Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in n
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RESEARCH
Open Access
Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in non-immunocompromised hosts Siok-Bian Ng1,8*, Koichi Ohshima2, Viknesvaran Selvarajan3, Gaofeng Huang4, Shoa-Nian Choo3, Hiroaki Miyoshi2, Shi Wang3, Hsin-Chieh Chua5, Allen Eng-Juh Yeoh5, Thuan-Chong Quah5, Liang-Piu Koh6, Poh-Lin Tan5 and Wee-Joo Chng7*
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). (Continued on next page)
* Correspondence: [email protected]; [email protected] 1 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 7 Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Yong Loo Lin School of Medicine, Cancer Sc
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