non-GCB Phenotype Research Articles

Matched control analysis suggests that R-CHOP followed by (R)-ICE may improve outcome in non-GCB DLBCL compared with R-CHOP

AbstractRituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

Clinicopathological features of intravascular large B-cell lymphoma and collision tumors of five cases

Objective: To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Methods: Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. Results: There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. Conclusions: IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.

Germinal Center B-Cell-like (GCB) Phenotype Predicts Improved Outcomes in Central Nervous System Diffuse Large B-Cell Lymphoma Patients Receiving Stereotactic Radiosurgery (SRS)

Background: Diffuse large B cell lymphoma (DLBCL) constitutes most cases of both primary and secondary central nervous system lymphoma (CNSL). They represent a highly aggressive subset of non-Hodgkin lymphoma and prognosis varies depending on the cell of origin. Immunohistochemistry using antibodies for CD10, BCL-6, and MUM-1, also known as the Hans algorithm, is the most common method for determining the cell of origin and predicting outcomes in DLBCL. The study by Hans et al. found that the germinal center B-cell-like (GCB) group had a much better prognosis compared to the non-GCB group, with 5-year overall survival (OS) of 76% and 34% respectively. Despite chemotherapy, recurrence is common in these patients, and up to 40-50% do not achieve durable remission. It is important to identify who may benefit from more aggressive or experimental therapy at diagnosis. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation and limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) CNSL or prognostic implications of the Hans algorithm in these patients. Aim/Objective: To perform a retrospective analysis of outcomes of patients with CNSL, phenotypes determined by the Hans algorithm, treated with SRS at a single comprehensive cancer center. Methods: We studied the demographic, clinical, pathological, and treatment characteristics of r/r CNSL patients (N=27), age ≥ 18 years, who received SRS at Roswell Park Comprehensive Cancer Center between 01/2000 and 01/2023. The Hans algorithm was used to group the patients into non-GCB (N=17) and GCB (N=10) cohorts. Overall survival (OS) and progression-free survival (PFS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Cox regression models were used to describe cross-cohort comparisons of survival. Results: The median Karnofsky performance status at diagnosis was 70 for both groups. The overall response rate (ORR) to SRS in GCB-type was 80% (7 complete response and 1 partial response; CR, PR). The ORR in non-GCB type was 58% (6 CR and 4 PR). Post-SRS, stem cell transplant (SCT) was avoided in 100% of the patients in the GCB group, while 17% of the patients in the non-GCB group received SCT. The 6-month overall survival (OS) rate was 100% and 46% for the GCB-type and non-GCB type respectively (p=0.096, Figure 1A). The 6-month progression-free survival (PFS) rate was 80% for the GCB-type and 33% for the non-GCB type (p=0.024, Figure 1B). In the GCB group, the median OS was 18.0 months while the median PFS was 13.8 months. In the non-GCB group, the median OS was 4.9 months while the median PFS was 3.6 months. The median time from chemotherapy completion to SRS administration was 8.0 months in the GCB-type and 2.0 months in the non-GCB type. Conclusion: Our data support that the GCB-type predicts a more favorable outcome in CNSL, with improved OS and PFS rates compared to the non-GCB type. In addition, the non-GCB type patients required earlier SRS administration and had a lower ORR to SRS. Classifying CNSL into GCB and non-GCB phenotypes using the Hans algorithm might help characterize patients into groups with different prognoses.

A Multi-Omic Study Unveils a Clonal Population of TET2-Mutated Infiltrating T-Cells in Germinal Center B Cell Lymphomas (DLBCL and FL)

