Top

Published in:

Open Access 01-07-2009 | Original Article

Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network

Authors: Wolfram Klapper, Eva Hoster, Olaf Determann, Ilske Oschlies, Jeroen van der Laak, Françoise Berger, Heinz Wolfram Bernd, José Cabeçadas, Elias Campo, Sergio Cogliatti, Martin Leo Hansmann, Philip M. Kluin, Roman Kodet, Yuri A. Krivolapov, Christoph Loddenkemper, Harald Stein, Peter Möller, Thomas E. F. Barth, Konrad Müller-Hermelink, Andreas Rosenwald, German Ott, Stefano Pileri, Elisabeth Ralfkiaer, Grzegorz Rymkiewicz, Johan H. van Krieken, Hans Heinrich Wacker, Michael Unterhalt, Wolfgang Hiddemann, Martin Dreyling, for the European MCL Network

Published in: Journal of Hematopathology | Issue 2/2009

Abstract

Mantle cell lymphoma (MCL) has a heterogeneous clinical course and is mainly an aggressive B cell non-Hodgkin lymphoma; however, there are some indolent cases The Ki-67 index, defined by the percentage of Ki-67-positive lymphoma cells on histopathological slides, has been shown to be a very powerful prognostic biomarker. The pathology panel of the European MCL Network evaluated methods to assess the Ki-67 index including stringent counting, digital image analysis, and estimation by eyeballing. Counting of 2 × 500 lymphoma cells is the gold standard to assess the Ki-67 index since this value has been shown to predict survival in prospective randomized trials of the European MCL Network. Estimation by eyeballing and digital image analysis showed a poor concordance with the gold standard (concordance correlation coefficients [CCC] between 0.29 and 0.61 for eyeballing and CCC of 0.24 and 0.37 for two methods of digital image analysis, respectively). Counting a reduced number of lymphoma cells (2 × 100 cells) showed high interobserver agreement (CCC = 0.74). Pitfalls of the Ki-67 index are discussed and guidelines and recommendations for assessing the Ki-67 index in MCL are given.

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (2008) WHO classification of tumors of the haematopoietic and lymphoid tissues. IARC, Lyon

Bottcher S, Ritgen M, Buske S, Gesk S, Klapper W, Hoster E, Hiddemann W, Unterhalt M, Dreyling M, Siebert R, Kneba M, Pott C (2008) Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations. Haematologica 93:551–559PubMedCrossRef

Bottcher S, Ritgen M, Pott C, Bruggemann M, Raff T, Stilgenbauer S, Dohner H, Dreger P, Kneba M (2004) Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation. Leukemia 18:1637–1645PubMedCrossRef

Coleman KE, Brat DJ, Cotsonis GA, Lawson D, Cohen C (2006) Proliferation (MIB-1 expression) in oligodendrogliomas: assessment of quantitative methods and prognostic significance. Appl Immunohistochem Mol Morphol 14:109–114PubMedCrossRef

de Jong D, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W, Lee A, Sander B, Thorns C, Campo E, Molina T, Norton A, Hagenbeek A, Horning S, Lister A, Raemaekers J, Gascoyne RD, Salles G, Weller E (2007) 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 25:805–812PubMedCrossRef

Determann O, Hoster E, Ott G, Wolfram BH, Loddenkemper C, Leo HM, Barth TE, Unterhalt M, Hiddemann W, Dreyling M, Klapper W (2008) Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood 111:2385–2387PubMedCrossRef

Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, Metzner B, Truemper L, Reiser M, Steinhauer H, Boiron JM, Boogaerts MA, Aldaoud A, Silingardi V, Kluin-Nelemans HC, Hasford J, Parwaresch R, Unterhalt M, Hiddemann W (2005) Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 105:2677–2684PubMedCrossRef

Fernandez V, Hartmann E, Ott G, Campo E, Rosenwald A (2005) Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. J Clin Oncol 23:6364–6369PubMedCrossRef

Hoster E, Dreyling M, Klapper W, Gisselbrecht C, Van Hoof A, Kluin-Nelemans HC, Pfreundschuh M, Reiser M, Metzner B, Einsele H, Peter N, Jung W, Wormann B, Ludwig WD, Duhrsen U, Eimermacher H, Wandt H, Hasford J, Hiddemann W, Unterhalt M (2008) A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111:558–565PubMedCrossRef

10.

Jaffe E, Harris N, Stein H, Vardiman JW (2001) Pathology and genetics of tumours of haematopoetic and lymphoid tissues. IARC, Lyon, France

11.

Katzenberger T, Petzoldt C, Holler S, Mader U, Kalla J, Adam P, Ott MM, Muller-Hermelink HK, Rosenwald A, Ott G (2006) The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood 107:3407PubMedCrossRef

12.

