Relapsed/Refractory (R/R) diffuse large B-cell lymphoma (DLBCL) represents a subgroup with a high incidence and dismal prognosis. Currently, there is a lack of robust models for predicting R/R DLBCL. Therefore, we conducted a retrospective study to identify key determinants to be incorporated into a novel nomogram to enhance the identification of DLBCL patients at elevated risk of refractoriness/recurrence.

We included 293 newly-diagnosed DLBCL patients from Harbin Medical University Cancer Hospital, collected from 2008-2017. Patients were randomly divided into a training cohort (n = 206) and a validation cohort (n = 87) at a 7:3 ratio. The training cohort underwent univariable analysis to select variables for a binary logistic regression model. These variables were also prioritized using a random forest algorithm. The developed nomogram was evaluated with the receiver-operator characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) for its clinical utility.

Univariable analysis pinpointed several factors significantly associated with refractoriness/recurrence, including pathological subtype, lactate dehydrogenase (LDH), International Prognostic Index (IPI), treatment, absolute lymphocyte count (ALC), lymphocyte/monocyte ratio (LMR), and prognostic nutritional index (PNI). Binary logistic regression highlighted pathological subtype, LDH, treatment, and ALC as key predictors, which were incorporated into the nomogram. The nomogram showed excellent calibration and accuracy in both cohorts, and comparative DCA and ROC analysis demonstrated its superior net benefit and area under the curve (AUC) compared to traditional indexes like IPI, R-IPI, and NCCN-IPI.

This nomogram serves as a valuable tool for predicting the likelihood of refractoriness or recurrence in DLBCL patients.

Over 60% of relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with chimeric antigen receptor (CAR) T-cells experience progressive disease. The impact of site-specific extranodal involvement on CAR-T outcomes has not been fully elucidated. This multicenter study included 516 R/R LBCL patients infused with CD19-targeted CAR T-cells; 177 (34%) had only-nodal (N), 66 (13%) only-extranodal (E) and 273 (53%) nodal and extranodal (NE) disease at time of CAR T-cells. The NE cohort included more patients with a poor performance status and high tumor burden. In the multivariable analysis, the NE group had a shorter progression-free survival (PFS) (HR 1.27 [95%CI 0.98-1.64], p = 0.07) and overall survival (HR 1.41 [95%CI 1.05-1.88], p = 0.02) compared to N. Conversely, we did not identify efficacy differences between N and E patients. A higher number of extranodal sites and specific organ involvement (liver, adrenal glands, pancreas), were associated with shorter PFS. Finally, extranodal involvement increased at time of relapse, displaying heterogeneous individual site clearance rates. In conclusion, patients with concomitant nodal and extranodal involvement at time of CAR-T had worse outcomes, but this cohort harbored high-risk baseline characteristics. An increasing number of extranodal sites and certain disease locations were associated with lower CAR-T efficacy.

Primary central nervous system (CNS) lymphomas account for 1.9-3% of all brain tumors, with the majority being histologically classified as primary large B-cell lymphoma of the CNS (PCNS-LBCL). PCNS-LBCL is characterized by mature germinal center-exit B cells, and most cases of this phenotype are classified as activated B-cell-like phenotype according to gene expression profiling, or as non-germinal center B-cell-like phenotype (non-GCB type) according to Hans's algorithm. Genetically, PCNS-LBCL often shows mutations in MYD88L265P and CD79BY196, and is similar to MCD or C5 in genetic subtypes. Therefore, we here investigated the clinicopathological and molecular characteristics of primary CNS B-cell lymphomas (PCNSBLs), focusing on the differences in the frequency of MYD88L265P and CD79BY196 mutations, as well as the prognosis between GCB and non-GCB types. Forty-two patients with PCNSBLs were included in this study, with 12 (28.6%) classified as GCB type and 30 (71.4%) as non-GCB type. There were no significant differences between the two types in gender, tumor location, or frequency of MYD88L265P and CD79BY196 mutations. Even after consideration of the confounding of age and the presence of R-MPV therapy, the GCB type PCNSBLs tended to exhibit better prognosis. Overall survival tended to be better in those with the GCB/MYD88L265P mutation (-) group, followed by the GCB/MYD88L265P mutation (+) group, and the non-GCB type. We speculate that Hans's algorithm and MYD88L265P mutation may have potential prognostic value for PCNSBLs.

