Published online 4 December 2008
Haematologica, Vol 94, Issue 1, 70-77 doi:10.3324/haematol.13574
Copyright © 2009 by Ferrata Storti Foundation

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by de Jong, D. Articles by van Glabbeke, M. Search for Related Content PubMed PubMed Citation Articles by de Jong, D. Articles by van Glabbeke, M. Related Collections Related Article

Malignant Lymphomas

Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols

Daphne de Jong¹, Ad Koster², Anton Hagenbeek³, John Raemaekers⁴, Dennis Veldhuizen¹, Sabien Heisterkamp¹, Jan Paul de Boer⁵, Martine van Glabbeke⁶

¹ Dept. of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
² Dept. of Internal Medicine, Vie Curi Medical Center, Venlo, the Netherlands
³ Dept. of Hematology, Academic Medical Center, Amsterdam, the Netherlands
⁴ Dept. of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
⁵ Dept. of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
⁶ European Organization for Research and Treatment of Cancer (EORTC) Data Center, Brussels, Belgium

Correspondence: Daphne de Jong, Dept. of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam the Netherlands. E-mail:d.d.jong{at}nki.nl

Background: The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to heterogeneous composition and treatments.

Design and Methods: Pre-treatment biopsy samples of patients with follicular lymphoma treated in an EORTC/BNLI trial comparing fludarabine to cyclophosphamide, vincristine and prednisone (CVP) chemotherapy could be retrieved for 61 patients in five European countries. Immunohistochemical investigations were performed evaluate tumor cell characteristics, T-cell subsets, follicular dendritic cells and macrophages and associations with clinical outcome were studied.

Results: Some markers showed a homogeneous prognostic impact, while others had a different nd sometimes opposite effect in the treatment arms. CD69 expression on tumor cells was a poor prognostic sign and an interfollicular infiltrate of FoxP3-positive T cells was a good prognostic sign irrespective of the treatment arm. It is suggestive that a dense infiltrate of FoxP3-positive T cells, dense and interfollicular infiltrate of CD68-positive macrophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being poor prognostic sign in fludarabine-treated patients.

Conclusions: Our results suggest that characteristic properties of the microenvironment in follicular lymphoma determines the responses to essentially different chemotherapeutic approaches. These data may provide an explanation for the highly conflicting results on immunohistochemical markers and the prognostic role of the microenvironment in follicular lymphoma reported thus far and lay the basis for the development of predictive assays to tailor treatment in patients with follicular lymphoma.

Key words: follicular lymphoma, microenvironment, prognostic factors, immunohistochemistry.

Related Article

Clinicobiological, prognostic and therapeutic implications of the tumor microenvironment in follicular lymphoma

Marylène Lejeune, Tomás Álvaro
Haematologica 2009 94: 16-21. [Full Text] [PDF]

This article has been cited by other articles:

				B. E. Wahlin, M. Aggarwal, S. Montes-Moreno, L. F. Gonzalez, G. Roncador, L. Sanchez-Verde, B. Christensson, B. Sander, and E. Kimby A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1-Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages Clin. Cancer Res., January 15, 2010; 16(2): 637 - 650. [Abstract] [Full Text] [PDF]

				P. Farinha, A. Al-Tourah, K. Gill, R. Klasa, J. M. Connors, and R. D. Gascoyne The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation Blood, January 14, 2010; 115(2): 289 - 295. [Abstract] [Full Text] [PDF]

				A. G. Ramsay, A. J. Clear, G. Kelly, R. Fatah, J. Matthews, F. MacDougall, T. A. Lister, A. M. Lee, M. Calaminici, and J. G. Gribben Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy Blood, November 19, 2009; 114(21): 4713 - 4720. [Abstract] [Full Text] [PDF]

				W. GOLLUB, B. STASSEK, T. HUCKHAGEL, H.-W. BERND, M. KROKOWSKI, H. MERZ, A. C. FELLER, and C. THORNS BCL6-translocations Affect the Phenotype of Follicular Lymphomas Only in the Absence of t(14;18)IgH/BCL2 Anticancer Res, November 1, 2009; 29(11): 4649 - 4655. [Abstract] [Full Text] [PDF]

				J. W. Sweetenham, B. Goldman, M. L. LeBlanc, J. R. Cook, R. R. Tubbs, O. W. Press, D. G. Maloney, R. I. Fisher, L. M. Rimsza, R. M. Braziel, et al. Prognostic value of regulatory T cells, lymphoma-associated macrophages, and MUM-1 expression in follicular lymphoma treated before and after the introduction of monoclonal antibody therapy: a Southwest Oncology Group Study Ann. Onc., October 29, 2009; (2009) mdp460v1. [Abstract] [Full Text] [PDF]

				J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio The microenvironment in mature B-cell malignancies: a target for new treatment strategies Blood, October 15, 2009; 114(16): 3367 - 3375. [Abstract] [Full Text] [PDF]

				M. Lejeune and T. Alvaro Clinicobiological, prognostic and therapeutic implications of the tumor microenvironment in follicular lymphoma Haematologica, January 1, 2009; 94(1): 16 - 21. [Full Text] [PDF]