Primary B-cell Lymphoma Research Articles

CD72 Nanobody-Based CAR-T Cells Have Potent Anti-Tumor Efficacy in B Cell Malignancies

Background: Approximately 50% of pediatric B-ALL patients treated with clinically approved CD19-targeting CAR-T cells do not remain in remission one year after therapy. CD22-targeting CAR-T cells appear to be curative in only a small fraction of CD19-refractory patients and this therapeutic strategy is primarily used as a bridge to stem cell transplant. Additional immunotherapeutic targets thus remain urgently needed. Our laboratory recently used cell surface proteomics to identify CD72 as a B-cell specific marker especially upregulated on poor prognosis, KMT2A/MLL-rearranged B-ALL (Nix et al., Cancer Discovery (2021)). In this published work, we used a best-in-class nanobody library displayed on yeast to develop binders to CD72. We demonstrated for the first time that fully synthetic nanobodies can generate CAR-T cells that are highly potent in vitro and in vivo. While we previously focused on these “nanoCARs” in KMT2A/MLLr B-ALL, in this follow-up study we aimed to 1) further expand our nanoCAR indications to other CD72-expressing B-cell malignancies; 2) biophysically characterize our synthetic nanobodies; 3) evaluate the potential for further humanization of the nanobody binder amino acid sequence while retaining anti-tumor efficacy; and 4) characterize the potency and T-cell immunophenotypes in the context of our lead nanobody binder (“NbD4”) placed on different CAR backbones.Methods: Flow cytometry of primary patient samples for CD72 was performed in a CLIA-certified laboratory. NbD4 nanobody was recombinantly expressed in E. coli and biolayer interferometry was used to determine the binding affinity to recombinantly-expressed CD72 extracellular domain. CAR-T cells were generated from peripheral blood donor CD4+ and CD8+ cells (1:1) ratio via lentiviral transduction. In vitro cytotoxicity assays were performed at a range of effector:tumor ratios. In vivo studies were performed in human cell line orthotopic xenografts in NSG mice. 1e6 luciferase-labeled Jeko cells were implanted at Day 0 followed by administration of 4e6 CAR-T cells at Day 6. Tumor burden was assessed by bioluminescence.Results: Flow cytometry on primary non-Hodgkin B-cell lymphoma obtained from fine needle aspiration biopsy (n = 5) confirmed CD72 surface expression (not shown), consistent with RNA-seq across larger cohorts. Biolayer interferometry demonstrated that NbD4 bound with surprisingly low affinity to recombinant CD72 (K D ~800 nM) (Fig. 1A), with both slow on rate (k on 8.38e4 M -1s -1) and rapid off rate (k off 6.82e-2 s -1). This affinity stands in contrast to that reported for FMC63 single chain variable fragment (scFv) used in clinically approved CD19-targeting CAR-T cells (K D 0.3-5 nM), despite similar in vitro and in vivo efficacy of both products. Our NbD4 framework region shows ~82% homology to a human IgG variable heavy domain, significantly higher than FMC63 (~59% homology). We made additional substitutions in the framework domain to increase human homology up to 89%. In vitro cytotoxicity assays with SEM B-ALL cells showed several humanized variants with similar efficacy to NbD4 (Fig. 1B). We further evaluated the impact of placing NbD4 on different CAR backbones, including combinations of CD28 or 4-1BB costimulatory domains and CD8 or IgG4-based transmembrane and hinge regions (Fig. 1C). In vivo, CD72 nanoCARs with Backbone 3 showed significantly increased potency (Fig. 1D). Indeed, tumors treated with Backbone 3 CAR-Ts showed complete tumor clearance and did not develop new tumors even after re-challenge with 1e6 Jeko cells at Day 52 (Fig. 1D). Preliminary characterization of effector and memory CAR-T cell phenotypes before exposure to tumor suggested that Backbone 3 had an increased number of naïve T cells compared to empty CAR and CD19 CAR-T cells (data not shown).Conclusions: Our results demonstrate that our fully synthetic CD72 nanoCARs can effectively eliminate CD72-expressing B-cell malignancy models despite low nanobody binding affinity. Humanized NbD4 variants may serve as clinical candidates with even further reduction in possible immunogenicity of the llama amino acid framework. Alterations to the CAR backbone have a major impact on anti-tumor efficacy and phenotypes of our synthetic nanobodies. CD72-targeting therapies may be effective therapeutics not only KMT2A/MLLr B-ALL but also across a broader spectrum of refractory B-cell malignancies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical characteristics and prognosis of 49 newly diagnosed primary central nervous system diffuse large B-cell lymphoma

