Clinical significance of cytogenetic aberrations in bone marrow of patients with diffuse large B-cell lymphoma: prognostic significance and relevance to histologic involvement

Journal of Hematology & Oncology

Dong Soon Lee³  Cheolwon Suh¹  Sung-Soo Yoon²  Tae Min Kim²  Hyeon Seok Eom⁷  Jin Seok Kim⁵  Hye Jin Kang⁴  Hyo Jung Kim⁶  Seon Young Kim³ 

[1] Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbeongwon-gil, Songpa-gu, Seoul 138-736, Republic of Korea;Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea;Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea;Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea;Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea;Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea;Hematology-Oncology Clinic, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea

关键词: Prognosis;    Bone marrow involvement;    Chromosomal abnormalities;    Cytogenetics;    Diffuse large B-cell lymphoma;   

Others  :  802954
DOI  :  10.1186/1756-8722-6-76

 received in 2013-08-12, accepted in 2013-09-30,  发布年份 2013

【 摘 要 】

Background

Although knowledge of the genetics of diffuse large B-cell lymphoma (DLBCL) has been increasing, little is known about the characteristics and prognostic significance of cytogenetic abnormalities and the clinical utility of cytogenetic studies performed on bone marrow (BM) specimens. To investigate the significance of isolated cytogenetic aberrations in the absence of histologic BM involvement, we assessed the implication of cytogenetic staging and prognostic stratification by a retrospective multicenter analysis of newly diagnosed DLBCL patients.

Methods

We analyzed cytogenetic and clinical data from 1585 DLBCL patients whose BM aspirates had been subjected to conventional karyotyping for staging. If available, interphase fluorescence in situ hybridization (FISH) data were also collected from patients.

Results

Histologic BM involvement were found in 259/1585 (16.3%) patients and chromosomal abnormalities were detected in 192 (12.1%) patients (54 patients with single abnormalities and 138 patients with 2 or more abnormalities). Isolated cytogenetic aberrations (2 or more abnormalities) without histologic involvement were found in 21 patients (1.3%). Two or more cytogenetic abnormalities were associated with inferior overall survival (OS) compared with a normal karyotype or single abnormality in both patients with histologic BM involvement (5-year OS, 22.0% vs. 52.7%; P < 0.001) and those without BM involvement (31.8% vs. 66.5%; P < 0.001). This result demonstrated that BM cytogenetic results have a significant prognostic impact that is independent of BM histology. The following abnormalities were most frequently observed: rearrangements involving 14q32, 19q13, 19p13, 1p, 3q27, and 8q24; del(6q); dup(1q); and trisomy 18. In univariate analysis, several specific abnormalities including abnormalities at 16q22-q24, 6p21-p25, 12q22-q24, and -17 were associated with poor prognosis. Multivariate analyses performed for patients who had either chromosomal abnormalities or histologic BM involvement, revealed IPI high risk, ≥ 2 cytogenetic abnormalities, and several specific chromosomal abnormalities, including abnormalities at 19p13, 12q22-q24, 8q24, and 19q13 were significantly associated with a worse prognosis.

Conclusions

We suggest that isolated cytogenetic aberrations can be regarded as BM involvement and cytogenetic evaluation of BM improves staging accuracy along with prognostic information for DLBCL patients.

