title: Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis.
abstract: BACKGROUND
  Ki-67 is a nuclear protein involved in cell proliferation regulation, and its expression has been widely used as an index to evaluate the proliferative activity of lymphoma. However, its prognostic value for lymphoma is still contradictory and inconclusive.
  
  
  METHODS
  PubMed and Web of Science databases were searched with identical strategies. The impact of Ki-67 expression on survival with lymphoma and various subtypes of lymphoma was evaluated. The relationship between Ki-67 expression and Diffuse Large B Cell Lymphoma (DLBCL) and Mantle Cell Lymphoma (MCL) was also investigated after the introduction of a CD-20 monoclonal antibody rituximab. Furthermore, we evaluated the association between Ki-67 expression and the clinical-pathological features of lymphoma.
  
  
  RESULTS
  A total of 27 studies met the inclusion criteria, which comprised 3902 patients. Meta-analysis suggested that high Ki-67 expression was negatively associated with disease free survival (DFS) (HR = 1.727, 95% CI: 1.159-2.571) and overall survival (OS) (HR = 1.7, 95% CI: 1.44-2) for lymphoma patients. Subgroup analysis on the different subtypes of lymphoma suggested that the association between high Ki-67 expression and OS in Hodgkin Lymphoma (HR = 1.511, 95% CI: 0.524-4.358) was absent, while high Ki-67 expression was highly associated with worse OS for Non-Hodgkin Lymphoma (HR = 1.777, 95% CI: 1.463-2.159) and its various subtypes, including NK/T lymphoma (HR = 4.766, 95% CI: 1.917-11.849), DLBCL (HR = 1.457, 95% CI: 1.123-1.891) and MCL (HR = 2.48, 95% CI: 1.61-3.81). Furthermore, the pooled HRs for MCL was 1.981 (95% CI: 1.099-3.569) with rituximab and 3.123 (95% CI: 2.049-4.76) without rituximab, while for DLBCL, the combined HRs for DLBCL with and without rituximab was 1.459 (95% CI: 1.084-2.062) and 1.456 (95% CI: 0.951-2.23) respectively. In addition, there was no correlation between high Ki-67 expression and the clinical-pathological features of lymphoma including the LDH level, B symptoms, tumor stage, extranodal site, performance status and IPI score.
  
  
  CONCLUSIONS
  This study showed that the prognostic significance of Ki-67 expression varied in different subtypes of lymphoma and in DLBCL and MCL after the introduction of rituximab, which was valuable for clinical decision-making and individual prognostic evaluation.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Fu
authors.forename: Xueli
authors.initials: X
authors.lastname: Jin
authors.forename: Teng
authors.initials: T
authors.lastname: Yu
authors.forename: Yun
authors.initials: Y
authors.lastname: Liang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. hlsdoctor@126.com.
authors.forename: Liansheng
authors.initials: L
authors.lastname: Huang
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D015870:Gene Expression; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D008223:Lymphoma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D016017:Odds Ratio; D011379:Prognosis; D016016:Proportional Hazards Models; D017594:Publication Bias; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D000069283:Rituximab