Introduction Follicular lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) share a common germinal center (GC) B cell precursor. Nevertheless, these lymphomas appear to originate from different developmental stages, through distinct pathogenetic mechanisms and their clinical behavior varies significantly, even among FL or DLBCL patients. To understand the molecular and transcriptional heterogeneity underlying this clinical diversity we conducted a multi-omic study in GC B cell lymphomas. Methods Our study comprised 3 DLBCL patients (1 non-GCB (germinal center B), 1 non-GCB CD5+, and 1 GCB) and 2 FL (1 with no transformation (ntFL) and 1 patient with transformation (tFL)) at diagnosis. We performed single-cell multiome-sequencing (scDNA-seq + scProtein) ( Tapestri platform -Mission Bio-) and single cell RNA-sequencing (scRNA-seq) ( Chromium system -10xGenomics-) from cell suspensions and spatial transcriptomics ( Visium technology -10xGenomics-) from paraffin blocks. Results Genotyping data were available for 19,700 cells. A total of 311 variants across the 5 samples passed all quality controls. We selected probably pathogenic and pathogenic variants for downstream analysis. Germline variants were discarded. In 3 of 5 patients, we detected 1 somatic and nonsynonymous variant defining the first clone (variants in KMT2D and NOTCH2 mutated in 6-38% of the cells) and another somatic and nonsynonymous variant, defining a subclone (variants in KMT2D, ATM, EZH2 mutated in 1-15% of the cells). In 1 of 5 patients (ntFL), we detected up to 4 mutations, acquired linearly ( B2M, GNA13, EZH2, RHOA mutated clone represents 8% of the cells). Remarkably, all patients showed the same pathogenic variant in TET2 (1-2% of the cells), as an independent clone. The highest molecular similarity was observed between the GCB DLBCL patient and the tFL patient. Both had the same variant in KMT2D as the first hit (later GCB-DLBCL acquired ATM, while tFL acquired EZH2 as a second hit). ATM and EZH2 mutations have been described in “bulk” studies conducted on DLBCL and FL patients, respectively. Regarding protein expression, there was a good correlation between GCB and non-GCB phenotypes studied by immunohistochemistry and scProtein (the expression of CD10 by proteomics was lower in non-GCB patients). TET2 clones described by scDNA-seq were enriched in CD5+ and CD19- cells, suggesting they belong to the T-lymphoid lineage. The other clones and subclones were enriched in CD19+ and CD5- cells ( Figure 1). Data from 54,024 single cells were obtained for scRNA-seq analysis, with an average of 10,805 cells (7,335-18,205) for each sample. Cell type annotation was performed based on the expression of canonical markers. We identified 13 different clusters, the main ones being: GC B cells, post-GC B cells, naïve B cells, myeloid cells, CD8+ cytotoxic T cells, CD4+ naïve T cells, CD4+ reg T cells, CD4+ helper T cells. All samples contained subpopulations of both GC and post-GC B cell clusters. However, GCB DLBCL and FL patients were significantly enriched in GC B cells (63.2 vs 22.2%; p<0.01), whereas non-GCB patients were significantly enriched in post-GC B cells (35.5 vs 2.9%; p<0.01). Part of the normal B-cell transcriptional function was preserved in all samples ( Figure 2). The analysis of the infiltrating T cells revealed that the CD4+/CD8+ T cells ratio progressively increased from ntFL (1.14) to tFL (2.25) and DLBCL (2.58). Furthermore, we estimated the exhaustion status of T cells by the expression of these five markers ( TIGIT, LAG3, CTLA4, HAVCR2, PDCD1). Exhaustion T cell markers were highly expressed in CD8+ cytotoxic T cells and cycling T cells and lower expressed in CD4+ reg T cells. Both DLBCL and tFL have a stronger pattern of exhaustion than ntFL. Finally, by the spatial transcriptomics analysis, we have identified distinct cell type proportions according to their matched single-cell RNA data. Conclusions Our results confirm the intra and intertumor heterogeneity in GC B cell lymphomas. Notably, the greatest molecular and transcriptional similarities are observed between the GCB DLBCL and tFL patients at diagnosis. Moreover, our findings support the critical role of the tumor microenvironment for the persistence and development of the tumor clone. The finding of a TET2 mutated clone in the infiltrating T cells of all the patients is particularly noteworthy, as it may suggest the possible presence of clonal lymphopoiesis.

Clinicopathologic and mutational profiles of primary breast diffuse large B cell lymphoma in a male patient: case report and literature review

IntroductionPrimary breast lymphoma (PBL) is rare, and most cases occur in female patients, with few reported cases in male patients. The clinical presentation is similar to that of breast cancer, but the condition needs to be well understood, as treatment options and clinical course vary. Hence, we provide a relatively rare case of primary breast diffuse large B cell lymphoma (PB-DLBCL) in a male, including its complete clinicopathological features, radiological findings, genomic mutational profiles, and clinical course.Case presentationA 45-year-old male presented with a lump in his right breast for 1 week and was pathologically diagnosed with breast malignancy after a breast puncture biopsy at the local hospital. He came to our hospital for further treatment and underwent breast ultrasound and systemic positron emission tomography/computed tomography (PET/CT) imaging, followed by right mastectomy and sentinel lymph node biopsy. Histomorphology showed diffuse hyperplasia of tumor cells with clear boundaries and surrounding normal breast ducts. The adhesion of tumor cells was poor with obvious atypia. Immunohistochemical results showed that the tumor cells were positive for CD20, Bcl6, and MUM-1 but negative for CK (AE1/AE3), ER, PR, CD3, and CD10. Forty percent of the tumor cells were positive for c-Myc, and 80% of tumor cells were positive for Bcl2. The Ki-67 proliferation index was up to 80%. The tumor cells were negative for MYC and BCL2 rearrangements but positive for BCL6 rearrangement by fluorescent in situ hybridization. No abnormality was found in the pathological examination of bone marrow aspiration. Therefore, the male was diagnosed with PB-DLBCL, nongerminal center (non-GCB) phenotype, dual-expression type. The sample were sequenced by a target panel of 121 genes related to lymphoma. Next-generation sequencing revealed six tumor-specific mutated genes (IGH/BCL6, TNFAIP3, PRDM1, CREBBP, DTX1, and FOXO1). The patient was given six cycles of orelabrutinib plus R-CHOP chemotherapy and two cycles of intrathecal injection of cytarabine. The last follow-up was on April 13, 2023 (17 months). No recurrence or metastasis was found in laboratory and imaging examinations.ConclusionWe reported a relatively rare PB-DLBCL in a male, non-GBC phenotype, dual-expression type. It is worth mentioning that this case had IgH/BCL6 fusion, nonsense mutations in TNFAIP3, frameshift mutations in PRDM1, and missense mutations in CREBBP, DTX1, and FOXO1. To the best of our knowledge, this case is the first report of genomic mutational profiles of PB-DLBCL in males.

