Nodal Diffuse Large B-cell Lymphoma Research Articles

Biological Findings and Clinical Outcomes in Patients Treated With R-CHOP Plus High-Dose Methotrexate as First-Line Therapy in Large B-Cell Lymphoma With Testis Involvement.

Primary testicular lymphoma (PTL) is a rare occurrence of diffuse large B-cell lymphoma (DLBCL) that accounts for 1%-2% of all cases. Nodal DLBCL with testis involvement (DLBCL-T) and PTL are associated with poor prognosis, with high incidence of central nervous system relapse. Fifteen patients (median age 60 years) with PTL (n = 5) or DLBCL-T (n = 10) received high-dose methotrexate + R-CHOP. Overall, complete response (CR) rate was 73% and overall response rate 86%. With a 3.9-year median follow-up, 100% of patients with PTL had CR and none relapsed. On the contrary, 55% of DLBCL-T patients achieved CR among which only one was still in remission at the end of follow-up. Molecular parallels between PTL and Primary CNS Lymphoma (PCNSL) suggest shared origins, urging further research for tailored treatments and enhanced understanding of these lymphomas' biology.

Histomorphologic spectrum of nodal marginal zone lymphoma as defined by its methylome.

Primary nodal marginal B-cell lymphoma (NMZL) is rare and histologically very variable. Its large-cell presentation is difficult to distinguish from nodal diffuse large B-cell lymphoma (nDLBCL) due to the absence of specific markers for nodal marginal zone lymphomas in general. Using a comprehensive cohort of NMZLs and a control cohort of nDLBCLs, we conducted a methylome analysis on subgroups of both. The methylomes were strikingly different between the cohorts but unexpectedly homogeneous within the NMZL cohort. This allowed us to describe the morphologic spectrum of NMZL in all its value ranges. The considerable overlap in growth pattern and cytology of NMZL with nDLBCL was explored morphometrically, leading to an operational tool for separating both by a simple measurement of cell size and nuclear size. This was integrated in a hierarchical approach, including a scoring system for the parameter growth pattern, follicular colonization, follicular dendritic network, IgD expression, and Ki-67 rate, and led to a proposal for a classifier that we present here. This methylome-based study extends the morphological spectrum of NMZL towards large cell morphology and offers a conventional way to distinguish it from nDLBCL.

Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL.

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88 L265P , CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.

Primary extra – nodal DLBCL at rare sites: A case series

Primary extra – nodal DLBCL at rare sites: A case series

Clinicopathological differences in MYC and BCL2 protein expression between primary extranodal and nodal diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL.

Mutation landscape in Chinese nodal diffuse large B-cell lymphoma by targeted next generation sequencing and their relationship with clinicopathological characteristics

BackgroundDiffuse large B-cell lymphoma (DLBCL), an aggressive and heterogenic malignant entity, is still a challenging clinical problem, since around one-third of patients are not cured with primary treatment. Next-generation sequencing (NGS) technologies have revealed common genetic mutations in DLBCL. We devised an NGS multi-gene panel to discover genetic features of Chinese nodal DLBCL patients and provide reference information for panel-based NGS detection in clinical laboratories.MethodsA panel of 116 DLBCL genes was designed based on the literature and related databases. We analyzed 96 Chinese nodal DLBCL biopsy specimens through targeted sequencing.ResultsThe most frequently mutated genes were KMT2D (30%), PIM1 (26%), SOCS1 (24%), MYD88 (21%), BTG1 (20%), HIST1H1E (18%), CD79B (18%), SPEN (17%), and KMT2C (16%). SPEN (17%) and DDX3X (6%) mutations were highly prevalent in our study than in Western studies. Thirty-three patients (34%) were assigned as genetic classification by the LymphGen algorithm, including 12 cases MCD, five BN2, seven EZB, seven ST2, and two EZB/ST2 complex. MYD88 L265P mutation, TP53 and BCL2 pathogenic mutations were unfavorable prognostic biomarkers in DLBCL.ConclusionsThis study presents the mutation landscape in Chinese nodal DLBCL, highlights the genetic heterogeneity of DLBCL and shows the role of panel-based NGS to prediction of prognosis and potential molecular targeted therapy in DLBCL. More precise genetic classification needs further investigations.

Prognostic Significance of T-Cells and Macrophages in the Tumour Microenvironment of Nodal DLBCL.

Revised International Prognostic (R-IPI) score is used widely for risk stratification of DLBCL cases, yet some patients belonging to same risk category tend to exhibit different outcomes. The role of T-cells and macrophages in prognostication of lymphomas has been a point of interest of late. We aimed to study the association of FOXP3 positive T-regulatory cells, cytotoxic T-cells and macrophages with the immunophenotypic subtypes, clinicopathological characteristics, treatment response and survival in nodal diffuse large B-cell lymphoma (DLBCL) patients. The clinicopathological and treatment data of 83 DLBCL patients diagnosed and treated at our institute from January 2015 to December 2018 were collected and followed up till June 2020. CD8, FOXP3 and CD68 immunostains were performed to highlight the cytotoxic T-cells, T-regulatory cells and macrophages respectively on the lymph node biopsies and the distribution of these cells and their association with clinico-pathological factors, treatment response and survival was analyzed. DLBCL cases with higher percentage of CD3 positive T-cells and CD8 positive cytotoxic T-cells had significant association with attainment of complete response to treatment. In addition, CD8 positive T-cells of more than 6.5% proved to be an independent predictor of treatment outcome (p = 0.022). Multivariate Cox regression survival analysis revealed that cases with 'good' R-IPI prognostic score and 'high CD68 positive macrophages in tumor microenvironment' had a significantly longer overall survival. Increased number of cytotoxic T-cells was significantly associated with complete response to treatment and higher number of macrophages correlated significantly with better overall survival signifying their antitumor effects.

Primary Extranodal Diffuse Large B-cell Lymphoma Presenting in the Lips: A Case Report and Literature Review.

Approximately 30-40% of malignant lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), with 30% of DLBCL cases manifesting as extranodal lymphomas. Among these extranodal DLBCLs, primary DLBCL in oral lesions, particularly in the lips, is rare. While the treatment methods, chemotherapy assessment, and prognosis for nodal and extranodal DLBCLs are generally similar, diagnostic challenges can lead to delayed therapeutic intervention. We herein present a recent case of primary extranodal DLBCL in the lips that was swiftly diagnosed and managed using rituximab-containing chemotherapies. Our experience underscores the important role that hematologists play in identifying the possibility of oral hematological tumors, thereby allowing for a rapid diagnosis and timely intervention.

Deciphering Transcriptomic and (Epi)Genetic Signatures of Central Nervous System Infiltration in Patients Diagnosed with Diffuse Large B-Cell Lymphoma

Introduction Central Nervous System (CNS) involvement in Diffuse Large B Cell Lymphoma (DLBCL) is a rare complication with bad prognosis. The CNS Prognostic Index is employed to categorize patients at a high risk of CNS relapse; however, its effectiveness is not accurate. The discovery of precise biomarkers for predicting CNS involvement in DLBCL patients remains unmet. Our objective was to characterize the immune, transcriptomic, genomic and epigenomic hallmarks of systemic tumors at diagnosis of patients who later experienced relapse in the CNS. By exploring these biological profiles, we sought to gain valuable insights into the underlying mechanisms and potential biomarkers associated with CNS relapse in DLBCL. Methods We conducted a retrospective study including 38 patients diagnosed with nodal DLBCL who experienced relapse within the first two years after diagnosis. Among these patients, 12 individuals relapsed specifically in the CNS, while 26 relapsed in systemic sites. As a control group, we included 21 patients who did not relapse. DNA and RNA were extracted from FFPE tumor samples collected at diagnosis. To evaluate immune cell infiltration, we utilized the nCounter PanCancer Immune Profiling Panel (Nanostring); cell-of-origin (COO) was determined using the Lymph2Cx assay. Transcriptomic profiles were generated by bulk RNA sequencing and mutational analysis was performed using a custom targeted NGS panel, which included the most frequently mutated genes observed in lymphoid neoplasms. Methylation profiles were obtained using the Illumina Infinium MethylationEPIC Array 850K. Results Immune profiling analysis showed cell composition was not significantly different between groups; however, we observed distinct immune gene expression patterns at diagnosis in patients who experienced CNS relapse. Multiple genes were overexpressed in the CNS-relapsed group compared to non-relapsed group, which encompassed various functional categories including chemokine signaling such as IL7R (FC=2; P=0.05) and CCR6 (FC=3.4; P=0.01); adhesion like VCAM1 (FC=1.6; P=0.03) and ITGA4 (FC=2.2; P=0.006); and immune regulation such as CD1A (FC=4.8; P=0.001), LTB (FC=3.3; P=0.009) and BTLA (FC=2.3; P=0.02) (Fig.1A). The ITGA4 gene also presented higher expression levels in the CNS-relapsed group when compared to both systemic-relapsed and non-relapsed groups combined (FC=1.7; P=0.03). No significant differences were observed in the COO classification between groups. Whole-genome transcriptomic data revealed enrichment in gene sets associated with proliferation and survival in the CNS-relapsed group (Fig.1B). Analysis of genetic alterations indicated that patients with CNS relapse exhibited an increased mutation load and frequency in PIM1, IGLL5, and KMT2D genes. Finally, analysis of the CNS relapse-related epigenome showed 343 differentially hypomethylated CpG sites compared to both systemic and non-relapsed groups together, affecting a total of 211 genes. Pathway enrichment analysis of these genes revealed a link between CNS infiltration and cell migration and locomotion. Conclusions Tumors from DLBCL patients that will relapse in the CNS present a higher chemokine, adhesion and proliferation signatures at diagnosis. Of notice, BTLA, CCR6 and IL7R proteins have been previously reported to be implicated in B cell entry into the CNS in B-cell malignancies. Interestingly, patients with CNS relapse demonstrated significant overexpression of the ITGA4 gene, which encodes the integrin α4 subunit (CD49d) of the Very Late Antigen-4. Engagement between CD49d on B cells and its endothelial ligand VCAM-1 is required for migration of these cells across the blood-brain barrier. In fact, Natalizumab (anti-CD49d mAb) is administered in multiple sclerosis to impede entrance and accumulation of B cells in the brain. Initial experiments in mice have shown increased expression of CD49d in lymphoma B cells that have infiltrated the brain, compared to those in the spleen. Herein, we have demonstrated that DLBCL cells at diagnosis already own specific transcriptomic and (epi)genetic hallmarks that could confer a higher capacity to infiltrate the CNS. Validation of these findings in larger cohorts of patients could improve selection of patients with an increased risk of CNS involvement in need of prophylactic CNS-directed therapies at diagnosis.

Profiling risk factors for separation of infection complications in patients with gastrointestinal and nodal diffuse large B-cell lymphoma

ObjectiveTo identify risk factors for infection complications in patients with gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) and nodal DLBCL (N-DLBCL) during treatment, respectively.MethodsTotal 51 GI-DLBCL patients and 80 N-DLBCL patients were included after retrieving clinical data from a single medical center in the past ten years. Logistic regression analysis was utilized to analyze patients’ data, including baseline demographics, treatments and laboratory values, to determine independent risk factors of infection in these patients.ResultsTotal 28 of 51 patients (54.9%) in the GI-DLBCL group and 52 of 80 patients (65%) in the N-DLBCL group were observed infection events during treatment. A multivariate logistic regression model revealed that Ann-arbor stage IV (P = 0.034; odds ratio [OR]: 10.635; 95% confidence interval [CI]: 1.152-142.712), extra-nodal lesions ≥ 2 (P = 0.041; OR: 23.116; 95%CI: 1.144-466.949) and high serum lactate dehydrogenase (LDH) at the time of diagnosis (LDH > 252U/L; P = 0.033; OR: 6.058; 95%CI: 1.159–31.659) were independent risk factors for the development of infection in patients with GI-DLBCL after systemic treatment. In the N-DLBCL group, high serum C-reactive protein (CRP) (P = 0.027; OR: 1.104; 95%CI: 1.011–1.204) and a low platelet count (P = 0.041; OR: 0.991; 95%CI: 0.982-1.000) at routine blood tests just before infection occurred were identified as significant risk factors related to infection events during treatment.ConclusionsDiscordant independent risk factors induced infection may be present during the treatment in patients with GI-DLBCL and N-DLBCL. Close monitoring these risk factors is likely an effective strategy to prevent microbial infections in these patients.

