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Primary Bone Lymphoma Exhibits a Favorable Prognosis and Distinct Gene Expression Signatures Resembling Diffuse Large B-Cell Lymphoma Derived From Centrocytes in the Germinal Center

Li, Xin MD, PhD*,†; Xu-Monette, Zijun Y. PhD; Yi, Shuhua MD, PhD; Dabaja, Bouthaina S. MD; Manyam, Ganiraju C. PhD§; Westin, Jason MD; Fowler, Nathan MD; Miranda, Roberto N. MD*; Zhang, Mingzhi MD, PhD*; Ferry, Judith A. MD; Medeiros, L. Jeffrey MD; Harris, Nancy L. MD; Young, Ken H. MD, PhD†,#

American Journal of Surgical Pathology: October 2017 - Volume 41 - Issue 10 - p 1309–1321
doi: 10.1097/PAS.0000000000000923
Original Articles

Primary bone (PB) diffuse large B-cell lymphoma (DLBCL) is rare and has a favorable prognosis, but the underlying biological mechanisms remain unknown. In this study we analyzed the clinicopathologic features of 160 patients with PB-DLBCL in comparison with 499 nonosseous DLBCL. Compared with patients with nonosseous DLBCL and secondary involvement of bone by DLBCL, PB-DLBCL patients less frequently had elderly age, B-symptoms, elevated serum lactate dehydrogenase levels, and high International Prognostic Index at diagnosis, more frequently had germinal center (GC) subtype (approximately 90%) and complete remission, and had significantly better survival. The 5-year progression-free and overall survival rates of PB-DLBCL patients were 80% and 93%, respectively, superior to both GC B-cell–like (GCB) and activated B cell–like subtypes of DLBCL. Further stratifying nonosseous DLBCL cell-of-origin subtypes by clinical factors showed that PB-DLBCL had similar survival rates as the centrocyte-origin (CC) subtype of DLBCL-GCB classified by the B-cell–associated gene signature algorithm. To better understand the favorable outcome of PB-DLBCL patients, gene expression profiling and microRNA profiling were performed in a small subset of PB-DLBCL. The gene expression profiles of PB-DLBCL resembled those of nonosseous DLBCL-GCB-CC, but were distinct from other DLBCL cell-of-origin especially the centroblast-origin (CB) subtype. Compared with DLBCL-GCB-CB, PB-DLBCL and DLBCL-GCB-CC also had much higher levels of miR-125a-3p, miR-34-3p, and miR-155-5p, and significantly lower levels of miR-17-5p and miR-17-3p. These results demonstrated that PB-DLBCL is clinically distinct, and the cell-of-origin of PB-DLBCL stems from centrocytes in the GC, that are biologically attributed for the favorable prognosis of PB-DLBCL.

*Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, China

Departments of Hematopathology

Radiation Oncology

§Bioinformatics and Computational Biology

Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center

#Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX

Department of Pathology, Harvard University Medical School, Boston, MA

X.L., Z.Y.X.-M., and S.Y. contributed equally.

X.L. and K.H.Y.: conception and design. X.L., Z.Y.X.-M., S.Y., and K.H.Y.: research performance. X.L., Z.Y.X.-M., S.Y., B.S.D., G.C.M., J.W., N.F., R.N.M., M.Z., J.A.F., L.J.M., N.L.H., and K.H.Y.: intellectual contributions, materials, key reagents, and technology. X.L., Z.Y.X.-M., S.Y., B.S.D., J.A.F., and K.H.Y.: collection and assembly of data under approved IRB and Material Transfer Agreement. X.L., Z.Y.X.-M., S.Y., J.A.F., L.J.M., N.L.H., and K.H.Y.: data analysis and interpretation. X.L., L.J.M., and K.H.Y.: manuscript editing.

Conflicts of Interest and Source of Funding: Supported by National Cancer Institute and National Institutes of Health grants (R01CA138688 and R01CA187415 to KHY). X.L. and S.Y. are the recipient of Hematology/Oncology Scholarship Award. K.H.Y. is also supported by The University of Texas MD Anderson Cancer Center Lymphoma Moonshot Program and Institutional Research Grant Award. The study is also partially supported by P50CA136411 and P50CA142509 and the MD Anderson Cancer Center Support Grant CA016672. K.H.Y. receives research support from Roche Molecular Diagnostics, Gilead Sciences, Seattle Genetics, Daiichi Sankyo, Adaptive Biotechnologies, Incyte, and HTG Molecular Diagnostics. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Xin Li, MD, PhD, Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, Zhengzhou 450052, China (e-mail: Lixiaoxin86@126.com). Correspondence: Ken H. Young, MD, PhD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009 (e-mail: khyoung@mdanderson.org).

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