Poor Prognosis of CD5 Positive with Non Germinal Center Type of Diffuse Large B Cell Lymphoma Especially Having the Aberration of 19q13

Introduction ; One of biological molecule markers, CD5 positive (CD5⁺) DLBCL has been recognized as one of the poor prognostic factors. Almost all CD5⁺DLBCL cases have higher age, aggressive clinical features, poor performance status (PS), and high LDH level compared to CD5 negative (CD5^-) DLBCL. These clinical features are close to ABC type DLBCL and also some gene expression profiling detected the similar point of CD5⁺ DLBCL with ABC type of DLBCL, such as down-regulation of ECUM genes. Various chromosomal aberrations and polyploidy also have been detected in CD5⁺ DLBCL, although, specific features of karyotype or markers of gene expression have not been identified. In previous data, we presented the poor prognosis of CD5⁺non germinal center (NGC) type of DLBCL compared to CD5⁺ germinal center (GC) type DLBCL and CD5^-DLBCL, furthermore additional 19q13 were frequently exhibited in CD5⁺NGC DLBCL (ASH 2015, poster). In this time we added the more analysis of G-band analysis of DLBCL and CGH array of CD5⁺NGC with additional 19q13 and analyzed the prognostic factor of CD5⁺NGC DLBCL.

Methods and Results ; We analyzed our treated 373 DLBCL patients by R-CHOP during 2005-2015 in our institute retrospectively. This protocol was approved by our Institutional Review Board and Genomic review Board. All cases were classified depend on CD5⁺ or CD5^- expression by immuno-staining and/or flowcytometry from tumor-biopsy specimen and furthermore sub-divided to GCB or NGC by immuno-staining, as CD10, bcl-6, and MUM-1. 350 cases were encluded, then CD5⁺ were 41 (41/350; 11.7%) CD5⁺NGC type were 30 (30/41; 73.2%). 3.5 year-PFS was as follows, CD5^-GCB; 84.0% (95%CI 77.4-88.8%), CD5⁺GCB; 65.9% (95%CI 56.2-74.0%), CD5^-NGC; 81.8% (95%CI 44.7-95.1%), and CD5⁺NGC; 40.6% (95%CI 22.5-58.0%), respectively. The 3.5 year-OS was as follows, CD5^-GCB; 85.0% (95%CI 78.4-89.8%), CD5⁺GCB; 79.7% (95%CI 70.9-86.1%), CD5^-NGC; 90.9% (95%CI 50.8-98.7%), and CD5⁺NGC; 44.5% (95%CI 25.2-62.1%), respectively. CD5⁺NGC type of DLBCL were demonstrated the worst prognosis in both PFS (P=0.00104) and OS (P <0.001), respectively. By the multivariate analysis of prognostic factors, CD5⁺ (HR; 2.180, 95%CI; 1.263-3.764, P=0.0051) and IPI (HR; 1.678, 95%CI; 1.151-2.449, P=0.0071) were estimated as individual factors for OS. CD5⁺NGC type of DLCBL frequently showed the chromosomal aberration of additional 19q13 (7/13 cases; 53.8%). additional 19q13 was also showed only one case of CD5^-NGC type of DLBCL. Six cases (6/7; 85.7%) in CD5⁺NGC had disease progression (two cases relapsed after CR and four had progression during R-CHOP therapy) and followed by death. CGH analysis was performed with the five cases having additional 19q13 in CD5⁺NGC type. All cases exhibited the aberration of 19q13.41-42 lesions. Three cases showed wide gene amplification in 19q13.32-q13.42. Three cases showed gene loss at the 19q13.41 or 19q13.42. Regarding other chromosomes, all five cases showed gene loss at 1p31.3 and gain at 1q25.1, 2p22.1, 2p22.3, 4p16.1, 4p15.1, 7q33, 12p13.2, 14q32.33.

Discussion and Conclusion ;Our study showed significant poor prognosis CD5⁺NGC type of DLBCL. The gene aberration of 19q13 was frequently expressed in CD5⁺NGC type of DLBCL and it suggested the relationships between aberration of 19q13 and the poor prognosis. Several study also demonstrated the relationships between aberration of 19q13 and the poor prognosis of the DLBCL. Our CGH analysis demonstrated the aberration of 19q13.41-42 lesions. Already known representative CNVs in this area include CYP2A, SIGLEC14, and LILRA. Those candidate genes have reported to have the relationships with stimulation of leukocyte or lymphoid cell signaling. The further investigation of gene aberration regarding to additional 19q13 might be one of the procedure to overcome the tolerability for the treatment of CD5⁺NGC DLBCL. From our data we could consider that it is important to identify the CD5⁺NGC type of DLBCL as poor prognostic factor in DLBCL, and R-CHOP therapy could not improved their prognosis. The new treatment strategy should be planned as soon as possible, such as intensive chemotherapy or immunotherapy.