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

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.

Fig. 1

Variability of Ki-67 eyeballing. Plot of Ki-67 values estimated by eyeballing by 11 experienced hematopathologists vs. Ki-67 values obtained via counting of 2 × 500 cells (gold standard). Each pathologist is represented by one color. In order to visualize identical estimation values corresponding to the same counting values, counting values are minimally scattered around the true values

Fig. 2

Interobserver agreement for Ki-67 assessment by counting 1 × 100 to 5 × 100 cells and using the average. The concordance correlation coefficient (CCC) was estimated with four raters on eight samples

Fig. 3

Areas of proliferating T cells in the case of a classical MCL. The MCL cells are characterized by CD20 expression and infiltrating T cells by staining for CD3. The Ki-67 index is higher in the T cell-rich area (corresponding areas are marked by an arrow). Double staining for CD20/Ki-67 of the T cell-rich area at a higher magnification shows numerous Ki-67 positive T cells (red) which are negative for the B cell marker CD20 (brown)

Fig. 4

Pitfalls in the selection of representative areas for the Ki-67 index in MCL. The upper panel shows two examples of Ki-67 staining. In the middle panel, residual germinal centers are marked by an arrow, hot spots of proliferation by an asterisk, and proliferating T cells by an arrowhead. In the lower panel, suggested representative areas for assessing the Ki-67 index are indicated by circles