Patients with rheumatoid arthritis (RA) are at increased risk of diffuse large B cell lymphoma (DLBCL) compared to the general population. Here, we explored the inflammatory profiles in the blood of RA patients who had developed DLBCL. RA-DLBCL patients had significantly higher levels of the pro-inflammatory markers TNF, IL-8, CXCL9, APRIL, and particularly CXCL13 (median 796 vs. 206 pg/mL, p = 0.001), compared to RA controls. By including an extensive autoantibody panel of rheumatoid factor, IgG anti-CCP2, anti-citrullinated protein antibodies (ACPA) fine-specificities, and other anti-modified protein antibodies, all RA-DLBCL patients were autoantibody seropositive. Yet, RA-DLBCL patients did not display significantly different autoantibody signatures compared to RA controls. The levels of immunoglobulin free light chains and C-reactive protein were similar in RA-DLBCL patients and RA controls. In conclusion, RA-DLBCL patients exhibit pro-inflammatory signatures with elevated markers that are important for B cells and may contribute to enhanced B-cell activation and promote lymphoma development.

Double expressor lymphoma (DEL) refers to diffuse large B-cell lymphoma (DLBCL) cases characterized by the overexpression of both MYC and BCL2 proteins, as determined by immunohistochemistry (IHC), without requiring underlying genetic rearrangements. DEL is associated with more aggressive disease behavior and poorer prognosis. This study aimed to assess the impact of DEL on progression-free survival (PFS) and overall survival (OS) compared to non-DEL patients. We conducted a retrospective study at the Hospital, analyzing 177 patients diagnosed with DLBCL between March 2014 and March 2021. Patients were classified as DEL or non-DEL based on immunohistochemical analysis. Survival rates, clinical characteristics, and treatment responses were compared using Kaplan-Meier survival analysis, and multivariable Cox regression was performed to identify independent prognostic factors. Among 177 patients, 113 (63.8%) were DEL and 64 (36.2%) non-DEL. DEL patients had significantly worse outcomes, with a median follow-up of 39.4 months. The 3-year PFS (44.2% vs. 68.8%) and OS (54.9% vs. 81.3%) were significantly lower in DEL (PFS: p < 0.001; OS: p = 0.001). Median PFS in DEL was 19 months. Multivariable analysis confirmed DEL as an independent predictor of worse PFS (HR: 1.488, 95% CI: 1.091-2.03, p = 0.012) and OS (HR: 1.376, 95% CI: 1.011-1.873, p = 0.043). DEL status is strongly linked to poor survival in DLBCL, highlighting the need for targeted therapies beyond R-CHOP. Future research should explore personalized treatment strategies to improve outcomes in this high-risk group.

We describe a rare case of discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma (DLBCL) in the brain and mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow. A 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography scan and contrast-enhanced magnetic resonance imaging showed a mass in the right temporal lobe and rectal wall thickening. Brain biopsy revealed DLBCL, and bone marrow and rectum biopsy showed MCL. According to a polymerase chain reaction analysis of immunoglobulin heavy-chain gene rearrangements using brain and bone marrow specimens, the two lesions were clonally unrelated lymphomas. After five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy and three cycles of R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy, the patient received autologous hematopoietic stem cell transplantation using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen after bridging therapy with ibrutinib. In addition, he received whole-brain irradiation at a dose of 40 Gy in 20 fractions as consolidation therapy. He did not relapse within 3 years of transplantation. To the best of our knowledge, this is the first case report of DLBCL and MCL coexistence.

Primary central nervous system lymphoma (PCNSL) exhibits substantial intratumoural and intertumoural heterogeneity, complicating the development of effective treatment methods. Existing in vitro models fail to simulate the cellular and mutational diversity of native tumours and require prolonged generation times. Therefore, we developed a culture method for patient-derived PCNSL organoids (CLOs) and evaluated the organoids through extensive molecular characterisation, histopathological analysis, single-nucleus RNA sequencing, bulk RNA sequencing and whole-exome sequencing. These CLOs accurately mimicked the histological attributes, gene expression landscapes and mutational profiles of their original tumours. Single-nucleus RNA sequencing also revealed that CLOs maintained cell-type heterogeneity and the molecular signatures of their original tumours. CLOs were generated within 2 weeks, demonstrating rapid development and reliability. Therapeutic profiling was performed on three selected CLOs treated with four standard drugs. The CLOs exhibited specific sensitivity to methotrexate, and resistance to dexamethasone, ibrutinib and rituximab, suggesting that CLOs may be valuable tools for reflecting drug sensitivities. Taken together, these results emphasise that CLOs effectively emulate the key characteristics of PCNSL, increasing the understanding of the genetic landscape of this complex disease. CLOs provide a rapid and reliable platform for exploring individualised treatment strategies, potentially accelerating the transition of research findings to clinical practice.

Background and Objectives: Tumours of the lacrimal drainage system are rare and most located in the lacrimal sac. The authors of this study aimed to conduct a literature review to find out which malignant tumours most often occurred in the lacrimal sac and what symptoms patients reported in the early stages of the disease. Materials and Methods: The PubMed database was searched for papers published between 2019 and 2024. The inclusion criteria were presence of an abstract, malignant lacrimal sac tumours, papers written in English, studies on humans, and case reports. The exclusion criteria were lack of an abstract, pathologies other than malignant tumours, including benign tumours of the lacrimal drainage system, malignant tumours of a part of the drainage system other than the lacrimal sac, papers in languages other than English, studies not involving humans, and no case report. No gender criterion was used. Results: Based on the data available in the literature, 31 studies were included in the article, describing 34 cases of malignant lacrimal sac tumours. Moreover, a case of a 58-year-old patient diagnosed with non-Hodgkin lymphoma was presented. Conclusions: As a result of the literature analysis, it was impossible to find any symptoms reported by patients with lacrimal sac tumours that would clearly suggest their diagnosis.

Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin, 59% were germinal center B-cell-like (GCB), and 25% were activated B-cell-like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC -rearrangement (47% vs. 6%), dark zone signature (DZsig) expression (45% vs. 7%), and more frequent mutation of ID3 , MYC , CCND3 , and TP53 - all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, with those classified as DLBCL-like frequently BCL2 -rearranged. Among DZsig-GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.

Molecular analyses reveal that HGBCL-NOS encompasses a heterogeneous collection of tumors.A subset of HGBCL-NOS can be assigned to established molecular groups, while others remain unclassified.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL) [...].

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in humans, and it is a highly heterogeneous malignancy with a 40% to 50% risk of relapsed or refractory (R/R), leading to a poor prognosis. So early prediction of R/R risk is of great significance for adjusting treatments and improving the prognosis of patients.

We collected clinical information and H&E images of 227 patients diagnosed with DLBCL in Xuzhou Medical University Affiliated Hospital from 2015 to 2018. Patients were then divided into R/R group and non-relapsed & non-refractory group based on clinical diagnosis, and the two groups were randomly assigned to the training set, validation set and test set in a ratio of 7:1:2. We developed a model to predict the R/R risk of patients based on clinical features utilizing the random forest algorithm. Additionally, a prediction model based on histopathological images was constructed using CLAM, a weakly supervised learning method after extracting image features with convolutional networks. To improve the prediction performance, we further integrated image features and clinical information for fusion modeling.

The average area under the ROC curve value of the fusion model was 0.71±0.07 in the validation dataset and 0.70±0.04 in the test dataset. This study proposed a novel method for predicting the R/R risk of DLBCL based on H&E images and clinical features.

For patients predicted to have high risk, follow-up monitoring can be intensified, and treatment plans can be adjusted promptly.

Diffuse large B-cell lymphoma (DLBCL) exhibits striking clinical and biological heterogeneity. Recent studies have identified new subgroups within germinal center B-cell like (GCB) DLBCL, associated with inferior prognosis, irrespective of MYC and BCL2 translocations. We explored the existence of such a DLBCL high-risk subgroup, based on multilevel aberrations, especially focusing on MYC and BCL2.

Tissue samples from 111 DLBCL patients were sequenced with a 90-gene lymphoma panel, followed by integrative analyses combining sequencing data, immunohistochemistry, fluorescent in situ hybridization, and clinical data.

We identified a high-risk subgroup in DLBCL defined by: dual immunohistochemical MYC and BCL2 expression (DEL), concurrent MYC and BCL2 translocations (DHL-BCL2), mutations in MYC, CXCR4, or both, and/or BCL2 amplification. The high-risk subgroup constituted 41% of the cohort and included DHL-BCL2, DEL, a GCB subgroup likely representing the recently described GCB subgroups, and a subset of non-GCB patients. In multivariate analysis, high-risk features provided independent predictive value from age and IPI. The 5-year overall survival was 36% in high-risk patients, compared to 76% in non-high-risk patients.

We identified a distinct high-risk DLBCL subgroup, characterized by MYC and BCL2 aberrations, beyond conventional DHL-BCL2 and DEL, and irrespective of cell-of-origin, thereby expanding the poor-prognosis group.

Large B-cell lymphoma (LBCL) taxonomy has moved in the direction of a molecular classification, but further clinical experience is needed. We present high-risk gene mutations, which predict outcome in an exploratory study of a consecutive real-world cohort of patients with primary LBCL treated with R-CHOP or R-CHOP-like therapy.

The study was a Registry Study Research Project. Sixty-one patients with LBCL, who had a diagnostic tumor sample successfully examined with a 59-gene next-generation sequencing (NGS) panel as a part of routine clinical work, were included in an otherwise unselected cohort. Data were extracted from patient files and pathology reports.

Mutations in NOTCH2 (HR 9.69; 95% CI [2.46-38.11]; p = 0.0012), PRDM1 (HR 3.54; 95% CI [1.03-12.22]; p = 0.045), and TP53 (HR 5.89; 95% CI [1.71-20.32]; p = 0.005) were significantly associated with inferior survival in patients with primary LBCL treated with intention to cure with at least three series of R-CHOP or R-CHOP-like therapy. Neither MYD88 (HR 0.66; 95% CI (0.17-2.49), p = 0.54) nor CD79B (HR 0.84;95% CI (0.18-3.88), p = 0.82) mutations were associated with inferior survival.

With a targeted gene panel and NGS methodology feasible in daily diagnostic routine, we identified high-risk gene mutations with a significant prognostic impact of which TP53 mutations were reproducible across validation cohorts.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common histological types of B-cell lymphoma, but have significantly different pathological and biological characteristics. In recent years, understanding of the genetic abnormalities and microenvironmental structures of these lymphomas has progressed, and various molecular targeted drugs and immunotherapies have been introduced into clinical practice. Therefore, accurate understanding of etiology and its clinical relevance is required for the appropriate management of these lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid tumor, and accounts for approximately 30-40% of non-Hodgkin lymphomas. Although the prognosis has significantly improved with the advent of rituximab combination chemotherapy in the early 2000s, recurrence still occurs in about 40% of cases. Even though chemotherapy with increased dose-intensity is used in recurrent cases, the prognosis of such patients remains poor. Thus, the development of personalized medicine, including molecular-targeted drugs, is required to improve the prognosis of DLBCL patients, and further understanding of the molecular pathogenesis of DLBCL is essential for this purpose. With recent advances in genetic analysis technology, unknown genetic abnormalities and gene expression patterns have been discovered, and based on these discoveries, progress is being made in elucidating and subdividing molecular pathologies. This article summarizes recent findings regarding molecular pathogenesis in DLBCL using transcriptome and genomics technologies, and outlines the path to personalized medicine.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common form of non-Hodgkin lymphoma (NHL) that occurs worldwide. To discover risk factors and pathogenesis of DLBCL, we performed the largest GWAS of DLBCL to date in samples of East Asian ancestry, consisting of 2,888 patients with DLBCL and 12,458 controls. The meta-analysis identified three novel loci, rs2233434 on 6p21.1 (OR = 1.26, P = 1.17 × 10-8), rs11066015 on 12q24.12 (OR = 1.24, P = 6.57 × 10-9) and rs6032662 on 20q13.12 (OR = 1.24, P = 5.22 × 10-12). Fine mapping analysis revealed that the extensive association within the MHC region was driven by two novel HLA alleles, HLA-A*02 and HLA-DQB1*03. Functional annotation, eQTL and colocalization analyses of the susceptibility loci implicated NFKBIE/TCTE1, ALDH2/BRAP and CD40 as candidate disease genes. The pleiotropic effect analysis of the DLBCL loci revealed shared genetic susceptibility between DLBCL and several autoimmune diseases. Our study also suggested genetic heterogeneity between Asian and European populations by identifying ancestry-specific genetic associations. Overall, this study has implicated novel disease genes and molecular mechanism for DLBCL.

Primary central nervous system lymphoma (PCNSL) is non-Hodgkin's lymphoma (NHL) confined to the central nervous system. Most of the patients eventually develop relapsed/refractory (R/R) PCNSL, and the overall prognosis for PCNSL remains dismal. Recently, gene sequencing, transcriptome sequencing, and single-cell sequencing platforms have provided a large amount of data revealing the mechanisms underlying the pathogenesis and drug resistance in PCNSL, including the activation of the NF-κB signaling pathway in tumor cells, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Advances in molecular pathology studies for PCNSL have led to identifying new therapeutic targets and developing novel drugs. New therapeutic strategies, such as creating small molecule targeted agents, immunomodulatory drugs, immune checkpoint inhibitors, and chimeric antigen receptor T (CAR-T) cell therapy, have brought new hope for patients with PCNSL, especially for R/R PCNSL. This review presents recent advances in the treatment of PCNSL, reviews and discusses the efficacy and challenges of targeted therapy and immunotherapy, and provides an outlook on the future development of PCNSL treatment strategies.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin's lymphoma that arises from the germinal center. It represents a heterogeneous disease characterized by different pathological, clinical, and molecular entities. Gene expression profiling based on the alleged cell of origin differentiates transcriptional subtypes such as germinal center and activated B cell-like. DLBCL accounts for around 40% of all non-Hodgkin's lymphomas worldwide. Its incidence generally increases with age. The international prognostic index remains the most important tool for disease stratification.The diagnosis of DLBCL is best made through an excisional biopsy of a suspicious lymph node. Nowadays, advanced techniques are employed to accurately diagnose and determine the clinical outcomes of patients. Immunohistochemistry, next-generation sequencing, and array-based comparative hybridization facilitate the global identification of diverse and numerous genetic alterations. However, further validation should be necessary to apply advanced techniques in clinical practice. In this review, we summarize the current literature and discuss the pathophysiology, epidemiology, and diagnostic advancements of DLBCL.

Classic Hodgkin lymphoma (CHL) is characterized by infrequent neoplastic Hodgkin and Reed-Sternberg (HRS) cells in an inflammatory background. The diagnostic utility of CC-chemokine receptor 7 (CCR7) in CHL was explored using flow cytometry and immunohistochemistry (IHC).

Neoplastic specimens and non-neoplastic lymph nodes were immunophenotyped and CCR7 expression was measured semiquantitatively by flow cytometry (clone 3D12) and IHC (clone 150503).

Our results showed that CCR7 was expressed on HRS cells in the vast majority of CHL cases (45/48 by flow cytometry, 57/59 by IHC) but rarely expressed in neoplastic cells in diffuse large B-cell lymphoma, not otherwise specified (1/25 by flow cytometry, 2/40 by IHC) and nodular lymphocyte predominant Hodgkin lymphoma (0/4 by flow cytometry, 1/13 by IHC). Primary mediastinal large B-cell lymphoma (PMLBCL) revealed weak CCR7 expression by flow cytometry in most cases (8/10) but only occasionally by IHC (2/12). Both cases (2/2) of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) also showed CCR7 expression detected by flow cytometry compared with IHC (0/7). The HRS cells demonstrated a greater percentage of positive cells and greater antigen intensity than the other B-cell lymphomas by IHC. The expression identified by flow cytometry in PMLBCL and THRLBCL but not by IHC suggests that there may be differences in the detection capabilities of the 2 techniques or the 2 CCR7 clones used.

The expression of CCR7 in HRS cells suggests its potential utility in differentiating CHL from other B-cell lymphomas. Incorporating CCR7 into flow cytometry and IHC panels may further enhance the diagnostic sensitivity of CHL.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a highly aggressive malignancy with inferior outcomes after treatment, which might be largely attributed to the immune escape induced by EBV via modulation of the immune checkpoint programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1). This study aimed to explore the role that EBV-encoded latent membrane protein 2A (LMP2A) played in the mechanisms of immune escape of EBV+ DLBCL cells. Ten cases each of EBV+ DLBCL with and without immunohistochemical expression of LMP2A were submitted for evaluation of PD-L1, p65/nuclear factor-κB (NF-κB), phosphorylated SYK (pSYK), and p-p65 expression by immunohistochemistry. To observe the relationship between LMP2A expression and the tumor immune microenvironment, tumor-infiltrating CD4+ and CD8+ T-cell levels were also evaluated by immunofluorescence assay. Compared with LMP2A- cases, LMP2A+ cases exhibited more pronounced biologic aggressiveness and featured a significantly higher level of pSYK, p-p65, and PD-L1 and increased CD4+/CD8+ ratio. In vitro experiments were conducted to ascertain the effects of SYK and p65/NF-kB signaling on PD-L1 expression in the OCI-LY8 cells. After transfection with LMP2A, the expression levels of pSYK, p65, p-p65, and PD-L1 were all elevated, and knockdown of p65 or pSYK in LMP2A-transfected DLBCL cells resulted in PD-L1 inhibition. Our work indicates that LMP2A may mimic B-cell receptor and trigger the SYK/NF-κB signaling, which subsequently influences the PD-L1 levels of tumor cells and the tumor immune microenvironment, thus facilitating the immune evasion of lymphoma cells. These findings may have clinical implications for modulating or improving the therapeutic strategies of patients with EBV+ DLBCL.

Immune cells within the lymphoma tumor microenvironment promote immune evasion and are rational therapeutic targets. Alemtuzumab targets CD52 expressed on malignant B-cells and infiltrating nonmalignant T-cells. We evaluated the safety and efficacy of alemtuzumab with DA-EPOCH-R in 48 patients with relapsed/refractory aggressive B-cell lymphoma. Febrile neutropenia occurred in 18% of cycles and serious infections in 21% of patients. Responses were observed in 30 (62%) patients, including 12 (80%) patients with classical HL and 3 (75%) patients with T-cell/histiocyte-rich large B-cell lymphoma (THRLCL). Seventeen (35%) patients achieved complete responses, and 12 (25%) were bridged to consolidation. The 2-year progression-free survival (PFS) and overall survival were 22.1% (95% CI, 11.5-34.7%) and 45.2% (95% CI, 34.3-58.9%), respectively. The 2-year PFS for HL and THRLCL patients was 35% and 50%, respectively. Alemtuzumab can be safely combined with DA-EPOCH-R in relapsed/refractory aggressive B-cell lymphomas and can induce durable responses in patients with T-cell-rich microenvironments.

