Case Of Large B-cell Lymphoma Research Articles

Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.

Abstract ND05: The discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma

Abstract Discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma (NHL)Dan Sherman, Sheryl M. Gough, Lynn DeCarr, Sarah Eaton, Mark Bookbinder, Jennifer Pizzano, Elizabeth Bortolon, John Corradi, Rashaun Wilson, Daniel Rogoz, Ram Lingamaneni, Wei Zhang, Michelle Zhang, Xin Chen, Gan Wang, Hanqing Dong, Michael Berlin, Keith R. Hornberger, Lawrence Snyder, Achal Pashine and Ian Taylor. Arvinas, Inc., 5 Science Park, New Haven, CT, USA. Approximately 18,000 cases of Diffuse large B-cell lymphomas (DLBCL) are diagnosed worldwide per year making this cancer the most prevalent (30%) of the non-Hodgkin’s Lymphomas (NHL). Despite the success of R-CHOP treatment, approximately 40% of patients are refractory or relapse. While much progress has been made with CAR-Ts and bi-specific antibodies following frontline therapy in recent years, there remains a need for an orally bioavailable small-molecule that targets molecular drivers of NHL. The BCL6 transcription factor has long been known as an oncogenic driver of B-cell malignancy. The BCL6 gene has been found to be translocated and/or mutated resulting in deregulation of its expression, predominantly in DLBCL and Burkitt’s lymphoma (BL). The deregulated expression and scaffolding role of BCL6 in the transcriptional repressor complex make it an ideal target for the PROteolysis Targeting Chimera (PROTAC®) technology with one BCL6 degrader recently entering Phase 1 trials. We undertook a medicinal chemistry campaign to identify a BCL6-targeting PROTAC®. This effort identified ARV-393, an orally bioavailable PROTAC® that recruits BCL6 and the E3 ligase cereblon to rapidly degrade BCL6 via the cell’s natural ubiquitin proteasome system. ARV-393 is potent, demonstrating DC50 and GI50 values <1 nM in numerous DLBCL and BL cell lines. This agent demonstrates deep BCL6 degradation in vitro and in vivo, resulting in excellent TGI in several tumor xenograft models supporting a first-in-human trial in 1H 2024. We will present the chemical structure of ARV-393 and selected pre-clinical data. Citation Format: Dan Sherman. The discovery of ARV-393, a potent, orally bioavailable BCL6 targeting PROTAC® for the treatment of Non-Hodgkin’s Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND05.

LMP1 Expression of Esptein Baar Virus in Pediatric Lymphomas: A 06-Year Retrospective Series in Dakar

Persistent Epstein Baar Virus (EBV) infection may be a perfect target for the treatment of EBV-associated lymphomas and improved patient outcomes. The aim of this work was to evaluate the frequency of LMP1 (Latence membrane Protein 1) expression in pediatric lymphomas in Dakar. <i>Material and Methods</i>: This was a retrospective, descriptive study from January 1, 2015 to December 31, 2020. It was based on blocks and anatomopathological reports of pediatric Lymphomas in 04 ACP laboratories in Dakar. The immunohistochemical study was carried out at the IBN ROCHD Hospital in Casablanca, Morocco, using a manual method. LMP1 immunostaining was considered positive if 10% of tumour cells showed cytoplasmic staining. <i>Results</i>: Positive staining for LMP1 was noted in 13 of the 42 cases of pediatric lymphomas tested, i.e. 31% of cases. These included 09 cases of Hodgkin's lymphoma, i.e. 69% (9/13), and 04 cases of non-Hodgkin's lymphoma, i.e. 31%. LMP1-positive classical Hodgkin's lymphomas accounted for 40.09% (9/22) of Hodgkin's lymphomas, and were of the mixed cellularity (6/22) and scleronodular (3/22) subtypes. The frequency of LMP1-positive samples in non-Hodgkin's lymphomas was 20% (4/20). These included 3 cases of Burkitt's lymphoma and 1 case of diffuse large B-cell lymphoma. <i>Conclusion</i>: The frequency of EBV infection in pediatric lymphomas in Senegal is lower than in endemic areas of Africa.

Rare Case of Refractory Shock Secondary to Large B Cell Lymphoma

A previously healthy 69-year-old female admitted to the hospital with refractory hypotension fevers and diarrhea. She had two prior hospitalizations with similar presentations and no clear etiology could be identified. During her current hospitalization, she was admitted to the intensive care unit (ICU) due to refractory shock. Despite an extensive work up with multiple subspecialty consultation, the patient ultimately transitioned to comfort care. Autopsy report revealed extensive large b-cell lymphocyte involvement within the vasculature of the majority of her organs. This case of intravascular large B-cell lymphoma (ILBCL) exemplifies the necessity to include it on a broadened differential when shock becomes refractory.

The pattern of back pain: from spondyloarthritis to lymphoma

inflammatory back pain, which rheumatologists often deal with in their practice, has certain characteristics. However, other non-rheumatological diseases can mimic inflammatory back pain. Non-compliance with the diagnostic criteria and the presence of additional symptoms, especially from the group of "red flags", such as weight loss, fever, night sweats, etc., require careful diagnosis. The purpose of the work is to analyze a clinical case of diffuse large B-cell lymphoma in a young patient with non-specific symptoms, differential diagnosis with seronegative spondyloarthritis associated with inflammatory bowel disease. The article uses the data of objective, instrumental and laboratory examination of the patient. The work presents a clinical case of back pain in a 27-year-old patient, in which a multidisciplinary approach and specific diagnostic procedures (lymph node biopsy, histological and immunohistochemical examination) made it possible to establish the final diagnosis - diffuse large B-cell lymphoma. Based on a clinical case, a review of the literature was performed with an emphasis on the differential diagnosis between rheumatic inflammatory back pain and other causes, including paraneoplastic pain and metastatic processes. The most common causes of chronic back pain in young men are spondyloarthritis, however, in the presence of weight loss, fever, night sweats and lymphadenopathy, back pain requires careful clinical, laboratory and instrumental examination of patients. Diffuse large B-cell lymphoma can be the cause of back pain, which requires the involvement of specialists of various profiles in order to verify the final diagnosis.

Mutational, immune microenvironment, and clinicopathological profiles of diffuse large B-cell lymphoma and follicular lymphoma with BCL6 rearrangement.

BCL6-rearrangement (BCL6-R) is associated with a favorable prognosis of follicular lymphoma (FL), but the mechanism is unknown. We analyzed the clinicopathological, immune microenvironment (immune checkpoint, immuno-oncology markers), and mutational profiles of 10 BCL6-R-positive FL, and 19 BCL6-R-positive diffuse large B-cell lymphoma (DLBCL) cases (both BCL2-R and MYC-R negative). A custom-made panel included 168 genes related to aggressive B-cell lymphomas and FL. FL cases were nodal, histological grade 3A in 70%, low Ki67; and had a favorable overall and progression-free survival. DLBCL cases were extranodal in 60%, IPI high in 63%, non-GCB in 60%, EBER-negative; and had a progression-free survival comparable to that of DLBCL NOS. The microenvironment had variable infiltration of M2-like tumor-associated macrophages (TAMs) that were CD163, CSF1R, LAIR1, PD-L1, and CD85A (LILRB3) positive; but had low IL10 and PTX3 expression. In comparison to FL, DLBCL had higher TAMs, IL10, and PTX3 expression. Both lymphoma subtypes shared a common mutational profile with mutations in relevant pathogenic genes such as KMT2D, OSBPL10, CREBBP, and HLA-B (related to chromatin remodeling, metabolism, epigenetic modification, and antigen presentation). FL cases were characterized by a higher frequency of mutations of ARID1B, ATM, CD36, RHOA, PLOD2, and PRPRD (p < 0.05). DLBCL cases were characterized by mutations of BTG2, and PIM1; and mutations of HIST1H1E and MFHAS1 to disease progression (p < 0.05). Interestingly, mutations of genes usually associated with poor prognosis, such as NOTCH1/2 and CDKN2A, were infrequent in both lymphoma subtypes. Some high-confidence variant calls were likely oncogenic, loss-of-function. MYD88 L265P gain-of-function was found in 32% of DLBCL. In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.

Long noncoding RNA XIST: A novel independent prognostic biomarker for patients with ABC-DLBCL receiving R-CHOP treatment.

