CIITA and PDL1/PDL2 Gene Rearrangements in Primary Testicular Diffuse Large B Cell Lymphoma
Tawny Hung, King L Tan, Susana Ben-Neriah, Kerry J Savage, David Telio, Joseph M Connors, David W Scott, Graham W Slack, Christian Steidl, Randy D Gascoyne. British Columbia Cancer Agency, Vancouver, Canada
Background: The MHC class II transactivator, CIITA, is a master regulator of MHC class II gene expression, and is a reported recurrent gene fusion partner in both primary mediastinal large B cell lymphoma (PMBCL) and classical Hodgkin lymphoma (cHL) (Steidl et al. Nature 2011; 471: 377-381). CIITA and PDL1/PDL2 gene fusions is described, resulting in downregulation of surface HLA class II expression, and overexpression of ligands of the receptor molecule programmed cell death 1 (PDL1 and PDL2), leading to inhibition of T cells. These mechanisms may allow tumour cells to escape from immunosurveillance. We investigated whether CIITA and PDL1/PDL2 gene rearrangements occur in primary testicular diffuse large B cell lymphoma (DLBCL), a lymphoma arising in a site of immune privilege.
Design: A tissue microarray was constructed using duplicate 1.0mm cores from diagnostic paraffin blocks of 85 patients with primary testicular DLBCL. For survival analysis, patients not treated with curative intent or were HIV positive were excluded, leaving 66 patients; 35 treated with R-CHOP and 31 with CHOP-like chemotherapy. FISH was performed using in-house bacterial artificial chromosome break-apart probes for CIITA and PDL1/PDL2. FISH was scored by at least 2 independent scorers in relation to CD20-positive tumour cell content on the Ariol imaging system. Survival analysis was determined by Kaplan-Meier method with differences evaluated by log-rank test.
Results: 79/85 cases (93%) could be analyzed for both CIITA and PDL1/PDL2 signals. CIITA break-apart was seen in 7/79 cases (8%) and PDL1/PDL2 break-apart was seen in 6/79 cases (7%). In contrast to PMBCL, CIITA and PDL1/PDL2 break-apart were mutually exclusive. In the subgroup for survival analysis, 5/60 cases (8%) showed PDL1/PDL2 break-apart; 2 were treated with R-CHOP and 3 without. On univariate analysis with both R-CHOP and CHOP-like chemotherapy together as a single group, the presence of a PDL1/PDL2 break-apart was significantly associated with inferior progression free survival (PFS) (p= 0.027) and greater risk of CNS relapse (p<0.001). CIITA break-apart was seen in 4/60 cases (7%); 1 treated with R-CHOP and 3 without. No significant association with survival was seen with CIITA break-apart.
Conclusions: CIITA and PDL1/PDL2 gene rearrangements occur at a moderate frequency in primary testicular DLBCL, and are mutually exclusive. PDL1/PDL2 break-apart is associated with inferior PFS and greater risk of CNS relapse.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 189, Tuesday Afternoon