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare aggressive lymphoma. Recently, genetic classification using Next Generation Sequencing (NGS) demonstrated that PSDLBCL largely consists of the MCD genotype, which has a poor prognosis mainly driven by MYD88 L265P and CD79B gene abnormalities. This study investigated the prevalence and clinicopathological significance of MYD88 L265P and CD79B Y196 mutations using droplet digital PCR in 55 patients with PSDLBCL, as well as the translocation of BCL2 / BCL6 / c-Myc with FISH. We found mutations in MYD88 L265P (29/55, 52.7%) and CD79B Y196 (20/55, 36.4%). The MCD-like subtype, defined by the mutation of MYD88 and/or CD79B , was found in 32 out of 55 cases (58.2%). This subtype largely consists of non-GCB type (31/32, 96.9%; P <0.01) and double-expressor cases (20/32, 62.5%; P =0.01) compared with the MYD88 / CD79B co-wild type, with BCL6 translocation in a small subset (2/32, 6.3%) and no translocations of BCL2 (0/32) or c-Myc (0/32). The MCD-like subtype tended to relapse in specific sites such as the central nervous system, testis, and/or skin compared with the co-wild type ( P =0.03), showing poorer outcomes in overall survival ( P =0.02) and progression-free survival ( P =0.01). In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of aggressive large B-cell lymphoma (aLBCL). Patients with transformed indolent non-Hodgkin lymphoma (tiNHL) were included in key CAR trials, but outcomes of CAR for this distinct, historically high-risk group are poorly understood. We conducted a multicenter retrospective study of 1182 patients with aLBCL receiving standard-of-care CAR T between 2017 and 2022, including 338 (29%) with tiNHL. Rates of grade ≥ 3 cytokine release syndrome (CRS) were similar between tiNHL and de novo cohorts (7% vs. 8%, p = 0.6), while grade ≥ 3 immune effector cell-associated neurotoxicity syndrome was lower in tiNHL (21% vs. 27%, p = 0.02). Overall response rate was similar in both cohorts (83% vs. 81%, p = 0.3), while complete response rate was higher in tiNHL (67% vs. 59%, p = 0.017). With a median follow-up of 22.3 months, the progression/relapse-free (PFS) and overall survival (OS) were similar between the tiNHL and de novo cohorts (24-month PFS 41% [95% CI: 35%-46%] vs. 38% [95% CI: 35%-42%]; 24-month OS 58% [95% CI: 52%-63%] vs. 52% [95% CI: 48%-56%], respectively). After adjusting for key risk factors, there was a trend toward a lower hazard of disease progression, relapse or death post-CAR for tiNHL patients compared to de novo aLBCL patients (HR: 0.84 [95% CI: 0.69-1.0], p = 0.07). Elevated LDH, advanced stage, prior bendamustine within 12 months of CAR, receipt of bridging therapy, CNS involvement, and ≥ 3 prior lines of therapy were each associated with inferior PFS. In conclusion, CAR T therapy is highly effective with an acceptable toxicity profile in patients with tiNHL.

Previous researches mainly focused on whether cancer stem cells exist in diffuse large B-cell lymphoma (DLBCL). However, subgroups with dismal prognosis and stem cell-like characteristics have been overlooked.

Using large scale data (n = 2133), we conducted machine learning algorithms to identify a high risk DLBCL subgroup with stem cell-like features, and then investigated the potential mechanisms in shaping this subgroup using transcriptome, genome and single-cell RNA-seq data, and in vitro experiments.

We identified a high-risk subgroup (25.6 % of DLBCL) with stem cell-like characteristics and dismal prognosis. This high-risk group (HRG) was featured by upregulation of key enzyme (ODC1) in polyamine metabolism and cold tumor microenvironment (TME), and had a poor prognosis with lower 3-year overall survival (OS) (54.3 % vs. 83.6 %, P < 0.0001) and progression-free survival (PFS) (42.8 % vs. 74.7 %, P < 0.0001) rates compared to the low-risk group. HRG also exhibited malignant proliferative phenotypes similar to Burkitt lymphoma. Patients with MYC rearrangement, double-hit, double-expressors, or complete remission might have either favorable or poor prognosis, which could be further distinguished by our risk stratification model. Genomic analysis revealed widespread copy number losses in the chemokine and interferon coding regions 8p23.1 and 9p21.3 in HRG. We identified ODC1 as a therapeutic vulnerability for HRG-DLBCL. Single-cell analysis and in vitro experiments demonstrated that ODC1 overexpression enhanced DLBCL cell proliferation and drove macrophage polarization towards the M2 phenotype. Conversely, ODC1 inhibition reduced DLBCL cell proliferation, induced cell cycle arrest and apoptosis, and promoted macrophage polarization towards the M1 phenotype. Finally, we developed a comprehensive database of DLBCL for clinical application.

