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The density of CD8+ T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone

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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.

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Abbreviations

ABC:

Activated B-cell

AKT:

Acutely transforming retrovirus

BCL2:

B-cell lymphoma 2

DLBCL:

Diffuse large B-cell lymphoma

GCB:

Germinal center B-cell

IPI:

International prognostic index

PBL:

Primary bone lymphoma

PB-DLBCL:

Primary bone diffuse large B-cell lymphoma

PI3K:

Phosphatidylinositol 3-kinase

mTOR:

Mammalian target of rapamycin

MYC:

Myelocytomatosis viral oncogene homolog

NHL:

Non-Hodgkin's lymphoma

TMA:

Tissue microarray

pS6:

Phosphorylated ribosomal-S6 protein

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Acknowledgments

This work was supported by the Tumor Progression Research Group—Joint Research Organization of The Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary and by a grant from OTKA K76204.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary

    Hajnalka Rajnai, Anna Sebestyén, András Matolcsy & Ágota Szepesi

  2. Department of Internal Medicine, Medical Center Haaglanden, The Hague, The Netherlands

    Fenna H. Heyning

  3. Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest, Hungary

    Hajnalka Andrikovics

  4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Lianne Koens & Pancras C. W. Hogendoorn

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  1. Hajnalka Rajnai
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Correspondence to Ágota Szepesi.

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Rajnai, H., Heyning, F.H., Koens, L. et al. The density of CD8+ T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone. Virchows Arch 464, 229–239 (2014). https://doi.org/10.1007/s00428-013-1519-9

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