Value of GCET1, HGAL (GCET2), and LMO2 in the Determination of Germinal Center Phenotype in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease that is classified into germinal center B-cell (GCB) and non-GCB subtypes, which are prognostically different. The Hans algorithm is the most widely used tool based on CD10, BCL6, and MUM1 expression, but some cases with the non-GCB phenotype are still known to be misclassified. In this study, we investigate the extent to which GCET1, HGAL, and LMO2 protein expressions reflect GCB phenotype together with their roles in determining the GCB phenotype of DLBCL and their contributions to the performance of the Hans algorithm. Sixty-five cases of DLBCL-not otherwise specified, 40 cases of follicular lymphoma (FL), and 19 non-GC-derived lymphoma cases were included in this study. The DLBCL cases were grouped as CD10+ (Group A) or only MUM1+ (Group B), and the remaining cases constituted the intermediate group (Group C). GCET1, HGAL, and LMO2 expressions were evaluated. In the FL group, GCET1, HGAL, and LMO2 were positive in 85%, 77.5%, and 100% of the cases, respectively. Among the non-GC-derived lymphoma cases, all three markers were negative in cases of small lymphocytic lymphoma, plasmablastic lymphoma, peripheral T-cell lymphoma, and anaplastic large cell lymphoma. GCET1 and HGAL were negative in cases of marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). Two of the 3 MZL and 2 of the 4 MCL cases were positive for LMO2. In the DLBCL group, the number of cases with GCET1, HGAL, and LMO2 positivity was 18 (90%), 17 (85%), and 20 (100%), respectively, in Group A and 0 (0%), 2 (13.3%), and 2 (13.3%), respectively, in Group B. Considering these rates, when the cases in the intermediate group were evaluated, it was concluded that 13 cases typed as non-GCB according to the Hans algorithm may have the GCB phenotype. GCET1, HGAL, and LMO2 are highly sensitive markers for determining the germinal center cell phenotype and can increase the accuracy of the subclassification of DLBCL cases, especially for cases that are negative for CD10.

Tumor Microenvironment and It's Prognostic Value Is Different in Testicular and Systemic Diffuse Large B-Cell Lymphoma

Testicular diffuse large B-cell lymphoma (T-DLBCL) is an aggressive lymphoid cancer with distinct clinical and biological features. Majority of the cases represent non-GCB phenotype, but the genetic landscape with frequent aberrations in MYD88, NFKBIZ, PDCD1LG2, and CD274 differ from systemic non-GCB DLBCL and highlight the significance of immune-escape and tumor microenvironment (TME). We have previously shown that high T-cell gene expression signature and high tumor-infiltrating lymphocyte (TIL) content translate to better survival in testicular but not in systemic DLBCL. We have also described a subpopulation of T-bet+FoxP3+ Tregs that have a significant adverse impact on survival in T-DLBCL but not in in systemic DLBCL. In order to further characterize the differences in the TME between T- and systemic DLBCL, we used NanoString digital gene expression profiling to assess the expression of 770 immune response genes in 60 T-DLBCL and 84 systemic DLBCL samples. In addition, we used multiplex immunohistochemistry (mIHC) to characterize TILs, tumor-associated macrophages (TAMs), NK-cells, checkpoint molecules, cell proportions, and cell interactions in 80 T-DLBCLs and 192 systemic DLBCLs. Unsupervised hierarchical clustering of the gene expression data revealed clusters of genes with differential expression between T- and systemic DLBCLs. In T-DLBCL, 11 HLA genes were downregulated and genes related to B-cell receptor (BCR) signaling upregulated compared to systemic DLBCL. All T-DLBCL patients that clustered among the patients with systemic DLBCL had high T-cell signature expression, and systemic DLBCL patients that clustered among patients with T-DLBCL had significantly higher Ki-67 expression (p=0.00085). Based on the mIHC data, we observed not only a significantly lower proportion of FoxP3+ Tregs altogether but also a higher proportion of T-bet+FoxP3+ double positive Tregs in T-DLBCL compared to systemic DLBCL, confirming our previous findings on the significant role of T-bet+FoxP3+ double positive Tregs in the T-DLBCL TME. We also observed less TAMs in T-DLBCL TME. Unsupervised hierarchical clustering of the cell interaction data verified that distinct interaction clusters are found and separate the patients into different subgroups. Interactions of cytotoxic T-cells were more commonly seen in T-DLBCL whereas interactions of PD-1 expressing cells and interactions between TILs and TAMs were more frequent in systemic DLBCL. Taken together, our results reveal differences in the TME between T- and systemic DLBCL, and further emphasize the impact of immune escape and distinct immune cells in T-DLBCL. Future studies are ongoing in order to further characterize the cell-to-cell interactions, their association with survival, and TME differences between T- and systemic DLBCL, in particular non-GCB DLBCL.

