Central Nervous System Diffuse Large B-cell Lymphoma Research Articles

Clinical Features and Prognosis Analysis of 168 Cases of MYC/BCL2 Double Expression Diffuse Large B Lymphoma

Objective: A retrospective study of the clinical features and prognosis of MYC/BCL2 double-expressor diffuse large B-cell lymphoma (DEL). Methods: A retrospective analysis was conducted on patients diagnosed with MYC/BCL2 double-expressor diffuse large B-cell lymphoma (DEL) for the first time by pathological and fluorescence in situ hybridization (FISH) techniques at Fujian Medical University Affiliated Union Hospital from January 2017 to December 2021. Clinical features, immunohistochemistry, laboratory tests, treatment plans, and follow-up information of all patients were collected. Kaplan-Meier analysis was used for univariate analysis, and Cox proportional hazards model was used for multivariate analysis. Results: Clinical characteristics:Among the 168 patients with diffuse large B-cell lymphoma (DLBCL), 13 cases (7.7%) involved the primary central nervous system. Of the patients, 95 (56.55%) were male and 73 (43.45%) were female, resulting in a male-to-female ratio of 1.3:1. The age of onset was at least 60 years for 93 cases (55.36%), with the youngest being 22 years old and the oldest being 88 years old. The median age was 62 years old. A total of 113 cases (72.90%) were classified as stage III-IV by the Ann Arbor staging system, 40 cases (23.81%) had B symptoms, 82 cases (52.90%) had an International Prognostic Index (IPI) score of 3-4, 84 cases (54.19%) had involvement of two or more extranodal sites, 87 cases (51.79%) had a β2-microglobulin (β2-MG) level of ≥2.53mg/L, 122 cases (72.62%) had a serum albumin (SA) level of <35g/L, and 103 cases (61.31%) had elevated levels of lactate dehydrogenase (LDH).Survival status: Complete follow-up data were available for 162 DEL patients, with a median follow-up time of 20.38 (1-73) months. The median overall survival (OS) was not reached, while the median progression-free survival (PFS) was 37.1 months. Among them, and 58 (34.5%) died. Survival analysis was performed on 168 DEL patients, with 1-year, 3-year, and 5-year OS rates of 82.1%, 61.1%, and 58.9%, respectively. The 1-year, 3-year, and 5-year PFS rates were 69.5%, 51.4%, and 45.6%, respectively. Among the 93 elderly (≥60 years old) DEL patients, the 1-year, 3-year, and 5-year OS rates were 77.2%, 52.7%, and 48.6%, respectively, and the 1-year, 3-year, and 5-year PFS rates were 67.4%, 47.4%, and 43.7%, respectively. The 1-year and 3-year OS rates of the 13 patients with primary central nervous system DLBCL were 25.50%, and the 1-year and 3-year PFS rates were 16.70%.Clinical efficacy analysis: Among 168 patients with DEL, the complete remission (CR) rate was 62.5% (105/168), the partial remission (PR) rate was 3.5% (6/168), the overall effective rate (ORR) was 66.1%, and the relapse/progression rate was 25.6% (43/168). Comparing the efficacy of 88 patients treated with the R-CHOP regimen with 32 patients treated with sildalafil combined with the R-CHOP regimen, the results showed a higher CR rate (81.25% vs. 67.05%) and a lower relapse rate (3.13% vs. 12.5%) in patients treated with sildalafil combined with the R-CHOP regimen.4. Univariate analysis: Age over 60 years ( P=0.031), B symptoms ( P=0.031), advanced Ann Arbor stage (P=0.003), high IPI score ( P<0.001), elevated LDH ( P=0.031), and elevated β2-MG( P<0.001) were significantly correlated with poor prognosis in DEL patients, and were identified as adverse prognostic factors. Non-GCB subtype ( P=0.029), B symptoms ( P<0.001), advanced Ann Arbor stage ( P<0.001), high IPI score ( P<0.001), decreased serum albumin ( P<0.001), elevated LDH (P=0.085), and elevated β2-MG(P<0.001) were significantly associated with poorer progression-free survival (PFS) among DEL patients.5.Multivariate analysis revealed that elevated β2-MG levels and high IPI scores were independent risk factors for poor overall survival (OS) in DEL patients, with HR values of 2.363 and 7.090, respectively. B symptoms, elevated β2-MG levels, and reduced serum albumin (SA) levels were independent risk factors for poor progression-free survival (PFS) in DEL patients, with HR values of 1.819, 2.879, and 1.987, respectively. Conclusion: Elevated β2-microglobulin and high IPI scores in DEL patients are risk factors for OS, while B symptoms, elevated β2-microglobulin, and decreased serum albumin are risk factors for PFS. Keywords: Lymphoma, diffuse large B-cell, clinical features, prognosis, double- expression lymphoma

Double-hit and double-expressor primary central nervous system lymphoma: Experience from North India of an infrequent but aggressive variant.

High-grade non-Hodgkin B-cell lymphoma is an aggressive mature B-cell lymphoma that depicts poor treatment response and worse prognosis. The presence of MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements qualifies for triple-hit and double-hit lymphomas (THL/DHL), respectively. We attempted to explore the incidence, distribution, and clinical characteristics of the primary high-grade B-cell lymphoma of the central nervous system (CNS) in our cohort from North India. All the histologically confirmed cases of primary CNS diffuse large B-cell lymphoma (PCNS-DLBCL) over a period of 8 years were included. Cases showing MYC and BCL2 and/or BCL6 expression on immunohistochemistry (IHC) (double- or triple-expressor) were further analyzed by fluorescence in situ hybridization for MYC, BCL2 and /or BCL6 rearrangements. The results were correlated with other clinical and pathological parameters, and outcome. Of total 117 cases of PCNS-DLBCL, there were seven (5.9%) cases of double/triple-expressor lymphomas (DEL/TEL) (six double- and one triple-expressor) with median age of 51 years (age range: 31-77 years) and slight female predilection. All were located supratentorially and were of non-geminal center B-cell phenotype. Only triple-expressor case (MYC+/BCL2+/BCL6+) demonstrated concurrent rearrangements for MYC and BCL6 genes indicating DHL (n = 1, 0.85%), while none of the double-expressors (n = 6) showed MYC, BCL2, or BCL6 rearrangements. The mean overall survival of the DEL/TEL was 48.2 days. DEL/TEL and DHL are uncommon in CNS; mostly located supratentorially and are associated with poor outcome. MYC, BCL2, and BCL6 IHC can be used as an effective screening strategy for ruling out double/ triple-expressor PCNS-DLBCLs.

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas.

Standard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors. All consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Among 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively]. In patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.

5-Hydroxymethylation alterations in cell-free DNA reflect molecular distinctions of diffuse large B cell lymphoma at different primary sites

Background5-Hydroxymethylcytosine (5hmC), an important DNA epigenetic modification, plays a vital role in tumorigenesis, progression and prognosis in many cancers. Diffuse large B cell lymphoma (DLBCL) can involve almost any organ, but the prognosis of patients with DLBCL at different primary sites varies greatly. Previous studies have shown that 5hmC displays a tissue-specific atlas, but its role in DLBCLs at different primary sites remains unknown.ResultsWe found that primary gastric DLBCL (PG-DLBCL) and lymph node-involved DLBCL (LN-DLBCL) patients had a favorable prognosis, while primary central nervous system DLBCL (PCNS-DLBCL) patients faced the worst prognosis, followed by primary testicular DLBCL (PT-DLBCL) and primary intestinal DLBCL (PI-DLBCL) patients. Thus, we used hmC-CATCH, a bisulfite-free and cost-effective 5hmC detection technology, to first generate the 5hmC profiles from plasma cell-free DNA (cfDNA) of DLBCL patients at these five different primary sites. Specifically, we found robust cancer-associated features that could be used to distinguish healthy individuals from DLBCL patients and distinguish among different primary sites. Through functional enrichment analysis of the differentially 5hmC-enriched genes, almost all DLBCL patients were enriched in tumor-related pathways, and DLBCL patients at different primary sites had unique characteristics. Moreover, 5hmC-based biomarkers can also highly reflect clinical features.ConclusionsCollectively, we revealed the primary site differential 5hmC regions of DLBCL at different primary sites. This new strategy may help develop minimally invasive and effective methods to diagnose and determine the primary sites of DLBCL.

PB2103: CAN WE ACCURATELY PREDICT SURVIVAL IN DIFFUSE LARGE B CELL LYMPHOMA IN THE RITUXIMAB ERA? RETROSPECTIVE COMPARISON OF IPI, AAIPI, R-IPI AND NCCN-IPI

