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Correlation of high numbers of intratumoral FOXP3⁺ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma

¹ Institute of Pathology, University Hospital Basel, Switzerland;
² Institute of Pathology, Triemli Hospital, Zurich, Switzerland;
³ Chair of Pathology and Unit of Hematopathology, Institute of Hematology and Clinical Oncology "L. and A. Seràgnoli", University of Bologna, Italy

Correspondence: Alexandar Tzankov, MD, Department of Pathology, University Hospital Basel, Schoenbeinstr. 40, CH-4031 Basel, Switzerland. E-mail: atzankov{at}uhbs.ch

Background: The tumor microenvironment is important for the behavior of cancer. We assessed the distribution and biological significance of FOXP3⁺ regulatory T-cells (Treg) in lymphomas.

Design and Methods: The absolute number of intratumoral FOXP3⁺ cells was immunohistochemically studied on lymphoma tissue microarrays from 1019 cases of different types of lymphomas and correlated to phenotypic and clinical parameters in uni- and multivariate models. Receiver operating characteristic -curves were used to determine prognostic cut-off values of FOXP3⁺ cell density.

Results: Of the 1019 cases, 926 (91%) were evaluable. FOXP3⁺ cell density varied between the lymphoma entities, and was highest in follicular lymphoma. An increased number of tumor-infiltrating FOXP3⁺ cells over the receiver operating characteristic-determined cut-offs positively influenced both disease-specific and failure-free survival in follicular lymphoma (p=0.053) and disease-specific survival in germinal center-like diffuse large B-cell lymphoma (p=0.051) and overall and failure-free survival in classical Hodgkin’s lymphoma (p=0.004), but had a negative prognostic effect in non-germinal center diffuse large B-cell lymphoma (p=0.059). In a Cox regression model, considering stage and age, the amount of FOXP3⁺ cells was of independent prognostic significance for failure-free survival in classical Hodgkin’s lymphoma and of borderline significance for overall survival in classical Hodgkin’s lymphoma and disease-specific survival in germinal center-like and non-germinal center diffuse large B-cell lymphoma.

Conclusions: FOXP3⁺ cells represent important lymphoma/host microenvironment modulators. Assessment of FOXP3⁺ cell density can contribute to the prediction of outcome in diffuse large B-cell lymphoma, fallicular lymphoma and classical Hodgkin’s lymphoma.

Key words: lymphoma, Treg, FOXP3, tissue microarray, receiver operating characteristic curves.

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