Lenz G, Dreyling M, Hiddemann W (2004) Mantle cell lymphoma: established therapeutic options and future directions. Ann Hematol 83:71–77PubMedCrossRef

13.

Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W (2005) Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23:1984–1992PubMedCrossRef

14.

Lenz G, Dreyling M, Schiegnitz E, Forstpointner R, Wandt H, Freund M, Hess G, Truemper L, Diehl V, Kropff M, Kneba M, Schmitz N, Metzner B, Pfirrmann M, Unterhalt M, Hiddemann W (2004) Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study. Blood 104:2667–2674PubMedCrossRef

15.

Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, Murphy EJ, Koduru P, Ferrarini M, Zupo S, Cutrona G, Damle RN, Wasil T, Rai KR, Hellerstein MK, Chiorazzi N (2005) In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 115:755–764PubMed

16.

Rosenwald A, Wright G, Wiestner A, Chan WC, Connors JM, Campo E, Gascoyne RD, Grogan TM, Muller-Hermelink HK, Smeland EB, Chiorazzi M, Giltnane JM, Hurt EM, Zhao H, Averett L, Henrickson S, Yang L, Powell J, Wilson WH, Jaffe ES, Simon R, Klausner RD, Montserrat E, Bosch F, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Fisher RI, Miller TP, LeBlanc M, Ott G, Kvaloy S, Holte H, Delabie J, Staudt LM (2003) The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 3:185–197PubMedCrossRef

17.

Schrader C, Janssen D, Klapper W, Siebmann JU, Meusers P, Brittinger G, Kneba M, Tiemann M, Parwaresch R (2005) Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma. Br J Cancer 93:939–945PubMedCrossRef

18.

Schrader C, Janssen D, Meusers P, Brittinger G, Siebmann JU, Parwaresch R, Tiemann M (2005) Repp 86: a new prognostic marker in mantle cell lymphoma. Eur J Haematol 75:498–504PubMedCrossRef

19.

Schrader C, Meusers P, Brittinger G, Teymoortash A, Siebmann JU, Janssen D, Parwaresch R, Tiemann M (2004) Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome. Leukemia 18:1200–1206PubMedCrossRef

20.

Stanton KJ, Sidner RA, Miller GA, Cummings OW, Schmidt CM, Howard TJ, Wiebke EA (2003) Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas. Am J Surg 186:486–492PubMedCrossRef

21.

Tiemann M, Schrader C, Klapper W, Dreyling MH, Campo E, Norton A, Berger F, Kluin P, Ott G, Pileri S, Pedrinis E, Feller AC, Merz H, Janssen D, Hansmann ML, Krieken H, Moller P, Stein H, Unterhalt M, Hiddemann W, Parwaresch R (2005) Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol 131:29–38PubMedCrossRef

22.

Zhang K, Prichard JW, Yoder S, De J, Lin F (2007) Utility of SKP2 and MIB-1 in grading follicular lymphoma using quantitative imaging analysis. Hum Pathol 38:878–882PubMedCrossRef

Title: Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network
Authors: Wolfram Klapper
Eva Hoster
Olaf Determann
Ilske Oschlies
Jeroen van der Laak
Françoise Berger
Heinz Wolfram Bernd
José Cabeçadas
Elias Campo
Sergio Cogliatti
Martin Leo Hansmann
Philip M. Kluin
Roman Kodet
Yuri A. Krivolapov
Christoph Loddenkemper
Harald Stein
Peter Möller
Thomas E. F. Barth
Konrad Müller-Hermelink
Andreas Rosenwald
German Ott
Stefano Pileri
Elisabeth Ralfkiaer
Grzegorz Rymkiewicz
Johan H. van Krieken
Hans Heinrich Wacker
Michael Unterhalt
Wolfgang Hiddemann
Martin Dreyling
for the European MCL Network
Publication date: 01-07-2009
Publisher: Springer-Verlag
Published in: Journal of Hematopathology / Issue 2/2009
Print ISSN: 1868-9256
Electronic ISSN: 1865-5785
DOI: https://doi.org/10.1007/s12308-009-0036-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Ki-67 as a prognostic marker in mantle cell lymphoma—consensus guidelines of the pathology panel of the European MCL Network

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2009

Commentary on the WHO classification of tumors of lymphoid tissues (2008): indolent B cell lymphomas

The 2008 WHO-classification: small and big changes!

Commentary on the 2008 WHO classification of mature T- and NK-cell neoplasms

Commentary on the WHO classification of tumors of lymphoid tissues (2008): “Gray zone” lymphomas overlapping with Burkitt lymphoma or classical Hodgkin lymphoma

Epstein–Barr virus-associated inflammatory pseudotumor of the spleen: report of two cases and review of the literature

T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary