Ng SB1, Chung TH2, Kato S3, Nakamura S3, Takahashi E4, Ko YH5, Khoury JD6, Yin CC6, Soong R7, Jeyasekharan AD2, Hoppe MM2, Selvarajan V8, Tan SY9, Lim ST10, Ong CK11, Nairismägi ML11, Maheshwari P12, Choo SN8, Fan S8, Lee CK8, Chuang SS13, Chng WJ14.
1 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore; email@example.com.
2 Cancer Science Institute of Singapore, National University of Singapore.
3 Department of Pathology and Laboratory Medicine, Nagoya University Hospital.
4 Department of Pathology, Aichi Medical University Hospital, Nagakute, Japan.
5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
6 Department of Hematopathology, University of Texas, MD Anderson Cancer Center, Houston, TX.
7 Department of Pathology, Cancer Science Institute of Singapore, National University of Singapore.
8 Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore.
9 Department of Pathology, National University of Singapore, National University Health System.
10 Division of Medical Oncology, National Cancer Centre Singapore.
11 Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore.
12 Department of Pathology, National University Hospital, National University Health System.
13 Department of Pathology, Chi-Mei Medical Center, Taiwan.
14 Dept. of Hematology-Oncology, National University and National Cancer Institute of Singapore.
The molecular biology of primary nodal T- and NK-cell lymphoma and its relationsihp with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal EBV-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed GEP and CNA analysis on 66 cases of EBV-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathologic features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). TNKL with nodal presentation (N-group) was significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with extranodal presentation (EN-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. The molecular signature of N-group compared to EN-group was characterized by upregulation of PD-L1 and T-cell related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56- immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, N-group was associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that TNKL with nodal presentation is distinct and deserves to be classified separately from those with extranodal presentation. Upregulation of PD-L1 indicates the possibility of anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.
KEYWORDS: Copy number aberration; Cytogenetics and Molecular Genetics; Lymphoproliferative Disorders; Nodal NK/T cell lymphoma; PD-L1