Research

Prognostic implication of morphology, cyclinE2 and proliferation in EBV-associated T/NK lymphoproliferative disease in non-immunocompromised hosts (Orphanet J. Rare Dis, Dec 2014)

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,*

1Department 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.
2 Department of Pathology, Kurume University, Asahimati 67, Kurume 830-0011, Japan.
3 Department of Pathology, National University Health System, Singapore, Singapore.
4 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
5 Department of Paediatrics, National University Health System, Singapore, Singapore.
6 Department of Haematology-Oncology, National University Health System, Singapore, Singapore.
7 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.
8 Department of Pathology, National University Hospital, 5 Lower Kent Ridge Road, Main Building, Level 3, Singapore 119074, Singapore.

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).
Conclusion: Our data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD.

orphanet

Cyclin E2 expression was associated with high proliferation rate and poor outcome in TNKLPD.Significantly higher cyclin E2 expression was present in M-group compared to P-group patients (A, median expression of 42% compared with 8%, p = 0.0005). Patients with high tumor cyclin E2 expression of 15% or greater had statistically significant shorter survival compared with those with low cyclin E2 expression less than 15% (B, p = 0.0002). High cyclin E2 expression is highly correlated with high Ki-67 proliferation rate (C, spearman r = 0.73, p = 0.0006).