目的回顾性分析原发中枢神经系统淋巴瘤中弥漫大B细胞淋巴瘤（PCNSL-DLBCL）患者的临床特征及不同治疗方案对患者生存及预后的影响。方法回顾性分析天津医科大学总医院自2014年7月至2020年12月收治的49例PCNSL-DLBCL患者的临床资料，根据治疗方案分为MTX组、R-CDOP组、BTKi-R-MTX组和RLZT组，计算各组中位总生存（OS）与无进展生存（PFS）时间，并进行单因素、多因素预后分析，比较各组患者的生存预后。结果MTX组、R-CDOP组、BTKi-R-MTX组和RLZT组的中位OS时间分别为16.5个月、4.5个月、42个月和未达到（P<0.001），中位PFS时间分别为7个月、1.5个月、20个月和5个月（P＝0.005）。多因素预后分析表明是否双表达、IESLG评分和治疗方案是PCNSL-DLBCL患者的预后影响因素。结论PCNSL-DLBCL患者的生存预后受治疗方案影响，CD20单抗在PCNSL-DLBCL 治疗中的作用尚有争议，含BTKi的治疗方案有巨大潜力，RLZT方案对于高龄、不耐受大剂量化疗及放疗患者有良好前景。

Rare presentation of primary hepatic marginal zone B-cell lymphoma and membranous glomerulopathy in a 3-year-old boy

Abstract Introduction/Objective Primary hepatic marginal zone B-cell lymphoma (MZL) is a rare entity that has been described with chronic inflammatory disorders such as chronic viral hepatitides B and C and primary biliary cholangitis. We report MZL in a 3-year-old African-American boy that was discovered incidentally at autopsy. Methods/Case Report The patient first came to medical attention at 9-months of age with bilateral periorbital edema that progressed to generalized edema of the[PL1] face, extremities, and abdomen. Laboratory testing showed nephrotic syndrome with massive proteinuria (50-60 g/day). A percutaneous renal biopsy specimen showed membranous glomerulopathy with PLA2R detected by immunofluorescence, and granular IgG deposition along tubular basement membranes. Serum was negative for anti-PLA2R antibodies. The patient suffered recurrent upper respiratory tract infections requiring several intensive care hospitalizations. At 3 years of age, he was transported unresponsive and pulseless to the emergency department where he was pronounced dead. A brother with the infantile nephrotic syndrome had died from sepsis at 2 years of age. Suspicion of abuse led to an autopsy by the medical examiner, who discovered nodular masses in the right and left liver lobes, which histologically showed a serpiginous infiltrate of small B-lymphocytes positive for CD20, CD43 admixed with plasmacytoid cells with kappa light chain restriction. There were no extrahepatic tumors. Transmission electron microscopy of glomeruli showed membranous glomerulopathy. Kidneys showed dense reactive interstitial lymphocytic infiltrate with germinal centers Results (if a Case Study enter NA) NA Conclusion To our knowledge, this is the first reported case of MZL presenting in a pediatric patient with membranous glomerulopathy. Both diagnoses are associated with autoimmune diseases and persistent, chronic inflammation. Recurrent infections in this patient suggest an immunoregulatory disorder, setting the stage for chronic inflammation, as seen in the kidney, with progression to MZL in the liver.

INCIDENTAL FINDING OF PULMONARY MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Primary pulmonary lymphomas (PPLs) comprise 1% of lung neoplasias, with pulmonary mucosa associated lymphoid tissue (MALT) lymphoma making up approximately 80% of these lesions. Pulmonary MALT lymphoma is a rare extranodal marginal zone B-cell lymphoma that is typically indolent in nature. Clinical manifestations of pulmonary MALT include fever, malaise, cough, dyspnea, and chest pain, although 30% of patients can be asymptomatic. We present a case of an incidental discovery and diagnosis of pulmonary MALT lymphoma. CASE PRESENTATION: 72-year-old male lifelong non-smoker with medical history of hypertension presented to pulmonology clinic due to incidental central left lower and perihilar ground glass density seen on CT performed for coronary calcium scoring. He denied symptoms, and his physical examination and laboratory values were normal. Follow-up CT chest with contrast showed a persistent 3.5 cm ground-glass lesion in the superior segment of the left lower lobe. Navigational bronchoscopy with biopsy and bronchoalveolar lavage was performed. The pathology revealed bronchial mucosa with a dense atypical lymphoid infiltrate and predominance of CD20 positive and CD5 negative B lymphocytes. These findings were consistent with a lymphoproliferative disorder of MALT lymphoma. FDG PET-CT demonstrated moderate uptake in the left lower lobe nodule with no other significant uptake elsewhere in the body. The patient was evaluated by medical oncology and is undergoing active surveillance with repeat CT anticipated in 3 months. DISCUSSION: Onset of PPL occurs around 50-60 years of age and the rate of smoking in these patients is not higher than that of the general population. Pulmonary MALT lymphoma is associated with chronic antigen stimulation, but unlike other MALT lymphomas, they have not yet been associated with chronic infection. They are often associated with cytogenetic abnormalities, 42% of cases having the translocation t(11;18)(q21;q21). Diagnosis is made by tissue biopsy, usually bronchoscopic versus CT guided. Pathology and immunohistochemistry are significant for lymphoid infiltrates expanding lymphoid follicle marginal zones with CD20 positive and CD5 negative cells. Treatment options include chemotherapy, radiation therapy, immunotherapy, surgical management, or an expectant approach in cases of limited disease. Overall five-year survival for patients is greater than 80%. CONCLUSIONS: The pathogenesis of pulmonary MALT lymphoma is not well understood. Due to its rare occurrence, there are limited studies of treatment of these lymphomas and therefore no true consensus regarding best treatment strategies. With slow growth rates, a watch and wait plan may be a suitable approach to isolated pulmonary lesions and has not been shown to negatively affect overall survival. However, a better understanding of the pathophysiology and optimal treatment of these lymphomas requires further studies. REFERENCE #1: Sanguedolce F, et al. Primary pulmonary B-cell lymphoma: A review and update. Cancers. 2021; 13(3): 415. REFERENCE #2: Borie R. Pulmonary mucosa-associated lymphoid tissue lymphoma revisited. Eur Respir J. 2016;47(4):1244-60 REFERENCE #3: Yan W. Watch-and-wait or immediate immunotherapy/immunochemotherapy in patients with phase IE primary pulmonary MALT lymphoma? A multicenter retrospective study. Annals of Hematology. 2021; 100(3): 709-714. DISCLOSURES: No relevant relationships by Nicole Bernskoetter, source=Web Response Speaker/Speaker's Bureau relationship with Astra Zeneca, GSK Please note: $1001 - $5000 by Daniel Gerardi, source=Web Response, value=Honoraria No relevant relationships by Simrina Sabharwal, source=Web Response

Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma

Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.

Primary Dural Diffuse Large B-Cell Lymphoma Is Associated with Good Prognosis and Is Effectively Treated with CHOP-R Alone

Introduction: Primary dural diffuse large B-cell lymphoma (PD-DLBCL) is a rare and aggressive B-cell non-Hodgkin lymphoma that arises in the dura mater, mimicking primary central nervous system lymphoma (PCNSL). While the optimal management is unknown, PD-DLBCL therapy is often mirrored after PCNSL, and aggressive therapy is frequently used. Combining data collected at our institution along with a review of the literature, we provide the most complete analysis of this rare disease entity including data on biology, treatment outcomes, and survival to assist in clinical management.Patients and Methods: A comprehensive review of the literature was conducted on pathologically confirmed intra-cranial and intra-spinal cases of PD-DLBCL reported from Jan 1st 1992 to July 1st 2017 in PubMed. Key words used (single or in combination) included: primary dural lymphoma, PDL, diffuse large B-cell lymphoma, DLBCL, and primary diffuse large B-cell lymphoma dura mater. Data were tabulated regarding the following 16 variables: tumor location (cranial vs. spinal), age, gender, disease stage, cell of origin (germinal center B-cell like (GCB)-DLBCL vs. activated B-cell like (ABC)-DLBCL), CD20, CD10, CD79a, CD30, BCL2, BCL6, MUM1, Ki-67 (above or below 70%), type of chemotherapy, use of radiation therapy, and overall survival (OS). Data were reported as percent and total number of cases with available information of each variable.Results and Discussion: Out of 235 screened cases, 47 cases of PD-DLBCL were detected from 26 distinct sources. Two cases were excluded for unclear definition about site of origin (dural vs. subdural). In total 45 cases were included in our analysis. Sixteen of these cases were intra-cranial and 29 were intra-spinal. Median age was 59 years at the time of diagnosis. Incidence was nearly equal between women (22/45) and men. When tested, CD20 was positive in each instance (21/21). Using Hans criteria when possible to determine cell of origin, 3 cases were classified as ABC-DLBCL and 5 as GCB-DLBCL, confirming the representation of both subtypes in PD-DLBCL. Ki-67 fraction was given in 9 cases, 6 of which were less than 70%, reflecting an overall less aggressive tumor behavior. The remainder of studied markers are detailed in Figure 1A. Interestingly, all cases were stage IE. Survival data available from 40 cases showed an OS of 84% at 1 year, and 81% at 5 years (Figure 1B), which compares favorably to PCNSL and matches early-stage DLBCL. Tumor location (intra-cranial vs. intra-spinal) did not impact OS (P=0.82; Figure 1C). Significant heterogeneity existed in regards to treatment choices. Initial chemotherapy regimen was reported in 19 cases with available survival data. Eleven patients received a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), 6 of which additionally received rituximab (CHOP-R). Eight patients received high-dose methotrexate (MTX) based therapy. Interestingly, no difference in OS was observed between CHOP vs. MTX-based therapy (P=0.97; Figure 1D), suggesting that PD-DLBCL should be treated as DLBCL rather than PCNSL. Moreover, all patients who received rituximab in addition to CHOP remained disease free and alive. Radiation therapy was given often (25/29) in treatment of spinal disease, but rarely (4/16) when treating cranial disease. Three patients received whole brain radiation therapy, twice following CHOP and once following MTX. The use of radiation therapy did not impact OS (data not shown).Conclusion: PD-DLBCL is an exceedingly rare subtype of DLBCL, GCB- or ABC-derived, and equally seen in both genders. The good outcomes seen with CHOP-R suggest that these cases should be treated like DLBCL rather than PCNSL, obviating the need for the more toxic high-dose MTX-based regimens or radiation therapy. The durable responses following CHOP-R also confirm that PD-DLBCL is not protected by the blood brain barrier. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mutations in the Phosphoinositide 3-Kinase Pathway (PI3K) Are Associated with Poor Overall Survival (OS) in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Introduction:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease that is characterized by recurrent translocations and somatic mutations. Prognosis has been associated with clinical presentation, cell-of-origin, and genetic aberrations. The aim of this study was to determine whether somatic mutations are associated with OS in patients with DLBCL who have been treated with R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).Methods:We identified 354 patients between 2000-2016 at City of Hope and University of Manitoba with a diagnosis of de novo DLBCL who were treated with R-CHOP therapy. Patients with primary mediastinal large B-cell lymphoma, primary CNS B-cell lymphoma, and those with HIV or immunodeficiency were excluded. A custom targeted panel with 334 genes which included the most frequently mutated genes in B-cell lymphoma was used. Library prep with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Cases were evaluated by immunohistochemistry (IHC) for cell-of-origin by the Hans algorithm, as well as MYC (>40%) and BCL-2 (>50%) protein overexpression. Fluorescence in situ hybridization analysis also was performed using BCL2/IGH, BCL6/IGH, and MYC probes. Pathway analysis was performed using Gene Ontology and Ingenuity Pathway Analysis (IPA). Overall survival estimates for 5-year survival were estimated using Kaplan Meier methods. Both univariate and multivariable hazard ratios were calculated by Cox regression with two-sided p-values presented. The final multivariable model includes significant terms controlling for patient International Prognostic Index (IPI) score.Results:To date, 215 patients (median age 59 years, Male:Female ratio of 1.44:1) had complete clinical information and tissue available for sequencing. Between the two centers, there were no significant differences in patient demographics, International Prognostic Index (IPI) score, or clinical recurrence status. Germinal center B-cell origin (GCB) type DLBCL was more common (57%) compared to non-GCB type (43%). The most frequently mutated genes were KMT2D (29%), CREBBP (20%), TP53 (20%), TET2 (16%), B2M (14%), and MYD88 (13%), as well as 14 other genes (>10% each). There were 24 (11%) double- or triple-hit lymphomas (MYC, BCL2, and or BCL6) and 35 (16%) double-protein expressors (MYC and BCL2). Mutations in the phosphoinositide 3-kinase/Akt/mTOR pathway (5%, NF1, PIK3CD) (5-yr OS 50% vs 74%, HR = 6.3, p=0.0009), B-cell differentiation genes (13%, BCL6, PRDM1) (5-yr OS 47% vs 77%, HR = 3.1, p=0.0015), ubiquitination pathway (7%, KLHL14, UBR5) (5-yr OS 48% vs 75%, HR = 2.5, p=0.018), and histone and histone modifier genes (31%, HIST1H2BC, KMT2D) (5-yr OS 58% vs 79%, HR = 2.1, p=0.012) were associated with poor OS in DLBCL, independent of IPI score.Conclusion:Targeted sequencing is effective for identifying known mutations associated with the pathogenesis of DLBCL. In this study, mutations involving the PI3K/Akt/mTOR pathway were associated with the worst outcome in patients treated with R-CHOP therapy. Identifying mutations in major pathways may help with prognostication in this heterogenous disease, and provide information useful for targeted therapy. DisclosuresHerrera:Immune Design: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Research Funding; BMS: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Pillai:Trillium Therapeutics: Research Funding. Nademanee:seattle Genetics: Speakers Bureau.

Outpatients with Lymphoma on Chemotherapy: Specific Thromboembolic Risk Factors and Venous Thrombosis Incidence

INTRODUCTIONIncidence of venous thrombotic events (VTE) in patients with lymphomas is approximately 4%. There are a number of thrombotic risk factors (TRF) identified in this group of patients in general, like leukocytosis, dexamethasone, central nervous system lymphoma and primary mediastina large b-cell lymphoma and poor performance status. These TRF have not been evaluated specifically in patients with lymphoma under non-hospitalization chemotherapy regimen. OBJETIVES•To evaluate the prevalence of general and specific TRF in patients with lymphomas under out hospital chemotherapy regimen in our center.•To describe the incidence of thrombosis and ischemic events in this group of patients during treatment in our area.•To describe the characteristics of vascular events.•To evaluate the safety of antiplatelet and anticoagulant treatment during chemotherapy treatment in this group. MATERIAL AND METHODSThis is a retrospective, one center study and single physician for the treatment and follow-up of patients. Patients with lymphoma diagnosed at our center and under out-hospitalization chemotherapy schemes of treatment, between January 2014 and December 2016, were included. We analyzed age at diagnosis, histology, stage, chemotherapy schemes, vascular events prior lymphoma diagnosis, antiplatelet or antithrombotic prophylaxis, use of erythropoietin, Hb<10g/dl, platelets (Plat)>350x109/L, leucocyte (LEU)>11x109/L, immobilization, Charlson, IMC >35, use of dexamethasone, doxorrubicine, radiotherapy, catheters and incidence and characteristics of vascular events. A descriptive analysis was performed, using absolute and relative frequencies for qualitative variables and measures of central tendency and dispersion for continuous variables. The study was carried out according to the Declaration of Helsinki and was approved by the Ethics Committee of the Regional University Hospital of Málaga. RESULTSWe included 137 subjects, median age 54.3+/-18 years old, 51% of group were males. The most frequent types of lymphoma were diffuse large B-cell lymphoma (LDCGB) (30,6%), follicular Lymphoma (FL) (24,8%) and Hodgkin lymphoma (HL) (22,6%). Most of patients presented advance disease, 61,6% were stages III or IV, and 87.4% did not presented B symptoms. Schemes of treatment were R-CHOP or bortezomid-R-CHOP for LDCGB, R-Bendamustine or R-FC in FL and AVBD +/- radiotherapy in HL. Most of them got complete remission, 74,5% with only 17.5% con stable disease or progression. Median follow up of the serie was 20,3+/-16 months.The 40,9% of patients had 3 or more TRF, incidence of each TRF: use of erythropoietin 4,4%, Hb<10g/dl 14%, platelets (Plat)>350x109/L 19%, leucocyte (LEU)>11x109/L 19%, immobilization 3,6%, Charlson 41%, IMC >35 2,9%, use of dexamethasone 5,1%, doxorrubicine 32,8%, radiotherapy 8%, catheters 3,6%.Three patients (2,2%) patients presented VTE: •Female 19 years old, EH 2B, plat>350x109/L, Hb <10gr/L, leu 11x109/L, doxorubicin. Upper limb thrombosis 22 months after diagnosis. Treatment LMWH 3 months.•Patient 2: Female 74 years old, LDCGB 2A, plat>350x109/L, Hb <10gr/L, charlson 4. Lower limb thrombosis 8 months after diagnosis. Treatment antivitamin-K 6 months.•Patient 3: Male 40 years old, LDCGB 1A, plat>350x109/L, doxorubicin. Upper limb thrombosis 8 months after lymphoma. Treatment LMWH 3 months.Three patients were under secondary antiplatelet prophylaxis for prior arterial ischemia. One of them presented a gastrointestinal bleeding after 8 months under chemotherapy and concomitant antiplatelet secondary prophylaxis. Of the 3 patients who develop VTE events after lymphoma diagnosis, one presented an upper gastrointestinal bleed, 20 days after anticoagulation started. Coagulation test were normal and Platelets number higher than 100x109/L at bleeding event. According to these data, 2 of 6 patients under chemotherapy and antiplatelet o anticoagulant treatment presented grade 3 bleedings (30%). CONCLUSIONSPrevalence of VTE in patients with outpatient with lymphoma looks lower than global lymphoma. Three VTE affected patients presented 3 or more TRF. Upper limb thrombosis was the most frequent one, probably related with the local administration of chemotherapy. Bleeding risk in patients with chemotherapy treatment and concomitant antiplatelet or anticoagulant drugs has to be carefully evaluated. DisclosuresNo relevant conflicts of interest to declare.

