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Find video protocols related to scientific articles indexed in Pubmed.
Clonal Epstein-Barr Virus-Positive Mucocutaneous Ulcer Mimicking A Mature B-Cell Lymphoma In A Patient With Mycophenolate-Induced Immune Suppression.
Leuk. Lymphoma
PUBLISHED: 11-08-2014
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Abstract Epstein-Barr Virus-positive mucocutaneous ulcer (EBVMCU) is a recently described, under-recognized B-cell lymphoproliferative disorder, which is closely associated with immunosuppression. While it may clinically and pathologically mimic mature B-cell lymphomas and classical Hodgkin lymphoma, EBVMCU has an indolent clinical course and often responds to withdrawal and/or decrease in the immunosuppressive source. Here we present a unique case of EBVMCU associated with mycophenolate administration.
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Lymphomatoid Granulomatosis-A Single Institute Experience: Pathologic Findings and Clinical Correlations.
Am. J. Surg. Pathol.
PUBLISHED: 10-17-2014
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Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high-grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice.
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Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression.
J. Clin. Invest.
PUBLISHED: 10-03-2014
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It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)+ memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)+ precursors and shapes the systemic presentation of FL patients.
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Early lymphoid lesions: conceptual, diagnostic and clinical challenges.
Haematologica
PUBLISHED: 09-02-2014
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There are no "benign lymphomas", a fact due to the nature of lymphoid cells to circulate and home as part of their normal function. Thus, benign clonal expansions of lymphocytes are only rarely recognized when localized. Recent studies have identified a number of lymphoid proliferations that lie at the interface between benign and malignant. Some of these are clonal proliferations that carry many of the molecular hallmarks of their malignant counterparts, such as BCL2/IGH and CCND1/IGH translocations associated with the in situ forms of follicular lymphoma and mantle cell lymphoma, respectively. There are other clonal B-cell proliferations with low risk of progression; these include the pediatric variants of follicular lymphoma and marginal zone lymphoma. Historically, early or incipient forms of T/NK-cell neoplasia also have been identified, such as lymphomatoid papulosis and refractory celiac disease. More recently an indolent form of T-cell lymphoproliferative disease affecting the gastrointestinal tract has been described. Usually, CD8(+), the clonal cells are confined to the mucosa. The clinical course is chronic, but non-progressive. NK-cell enteropathy is a clinically similar condition, composed of cytologically atypical NK-cells that may involve the stomach, small bowel or colon. Breast implant-associated anaplastic large cell lymphoma is a cytologically alarming lesion that is self-limited if confined to the seroma cavity. Atypical lymphoid proliferations that lie at the border of benign and malignant can serve as instructive models of lymphomagenesis. It is also critical that they be correctly diagnosed to avoid unnecessary and potentially harmful therapy.
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Rapid, de novo development of isolated intracranial rosai-dorfman disease: A case report.
Br J Neurosurg
PUBLISHED: 08-21-2014
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Isolated intracranial Rosai-Dorfman Disease is rare. Here, we describe a patient who developed an asymptomatic, right parietal RDD lesion over 18 months while being followed radiographically for another brain lesion. To our knowledge, rapid, de novo radiographic formation of isolated intracranial RDD has never been reported in an asymptomatic patient.
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Aberrations of MYC are a common event in B-cell prolymphocytic leukemia.
Am. J. Clin. Pathol.
PUBLISHED: 08-16-2014
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B-cell prolymphocytic leukemia (B-PLL) remains a controversial entity, and its molecular pathogenesis is largely unknown. Patients are older, typically having marked lymphocytosis and splenomegaly in the absence of lymphadenopathy. It is defined as a mature B-cell leukemia with more than 55% circulating prolymphocytes. Leukemic mantle cell lymphoma and chronic lymphocytic leukemia in prolymphocytic transformation must be excluded.
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Cytotoxic T-cell and NK-cell lymphomas: current questions and controversies.
Am. J. Surg. Pathol.
PUBLISHED: 07-16-2014
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The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (??-type T cell, ?? T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented.
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A prospective study of mediastinal gray-zone lymphoma.
Blood
PUBLISHED: 07-14-2014
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Mediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses ?10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337).
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ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes.
Blood
PUBLISHED: 06-03-2014
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Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.
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Nature and importance of follicular lymphoma precursors.
