Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Lymphocytic Leukemia

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays

Leukemia volume 26, pages 499–508 (2012)Cite this article

Abstract

To better define the significance of proliferation centers (PCs), the morphological hallmark of chronic lymphocytic leukemia (CLL), lymph node biopsies taken from 183 patients were submitted to histopathologic and fluorescence in situ hybridization (FISH) studies using a 5-probe panel on tissue microarrays. Seventy-five cases (40.9%) with confluent PCs were classified as ‘PCs-rich’ and 108 cases (59.1%) with scattered PCs were classified as ‘typical’. Complete FISH data were obtained in 101 cases (55.1%), 79 of which (78.2%) displayed at least one chromosomal aberration. The incidence of each aberration was: 13q- 36,7%, 14q32 translocations 30.8%, 11q- 24.7%, trisomy 12 19.5% and 17p- 15.6%. Five cases showed extra copies of the 14q32 region. The ‘PCs-rich’ group was associated with 17p-, 14q32/IgH translocation, +12, Ki-67>30%. The median survival from the time of tissue biopsy for PCs-rich and typical groups was 11 and 64 months, respectively (P=0.00001). The PCs-rich pattern was the only predictive factor of an inferior survival at multivariate analysis (P=0.022). These findings establish an association between cytogenetic profile and the amount of PC in CLL, and show that this histopathologic characteristic is of value for risk assessment in patients with clinically significant adenopathy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990; 323: 720–724.

    Article  CAS  PubMed  Google Scholar 

  2. Stilgenbauer S, Bullinger L, Lichter P, Döhner H . Chronic lymphocytic leukemia. Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia 2002; 16: 993–1007.

    Article  CAS  PubMed  Google Scholar 

  3. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  PubMed  Google Scholar 

  4. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    PubMed  Google Scholar 

  5. Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997; 89: 2516–2522.

    PubMed  Google Scholar 

  6. Offit K, Louie DC, Parsa NZ, Filippa D, Gangi M, Siebert R et al. Clinical and morphologic features of B-cell small lymphocytic lymphoma with del(6)(q21q23). Blood 1994; 83: 2611–2618.

    CAS  PubMed  Google Scholar 

  7. Stilgenbauer S, Bullinger L, Benner A, Wildenberger K, Bentz M, Döhner K et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia 1999; 13: 1331–1334.

    Article  CAS  PubMed  Google Scholar 

  8. Cuneo A, Rigolin GM, Bigoni R, De Angeli C, Veronese A, Cavazzini F et al. Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis. Leukemia 2004; 18: 476–483.

    Article  CAS  PubMed  Google Scholar 

  9. Cavazzini F, Hernandez JA, Gozzetti A, Russo Rossi A, De Angeli C, Tiseo R et al. Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis. Br J Haematol 2008; 142: 529–537.

    Article  PubMed  Google Scholar 

  10. Haferlach C, Dicker F, Weiss T, Schnittger S, Beck C, Grote-Metke A et al. Toward a comprehensive prognostic scoring system in chronic lymphocytic leukemia based on a combination of genetic parameters. Genes Chromosomes Cancer 2010; 49: 851–859.

    CAS  PubMed  Google Scholar 

  11. Müller-Hermelink HK, Montserrat E, Catovsky D, Campo E, Harris NL, Stein H . Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe E, Pileri SA, Stein H, Thiele J, Vardimin JW (eds). WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, 4th edn IARC (International Agency for Research on Cancer): Lyon, 2008, pp 180–184.

    Google Scholar 

  12. Schmid C, Isaacson PG . Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology 1994; 24: 445–451.

    Article  CAS  PubMed  Google Scholar 

  13. Caligaris-Cappio F . Role of the microenviroment in chronic lymphocitic leukemia. Br J Haematol 2003; 123: 380–388.

    Article  PubMed  Google Scholar 

  14. Caligaris-Cappio F, Ghia P . Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol 2008; 26: 4497–4503.

    Article  CAS  PubMed  Google Scholar 

  15. Ben-Ezra J, Burke JS, Swartz WG, Brownell MD, Brynes RK, Hill LR et al. Small lymphocytic lymphoma: a clinicopathological analysis of 268 cases. Blood 1989; 73: 579–587.

    CAS  PubMed  Google Scholar 

  16. Asplund SL, McKenna RW, Howard MS, Kroft SH . Immunophenotype does not correlate with lymph node histology in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Surg Pathol 2002; 26: 624–629.

    Article  PubMed  Google Scholar 

  17. Swerdlow SH, Murray LJ, Habeshaw JA, Stansfeld AG . Lymphocytic lymphoma/B-chronic lymphocytic leukaemia: an immunohistopathological study of peripheral B lymphocyte neoplasia. Br J Cancer 1984; 50: 587–599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gin E, Martinez A, Villamor N, López-Guillermo A, Camos M, Martinez D et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (‘accelerated’ chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 2010; 95: 1526–1533.