Approximately one-third of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cases were unresponsive to standard first-line therapy; thus, identifying biomarkers to evaluate therapeutic efficacy and assessing the emergence of drug resistance is crucial. Through early-stage screening, long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) was found to be correlated with the R-CHOP treatment response. This study aimed to clarify the characteristics of XIST in ABC-DLBCL. The expression level of XIST in 161 patients with ABC-DLBCL receiving R-CHOP therapy was examined via RNA in situ hybridization, and the association between XIST expression and clinicopathological features, treatment response, and prognosis was analyzed in the study cohort and validated in the Gene Expression Omnibus cohort. Cell biological experiments and bioinformatics analyses were conducted to reveal aberrant signaling. The proportion of complete response in patients with high XIST expression was lower than that in patients with low XIST expression (53.8% vs. 77.1%) (P = 0.002). High XIST expression was remarkably associated with the characteristics of tumor progression and was an independent prognostic element for overall survival (P = 0.039) and progression-free survival (P = 0.027) in ABC-DLBCL. XIST was proven to be involved in m6A-related methylation and ATF6-associated autophagy. XIST knockdown repressed ABC-DLBCL cellular proliferation by regulating Raf/MEK/ERK signaling. High XIST expression was associated with ABC-DLBCL tumorigenesis and development and contributed to R-CHOP treatment resistance. XIST may be a promising signal to predict ABC-DLBCL prognosis.

The impact of MYD88 and PIM1 in mature large B-cell non-Hodgkin lymphomas: Defining element of their evolution and prognosis.

Sequence studies of the entire exome and transcriptome of lymphoma tissues have identified MYD88 and PIM1 as involved in the development and oncogenic signaling. We aimed to determine the frequency of MYD88 and PIM1 mutations, as well as their expressions in conjunction with the clinicopathological parameters identified in mature large B-cell non-Hodgkin lymphomas. The ten-year retrospective study included 50 cases of mature large B-cell lymphoma, diagnosed at the Pathology Department of the Emergency County Hospital of Constanţa and Săcele County Hospital of Brasov. They were statistically analyzed by demographic, clinicopathological, and morphogenetic characteristics. We used a real-time polymerase chain reaction technique to identify PIM1 and MYD88 mutations as well as an immunohistochemical technique to evaluate the expressions of the 2 genes. Patients with lymphoma in the small bowel, spleen, brain, and testis had a low-performance status Eastern Cooperative Oncology Group (P = .001). The Eastern Cooperative Oncology Group performance status represented an independent risk factor predicting mortality (HR = 9.372, P < .001). An increased lactate dehydrogenase value was associated with a low survival (P = .002). The international prognostic index score represents a negative risk factor in terms of patient survival (HR = 4.654, P < .001). In cases of diffuse large B-cell lymphoma (DLBCL), immunopositivity of MYD88 is associated with non-germinal center B-cell origin (P < .001). The multivariate analysis observed the association between high lactate dehydrogenase value and the immunohistochemical expression of PIM1 or with the mutant status of the PIM1 gene representing negative prognostic factors (HR = 2.066, P = .042, respectively HR = 3.100, P = .004). In conclusion, our preliminary data suggest that the oncogenic mutations of PIM1 and MYD88 in our DLBCL cohort may improve the diagnosis and prognosis of DLBCL patients in an advanced stage.

Leksell Frame-Based Stereotactic Biopsy for Infratentorial Tumor : Practical Tips and Considerations.

The Leksell frame-based transcerebellar approach was proposed with the arc support frame attached upside down to the Z coordinate. This study presented practical tips and considerations for obtaining adequate tissue samples for deep-seated cerebellar lesions or lower brainstem lesions specifically those accessible via the cerebellar peduncle. For practical insights, the Leksell coordinate frame G was fixed to prevent the anterior screw implantation within the temporalis muscle, to avoid interference with the magnetic resonance (MR)-adapter, and taking into account the magnetic field of MR in close proximity to the tentorium. After mounting of indicator box, the MR imaging evaluation should cover both the indicator box and the infratentorial region that deviated from it. The coordinates [X, Y, Za, Arc0, Ringa0] obtained from Leksell SurgiPlan® software (Elekta, Stockholm, Sweden) with arc 00 located on the patient's right side were converted to [X, Y, Zb=360-Za, Arc0, Ringb0=Ringa0-1800]. The operation was performed in the prone position under general anesthesia in four patients with deep cerebellar (n=3) and brainstem (n=1) tumors. The biopsy results showed two cases of diffuse large B-cell lymphoma, one metastatic braintumor and one glioblastoma. One patient required frame repositioning as a complication. Drawing upon the methodology outlined in existing literature, we anticipate that imparting supplementary expertise could render the stereotactic biopsy of infratentorial tumors more consistent and manageable for the practitioner, thereby facilitating adequate tissue samples and minimizing patient complications.

A Case of Diffuse Large B-cell Lymphoma Transformed from Primary Thyroid MALT Lymphoma

Diffuse large B cell lymphoma (DLBCL) is main subtype of primary thyroid lymphoma and can be histologically transformed from a low-grade B-cell lymphoma. The characteristics and treatment guidelines of these particular DLBCL have not been fully established. The mainstay of treatment of primary thyroid DLBCL is multimodality treatment with chemotherapy and radiotherapy. Meanwhile, surgery can be considered only for diagnosis or alleviation of airway compressive symptoms.A 57-year-old female visited our outpatient clinic for recently enlarged long-held anterior neck mass. A thyroid mass compressing the airway and esophagus was identified on imaging, which was diagnosed as MALT lymphoma by excisional biopsy. After staging, the patient underwent total thyroidectomy with regional lymph node dissection for treatment of stage IIE MALT lymphoma and relieving airway compromise symptoms. The final diagnosis was DLBCL transformed from MALT Lymphoma, and chemotherapy was additionally performed. We report this rare experience with a review of literature.

Cinobufagin Induces Apoptosis of DLBCL Cells By Targeting the Inhibition of G6PD Activity

Background:Globally, there are 150,000 new cases of diffuse large B-cell lymphoma (DLBCL) each year, accounting for approximately 30% of all non-Hodgkin lymphoma cases. Although most patients can be cured with R-CHOP immunochemotherapy, 30-40% of patients progress or relapse after treatment. Therefore, there is an urgent need to find new treatments to improve the survival rate of this group of patients. Natural small molecule drugs have unique advantages as anticancer agents due to their low toxicity and multiple targets. This project aims to explore potentially effective natural compounds as new therapeutic strategies for DLBCL. Methods:Search for suitable natural compounds through GEO database, CMAP server and bioinformatics analysis. The effects of natural compounds on the biological function of DLBCL cells were studied by IC50 assay, apoptosis assay, cell cycle assay and subcutaneous transplanted tumor model. RNA sequencing, metabolomics detection, SEA server and 3D molecular simulation docking analysis were used to explore the drug target. The drug mechanism was verified by G6PD activity assay, EdU incorporation assay, NADPH assay and ROS assay. Results:We used GEO and CMAP databases to identify 20 natural compounds that target DLBCL prognostic genes. Cinobufagin, a natural bufodienol isolated from toad venom, became the main object of this study because of its low IC50 value. Flow cytometry analysis showed that cinobufagin can effectively induce G2 arrest and apoptosis of DLBCL cells. In addition, cinobufagin significantly inhibited the growth of tumor tissue in a mouse model of heterotopic subcutaneous tumor transplantation. The results of transcriptome sequencing suggested that cinobufagin treatment inhibited multiple metabolism-related pathways. Metabolomic analysis showed a decrease in nucleoside metabolite content and inhibition of niacinamide synthesis. Through SEA server and 3D molecular docking simulation analysis, it was found that glucose-6-phosphate dehydrogenase (G6PD) may be a potential target of cinobufagin. G6PD activity assay showed that cinobufagin could inhibit the catalytic ability of G6PD. EdU incorporation experiments showed that cinobufagin inhibited DNA synthesis in DLBCL cells. In addition, cinobufagin also promoted the up-regulation of NADP+/NADPH ratio and the increase of ROS. The addition of ROS scavengers and nucleotides partially reversed the apoptosis-inducing ability of cinobufagin. Conclusion:G6PD is a target of cinobufagin. By inhibiting the enzyme activity of G6PD, cinobufagin can inhibit DNA synthesis and the production of reducing NADPH, thereby inducing apoptosis of DLBCL cells. This suggests that Cinobufagin has potential application as a new drug for the treatment of DLBCL.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Primary testicular lymphoma in undescended testis of a middle-age man: a case report

Background: Primary testicular lymphoma (PTL) is an uncommon and aggressive form of extra-nodal non-Hodgkin lymphoma (NHL), accounting for &lt;5.0% of testicular malignancies and 1.0% to 2.0% of NHL cases with a median age at diagnosis of 66 to 68 years. PTL accounts for 1–9% of testicular malignancies and 1–2% of NHLs. There are a handful of described lymphomas in the literature affecting normally positioned testis of aged men, yet none were reported in a cryptorchid middle-aged man. PTL is an extremely aggressive malignancy with poor progression-free survival and overall survival. Case presentation: A 47-year-old man presented to the urology clinic complaining of multiple painless swellings in the neck and groins. He also complains of back pain, drenching night sweats, a swollen right lower limb, constipation, anorexia, weight loss, and occasional vomiting. The illness's duration is 2 months. He had a right inguinal testis. Histology examination of the excised testis and lymph nodes revealed an advanced “diffuse large beta-cell lymphoma” in both. The patient was referred for oncology care. Conclusion: It is an extremely rare case of Diffuse Large B-Cell Lymphoma (DLBCL) in the undescended testis of a middle-aged man. To the best of our knowledge, this is the first published case of its kind about the tumor's type, testis anomaly, and patient's age.

Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma

TP53 mutation (TP53mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53mut remains a significant challenge in DLBCL treatment. Here we assessed TP53mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53mut patient-derived xenograft models and TP53mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53mut-driven cancers.

GNA13 is a new marker for germinal center-derived B cell lymphomas

AimsWe aim to evaluate the expression of GNA13 in germinal center (GC)-derived B cell lymphomas to evaluate its potential use as marker for diagnosis. Methods and ResultsIn this study, GNA13 expression was detected by immunohistochemistry in 129 cases of B-cell non-Hodgkin lymphomas (B-NHLs) and 8 cases of angioimmunoblastic T-cell lymphoma (AITL). Furthermore, mutations in the GNA13 gene in 114 cases of B-NHLs were detected by exome sequencing. In 50 cases of diffuse large B-cell lymphoma (DLBCL), 11 cases were positive for GNA13, and all GNA13-positive cases were of the germinal center B-cell-like (GCB) subtype. In 42 cases of follicular lymphoma (FL), the GNA13-positive rate was 100% in FL grade 1, 100% in FL grade 2, 80.0% in FL grade 3 A, and 63.2% in FL grade 3B. In 6 cases of Burkitt lymphoma, 3 cases were positive for GNA13. However, in small lymphocytic lymphoma, mantle cell lymphoma and marginal zone lymphoma, GNA13 was negative or only expressed in the GC. In addition, the GNA13-positive rate was 100% in AITL. The mutation of the GNA13 gene was 27.8% (5/18) in GCB-DLBCL and 10.3% (3/29) in FL, respectively, and mutation of GNA13 occurred in cases with weak positive or negative expression of the GNA13 protein. ConclusionGNA13 may be a reliable new marker for GC cells applied in the diagnosis of GC-derived B-cell lymphomas. Its deficiency or low expression may be related to the degree of invasion of GC-derived B-cell lymphomas, and may result from genetic mutations.

A case of diffuse large B-cell lymphoma using random skin biopsy as a diagnostic aid

A case of diffuse large B-cell lymphoma using random skin biopsy as a diagnostic aid

Pseudotemporal ordering of spatial lymphoid tissue microenvironment profiles trails Unclassified DLBCL at the periphery of the follicle.

We have established a pseudotemporal ordering for the transcriptional signatures of distinct microregions within reactive lymphoid tissues, namely germinal center dark zones (DZ), germinal center light zones (LZ), and peri-follicular areas (Peri). By utilizing this pseudotime trajectory derived from the functional microenvironments of DZ, LZ, and Peri, we have ordered the transcriptomes of Diffuse Large B-cell Lymphoma cases. The apex of the resulting pseudotemporal trajectory, which is characterized by enrichment of molecular programs fronted by TNFR signaling and inhibitory immune checkpoint overexpression, intercepts a discrete peri-follicular biology. This observation is associated with DLBCL cases that are enriched in the Unclassified/type-3 COO category, raising questions about the potential extra-GC microenvironment imprint of this peculiar group of cases. This report offers a thought-provoking perspective on the relationship between transcriptional profiling of functional lymphoid tissue microenvironments and the evolving concept of the cell of origin in Diffuse Large B-cell Lymphomas.

Histopathological Experience of Primary Adrenal Lymphoma From Two Tertiary Hospitals.

