Gene Expression Profiling Analysis in Splenic Marginal Zone Lymphoma Allows To Predict Survival and Histological Transformation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1125-1125
Author(s):  
C. Thieblemont ◽  
B. Ballester ◽  
V. Nasser ◽  
S. Gazzo ◽  
G. Doucet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Prognostic Factors ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Matched Pair ◽  
Splenic Marginal Zone Lymphoma ◽  
Term Survival ◽  
Disease Evolution ◽  
Histological Transformation

Abstract Splenic Marginal Zone Lymphoma (MZL) is described as an indolent lymphoma with a long term survival. However classical prognostic factors can not distinguish between patients who are likely to have good or poor outcomes. Moreover histological progression occurs in 10–20% of cases at the time of recurrence, but may be present at diagnosis, inducing a shorter survival with a median around 2 years. New model based on molecular understanding are needed to better discriminate these patients for their prognosis and disease evolution. Biopsy samples of splenic MZL from 43 patients treated in one institution and 8 with transformed splenic MZL were examined for gene expression using a nylon cDNA microarray consisting of 7, 000 human genes. Two of them came from a group of matched pair of splenic MZL and the transformed counterpart. An additional group comprising 4 transformed follicular lymphomas and 1 transformed small lymphocytic lymphoma were also analysed. Hierarchical clustering realized with all samples allowed to visualized patterns of gene expression already described in our previous work1 and corresponding to precise functions (proliferation, early response...), cell or tissue subtype (T cells, stroma …) or lymphoma subtype (MZL, MCL, SLL). The ability of individual genes to distinguish 1/ MZL and transformed-MZL subtypes, and 2/ alive patients and dead patients was calculated using a supervised method (discriminating score and bootstrap resampling). This allowed us to construct molecular predictors of survival and histological transformation. Transformation discriminating genes regrouped 73 genes related to cell proliferation such as CDC10, CDK4, PRKDC, PLCG2, LDHA, MCL2, and NPM1. P53 was down-expressed in all the transformed samples. Survival discriminating genes regrouped 26 genes from a unique cluster related to cell proliferation such as LDHA, NME1, MYC, ENO1. Although these genes seem to participate to the same function, only one gene was found discriminating the 2 parameters (LDHA). Gene ontology analysis using GOminer showed that the histological transformation was more related to cyclin-dependent protein kinase and that the survival was more related to metabolism. We used 26 genes to construct a predictor for survival in MZL patients. This gene-based predictor allowed predicting survival (p <0.00001) in MZL patients better than with classical prognostic factors (age, performance status, stage, LDH, monoclonal component, IPI…), but also in transformed MZL patients. In conclusion, genes involved in histological transformation and survival in MZL patients are implicated in independent but complementary functions leading to cell proliferation.

Unmutated Immunoglobulin Heavy Chain Variable Region Genes and Disease Progression Post Splenectomy Are Poor Prognostic Factors in Splenic Marginal Zone Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3254-3254
Author(s):  
David Graham Oscier ◽  
Sarah J. Mould ◽  
Anne C. Gardiner ◽  
Sharron Glide ◽  
Anton E. Parker ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Median Survival ◽  
Lymphocyte Count ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
High Grade ◽  
Spleen Size ◽  
Need For Treatment ◽  
Mutational Status

Abstract Splenic marginal zone lymphoma (SMZL) is generally an indolent disorder which has a median survival of 10 – 13 years, but a minority of patients pursue a more aggressive clinical course. A number of adverse prognostic factors including the level of haemoglobin, lymphocyte count and platelet count, B2 microglobulin, presence of a paraprotein, IgVH gene mutational status and p53 loss or mutation have been identified, but these have not been consistent among recent series. We have studied 89 patients with SMZL, diagnosed on the basis of lymphocyte morphology, immunophenotype and marrow and splenic histology, when available, and have evaluated the impact of presenting Hb, lymphocyte count, spleen size, presence of a paraprotein, cytogenetic abnormalities and IgVH gene mutational status on both the need for treatment and on overall survival. In 43 patients the diagnosis was made following a routine blood count performed for an incidental reason. The M:F ratio was 1:1.78, median age at presentation was 67.5 years (range; 49 – 91) and mean follow-up was 78.1 months. 63/89 (71%)patients presented with palpable splenomegaly, and a further 5 developed splenomegaly during the course of their disease. 42/89 (47%) patients required treatment of whom 29 (32%) underwent splenectomy. 36 patients have not required treatment, 25 have received an alkylating agent, 12 have received fludarabine and 4 were treated with rituximab.15/29 (17%) received chemotherapy for progressive disease post splenectomy. In six patients there was transformation to a high grade lymphoma. 14 patients (16%) died, 11 of whom had a disease-related death. 24/83 patients (29%) had a paraprotein, 67/87 (77%) had an abnormal karyotype of whom 39 (45%) had an abnormality of 7q. Using interphase FISH, 7/78((9%) showed trisomy 3 and 7/74(9%) had p53 loss. Of the patients with high grade transformation, 3/6 had p53 loss. 47/67 patients (70%) had mutated IgVH genes, and 15 cases utilised the VH1-02 gene segment. Only spleen size >10cm (p=0.0002) and Hb <100 gm/l (p=0.008) correlated with the need for treatment. Only unmutated IgVH genes (p=0.032) and the need for further therapy following initial treatment with splenectomy (p=0.034) correlated with overall survival.The median survival of unmutated cases was 113 months and was not reached for mutated cases.The median survival of patients for whom splenectomy has been their only treatment has not been reached, but was 110 months for patients requiring additional treatment post splenectomy. There is a need for larger, multi-centre studies to identify poor risk patients with SMZL.

scholarly journals Splenic marginal zone lymphoma: Clinical characteristics and prognostic factors in a series of 52 patients

2019 ◽  
Vol 30 ◽  
pp. v441
Author(s):  
G. Cengiz Seval ◽  
P. Topcuoglu ◽  
O. Arslan ◽  
G. Gurman ◽  
T. Demirer ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Clinical Characteristics ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma

Gene Expression Profiling of Post-Follicular B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 617-617
Author(s):  
Wee-Joo Chng ◽  
Gaofeng Huang ◽  
Paul J. Kurtin ◽  
Ahmet Dogan ◽  
Ellen Remstein
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Splenic Marginal Zone Lymphoma ◽  
Major Cluster ◽  
Significant Enrichment

Abstract Although classified as marginal zone lymphomas under the WHO classification, the molecular relationship between splenic marginal zone lymphoma (SMZL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and nodal marginal zone lymphoma (NMZL) has not been clarified. Furthermore, lymphoplasmacytic lymphoma (LPL) can show clinical morphologic and immunophenotypic overlap with these entities and may present a diagnostic challenge. In this analysis of gene expression data generated using the Affymetrix U133plus 2.0 chip from 32 SMZL, 25 MALTs (GI, salivary gland and lung), 23 NMZL and 25 LPL, we aim to identify the molecular relationship between these pathological entities using unsupervised methods, identify disease specific signatures and markers using supervised methods and also the functional implications of these signatures using a modified gene-set enrichment analysis. Using hierarchical clustering, MALT lymphoma forms a tight cluster regardless of tumor site. In addition, SMZL and NMZL form another large cluster. LPLs are divided into 2 main clusters with occasional samples interspersed amongst the SMZL and NMZL. There is no correlation between the percentage of CD20-positive B-cells, CD3-positive T-cells or CD138- positive plasma cells or tissue origin of the tumor and the way the samples are clustered. However, the separation of the LPLs into 2 major cluster correspond to the presence and absence of underlying Waldenstrom Macroglobulinaemia (WM), suggesting that the genes distinguishing the 2 clusters are potential markers for differentiating WM LPL from non-WM LPL. Next, using supervised analysis we identified a cluster of genes including MMP7, LTF and SFRP2 with high signals specific to MALTs, while other genes including PRDM1 (BLIMP1), XBP1 and TNFRSF17 (BCMA) were specifically over-expressed in LPL. These may therefore represent novel diagnostic marker differentiating these entities. Several of these are further validated at the protein level using immunohistochemistry on a tissue microarray. Consistent with the unsupervised analysis, SMZL and NMZL have little difference and share the over-expression of CD22 and WNT3 among other genes. Clustering of these samples based on the pathways and genesets that are enriched in the individual tumors as compared to their normal tissue counterpart showed a mutually exclusive pattern with significant enrichment of NFKB-related genesets and genes in LPL and MALT, and significant enrichment of B-cell receptor signaling genesets and genes in SMZL and NMZL. Our analysis, for the first time, describes the molecular relationship between these closely related lymphomas. In the process, we identified novel diagnostic markers that may differentiate these conditions and also new insights into molecular pathways that are differentially activated in the different conditions. These may represent potential therapeutic targets

Prognostic Impact Of Somatic NOTCH2 Mutation In Splenic Marginal Zone Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4247-4247 ◽  
Author(s):  
Caroline Algrin ◽  
Gabriel Brisou ◽  
Kheira Beldjord ◽  
Nicolas Mounier ◽  
Francoise Berger ◽  
...  
Keyword(s):  
Marginal Zone ◽  
Cox Model ◽  
International Prognostic Index ◽  
Marginal Zone Lymphoma ◽  
Coagulation Disorder ◽  
Splenic Marginal Zone Lymphoma ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Histological Transformation ◽  
Recurrent Mutations

Abstract Introduction New insights in the pathogenesis of the splenic marginal zone lymphoma (SMZL) has been recently enlightened by next generation sequencing technology discovering recurrent mutations in several genes implicated in major signalling pathways. In 2 recent reports (JEM 2012), mutations in NOTCH2, a gene encoding a protein required for marginal zone B-cell development, were identified in nearly 25% of the patients, with controversial impact on clinical outcome. The aim of our analysis was to analyse the incidence and the prognostic impact of somatic NOTCH2 mutations in a large cohort of patients with SMZL homogeneously treated. Methods A series of 105 consecutive SMZL patients requiring treatment and referred in 2 expert centers was analysed. Genomic DNA was extracted from frozen tumor samples of involved spleen or blood or bone marrow obtained at diagnosis. Tumor cell clonality was established by amplification of the rearranged IGH genes. Targeted sequencing of the NOTCH2 C-terminal coding exons 26, 27 and 34 was performed using Sanger sequencing and primers described by Kiel MJ et al (J.Exp.Med.209:9,2012). All mutations were verified in at least two independent PCR amplification and sequencing reactions. Log-rank tests were used to compare survival times -overall survival (OS) and progression-free survival (PFS)- between patients with mutated NOTCH2 and patient with wild-type NOTCH2. We controlled the effects of prognostic factors on outcome using multivariate Cox model analysis. Results The median follow-up was 7 years. At diagnosis, median age was 63 years. Sex ratio was M/F 1:1.35. Nearly all patients presented with a disseminated disease and a good performance status. Forty-four percent of the patients had a high LDH level. A monoclonal component was detected in 31% of the patients. An immunological event such as haemolytic anemia, thrombocytopenia, neutropenia, coagulation disorder, and cryoglobulinemia, was observed in 27% of the patients. None of the patients was infected with hepatitis C virus. Patients were scored according to the age-adjusted International Prognostic Index (n=95), and to the IIL score system (n=76). Splenectomy was realized in 97% of the patients. Three patients were treated with R-Bendamusine without splenectomy. Adjuvant treatment after splenectomy was proposed for 24% of the patients, and included CHOP+/-R (n=16), HLX-VP16 (n=1), chlorambucil (n=4), and rituximab alone (n=1). Five and 10-year OS was estimated at 82% and 69%, respectively. Five and 10-year PFS was estimated at 61% and 46%, respectively. Age>60 was significantly associated to a shorter OS (p=0.0135). We identified NOTCH2 mutations in 10 (10%) of the patients. The detected mutations occurred only within the exon 34 (TAD and PEST domains) and represented mostly truncating or insertional events leading to frameshift mutations (8 of the 10 cases) (also 1 nonsense and 1 missense mutations). Comparison of the clinical characteristics at diagnosis between patients with or without NOTCH2 mutations did not show any significant differences. Patients with NOTCH2 mutations were characterized by a significantly worse OS (at 5 years, 32% vs 87%, p<0.0001). Presence of NOTCH2 mutations was also significantly associated with a shorter PFS (at 5-years, 16% vs 66%; p=.0008), and with a shorter time to histological transformation (at 5 years, 26% vs 6%; p=0.0051). NOTCH2 mutational status did not influence the time to first treatment. Multivariate analysis showed an independent prognostic impact of NOTCH2 mutational status on OS (RR 4.7, p=0.02). Conclusion NOTCH2 mutation was identified in 10% of the SMZL patients in our series. Our data demonstrate also, as described, than patients with NOTCH2 mutations have a significant poorer prognosis than patients without NOTCH2 mutations, with a shorter PFS and a shorter OS. NOTCH2 mutational status seems to be an independent prognostic factor. This needs to be confirmed in prospective trials in the context of new therapeutics. CA and GB equally contributed Disclosures: Coiffier: Millennium Pharmaceuticals : Consultancy.

Splenic marginal zone lymphoma: Prognostic factors, role of watch and wait policy, and other therapeutic approaches in the rituximab era

2016 ◽  
Vol 44 ◽  
pp. 53-60 ◽  
Author(s):  
Salvatore Perrone ◽  
Gianna Maria D’Elia ◽  
Giorgia Annechini ◽  
Antonietta Ferretti ◽  
Maria Elena Tosti ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Watch And Wait ◽  
Therapeutic Approaches

scholarly journals Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 60 patients

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1648-1654 ◽  
Author(s):  
Jose I. Chacón ◽  
Manuela Mollejo ◽  
Enriqueta Muñoz ◽  
Patricia Algara ◽  
Marisol Mateo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Marginal Zone ◽  
Performance Status ◽  
Univariate Analysis ◽  
Bone Marrow Involvement ◽  
Eastern Cooperative Oncology Group ◽  
Marginal Zone Lymphoma ◽  
Response To Therapy ◽  
Splenic Marginal Zone Lymphoma ◽  
P53 Overexpression

A precise description of clinical features at presentation and analysis of clinical and biologic prognostic factors in splenic marginal zone lymphoma (SMZL) are still lacking. Here we describe the clinical and biologic features of a series of 60 SMZL patients diagnosed after splenectomy. Analysis for overall survival (OS), failure-free survival (FFS), and the probability of obtaining a response was performed using univariate and multivariate tests. The median age of the patient was 63 years (range, 35-84 years). Performance status according to the Eastern Cooperative Oncology Group (ECOG scale) was 0 = 16%, 1 = 58%, and 2 = 25%. Of the 60 patients, 53 (86.6%) were at Ann Arbor stage IV. All 60 patients received splenectomies, 29 of 60 also received chemotherapy, and 2 received spleen radiotherapy. A complete response (CR) was achieved by 38.3% of patients, and a partial response (PR) was achieved by 55%. Mean OS of the series was 103 months (range, 2-164 months); mean FFS was 40 months (range, 3-164 months). At 5 years from diagnosis, 39 patients (65%) were alive. Patients dying from the disease had a relatively aggressive clinical course, with a short survival (17.5 months [range, 2-72 months]). Significant prognostic factors in multivariate analysis were (1) (for OS and FFS) lack of response to therapy (CR versus noncomplete response [nCR]) and involvement of nonhematopoietic sites, and (2) (for the probability of obtaining CR) bone marrow involvement. Chemotherapy did not influence OS or FFS. p53 overexpression predicted a shorter OS in the univariate analysis. These data confirm the relative indolence of this disease, indicating the existence of a subset of more aggressive cases, which should stimulate the search for predictive biologic factors and alternative therapies.

scholarly journals Splenic Marginal Zone Lymphoma: Risk of Transformation, Clinico-Biological Features at Transformation and Prognosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4015-4015
Author(s):  
Gabriela Bastidas ◽  
Silvia Bea ◽  
Alba Navarro ◽  
Eva Gine ◽  
Julio Delgado ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Marginal Zone ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Complex Karyotype ◽  
Biological Features ◽  
Histological Transformation