Ankle Localization of a Primary Bone Large B-Cell Lymphoma

Plain X-Ray of a primary bone large B-cell lymphoma in an 84-year-old patient (Figure 1 and 2). She consulted for a swelling of the right ankle with functional impotence, in a context of altered general condition for many months. The radiographic appearance was typical, showing a shaft and metaphyseal “moth-eaten” osteolytic lesion, with periosteal reaction and thickening of the opposite soft tissues. The diagnosis of B-cell lymphoma was confirmed with histological examination of tissue samples from percutaneous computed tomography-guided biopsy of the lesion. Primary bone lymphoma is rare, accounting for 5% of malignant bone tumors, and mostly large B-cell lymphomas. Moreover, localization usually predominating at the roots of the axial skeleton, explained by the persistence of red bone marrow. Even if it presents in an unusual site, this case highlights the importance of considering typical imaging characteristics of a lesion.

Intradural primary marginal zone lymphoma of the cervical spine 2years following a posterior cervical instrumented fusion.

Primary low grade central nervous system lymphoma is a rare entity, with the majority being intracranial marginal zone B-cell lymphoma. Primary spinal lymphoma is unusual, and commonly presents as an epidural lesion with diffuse large B-cell histology, as described in prior literature. We present a case of a 56year-old woman diagnosed with a primary intradural spinal lymphoma two years after a posterior cervical fusion at the same level. She was treated successfully with surgical resection and postoperative radiotherapy. To our knowledge, this is the first case in the literature describing an intradural primary marginal zone B-cell lymphoma of the spine.

Primary Breast Diffuse Large B-Cell Lymphoma in a 42-Year-Old Female: A Case Report and Review of Literature

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare localized extranodal lymphoma. It is mainly diagnosed by pathological examination due to the lack of specific clinical and imaging manifestations. Whole-body positron emission tomography-computed tomography (PET-CT) is widely used in determining clinical staging and guiding clinical treatment. As part of comprehensive treatment, targeted therapy with rituximab, intrathecal methotrexate injection and consolidation radiotherapy remain controversial in treating PB-DLBCL, but the comprehensive treatment based on full-course of chemotherapy is still widely used as the first-line treatment. Comprehensive treatment often leads to a sharp decline in the immunity of elderly patients with malignancy. In this situation, surgery may be a good chance to improve their life quality without serious complications. We present a rare case of PB-DLBCL during the coronavirus disease 2019 (COVID-19) pandemic. The patient underwent chest CT scan to screen COVID-19 and a mass of left breast was accidentally found. Because of the city lockdown policy in Wuhan, she did not seek medical help until noticing that the mass was gradually enlarged. Both ultrasonography and mammography indicated that the lesion was breast cancer. However, ultrasound-guided core needle biopsy revealed diffuse large B-cell lymphoma of breast and PET-CT scan showed that the lesion was a primary hypermetabolic tumor of left breast. The patient subsequently received comprehensive treatment based on six cycles of rituximab-cyclophosphamide, hydroxydaunomycin, oncovin, prednisone (R-CHOP) chemotherapy. J Med Cases. 2021;12(5):181-185 doi: https://doi.org/10.14740/jmc3660

Primary marginal zone B-cell lymphoma of the cavernous sinus: a case report and review of the literature

BackgroundPrimary lymphoma of the cavernous sinus is a rare form of extranodal non-Hodgkin lymphoma, of which very few cases have been reported in the published literature. This report presents the MRI findings with apparent diffusion coefficient (ADC) value in an exceedingly rare primary marginal zone B-cell lymphoma (MZBCL) of the cavernous sinus.Case presentationThe case in this study is a 59-year-old immunocompetent male patient with a 2-month history of right ptosis and blurred vision. Right third cranial nerve palsy and binocular diplopia were observed upon neurological examination. Preoperative brain CT showed an extra-axial enhancing mass lesion in the right cavernous sinus. On MRI, ipsilateral internal carotid arterial encasement was noted without causing stenosis of the vessel. Isointense signal on T1-weighted and T2-weighted images, homogeneous contrast enhancement, and diffusion restriction were also observed. The mean ADC value of the tumor is 0.64 × 10–3 mm2/s (b value = 1000 s/mm2). Subtotal resection of the tumor was performed, and improvement of clinical symptoms were observed. The pathologic diagnosis of MZBCL was established by immunohistochemical examinations.ConclusionsPrimary MZBCL of the cavernous sinus is exceedingly rare, and preoperative confirmation poses a major challenge with CT and conventional MRI only. In this case, preoperative quantitative ADC value is shown to offer valuable additional information in the diagnostic process.

Primary Pulmonary B-Cell Lymphoma: A Review and Update.

Simple SummaryThe group of B-cell lymphomas primarily involving the lung encompasses different histological entities with distinct biological aspects, while sharing some clinical and radiological features related to their common anatomic site of occurrence. Recent molecular advances in the molecular genetics of these lesions have substantially improved of our understanding of the mechanisms of lymphomagenesis, adding novel information to histology in order to better characterize and manage these diseases. This review summarizes the available clinical, radiological, pathological, and molecular data on primary pulmonary B-cell lymphomas, discusses the mechanisms of lymphomagenesis, and highlights the role of a multi-disciplinary management in overcoming the diagnostic and therapeutic challenges in this setting.Primary pulmonary B-cell lymphomas (PP-BCLs) comprise a group of extranodal non-Hodgkin lymphomas of B-cell origin, which primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis and up to 3 months afterwards. Primary lymphoid proliferations of the lung are most often of B-cell lineage, and include three major entities with different clinical, morphological, and molecular features: primary pulmonary marginal zone lymphoma of mucosa-associated lymphoid tissue (PP-MZL, or MALT lymphoma), primary pulmonary diffuse large B cell lymphoma (PP-DLBCL), and lymphomatoid granulomatosis (LYG). Less common entities include primary effusion B-cell lymphoma (PEL) and intravascular large B cell lymphoma (IVLBCL). A proper workup requires a multidisciplinary approach, including radiologists, pneumologists, thoracic surgeons, pathologists, hemato-oncologists, and radiation oncologists, in order to achieve a correct diagnosis and risk assessment. Aim of this review is to analyze and outline the clinical and pathological features of the most frequent PP-BCLs, and to critically analyze the major issues in their diagnosis and management.

The primary B-cell lymphoma of the breast: a clinical case

В-cell lymphoma is manifested by a variety of forms, which makes it difficult to establish an accurate lifetime diagnosis and has an unfavorable prognosis. Therefore, every case of primary B-cell lymphoma of the breast, demands attention close attention of doctors of different specialties. The feature of the presented investigation is B-cell lymphoma, that primarily affects the right breast. This type of breast cancer develops as chronic mastitis, confirming the variety of forms of its manifestation, what cause difficulties in making accurate primary diagnosis.