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) shows a high degree of clinical and biological heterogeneity. Primary testicular lymphoma (PTL) is an extranodal variant of DLBCL associated with a higher risk of recurrence, including contralateral testicles and central nervous system sanctuary sites. Several molecular aberrations, including somatic mutation of MYD88, CD79B, and upregulation of NF-kB, PDL-1, and PDL-2, are thought to contribute to the pathogenesis and poor prognosis of PTL. However, additional biomarkers are needed that may improve the prognosis and help understand the PTL biology and lead to new therapeutic targets. RNA from diagnostic tissue biopsies of the PTL-ABC subtype and matched nodal DLBCL-ABC subtype patients was evaluated by mRNA and miRNA expression. Screening of 730 essential oncogenic genes was performed, and their epigenetic connections were examined using the nCounter PAN-cancer pathway, and Human miRNA assays with the nCounter System (NanoString Technologies). PTL and nodal DLBCL patients were comparable in age, gender, and putative cell of origin (p>0.05). Wilms tumor 1 (WT1) expression in PTL exceeded that in nodal DLBCL (>6-fold; p=0.01, FDR <0.01) and WT1 associated pathway genes THBS4, PTPN5, PLA2G2A, and IFNA17 were upregulated in PTL (>2.0-fold, p<0.01, FDR <0.01). Additionally, miRNAs targeting WT1 (hsa15a-5p, hsa-miR-16-5p, has-miR-361-5p, has-miR-27b-3p, has-miR-199a-5p, has-miR-199b-5p, has-miR-132-3p, and hsa-miR-128-3p) showed higher expression in PTL compared to nodal DLBCL (≥2.0-fold; FDR 0.01). Lower expression of BMP7, LAMB3, GAS1, MMP7, and LAMC2 (>2.0-fold, p<0.01) was observed in PTL compared to nodal DLBCL. This research revealed higher WT1 expression in PTL relative to nodal DLBCL, suggesting that a specific miRNA subset may target WT1 expression and impact the PI3k/Akt pathway in PTL. Further investigation is needed to explore WT1's biological role in PTL and its potential as a therapeutic target.

TESTICULAR LARGE B‐CELL LYMPHOMA IS GENETICALLY SIMILAR TO PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA AND DISTINCT FROM NODAL DIFFUSE LARGE B‐CELL LYMPHOMA

Introduction: Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma presenting in an immune-privileged site, recently recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). Here, we performed the genetic characterization of TLBCL and compare it with a published series of nodal DLBCL and primary central nervous system lymphoma (PCNSL). Patients and Methods: We collected 61 patients with TLBCL diagnosed between 2002 and 2021. Cell-of-origin was determined by immunochemistry and Lymph2Cx assay. To characterize the genomic profile of TLBCL we performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization, and compared them to those of DLBCL and PCNSL. Results: The median age was 70 years and 30% of the patients had disseminated disease at diagnosis, including six cases with CNS involvement. Using Hans' algorithm, 83% (44/53) were identified as a non-germinal center while the Lymph2Cx assay categorized 71% (30/42) as activated B-cell phenotype and 12% (5/42) as unclassified. BCL6 rearrangements were detected in 36% (17/47) of cases, and no concomitant BCL2 and MYC rearrangements were found. Integrative analysis of 40 cases with single nucleotide variants, indels, and copy number alterations (CNA) data showed that the most frequent alterations (>50%) in TLBCL were PRDM1, CDKN2A/B, TNFAIP3, SGK1, ARID1B, MYD88L265P, SPIB, PIM1, and CD79B (Figure). Concomitant variants in MYD88L265P, CD79B, and PIM1 were detected in twelve (29%) cases. Using the LymphGen tool, 71% (30/42) of the cases could be classified into a molecular subgroup, with MCD being the most frequent group (66%, 20/30). Interestingly, patients with localized or disseminated disease displayed similar genomic complexity based on the number of CNAs and the number of mutated genes. Compared with nodal DLBCL, localized and disseminated TLBCL have less CNA complexity (P = 0.01 and P < 0.04, respectively) but showed a higher number of variants (P = 0.01 and P < 0.001, respectively). TLBCL also presented more frequently 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 variants were enriched in TLBCL, and BCL10 mutations in nodal DLBCL. There were no genetic differences between TLBCL and PCNSL. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees). The research was funded by: Asociación Española Contra el Cancer AECC/CIBER: PROYE18020BEA (SB); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III Instituto de Salud Carlos III, “Cofinanciado por la Unión Europea” and Fondos FEDER: European Regional Development Fund “Una manera de hacer Europa”: PI17/01061 (SB), PI19/00887 (ALG and EG), and INT20/00050 (ALG); Marató TV3 TV3-Cancer/ 201904-30 (SB). ARD is supported by a grant from Sociedad Española de Hematología y Hemoterapia. CL is supported by postdoctoral Beatriu de Pinós grant from Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and by Marie Sklodowska-Curie COFUND program from H2020 (2018-BP-00055). Keywords: Extranodal non-Hodgkin lymphoma, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract. F. Nadeu Honoraria: Janssen, AbbVie E. Campo Consultant or advisory role: Takeda, NanoString, AbbVie, Illumina Honoraria: Janssen, EUSPharma, Roche Research funding: AstraZeneca A. López-Guillermo Consultant or advisory role: Roche, Gilead, Kite Pharma, Celgene, Bristol Myers Squibb, Incyte, Takeda, Kern Pharma, Pfizer, Janssen Honoraria: Janssen, Roche, Kite Research funding: Gilead, Janssen, Celgene, Bristol Myers Squibb Educational grants: Roche, Kite/Gilead

