Prognostic Impact of Tumor Microenvironment on Diffuse Large B-Cell Lymphoma Treated with R-CHOP
JC Gomez-Gelvez, M Salama, Chad Cogan, M Leavitt, K Inamdar. Henry Ford Hospital, Detroit, MI; University of Utah, Salt Lake City, UT
Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors with variable clinical behavior. Gene expression profiling studies have shown that tumor microenvironment plays a significant role in the prognosis of these patients. This study assessed the impact of regulatory T cells(T-regs), macrophages (M) and microvessel density (MVD) in the tumor microenvironment on the prognosis of DLBCL uniformly treated with R-CHOP.
Design: We reviewed 168 patients with DLBCL diagnosed between 01/99 and 12/08. Tissue microarrays (TMA) were prepared from 96 biopsy samples of patients treated with R-CHOP and were analyzed immunohistochemically for CD10, BCL6 and MUM-1; as well as CD34 for MVD, CD68 for M and FOXP3 for T-regs. The median follow-up period for surviving patients was 62.4 months. Stained TMA slides were scanned with a whole slide scanner (Aperio, Vista, CA). Digital images of were analyzed by algorithms built using specialized software (Aperio ImageScope) for the interpretation of MVD, M and T-regs. The performance of each marker in predicting overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) was evaluated by producing receiver operator characteristic (ROC) curves using simple logistic regression models. A prognostic predictor scoring system (PPSS) was built by assigning 1 point for each adverse prognostic factor (FOXP3+ T-regs ≥18%, CD68+ M <0.9% or ≥33 vessels with lumen/mm2). Cases with 0/1 points were classified as low risk and 2/3 points as high risk. OS, PFS and EFS were compared between risk groups using Kaplan Meier log-rank tests. Tests were considered significant at p<0.05. All analyses were performed using SAS 9.2.
Results: Using Hans algorithm DLBCL were categorized as GCB (47/92; 51%) or non-GCB subtype (45/92; 49%). In univariate analysis cases with FOXP3+ T-regs <18% (p=0.002), CD68+ M ≥ 0.9% (p=0.013) or low disease stage (I/II) (p=0.042) had better EFS. FOXP3+ T-cells <18% remained an independent predictor of better EFS after multivariate analysis (p<0.01). When cases were stratified into low vs. high risk groups, we found a significantly higher OS (p=0.043), PFS (0.047) and EVS (p<0.003) for low risk group.
Conclusions: Cell components of tumor microenvironment are powerful predictors of survival in patients with DLBCL in the rituximab era. Assessment of regulatory T-regs, M and MVD in a prognostic model allows stratification of patients into low versus high risk groups with significant differences in OS, PFS and EFS.
Monday, March 4, 2013 1:45 PM
Proffered Papers: Section C, Monday Afternoon