Haematologica
PUBLISHED: 05-03-2014
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It is now widely recognized that cancer development is a protracted process requiring the stepwise acquisition of multiple oncogenic events. In humans, this process can take decades, if not a lifetime, blurring the notion of 'healthy' individuals. Follicular lymphoma exemplifies this multistep pathway of oncogenesis. In recent years, variants of follicular lymphoma have been recognized that appear to represent clonal B-cell expansions at an early stage of follicular lymphoma lymphomagenesis. These include follicular lymphoma in situ, duodenal follicular lymphoma, partial involvement by follicular lymphoma, and in the blood circulating follicular lymphoma-like B cells. Recent genetic studies have identified similarities and differences between the early lesions and overt follicular lymphoma, providing important information for understanding their biological evolution. The data indicate that there is already genomic instability at these early stages, even in instances with a low risk for clinical progression. The overexpression of BCL2 in t(14;18)-positive B cells puts them at risk for subsequent genetic aberrations when they re-enter the germinal center and are exposed to the influences of activation-induced cytidine deaminase and somatic hypermutations. The emerging data provide a rationale for clinical management and, in the future, may identify genetic risk factors that warrant early therapeutic intervention.
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Loss of signalling via G?13 in germinal centre B-cell-derived lymphoma.
Nature
PUBLISHED: 04-26-2014
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Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a G?12 and G?13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding G?13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. G?13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and G?13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in G?13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the G?13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of G?13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via G?13. These findings identify a G?13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.
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Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma.
Clin. Immunol.
PUBLISHED: 04-10-2014
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Interleukin-2 receptor ? chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor ? chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8mg/kg. Up to 8mg/kg of daclizumab administered every 3weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics/pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites.
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Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.
Blood
PUBLISHED: 03-14-2014
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Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).
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EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults.
Am. J. Surg. Pathol.
PUBLISHED: 02-15-2014
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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and classical Hodgkin lymphoma (CHL) are classified separately because of their distinct clinical and pathologic features. Whereas Epstein-Barr virus (EBV) is detected in the neoplastic cells of 25% to 70% of CHL, NLPHL is generally considered to be EBV(-). We assessed EBV status in 302 pediatric and adult cases of NLPHL. A total of 145 pediatric (age 18 y or younger) and 157 adult cases of NLPHL were retrieved from 3 North American centers and tested for EBV by in situ hybridization (EBV-encoded small RNA). Clinical and pathologic features were analyzed. Five (3.4%) pediatric and 7 (4.5%) adult NLPHL cases contained EBV(+) lymphocyte-predominant (LP) cells. Although all 12 cases met the criteria for diagnosis of NLPHL, atypical features were present, including capsular fibrosis, atrophic germinal centers, and pleomorphic or atypical LP cells. CD20 and OCT-2 were strongly and diffusely positive in all except 1 case. However, PAX5 and CD79a were weak and/or variable in 7/8 and 6/6 cases tested, respectively. EBV(+) cases were more likely to be CD30(+) (75%) compared with EBV(-) cases (25%) (P=0.0007); CD15 was negative in all cases. Our results show that EBV(+) LP cells may occur in NLPHL. Distinguishing EBV(+) NLPHL from CHL can be challenging, as EBV(+) NLPHL can have partial expression of CD30 and weak PAX5 staining as well as pleomorphic-appearing LP cells. However, the overall appearance and maintenance of B-cell phenotype, with strong and diffuse CD20 and OCT-2 expression, support the diagnosis of NLPHL in these cases.
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Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.
Cancer Discov
PUBLISHED: 02-03-2014
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Constitutive activation of NF-?B is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to I?B kinase-?, a necessary event in some pathways that engage NF-?B. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (?1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 ?-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-?B engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 ?-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-?B activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.
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Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.
Blood
PUBLISHED: 01-07-2014
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Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor ??(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350.
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Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue.
Blood
PUBLISHED: 01-07-2014
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The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell-like or activated B cell-like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)-based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.
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A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.
Blood
PUBLISHED: 01-07-2014
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The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.
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BCL2 antibodies targeted at different epitopes detect varying levels of protein expression and correlate with frequent gene amplification in diffuse large B-cell lymphoma.
Hum. Pathol.
PUBLISHED: 01-06-2014
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Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare 2 alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in 2 independent DLBCL cohorts, E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse overall survival. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in situ hybridization as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence in situ hybridization for translocation but a higher amplification frequency, indicating that BCL2 amplification may be underreported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies.
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Low-intensity therapy in adults with Burkitts lymphoma.
N. Engl. J. Med.
PUBLISHED: 11-15-2013
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Burkitts lymphoma is an aggressive B-cell lymphoma that occurs in children and adults and is largely curable with the use of intensive and toxic chemotherapy. Current treatments are less effective and have more severe side effects in adults and patients with immunodeficiency than in children.
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Activation of the STAT3 Signaling Pathway Is Associated With Poor Survival in Diffuse Large B-Cell Lymphoma Treated With R-CHOP.
J. Clin. Oncol.
PUBLISHED: 11-12-2013
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We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL.
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Early lesions of follicular lymphoma: a genetic perspective.
Haematologica
PUBLISHED: 10-25-2013
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Follicular lymphoma pathogenesis is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early transformation steps and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to potentially represent the earliest stages in the evolution of follicular lymphoma. Reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but in a significantly lower proportion than overt follicular lymphoma. Nonetheless, while the number of alterations thus clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to follicular lymphoma indicating significant selective pressure in line with its higher progression rate. Among the most noticeable alterations, we observed and validated the deletion of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). Altogether, by further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis adds to the importance of applying appropriate criteria for differential diagnosis. It also provides a first set of candidate gene alterations likely involved in the cascade of hits paving the various progression phases of early follicular lymphoma development.
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Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology.
Histopathology
PUBLISHED: 10-16-2013
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Mature T-cell and T/NK-cell neoplasms are both uncommon and heterogeneous, among the broad category of non-Hodgkin lymphomas. Owing to the lack of specific genetic alterations in the vast majority, most currently defined entities show overlapping morphological and immunophenotypic features, and therefore pose a challenge to the diagnostic pathologist. In the light of recent immunophenotypic, cytogenetic and molecular genetics advances in the field of T-cell and T/NK-cell lymphomas, the focus of the lymphoma workshop of the European Association for Haematopathology/Society for Hematopathology meeting in Lisbon, Portugal, in October 2012 was to refine existing diagnostic criteria and clarify the borders between overlapping entities. The panel reviewed over 200 submitted cases, which were grouped into five categories: (i) angioimmunoblastic T-cell lymphoma and T-follicular-helper-cell-associated lymphomas; (ii) CD30-positive T-cell lymphomas/lymphoproliferative diseases; (iii) extranodal T-cell and NK-cell neoplasms; (iv) EBV-associated T-cell/NK-cell lymphomas/lymphoproliferative diseases; and (v) peripheral T-cell lymphoma, not otherwise specified, post-transplant lymphoproliferative disorders, and mimics. This report summarizes the discussions and conclusions of the workshop, which question current diagnostic criteria and provide recommendations for refining existing classifications.
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Genome-wide copy number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma.
Blood
PUBLISHED: 09-13-2013
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Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples [198 FL and 79 transformed FL (tFL)] using a single nucleotide polymorphism (SNP) array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma (DLBCL). Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the NF-?B pathway, and deregulate p53 and B-cell transcription factors.
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Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.
Blood
PUBLISHED: 09-05-2013
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Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-? chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.
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Pathobiology of T-cell and NK-cell lymphomas.
Best Pract Res Clin Haematol
PUBLISHED: 05-23-2013
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T-cell and NK-cell lymphomas are uncommon lymphomas with an aggressive clinical course. The causes and precise cellular origins of most T-cell lymphomas are still not well defined. The WHO classification utilizes morphologic and immunophenotypic features in conjunction with clinical aspects and in some instances genetics to delineate a prognostically and therapeutically meaningful categorization. The anatomic localization of neoplastic T-cells and NK-cells parallels in part their proposed normal cellular counterparts and functions. T-cells of the adaptive immune system are mainly based in lymph nodes and peripheral blood, whereas lymphomas derived from T-cells and NK-cells of the innate immune system are mainly extranodal. This approach allows for better understanding of some of the manifestations of the T-cell and NK-cell lymphomas, including their cellular distribution, some aspects of morphology and even associated clinical findings.
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Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features.
Int. J. Cancer
PUBLISHED: 04-23-2013
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Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors.