The Prognostic Impact of Tumor Microenvironment and Checkpoint Blockade-Associated Molecules (PD-1, PD-L1, CD163 and CD14) in Nodal Diffuse Large B-cell Lymphoma, NOS.

It is aimed to determine expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), CD163 and CD14 in diffuse large B-cell lymphomas (DLBCL), and whether these markers may predict prognosis in DLBCL cases. A total of 52 nodal DLBCL, NOS cases with no known extranodal involvement at the time of diagnosis were evaluated. PD-1, PD-L1, CD163, and CD14 were studied by immunohistochemistry. The relationships between the results and clinical and laboratory prognostic markers were investigated. It was observed that patients with PD-1 expression < 5 positive cells/HPF had worse overall survival. No significant relationship was found between survival and PD-L1, CD163 and CD14 expressions. In addition, cases that are > 60years of age, that have Eastern Cooperative Oncology Group (ECOG) performance score ≥ 2, stage IV disease, high International Prognostic Index score score (≥ 3), elevation of LDH, low albumin level, low hemoglobin level, low peripheral blood lymphocyte count, high peripheral blood neutrophil/lymphocyte ratio, high peripheral blood platelet/lymphocyte ratio were found to have worse overall survival. It was concluded that in patients with low number of PD-1 positive tumor-infiltrating lymphocytes have low survival rates and therefore PD-1 expression may be useful in indicating prognosis.

Clinical features and prognosis of double primary malignant neoplasms in patients with non-hodgkin lymphoma

To investigate the clinical features, survival, and prognostic factors of patients with double primary malignant neoplasms (DPMNs) comprising non-Hodgkin lymphoma (NHL) and malignant solid tumors. Of the 2352 patients diagnosed with NHL, 105 (4.46%) patients were diagnosed with DPMNs, 42 (40.0%) had NHL first (the NHL-first group) and 63 (60.0%) had solid tumor first (the ST-first group). Females were more frequent in the ST-first group, and the interval time between the two tumors was longer. More NHLs in early stages and originating from extranodal sites were observed in the NHL-first group. Male, age ≥ 55 years at diagnosis of the first tumor, interval time <60 months, NHL diagnosed first, NHL arising from an extranodal site, DPMNs without breast cancer, and no surgery for the first primary tumor were associated with poorer overall survival (OS). Interval time <60 months and NHL diagnosed first were independent risk factors that affected the prognosis of patients with DPMNs. Therefore, careful monitoring and follow-up are especially important for these patients. 50.5% (53/105) of patients with DPMNs did not receive chemotherapy or radiotherapy prior to the diagnosis of the second tumor. We further compared the baseline characteristics of diffuse large B-cell lymphoma(DLBCL) patients with and without solid tumors, the former had a higher proportion of extranodal DLBCL, suggesting that extranodal DLBCL is more likely to develop solid tumors than nodal DLBCL.