    Article  Google Scholar 

  19. Ventura RA, Martin-Subero JI, Jones M, McParland J, Gesk S, Mason DY et al. FISH analysis for the detection of lymphoma-associated chromosomal abnormalities in routine paraffin-embedded tissue. J Mol Diagn 2006; 8: 141–151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Matsumoto Y, Nomura K, Matsumoto S, Ueda K, Nakao M, Nishida K et al. Detection of t(14;18) in follicular lymphoma by dual-color fluorescence in situ hybridization on paraffin-embedded tissue sections. Cancer Genet Cytogenet 2004; 150: 22–26.

    Article  CAS  PubMed  Google Scholar 

  21. Voduc D, Kenney C, Nielsen TO . Tissue microarrays in clinical oncology. Semin Radiat Oncol 2008; 18: 89–97.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O′Brien S et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  23. Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008; 142: 202–215.

    Article  CAS  PubMed  Google Scholar 

  24. Bubendorf L, Nocito A, Moch H, Sauter G . Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol 2001; 195: 72–79.

    Article  CAS  PubMed  Google Scholar 

  25. Brown LA, Huntsman D . Fluorescent in situ hybridization on tissue microarrays: challenges and solutions. J Mol Histol 2007; 38: 151–157.

    Article  CAS  PubMed  Google Scholar 

  26. Wlodarska I, Matthews C, Veyt E, Pospisilova H, Catherwood MA, Poulsen TS et al. Telomeric IGH losses detectable by fluorescence in situ hybridization in chronic lymphocitic leukemia reflect somatic VH recombination events. J Mol Diagn 2007; 9: 47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Meier C, Hoeller S, Bourgau C, Hirschmann P, Schwaller J, Went P et al. Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas. Mod Pathol 2009; 22: 476–487.

    Article  CAS  PubMed  Google Scholar 

  28. Rossi D, Berra E, Cerri M, Deambrogi C, Barbieri C, Franceschetti S et al. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma. Haematologica 2006; 91: 1405–1409.

    CAS  PubMed  Google Scholar 

  29. Flanagan MB, Sathanoori M, Surti U, Soma L, Swerdlow SH . Cytogenetic abnormalities detected by fluorescence in situ hybridization on paraffin-embedded chronic lymphocytic leukaemia/small lymphocytic lymphoma lymphoid tissue biopsy specimens. Am J Clin Pathol 2008; 130: 620–627.

    Article  PubMed  Google Scholar 

  30. Caraway NP, Thomas E, Khanna A, Payne L, Zhang HZ, Lin E et al. Chromosomal abnormalities detected by multicolr fluorescence in situ hybridization in fine-needle aspirates from patients with small lymphocytic lymphoma are useful for predicting survival. Cancer 2008; 114: 315–322.

    Article  PubMed  Google Scholar 

  31. Dagklis A, Fazi C, Sala C, Cantarelli V, Scielzo C, Massacane R et al. The immunoglobulin gene repertoire of low-count chronic lymphocytic leukemia (CLL)-like monoclonal B lymphocytosis is different from CLL: diagnostic implications for clinical monitoring. Blood 2009; 114: 26–32.

    Article  CAS  PubMed  Google Scholar 

  32. Del Giudice I, Chiaretti S, Tavolaro S, De Propris MS, Maggio R, Mancini F et al. Spontaneous regression of chronic lymphocytic leukemia: clinical e biological features of 9 cases. Blood 2009; 114: 638–646.

    Article  CAS  PubMed  Google Scholar 

  33. Dal-Bo M, Del Giudice I, Bomben R, Capello D, Bertoni F, Forconi F et al. B- cell receptor, clinical course and prognosis in chronic lymphocytic leukemia: the growing saga of IGHV3 subgroup gene usage. Br J Haematol 2011; 153: 3–14.

    Article  CAS  PubMed  Google Scholar 

  34. Zenz T, Döhner H, Stilgenbauer S . Genetics and risk-stratified approach to therapy in chronic lymphocytic leukemia. Best Pract Res Clin Haematol 2007; 20: 439–453.

    Article  CAS  PubMed  Google Scholar 

  35. Byrd JC, Stilgenbauer S, Flinn IW . Chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program 2004, 163–183.

    Article  Google Scholar 

  36. Liso V, Capalbo S, Lapietra A, Pavone V, Guarini A, Specchia G . Evaluation of trisomy 12 by fluorescence in situ hybridization in peripheral blood, bone marrow and lymph nodes of patients with B-cell chronic lymphocytic leukemia. Haematologica 1999; 84: 212–217.

    CAS  PubMed  Google Scholar 

  37. Juliusson G, Friberg K, Gahrton G . Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients. Cancer 1988; 62: 500–506.

    Article  CAS  PubMed  Google Scholar 

  38. Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Cavazzini F et al. Late appearance of the 11q22.3-23.1 deletion involving the ATM locus in B-cell chronic lymphocytic leukemia and related disorders. Clinico-biological significance. Haematologica 2002; 87: 44–51.