Our study effectively advances the precise risk stratification of DLBCL and reveals that ODC1 and immune-deserted microenvironment jointly shape a group of DLBCL patients with stem cell-like features. Targeting ODC1 regulates immunotherapies in DLBCL, offering new insights for DLBCL treatment.

A cholecystocutaneous fistula is a type of external biliary fistula that occurs when there is an abnormal connection between the gallbladder and skin. We report the first case of a cholecystocutaneous fistula that occurred in association with the development of lymphoma in the gallbladder. A 76-year-old woman who was under observation for follicular lymphoma with a low tumor burden presented with fatigue and abdominal pain. Imaging studies revealed cholecystitis associated with an abdominal subcutaneous abscess, and lymphoma transformation was confirmed by a lymph node biopsy. Edwardsiella tarda was cultured from both the abdominal subcutaneous abscess and percutaneous transhepatic gallbladder drainage, demonstrating cholecystocutaneous fistula, and open cholecystectomy revealed lymphoma cell infiltration into the gallbladder. Our case showed unique complications, and its successful management was associated with aggressive lymphoma development.

A 70-year-old woman presented to our hospital with abdominal pain. Imaging examinations showed diffuse and extensive wall thickening at the perihilar bile duct; however, the degree of stricture was mild, and the mucosal epithelium was smooth. A transpapillary biopsy was performed considering cholangiocarcinoma and IgG4 sclerosing cholangitis as differential diagnoses; however, no pathologic diagnosis was obtained. Peroral cholangioscopy revealed a regular epithelium at the stricture, and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the enlarged lymph node confirmed the diagnosis of diffuse large B-cell lymphoma. Multiagent chemotherapy was administered, which led to complete remission. Because primary bile duct malignant lymphomas are rare and specific, clinical, and imaging findings are lacking, and many of those reported so far have been diagnosed by postoperative pathology. As chemotherapy is the first-line treatment for malignant lymphoma, obtaining an accurate diagnosis is crucial. Our findings support that smooth and mild biliary strictures with mainly submucosal wall thickening may be characteristic imaging findings of primary bile duct malignant lymphoma, and that peroral cholangioscopy and EUS-FNA may be helpful for an accurate diagnosis.

Central nervous system (CNS) involvement in Waldenström macroglobulinemia (WM) is a rare complication that can manifest as Bing-Neel syndrome (BNS) or as histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL). We report data from a single-center cohort of 469 patients consecutively diagnosed with WM between 2000 and 2022. BNS was identified in 1.5% (n = 7) and HT with CNS involvement (CNS-HT) in 1.7% (n = 8) of patients. The cumulative incidence of BNS and CNS-HT at 15 years was 2.6% and 2.7%, respectively, with CNS-HT more likely to develop in closer proximity to the initial WM diagnosis. One patient with CNS-HT exhibited a preceding phase of BNS before transformation. In general, patients with BNS and CNS-HT presented with diverse neurological symptoms and clinical features. Parenchymal lesions were uniformly found in all patients with CNS-HT, while neuroimaging findings were less consistent in patients with BNS. Involvement of multiple extramedullary sites was observed in approximately half of the patients with both BNS and CNS-HT. Patients with CNS-HT had poor outcomes, with a median overall survival of 10 months following the onset of CNS involvement, whereas BNS was associated with a more favorable prognosis, particularly in patients treated with ibrutinib. This study is the first to present a comparative analysis of BNS and CNS-HT in WM, providing novel insights into their incidence, clinical features, and outcomes.

CD5+ diffuse large B-cell lymphoma (DLBCL) is a rare subtype characterized by an inferior outcome. While dose-dense therapy shows promising activity, the optimal management remains to be determined. To evaluate the benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT), we retrospectively reviewed the medical records of 47 consecutive patients with newly diagnosed de novo CD5+ DLBCL. Of 19 patients ≤ 70 of age with age-adjusted International Prognostic Index 2-3, eight underwent upfront ASCT, and nine did not, despite preserved organ function and response after induction therapy. The remaining two, ineligible for ASCT due to early progression or comorbidities, had a dismal clinical course. Among younger 17 high-risk patients eligible for ASCT, ASCT was associated with better overall (p = 0.0327) and progression-free survival (p = 0.0184). Younger patients without ASCT demonstrated similar outcomes to older patients with similar risk profiles. ASCT could be considered for high-risk CD5+ DLBCL with a response after induction therapy.

