title: Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in non-immunocompromised hosts.
abstract: BACKGROUND
  EBV-associated T/NK-cell lymphoproliferative diseases (TNKLPD) is a rare spectrum of disease that occurs more commonly in Asia, and Central and South America. It commonly affects children and young adults and is an aggressive disease that is poorly understood with no known biologic markers that can predict prognosis. The systemic form of TNKLPD includes chronic active EBV infection of T/NK type, aggressive NK cell leukemia and systemic EBV + T-cell lymphoproliferative disease of childhood.
  
  
  METHODS
  In this study, we analyse the clinicopathologic and genetic features of 22 cases of systemic TNKLPD in non-immunocompromised patients, including chronic active EBV infection of T/NK cell type and systemic EBV + T-cell lymphoproliferative disease of childhood. We also performed gene expression profiling in a subset of cases to identify markers that may be of prognostic relevance and validated our results using immunohistochemistry.
  
  
  RESULTS
  The median age is 14.9 years and two of our 22 cases occurring in patients older than 30 years. Fifteen of 17 cases (88%) with adequate data were of T-cell origin. Eleven of 22 cases revealed polymorphic cellular infiltrate (P-group) while the rest showed monomorphic lymphoid infiltrate (M-group). We found a significant difference in survival between P-group vs M-group patients with median survival not yet reached in P-group, and 1 month in M-group (p = 0.0001), suggesting a role for morphology in predicting patient outcome. We also performed gene expression profiling in a subset of patients and compared the genes differentially expressed between P-group and M-group cases to identify markers of prognostic value. We identified cyclin E2 gene and protein to be differentially expressed between patients with good outcome (P-group, median expression 8%) and poor outcome (M-group, median expression 42%) (p = 0.0005). In addition, the upregulation of cyclin E2 protein in M-group cases correlated with a higher Ki67 proliferation rate (Pearson correlation r = 0.73, p = 0.0006) detected by immunohistochemistry. High cyclin E2 expression was also significantly associated with shorter survival (p = 0.0002).
  
  
  CONCLUSIONS
  Our data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD.
authors.affiliation: Department of Pathology, National University Cancer Institute of Singapore, National University Health System, Yong Loo Lin School of Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. patnsb@nus.edu.sg.|Department of Pathology, National University Hospital, 5 Lower Kent Ridge Road, Main Building, Level 3, Singapore, 119074, Singapore. patnsb@nus.edu.sg.
authors.forename: Siok-Bian
authors.initials: SB
authors.lastname: Ng
authors.affiliation: Department of Pathology, Kurume University, Asahimati 67, Kurume, 830-0011, Japan. ohshima_kouichi@med.kurume-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.affiliation: Department of Pathology, National University Health System, Singapore, Singapore. viknesvaran_selvarajan@nuhs.edu.sg.
authors.forename: Viknesvaran
authors.initials: V
authors.lastname: Selvarajan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. g.huang@balliol.oxon.org.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Pathology, National University Health System, Singapore, Singapore. shoa_nian_choo@nuhs.edu.sg.
authors.forename: Shoa-Nian
authors.initials: SN
authors.lastname: Choo
authors.affiliation: Department of Pathology, Kurume University, Asahimati 67, Kurume, 830-0011, Japan. h.m-med@hotmail.co.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Pathology, National University Health System, Singapore, Singapore. shi_wang@nuhs.edu.sg.
authors.forename: Shi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Paediatrics, National University Health System, Singapore, Singapore. hsinchiehchua@yahoo.com.
authors.forename: Hsin-Chieh
authors.initials: HC
authors.lastname: Chua
authors.affiliation: Department of Paediatrics, National University Health System, Singapore, Singapore. allen_yeoh@nuhs.edu.sg.
authors.forename: Allen Eng-Juh
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Department of Paediatrics, National University Health System, Singapore, Singapore. thuan_chong_quah@nuhs.edu.sg.
authors.forename: Thuan-Chong
authors.initials: TC
authors.lastname: Quah
authors.affiliation: Department of Haematology-Oncology, National University Health System, Singapore, Singapore. liang_piu_koh@nuhs.edu.sg.
authors.forename: Liang-Piu
authors.initials: LP
authors.lastname: Koh
authors.affiliation: Department of Paediatrics, National University Health System, Singapore, Singapore. poh_lin_tan@nuhs.edu.sg.
authors.forename: Poh-Lin
authors.initials: PL
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Yong Loo Lin School of Medicine, Cancer Science Institute of Singapore, 1E, Kent Ridge Rd, Singapore, 119228, Singapore. mdccwj@nus.edu.sg.
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000293:Adolescent; D000328:Adult; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000473:pathology* / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007223:Infant; D007564:Japan; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012846:Singapore; D015996:Survival Rate; D013601:T-Lymphocytes / Q000473:pathology*; D055815:Young Adult
chemical_list: C503688:CCNE2 protein, human; D016213:Cyclins; D019394:Ki-67 Antigen