Central Nervous System Diffuse Large B-cell Lymphoma Research Articles

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.

Expression of OCT4 and SALL4 in Diffuse Large B-cell Lymphoma: An Analysis of 145 Consecutive Cases and Testicular Lymphomas.

OCT4 and SALL4 are transcription factors within a complex network that functions to maintain pluripotency in primitive stem cells and germ cells. Nuclear expression of OCT4 is widely cited as sensitive and specific for primary and metastatic germ cell tumors and is commonly used in the diagnosis of central nervous system (CNS) germinomas. Studies have failed to systematically examine the expression of OCT4 or SALL4 in diffuse large B-cell lymphoma (DLBCL), although this entity enters the morphologic differential diagnosis of some germ cell tumors. A retrospective review was conducted on 145 consecutive cases of DLBCL and testicular lymphoma to evaluate the prevalence of OCT4 and SALL4 expression. Nuclear OCT4 expression was present in 2/11 (18%) testicular DLBCLs and 6/134 (4.5%) nontesticular DLBCLs. Most OCT4 cases demonstrated moderate to strong expression in >50% of neoplastic cells. Rare, weak nuclear SALL4 expression was detected in only 3 nontesticular DLBCLs. Within the extratesticular DLBCL group, 2/6 (33%) primary CNS DLBCLs expressed nuclear OCT4. In addition, OCT4 DLBCL showed an overall predilection toward non-germinal center B-cell phenotype (7/8; 88%) and had a higher than expected rate of CD5 coexpression (4/8, 50%). These results are cautionary against using OCT4 as a sole marker of germ cell differentiation in testicular and extratesticular sites, especially in the CNS. The apparent associations of OCT4 expression with primary CNS DLBCL, non-germinal center B-cell phenotype, and CD5 coexpression raise the question of whether OCT4 expression in DLBCL may reflect more aggressive biology.

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses.

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Akt activation confers an inferior survival in patients with activated B-cell subtype of diffuse large B-cell lymphoma: a report from The International DLBCL Rituximab-CHOP Consortium Program

Context Akt plays an essential role in diverse cellular processes such as cell proliferation, cell growth and apoptosis. Dysregulation of Akt signaling has been shown to correlate with an inferior survival in patients with a number of solid tumors and some hematologic malignances. The prognostic significance of Akt expression and the gene expression profile of Akt activation in diffuse large B-cell lymphoma (DLBCL) have not been thoroughly assessed. Objective In this study, we investigated Akt activation and analyzed its prognostic importance in a large cohort of patients with de novo DLBCL treated with R-CHOP immunochemotherapy. We also characterized the gene expression profile of DLBCL with activated Akt. Patients The study group consisted of 493 DLBCL patients treated with R-CHOP. These cases were organized as a part of the International DLBCL R-CHOP Consortium Program Study, and diagnosed according to the WHO criteria. Patients with primary mediastinal large B-cell lymphoma, primary cutaneous DLBCL, primary central nervous system DLBCL, and DLBCLs transformed from a low-grade B-cell lymphoma or associated with HIV infection were excluded. Methods Immunohistochemical studies (IHC) were performed in formalin-fixed paraffin-embedded sections of tissue microarrays to evaluate the expression of phosphorylated (activated) Akt and other relevant markers. Genetic alterations were examined by FISH for MYC , BCL-2 , and BCL-6 translocations and sequencing for TP53 mutation. Gene expression profiling (GEP) was performed to characterize the gene expression profile in Akt-activated DLBCL. The cell-of-origin (COO) subtypes were determined by GEP (gold standard) and IHC. Results Phosphorylated (activated) Akt (pAkt) expression was detected in 98 of 493 (20%) DLBCL tumors including 49 of 253 (19%) GCB DLBCL and 49 of 240 (20%) ABC DLBCL. In the GCB subtype, MYC, BCL-2 and MYC/BCL-2 translocations were more frequently found in pAkt+ DLBCL compared with pAkt- DLBCL ( P =0.04, 0.007 and 0.03, respectively). In contrast, translocations of these genes were rare and detected equally in pAkt+ and pAkt- subgroups within the ABC subtype ( P =0.7, 0.9 and 0.9, respectively). In the GCB group, TP53 mutation frequency was similar between pAkt+ and pAkt- DLBCL ( P =0.45). In contrast, TP53 mutations were significantly less frequent in ABC group (5% versus 22%; P = 0.01). Akt activation predicted a poorer survival, but the negative prognostic impact of Akt activation was significant in the ABC (5-year survival rate: 44% in pAkt+ versus 65% in pAkt-; P =0.01; 5-year PFS: 40% in pAkt+ versus 59% in pAkt-; P =0.01), but not GCB subtype (5-year survival rate: 67% in pAkt+ versus 74% in pAkt-, P =0.31; 5-year PFS rate: 61% in pAkt+ versus 69% in pAkt-, P =0.27). The negative impact of Akt activation appeared to be independent of Myc/Bcl-2 expression and TP53 mutation. In multivariate analysis, pAkt expression was an independent predictor of poorer OS (HR=2.72, 95% CI, 1.50-4.98, P =0.001) and PFS (HR=2.16, 95% CI, 1.22-3.82, P =0.008) in patients with ABC wild type- TP53 . In addition, AKT1 mRNA expression conferred significantly poor survival in DLBCL. Gene expression profiling revealed a distinct high-risk signature characterized by increased expression of multiple pro-survival genes (6 of 16 up-regulated genes; 40%) and decreased expression of genes encoding tumor suppressors (5 of 20 down-regulated genes; 25%) in pAkt+ ABC DLBCL. Conclusions Akt is activated in DLBCL, is equally distributed in COO subtypes, and has prognostic significance in patients with ABC DLBCL. Given the promising anti-lymphoma activity of Akt inhibitors in clinical trials, these findings may have clinical implications for DLBCL patients. Akt activation may be useful for prognostic stratification and could serve as a biomarker to guide patient selection and predict response to targeted anti-Akt therapy. Disclosures No relevant conflicts of interest to declare.

