage III–IV, R3–R4 risk groups were revealed in all patients (100%). GCB/non-GCB DLBCL subtypes were assessed by Hans and Visco-Young immunohistochemical algorithms. Cutoff values of 40% for MYC, 70% for BCL2, 20% for STAT3, 50% for pSTAT3tyr705, TRAF1, TNFAIP2 were established. MYC gene rearrangement and amplification were assessed by FISH using locus-specific MYC (8q24) tricolor breakapart probe and MYC (8q24) SE8 control probe. Results. According to the data of this clinical trial there were revealed distinctive features of molecular portrait childhood primary mediastinal (thymic) large B-cell lymphoma that include: CD20 expression in all patients, high frequency of CD23, CD30, C-MYC, PAX5, TRAF1, TNFAIP2 expression, absence of CD10, pSTAT3tyr705 expression, low frequency of IgM expression, absence of C-MYC gene rearrangement and/or amplification despite the level of C-MYC expression more 70%, high activity of JAK2-JMJD2C epigenetic regulation of pSTAT3tyr705 independent C-MYC expression. There is the tendency to the formation of molecular portrait of childhood diffuse large B-cell lymphoma with mediastinum involvement: CD20 expression in all patients, non-GCB variant, high frequency of C-MYC expression, C-MYC gene rearrangement, absence of CD23, TRAF1, TNFAIP2 expression, low frequency of CD30 expression.
Using protocol B-NHL-BFM 95 plus rituximab we have achieved high level of relapse-free survival in patients with large B-cell lymphomas with mediastinum involvement. There is not revealed any influence of investigated markers (CD23, CD30, C-MYC) on overall survival, event-free survival and relapse-free survival. Conclusion. Number of patients in this study is not enough to estimate authentic prognostic significance of these markers but high-intensive B-NHL-BFM95 + rituximab chemotherapy showed good therapeutic effect in our patients. This study will be continued.
Key words: diffuse large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, differential diagnosis, treatment, children, adolescents.
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________________________________________________
1. Reiter A. Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma. Hematology 2007; 1: 285–96.
2. Burkhardt В, Oschlies I, Klapper W. Non-Hodgkin’s lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 2011; 25: 153–60.
3. Kovrigina A.M., Probatova N.A. Limfoma Khodzhkina i krupnokletochnye limfomy. M.: MIA, 2007. [in Russian]
4. Seidemann K, Tiemann M, Lauterbach I. Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescents patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Munster group. J Clin Oncol 2003; 21 (9): 1782–9.
5. Swerdlow SH, Campo E, Harris NL. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Fourth edition. 2008.
6. Jaffe ES, Pittaluga S. Aggressive B-cell lymphomas: a review of new and old entities in the WHO classification. Hematology 2011; p. 506–14.
7. Heerema NA, Bernheim AB, Lim MS. Meeting report, State of the art and future needs in cytogenetic/molecular genetics/arrays in childhood lymphoma: summary report of workshop at the first international symposium on childhood and adolescent non-Hodgkin lymphoma. Ped Blood Can 2005; 45: 616–22.
8. Faris JE, LaCasce AS. Primary mediastinal large B-cell lymphoma. Clin Adv Hematol Oncol 2009; 7 (2): 125–32.
9. Maeshima A, Taniguchi H, Miyamoto K. Prognostic significance of immunophenotypes and a nodular pattern in primary mediastinal large B-cell lymphoma. Pathol Int 2014; 64: 382–7.
10. Oschlies I, Burkhardt B, Salaverria I. Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 2011; 96 (2): 262–8.
11. Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma – treatment approaches in the molecular era. Nat Rev Clin Oncol 2014; 11 (1): 12–23.
12. Schneider C, Pasqualucci L, Dalla-Favera R. Molecular pathogenesis of diffuse large B-cell lymphoma. Sem Diagn Pathol 2011; 28: 167–77.
13. Twa DD, Chun Chan F, Ben-Neriah S. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014; 123: 2062–5.
14. Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood 2011; 118 (10): 2650–69.
15. Hu S, Xu-Monette ZY, Tzankov A. 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.
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18. Tzankov A, Xu-Monette Z, Gerhard M. Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP. Modern Pathol 2014; 27: 958–71.
19. Wu ZL, Song YQ, Shi YF. High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphoma. J Hematol Oncol 2011; 4: 31. http://www.jhoonline.org/content/pdf/1756-8722-4-31.pdf
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1 ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23;
2 ФГБУ Гематологический научный центр Минздрава России. 125167, Россия, Москва, Новый Зыковский пр-д, д. 4
*andreyslevashov@mail.ru
1 N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23;
2 National Research Center for Hematology of the Ministry of Health of the Russian Federation. 125167, Russian Federation, Moscow, Novyi Zykovskii pr-d, d. 4
*andreyslevashov@mail.ru