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Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist.
Am. J. Surg. Pathol.
PUBLISHED: 04-20-2013
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Peripheral T-cell lymphomas (PTCLs) are functionally and morphologically complex. Epstein-Barr virus (EBV)-positive B cells have been reported in angioimmunoblastic T-cell lymphoma (AITL) and other PTCLs and may mimic Hodgkin/Reed-Sternberg (HRS) cells, but EBV-negative HRS-like B cells have not been described. We wished to assess the nature of the PTCL associated with HRS-like cells and to determine whether EBV-negative HRS-like cells may be seen. We identified 57 PTCL cases reported as containing HRS-like cells. These included 32 AITL, 19 PTCL, not otherwise specified (NOS), 3 PTCL-NOS, follicular variant, 1 PTCL-NOS, T-zone variant, and 2 adult T-cell leukemia/lymphoma cases. All patients were adults with a median age of 63 and presented with lymphadenopathy. The male:female ratio was 31:26 (1.2:1). Clonal TRG rearrangement was detected in 46/53 cases. Six of 38 cases had a concomitant clonal immunoglobulin gene rearrangement. In 52/57 cases the HRS cells were positive for EBV. Five cases, 3 classified as AITL and 2 as PTCL-NOS, follicular variant, contained HRS-like cells negative for EBV. All PTCLs with EBV-negative HRS cells had a T follicular helper cell immunophenotype. The neoplastic T cells expressed CD3, CD4, and PD-1 and formed rosettes around the HRS-like cells. The HRS-like cells were positive for CD20 (variable intensity), PAX5, CD30, and CD15 (4/5). We conclude that both EBV-positive and EBV-negative HRS-like B cells may occur in the background of PTCL; caution is needed to avoid misdiagnosis as classical Hodgkin lymphoma. The close interaction between the HRS-like cells and the rosetting PD-1-positive T cells suggests a possible pathogenetic role in this phenomenon and provides new insights into the abnormal B-cell proliferations that occur in the context of TFH malignancies.
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Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma.
N. Engl. J. Med.
PUBLISHED: 04-12-2013
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Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkins lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.
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Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma.
Am. J. Surg. Pathol.
PUBLISHED: 04-10-2013
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Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. Most pediatric cases have been described as grade 3, but the criteria to distinguish the pediatric variant of FL (PFL) from usual FL (UFL) seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as PFL: 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as UFL, 28 of which presented in lymph nodes. The nodal PFLs were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. PFLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. UFLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results indicate that histologic and immunophenotypic criteria can reliably separate PFL and UFL and that UFL is exceptionally rare in the pediatric age group. PFL associated with particular anatomic sites have distinctive features and should be evaluated separately in future clinical and biological studies.
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Antineutrophil Cytoplasmic Autoantibody Associated Systemic Vasculitis Is Associated with Epstein - Barr virus in the Setting of HIV Infection.
Infect Dis Clin Pract (Baltim Md)
PUBLISHED: 03-14-2013
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EBV has been a leading candidate as a trigger for several autoimmune diseases. We describe an antineutrophil cytoplasmic autoantibody (ANCA) -associated systemic vasculitis as the initial presenting illness of AIDS.
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ALK-positive large B-cell lymphomas express a terminal B-cell differentiation program and activated STAT3 but lack MYC rearrangements.
Mod. Pathol.
PUBLISHED: 02-25-2013
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ALK-positive large B-cell lymphoma is an aggressive lymphoid neoplasm characterized by a monomorphic proliferation of immunoblast-like cells expressing a plasmablastic phenotype and carrying ALK rearrangements. MYC rearrangements are frequent in plasmablastic lymphomas, advanced plasma cell myelomas and a subgroup of diffuse large B-cell lymphomas, but their presence in ALK-positive large B-cell lymphomas is unknown. MYC expression is downregulated by BLIMP1, a master modulator of plasma cell differentiation. BLIMP1 and MYC are upregulated by STAT3, a signal transducer activated by ALK. To determine the role of BLIMP1, MYC and STAT3 in the pathogenesis of ALK-positive large B-cell lymphomas, we investigated MYC rearrangement and the expression of MYC, phosphorylated STAT3, BLIMP1, PAX5 and XBP1 in 12 ALK-positive large B-cell lymphomas. All cases expressed ALK with a granular cytoplasmic pattern. Nine cases had a split signal consistent with an ALK rearrangement. Three additional cases showed a deletion of the 5 or 3 end of the ALK probe consistent with cryptic translocation. PAX5 was virtually negative in all cases tested, whereas BLIMP1 was expressed in all tumors and XBP1 in 11 of 12. Phosphorylated STAT3 was observed in all cases with a strong and diffuse nuclear pattern. MYC rearrangements were not identified in any tumor, but MYC gains and amplification were detected in six cases and one case, respectively. MYC protein was expressed in all tumors independently of MYC gene alterations. These results indicate that ALK-positive large B-cell lymphomas express a complete plasmablastic differentiation program but, contrary to plasmablastic lymphomas, do not have MYC rearrangements. STAT3 is constantly activated and may be an alternative mechanism to promote MYC expression in these tumors. The relevance of the ALK/STAT3 pathway in the pathogenesis of ALK-positive large B-cell lymphomas may offer an attractive target for new therapies.