【 授权许可】

   
2013 Kim et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Anon : A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997, 89:3909-3918.
• [2]Shipp MA, Harrington DP, Anderson JR, Armitage JO, B G: A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993, 329:987-994.
• [3]Campbell J, Seymour JF, Matthews J, Wolf M, Stone J, Juneja S: The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement. Eur J Haematol 2006, 76:473-480.
• [4]Chung R, Lai R, Wei P, Lee J, Hanson J, Belch AR, Turner AR, Reiman T: Concordant but not discordant bone marrow involvement in diffuse large B-cell lymphoma predicts a poor clinical outcome independent of the International Prognostic Index. Blood 2007, 110:1278-1282.
• [5]Gomyo H, Shimoyama M, Minagawa K, Yakushijin K, Urahama N, Okamura A, Yamamoto K, Ito M, Chihara K, Hayashi Y, Matsui T: Morphologic, flow cytometric and cytogenetic evaluation of bone marrow involvement in B-cell lymphoma. Haematol 2003, 88:1358-1365.
• [6]Talaulikar D, Shadbolt B, Dahlstrom JE, McDonald A: Routine use of ancillary investigations in staging diffuse large B-cell lymphoma improves the International Prognostic Index (IPI). J Hematol Oncol 2009, 2:49. BioMed Central Full Text
• [7]Merli M, Arcaini L, Boveri E, Rattotti S, Picone C, Passamonti F, Tenore A, Sozzani L, Lucioni M, Varettoni M, et al.: Assessment of bone marrow involvement in non-Hodgkin's lymphomas: comparison between histology and flow cytometry. Eur J Haematol 2010, 85:405-415.
• [8]Lenz G, Staudt LM: Aggressive lymphomas. N Engl J Med 2010, 362:1417-1429.
• [9]Swerdlow SH, International Agency for Research on Cancer., World Health Organization: WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edition. Lyon, France: International Agency for Research on Cancer; 2008.
• [10]Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, et al.: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004, 103:275-282.
• [11]Thiele J, Zirbes TK, Kvasnicka HM, Fischer R: Focal lymphoid aggregates (nodules) in bone marrow biopsies: differentiation between benign hyperplasia and malignant lymphoma–a practical guideline. J Clin Pathol 1999, 52:294-300.
• [12]Shaffer LG, Slovak ML, Campbell LJ, International Standing Committee on Human Cytogenetic Nomenclature: ISCN 2009 : an international system for human cytogenetic nomenclature (2009). Basel ; Unionville, CT: Karger; 2009.
• [13]Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000, 96:4075-4083.
• [14]Gohring G, Michalova K, Beverloo HB, Betts D, Harbott J, Haas OA, Kerndrup G, Sainati L, Bergstraesser E, Hasle H, et al.: Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 2010, 116:3766-3769.
• [15]Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH, Nieuwint A, Jotterand M, Hagemeijer A, Beverloo HB, Lowenberg B: Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008, 26:4791-4797.
• [16]Vaidya R, Caramazza D, Begna KH, Gangat N, Van Dyke DL, Hanson CA, Pardanani A, Tefferi A: Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood 2011, 117:5612-5615.
• [17]Ciolino AL, Tang ME, Bryant R: Statistical treatment of fluorescence in situ hybridization validation data to generate normal reference ranges using Excel functions. J Mol Diagn 2009, 11:330-333.
• [18]Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 2007, 25:579-586.
• [19]Mitterbauer-Hohendanner G, Mannhalter C, Winkler K, Mitterbauer M, Skrabs C, Chott A, Simonitsch-Klupp I, Gleiss A, Lechner K, Jaeger U: Prognostic significance of molecular staging by PCR-amplification of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma (DLBCL). Leuk 2004, 18:1102-1107.
• [20]Tierens AM, Holte H, Warsame A, Ikonomou IM, Wang J, Chan WC, Delabie J: Low levels of monoclonal small B cells in the bone marrow of patients with diffuse large B-cell lymphoma of activated B-cell type but not of germinal center B-cell type. Haematol 2010, 95:1334-1341.
• [21]Gohring G, Giagounidis A, Busche G, Hofmann W, Kreipe HH, Fenaux P, Hellstrom-Lindberg E, Schlegelberger B: Cytogenetic follow-up by karyotyping and fluorescence in situ hybridization: implications for monitoring patients with myelodysplastic syndrome and deletion 5q treated with lenalidomide. Haematol 2011, 96:319-322.
• [22]United Kingdom Cancer Cytogenetics Group (UKCCG): Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosomes Cancer 1992, 5:83-88.
• [23]Van Dyke DL, Wiktor A: Monosomy 21 in hematologic diseases. Cancer Genet Cytogenet 2003, 142:137-141.
• [24]Gupta R, Soupir CP, Johari V, Hasserjian RP: Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation. Br J Haematol 2007, 139:265-268.
• [25]Giardino D, Corti C, Ballarati L, Colombo D, Sala E, Villa N, Piombo G, Pierluigi M, Faravelli F, Guerneri S, et al.: De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn 2009, 29:257-265.
• [26]Pasantes JJ, Wimmer R, Knebel S, Munch C, Kelbova C, Junge A, Kieback P, Kupferling P, Schempp W: 47, X, idic(Y), inv dup(Y): a non-mosaic case of a phenotypically normal boy with two different Y isochromosomes and neocentromere formation. Cytogenet Genome Res 2012, 136:157-162.
• [27]Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V, Burek C, Ott G, Puig X, Yang L, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 2005, 106:3183-3190.
• [28]Campbell LJ: Cytogenetics of lymphomas. Pathol 2005, 37:493-507.
• [29]Salido M, Baro C, Oscier D, Stamatopoulos K, Dierlamm J, Matutes E, Traverse-Glehen A, Berger F, Felman P, Thieblemont C, et al.: Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group. Blood 2010, 116:1479-1488.
• [30]Fleischman EW, Prigogina EL, Ilynskaya GW, Probatova NA, Konstantinova LN, Kruglova GV, Volkova MA, Osmanov DS: Chromosomal characteristics of malignant lymphoma. Hum Genet 1989, 82:343-348.
• [31]Hashimoto K, Miura I, Chyubachi A, Saito M, Miura AB: Correlations of chromosome abnormalities with histologic and immunologic characteristics in 49 patients from Akita, Japan with non-Hodgkin lymphoma. Cancer Genet Cytogenet 1995, 81:56-65.
• [32]Whang-Peng J, Knutsen T, Jaffe ES, Steinberg SM, Raffeld M, Zhao WP, Duffey P, Condron K, Yano T, Longo DL: Sequential analysis of 43 patients with non-Hodgkin's lymphoma: clinical correlations with cytogenetic, histologic, immunophenotyping, and molecular studies. Blood 1995, 85:203-216.
• [33]Jerkeman M, Johansson B, Akerman M, Cavallin-Stahl E, Kristoffersson U, Mitelman F: Prognostic implications of cytogenetic aberrations in diffuse large B-cell lymphomas. Eur J Haematol 1999, 62:184-190.
• [34]Dave BJ, Nelson M, Pickering DL, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Sanger WG: Cytogenetic characterization of diffuse large cell lymphoma using multi-color fluorescence in situ hybridization. Cancer Genet Cytogenet 2002, 132:125-132.
• [35]Nanjangud G, Rao PH, Hegde A, Teruya-Feldstein J, Donnelly G, Qin J, Jhanwar SC, Zelenetz AD, Chaganti RS: Spectral karyotyping identifies new rearrangements, translocations, and clinical associations in diffuse large B-cell lymphoma. Blood 2002, 99:2554-2561.
• [36]Yoshioka T, Miura I, Kume M, Takahashi N, Okamoto M, Ichinohasama R, Yoshino T, Yamaguchi M, Hirokawa M, Sawada K, Nakamura S: Cytogenetic features of de novo CD5-positive diffuse large B-cell lymphoma: chromosome aberrations affecting 8p21 and 11q13 constitute major subgroups with different overall survival. Genes Chromosomes Cancer 2005, 42:149-157.
• [37]Monni O, Joensuu H, Franssila K, Knuutila S: DNA copy number changes in diffuse large B-cell lymphoma–comparative genomic hybridization study. Blood 1996, 87:5269-5278.
• [38]Berglund M, Enblad G, Flordal E, Lui WO, Backlin C, Thunberg U, Sundstrom C, Roos G, Allander SV, Erlanson M, et al.: Chromosomal imbalances in diffuse large B-cell lymphoma detected by comparative genomic hybridization. Mod Pathol 2002, 15:807-816.
• [39]Bea S, Colomo L, Lopez-Guillermo A, Salaverria I, Puig X, Pinyol M, Rives S, Montserrat E, Campo E: Clinicopathologic significance and prognostic value of chromosomal imbalances in diffuse large B-cell lymphomas. J Clin Oncol 2004, 22:3498-3506.
• [40]Tagawa H, Suguro M, Tsuzuki S, Matsuo K, Karnan S, Ohshima K, Okamoto M, Morishima Y, Nakamura S, Seto M: Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. Blood 2005, 106:1770-1777.
• [41]Scandurra M, Mian M, Greiner TC, Rancoita PM, De Campos CP, Chan WC, Vose JM, Chigrinova E, Inghirami G, Chiappella A, et al.: Genomic lesions associated with a different clinical outcome in diffuse large B-Cell lymphoma treated with R-CHOP-21. Br J Haematol 2010, 151:221-231.
• [42]Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, et al.: Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood 1999, 94:3114-3120.
• [43]Paulsson K, Jonson T, Ora I, Olofsson T, Panagopoulos I, Johansson B: Characterisation of genomic translocation breakpoints and identification of an alternative TCF3/PBX1 fusion transcript in t(1;19)(q23;p13)-positive acute lymphoblastic leukaemias. Br J Haematol 2007, 138:196-201.
• [44]Calin GA, Croce CM: MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene 2006, 25:6202-6210.
• [45]Scholtysik R, Nagel I, Kreuz M, Vater I, Giefing M, Schwaenen C, Wessendorf S, Trumper L, Loeffler M, Siebert R, Kuppers R: Recurrent deletions of the TNFSF7 and TNFSF9 genes in 19p13.3 in diffuse large B-cell and Burkitt lymphomas. Int J Cancer 2012, 131:E830-835.
• [46]Young KH, Leroy K, Moller MB, Colleoni GW, Sanchez-Beato M, Kerbauy FR, Haioun C, Eickhoff JC, Young AH, Gaulard P, et al.: Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008, 112:3088-3098.
• [47]Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, Dyer MJ, Siebert R, Kuruvilla J, Klasa R, et al.: Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009, 114:2273-2279.
• [48]Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, Horsman DE, Gascoyne RD: MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood 2009, 114:3533-3537.
• [49]Tibiletti MG, Martin V, Bernasconi B, Del Curto B, Pecciarini L, Uccella S, Pruneri G, Ponzoni M, Mazzucchelli L, Martinelli G, et al.: BCL2, BCL6, MYC, MALT 1, and BCL10 rearrangements in nodal diffuse large B-cell lymphomas: a multicenter evaluation of a new set of fluorescent in situ hybridization probes and correlation with clinical outcome. Hum Pathol 2009, 40:645-652.
• [50]Kremer M, Spitzer M, Mandl-Weber S, Stecker K, Schmidt B, Hofler H, Quintanilla-Martinez L, Fend F: Discordant bone marrow involvement in diffuse large B-cell lymphoma: comparative molecular analysis reveals a heterogeneous group of disorders. Lab Invest 2003, 83:107-114.
• [51]Chigrinova E, Mian M, Scandurra M, Greiner TC, Chan WC, Vose JM, Inghirami G, Chiappella A, Baldini L, Ponzoni M, et al.: Diffuse large B-cell lymphoma with concordant bone marrow involvement has peculiar genomic profile and poor clinical outcome. Hematol Oncol 2011, 29:38-41.