title: The density of CD8+ T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone.
abstract: Primary bone lymphoma (PBL) comprises 5 % of all extranodal non-Hodgkin's lymphomas (NHLs). Diffuse large B-cell lymphoma (DLBCL) accounts for the majority of cases, which is the most heterogeneous group of lymphomas. Previous studies suggested that besides the tumor cell phenotype, phosphatidylinositol 3-kinase/acutely transforming retrovirus/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway activity and the composition of the immune-microenvironment of DLBCL influence the clinical behavior of the disease. The aim of our study was to determine the relationship between clinical factors, tumor cell phenotype, microenvironment, PI3K/AKT/mTOR pathway activity, and disease outcome in primary bone diffuse large B-cell lymphoma (PB-DLBCL). We constructed tissue-microarrays from 41 cases of PB-DLBCL. To characterize tumor cell phenotype, T-cell subsets, macrophages, and PI3K/AKT/mTOR pathway activity immunohistochemical stainings were evaluated. Kaplan-Meier survival analysis provided evidence that age (≤65), CD3 and CD8+ T cell infiltrations >5 %, low BCL2 expression of the tumor cells (≤30 %), and low proliferation index (Ki67 ≤ 57 %) were associated with favorable outcome of PB-DLBCL patients. Multivariate analysis revealed that CD8+ T cell infiltration >5 % and low BCL2 expression (≤30 %) were independent predictors of survival. Increased macrophage infiltration (>10 %) showed tendency toward an adverse prognostic effect. International prognostic index, tumor cell phenotype (GCB or ABC), MYC protein expression, and activation of PI3K/AKT/mTOR pathway had no significant impact on survival. However, mTOR activity showed a significant correlation with activated B-cell phenotype. We conclude that CD8 and BCL2 expressions are potential prognostic markers for PB-DLBCL patients and the PI3K/AKT/mTOR pathway appears to be an additional therapeutic target in PB-DLBCL with activated-B-cell phenotype.
authors.affiliation: 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary.
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Rajnai
authors.forename: Fenna H
authors.initials: FH
authors.lastname: Heyning
authors.forename: Lianne
authors.initials: L
authors.lastname: Koens
authors.forename: Anna
authors.initials: A
authors.lastname: Sebestyén
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Andrikovics
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: András
authors.initials: A
authors.lastname: Matolcsy
authors.forename: Ágota
authors.initials: Á
authors.lastname: Szepesi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000276:immunology; D055815:Young Adult
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2