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Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 02-19-2013
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Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis.
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Horizontal transmission of malignancy: in-vivo fusion of human lymphomas with hamster stroma produces tumors retaining human genes and lymphoid pathology.
PLoS ONE
PUBLISHED: 02-06-2013
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We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially-transplanted (over 5-6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy.
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Subcutaneous panniculitis-like T-cell lymphoma in the pediatric age group: a lymphoma of low malignant potential.
Pediatr Blood Cancer
PUBLISHED: 02-04-2013
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Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare neoplasm of mature ?? cytotoxic T-cells. Most commonly occurring in young adults, few reports are described in children. A separate analysis of a significant cohort of pediatric patients has not previously been performed.
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Colorimetric in situ hybridization identifies MYC gene signal clusters correlating with increased copy number, mRNA, and protein in diffuse large B-cell lymphoma.
Am. J. Clin. Pathol.
PUBLISHED: 01-29-2013
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Abnormalities of the MYC oncogene on chromosome 8 are characteristic of Burkitt lymphoma and other aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We recently described a colorimetric in situ hybridization (CISH) method for detecting extra copies of the MYC gene in DLBCL and the frequent occurrence of excess copies of discrete MYC signals in the context of diploidy or polyploidy of chromosome 8, which correlated with increased mRNA signals. We further observed enlarged MYC signals, which were counted as a single gene copy but, by their dimension and unusual shape, likely consisted of "clusters" of MYC genes. In this study, we sought to further characterize these clusters of MYC signals by determining whether the presence of these correlated with other genetic features, mRNA levels, protein, and overall survival. We found that MYC clusters correlated with an abnormal MYC locus and with increased mRNA. MYC mRNA correlated with protein levels, and both increased mRNA and protein correlated with poorer overall survival. MYC clusters were seen in both the germinal center and activated B-cell subtypes of DLBCL. Clusters of MYC signals may be an underappreciated, but clinically important, feature of aggressive B-cell lymphomas with potential prognostic and therapeutic relevance.
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Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T-cell lymphomas: a clinicopathologic study of three cases.
J. Cutan. Pathol.
PUBLISHED: 01-25-2013
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Primary cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical-stained sections were examined in all the cases. Molecular analysis for rearrangement of the T-cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T-cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8- phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.
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Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival.
Blood
PUBLISHED: 01-10-2013
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Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor ? rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.
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Peripheral T-cell and NK-cell lymphomas in the WHO classification: pearls and pitfalls.
Mod. Pathol.
PUBLISHED: 01-03-2013
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Peripheral T-cell and NK-cell lymphomas are functionally, pathologically, and clinically complex. Most nodal T-cell lymphomas belong to the adaptive immune system, whereas many extranodal T-cell and NK-cell lymphomas are derived from innate immune cells. The pathological manifestations often reflect the functional attributes of the neoplastic cells. Several forms of peripheral T-cell lymphoma are derived from T-follicular helper cells (T(FH)), and include angioimmunoblastic T-cell lymphoma, the follicular variant of peripheral T-cell lymphoma, not otherwise specified, and primary cutaneous small/medium CD4-positive T-cell lymphoma. T(FH)-derived neoplasms are often associated with atypical and clonal B-cell proliferations, which take a number of forms, sometimes mimicking classical Hodgkins lymphoma, and sometimes showing marked plasmacytic differentiation. Most extranodal T-cell lymphomas are cytotoxic and often arise in mucosal-associated sites. They can be derived from either ?? or ?? cytotoxic T cells, and include subcutaneous panniculitis-like T-cell lymphoma, and enteropathy-associated T-cell lymphomas, both Type I and Type II. Type I enteropathy-associated lymphomas occur in association with celiac disease, whereas Type II lymphomas are more often sporadic. For some T-cell lymphomas, such as hepatosplenic T-cell lymphoma, immunophenotypic heterogeneity is seen within a single disease entity. New data are emerging on the molecular pathogenesis of T-cell and NK-cell lymphoma, but most tumor types remain poorly characterized.