Primary mediastinal/thymic diffuse large B-cell lymphoma: a population-based study on incidence and survival.

Primary mediastinal large B-cell lymphoma is a rare subtype of lymphoma. The contemporary incidence of primary mediastinal large B-cell lymphoma remains unknown, and a large population-based study has not been reported. It is essential to provide guidance for further strategies in reducing the disease burden via population-based preventive initiatives. This study aims to explore the epidemiology and effect of therapeutic advances on the survival of patients with primary mediastinal large B-cell lymphoma. This population-based study was conducted using the Surveillance, Epidemiology, and End Results Program (SEER), covering the period from 1975 to 2018. A total of 774 patients in the SEER 9 and 1654 patients in the SEER 18 were analyzed. The age-adjusted incidence rate of primary mediastinal large B-cell lymphoma increased from 0.05/1,000,000 in 1975 to 2.38/1,000,000 in 2018. A significant positive linear increase in the incidence trend was found in primary mediastinal large B-cell lymphoma, with an annual percent change of 8.47% (95% confidence interval 7.7-9.2%, P < 0.001, z test). The survival in primary mediastinal large B-cell lymphoma was significantly superior to nodal diffuse large B-cell lymphoma. The incidence of PMBCL increases over the year. The survival of patients with primary mediastinal large B-cell lymphoma has improved over time.

Clinicopathological Characteristics and Prognosis of Diffuse Large B-Cell Lymphoma in Relation to CA-125 and CA 19-9 Expression.

Background: Some epithelial tumors express the carbohydrate antigen 125 (Cancer antigen-125, CA-125) and CA 19-9, especially ovarian and pancreatic tumors. Patients with non-Hodgkin lymphoma (NHL) were reported to have a close association between serum CA-125 levels and adverse prognostic factors with worse survival. We aimed to investigate CA-125 and 19-9 expression in nodal diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) tissues using immunohistochemistry (IHC) and their relations to clinicopathological manifestations and patients' survival. Methods: 65 cases of DLBCL NOS were examined. A modified mechanical pencil tip was used to construct Manual Tissue Micro-array (TMA) blocks. Immunohistochemical staining for CA-125 and CA 19-9 was performed and scored semi-quantitatively. All relations were analyzed using established statistical methodologies. Results: Aberrant expression of CA 19-9 was detected in 12% of cases without any expression of CA-125. Moreover, 75% of the CA 19-9 positive cases were statistically significantly associated with anemia and performance status 1. Also, 75% of the CA 19-9 positive cases were females. Conclusions: CA 19-9 was aberrantly expressed in 12% of nodal DLBCL NOS cases and significantly related to anaemia and performance status but not to survival. In cases of DLBCL NOS, CA 19-9 expression cannot be considered an independent prognostic factor. CA-125 was not expressed in nodal DLBCL NOS tissues, necessitating re-evaluation studies. Therefore, it is advised to conduct more research to clarify the potential correlation between serum and tissue CA 19-9 levels and other clinic-pathological characteristics of nodal and extranodal DLBCL NOS patients.

Development and validation of nomograms by radiomic features on ultrasound imaging for predicting overall survival in patients with primary nodal diffuse large B-cell lymphoma.

