title: Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma.
abstract: OBJECTIVE
  Transformation of follicular lymphoma is a critical event associated with a poor prognosis. The role of the tumor microenvironment in previous transformation studies has yielded conflicting results.
  
  
  METHODS
  To define cell subtypes associated with transformation, we examined tissue specimens at diagnosis from patients with follicular lymphoma that later transformed and, using immunohistochemistry (IHC), stained for CD68, CD11c, CD21, CXCL13, FOXP3, PD1, and CD14. Cell content and the pattern of expression were evaluated. Those identified as significantly associated with time to transformation (TTT) and overall survival (OS) were further characterized by flow cytometry and multicolor IHC.
  
  
  RESULTS
  Of note, 58 patients were analyzed with median TTT of 4.7 years. The pattern of PD1(+) and CD14(+) cells rather than the quantity of cells was predictive of clinical outcomes. On multivariate analysis, including the follicular lymphoma international prognostic index score, CD14(+) cells localized in the follicle were associated with a shorter TTT (HR, 3.0; P = 0.004). PD1(+) cells with diffuse staining were associated with a shorter TTT (HR, 1.9; P = 0.045) and inferior OS (HR, 2.5; P = 0.012). Multicolor IHC and flow cytometry identified CD14(+) cells as follicular dendritic cells (FDC), whereas PD1(+) cells represented two separate populations, TFH and exhausted T cells.
  
  
  CONCLUSIONS
  These results identify the presence of PD1(+) T cells and CD14(+) FDC as independent predictors of transformation in follicular lymphoma. Clin Cancer Res; 20(11); 2862-72. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Smeltzer
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Jones
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Grote
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiu
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Kay M
authors.initials: KM
authors.lastname: Ristow
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Zhi Zhang
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.affiliation: Authors' Affiliations: Division of Hematology; Division of Epidemiology; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China ansell.stephen@mayo.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D016016:Proportional Hazards Models; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D018950:Lipopolysaccharide Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
references.citation: Histopathology. 2011 Mar;58(4):586-92
references.pmid: 21401698
references.citation: Clin Diagn Lab Immunol. 2004 Jan;11(1):161-7
references.pmid: 14715564
references.citation: Oncol Rep. 2008 Oct;20(4):953-6
references.pmid: 18813839
references.citation: Neuro Oncol. 2010 Jul;12(7):631-44
references.pmid: 20179016
references.citation: J Clin Oncol. 2007 Jun 10;25(17):2426-33
references.pmid: 17485708
references.citation: Blood. 2004 Sep 1;104(5):1258-65
references.pmid: 15126323
references.citation: J Clin Oncol. 2007 Feb 1;25(4):390-8
references.pmid: 17200149
references.citation: Nat Rev Immunol. 2002 Feb;2(2):116-26
references.pmid: 11910893
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5165-9
references.pmid: 18838711
references.citation: J Clin Oncol. 2007 Jun 20;25(18):2546-53
references.pmid: 17577033
references.citation: Blood. 2005 Sep 15;106(6):2169-74
references.pmid: 15933054
references.citation: J Clin Oncol. 2008 Jan 20;26(3):440-6
references.pmid: 18086798
references.citation: Immunology. 2005 Jan;114(1):2-10
references.pmid: 15606789
references.citation: J Histochem Cytochem. 2009 Oct;57(10):899-905
references.pmid: 19365090
references.citation: J Clin Oncol. 1986 Oct;4(10):1470-80
references.pmid: 3531422
references.citation: J Clin Oncol. 2009 Mar 20;27(9):1470-6
references.pmid: 19224853
references.citation: Prostate. 2010 Mar 1;70(4):443-55
references.pmid: 19902470
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):637-50
references.pmid: 20068089
references.citation: J Clin Oncol. 1997 Apr;15(4):1587-94
references.pmid: 9193357
references.citation: Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):388-97
references.pmid: 17255259
references.citation: Br J Haematol. 2012 Apr;157(2):188-96
references.pmid: 22348437
references.citation: Annu Rev Immunol. 2011;29:621-63
references.pmid: 21314428
references.citation: N Engl J Med. 2004 Nov 18;351(21):2159-69
references.pmid: 15548776
references.citation: Blood. 2011 Jan 20;117(3):872-81
references.pmid: 21063024
references.citation: Blood. 2010 Jan 14;115(2):289-95
references.pmid: 19901260
references.citation: J Clin Invest. 2012 Apr;122(4):1271-82
references.pmid: 22426209
references.citation: Clin Adv Hematol Oncol. 2012 Dec;10(12):810-8
references.pmid: 23271353
references.citation: Eur J Immunol. 1990 May;20(5):1013-8
references.pmid: 2358015
references.citation: J Clin Oncol. 2006 Nov 1;24(31):5052-9
references.pmid: 17033038
references.citation: Immunol Cell Biol. 2005 Oct;83(5):462-7
references.pmid: 16174094
references.citation: Blood. 2006 Nov 1;108(9):2957-64
references.pmid: 16825494
references.citation: J Clin Oncol. 2013 Sep 10;31(26):3272-8
references.pmid: 23897955
references.citation: Clin Cancer Res. 2005 Apr 15;11(8):2947-53
references.pmid: 15837746
references.citation: Haematologica. 2008 Aug;93(8):1169-77
references.pmid: 18556415
references.citation: J Clin Oncol. 1983 Jan;1(1):11-6
references.pmid: 6366124
references.citation: Cancer Res. 2006 Apr 1;66(7):3381-5
references.pmid: 16585157
references.citation: Leukemia. 2012 May;26(5):1053-63
references.pmid: 22015774
references.citation: Hum Pathol. 2011 Apr;42(4):552-7
references.pmid: 21237493
references.citation: Ann Oncol. 2006 Oct;17(10):1539-45
references.pmid: 16940035
references.citation: J Exp Med. 1989 Jun 1;169(6):2043-58
references.pmid: 2471772
references.citation: Ann Oncol. 2010 Jun;21(6):1196-1202
references.pmid: 19875761