BACKGROUND: The clinical course of splenic marginal zone lymphoma (SMZL) is usually indolent, but development of transformation to aggressive lymphoma (SMZL-T) is seen in 10 to 15% of the cases. Risk factors to predict SMZL-T are poorly defined. AIM: The aims of our study were: 1.- to assess the risk of transformation in a large series of SMZL patients; 2.- to analyze the prognostic factors for this event and 3.- to analyze clinical and biological features of SMZL-T. PATIENT AND METHODS: We identified 84 SMZL diagnosed at the HCB between 1994 and 2017 and 15 of them (18%) had developed histological transformation (SMZL-T). In addition, we reviewed 21 SMZL with transformation referred to HCB from other centers. Median age at diagnosis of low-grade SMZL in the 84 patients was 63 years (range, 32-91), and male/female ratio was 34/50. Complex karyotype (CK) defined as ≥3 chromosomal aberrations by conventional cytogenetics was observed in 22% and del(7q) in 59% of cases. The risk distribution according to the Splenic Marginal Zone Lymphoma Study Group simplified score HPLL/ABC was: low: 34, intermediate: 51 and high: 15. After a median follow-up of 80 months (range, 1-265), 37 of 84 (44%) patients have died, with a median overall survival (OS) of 146 months. To assess the risk of transformation and to identify predictive factors for such event, we exclusively evaluated the cohort of 84 patients from HCB. RESULTS: Fifteen of the 84 patients in the HCB cohort (18%) developed histological transformation. The cumulative incidence of transformation at 60 months from diagnosis was 15% (95% CI: 7 - 23) (Figure). In univariate analysis, variables predicting transformation were anemia, lymphopenia, thrombocytopenia, hypoalbuminemia, CK and high-risk scores of Intergruppo Italiano Linfomi (IIL) and HPLL (p<0.05 for all variables). In addition, lack of response to front-line treatment, relapse, and an early relapse at 12 and 24 months from treatment (p<0.05 for all variables) predicted for a higher risk of transformation. In multivariate analysis, only CK maintained significance to predict transformation (HR 4.85 (CI 95%: 1.15-20.56) p=0.03). Main clinico-biological features of all 36 SMZL-T patients (including HCB patients and those referred from other centers) are described in the Table. Thirty-five patients transformed to diffuse large B-cell lymphoma (DLCBL) and 1 to Hodgkin lymphoma. Treatment at transformation is detailed in Table. Response was assessable in 34 cases: 21 (62%) achieved a complete response (CR), and 13 patients did not respond. Among responders, 11 continue in CR, 9 relapsed during the follow-up and 1 patient died from therapy related acute myeloid leukemia (AML) when still in CR. Twenty SMZL-T patients (56%) eventually died, 19 related to lymphoma and 1 from AML. The median survival of the 36 SMZL-T patients from the time of transformation (SFT) was 59 months; with 60-months SFT of 46% (95% CI: 28-64) (Figure). Variables at the time of transformation predicting survival were age >60 years, thrombocytopenia and renal impairment. In addition, patients not achieving a CR, those not receiving an ASCT, and those who relapsed had a poorer SFT (p<0.05 for all variables). In multivariate analysis the independent variables predicting a worse SFT were: age > 60 years (HR 6.28 (95% CI: 1.55-25.39), p=0.01), thrombocytopenia (HR 32.77 (95% CI: 1.97-546.06), p=0.01), and response < CR (HR 8.75 (95% CI: 2.76-27.72), p<0.0001). Finally, SMZL-T was analyzed as a time-dependent variable for OS, showing that patients who eventually developed transformation had a significant higher risk of death (HR 3.894 (95% IC: 1.816-8.350), p<0.001). CONCLUSION: The risk of SMZL-T in our series of HCB was 15% at 60 months. The only factor that significatively predicted risk of SMZL-T in a multivariant analysis was the presence of complex karyotype. SMZL-T patients had a significative shorter survival compared to not transformed patients. Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding.

scholarly journals Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling

2013 ◽  
Vol 26 (7) ◽  
pp. 889-901 ◽  
Author(s):  
Alberto J Arribas ◽  
Cristina Gómez-Abad ◽  
Margarita Sánchez-Beato ◽  
Nerea Martinez ◽  
Lorena DiLisio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Marginal Zone ◽  
Comprehensive Analysis ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Mirna Profiling

scholarly journals Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma

2012 ◽  
Vol 209 (9) ◽  
pp. 1553-1565 ◽  
Author(s):  
Mark J. Kiel ◽  
Thirunavukkarasu Velusamy ◽  
Bryan L. Betz ◽  
Lili Zhao ◽  
Helmut G. Weigelin ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Lymphocytic Leukemia ◽  
Primary Lymphoma ◽  
Reactive Lymphoid Hyperplasia ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
Whole Genome ◽  
Histological Transformation

Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.

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