To develop and validate a nomogram to predict the overall survival (OS) of patients with primary nodal diffuse large B-cell lymphoma(N-DLBCL) based on radiomic features and clinical features. A retrospective analysis was performed on 145 patients confirmed with N-DLBCL and they were randomly assigned to training set(n=78), internal validation set(n=33), external validation set(n=34). First, a clinical model (model 1) was established according to clinical features and ultrasound (US) results. Then, based on the radiomics features extracted from conventional ultrasound images, a radiomic signature was constructed (model 2), and the radiomics score (Rad-Score) was calculated. Finally, a comprehensive model was established (model 3) combined with Rad-score and clinical features. Receiver operating characteristic (ROC) curves were employed to evaluate the performance of model 1, model 2 and model 3. Based on model 3, we plotted a nomogram. Calibration curves were used to test the effectiveness of the nomogram, and decision curve analysis (DCA) was used to asset the nomogram in clinical use. According to multivariate analysis, 3 clinical features and Rad-score were finally selected to construct the model 3, which showed better predictive value for OS in patients with N-DLBCL than mode 1 and model 2 in training (AUC,0. 891 vs. 0.779 vs.0.756), internal validation (AUC, 0.868 vs. 0.713, vs.0.756) and external validation (AUC, 914 vs. 0.866, vs.0.789) sets. Decision curve analysis demonstrated that the nomogram based on model 3 was more clinically useful than the other two models. The developed nomogram is a useful tool for precisely analyzing the prognosis of N-DLBCL patients, which could help clinicians in making personalized survival predictions and assessing individualized clinical options.

Localized Nodal Diffuse Large B Cell Lymphoma: Is Radiotherapy Needed?

Introduction: Diffuse large B-cell lymphoma (DLBCL) is clinically, morphologically and genetically a heterogeneous group of malignant proliferation of large B-cell lymphoid cells. At diagnosis, 25% of DLBCL presents as a localized disease.Therapeutic options for localized DLBCL include short-course or extended-course chemotherapy regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with or without radiotherapy. Regarding the number of cycles, the choice differs in the different oncology services and the role of radiotherapy remains controversial. Another frequent issue regarding this pathology is the prognosis of the cell of origin (COO) in the localized form. In the literature, non-germ center (N-GC) subtype is correlated with lower overall survival (OS) when compared to germinal center (GC) . This lower overall survival of the non-GC subtype has not been reported in patients with localized DLBCL. Objectives: The primary objective is to compare progression-free survival (PFS) and overall survival (OS) at 5 years of different therapeutic strategies, including 3-4 cycles of chemotherapy with or without radiotherapy and 6 cycles of chemotherapy with or without radiotherapy. The study's secondary objective is to compare the prognostic significance of COO, GC and non-GC phenotypes in localized DLBCL. Methods: This is a single-center Brazilian, observational, retrospective, descriptive and analytical study, to be carried out at the referenced Brazilian cancer center, A.C. Camargo Cancer Center. The study included patients aged 18 years and over, with a nodal DLBCL diagnosis located in the period between 2007 and 2020. PFS and OS curves were performed in 5 years of the population stratified by treatment and cell of origin. Results: A total of 90 patients with limited-stage nodal DLBCL were included. The group that received 3 or 4 cycles of chemotherapy (n=5) had PFS and OS at 5 years of 75%. The second group received 6 cycles of chemotherapy (n=41) and had PFS and OS at 5 years of 89% and 92%, respectively. The third group (n=17) received 3 or 4 cycles of chemotherapy and radiotherapy, and had 100% PFS and OS at 5 years. The fourth group (n=27) received 6 cycles of chemotherapy and radiotherapy and had PFS and OS at 5 years of 87%. There was no statistical difference between the groups. A total of 76 patients had immunohistochemical data extracted from pathology reports to determine COO by Hans' algorithm. A GC phenotype was observed in 47% of patients (n=36). At 5 years, the PFS and OS for the GC cohort were 94% for both, and for the non-GC cohort 85% and 87% respectively. Conclusion: There was no significant difference in PFS or OS for the therapeutic strategies, including 3-4 cycles of chemotherapy with or without radiotherapy and 6 cycles of chemotherapy with or without radiotherapy. In this analysis, the cell of origin did not show a difference in 5 year PFS or OS for localized nodal DLBCL.

Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed.MethodsWe performed whole-exome sequencing of matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed.ResultsA total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were IGLL5 (47%), TP53 (42%), BTG2 (28%), P2RY8 (26%) and PCLO (23%). Compared to the common DLBCL, significantly less or absence of MYD88 (0%), EZH2 (0%), BCL2 (2%) or CD79B (8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the TP53 and LRP1B mutations, two established tumor suppressor genes in many human cancers. Moreover, IGLL5 and LRP1B mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL.ConclusionsOur study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL.