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.
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.


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.
Tzankov
Alexandar
A
Department of Pathology, University Hospital Basel, Schoenbeinstr. 40, CH-4031 Basel, Switzerland. atzankov@uhbs.ch
Meier
Cecile
C
Hirschmann
Petra
P
Went
Philip
P
Pileri
Stefano A
SA
Dirnhofer
Stephan
S
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002452:Cell Count; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006689:Hodgkin Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors