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

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.

[1]  O. Cummings,et al.  Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas. , 2003, American journal of surgery.

[2]  P. Vyas,et al.  Pathology and genetics: Tumours of haematopoietic and lymphoid tissues , 2001 .

[3]  H. Döhner,et al.  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 , 2004, Leukemia.

[4]  Marc K Hellerstein,et al.  In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. , 2005, The Journal of clinical investigation.

[5]  Daniel J Brat,et al.  Proliferation (MIB-1 Expression) in Oligodendrogliomas: Assessment of Quantitative Methods and Prognostic Significance , 2006, Applied immunohistochemistry & molecular morphology : AIMM.

[6]  G. Brittinger,et al.  Repp86: a new prognostic marker in mantle cell lymphoma , 2005, European journal of haematology.

[7]  L. Staudt,et al.  The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. , 2003, Cancer cell.

[8]  Andrew Lister,et al.  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. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  W. Klapper,et al.  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 , 2008, Haematologica.

[10]  A. Rosenwald,et al.  Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  W. Klapper,et al.  Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma , 2005, British Journal of Cancer.

[12]  Martin Dreyling,et al.  A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. , 2006, Blood.

[13]  V. Diehl,et al.  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 Group. , 2004, Blood.

[14]  E. Hoster,et al.  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 Germa , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  W. Hiddemann,et al.  Mantle cell lymphoma: established therapeutic options and future directions , 2004, Annals of Hematology.

[16]  G. Brittinger,et al.  Topoisomerase IIα expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome , 2004, Leukemia.

[17]  Kai Zhang,et al.  Utility of SKP2 and MIB-1 in grading follicular lymphoma using quantitative imaging analysis. , 2007, Human pathology.

[18]  A. Rosenwald,et al.  The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. , 2006, Blood.

[19]  N. Shinton.  WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues , 2007 .

[20]  E. Hoster,et al.  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. , 2004, Blood.

[21]  W. Klapper,et al.  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. , 2008, Blood.

[22]  W. Klapper,et al.  Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network , 2005, British journal of haematology.