Double‑hit Lymphomas – Review of the Literature and Case Report

Česká verzia

Authors: J. Šmardová ¹; M. Moulis ¹; K. Lišková ¹; J. Koptíková ²; R. Hrabálková ¹; J. Klusáková ³
Authors place of work: Ústav patologie, LF MU a FN Brno ¹; Institut biostatiky a analýz, LF MU, Brno ²; MDgK‑ plus spol. s r. o., Újezd u Brna ³
Published in the journal: Klin Onkol 2014; 27(1): 24-32
Category: Review

Summary

B‑lymphocytes are cells of the immune system responsible for the antibody‑ mediated immune response. As estimated, a human body can produce as much as 10¹¹ specific antibodies. There are no specific genes coding for every individual antibody in the human genome. Discrepancy between the huge diversity of antibodies and limited coding capacity of the genome is solved by combination of unique arrangement of genetic information for immunoglobulin and unique genetic and somatic processes providing this wide spectrum of antibodies. On one side, these mechanisms represent a life protecting source of a wide spectrum of antibodies but at the same time, they can be life threatening by raising the risk of a serious tumor disease, the B‑ cell lymphoma. Double‑hit lymphomas represent a specific group of B‑ cell lymphomas often featuring concurrent rearrangements of BCL2 and MYC genes. Activation of the MYC oncogene, typical for Burkitt lymphoma (BL), causes strong stimulation of cell proliferation. High activity of BCL‑ 2, typical for follicular lymphoma, induces resistance to apoptosis. Concurrent damage of regulation of apoptosis and proliferation is probably responsible for the typical clinical manifestation of double‑hit lymphomas – aggressive course, resistance to conventional chemotherapy, high-risk of early relapse, short overall survival, frequent extranodal and central nervous system involvement. Recently, these lymphomas have attracted a strong attention of researchers as they provide sharp insights into processes of lymphocytes maturing and lymphomas development and highlight the double‑edged nature of mechanisms allowing the antibody broad diversity.

Case report:
Fifty‑ three‑year‑ old man was diagnosed with B‑ cell lymphoma unclassifiable with features intermediate between diffuse large B‑ cell lymphoma (DLBCL) and BL, based on morphology and immunophenotype. Fluorescent in situ hybridization analysis revealed double‑hit lymphoma diagnosis as the tumor cells bear t(14;18) translocation concurrently with the MYC gene rearrangement. The patient died five months after diagnosis.

Key words:
B‑lymphocytes – antibody formation – B‑ cell lymphoma – double‑hit lymphoma

This study was supported by grant of Internal Grant Agency of the Czech ministry of Health No. NT/13519-4/2012.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
2. 8. 2013

Accepted:
11. 9. 2013

Zdroje

1. Krejsek J, Kopecký O. B lymfocyty a protilátková imunita. In: Krejsek J, Kopecký O (eds). Klinická imunologie. 1. vyd. NUCLEUS HK 2004: 241– 270.

2. Nagasawa T. Microenvironmental niches in the bone marrow required for B‑ cell development. Nat Rev Immunol 2006; 6(2): 107– 116.

3. Jares P, Colomer D, Campo E. Genetic and moleular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 2007; 7(10): 750– 762.

4. Klein U, Dalla‑ Favera R. Germinal centres: role in B‑ cell physiology and malignancy. Nat Rev Immunol 2008; 8(1): 22– 33.

5. Di Noia JM, Neiberger MS. Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 2007; 76: 1– 22.

6. Robbiani DF, Nussenzweig MC. Chromosome translocation, B cell lymphoma, and activated‑induced cytidine deaminase. Annu Rev Pathol 2013; 8: 79– 103.

7. Wang JH. The role of activation‑induced deaminase in antibody diversification and genomic instability. Immunol Res 2013; 55(1– 3): 287– 297.

8. Keim C, Kazadi D, Rothschild G et al. Regulation of AID, the B‑ cell genome mutator. Genes Dev 2013; 27(1): 1– 17.

9. Vega F, Medeiros LJ. Chromosomal translocations involaved in non‑Hodgkin lymphomas. Arch Pathol Lab Med 2003; 127(9): 1148– 1160.

10. Tomita N, Tokunaka M, Nakamura N et al. Clinicopathological features of lymphoma/ leukemia patients carrying both BCL2 and MYC translocations. Haematologica 2009; 94(7): 935– 943.

11. Aukema SM, Siebert R, Schuuring E et al. Double‑hit B‑ cell lymphomas. Blood 2011; 117(8): 2319– 2331.

12. Lindsley RC, LaCasce AS. Biology of double‑hit B‑ cell lymphomas. Curr Opin Hematol 2012; 19(4): 299– 304.

13. Salaverria I, Siebert R. The gray zone between Burkitt’s lymphoma and diffuse large B‑ cell lymphoma from genetics perspective. J Clin Oncol 2011; 29(14): 1835– 1843.

14. Kluin P, Harris N, Stein H et al. B‑ cell lymphoma, unclassifiable, with features intermediate between diffuse large B‑ cell lymphoma and Burkitt’s lymphoma. In: Swerdlow SH, Campo E, Harris NL (eds). WHO, Classification of tumors of haematopoietic, lymphoid tissues. 4th ed. Lyon: IARC Press 2008: 265– 266.

15. Foot NJ, Dunn RG, Geoghegan H et al. Fluorescence in situ hybridisation analysis of formalin‑fixed paraffin‑embedded tissue sections in the diagnostic work‑ up of non‑Burkitt high grade B‑ cell non‑Hodgkin’s lymphoma: a single centre’s experience. J Clin Pathol 2011; 64(9): 802– 808.

16. Pedersen MO, Gang AO, Poulsen TS et al. Double‑hit BCL2/ MYC translocations in a consecutive cohort of patients with large B‑ cell lymphoma – a single centre’s experience. Eur J Haematol 2012; 89(1): 63– 71.

17. Barrans S, Crouch S, Smith A et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B‑ cell lymphoma treated in the era of rituximab. J Clin Oncol 2010; 28(20): 3360– 3365.

18. Kobayashi T, Tsutsumi Y, Sakamoto N et al. Double‑hit Lymphomas constitute a highly a ggressive subgroup in diffuse large B‑ cell lymphomas in the era of rituximab. Jpn J Clin Oncol 2012; 42(11): 1035– 1042.

19. Johnson NA, Savage KJ, Ludkovski O et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009; 114(11): 2273– 2279.

20. Hummel M, Bentink S, Berger H et al. A biological definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med 2006; 354(23): 2419– 2430.

21. Pillai RK, Sathanoori M, Van Oss SB et al. Double‑hit B‑ cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double‑hit lymphomas. Am J Surg Pathol 2013; 37(3): 323– 332.

22. Salaverria I, Royo C, Carvajal‑ Cuenca A et al. CCND2 rearrangements are the most frequent genetic events in cyclin D1– mantle cell lymphoma. Blood 2013; 121(8): 1394– 1402.

23. Rocha CK, Praulich I, Gehrke I et al. A rare case of t(11;22) in a mantle cell lymphoma like B‑ cell neoplasia resulting in a fusion of IGL and CCND1: case report. Mol Cytogenet 2011; 4(1): 8– 12.

24. Setoodeh R, Schwartz S, Papenhausen P et al. Double‑hit mantle cell lymphoma with MYC gene rearrangement or amplification: a report of four cases and review of the literature. Int J Clin Exp Pathol 2013; 6(2): 155– 167.

25. Delas A, Dobbelstein S, Brousset P et al. Unusual concomitant rearrangements of Cyclin D1 and MYC genes in blastoid variant of mantle cell lymphoma: Case report and review of literature. Pathol Res Pract 2013; 209(2): 115– 119.

26. Yamazaki T, Ohno H. Double‑hit lymphoma with t(8;14)(q24;q32) and t(12;14)(q24;q32) chromosamal translocations. Intern Med 2011; 50(21): 2659– 2662.

27. Nacheva E, Fischer P, Karpas A et al. Complex translocation t(8;12;14) in a cell line derived from a child with nonendemic Burkitt‑type acute lymphoblastic leukemia. Cancer Genet Cytogenet 1987; 28(1): 145– 153.

28. Blenk S, Engelmann J, Weniger M et al. Germinal center B cell‑like (GCB) and activated B‑ cell‑like (ABC) type of diffuse large B cell lymphoma (DLBCL): analysis of molecular predictors, signatures, cell cycle state and patient survival. Cancer Informatics 2007; 3: 399– 420.

29. Morton LM, Purdue MP, Zheng T et al. Risk of non‑Hodgkin lymphoma associated with germline variation in genes that regulate the cell cycle, apoptosis, and lymphocyte development. Cancer Epidemiol Biomarkers Prev 2009; 18(4): 1259– 1270.

30. Kato L, Begum NA, Burroughs AM et al. Nonimmunoglobulin target loci of activation‑induced cytidine deaminase (AID) share unique features with immunoglobulin genes. Proc Natl Acad Sci USA 2012; 109(7): 2479– 2484.

31. Parker SM, Olteanu H, VanTuinen P et al. Follicular lymphoma transformation to dual translocated Burkitt‑like lymphoma: improved disease control associated with radiation therapy. In J Haematol 2009; 90(5): 616– 622.

32. Xu X, Zhang L, Wang Y et al. Double‑hit nd triple‑ hit lymphomas arising from follicular lymphoma following acquisition of MYC: report of two cases and litarture review. Int J Clin Exp Pathol 2013; 6(4): 788– 794.

33. Hwang YY, Loong F, Chung LP et al. Atypical burkitt’s lymphoma transforming from follicular lymphoma. Diagn Pathol 2011; 6: 63– 69.

34. Kobayashi H, Ichikawa M, Hangaiashi A et al. Concurrent development of the „Burkitt‑like“ lymphoma and BCL‑ 2- rearranged low‑ grade B cell lymphoma sharing the same germinal center origin. Int J Hematol 2011; 93(1): 112– 117.

35. Felten CL, Stephenson CF, Ortiz RO et al. Burkitt transformation of mantle cell lymphoma. Leuk Lymph 2004; 45(10): 2143– 2147.

36. Friedberg JW. Double‑hit diffuse large B‑ cell lymphoma. J Clin Oncol 2012; 30(28): 3439– 3443.

37. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008; 112(5): 1570– 1580.