Background: In diffuse large B cell lymphoma (DLBCL), the value of the International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) changed with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as standard first line. The revised (R-IPI) and enhanced (NCCN-IPI) indices have emerged to improve prognostic ability. An analysis from Surrogate Endpoints for Aggressive Lymphoma (SEAL) database suggests NCCN-IPI better discriminates prognosis. Aims: In light of data scarcity and future changes in second line therapy for relapsed/refactory patients, we aimed to analyse the suitability of 4 survival prognostic indices in a DLBCL cohort. Methods: Single centre analysis of 169 patients diagnosed with de novo DLBCL from 2008 to 2016 and treated with R-CHOP. Primary central nervous system DLBCL or upfront stem cell transplant were exclusion criteria. IPI, aaIPI, R-IPI and NCCN-IPI scores at diagnosis were calculated. Analysis for 5-year overall survival (5y-OS) and progression free survival (5y-PFS) were performed using Kaplan-Meier curves and compared using the log-rank test. For each prognostic index, C-index test from receiver operating characteristic curves was calculated and area under the curve comparisons between prognostic indices were made using DeLong’s test. Results: Median age was 61 years (interval 18-82), 55% of patients had >60 years and 54% were male. At diagnosis, 23% had an ECOG performance status ≥2, 68% had Ann-Arbor stage III-IV, 63% had increased lactic dehydrogenase levels and 77% had extranodal disease (24% >1 site). Median follow-up was 71 months and 5y-OS and 5y-PFS were 74% and 67%, respectively. For the whole cohort, C-index for 5y-OS was 0.701, 0.629 and 0.751 for IPI, R-IPI and NCCN-IPI, respectively, and R-IPI was outperformed by IPI and NCCN-IPI (p=0.007 and p<0.001, respectively). For 5y-PFS C-index was 0.673, 0.695 and 0.689 for IPI, R-IPI and NCCN-IPI, with no statistically significant differences between indices. NCCN-IPI managed to discriminate the intermediate low (IL) and intermediate high (IH) risk groups for both 5y-OS (IL 89% versus (vs) IH 64%, p=0.001) and 5y-PFS (IL 77% vs IH 60%, p=0.029), contrary to IPI (5y-OS IL 69% vs IH 74%, p=0.552; 5y-PFS IL 63% vs HI 64%, p=0.925). The cohort was divided into age groups so that R-IPI and NCCN-IPI could be compared with aaIPI. For patients with ≤60 years, C-index for 5y-OS was 0.722, 0.585 and 0.724 for aaIPI, R-IPI and NCCN-IPI, respectively, and R-IPI was outperformed by NCCN-IPI but not by aaIPI (p=0.023 and p=0.077, respectively). For 5y-PFS C-index was 0.705, 0.622 and 0.625 for aaIPI, R-IPI and NCCN-IPI, with no statistically significant differences between indices. IL and IH risk groups could not be differentiated neither by aaIPI (5y-OS IL 85% vs IH 82%, p=0.725; 5y-PFS 76% vs 69%, p=0.556) nor NCCN-IPI (5y-OS IL 85% vs IH 70%, p=0.162; 5y-PFS IL 70% vs IH 70%, p=0.905), although in the last index there were no high-risk patients. Summary/Conclusion: NCCN-IPI seems the most robust prognostic tool for OS with frontline R-CHOP. Our results are in accordance with the SEAL analysis, although our sample was significantly smaller and SEAL included other immunochemotherapy regimens. However, improvements are needed for PFS prognostication, especially in younger patients within intermediate risk groups, and all indices performed similarly. Accurate prediction of PFS will ultimately allow for early benchmarking of patients for advanced or more aggressive therapies, and future research will be needed from bigger cohorts.

Case Report: Predominant brain superficial location of Epstein-Barr virus-related primary central nervous system diffuse large B cell lymphoma in a young woman with primary Sjögren’s syndrome

Epstein-Barr virus (EBV)- related primary central nervous system (CNS) diffuse large B cell lymphoma (DLBCL) is very rare in young patients without immunodeficiency. The predominant brain superficial location of EBV-related primary CNS DLBCL, and its’ concurrence with EBV-related lumbar-sacral radiculitis are special and have not been described previously. A young female patient presented with multiple cranial neuropathies, radiculopathy of lower limbs, and urinary retention. Her series brain magnetic resonance imaging (MRI) revealed dynamic changes, starting from lesions mainly in cranial nerves to mammillary body, pineal body, meninges, and finally in the bilateral cerebellum and cerebral lobes. Lumber spinal MRI showed enhancement in meninges and cauda equine roots. 18-fluorodeoxyglucose PET-CT revealed remarkably increased glucose metabolism in the lesions shown on the aforementioned brain MRI and lumbar spinal MRI, as well as right axillary lymph nodes. The biopsy of a whole axillary node on right side indicated EBV-related lymphoproliferation. Lumbar meninges and cauda nerves biopsy revealed chronic inflammation. By cerebral spinal fluid cytology and in situ hybridization, EBV-encoded small RNA (EBER) positive large B cell lymphoma was identified. The patient also had primary Sjögren’s syndrome (PSS). The patient died two weeks after treatment with rituximab, lenalidomide and methylprednisolone. She had survived for four and a half months since symptom onset. The patient presented with several stages of EBV-related complications in the nervous system, chronic EBV infection of lumbar-sacral radiculitis, and primary CNS DLBCL, indicating the process from chronic EBV infection to DLBCL in nervous system. Intracranial acute bacterium infection probably exacerbated the progression of CNS DLBCL. The concomitant sufferings of PSS reflected immune-dysfunction might have increased the risk of EBV-related CNS DLBCL in this young patient.

