title: Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols.
abstract: 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.
  
  
  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.
authors.affiliation: Dept. of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. d.d.jong@nki.nl
authors.forename: Daphne
authors.initials: D
authors.lastname: de Jong
authors.forename: Ad
authors.initials: A
authors.lastname: Koster
authors.forename: Anton
authors.initials: A
authors.lastname: Hagenbeek
authors.forename: John
authors.initials: J
authors.lastname: Raemaekers
authors.forename: Dennis
authors.initials: D
authors.lastname: Veldhuizen
authors.forename: Sabien
authors.initials: S
authors.lastname: Heisterkamp
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: de Boer
authors.forename: Martine
authors.initials: M
authors.lastname: van Glabbeke
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D024221:Antineoplastic Protocols; D015415:Biomarkers; D006801:Humans; D007150:Immunohistochemistry; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers