Splenic Marginal Zone Lymphoma Research Articles

Cyclin-D1 rearrangement as a secondary event in the large cell transformation of splenic marginal zone lymphoma with a TP53 deletion.

IGH::CCND1 translocation has been implicated as a preliminary finding in mantle cell lymphoma (MCL) and plasma cell myeloma, with cyclin D1 over-expression by immunohistochemistry stain, without gene rearrangement, reported in other hematologic neoplasms. CCND1 rearrangement has been reported infrequently as a secondary event in high-grade B-cell lymphomas. We present the case of an elderly man who was found to have a splenic marginal zone lymphoma with a heterozygous TP53 deletion. Years later at the time of relapse, the patient acquired a CCND1 rearrangement, in addition to apersistent TP53 deletion. Sequencing of the two lymphomas demonstrated clonal relatedness of the two processes. To our knowledge, this is the first report of a splenic marginal zone lymphoma witha TP53 deletion at diagnosis, evolving into a large B-cell lymphoma with a CCND1 rearrangement.

Evaluation of Ki-67 expression and large cell content as prognostic markers in MZL: a multicenter cohort study

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03–2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT.

Utility of MEF2B Immunohistochemistry in Distinguishing Follicular Lymphoma and Marginal Zone Lymphoma in Diagnostically Challenging Cases

Abstract Introduction/Objective Distinguishing follicular lymphoma (FL) from marginal zone lymphoma (MZL) can be challenging, as the morphology and immunophenotype can overlap particularly in CD10-negative cases or those with marginal zone differentiation (MZD). MEF2B (Myocyte enhancer binding factor B) is a transcription factor that controls BCL6 expression in germinal center (GC) B-cells. Previous studies report MEF2B to have a high sensitivity and specificity for FL compared to other GC markers. We investigated the expression of MEF2B in low grade B cell lymphomas (LGBCL) to evaluate its utility in classifying diagnostically challenging cases and FL with MZD. Methods/Case Report Our archives were searched from 2005-2023 to identify excisional biopsies of LGBCL with MZD, including (FL), splenic MZL (SMZL), MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL (NMZL) and difficult-to-classify (DTC) cases with a differential diagnosis of MZL and FL. MEF2B immunohistochemistry was performed retrospectively (Atlas Antibodies). Two hematopathologists assigned a pre-and post-MEF2B diagnosis to DTC cases. Results (if a Case Study enter NA) 57 cases were included: 21 FL (12 with MZD), 11 SMZL, 13 MALT, 4 NMZL, and 8 DTC cases. 19/21 FL cases (90%) were positive for MEF2B, including 11/12 (92%) cases with MZD. However, MEF2B expression was restricted to the follicles and negative in MZD areas in 7/11 cases (64%), while 4 cases showed partial weak expression in the areas of MZD. 0/11 SMZL (0%), 0/13 MALT (0%), and 0/4 (0%) NMZL were positive for MEF2B. 6/8 DTC cases (75%) were positive for MEF2B. Within DTC cases, retrospective inclusion of MEF2B results helped to render a more definitive diagnosis in 5 cases (2 negative/3 positive). Conclusion MEF2B immunohistochemistry can aid in distinguishing FL from MZL in challenging cases. However, it is often negative in areas of FL with MZD so care must be taken on interpretation in small biopsies.

Real-world data for marginal zone lymphoma patients in the French REALYSA cohort: The REALMA study.

Marginal Zone Lymphoma (MZL) comprises three subtypes: extranodal MZL (EMZL), splenic MZL (SMZL) and nodal MZL (NMZL). Since clinical trials have limited representativeness, there is a need for real-world data (RWD) evidence in MZL. Real-world data in Lymphoma and survival in Adults (REALYSA) is a prospective multicentric French cohort of newly diagnosed lymphoma patients. This study consists of the first abstraction of MZL patients prospectively included in REALYSA between 12/2018 and 01/2021 with at least 1year of follow-up. It provides a landscape description of clinical characteristics, initial workup, quality of life and first-line therapy performed in routine practice. Among 207 included patients, 122 presented with EMZL, 51 with SMZL and 34 with NMZL. At baseline, median age was 67years (range 28-96), and patients reported a favorable global health status (75/100 (IQR 58,83)) - which was higher in NMZL and lower in SMZL patients (p=0.006). 18FDG-PET/CT was frequently performed at initial workup (EMZL 72%, SMZL 73%, NMZL 85%). Active surveillance was the initial management for 58 (28%) patients. The most prescribed therapies were rituximab-chlorambucil in the EMZL population (30%), rituximab monotherapy in the SMZL population (37%) and R-CHOP (24%)/bendamustine-rituximab (15%) in the NMZL population. At end of first line, overall response rate was 93% among treated patients with 75% of complete response. This French nationwide study provided for the first time prospective RWD on clinical characteristics, initial management and treatment response of MZL patients.