    CAS  PubMed  Google Scholar 

  39. Stilgenbauer S, Sander S, Bullinger L, Benner A, Leupolt E, Winkler D et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica 2007; 92: 1242–1245.

    Article  PubMed  Google Scholar 

  40. Cuneo A, Bardi A, Wlodarska I, Selleslag D, Roberti MG, Bigoni R et al. A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B cell lymphoma. Leukemia 2001; 15: 1262–1267.

    Article  CAS  PubMed  Google Scholar 

  41. Aoun P, Blair HE, Smith LM, Dave BJ, Lynch J, Weisenburger DD et al. Fluorescence in situ hybridization detection of cytogenetic abnormalities in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma 2004; 45: 1595–1603.

    Article  CAS  PubMed  Google Scholar 

  42. Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L et al. Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 1997; 11: 747–758.

    Article  CAS  PubMed  Google Scholar 

  43. Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B et al. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci USA 2004; 101: 1039–1044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wright SM, Woo YH, Alley TL, Shirley BJ, Akeson EC, Snow KJ et al. Complex oncogenic translocations with gene amplification are initiated by specific DNA breaks in lymphocytes. Cancer Res 2009; 69: 4454–4460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood 2011; 117: 3391–3401.

    Article  CAS  PubMed  Google Scholar 

  46. Badoux XC, Keating MJ, Wang X, O′Brien SM, Ferrajoli A, Faderl S et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 2011; 117: 3016–3024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 2010; 116: 2438–2447.

    Article  CAS  PubMed  Google Scholar 

  48. Michallet M, Sobh M, Milligan D, Morisset S, Niederwieser D, Koza V et al. The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry. Leukemia 2010; 24: 1725–1731.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by funding from AIL-FE, AIRC regional grants, MIUR (PRIN), by Emilia Romagna regional grants to AC and by grants from: 1) the Associazione Italiana Ricerca contro il Cancro (AIRC, Milan, Italy), including the Special Program Molecular Clinical Oncology, 5‰, No. 10007 (SAP) and 2) Interdepartmental Centre for Cancer Research ‘Giorgio Prodi’ (Bologna, Italy). LR is supported by AIL-FE. We thank the following clinicians who provided follow-up data: Giampiero Bellesi (Firenze), Bruno Benci (Arezzo), Cinzia Bonanno (Palermo), Nicola Cantore (Benevento), Stefania Ciolli (Firenze), Alfonso Maria D’Arco (Nocera Inferiore), Maurizio Martelli (Roma), Roberto Ranalli (Sulmona), Alfonso Zaccaria (Ravenna), Francesco Zaja (Udine), Alberto Grossi (Firenze), Alberto Fragasso (Matera), Vallone Roberto (BN), Fortunato Morabito (Cosenza), Guglielo Mariani (AQ), Roberto Ranalli (Sulmona) and Paolo Vivaldi (TN).

Author information

Author notes

  1. A Cuneo and S Pileri: These authors contributed equally to this paper.

Authors and Affiliations

  1. Department of Biomedical Sciences, Hematology Section, S.Anna Hospital, University of Ferrara, Ferrara, Italy

    M Ciccone, G M Rigolin, F Cavazzini, O Sofritti, L Rizzotto, E Saccenti & A Cuneo

  2. Department of Hematology and Oncology ‘L. e A. Seragnoli’, Hematopathology Section, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    C Agostinelli, P P Piccaluga, S Righi, M T Sista, E Sabattini & S Pileri

  3. Department of Hematology, Civic Hospital, Pescara, Italy

    G Fioritoni & S Falorio

  4. Hematology Unit, Azienda Ospedaliero Bianchi-Melacrino-Morelli, Reggio Calabria, Italy

    C Stelitano

  5. Institute of Hematology and Bone Marrow Transplantation, Ospedale S. Carlo, Potenza, Italy

    A Olivieri & I Attolico

  6. Institute of Hematology, Ospedale Papardo, Messina, Italy

    M Brugiatelli

  7. Institute of Hematology ‘L. e A. Seragnoli’, University of Bologna, Bologna, Italy

    P L Zinzani

  8. Institute of Hematology, Università del Piemonte Orientale Amedeo Avogadro, Novara, Italy

    D Capello

  9. Department of Experimental Diagnostic, University of Ferrara, Ferrara, Italy

    M Negrini

Authors
  1. M Ciccone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Agostinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G M Rigolin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P P Piccaluga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Cavazzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Righi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M T Sista
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. O Sofritti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Rizzotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Sabattini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Fioritoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Falorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C Stelitano
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. I Attolico
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Brugiatelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. P L Zinzani
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. E Saccenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. D Capello
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. M Negrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. A Cuneo
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. S Pileri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Cuneo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Partially presented in abstract at the 15th annual meeting of the European Hematology Association.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciccone, M., Agostinelli, C., Rigolin, G. et al. Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays. Leukemia 26, 499–508 (2012). https://doi.org/10.1038/leu.2011.247

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.247

Keywords

Search

Advanced search

Quick links