CD47 interacts with signal regulatory protein alpha (SIRPα) on macrophages to deliver an anti-phagocytic signal, enabling tumor cells to evade immune destruction. This study explores the relationship between CD47 and SIRPα expression and key clinical prognostic factors, microvascular density (MVD), and tumor-infiltrating lymphocytes (TIL) in Diffuse Large B Cell Lymphoma (DLBCL) cases. We analyzed tissue samples from 122 DLBCL cases using tissue microarray (TMA) blocks and immunohistochemical staining for CD47, SIRPα, CD31, and CD3. CD47 expression was scored using the Allred scoring system, and SIRPα expression was quantified based on the percentage of positive membranous and cytoplasmic expression. Clinical data, including IPI scores, relapse rates, and gene expression profiles, were correlated with the immunohistochemical findings.CD47 expression score ≥ 6 was significantly associated with the DLBCL-ABC phenotype (p = 0.029), higher IPI scores (p = 0.020), and increased relapse rates (p = 0.021). High SIRPα expression (≥25 % staining) was also linked to the ABC phenotype (p = 0.022) and frequent relapses (p = 0.021). Notably, cases with high microvascular density exhibited lower SIRPα expression (p = 0.013). There was no significant relationship between MVD and CD47 or other clinical prognostic factors. Additionally, higher CD3-positive TIL percentages were inversely correlated with IPI scores (p = 0.005), although no significant association was found between CD3 and CD47-SIRPα. The study reveals that increased CD47-SIRPα expression is partially linked to adverse prognostic indicators and reduced MVD in DLBCL cases. These findings suggest that targeting the CD47-SIRPα axis could offer a novel therapeutic approach in DLBCL, particularly for patients with poor prognostic features.

Oxidative stress is a cellular characteristic that might induce the proliferation and differentiation of tumor cells and promote tumor progression in diffuse large B-cell lymphoma (DLBCL).

The DLBCL gene sequencing dataset, tumor mutation burden data, copy number variation data of Somatic cell mutation data in TCGA were downloaded for data training analysis, along with four DLBCL datasets in GEO for validation analysis. The known oxidative stress related genes (OSRGs) were collected from websites. The weighted gene co-expression network analysis (WGCNA) was conducted on the TCGA DLBCL dataset to obtain gene modules related to oxidative stress and intersected with the known OSRGs to obtain the hub genes, which were used to perform consensus clustering on the samples to obtain new phenotypes. Next, the prognosis related OSRGs were selected through regression analysis algorithms and key genes were identified. These genes were used to establish the prognostic risk model and predictive model, and to compare functional and pathway differences among different risk groups.

Through website search, we obtained 297 known OSRGs, and after intersecting with WGCNA results, we obtained 26 OSRGs. The TCGA-DLBC samples were clustered into 2 subtypes with these genes and there were significant differences in immune infiltration between subtypes. After regression analysis, we obtained a total of four key genes, BMI1, CDKN1A, NOX1, and SESN1. The risk prediction model established with these four genes as variables has accurate prognostic prediction ability. The key genes interact with 65 miRNAs, 57 TFs, 47 RBPs, and 62 drugs, respectively, and are closely related to immune infiltration of the disease. Among them, CDKN1A and SESN1 had the highest variability.

The key genes involved in oxidative stress could predict the prognosis of DLBCL and potentially become therapeutic targets.

Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox's proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive, yet curable, malignancy, but older patients are at higher risk of relapsed disease because they may not be eligible for full-intensity frontline chemoimmunotherapy or have comorbidities that limit standard treatments. Recent years have brought more treatment options than ever for this patient population, but it remains challenging to determine which can be safely and effectively offered to older patients. Formal determinations of fitness including geriatric assessments remain critical, but there is less guidance on how to best use this tool in the relapsed setting. Chimeric antigen receptor T-cell therapy is accessible to older patients, provided they can be supported through the intensive road to this treatment. If relapse occurs despite this or alternative therapies are preferred, many novel therapeutic options and combinations exist with some potential modifications for older adults, such as bispecific antibodies, tafasitamab and lenalidomide, polatuzumab-containing regimens, or loncastuximab tesirine. This article provides a summary of our approach to the management of this diverse population of older patients with relapsed or refractory DLBCL.