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

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.

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

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