title: The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era.
abstract: The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+  follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+  macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+  T cells and high intrafollicular scores of CD4+  T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway. ynblak@rr-research.no.|Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. ynblak@rr-research.no.
authors.forename: Yngvild Nuvin
authors.initials: YN
authors.lastname: Blaker
authors.affiliation: Department of Pathology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors.forename: Signe
authors.initials: S
authors.lastname: Spetalen
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors.forename: Marianne
authors.initials: M
authors.lastname: Brodtkorb
authors.affiliation: Section for Biomedical Informatics, Department of Computer Science, University of Oslo, Oslo, Norway.
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjaerde
authors.affiliation: Department of Pathology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors.forename: Klaus
authors.initials: K
authors.lastname: Beiske
authors.affiliation: Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Østenstad
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.affiliation: Division of Haematology, Department of Medicine at Huddinge, Karolinska Institutet and Haematology Centre, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Björn Engelbrekt
authors.initials: BE
authors.lastname: Wahlin
authors.affiliation: Division of Haematology, Department of Medicine at Huddinge, Karolinska Institutet and Haematology Centre, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Christopher Michael
authors.initials: CM
authors.lastname: Melen
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: June Helen
authors.initials: JH
authors.lastname: Myklebust
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Holte
authors.affiliation: Department of Pathology, University of Toronto, Toronto, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Erlend Bremertun
authors.initials: EB
authors.lastname: Smeland
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers; D001706:Biopsy; D002471:Cell Transformation, Neoplastic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D016016:Proportional Hazards Models; D000069283:Rituximab / Q000627:therapeutic use; D013997:Time Factors; D059016:Tumor Microenvironment / Q000276:immunology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D000069283:Rituximab
keywords: follicular dendritic cell; follicular lymphoma; immunohistochemistry; prognostic factors; tumour microenvironment