Clinical Outcomes and CNS Relapse Risk in Patients with Primary Cutaneous DLBCL, Leg Type Treated in the Rituximab Era: Long-Term Follow-up of a Single-Center Experience

Clinical Outcomes and CNS Relapse Risk in Patients with Primary Cutaneous DLBCL, Leg Type Treated in the Rituximab Era: Long-Term Follow-up of a Single-Center Experience

Primary central nervous system lymphomas with massive intratumoral hemorrhage: Clinical, radiological, pathological, and molecular features of six cases.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

High Amount of PD-L1+ Tumor Associated Macrophages Is Associated with Better Survival in Patients with Primary Testicular Lymphoma

Introduction:Primary testicular lymphoma (PTL) is a rare and aggressive extranodal lymphoid malignancy with poor outcome to therapy and largely uncharacterized biology. Majority of PTLs are diffuse large B-cell lymphomas (DLBCL). Tumor associated macrophages (TAMs) are known to have prognostic impact in DLBCLs, but their role in PTLs has not been addressed. The aim of this study was to examine the association of TAMs with disease characteristics and survival in patients with PTL.Patients and methods:We identified 74 patients with PTL, all representing DLBCL histologically. Tissue microarray (TMA) was constructed from PTL samples and TMA slides were stained using multiplex immunohistochemistry (mIHC), allowing a detection of four markers (CD68, cMAF, PD-L1 and PD-L2) and nuclei simultaneously. Expression profiles were analyzed quantitatively with the image analysis software Cell Profiler. In addition, CD68, PD-L1, and PD-L2 mRNA levels were measured from 60 PTL samples.Results:For the 74 patients in the mIHC cohort, median age at diagnosis was 70 years (36-92 years) and median follow-up 67 months (range 6.7 to 120 months). Majority of the patients represented non-germinal center B-cell (non-GCB) phenotype (76%), low stage (I-II, 64%), and low/intermediate International Prognostic Index (IPI 0-2, 68%). Thirty-five patients (47%) were treated with rituximab containing chemotherapy and 36 patients (49%) received central nervous system (CNS) prophylaxis, most of them (n=34) with CNS penetrating intravenously administered chemotherapy. Altogether 34 deaths, 24 relapses and 24 lymphoma associated deaths occurred during the follow-up. 5-year overall survival (OS), disease specific survival (DSS) and progression free survival (PFS) rates were 56%, 68%, and 53%, respectively.The median proportions of PD-L1+ cells, CD68+, PDL1+CD68+, CD68+cMAF+ (M2 type), and PD-L1+CD68+cMAF+ macrophages of all cells in the tumor tissue were 15.3%, 23.7%, 9.1%, 1.3%, 0.5%, respectively. In univariate analyses with continuous variables, the proportion of PD-L1+ cells (p=0.039) and PDL1+CD68+ macrophages (p=0.043) correlated with a favorable OS. A trend towards a better OS was also observed for PD-L1+CD68+cMAF+ (p=0.090) macrophages, whereas neither PD-L1-CD68+cMAF+ macrophages nor PD-L1+CD68- cells had an impact on survival. Furthermore, no correlation with survival was found for any of the PD-L2+ cells. According to Kaplan-Meier estimates, the patients with the high proportion of PD-L1+CD68+ macrophages had a 5-year OS of 65% in comparison to 41% for those with the lower counts (p=0.026). The difference was more clear in the subgroup of patients with a stage III-IV disease (n=24, 5-year OS, 67% vs 25%, p=ns). When clinical characteristics of the patients were compared according to PD-L1+CD68+ cell counts, no significant differences in age or molecular subtype were observed between the subgroups. However, in the high PDL1+CD68+ group, more patients had stage I-II disease (p<0.001) and low/intermediate IPI score (IPI 0-2, p=0.023). PD-L1 and CD68 gene expressions correlated with corresponding cell counts (for both, rs≥0.673, p<0.001) and favorable OS (PD-L1, p=0.007; CD68, p=0.016).Conclusion:Our data demonstrate a significant variation in TAM contents and their phenotypes in PTL, and an association of PD-L1+ TAMs with more localized disease and favorable survival in patients with PTL. DisclosuresPollari:Novartis: Other: Conference attendance fees and travel expences; Pierre Fabre: Other: Conference attendance fees and travel expences; BMS: Other: Conference attendance fees and travel expences; Takeda: Other: Conference attendance fees and travel expences; Roche: Consultancy. Mannisto:Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; Roche: Honoraria, Other: Travel expence; SOBI: Honoraria. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria; Ariad: Research Funding. Leppa:Takeda: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bayer: Research Funding.

Elevated Pre-Therapeutic Serum Levels of Soluble Programmed Death 1 Protein (sPD-1) Identify DLBCL Patients with Adverse Prognostic Features

* Contributed equally to this workBackgroundCheckpoint proteins regulate the immune system and their down-regulation of effector mechanisms is exploited by malignant cells to evade antitumor response. Membrane bound programmed death 1 protein (PD-1) and its ligand (PD-L1) are checkpoint proteins whose over-expression has been reported as an adverse prognostic factor in lymphoid malignancies. Monoclonal antibodies targeting these checkpoint proteins are therefore a rational therapy trying to re-establish an effective antitumor immunity.Soluble forms of PD-1 and PD-L1 (sPD-1 and sPD-L1) exist, but their biological and clinical significance is yet to be clarified. High pre-therapeutic levels of sPD-L1 have been reported to impact overall survival in diffuse large B cell lymphomas (DLBCL). However, the role and significance of soluble levels of the receptor protein sPD-1 are still largely unknown.AimsThe aims of the present study were to measure pre-therapeutic sPD-1 levels in selected lymphoid malignancies and, for de novo DLBCL, investigate the potential correlation with outcome-related parameters.MethodsWe established and validated a Time Resolved Immunoflourometric assay (TRIFMA) to determine levels of sPD-1. In total, 106 archival serum samples were analysed in duplicate. This single-institution study population consisted of patients with chronic lymphocytic leukemia (CLL; n=42), DLBCL (n=30), Hodgkin lymphoma (HL; n=12), and healthy controls (n=22).Information on clinical parameters was obtained from medical records. sPD-1 levels were compared between patient subgroups and controls using a non-parametric test (Mann-Whitney). Correlation with clinical parameters were analysed using a linear regression model and Spearman's rank correlation. P-values below 0.05 were considered statistically significant.ResultsIn general, sPD-1 levels were higher in patients, taken as one group, compared to controls (p=0.002, see table 1). When analysed according to individual diagnostic subgroups, patients with DLBCL and CLL still had, despite of their limited cohort size, significantly elevated sPD-1 levels compared to controls (p=0.009 and p=0.002, respectively), while patients with HL did not. Although not significantly different, DLBCL patients showed consistently higher mean values of sPD-1 compared to CLL and HL (see table 1).A separate analysis of patients with DLBCL revealed a positive correlation between pre-therapeutic sPD-1 and IPI-score (β1=0.579 (95% CI 0.169;0.990), p=0.007)(see figure 1). The correlation was confirmed with Spearman's test of no association (p=0.0043). More specifically, higher sPD-1 levels correlated with higher IPI score and with the presence of known adverse prognostic factors such as age >60 years, disseminated clinical stage, elevated p-LDH, ECOG performance score ≥2, presence of >1 extranodal site.DLBCL patents were also analysed according to whether their tumor cell population was of GCB (n=14) or non-GCB (n=16) origin (assessed by the immunohistochemistry-based Hans algorithm). Non-GCB cases (mean 671 pg/ml (95% CI 268; 1680)) had higher sPD-1 levels than GCB cases (mean 323 pg/ml (95% CI 174; 560)), however not statistically significant (p=0.1575).ConclusionPre-therapeutic serum levels of sPD-1 were found to be higher in selected lymphoid malignancies (DLBCL, CLL) than in healthy controls. Highest mean values were detected in DLBCL patients, where higher sPD-1 levels also significantly correlated to the presence of classical clinical prognosticators for adverse outcome and, possibly, also to a non-GCB phenotype. Correlation analyses between pre-therapeutic levels of sPD-1, sPD-L1 and clinico-pathological features as well as clinical behaviour and outcome are ongoing. [Display omitted] DisclosuresClausen:Takeda: Research Funding. d'Amore:Nordic Nanovector: Other: Advisory Board; Les Laboratoires Servier: Honoraria, Other: Advisory Board; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding; Sanofi: Research Funding.

High-Grade B-Cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Rearrangements Is Predominantly BCL6-Rearranged and BCL6-Expressing in Taiwan

Simple SummaryThis study highlights the epidemiological, cytogenetic and clinical difference between patients with multiple hit diffuse large B-cell lymphoma in Taiwan and those from western countries. Unlike in the West, the majority of patients with multiple hit lymphoma in Taiwan harbor a BCL6 rearrangement. Almost three in every five BCL6-rearranged double hit lymphoma cases in Taiwan are non-GCB phenotype, indicating, at least in part, that the preferential screening for double hit with BCL6 rearrangement may be a clinically-informative modality for patients with non-GCB phenotype DLBCL in Taiwan. This also suggests the need for a different treatment approach than is obtained in the West where BCL6 double hit lymphomas are seemingly GCB. Consistent with our present findings, mandatory screening for BCL6-rearrangement in suspected DLBCL cases in Taiwan may aid early diagnosis, therapy decision, and clinical outcome forecast.This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.

A Combination of Multilayer Perceptron, Radial Basis Function Artificial Neural Networks and Machine Learning Image Segmentation for the Dimension Reduction and the Prognosis Assessment of Diffuse Large B-Cell Lymphoma

The prognosis of diffuse large B-cell lymphoma (DLBCL) is heterogeneous. Therefore, we aimed to highlight predictive biomarkers. First, artificial intelligence was applied into a discovery series of gene expression of 414 patients (GSE10846). A dimension reduction algorithm aimed to correlate with the overall survival and other clinicopathological variables; and included a combination of Multilayer Perceptron (MLP) and Radial Basis Function (RBF) artificial neural networks, gene-set enrichment analysis (GSEA), Cox regression and other machine learning and predictive analytics modeling [C5.0 algorithm, logistic regression, Bayesian Network, discriminant analysis, random trees, tree-AS, Chi-squared Automatic Interaction Detection CHAID tree, Quest, classification and regression (C&amp;R) tree and neural net)]. From an initial 54,613 gene-probes, a set of 488 genes and a final set of 16 genes were defined. Secondly, two identified markers of the immune checkpoint, PD-L1 (CD274) and IKAROS (IKZF4), were validated in an independent series from Tokai University, and the immunohistochemical expression was quantified, using a machine-learning-based Weka segmentation. High PD-L1 associated with poor overall and progression-free survival, non-GCB phenotype, Epstein–Barr virus infection (EBER+), high RGS1 expression and several clinicopathological variables, such as high IPI and absence of clinical response. Conversely, high expression of IKAROS was associated with a good overall and progression-free survival, GCB phenotype and a positive clinical response to treatment. Finally, the set of 16 genes (PAF1, USP28, SORT1, MAP7D3, FITM2, CENPO, PRCC, ALDH6A1, CSNK2A1, TOR1AIP1, NUP98, UBE2H, UBXN7, SLC44A2, NR2C2AP and LETM1), in combination with PD-L1, IKAROS, BCL2, MYC, CD163 and TNFAIP8, predicted the survival outcome of DLBCL with an overall accuracy of 82.1%. In conclusion, building predictive models of DLBCL is a feasible analytical strategy.