MYC protein expression is associated with poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system.

MYC and BCL2 gene translocations and protein expression have recently demonstrated to be of prognostic significance in systemic diffuse large B-cell lymphoma (DLBCL). However, their role in primary central nervous system DLBCL (CNS-DLBCL) prognosis has been scarcely analyzed. We studied the immunophenotype, the status of the MYC, BCL2, and BCL6 genes and the clinical features of a series of 42 CNS-DLBCL and evaluated their prognostic significance. We found high MYC protein expression in 43% of cases, and this was associated with lower overall survival (OS). Cases with concurrent expression of MYC and BCL2 showed a lower OS, although the difference did not reach statistical significance. Translocations involving the MYC or BCL2 genes were not detected. The BCL6 gene was frequently translocated, but was unrelated to survival. We conclude that MYC protein expression detected by immunohistochemistry identifies a CNS-DLBCL subset with worse prognosis and may contribute to a more accurate risk stratification of CNS-DLBCL patients.

Primary diffuse large B-cell lymphomas of central nervous system exhibit remarkably high prevalence of oncogenic MYD88 and CD79B mutations

MYD88 and CD79B mutations that activate nuclear factor (NF)-κB signaling are prevalent in subsets of diffuse large B-cell lymphoma (DLBCL). We examined the prevalence of somatic mutations in the Toll/interleukin-1 receptor (TIR) domain of MYD88 and the tyrosine-based activation motif (ITAM) domain of CD79A/B in 18 primary central nervous system (CNS) DLBCLs, and their immunoprofile. MYD88 mutation was found in 17 cases (94.4%), all of which were L265P substitutions. CD79B mutation was found in 11 cases (61.1%), 10 (55.6%) of which were Y196C/D/H substitutions. Mutation of CD79A was completely absent. Immunohistochemically, all the tumors were CD3−/CD5−/CD20+/CD79a+/ GCET1−/BCL6+/MUM1+. Three (16.7%) cases were CD10+, but the majority (15 cases, 83.3%) were CD10−. Overall, all cases harbored either MYD88L265P or CD79BY196C/D/H, or both, irrespective of their immunoprofile. Our results suggest that CNS DLBCL is a group of tumors harboring a characteristic mutation profile which triggers NF-κB signaling in the immune-privileged site.

