Secondary Diffuse Large B-cell Lymphoma Research Articles

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

Clinical characteristics and prognosis of primary and secondary diffuse large B-cell lymphoma of the pancreas

Objective: To analyze the clinical characteristics and prognosis of primary and secondary pancreatic diffuse large B-cell lymphoma (DLBCL) . Methods: Clinical data of patients with pancreatic DLBCL admitted at Shanghai Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine from April 2003 to June 2020 were analyzed. Gene mutation profiles were evaluated by targeted sequencing (55 lymphoma-related genes). Univariate and multivariate Cox regression models were used to evaluate the prognostic factors of overall survival (OS) and progression-free survival (PFS) . Results: Overall, 80 patients were included; 12 patients had primary pancreatic DLBCL (PPDLBCL), and 68 patients had secondary pancreatic DLBCL (SPDLBCL). Compared with those with PPDLBCL, patients with SPDLBCL had a higher number of affected extranodal sites (P<0.001) and had higher IPI scores (P=0.013). There was no significant difference in the OS (P=0.120) and PFS (P=0.067) between the two groups. Multivariate analysis indicated that IPI intermediate-high/high risk (P=0.025) and double expressor (DE) (P=0.017) were independent adverse prognostic factors of OS in patients with pancreatic DLBCL. IPI intermediate-high/high risk (P=0.021) was an independent adverse prognostic factor of PFS in patients with pancreatic DLBCL. Targeted sequencing of 29 patients showed that the mutation frequency of PIM1, SGK1, BTG2, FAS, MYC, and MYD88 in patients with pancreatic DLBCL were all >20%. PIM1 (P=0.006 for OS, P=0.032 for PFS) and MYD88 (P=0.001 for OS, P=0.017 for PFS) mutations were associated with poor OS and PFS in patients with SPDLBCL. Conclusion: There was no significant difference in the OS and PFS between patients with PPDLBCL and those with SPDLBCL. IPI intermediate-high/high risk and DE were adverse prognostic factors of pancreatic DLBCL. PIM1, SGK1, BTG2, FAS, MYC, and MYD88 were common mutations in pancreatic DLBCL. PIM1 and MYD88 mutations indicated worse prognosis.

Survival outcomes in the elderly with limited stage diffuse large B-cell lymphoma treated with chemotherapy: SEER propensity-matched analysis.

e19046 Background: Current data shows a median age of diffuse large b-cell lymphoma (DLBCL) diagnosis of 70 years. More than 50% of elderly DLBCL patients can be expected to be cured by modern immunochemotherapy. Survival outcomes in elderly patients with limited stage DLBCL treated with chemotherapy outside of clinical trials are poorly characterized. Our objective is to determine survival pattern and factors that influence survival in elderly patients with limited stage DLBCL treated with chemotherapy through analysis of data from a large nationwide cancer registry in modern treatment era. Methods: The Surveillance Epidemiology and End Results (SEER 18) treatment database (2001-2013) was used to detect limited stage (Ann Arbor lymphoma stage I and II) DLBCL (ICD-O-3 code: 9680/3) adult cases with ages between 60-80 years treated with chemotherapy. Patients were divided into two cohorts. Cohort 1 included patients aged ≥60 to 70 yrs and Cohort 2 included patients aged &gt; 70 to 80 yrs. The variable "First Malignant Primary Indicator" was used to differentiate between primary DLBCL and secondary DLBCL cases. Overall survival (OS) was calculated using the Kaplan-Meier methods and multivariate cox regression model to determine the impact of race, gender, radiation use and primary malignant indicator on survival using 1:1 propensity score matching. Chi square test was applied to delineate for any significant difference between two cohorts. Results: Overall, 11138 patients were included with 5569 patients in each cohort. The relative incidence of limited stage secondary DLBCL was greater for cohort 2 when compared to cohort 1 (26% vs. 15%, p &lt; 0.01). The odds of receiving radiation was 27% higher in cohort 1 compared to cohort 2 (p &lt; 0.0001). Compared to cohort 1 (median OS-130 months), cohort 2 had worse median OS of 72 months (p &lt; 0.0001). Female gender, not receiving radiation and secondary status have shown strong relationship with increased risk of death on multivariate cox regression analysis in the elderly limited stage DLBCL patients. Conclusions: Overall survival was worse in age group 70-80 yrs when compared to age group 60-70 yrs in limited stage DLBCL patients treated with chemotherapy. This may be due to differences in treatment approaches. Female gender, not receiving radiation and secondary status are poor prognostic factors of survival in above group of patients. Race has no impact on survival.

Secondary diffuse large B-cell lymphoma of lung: report of one case and review of literature

目的 提高对继发性肺淋巴瘤的认识。 方法 报道滨州医学院烟台附属医院1例继发性肺弥漫大B细胞淋巴瘤患者的诊治经过，并对该病的影像学表现、发病率及治疗进行文献复习。 结果 该患者初诊为弥漫大B细胞淋巴瘤，治疗半年后肺CT示右肺下叶及肺门区多发团块灶，肺穿刺活组织检查诊断为继发性肺弥漫大B细胞淋巴瘤，给予二线方案R-EDOCH治疗有效。 结论 继发性肺淋巴瘤比较少见，临床医师应提高警惕，早期诊断、早期治疗。

Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap.

<b/> In this issue Grommes and colleagues elegantly show that the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, promotes a high proportion of durable responses in primary central nervous system lymphoma, a type of diffuse large B-cell lymphoma (DLBCL), and also in secondary DLBCL relapsing to the central nervous system. Mutations in the B-cell antigen receptor-associated protein CD79B with upregulation of the MTOR pathway were associated with diminished response, but preclinical combination of PIK3CA and PIK3CD inhibitors synergized with ibrutinib to overcome this resistance mechanism, providing opportunity for further targeted therapy of this difficult-to-treat disease. Cancer Discov; 7(9); 940-2. ©2017 AACRSee related article by Grommes et al., p. 1018.

Complex analysis of the TP53 tumor suppressor in mantle cell and diffuse large B-cell lymphomas.

Mutations and deletions of the tumor suppressor TP53 gene are the most frequent genetic alterations detected in human tumors, though they are rather less frequent in lymphomas. However, acquisition of the TP53 mutation was demonstrated to be one of the characteristic markers in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) and prognostic value of the TP53 status has been recognized for these diseases. We present the complex analysis of the TP53 aberrations in 57 cases of MCL and 131 cases of DLBCL. The TP53 status was determined by functional analyses in yeast (FASAY) followed by cDNA and gDNA sequencing. The level of the p53 protein was assessed by immunoblotting and loss of the TP53-specific locus 17p13.3 was detected by FISH. Altogether, we detected 13 TP53 mutations among MCL cases (22.8%) and 29 TP53 mutations in 26 from 131 DLBCL cases (19.8%). The ratio of missense TP53 mutations was 76.9% in MCL and 82.8% in DLBCL. The frequency of TP53 locus deletion was rather low in both diseases, reaching 9.3% in MCL and 15.3% in DLBCL. The presence of TP53 mutation was associated with shorter overall survival (OS) and progression-free survival (PFS) in MCL. Among DLBCL cases, the TP53 mutations shortened both OS and PFS of patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and decreased both OS and PFS of patients with secondary DLBCL disease.

Clinicopathologic features and survival outcomes of secondary diffuse large b-cell lymphoma after a primary solid malignancy: SEER propensity-matched analysis.

e19022Background: Outcomes of secondary DLBCL (sDLBCL) in patients with a prior diagnosis of a solid malignancy compared to de novo DLBCL (dnDLBCL) are not well understood. We sought to determine f...

The Molecular Profile of Richter Syndrome Predicts Survival From Transformation: The Role of Clonal Relationship

AbstractAbstract 3601Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma (DLBCL) in the context of chronic lymphocytic leukemia (CLL). Despite the availability of clinical predictors, the identification of RS patients projected to experience long survival represents an unresolved issue that may benefit from the development of novel RS prognosticators. The study was based on 86 RS classified as DLBCL after pathological review. Clonal relationship between CLL/RS pairs was assessed by immunoglobulin gene analysis. RS was clonally related to the CLL phase in 49/59 (83.1%) cases, and clonally unrelated in 10/59 (16.9%). In 27 cases, clonal relationship remained undetermined because of unavailability of paired CLL samples. Out of the molecular features investigated, the prevalence of TP53 disruption by mutations and/or deletion was significantly higher in clonally related RS (23/36, 63.9%) compared to clonally unrelated cases (1/8, 12.5%) (p=.015). Among immunogenetic features, usage of stereotyped VH CDR3 occurred in 25/49 (51.0%) clonally related RS, while was very rare among clonally unrelated cases (1/10, 10.0%) (p=.032). The difference in stereotyped VH CDR3 frequency occurred irrespective of IGHV gene mutation status. All clonally unrelated RS tested negative for EBV infection and none received alemtuzumab before DLBCL development. Clonally related and clonally unrelated RS were indistinguishable in terms of clinical features at presentation. However, RS survival was significantly shorter in clonally related (median: 14.2 months) versus clonally unrelated cases (median: 62.5 months) (p=.017) (Fig. 1A). This survival difference was observed even though clonally related RS received SCT in 8/48 (16.7%) cases, while clonally unrelated RS received in all cases conventional chemotherapy without SCT consolidation. Other variables that were associated with poor RS survival were TP53 disruption (p<.001), age >60 years (p=.005), ECOG PS >1 (p<.001), tumor size >5 cm (p=.001), platelets <100 × 109/l (p=.007), LDH >1.5 ULN (p=.002), and having received SCT (p=.027). None of the pathologic features of DLBCL diagnostic biopsies correlated with RS prognosis. After adjusting for clinical variables associated with RS survival, diagnosis of clonally unrelated RS translated into a 80% reduction in risk of death when compared to clonally related RS (HR: 0.22; p=.036). By recursive-partitioning analysis, clonal relationship, TP53 disruption and ECOG PS were the major determinants of RS survival, and classified RS patients according to risk of death (Fig. 1B). All clonally unrelated RS displayed a low risk of death (median survival 62.5 months; 95% CI: 33.7–91.3), irrespective of TP53 disruption and ECOG PS (Fig. 1B; Group 1). Among clonally related RS and RS with undetermined clonal relationship, patients presenting with ECOG PS ≤1 and no TP53 disruption had a low risk of death (median survival: 55.4 months) (Fig. 1B; Group 2). Patients presenting with ECOG PS ≤1 in the presence of TP53 disruption had an intermediate risk of death (median survival: 27.0 months) (Fig. 1B; Group 3). Patients presenting with ECOG PS >1 had a high risk of death, irrespective of TP53 disruption (median survival: 7.8 months) (Fig. 1B; Group 4). Based on c-statistics, the model including clonal relationship, ECOG PS and TP53 status had a 90% probability of correctly discriminating a priori RS survival (c-statistic=.90±.07). These observations suggest that clonally related and clonally unrelated RS are biologically and clinically distinct disorders, and that clonally unrelated RS should be considered as a secondary DLBCL arising de novo in the context of CLL, rather than a true RS. Therefore, we propose that the diagnosis of RS should be restricted to clonally related cases. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Early Low-grade Gastric MALToma Rarely Transforms Into Diffuse Large Cell Lymphoma or Progresses Beyond the Stomach and Regional Lymph Nodes

Gastric mucosa-associated lymphoid tissue lymphoma (MALToma) usually presents at an early stage involving only the stomach and/or regional lymph nodes. Although a sequential transformation from low-grade gastric MALToma (GM) to high-grade GM to secondary diffuse large B-cell lymphoma (DLBCL) is commonly assumed, documented cases of transformation are rare. We aim to determine the frequency of transformation. We identified 55 early low-grade GMs, 18 early high-grade GMs, and 13 advanced GMs at the National Taiwan University Hospital from 1995 to 2005. The median follow-up time was 59 months. We found that only one early low-grade GM and two early high-grade GMs transformed into secondary DLBCLs and progressed outside the stomach and regional lymph nodes. Significantly, we identified 13 low-grade GMs that were refractory to Helicobacter eradication therapy or relapsed after initial response. All 13 cases had been followed-up for at least 3 years without development of secondary DLBCLs. The frequency of transformation for early low-grade GM was less than 2% (1/55). Although two lymphoma-unrelated mortalities were identified, none of the 55 patients with early-low grade GMs died of the disease. Compared with chronic lymphocytic leukemia, which has a 16% transformation rate and a median transformation time of 24 months, we conclude that early low-grade GM rarely transforms into secondary DLBCL or progresses beyond the stomach. Without transformation or progression, patients with early low-grade GM rarely die of the disease and should be treated conservatively.

Transformation to Aggressive Lymphoma in Nodular Lymphocyte-Predominant Hodgkin's Lymphoma

PURPOSE Prior observations suggest a higher risk of transformation of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), than in classical Hodgkin's lymphoma. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency with long-term follow-up. PATIENTS AND METHODS The Lymphoid Cancer Database of the British Columbia Cancer Agency was searched to identify all patients diagnosed with NLPHL between 1965 and 2006. After pathologic review, 95 patients with NLPHL were confirmed. Results Patients with NLPHL had the following characteristics at diagnosis: median age of 37 years, 73% male, and 68% stage I or II disease. With a median follow-up time for living patients of 6.5 years (range, 2.5 to 33 years), 13 patients (14%) experienced transformation to aggressive lymphoma (median time to transformation, 8.1 years; range, 0.35 to 20.3 years). The actuarial risk of transformation to aggressive lymphoma was 7% and 30% at 10 and 20 years, respectively. Transformation was more likely in patients with initial splenic involvement (P = .006) at the time of diagnosis of NLPHL. The 10-year progression-free and overall survival rates in patients with transformed lymphoma were 52% and 62%, respectively. CONCLUSION The risk of transformation in patients with NLPHL to DLBCL is substantial and underappreciated. Because transformation can occur years after the primary diagnosis of NLPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL.

Frequency of transformation to diffuse large B-cell lymphoma in nodular lymphocyte predominant hodgkin lymphoma: The BCCA Experience

8566 Background: Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) accounts for approximately 5% of all HL. Although the prognosis of patients of NPHL is typically excellent, previous observations have suggested that there is a higher risk of transformation to diffuse large B cell lymphoma (DLBCL) than in classical HL. However, in many studies, follow-up has been limited and this event can occur years later. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency (BCCA) over a 40 y period. Methods: The Lymphoid Cancer Database of the BCCA was searched to identify all patients with NLPHL between 1965 and 2006. 149 cases of NLPHL were identified; 4 were excluded due to composite pathology with DLBCL at diagnosis, leaving 145 cases for this analysis. Results: Cases of NLPHL had the following characteristics at diagnosis: median age 36 y; 72% male; 70% stage I /II; 10% B symptoms; 88% normal LDH; 92% PS of 0/1. Patients with limited stage disease received radiotherapy (RT) alone (56%) or chemotherapy ± RT (44%). Patients with advanced stage disease received MOPP-like or ABVD-like chemotherapy ± RT. With a median follow-up of 8.2 y (1.4 y- 38 y), 15 (10%) cases of transformation to DLBCL have occurred (12 DLBCL; 2 T-cell rich B-cell lymphoma; 1 unknown). The median age at transformation was 49 y (26 y-76 y), 13 (87%) were males, 14 (93%) had stage III/IV disease and 9 (60%) had an elevated LDH. Transformation was more likely in those with stage III/IV disease (p=.015), B symptoms (p=.007) or poor performance status (p=.025) at diagnosis. The median time to transformation to DLBCL was 9.9 years (.34y to 19.6 years). The risk of transformation to DLBCL at 10 y is 7% and the projected risk at 20 y is 22%. Conclusions: The risk of transformation in NLPHL to DLBCL is substantial and underappreciated. In this population-based study it was more often seen in patients with advanced stage, poor PS and B symptoms at diagnosis. Given that transformation can occur years after the primary diagnosis of LPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL. No significant financial relationships to disclose.

A Case of Epstein-Barr Virus-positive Diffuse, Large B-cell Lymphoma after Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a systemic lymphoproliferative disorder that presents with profound immune dysfunction and immunodeficiency. As in many other immunodeficiencies, Epstein-Barr virus (EBV) associated B-cell lymphoid proliferation can occur in AITL but few cases of EBV-positive B-cell lymphoma have been reported in patients with preexisting AITL. We report a case of AITL in which EBV-positive diffuse large B-cell lymphoma (DLBCL) developed 13 months after the initial diagnosis of AITL. Although the exact mechanisms remain unclear, Epstein-Barr virus may have played a role in the pathogenesis of the secondary DLBCL. (Korean J Hematol 2008;43:174-178.)

Association between telomere length and BCL2 gene rearrangements in low- and high-grade non-Hodgkin lymphomas

Telomere length based on terminal restriction fragment (TRF) assay was evaluated in cells of bone marrow, lymph node, or both from 53 non-Hodgkin lymphoma (NHL) patients: 44 with follicular lymphoma (FL) and 9 with secondary diffuse large B-cell lymphoma (S-DLBCL) to FL. The TRF data were correlated with BCL2 gene rearrangement evaluated by nested and long-distance polymerase chain reaction approaches. Peripheral blood cells from 12 healthy donors were studied as controls. Both groups of NHL patients revealed significant telomere shortening compared with controls (8.50 ± 0.50 kb; P < 0.001), with significantly shorter TRFs in S–DLBCL (3.49 ± 0.26 kb) than in FL cases (4.09 ± 0.12 kb; P = 0.047). Patients carrying BCL2 gene rearrangements showed longer telomere length (4.19 ± 0.14 kb) than those without (3.51 ± 0.14 kb; P = 0.05). Among patients with FL, telomere length was shortest in patients without t(14;18), intermediate when breakpoints occurred in the minor breakpoint cluster region (3.97 ± 0.33 kb), and greater when breakpoints occurred in the major breakpoint region (MBR) (4.24 ± 0.15 kb), with significant differences between MBR and BCL2–negative cases ( P = 0.033). Our findings support the existence of alternative genetic pathways involved in the origin of these FL subsets. Even though the number of S-DLBCL cases was small, they showed the shortest telomere length, suggesting that this parameter reflects another genetic alteration involved in the progression from FL to a higher-grade lymphoma.

Analysis of the immunoglobulin heavy chain gene of secondary diffuse large B-cell lymphoma that subsequently developed in four cases with B-cell chronic lymphocytic leukemia or lymphoplasmacytoid lymphoma (Richter syndrome).

The immunoglobulin heavy chain gene (IgH gene) was analysed in four cases of B-cell Richter syndrome, in order to determine whether a secondary diffuse large B-cell lymphoma (DLBCL) could arise from the same clone as the initial B-cell chronic lymphocytic leukemia (B-CLL) and lymphoplasmacytoid lymphoma (LPL) or be a de novo event, and whether secondary DLBCL shows an intraclonal microheterogeneity. Both the initial B-CLL and secondary DLBCL in two cases expressed CD5 antigen. Both samples of the initial B-CLL or LPL and the secondary DLBCL in three cases were examined for comparison. The polymerase chain reaction-amplified IgH gene of secondary DLBCL in two cases (CD5+ case and CD5- case) were different from those of the initial B-CLL, revealing a new malignant clone. The other case (CD5-) showed that secondary DLBCL had a sequence identical to the initial LPL, indicating the same clonal origin. The variable region of the IgH gene of secondary DLBCL (CD5+ two cases and CD5- two cases) exhibited a 0.5-9.0% somatic mutation range and no intraclonal microheterogeneity.