Clinicopathological features of primary central nervous system diffuse large B cell lymphoma: Experience from a Tertiary Center in North India.

Background: Primary central nervous system-diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare extra-nodal Non-Hodgkin lymphoma. There is relative paucity of literature on PCNSL from Indian subcontinent. We aimed to analyze the clinicopathological features of PCNSL and categorize them into germinal center B cell (GCB) and non-GCB subtypes to assess their prognostic significance in Indian context.Methods: All patients with histopathologically diagnosed PCNSLs at our center over a period of 6 years were recruited and classified into GCB and non-GCB using Han’s algorithm (immunohistochemistry for CD10, BCL6 and MUM1). In situ hybridization (ISH) for Epstein-Barr virus (EBV)-encoded RNA was performed.Results: Eighty-six cases of PCNS-DLBCL were included with median age of 55 years. Majority of them were supratentorial in location (n = 62). All patients were immunocompetent. On immunohistochemical assessment, 69 (80.2%) were of NGCB subtype, 10 (11.6%) were of GCB subtype, and 7 (8.1%) were unclassified. Overall, MUM1, BCL-6, and CD10 expressions were seen in 69 (80.2%), 28 (32.6%), and 2 cases (2.3%), respectively. Four cases (4.6%) showed C-MYC expression. The median overall survival (OS) was 675 days. None of the factors (age, sex, location, immunomarkers, and GCB vs. NGCB phenotype) showed correlation with OS; however, BCL6 positive cases showed slight better OS (P > 0.05). All cases were negative for EBV-LMP1 on ISH.Conclusion: The majority of the CNS DLBCL belongs to non-GCB phenotype and uniformly carry poor prognosis, irrespective of their phenotype. Individual markers, such as BCL-6, MUM1, or CD10, are unable to predict outcome in PCNS-DLBCL.

Preliminary Results of a Response-Adapted Study of Ibrutinib and Isavuconazole with Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) for Secondary CNS Lymphoma

Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a very poor prognosis. Genetic subtypes of DLBCL with CNS tropism are enriched for chronic active B-cell receptor signaling and may respond to BTK inhibition (BTKi). CLL, MCL, and transformed lymphomas can also involve the CNS and are BTKi responsive. TEDDI-R achieves durable remissions in relapsed/refractory primary DLBCL of the CNS (PCNSL) but the profile of SCNSL tumors that are ibrutinib-responsive is unknown. We present preliminary results from a response-adapted trial of ibrutinib with TEDD-R in SCNSL. Methods: Pts with aggressive B-cell lymphomas with secondary CNS involvement are eligible if age ≥18 and adequate organ function. Pts must have relapsed after frontline therapy or can be untreated if brain parenchyma involved. Prior BTKi is allowed, but HIVinfection and EBV+ lymphomas are excluded. Baseline tests include brain MRI, FDG-PET brain and body, CSF with flow cytometry, Ommaya, and eye exam. Pts receive isavuconazole starting at 200mg BID x 3d prior to ibrutinib to prevent fungal infections associated with TEDDI-R and then 200mg daily unless ibrutinib stopped. Pts first receive ibrutinib 560mg daily x 14d in a window. If ≥20% reduction after ibrutinib, pts receive TEDDI-R for 4 cycles every 21d with IT cytarabine. Pts with &amp;lt;20% reduction after ibrutinib receive TEDD-R without ibrutinib for 4 cycles every 21d with IT cytarabine. No consolidation or maintenance is permitted. Surveillance for fungal infections includes chest CT after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI and CT scans are performed after cycles 1, 2, and 4 to determine response. All remissions by MRI are confirmed with FDG-PET and CSF analysis. Surveillance brain MRI and CT scans are q3m for 1y, q4m x 1y, q6m x 1y, then annually. Results: 16 pts with a median age 67 (range 40-79) enrolled between June 2019 and July 2020. 15 (94%) pts had DLBCL comprising 9 (60%) non-GCB, 5 (33%) GCB, and 1 (7%) transformed from MZL. One pt had plasmablastic lymphoma. Eight (50%) pts had a MYC-rearrangement including 4 (25%) with both MYC and BCL2 or BCL6 rearrangements. Eight (50%) pts had isolated CNS disease and 8 (50%) had synchronous CNS and peripheral disease. All pts relapsed after a median of 2 (range 1-4) prior therapies and all (100%) pts received prior anthracycline. Seven pts (44%) had prior CNS prophylaxis and 8 pts (50%) had prior HD-MTX based salvage therapy. Toxicity was evaluated across 35 cycles. G3 and G4 neutropenia occurred in 49% and 29% of cycles, respectively, while febrile neutropenia occurred in 9% of cycles. The median (range) duration of neutropenia was 6 (1-13) days. Five (14%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. One pt developed a bacterial infection during cycle 1 and died. G3 and G4 thrombocytopenia occurred in 34% and 23% of cycles, respectively, and 1 pt developed G3 hematuria. G3 mucositis occurred in 9% of cycles and palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 5 (36%) pts. Of 15 pts who completed the 14d ibrutinib window and were evaluable, 8 (53%) were ibrutinib-responsive and 7 (47%) were ibrutinib-resistant (Figure 1). Clinical responses were concordant across anatomic compartments; of 8 pts with both CNS and peripheral disease, 5 (63%) responded to ibrutinib in both compartments while 3 (37%) did not respond in either compartment. All 8 ibrutinib responders had a non-GCB phenotype and six (75%) achieved CR. One died of treatment-related toxicity after a PR and 1 is still on therapy. Only two (29%) pts with ibrutinib-resistant tumors achieved PR and none have achieved CR. After a median follow-up of 5.1m, a landmark analysis starting after the ibrutinib window demonstrated the PFS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors was not reached vs. 0.9m (95% CI: 0.1-2m)(p=0.002)(Figure 2). Conclusions: Patients with SCNSL tumors that are ibrutinib-responsive achieve a high rate of complete response to TEDDI-R in both CNS and peripheral disease. Patients with tumors that are ibrutinib-resistant also respond poorly to TEDD-R. Toxicity is mainly hematologic, and no Aspergillus infections have occurred with the use of isavuconazole prophylaxis. Updated clinical results from this ongoing study (NCT03964090) and will be presented at the meeting. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: ibrutinib for use in secondary cns lymphoma as part of a clinical trial