Поражение центральной нервной системы при диффузной В-клеточной крупноклеточной лимфоме

Introduction. Current approaches used to predict the recurrence of diffuse large B-cell lymphoma (DLBCL) with involvement of the central nervous system (CNS) need to be improved. Data from national studies on the incidence and clinical and laboratory characteristics of primary CNS DLBCL and secondary CNS involvement in systemic DLBCL are fragmentary and do not allow us to assess the overall picture. Aim. An assessment on the territory of the Siberian metropolis of data on the incidence and clinical and laboratory characteristics of DLBCL patients with primary CNS lymphoma (PCNSL) and secondary CNS involvement, as well as validation of the CNS-International Prognostic Index (CNS-IPI) on this sample. Materials and methods. The study group consisted of 47 patients with PCNSL and 35 with secondary CNS involvement in systemic DLBCL, the comparison group consisted of 202 patients with DLBCL without CNS involvement. Results. All patients with secondary CNS involvement in DLBCL belonged to the medium and high risk groups (p = 0.007) according to the CNS-IPI, which confirms its prognostic value. The risk factors for secondary CNS involvement in DLBCL were ECOG performance status ≥ 2, HIV infection, age over 60 years, a history of chronic kidney disease, ≥ 2 extranodal sites, and high expression of Ki-67 (&gt;75% positive tumor cells), non-GCB subtype of lymphoma, and presence of anemia. When assessing the characteristics of the clinical course of the disease, a number of peculiarities of the primary and secondary CNS involvement in DLBCL were identified. In particular, in terms of overall survival, the PCNSL group had a more favorable prognosis (p = 0.051). Conclusion. The results of the study confirm the importance of the CNS-IPI as a tool of a hematologist to determine the group of patients needing prevention of recurrence of DLBCL in the CNS. New data on a higher incidence of chronic kidney disease, arterial hypertension and thyroid disorders in the group of patients with PCNSL require further study.

Multifocal Primary Central Nervous System (CNS) Diffuse Large B-Cell Lymphoma (DLBCL) in a Patient with Aquired Immunodeficiency Syndrome (AIDS)

Abstract Introduction/Objective Primary CNS DLBCL is a rare entity, with an incidence of less than 0.47 per 100,000, however, in immunocompromised patients, especially those with Human Immunodeficiency Virus (HIV-1) infection, the incidence increases dramatically to 2-6 percent. Here we present a case of multifocal DLBCL in a young 28-year-old homeless male with untreated AIDS and polysubstance abuse. Methods/Case Report He presented to the hospital with altered state of consciousness; a Computerized Tomography (CT) scan showed three ring-enhancing masses; one in the left fronto-temporal region, the largest in the left basal ganglia and the third in the cerebellum. The main lesion was biopsied and diagnosed as DLBCL. The patient developed aspiration pneumonia and demised from respiratory failure Results (if a Case Study enter NA) NA Conclusion Coronal sections of the brain revealed a large grey-tan, soft lesion of poorly defined, irregular borders located in the left basal ganglia that measured 5 x 4 x 4 cm, extended dorsally and laterally. A similar lesion was observed in the deep left cerebral hemisphere, affecting the temporal lobe and extending rostrally into the frontal lobe, but completely separate from the tumor in the basal ganglia. A third, much smaller lesion was found in the right cerebellar hemisphere. Histologically, the tumor was composed of sheets of atypical lymphoid cells with increased nuclear to cytoplasmic ratio, increased mitotic activity, and showed scattered areas of necrosis. In the peripheral areas, tumor cells were located in the Virchow Robin space, and in more central areas they have broken into the brain parenchyma. Tumor cells were positive for CD20 and CD79a, indicating their B-cell origin. Other markers positive by immunohistochemistry were PAX5, MUM1 and BCL6 and the Epstein-Barr Virus (EBV) latent membrane protein (LMP). Fluorescence In situ hybridization (FISH) corroborated the presence of Eptein-Barr encoded RNAs.

Prognostic value of disease distribution in secondary central nervous system diffuse large B cell lymphoma treated with radiation therapy

This study aimed to assess the prognostic value of baseline disease distribution for patients with the secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy and radiation (RT). 44 patients with secondary CNS DLBCL were reviewed. Twenty patients had leptomeningeal disease (LMD), and 24 had localized/targetable disease (LTD). Of 8 patients who received stem cell transplantation (SCT) after RT, 6 had LTD with a complete or partial response after RT. Median time to CNS relapse after RT was 10.1 months; 3/24 patients with LTD and 5/15 with LMD had CNS relapse. The median overall survival (OS) was 8 and 20 months for patients with LMD and LTD, respectively (p = 0.20). On multivariable analysis, LTD, receipt of SCT, and response after RT were associated with better OS and CNS-disease-free survival. Patients with localized secondary CNS DLBCL may benefit from RT serving as a bridge to SCT.

HIGH-DOSE CHEMOTHERAPY FOR PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM. INTERIM RESULTS OF THE CNS-2015 PROTOCOL

Introduction. Induction chemotherapy (CT) for primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is based on the use of methotrexate in high doses. An optimal consolidation strategy involves high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation (auto-HSCT). The most effective conditioning regimen comprises a combination of chemotherapy agents including thiotepa.Aim. To present the authors’ experience of applying auto-HSCT/TBC in patients with primary DLBCL of the CNS.Methods. The prospective study CNS-2015 was carried out among 20 patients aged 20–52 years (median 42 years old) from 2015 to 2019. The male/female ratio came to 13/7. The somatic status of 17 (85 %) patients was 0–1 on the ECOG scale. Only 3 (15 %) patients showed the somatic status of 4 points. According to the criteria of the MSKCC prognostic system, 18 (90 %) and 2 (10 %) patients were assigned to the low-risk and medium-risk groups, respectively.Results. All patients included in the study received 3–5 cycles of chemotherapy with high doses of methotrexate, vincristine, procarbazine and rituximab (R-MPV), as well as underwent auto-HSCT following TBC-based conditioning regimen (thiotepa, busulfan, cyclophosphamide). Prior to auto-HSCT, 15 and 5 out of 20 patients having completed induction chemotherapy achieved complete remission and partial remission, respectively. Following auto-HSCT, complete remission was achieved in 5 patients with an initial partial response to treatment. All patients underwent temozolomide maintenance therapy for 2 years. With a median follow-up of 17 (1–46) months, 18 patients are alive and in remission. Two patients, who relapsed 4 and 5 months after auto-HSCT and achieved no response to the second line of chemotherapy and radiation therapy, died 24 and 26 months after auto-HSCT.Conclusion. R-MPV is an effective treatment for patients with primary DLBCL of CNS, which is not accompanied by severe toxicity. The use of high-dose chemotherapy with TBC allows a high remission rate to be achieved. The mortality associated with treatment in the group of patients included in the study came to 0 %.

Cytological diagnosis of vitreoretinal lymphomas: A case series.

To assess the cytological diagnosis and follow-up of patients suffering from vitreoretinal lymphoma (VRL) diagnosed in our institution. From January 2010 to June 2017, we collected 15 patients with VRL. Twelve patients had diffuse large B-cell lymphoma (DLBCL); of these, 11 had primary central nervous system (CNS) DLBCL, one had ocular localisation of follicular lymphoma, one had extranodal NK/T-cell nasal type lymphoma and one had chronic lymphocytic leukaemia. The results of the cytological examination (cell morphology and immunocytochemistry) of the vitreous fluid were available for 9/15 VRL. The interleukin-10/-6 ratio was >1 in eight of 12 DLBCL. Molecular testing was useful in 6/15 cases (clonality evaluation or MYD88 L265P mutation testing). Eight out of 11 primary CNS DLBCL patients had CNS involvement, with 22-month progression-free survival. In our series, only two out of 11 CNS DLBCL patients died of disease after 2 and 5years, respectively. The short delay to assert the diagnosis of VRL could explain the quite good prognosis in our series, which highlights the need to consider a diagnosis of DLBCL as first step. The cytological features, as a reliable way to identify VRL, must always guide the choice of techniques for further investigations given the small amount of vitreous fluid available for analysis.

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma.

Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL. Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes. According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥ 40%), 33 cases (41.8%) were positive for BCL2 (expression of ≥ 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival. Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

Can metabolic tumour parameters on primary staging 18F-FDG-PET/CT contribute to risk stratification of primary central nervous system lymphomas for patient management as a prognostic model?

ObjectivePrimary central nervous system (CNS) lymphoma is an aggressive and fatal extranodal non-Hodgkin lymphoma (NHL) jailed in CNS at initial diagnosis. Its prognosis is poor and the disease has a fatal outcome when compared with systemic NHL. A few baseline risk stratification scoring systems have been suggested to estimate the prognosis mainly based on serum lactate dehydrogenase (LDH) level, age, Karnofsky performance score (KPS), involvement of deep brain structures (DBS) and cerebrospinal fluid protein concentration. 18F-FDG-PET/CT has a high prognostic value with respect to overall survival (OS) and disease-free survival (DFS) in many cancers and lymphomas. We aimed to investigate metabolic tumour indexes on primary staging 18F-FDG-PET/CT as prognostic markers in primary CNS lymphoma. Material and methods14 patients with primary CNS diffuse large B-cell lymphoma (stage I) were enrolled in this retrospective cohort study. Primary staging 18F-FDG-PET/CT was performed and quantitative parameters like maximum standardized uptake value (SUVmax), average standardized uptake value (SUVmean), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated for all patients before the treatment. Cox regression models were performed to determine their relation with survival time. ResultsIn the evaluation of all potential risk factors impacting recurrence/metastases (age, sex, serum LDH, involvement of DBS, SUVmax, SUVmean, MTV, TLG) with univariate analysis, TLG remained statistically significant (p=0.02). ConclusionMetabolic tumour parameters are useful in prognosis estimation of primary CNS lymphomas, especially TLG, which is the most important one and may play a role in patient management.

