Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era:a report from the International PTL Consortium

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a unique subtype of DLBCL. The impact of rituximab on survival and patterns of treatment failure in PT-DLBCL patient remain controversial. We analyzed the clinical and biological feature of 280 PTDLBCL cases, 64% of which were treated with rituximab-containing regimens. Although most (95%) patients achieved complete remission, a continuous risk of relapse was observed. Rituximab significantly reduced the cumulative risk of relapse (P= 0.022) and improved both progression-free survival (PFS, P= 0.012) and overall survival (OS, P= 0.027) of PT-DLBCL patients (5-year PFS, 56% vs 36%; 5-year OS, 68% vs 48%). Central nervous system and contralateral testis were the most common sites of relapse, but other extranodal and nodal sites of relapse were also observed. Most cases of PT-DLBCL had a non-germinal center B-cell like (84%) immunophenotype and an activated B-cell like (86%) gene expression profile (GEP) subtype. The distinctive GEP signature of primary testicular lymphoma was relevant to tumor cell proliferation, dysregulated expression of adhesion molecules and immune response, likely accounting for the poor outcome. Accordingly, forkhead box P1 transcription factor (FOXP1) and T-cell leukemia/lymphoma 1 (TCL1) oncogenic activation were confirmed and predicted a significant trend of poor survival. This study provides valuable observations for better understanding of both clinical and biological features in PT-DLBCL patients.National Cancer Institute/National Institutes of Health [R01CA138688, 1RC1CA146299, P5OCA136411, P50CA142509]; University of Texas MD Anderson Cancer Center Lymphoma Moonshot Program; Institutional Research and Development Fund; Institutional Research Grant Award; MD Anderson Cancer Center Lymphoma Specialized Programs on Research Excellence (SPORE) Research Development Program Award; MD Anderson Cancer Center Myeloma SPORE Research Development Program Award; Gundersen Lutheran Medical Foundation Award; Michael and Susan Dell Foundation; Shannon Timmins Leukemia Fellowship Award at The University of Texas MD Anderson Cancer Center; Roche Molecular System; Gilead Sciences Pharmaceutical; Seattle Genetics; Dai Sanyo Pharmaceutical; Adaptive Biotechnology; HTG Molecular DiagnosticsSCI(E)[email protected]

Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice

Primary lymphoma of the central nervous system (CNS, PCNSL) is a specific diffuse large B cell lymphoma entity arising in and confined to the CNS. Despite extensive research since many decades, the pathogenetic mechanisms underlying the remarkable tropism of this peculiar malignant hematopoietic tumor remain still to be elucidated. In the present review, we summarize the present knowledge on the genotypic and phenotypic characteristics of the tumor cells of PCNSL, give an overview over deregulated molecular pathways in PCNSL and present recent progress in the field of preclinical modeling of PCNSL in mice. With regard to the phenotype, PCNSL cells resemble late germinal center exit IgM+IgD+ B cells with blocked terminal B cell differentiation. They show continued BCL6 activity in line with ongoing activity of the germinal center program. This together with the pathways deregulated by genetic alterations may foster B cell activation and brisk proliferation, which correlated with the simultaneous MYC and BCL2 overexpression characteristic for PCNSL. On the genetic level, PCNSL are characterized by ongoing aberrant somatic hypermutation that, besides the IG locus, targets the PAX5, TTF, MYC, and PIM1 genes. Moreover, PCNSL cells show impaired IG class switch due to s mu region deletions, and PRDM1 mutations. Several important pathways, i.e., the B cell receptor (BCR), the toll-like receptor, and the nuclear factor-kappa B pathway, are activated frequently due to genetic changes affecting genes like CD79B, SHIP, CBL, BLNK, CARD11, MALT1, BCL2, and MYD88. These changes likely foster tumor cell survival. Nevertheless, many of these features are also present in subsets of systemic DLBLC and might not be the only reasons for the peculiar tropism of PCNSL. Here, preclinical animal models that closely mimic the clinical course and neuropathology of human PCNSL may provide further insight and we discuss recent advances in this field. Such models enable us to understand the pathogenetic interaction between the malignant B cells, resident cell populations of the CNS, and the associated inflammatory infiltrate. Indeed, the immunophenotype of the CNS as well as tumor cell characteristics and intracerebral interactions may create a micromilieu particularly conducive to PCNSL that may foster aggressiveness of tumor cells and accelerate the fatal course of disease. Suitable animal models may also serve as a well-defined preclinical system and may provide a useful tool for developing new specific therapeutic strategies