Diffuse large B-cell lymphoma mimicking chronic osteomyelitis of the ankle joint: A case report

Lymphoma is the seventh most common type of malignancy in both males and females. It may develop in any location where lymphomatous tissue exists. Although extranodal presentation in the lower limb and pelvis are uncommon, it could present with diverse manifestations. We report an unusual case of primary extranodal large B-cell lymphoma of the ankle joint initially presumed to be a chronic osteomyelitis. This case report discusses the impact of imaging studies on decision-making and highlights the need to consider malignancy in chronic infections.

Massive splenomegaly due to splenic marginal zone B‐cell lymphoma

A 73-year-old man presented with an abdominal mass that gradually swells over 3months. He denied any subjective symptoms. Physical examination revealed massive enlargement of the spleen-the spleen had crossed the midline and its lower margin extended into the lower abdomen.

Linfoma Pulmonar Primario de Células B

El linfoma pulmonar primario es una proliferación linfoide que afecta el parénquima de uno o ambos pulmones sin compromiso extrapulmonar. Son infrecuentes, las manifestaciones clínica y radiológicas inespecíficas. El diagnóstico requiere de biopsia pulmonar mediante punción por TAC, videotoracoscopia o toracotomía. La inmunohistoquímica ayuda a diferenciar sus diferentes tipos; el tratamiento con quimioterapia y la detección temprana contribuyen a un mejor pronóstico. Presentamos el caso de un hombre de 56 años con Linfoma pulmonar primario de células B de bajo grado.

Clinicopathological features of primary central nervous system diffuse large B cell lymphoma: Experience from a Tertiary Center in North India.

Background: Primary central nervous system-diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare extra-nodal Non-Hodgkin lymphoma. There is relative paucity of literature on PCNSL from Indian subcontinent. We aimed to analyze the clinicopathological features of PCNSL and categorize them into germinal center B cell (GCB) and non-GCB subtypes to assess their prognostic significance in Indian context.Methods: All patients with histopathologically diagnosed PCNSLs at our center over a period of 6 years were recruited and classified into GCB and non-GCB using Han’s algorithm (immunohistochemistry for CD10, BCL6 and MUM1). In situ hybridization (ISH) for Epstein-Barr virus (EBV)-encoded RNA was performed.Results: Eighty-six cases of PCNS-DLBCL were included with median age of 55 years. Majority of them were supratentorial in location (n = 62). All patients were immunocompetent. On immunohistochemical assessment, 69 (80.2%) were of NGCB subtype, 10 (11.6%) were of GCB subtype, and 7 (8.1%) were unclassified. Overall, MUM1, BCL-6, and CD10 expressions were seen in 69 (80.2%), 28 (32.6%), and 2 cases (2.3%), respectively. Four cases (4.6%) showed C-MYC expression. The median overall survival (OS) was 675 days. None of the factors (age, sex, location, immunomarkers, and GCB vs. NGCB phenotype) showed correlation with OS; however, BCL6 positive cases showed slight better OS (P > 0.05). All cases were negative for EBV-LMP1 on ISH.Conclusion: The majority of the CNS DLBCL belongs to non-GCB phenotype and uniformly carry poor prognosis, irrespective of their phenotype. Individual markers, such as BCL-6, MUM1, or CD10, are unable to predict outcome in PCNS-DLBCL.

Asymptomatic pink nodules on a 28-year-old patient

Asymptomatic pink nodules on a 28-year-old patient

CTNI-64. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM

Abstract We report our experience treating 16 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 years (y); 8 patients were men and 8 were women. Fourteen had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 4 X 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 12 patients completed initial chemotherapy. Eleven of these 12 went on to transplantation; one patient had early disease progression and did not proceed to transplantation. All 4 patients over 70 y died early after 1–2 cycles; the median age of these was 80 y, and the causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia; the other 11 experienced no serious acute toxicity. One patient had late disease progression; one developed symptomatic leukoencephalopathy. Nine of the 16 patients remain alive. At a median follow-up of 23 months, median time to progression was 421 days and overall survival 564 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 70 y suggests that the regimen may be too toxic for elderly individuals.