An Autopsy Case of Epstein-Barr Virus-Associated Diffuse Large B-Cell Lymphoma of the Central Nervous System in an Immunocompromised Host.

Lymphomas arising in the central nervous system (CNS) of immunocompromised hosts are most commonly non-Hodgkin’s lymphomas and are highly associated with Epstein-Barr virus (EBV). Here we report an autopsy case of EBV-associated CNS diffuse large B-cell lymphoma (DLBCL) in a host suffering from systemic lupus erythematosus who underwent immunosuppressive therapy. After autopsy, EBV-associated CNS DLBCL as well as pulmonary mixed aspergillosis and Pneumocystis jirovecii pneumonia were added to the cause of clinical manifestations of complicated pneumonia and cerebral hemorrhage in this immunocompromised patient. In conclusion, complex disease processes were revealed by autopsy in this case, indicating that the clinicopathological correlations observed through autopsy can improve our understanding of disease progression and contribute to the management of similar patients in the future.

Primary central nervous system diffuse large B-cell lymphoma shows an activated B-cell-like phenotype with co-expression of C-MYC, BCL-2, and BCL-6

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, whose main prognostic factor is closely related to germinal center B-cell-like subtype (GCB- DLBCL) or activated B-cell-like type (non-GCB-DLBCL). The most common type of primary central nervous system lymphoma is diffuse large B-cell type with poor prognosis and the reason is unclear. This study aims to stratify primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) according to the cell-of-origin (COO) and to investigate the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53, further to elucidate the reason why primary central nervous system diffuse large B-cell lymphoma possesses a poor clinical outcome as well. Nineteen cases of primary central nervous system DLBCL were stratified according to immunostaining algorithms of Hans, Choi and Meyer (Tally) and we investigated the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53. The Epstein-Barr virus and Borna disease virus infection were also detected. Among nineteen cases, most (15–17 cases) were assigned to the activated B-cell-like subtype, highly expression of C-MYC (15 cases, 78.9%), BCL-2 (10 cases, 52.6%), BCL-6 (15 cases, 78.9%). Unfortunately, two cases were positive for PD-L1 while PD-L2 was not expressed in any case. Two cases infected with BDV but no one infected with EBV. In conclusion, most primary central nervous system DLBCLs show an activated B-cell-like subtype characteristic and have multiple expressions of C-MYC, BCL-2, BCL-6 protein, these features might be significant factor to predict the outcome and guide treatment of PCNS-DLBCLs.

Cerebrospinal Fluid Proteins Identification Facilitates the Differential Diagnosis of Central Nervous System Diffuse Large B Cell Lymphoma.

Background: Diagnosis of central nervous system (CNS) lymphoma remains a challenge. This study aimed to identify cerebrospinal fluid (CSF) proteins that distinguish patients with and without CNS lymphoma. Methods: We used one-dimensional SDS-polyacrylamide gel electrophoresis coupled with liquid chromatography- electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF MS) to identify CSF proteins in CNS diffuse large B cell lymphoma (DLBCL) patients and controls. Results: Approximately 166 CSF proteins were identified, 12 for the first time in the CSF of lymphoma patients. Three proteins with significantly increased expression in CNS lymphoma patients compared with controls - haemopexin, apolipoprotein A1, and transferrin were verified by immunohistochemistry, and found to be strongly expressed in CNS DLBCL and nodal DLBCL. These proteins were found to be localized in the cytoplasm of a human DLBCL cell line by indirect immunofluorescence. ELISA confirmed expression at higher concentrations in the CSF of CNS lymphoma patients. CSF haemopexin, apolipoprotein A1, and transferrin concentrations were detected in CNS lymphoma patients and had diagnostic sensitivities of 80%, 83%, and 70%, and specificities of 75%, 89%, and 90%, respectively. Conclusion: Our study suggests that CSF proteins may be potential diagnostic biomarker for CNS lymphoma, especially for patients in which imaging and cytology do not provide a clear diagnosis.

Primary central nervous system lymphoma: a new prognostic model for patients with diffuse large B-cell histology.

BackgroundAge and performance status are important prognostic factors in primary central nervous system (CNS) lymphoma. Although several prognostic models have been proposed, there is no consensus on the optimal model for patients with diffuse large B-cell histology.MethodsSeventy-seven patients with primary CNS diffuse large B-cell lymphoma were retrospectively analyzed to determine factors affecting survival. Three Western models were applied to our eligible patients; we devised a novel model based on our findings.ResultsThe median patient age was 59 years (range, 29–77); the median event-free and overall survival (OS) durations were 35.9 and 12.6 months, respectively. Nottingham/Barcelona and Memorial Sloan Kettering Cancer Center models were applicable to our cohorts. Multivariate analysis showed that advanced age, multifocal lesions, and high cerebrospinal fluid (CSF) protein concentrations were correlated significantly. A novel model for predicting prognosis was then developed based on these variables. Each variable was assigned 1 point; patients with a total score of 0, 1, 2, and 3 were categorized into the low- (N=17), moderate- (N=26), high- (N=14), and very high-risk groups (N=4), respectively. Sixty-one patients were eligible considering our model; the median OS was 58.2, 34.8, 9.0, and 1.8 months in the low-, moderate-, high-, and very high-risk groups, respectively (P<0.01).ConclusionAdvanced age, multifocal lesions, and high CSF protein concentration were adversely related with prognosis. Our model can be helpful in pre-treatment risk stratification for patients with primary CNS lymphoma with diffuse large B-cell histology.

The Role of HIV in Race-Based Differences in Diffuse Large B-Cell Lymphoma(DLBCL) Treatment and Outcomes

Introduction: African American (AA) race is associated with inferior survival in DLBCL compared to white (W) race (Shenoy, Cancer, 2011). This has been attributed to a disparity in administration of chemo-immunotherapy (Flowers, Cancer Epidemiol Biomarkers Prev 2012). Prevalence of human immunodeficiency virus (HIV) in AA with DLBCL is 8-fold higher than in W with DLBCL (Centers for Disease Control, 2014). We hypothesized that HIV infection is associated with a reduction in both administration of chemo-immunotherapy (rituximab) and overall survival (OS) in patients with DLBLC. We examined the relationship between race, HIV status, treatment with rituximab, and overall survival (OS) in a large cohort of United States Veterans with DLBCL with equal insurance access..Methods We identified 3,227 DLBCL pts between 1998 and 2008 in the Veterans Health Administration Central Cancer Registry. We excluded pts with primary cutaneous or central nervous system DLBCL and pts treated with unknown agents outside the VHA, 2,163 met this inclusion criterion. Given Rituximab did not become standard of care in aggressive lymphomas until approximately 2002; we did a planned sub-analysis of the 1,672 patients diagnosed and treated after January 1, 2002. Data on stage, lactate dehydrogenase (LDH), medical co-morbidities (Charlson Comorbidity Index), date of death, treatment and supportive care medications were obtained for each patient. OS was defined as time from DLBCL diagnosis to date of death. Univariate comparisons were performed to identify differences in treatment and other prognostic variables between race groups, where appropriate. Multivariable analyses were performed using logistic regression and Cox proportional hazards modeling, producing odds-ratios (OR) or hazard ratios (HR), respectively.Results: Of the 2,163 pts that met inclusion criteria, 88% were W and 12% AA. There was a higher prevalence of HIV in AA patients versus W patients (21% v. 4%, p <0.0001). Consistent with previous reports, African American race was associated with a higher frequency of elevated LDH (64% vs. 54%, p = 0.003) and younger age at diagnosis (57.6 years vs. 66 years, p=0.0001). There was no significant difference between AA race and use of rituximab compared to W race (70.4% vs. 73.7%, P= 0.271). Patients who were HIV positive were significantly less likely to receive rituximab (OR = 0.1, 95% CI 0.06 - 0.18). Patients who were HIV positive had an increased risk of death (HR = 1.67, 95% CI 1.27 - 2.2) compared to those who were HIV negative. After adjusting for HIV status in a multivariable Cox analysis, there was no racial disparity in overall survival (HR = 1.02, 95% CI 0.83 - 1.25). Kaplan-Meier analysis of age-adjusted overall survival stratified by race and HIV status is presented in Figure 1.Conclusions: Prior studies have shown detrimental survival outcomes in patient with HIV receiving Rituximab. Previously, it was also common practice to exclude Rituximab in treatment plans in HIV positive DLBCL patients (Kaplan, Blood, 2005).In this population of veterans with health insurance coverage, the observed racial disparity in survival after DLBCL diagnosis is largely explained by differences in the prevalence of HIV in the AA and W patient population. Thus, in order to reduce the racial outcome disparity among patients with DLBCL, public health efforts should focus on decreasing HIV transmission and enhancing HIV treatment in the AA community. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

CD30 Expression in Diffuse Large B-Cell Lymphoma (DLBCL) Correlates with Non-GCB Subtype but Does Not Have Prognostic Impact in Patients Treated with First Line R-CHOP/R-CHOP-like

Background: DLBCL is a heterogeneous disease with 30% of patients presenting as refractory/relapsing disease following R-CHOP treatment. Therefore, new prognostic factors to identify the poor-risk population and alternative therapies for them are needed. CD30 is a member of the tumour necrosis factor receptor (TNFR) super family and is expressed by several types of T- and B-cell non-Hodgkin lymphomas. Brentuximab vedotin, an anti CD30 antibody, is used in clinical practice for Hodgkin lymphoma and systemic anaplastic large cell lymphoma. The significance of CD30 expression in DLBCL remains unknown. We aimed to study the expression of CD30 in a large cohort of the novo DLBCL patients homogeneously treated with R-CHOP or R-CHOP-like protocols to evaluate its correlation with clinical and biological characteristics at diagnosis and its impact in clinical outcome.Methods: we prospectively registered 155 patients diagnosed of DLBCL between January 2012 to December 2015 in our center. Twenty-one patients with primary central nervous system DLBCL, transformed lymphoma or post-transplant DLBCL were excluded from the study. Anatomopathology review was performed in all cases, and 14 cases with not enough histological tissue to perform additional staining were also excluded. Immunohistochemistry was performed in 120 cases on 4 microns' paraffin sections using routine protocols,CD30 expression was analyzed using the antibodyCD30 clone BerH2, dilution 1:30; Dako; staining in more than 10% of the malignant cells was considered positive. Samples were classified as germinal center B-cell-like (GCB) vs. non-GCB subtypes by immunohistochemistry according to Hans algorithm. Univariate analyses were assessed by Chi square test. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses for progression-free survival (PFS) were assessed Cox proportional hazard regression model.Results: among the 120 cases analyzed, CD30 was expressed in 40 (33.3%). Clinical and biological characteristics at disease presentation are shown in Table 1. The expression of CD30 was significantly higher in the non-GCB subtype cases (p=0.0001). One hundred and six patients were homogeneously treated with R-CHOP (100 patients) or R-CHOP-like (1 R-COMP, 2 Burkitt scheme, 1 GA101-CHOP and 2 R-Bortezomib-CAP), and were included in the outcome analyses. Response rates and survival of this subgroup of patients are shown in Table 2. With a median follow-up of 16.4 months, no differences were found neither in PFS or OS between CD30 positive and CD30 negative patients (Table 2). In the multivariate analyses including the following independent variables: gender, B-symptoms, Bulky mass (>5cm), cell of origin (GCB vs non-GCB), International Prognostic Index (IPI) and CD30 expression, IPI 3-5 was de only factor significantly related with poor PFS (HR 2.92, 95% CI:1.18-7.24, p=0.02).Conclusion: CD30 is expressed in one third of DLBCL patients, in whom an anti-CD30 therapy could be used. CD30 expression is significantly higher in patients with non-CGB DLBCL, however and in our experience, its expression does not influence either response to R-CHOP or R-CHOP- like therapy or survival. [Display omitted] [Display omitted] DisclosuresGonzalez Barca:Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau.

Primary central nervous system diffuse large B cell lymphoma: a clinicopathologic and molecular study

Objective: To investigate clinicopathologic characteristics, immunophenotype and EB virus-related molecular genetic alterations in primary central nervous system diffuse large B cell lymphoma (DLBCL) along with correlation with clinical prognosis. Methods: A total of 30 cases of primary central nervous system DLBCL were retrospectively studied by retrieving clinical data, histological evaluation and immunophenotyping by EnVision two steps methods. The expression of EBER mRNA was detected by in situ hybridization and bcl-2, bcl-6 and C-MYC gene abnormalities were analyzed by interphase fluorescence in situ hybridization. Results: The cases included 18 males and 12 females (sex ratio of 1.5∶1.0) with an age ranging from 24 to 78 years (average age of 52 years, the median age of 53 years). The single primary clinical presentation was focal neurologic deficits. Tumor locations were supratentorial (21 cases), subtentorial (7 cases), involving both locations in 2 cases. Diffuse growth pattern was observed with large lymphoid cells mostly resembling centroblasts with abundant basophilic cytoplasm with oval to round, vesicular nuclei containing fine chromatin. An angiocentric and angiodestructive growth pattern was also present. Other features included perivascular space invasion. Immunohistochemical staining using a panel of CD10, bcl-6 and MUM1, six cases were germinal center-like (GCB) and 24 cases were non-germinal central-like (non-GCB). The positive rates of bcl-2, bcl-6 and C-MYC were 53.3% (16/30), 80.0% (24/30) and 20.0% (6/30), respectively. Genetic alterations were detected by FISH and the gene arrangement rates of bcl-2, bcl-6 and C-MYC were 3.3% (1/30), 16.7% (5/30) and 3.3% (1/30), respectively. There were 19 cases in stage 0-1 disease and 11 cases had stage 2-3 disease. Postoperative follow-up for average 13.6 months showed the median survival of 10 months, one-year survival of 46.7% and 16 patients died within a year. Conclusions: The clinical prognosis of primary central nerve system DLBCL depends on age, clinical performence status score, IPI score, immune classification and treatment. Patients typically progress rapidly with the high mortality within one year of diagnosis. Surgical resection combined with high-dose methotrexate or cytarabine chemotherapy offer the best treatment option.