Transformation in marginal zone lymphoma: results from a prospective cohort and a meta-analysis of the literature

AbstractMarginal zone lymphoma (MZL) includes extranodal MZL (EMZL), splenic MZL (SMZL), and nodal MZL (NMZL) subtypes. Histologic transformation (HT) to large B-cell lymphomas is well documented but with a large variability in published cumulative incidence rates. We report results from the Molecular Epidemiology Resource (MER) cohort on the cumulative incidence of HT (with death as competing risk) and the associated risk factors and outcomes. We also conducted a meta-analysis of available studies on the cumulative incidence of HT. From 2002 to 2015, 529 patients with MZL were enrolled in the MER study (69% EMZL, 16% SMZL, and 15% NMZL). The 10-year overall survival (OS) from diagnosis was 66%. HT occurred in 21 patients with a 5-year and 10-year cumulative incidence of 2.7% (95% confidence interval [CI], 0.02-0.05) and 3.6% (95% CI, 0.02-0.06), respectively. HT was associated with an increased risk for death (subdistribution hazard ratio [HR], 3.95; 95% CI, 2.06-7.55). Predictors of HT were ≥2 extranodal sites and mucosa-associated lymphoid tissue International Prognostic Index score ≥2. The OS was 79% at 5 years and 55% at 10 years after HT. In the meta-analysis of 12 studies (6161 patients), the 5- and 10-year cumulative incidence of HT across all subtypes were 5% (95% CI, 0.05-0.06) and 8% (95% CI, 0.07-0.09), respectively. These rates were lower in EMZL (3% and 5%) than in SMZL (7% and 13%) and NMZL (9% and 13%). Although HT is relatively uncommon in the first decade after MZL diagnosis, it is associated with an inferior outcome and needs new approaches for prevention and management.

Visceral Leishmaniasis Following A+AVD Treatment in a Patient with Classical Hodgkin's Lymphoma: A Case Report and Review of the Literature.

We present the case of a 43-year-old Caucasian man who developed visceral leishmaniasis (VL) following treatment with a combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (A+AVD) for advanced-stage classical Hodgkin's lymphoma (cHL). The patient initially showed a favorable response to the treatment, but shortly after completing six cycles, he experienced recurrent fever, splenomegaly, and severe anemia. Extensive infectious disease evaluations led to a diagnosis of VL, confirmed by PCR testing. The patient was treated with amphotericin B, resulting in full clinical recovery. In addition to presenting this rare case, we conducted a full review of the literature on VL in the context of hematological disorders, including non-Hodgkin's lymphoma, splenic marginal zone lymphoma, and other lymphoproliferative diseases. This review highlights the increasing prevalence of VL in immunocompromised individuals, particularly those undergoing treatments like chemotherapy or immunotherapy, and underscores the importance of considering VL in differential diagnoses when such patients present with persistent fever and splenomegaly.

Splenic marginal zone lymphoma: management specifics. Clinical observation

Despite having common histological and immunophenotypic characteristics with other marginal zone lymphomas, splenic marginal zone lymphoma (SMZL) has distinctive clinical and biological features. The main indications for therapy of this disease (of primarily indolent progression) are progressive splenomegaly and/or progressive cytopenia. Current clinical management guidelines do not conclusively point to advantages of one certain therapy, and there is no universal algorithm of management of patients with newly diagnosed SMZL manifesting through progressive splenomegaly. Therefore, determination of indications for surgical treatment is an important problem. A clinical observation of a female patient with newly diagnosed advanced SMZL is presented. Due to progressive splenomegaly and hypersplenism symptoms, the patient underwent splenectomy. Personalized multidisciplinary approach allowed to relieve hypersplenism symptoms as quickly as possible, and the absence of postoperative complications with indolent disease progression significantly increased the patient’s quality of life and allowed to continue dynamic observation.

Splenic marginal zone lymphoma with prolymphocytic transformation and cyclin D1 expression in the absence of CCND1 rearrangement.

Splenic marginal zone lymphoma (SMZL) is one of the most common B-cell lymphomas that affect the spleen. We report a case with splenomegaly and lymphocytosis that showed a clonal B-cell population lacking CD5 and CD10 expression. Notably, the atypical lymphoid cells showed prolymphocytoid morphology and expressed cyclin D1. Fluorescence in-situ hybridization was negative for CCND1/IgH rearrangement. The prolymphocytoid morphology and cyclin D1 expression present a diagnostic pitfall. The clinical presentation, morphology, immunophenotype, and molecular genetic findings are most consistent with a diagnosis of SMZL with prolymphocytic transformation and cyclin D1 expression. Here, we present this case along with a review of the literature, and summarize the clinicopathological characteristics of SMZL with prolymphocytic transformation.

Understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions.

The 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5) introduced a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN). The diagnostic entity B-cell prolymphocytic leukaemia (B-PLL) has been discontinued and the category of hairy cell leukaemia variant (HCLv) has been conceptually reframed. B-PLL and HCLv diagnoses were uncommon. Overlap existed between B-PLL and other indolent lymphomas like chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). HCLv lacked consistent cytomorphological, immunophenotypic and genetic features. To address these issues, the WHO-HAEM5 classification has introduced SBLPN to serve as a temporary holding ground for entities that do not neatly fit into the existing classification. Cases previously classified as CD5-negative B-PLL and HCLv fall under the SBLPN category. Some splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma cases with higher number of medium or large nucleolated B cells would also be classified as SBLPN under the WHO-HAEM5. This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.

Asymptomatic evanescent plaques on the buttocks of an elderly woman.

B-cell epidermotropism is an exceptional finding in cutaneous lymphomas. The few cases previously described in the literature mostly correspond to systemic lymphomas, with the most frequent being splenic marginal zone lymphoma. This lymphoma can manifest as a cutaneous eruption preceding the splenomegaly, with systemic involvement demonstrated by bone marrow and/or peripheral blood. This presentation is known as epidermotropic B-cell lymphoma. Herein, we present a new case that emphasizes B-cell epidermotropism as a feature that should alert the clinician of the possibility of a secondary involvement and, consequently, prompt them to expand the recommended initial staging.

The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications.

Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL's mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL's molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.

Integrated spatial and multimodal single-cell transcriptomics reveal patient-dependent cell heterogeneity in splenic marginal zone lymphoma.

Biological hallmarks of splenic marginal zone lymphoma (SMZL) remain poorly described. Herein, we performed in-depth SMZL characterization through multimodal single-cell analyses of paired blood/spleen samples. The 3'-single-cell RNA-sequencing, Cellular Indexing of Transcriptomes and Epitopes by sequencing, and 5'-V(D)J single-cell RNA-sequencing datasets were integrated to characterize SMZL transcriptome profiles, including B-cell receptor and T-cell receptor repertoires. Hyperexpanded B-cell clones in the spleen were at a memory-like stage, whereas recirculating tumor B-cells in blood encompassed multiple differentiation stages, indicating an unexpected desynchronization of the B-cell maturation program in SMZL cells. Spatial transcriptomics showed the enrichment of T-effector and T-follicular helper (TFH) signatures in the nodular subtype of SMZL. This latter also exhibited gene-based cell-cell interactions suggestive of dynamic crosstalk between TFH and cancer cells in transcriptomics, further substantiated by using imaging mass cytometry. Our findings provide a comprehensive high-resolution description of SMZL biological hallmarks and characterize, for the first time in situ, inter- and intra-patient heterogeneity at both transcriptomic and protein levels. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Splenectomy allows remission of angioedema with acquired C1-inhibitor deficiency associated with splenic marginal zone lymphoma

Splenectomy allows remission of angioedema with acquired C1-inhibitor deficiency associated with splenic marginal zone lymphoma

Marginal zone lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Marginal zone lymphomas (MZLs) are a rare, indolent group of non-Hodgkin lymphomas with different diagnostic, genetic and clinical features and therapeutic implications. The most common is extranodal MZL of mucosa-associated lymphoid tissue, followed by splenic MZL and nodal MZL. Patients with MZL generally have good outcomes with long survival rates but frequently have a relapsing/remitting course requiring several lines of therapy. The heterogeneous presentation and relapsing course present the clinician with several diagnostic and therapeutic challenges. This position statement presents evidence-based recommendations in the setting of Australia and New Zealand.

Clinicopathological features of CD5-positive splenic marginal zone lymphoma

AimsTo investigate the clinicopathological features, immunophenotypes and differential diagnosis of CD5-positive splenic marginal zone lymphoma (SMZL).MethodsWe retrospectively analysed 16 CD5-positive cases of SMZL. Assess their clinicopathological features and survival outcomes...

Lymphomas with massive splenomegaly – a case series

Hairy cell leukaemia (HCL) is an uncommon chronic B-cell lymphoma. Classical HCL and its variant are separate entities. Splenic marginal zone lymphoma (SMZL) is rare accounting for &lt;2%of lymphoid neoplasms2. A 62-year-old woman presented with constitutional symptoms and mild splenomegaly was having pancytopenia, monocytopenia and hairy cells in the peripheral blood. Bone marrow aspiration was a dry tap while trephine biopsy revealed diffuse lymphoid cell infiltration with characteristic fried egg appearance and fibrosis. Morphological and immunophenotypic diagnosis was HCL. She was successfully treated with IV-cladribine and G-CSF for chemotherapy induced severe neutropenia. She achieved complete remission in 6 months. A 56-year-old woman presented with abdominal distension and lower limb swelling was having marked splenomegaly, absolute lymphocytosis, mild neutropenia and anaemia. Blood film revealed lymphocytes showing moderate cytoplasm and cytoplasmic projections. With bone marrow biopsy and flow cytometry, splenic B-cell lymphoma/leukaemia with prominent nucleoli was diagnosed and was treated with rituximab monotherapy. A 76-year-old woman presented with progressive abdominal fullness, unintentional weight loss and early satiety was having splenomegaly, bicytopenia and absolute lymphocytosis consisting predominantly of small mature lymphocytes and occasional lymphocytes with polar villi. Morphological and immunopheno-typical results confirmed SMZL. She was treated with rituximab monotherapy.

Nodal Low-Grade B-Cell Lymphoma Co-Expressing CD5 and CD10 but Not CD23, IRTA1, or Cyclin D1: The Diagnostic Challenge of a Splenic Marginal Zone Lymphoma.

The diagnosis of lymphoma is based on histopathological and immunophenotypical features. CD5 and CD10 are traditionally considered a T-cell antigen and a germinal center B-cell antigen, respectively. It is very unusual for a low-grade B-cell lymphoma (BCL) to co-express CD5 and CD10. Although the biologic basis or clinical significance of such co-expression is unclear, this rare event may pose a significant diagnostic challenge. Here, we report a case of a 63-year-old male presenting with bilateral cervical lymphadenopathy and lymphocytosis. Histologically, the nodal tumor was largely diffuse with neoplastic small atypical lymphocytes co-expressing CD5, CD10, and CD20, but not CD23 or cyclin D1. The leukemic cells in the peripheral blood exhibited hairy projections. Taking together the marked splenomegaly, involvement of lymph nodes, bone marrow, and peripheral blood, a final diagnosis of splenic marginal zone lymphoma (SMZL) was reached. The patient was alive with partial response for 10 months after immunochemotherapy. The dual expression of CD5 and CD10 is extremely unusual for low-grade BCL and may lead to an erroneous diagnosis. Integrating the findings into peripheral blood smear tests, flow cytometry, histopathology, imaging, and clinical features is mandatory to exclude other lymphoma types and to reach a correct diagnosis, particularly for a case with nodal presentation.

Transformation risk and associated survival outcome of marginal zone lymphoma: A nationwide study.

Histological transformation into an aggressive B-cell lymphoma indicates a poor survival outcome for patients with indolent marginal zone lymphoma (MZL), which has been less studied. Large-scale data with long-term follow-up to investigate MZL transformation is limited. Here, by reporting a US-Nationwide cohort of 30,619 MZL patients diagnosed between 2000 and 2019, we found that transformation occurred in 2.08% (N = 624) of MZL cases, with the transformation incidence of 3.1 per 1,000 person-years. Advanced Ann Arbor stage, nodal MZL (NMZL) and splenic MZL (SMZL) were associated with an elevated risk of transformation. Certain subtype-specific characteristics, such as non-gastric extra-nodal MZL (vs. gastric, HR, 1.51, 95%CI 1.13-2.04; p = 0.006), and receiving splenectomy for SMZL (HR, 2.04, 95%CI 1.28-3.26; p = 0.003), also indicated a higher risk of transformation. Besides, transformation independently increased the overall mortality risk (HR, 1.38, 95%CI 1.24-1.53, p < 0.001), especially the higher lymphoma-caused mortality risk (HR, 3.21, 95%CI 2.81-3.67, p < 0.001). Transformation was also associated with a higher percentage of lymphoma-caused deaths. The post-transformation prognostic analyses demonstrated that female gender and age ≥ 65 years independently affected patients' mortalities. These findings, based on the largest cohort to date, contribute to a better understanding of transformed MZL, and provide valuable reference points for guidelines and patient counseling.

Optical genomic mapping is a helpful tool for detecting CCND1 rearrangements in CD5-negative small B-cell lymphoma: Two cases of leukemic non-nodal mantle cell lymphoma

Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.