Akt Activation Confers an Inferior Survival in Patients with Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program

ContextAkt plays an essential role in diverse cellular processes such as cell proliferation, cell growth and apoptosis. Dysregulation of Akt signaling has been shown to correlate with an inferior survival in patients with a number of solid tumors and some hematologic malignances. The prognostic significance of Akt expression and the gene expression profile of Akt activation in diffuse large B-cell lymphoma (DLBCL) have not been thoroughly assessed.ObjectiveIn this study, we investigated Akt activation and analyzed its prognostic importance in a large cohort of patients with de novoDLBCL treated with R-CHOP immunochemotherapy. We also characterized the gene expression profile of DLBCL with activated Akt.PatientsThe study group consisted of 493 DLBCL patients treated with R-CHOP. These cases were organized as a part of the International DLBCL R-CHOP Consortium Program Study, and diagnosed according to the WHO criteria. Patients with primary mediastinal large B-cell lymphoma, primary cutaneous DLBCL, primary central nervous system DLBCL, and DLBCLs transformed from a low-grade B-cell lymphoma or associated with HIV infection were excluded.MethodsImmunohistochemical studies (IHC) were performed in formalin-fixed paraffin-embedded sections of tissue microarrays to evaluate the expression of phosphorylated (activated) Akt and other relevant markers. Genetic alterations were examined by FISH for MYC, BCL-2, and BCL-6 translocations and sequencing for TP53 mutation. Gene expression profiling (GEP) was performed to characterize the gene expression profile in Akt-activated DLBCL. The cell-of-origin (COO) subtypes were determined by GEP (gold standard) and IHC.ResultsPhosphorylated (activated) Akt (pAkt) expression was detected in 98 of 493 (20%) DLBCL tumors including 49 of 253 (19%) GCB DLBCL and 49 of 240 (20%) ABC DLBCL. In the GCB subtype, MYC, BCL-2 and MYC/BCL-2 translocations were more frequently found in pAkt+ DLBCL compared with pAkt- DLBCL (P=0.04, 0.007 and 0.03, respectively). In contrast, translocations of these genes were rare and detected equally in pAkt+ and pAkt- subgroups within the ABC subtype (P=0.7, 0.9 and 0.9, respectively). In the GCB group, TP53 mutation frequency was similar between pAkt+ and pAkt- DLBCL (P=0.45). In contrast, TP53 mutations were significantly less frequent in ABC group (5% versus 22%; P= 0.01). Akt activation predicted a poorer survival, but the negative prognostic impact of Akt activation was significant in the ABC (5-year survival rate: 44% in pAkt+ versus 65% in pAkt-; P=0.01; 5-year PFS: 40% in pAkt+ versus 59% in pAkt-; P=0.01), but not GCB subtype (5-year survival rate: 67% in pAkt+ versus 74% in pAkt-, P=0.31; 5-year PFS rate: 61% in pAkt+ versus 69% in pAkt-, P=0.27). The negative impact of Akt activation appeared to be independent of Myc/Bcl-2 expression and TP53 mutation. In multivariate analysis, pAkt expression was an independent predictor of poorer OS (HR=2.72, 95% CI, 1.50-4.98, P=0.001) and PFS (HR=2.16, 95% CI, 1.22-3.82, P=0.008) in patients with ABC wild type-TP53. In addition, AKT1 mRNA expression conferred significantly poor survival in DLBCL. Gene expression profiling revealed a distinct high-risk signature characterized by increased expression of multiple pro-survival genes (6 of 16 up-regulated genes; 40%) and decreased expression of genes encoding tumor suppressors (5 of 20 down-regulated genes; 25%) in pAkt+ ABC DLBCL.ConclusionsAkt is activated in DLBCL, is equally distributed in COO subtypes, and has prognostic significance in patients with ABC DLBCL. Given the promising anti-lymphoma activity of Akt inhibitors in clinical trials, these findings may have clinical implications for DLBCL patients. Akt activation may be useful for prognostic stratification and could serve as a biomarker to guide patient selection and predict response to targeted anti-Akt therapy. DisclosuresNo relevant conflicts of interest to declare.

Combined treatment of rituximab, idarubicin, dexamethasone, cytarabine, methotrexate with radiotherapy for primary central nervous system lymphoma

The overall response rates and long-term survival of primary central nervous system lymphoma (PCNSL) are still significantly inferior to the results achieved in similar subtypes of extranodal non-Hodgkin's lymphoma. It is clearly necessary to investigate new therapeutic methods on PCNSL. We encountered three patients histologically documented PCNSL as diffuse large B-cell lymphoma (DLBCL). They were treated with R-IDARAM which comprised rituximab, idarubicin, dexamethasone, cytarabine and methotrexate. Patient 1 received stereotactic brachytherapy (SBT) prior to chemotherapy performed with iodine-125 seeds (cumulative therapeutic dose 50 Gy). After six cycles of R-IDARAM at 3-weekly intervals, radiotherapy was applied at a dosage of 2000–4000 cGy in conventional schedule (180 or 200 cGy/day) to whole brain or spinal cord in all patients. Complete remission (CR) was achieved after first two cycles of R-IDARAM in all patients. All three patients remained in CR at the time of this report with a median duration of follow-up of 23 months (ranging from 13 to 41 months). Three patients have been alive for 41, 13, 16 months respectively until now. The patient with the longest survival time was the one given SBT prior to chemotherapy. This study suggests that R-IDARAM combining with radiotherapy maybe a high effective regimen in PCNSL patients especially those with primary central nervous system DLBCL. A comprehensive treatment combining internal radiotherapy by SBT, modified R-IDARAM and followed reduced external radiotherapy may be a new treatment concept for PCNSL with higher efficiency and lower toxicity.

Primary central nervous system Epstein–Barr virus-positive diffuse large B-cell lymphoma of the elderly: a clinicopathologic study of five cases

We report five cases of primary central nervous system (CNS) Epstein-Barr virus (EBV)-positive lymphoma of the elderly. This represented an incidence of 4% of primary CNS diffuse large B-cell lymphoma (DLBCL) after EBV screening in 134 cases. All five patients were 65years or older with no previous history of congenital or iatrogenic immune deficiencies. The histologic morphology of all the cases was DLBCL, with variable amounts of necrosis. The cell of origin (COO) as determined by the Hans algorithm disclosed germinal center type in 2 cases and non-germinal center type in 3 cases. MYC translocation was not detected, and MYC overexpression was detected in only one case. Three patients died shortly after diagnosis, and the remaining 2 patients were in complete remission for 2 and 10years, respectively. We conclude that EBV+ DLBCL among the elderly is uncommon in primary CNS lymphoma in the Eastern United States. The patients usually present with a single mass lesion with headache and sensorimotor symptoms. The histologic morphology is DLBCL, but clonal T-cell gene rearrangement may be detected. The outcome varies from case to case and appears to be unrelated to the COO or MYC status.

Treatment of Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts) Age 80 and Older: Analysis of the Veterans Health Administration (VHA) National Database

AbstractAbstract ▪968▪This icon denotes a clinically relevant abstract Introduction:The incidence of DLBCL increases with age and the population ≥80 is the fastest growing segment of the elderly population. Optimal treatment of these very elderly DLBCL pts remains unclear. While chemo-immunotherapy can be curative, benefits of treatment must be balanced against toxicities in older, frail pts. Previous studies have suggested that doxorubicin treatment is associated with better survival in the very elderly population, though only on univariate analyses. To better understand the relationship between treatment and survival in pts ≥80, we performed a retrospective analysis of veterans to examine the relationship between treatment and overall survival (OS). Methods:We identified 523 DLBCL pts ≥80 diagnosed between 1998 and 2008 in the VHA Central Cancer Registry. We excluded pts with primary cutaneous or central nervous system DLBCL and pts treated with unknown agents outside the VHA. Data on stage, LDH, co-morbidities, date of death, treatment and supportive care medications were obtained for each pt. Treatment related mortality (TRM) was defined as death in the 30 days following any cycle of therapy. OS was defined as time from diagnosis to death. ECOG Performance Status (PS) at diagnosis was either obtained from pt charts or assessed from physician, nursing, and physical therapy notes available for each patient. Results:Of the 476 pts that met inclusion criteria, 193 received at least one dose of doxorubicin therapy (DT), 92 were treated without doxorubicin (non-DT) and 191 received no system therapy (NST). Median OS times were 30.2 months, 12.3 months, and 1.9 months in the DT, non-DT, and NST groups, respectively (Log-rank p<0.001). Baseline characteristics of 285 treated patients presented in Table 1. Among the 273 pts in whom treatment dates were available, 48 (18%) experienced TRM. Of these 48 deaths, 32 (67%) were associated with the first treatment cycle. On multivariate analysis, rituximab significantly reduced the risk of death (HR .62, CI .44 - .87), while GCSF use demonstrated a trend towards decreased death (HR .76, CI .57 – 1.03). Comorbidities (HR 1.1, CI 1.02 – 1.19) and PS were associated with increased risk of death. PS of 2–4 was associated with a marked increased risk of death within the first 45 days after diagnosis (HR 19.7, CI 2.6– 146) and a lesser risk after 45 days (HR 1.9, CI 1.4 –2.6). After controlling for other variables, doxorubicin use was no longer significantly associated with OS (HR .87, CI .64 – 1.17), suggesting the OS difference noted between the DT and non-DT groups was primarily due to differences in baseline patient characteristics. Conclusions:While we acknowledge the limitations of analyses of observational data, the observed 18% rate of TRM (compared to historical TRM rates of 4–6% seen in trials of R-CHOP) suggests that standard treatment paradigms are too toxic for many patients in this age group. The lack of association between doxorubicin and OS calls into question the importance of this drug in this patient population. In the absence of better risk stratification, treatment with less toxic regimens- either through attenuated doses or different drugs- may be appropriate in this population.Table 1:Demographic and clinical characteristics of US veterans with DLBCL aged 80 and older at time of diagnosis, stratified by treatment group (N=285)Demographic and Clinical CharacteristicsDoxorubicin n=193Non-Doxorubicin n=193p-valueAge at DX (mean years)83.183.60.086Stage (%)0.153Stage I28.522.8Stage II15.515.2Stage III23.819.6Stage IV32.142.4LDH (%)0.978Elevated49.750.0Not Elevated42.542.4Unknown7.87.6Performance status (%)0.0210–152.338.02–446.160.9Unknown1.61.1Age adjusted IPI (%)0.103015.57.6126.430.4231.627.2318.127.2Unknown8.37.6Co-morbidity (Charlson score) (Mean)1.82.30.028B-symptom( %)0.042Yes42.055.4No55.443.5Unknown2.61.1CSF use (%)78.847.2<.001Rituximab use (%)80.876.10.356TX DrugCHOP/R-CHOP190-CNOP/R-CNOP-5CVP/R-CVP-53R-EPOCH1-Rituximab-21Other213 Disclosures:Carson:Genentech: Consultancy, Honoraria, Speakers Bureau. Nabhan:Genentech: Research Funding, Speakers Bureau.

Immunophenotypes and prognosis of diffuse large B-cell lymphoma: a study of 500 cases

To study the immunophenotype and overall survival of diffuse large B-cell lymphoma (DLBCL) classified according to the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Five hundred cases of DLBCL were retrospectively analyzed with histologic review, immunohistochemistry, gene rearrangement study, in situ hybridization and fluorescence in situ hybridization. Follow-up data were collected. The overall survival rates of germinal center B-cell (GCB) and non-germinal center B-cell (non-GCB) subtypes, as well as those of DLBCL, not otherwise specified (NOS) and Epstein-Barr virus (EBV)-positive DLBCL of the elderly, were compared. DLBCL-NOS was the commonest subtype which accounted for 77.2% (386/500) of the cases. EBV-positive DLBCL of the elderly, primary DLBCL of central nervous system, primary mediastinal (thymic) large B-cell lymphoma and T cell/histiocyte-rich large B-cell lymphoma accounted for 9.4% (47/500), 4.4% (22/500), 2.8% (14/500) and 2.6% (13/500), respectively. 68.5% (219/320) of DLBCL-NOS belonged to non-GCB subtype. The percentage of GCB subtype and CD5-positive subtype were 28.4% (91/320) and 3.1% (10/320), respectively. Comparison of the overall survival, GCB and non-GCB immunophenotypic groups have no significant difference (P = 0.93). And the same result in which of the EBV-positive DLBCL of the elderly and DLBCL-NOS group, before and after age matched (P = 0.13 and 0.28, respectively). A double-hit lymphoma was found by FISH detection, which presenting as gray zone lymphoma in morphology. By using Hans algorithm, GCB and non-GCB subtypes show no significant difference in overall survival. EBV-positive DLBCL of the elderly and DLBCL-NOS also do not have significant difference in overall survival. Fluorescence in situ hybridization technique is helpful in identification of DLBCL with rare phenotypes.

Diffuse large B-cell lymphoma in the spinal epidural space: A study of the Osaka Lymphoma Study Group

Diffuse large B-cell lymphoma (DLBCL) involving spinal epidural space (SEDLBCL) is relatively rare, constituting 1.8% of DLBCLs in Osaka, Japan. The aim of this study was to analyze SEDLBCL cases for their clinical and histopathologic findings, including an association with Epstein-Barr virus (EBV) and immunohistochemical characteristics. We analyzed the clinicopathologic findings of 27 SEDLBCL cases. They consisted of 16 males and 11 females, their age ranging from 37–86 years (median 64 years). Eight patients had stage I disease, 3 had stage II, 5 had stage III, and 11 had stage IV. Based on the staining pattern for anti-CD10, bcl-6, and MUM-1, the cases were categorized into 17 cases of the germinal center B-cell (GCB) type and nine of the non-GCB type. There was a 4%-positive rate for EBV in the tumor cells. When compared to nodal DLBCL, the frequency of patients with a high performance status (PS) is higher in SEDLBCL. Compared to the DLBCL of the central nervous system (CNS), the frequency of cases with high stage, 2 or more extranodal lesions, high international prognostic index (IPI), and GCB-type is higher in SEDLBCL. There were no significant differences in the histologic features between SEDLBCL and nodal/CNS DLBCL. Univariate analysis revealed that advanced stage was an unfavorable factor for overall survival ( P=0.060). SEDLBCL is different from nodal and CNS DLBCL, but an association with EBV is unlikely in every group.

Primary diffuse large B-cell lymphoma of central nervous system belongs to activated B-cell-like subgroup: a study of 47 cases

To investigate the histogenetic origin of primary central nervous system diffuse large B-cell lymphoma (DLBCL) with respect to the stage of B-cell differentiation, and identification of the relevant prognostic markers. Immunohistochemical staining (EnVision method) for CD10, bcl-6, MUM-1, CD138 and FOXP1 antigens was performed on 47 paraffin-embedded sections. CD10, bcl-6, MUM-1 and FOXP1 expression in the tumor cells were 6.4%, 53.2%, 91.5% and 93.6% respectively. There was no expression of CD138 in all the cases. Among the 47 patients, 43 cases (91.5%) showed an activated B-cell-like (ABC) phenotype: 21 (44.7%) were bcl-6+ and MUM-1+, suggesting an "activated germinal center (GC) B-cell-like" in origin; 22 (46.8%) were exclusively MUM-1+, suggesting an "activated non-GCB" in origin. No significant correlation of the classification and FOXP1 expression found on the outcome (P=0.279 and P=0.154). Most primary central nervous system DLBCL are shown belonging to the ABC subgroup, suggesting that primary central nervous system DLBCL is quite similar to a DLBCL subset, which is derived from late GC to early post-GC B cell. The classification and FOXP1 expression do not show prognostic value in primary central nervous system DLBCL.

Expression of p53, c-Myc, or Bcl-6 suggests a poor prognosis in primary central nervous system diffuse large B-cell lymphoma among immunocompetent individuals.

Primary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) in immunocompetent individuals, although rare, has been rising in incidence. Currently, no reliable prognostic markers are available for these individuals. To study the implications of expression of a panel of oncogenic proteins (Bcl-2, Bcl-6, and c-Myc) and p53 for predicting clinical outcome, particularly overall survival, in immunocompetent individuals with primary CNS DLBCL. Fourteen primary CNS DLBCL cases were retrospectively studied by immunohistochemistry on formalin-fixed, paraffin-embedded sections for the expression of c-Myc, Bcl-2, Bcl-6, and p53. The overall frequencies of expression for p53, c-Myc, Bcl-2, and Bcl-6 in these cases were 29%, 50%, 71%, and 57%, respectively. Cases with expression of p53, c-Myc, or Bcl-6 had a poorer overall survival than those without (Kaplan-Meier survival analysis: 50% cumulative overall survival, 2 months vs 30-60 months, P =.02, log-rank test; 9-16 months vs 21-60 months, P =.03, log-rank test; and 9-16 months vs 21-60 months, P =.16, log-rank test, respectively). The expression of Bcl-2 or proliferation activity by MIB-1 showed no correlation with overall survival. Likewise, the clinical parameters, including age, location of tumors, multiplicity of tumor lesions, and lactase dehydrogenase levels revealed no impact on overall survival. Our results suggest that patients with expression of p53, c-Myc, or Bcl-6 have a poorer overall survival than those without. Since traditional prognostic markers in non-CNS DLBCL, such as staging and International Prognostic Index scores, are not applicable to primary CNS DLBCL, evaluation of p53, c-Myc, and Bcl-6 by immunohistochemistry may be warranted as part of prognostic evaluation in immunocompetent patients with primary CNS DLBCL. Further studies are indicated to confirm our observations.