Primary adrenal lymphoma (PAL) is a rare tumor. The aim of this study was to demonstrate the histopathological features of PAL at two tertiary hospitals. All PALs diagnosed between January 2003 and February 2023 were retrieved. Pathology and immunohistochemistry slides were reviewed. Additional immunohistochemical markers were done in selected cases.Follow-up data were obtained. There were 7 cases of PAL. The age range of the patients was 52 to 73 years (median 64 years; mean 63.3 years). There were 4 males (57.1%) and 3 females (42.9%). The clinical manifestations included abdominal pain nausea, vomiting, and loss of weight. There were 4 cases of diffuse large B-cell lymphoma (DLBCL), 2 cases of high-grade B-cell lymphomas, and 1 case of follicular lymphoma. There were 5 cases that were unilateral and 2 cases that were bilateral, and both were high-grade B-cell lymphoma. During follow-up, the 1-year and 2-year overall survival rates were 50% and 33%, respectively. PAL is a disease of the elderly, and DLBCL is the most common pathological type. The prognosis is generally poor.Further reporting of PAL cases might help in understanding this disease and could lead to improvement in its management.

Intravascular Large B-Cell Lymphoma Detected by Cutaneous Biopsy with Pancytopenia and Negative Bone Marrow Biopsy

Intravascular large B-cell lymphoma is a B-cell lineage neoplasm, which is typically recognized as a high-grade neoplasm with poor outcomes. Though rare, the cutaneous variant can present with multiple lesions of the skin and negative systemic staging. We present a case of intravascular large B-cell lymphoma first identified on cutaneous biopsy, with pancytopenia, in addition to negative bone marrow biopsy and serum protein electrophoresis. The patient is a 71-year-old male who presented with upper body pruritis and pancytopenia, as well as weight loss and fatigue. A full body skin exam incidentally revealed a well-demarcated, firm, bound down atrophic lichenified plaque on the right anterior thigh. A punch biopsy revealed large, atypical lymphoid cells exclusively localized within the lumina of variably sized blood vessels, immunoreactive for CD20, BCL6, MUM1, and CD5, but negative for CD3, CD10, cyclin D1, and TdT. A diagnosis of intravascular large B-cell lymphoma was made, and he was referred to oncology for further treatment. Full body skin exam is a mainstay of dermatologic practice, and it is essential to pursue biopsy with uncharacteristic lesions, regardless of the presenting concern.

Primary breast lymphoma: a case series and review of the literature

BackgroundPrimary breast lymphoma (PBL) is a very rare form of non-Hodgkin's lymphoma (NHL), defined as a malignant primary lymphoma occurring in the breast in the absence of previously detected lymphoma localizations. Our study aims to retrospectively evaluate the epidemiological, clinical, and imaging findings and therapeutic features of breast lymphomas in patients with primary lymphoma of the breast.Materials and methodsThis is a retrospective study including 13 patients with primary non-Hodgkin's lymphoma of the breast treated at the Salah Azaiez Institute of Oncology from 2000 to 2019. This sample includes 1 case of follicular lymphoma, 2 cases of large T-cell lymphoma, and 10 cases of large B-cell lymphoma.ResultsPatients included in the study were aged between 17 and 89 years (average age of 52.6 years). All patients were referred because of a lump in the breast, and only one patient consulted with inflammatory signs in the breast. The average clinical size of the tumor was 7.2 cm, with a maximum of 15 cm. Mammography showed an oval mass with circumscribed margins in the majority of cases. Ultrasound showed in most cases a hypoechoic irregular mass or multilobulated mass with irregular margins and hypervascular on color Doppler. Magnetic resonance imaging (MRI) was performed on only three patients and showed a spiculated lesion with polycyclic limits. Eight patients underwent surgery. In our study breast lymphomas involved 10 cases of large B-cell lymphoma, one case of follicular lymphoma, and two cases of large T-cell lymphoma. In this series, 11 patients had localized stages (I + II) at diagnosis, and 2 patients had disseminated stages (stage III) of primary breast lymphoma. Seven patients underwent chemotherapy treatment alone, and five had chemotherapy with radiotherapy. The median follow-up of our patients was 53 months, ranging from 1 to 177 months. Overall survival was 71% at 3 years and 51% at 5 years.ConclusionPrimary breast lymphoma is an uncommon type of breast malignancy. The optimal treatment modality is still in question because of the rarity of this disease. However, the use of combination therapy produces the most favorable results. Surgery is not yet recommended.