A Single Gene Expression Set Derived from Artificial Intelligence Predicted the Prognosis of Several Lymphoma Subtypes; and High Immunohistochemical Expression of TNFAIP8 Associated with Poor Prognosis in Diffuse Large B-Cell Lymphoma

Objective: We have recently identified using multilayer perceptron analysis (artificial intelligence) a set of 25 genes with prognostic relevance in diffuse large B-cell lymphoma (DLBCL), but the importance of this set in other hematological neoplasia remains unknown. Methods and Results: We tested this set of genes (i.e., ALDOB, ARHGAP19, ARMH3, ATF6B, CACNA1B, DIP2A, EMC9, ENO3, GGA3, KIF23, LPXN, MESD, METTL21A, POLR3H, RAB7A, RPS23, SERPINB8, SFTPC, SNN, SPACA9, SWSAP1, SZRD1, TNFAIP8, WDCP and ZSCAN12) in a large series of gene expression comprised of 2029 cases, selected from available databases, that included chronic lymphocytic leukemia (CLL, n = 308), mantle cell lymphoma (MCL, n = 92), follicular lymphoma (FL, n = 180), DLBCL (n = 741), multiple myeloma (MM, n = 559) and acute myeloid leukemia (AML, n = 149). Using a risk-score formula we could predict the overall survival of the patients: the hazard-ratio of high-risk versus low-risk groups for all the cases was 3.2 and per disease subtype were as follows: CLL (4.3), MCL (5.2), FL (3.0), DLBCL not otherwise specified (NOS) (4.5), multiple myeloma (MM) (5.3) and AML (3.7) (all p values &lt; 0.000001). All 25 genes contributed to the risk-score, but their weight and direction of the correlation was variable. Among them, the most relevant were ENO3, TNFAIP8, ATF6B, METTL21A, KIF23 and ARHGAP19. Next, we validated TNFAIP8 (a negative mediator of apoptosis) in an independent series of 97 cases of DLBCL NOS from Tokai University Hospital. The protein expression by immunohistochemistry of TNFAIP8 was quantified using an artificial intelligence-based segmentation method and confirmed with a conventional RGB-based digital quantification. We confirmed that high protein expression of TNFAIP8 by the neoplastic B-lymphocytes associated with a poor overall survival of the patients (hazard-risk 3.5; p = 0.018) as well as with other relevant clinicopathological variables including age &gt;60 years, high serum levels of soluble IL2RA, a non-GCB phenotype (cell-of-origin Hans classifier), moderately higher MYC and Ki67 (proliferation index), and high infiltration of the immune microenvironment by CD163-positive tumor associated macrophages (CD163+TAMs). Conclusion: It is possible to predict the prognosis of several hematological neoplasia using a single gene-set derived from neural network analysis. High expression of TNFAIP8 is associated with poor prognosis of the patients in DLBCL.

Central Nervous System Prophylaxis with High-Dose Intravenous Methotrexate or Intrathecal Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma and High-Risk of CNS Relapse Treated in the Rituximab Era

Central Nervous System Prophylaxis with High-Dose Intravenous Methotrexate or Intrathecal Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma and High-Risk of CNS Relapse Treated in the Rituximab Era

COO, MYC / BCL2 Status and R-IPI Define a Group of Poor Prognosis DLBCL Patients in a Real-World Clinical Setting

