Molecular Features of Primary Central Nervous System Lymphoma in a Large Tissue Microarray

Abstract Background The pathogenesis of primary central nervous system lymphoma (PCNSL) remains poorly understood. The objective of this study was to evaluate the distribution and prognostic impact of a broad range of molecular attributes in a large tissue microarray (TMA) from immunocompetent patients with PCNSL. Methods Patients with PCNSL diagnosed during 1998 - 2010 were identified using the BC Cancer Lymphoid Cancer clinical and pathology databases. Archival formalin-fixed, paraffin-embedded diagnostic biopsy tissue was retrieved, and TMAs were constructed. Immunohistochemistry (IHC) for CD10, BCL6, MUM-1, GCET1, FOXP1, and LMO2 protein expression was used to assign cell of origin (COO) by three different algorithms. IHC for MYC, BCL2, PDL-1, and HLA class II protein expression was also performed. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was performed. Fluorescent in-situ hybridization (FISH) was performed for MYC, BCL2, BCL6, PDL1/2 (9p24.1), and CIITA (16p13) rearrangements. Results A total of 115 patients with PCNSL with DLBCL histology were included in the final analysis: 59% male, 70% age >60 years, 77% performance status >1. Primary treatment modalities included high-dose methotrexate (HDMTX) based regimens in 52 (45%) patients, whole brain radiotherapy (WBRT) alone in 40 (35%) patients, and best supportive care in 23 (20%) patients. Among the 52 HDMTX-treated patients, 18 also received WBRT (pre-planned combined modality therapy or inability to tolerate HDMTX), and 11 also received rituximab. Failure of IHC/FISH occurred in 0-21% of individual assays, largely due to insufficient tissue material. The majority of patients had a non-GCB COO phenotype as determined by the Hans (76%), Choi (86%), and Tally (99%) algorithms. MYC protein expression was positive (≥40%) in 37/93 (40%) patients, BCL2 (≥50%) in 68/91 (75%) [124 antibody] and 87/111 (78%) [E17 antibody] patients, and dual MYC/BCL2 in 30/88 (35%) [124 antibody] and 32/92 (35%) [E17 antibody] patients. PDL-1 protein expression was positive (≥1%) in 31/107 (29%) patients. HLA class II antigen expression was positive (≥10%) in 75/112 (67%) patients, with staining restricted to cytoplasm (70%) or cell membrane (30%). EBER was positive (any staining) in 8/108 (7%) patients. Chromosomal rearrangements by FISH were very uncommon for MYC 1/93 (1%), BCL2 1/110 (1%), PDL1/2 1/101 (1%), and CIITA 3/105 (3%). There were no dual rearrangements involving MYC and BCL2, although the only patient with a MYC rearrangement also had a concurrent BCL6 rearrangement. In contrast, BCL6 rearrangements were present in 33/108 (31%) patients, while BCL6 protein expression was positive in 86/111 (77%) patients. With a median follow-up of 8 years (range 8 months - 16 years) in living patients, the 5-year PFS and OS estimates were 11% and 24%, respectively. In univariate analysis, elevated LDH, treatment with WBRT alone or supportive care, and the presence of BCL6 rearrangements (HR 1.73 [95% CI 1.12, 2.66], p=0.011) were significantly associated with worse PFS. Age >60, poor performance status, and treatment with WBRT alone or supportive care were significantly associated with worse OS, and a trend observed with the presence of BCL6 rearrangements (HR 1.46 [95% CI 0.95, 2.27], p=0.085). All other clinical and pathologic variables were not associated with PFS or OS. In the 52 patients treated with HDMTX-based regimens, the presence of a BCL6 rearrangement was the only variable associated with a worse PFS (HR 2.50 [95% CI 1.25 - 5.01], p=0.007), and no variables were associated with OS. Discussion and Conclusions This large TMA study shows that prominent molecular features of PCNSL are different from those of systemic DLBCL. There was a high TMA failure rate reflecting the limitations of brain biopsies, which are often stereotactic needle biopsies, small surgical samples, or obtained after a course of corticosteroids. Consistent with other reports, the majority of cases had a non-GCB phenotype by IHC algorithms, but cell of origin did not impact PFS or OS. MYC, BCL2, and PDL-1 protein expression were common but their corresponding gene rearrangements were extremely uncommon suggesting alternate mechanisms driving expression. BCL6 rearrangements were frequent and were the only factor associated with a poor prognosis in the overall cohort and in the subgroup of patients treated with HDTMX-based regimens. Disclosures Connors: Janssen: Research Funding; Genentech: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Merck: Research Funding; Bristol Myers-Squibb: Research Funding; Bayer Healthcare: Research Funding; F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding; Lilly: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Sehn:TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding. Steidl:Juno Therapeutics: Consultancy; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies.

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