BACKGROUND In DLBCL, and mainly in advanced-stage, the presence of an activated B-cell phenotype or a non-GCB phenotype, and the coexpression of Myc and Bcl2 protein by IHC, are usually considered to be associated with inferior outcomes. Some recent studies however found that non-GCB COO did not have prognostic impact in limited stage DLBCL patients. Further, in real life patient management, the clinical relevance of the assessment of the COO, and of Myc and Bcl2 protein overexpression (DE), is still not fully clarified. The aim of the research was to evaluate in a real-life context the prognostic impact of the COO and of DE status together with R-IPI. With this purpose we have therefore evaluated 142 DLBCL patients in stage I/IV by PET-CT. METHODS This is a retrospective multicenter study which recruited 142 DLBC patients with PET-CT-defined stage I/IV treated with R-CHOP or R-CHOP like between 2010 and 2016 in Modena, Rome and Pisa (Italy) and Haifa (Israel). Eligible patients had a morphologic diagnosis of DLBCL. All clinical data were recorded at diagnosis and during follow up including response assessment and survival outcome. COO was determined on FFPE diagnostic specimens either by IHC applying Hans algorithm, or at RNA level with Lymph2Cx assay by Nanostring technology. Expression of Myc and Bcl2 to define DE status was evaluated by IHC considering Myc and Bcl2 positive ≥40% and ≥50%, respectively. PET-CT imaging was interpreted locally utilizing Deauville criteria. The end points of the study were to determine the impact of COO, Myc/Bcl2 status and R-IPI on PFS and OS. PFS and OS were calculated using the Kaplan-Meyer method with 95 confidence interval (95C%CI), comparison between groups were made with logrank test. The effect of covariates was estimate by means of Cox PH regression, as hazard ratio (HR) with 95%CI. Statistical tests with P&lt;0.10 were considered clinically interesting. RESULTS We identified 142 patients with morphological diagnosis of DLBCL and with PET-CT-defined Stage I/IV treated with R-CHOP or CHOP-like regimens between 2011 and 2018. Patients with evidence of histologic transformation from indolent lymphoma, and double-hit high grade lymphoma were excluded. Median age was 63 yrs, 55% were more than 65 yrs old, 64% had stage III/IV, and 38% had R-IPI 3-5. Bcl2 and Myc were positive in 65% and 20%, respectively. Double expression of Bcl2 and Myc was found in 20% of cases. By Lympho2Cx, COO subtypes were ABC, CGB and Unclassified in 37 %, 46 % and 16 %, respectively. We observed a good concordance between COO determined by Lympho2Cx and Hans algorithm (0.718). Analysis of association between COO subtype by Lympho2Cx and baseline characteristics showed significant association of ABC subtype with B symptoms, R-IPI 3-5, BCL2+, but not with Myc+ , end of treatment PET+, and Response. After a median follow up of 49 months, 3 yrs and 5 yrs PFS and OS were 65% and 59%, respectively in PFS and 80% and 73 % in OS. By univariable analysis we observed significant differences between R-IPI 3-5 vs 0-2, stage III-IV vs I-II, and Bcl2 + vs -. GCB and Unclassified subtypes, Myc - and DE - showed better PFS and OS in comparison with ABC subtype, Myc + and DE +, but the differences were not statistically significant. Forty-seven of the 142 patients underwent SNC prophylaxis with MTX IT or IV. While in patients who received consolidation treatment no difference in PFS or OS between GCB and ABC were observed, patients with GCB subtype showed better PFS and OS in comparison with ABC patients (P=0.05). Based on the results of the univariable analysis, we have assembled a Score from 0 to 3 with R-IPI 3-5 (weight 1), Bcl2 + (weight 1) and ABC subtype (weight 1). The differences in 5 yrs PFS and OS between Score 0, 1, 2-3 were statistically significant (Fig 1). Discussion Although COO is considered a relevant prognostic factor, several studies have produced conflicting results. Our retrospective study conducted on a relatively small group of cases shows that patients with GCB and Unclassified subtypes and DE have a moderately improvement of survival outcome. However, a score based on ABC subtype, Bcl2 overexpression and a high R-IPI score is able to identify a group of poor prognosis patients. As determination of COO by Lympho2Cx is rapid to perform and potentially applicable to clinical practice as well as the determination of Bcl2 and Myc protein expression by IHC, we believe that the use of the Score is useful in patient management in the real life context. Figure 1 Disclosures No relevant conflicts of interest to declare.

Genomic Analysis of R2CHOP-Treated DLBCL Reveals a High-Risk Population Driven By Inflammatory Pathways

Genomic Analysis of R2CHOP-Treated DLBCL Reveals a High-Risk Population Driven By Inflammatory Pathways

Ventricle-predominant primary CNS lymphomas: clinical, radiological and pathological evaluation of five cases and review of the literature

Primary central nervous system lymphomas (PCNSLs) are typically intraparenchymal. A subset of PCNSLs predominantly arises in the ventricles, with minimal parenchymal involvement. We review the clinical, radiological, and pathological features of ventricle-predominant PCNSLs (VP-PCNSLs) in 40 previously reported cases and report 5 additional cases. Including all cases of VP-PCNSLs (n = 45), 38% were diffuse large B-cell lymphomas (DLBCL), 11% were Burkitt lymphomas, 7% were MALT lymphomas, 4% were T-cell lymphomas, and 40% were lymphomas, not otherwise classified. VP-PCNSLs show rapid clinical progression. Patients present at a median age of 60.5years. Unique clinical and radiological features distinguish them from other intraventricular tumors, including advanced age, edema, multifocality, hyperdensity, early and avid post-contrast enhancement, restricted diffusion, and positron emission tomography (PET) hypermetabolism. Including our cases, which were all DLBCL, and all previously reported DLBCL cases (n = 10), 8 of 10 show germinal center B-cell-like (GCB) phenotype, contrasting the high prevalence of non-germinal center B-cell-like (non-GCB) phenotype of parenchymal DLBCL PCNSLs. MYD88 L265P mutation was detected in three of our five cases. Ventricle-predominant PCNSLs are clinically and radiologically distinct, and the DLBCLs may be pathologically distinct. Further recognition of this entity may help to evaluate the role of therapies, possibly including surgical resection.