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Aggressive B-cell lymphomas: a review of new and old entities in the WHO classification.
Hematology Am Soc Hematol Educ Program
PUBLISHED: 12-14-2011
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Aggressive B-cell lymphomas are clinically and pathologically diverse and reflect multiple pathways of transformation. The 2008 World Health Organization (WHO) classification reflects this complexity with the addition of several new entities and variants. Whereas MYC translocations have long been associated with Burkitt lymphoma (BL), deregulation of MYC has been shown to occur in other aggressive B-cell lymphomas, most often as a secondary event. Lymphomas with translocations of both MYC and BCL2 are highly aggressive tumors, with a high failure rate with most treatment protocols. These "double-hit" lymphomas are now separately delineated in the WHO classification as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL. A MYC translocation is also found uncommonly in DLBCL, but the clinical consequences of this in the absence of a double hit are not yet fully delineated. Most recently, MYC translocations have been identified as a common secondary event in plasma cell neoplasms, seen in approximately 50% of plasmablastic lymphoma. Another area that has received recent attention is the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression; most of these occur in patients of advanced age and include the EBV-positive large B-cell lymphomas of the elderly.
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MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response.
Haematologica
PUBLISHED: 11-18-2011
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MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma.
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In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior.
Haematologica
PUBLISHED: 11-04-2011
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Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called "in situ mantle cell lymphoma". The clinical significance of this lesion remains uncertain.
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Nodular lymphocyte-predominant hodgkin lymphoma with atypical T cells: a morphologic variant mimicking peripheral T-cell lymphoma.
Am. J. Surg. Pathol.
PUBLISHED: 10-15-2011
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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct Hodgkin lymphoma subtype composed of few neoplastic lymphocyte-predominant (LP) cells in a background of reactive small B and T cells. We have seen occasional NLPHL cases that contain background T cells with prominent cytologic atypia, raising the differential diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) or a composite lymphoma. We sought to characterize the clinicopathologic features of such cases. Eleven NLPHL cases with atypical T cells diagnosed from 1977 to 2010 were identified at 2 institutions and compared with 24 control NLPHL cases lacking atypical T cells. All 9 male patients and 2 female patients presented with localized peripheral lymphadenopathy. In comparison with control patients, they were younger (median age, 13.8 vs. 36.1 y; P=0.015), with more frequent cervical lymph node involvement (54.5% vs. 8.3%, P=0.015). In all 11 cases, areas of NLPHL with typical B-cell-rich nodules containing LP cells were present. Nine cases contained sheets of atypical T cells surrounding primary and secondary follicles in a pattern mimicking the T-zone pattern of PTCL-NOS; the remaining 2 cases contained atypical T cells presented as large clusters at the periphery of B-cell-rich nodules. In all cases, the atypical T-cell-rich areas contained rare scattered LP cells, which were IgD in 5 of 7 cases (71.4%). The atypical T cells showed no pan-T-cell antigen loss or aberrant T-cell antigen expression in any case, and polymerase chain reaction or Southern blot analysis showed no evidence of T-cell clonality in 6 cases tested. The atypical T cells exhibited a variable immunophenotype with respect to germinal center, follicular T-helper, T-regulatory, and cytotoxic T-cell markers. Among 8 patients with clinical follow-up (median follow-up: 6.4 y), 5 patients had recurrent NLPHL at 6 months to 12 years after diagnosis and 6 patients are alive without disease at 9 months to 18 years after diagnosis. In comparison with control patients, NLPHL patients with atypical T cells were more likely to develop recurrent NLPHL (71.4% vs. 13.6%, P=0.008) and to have a shorter time to relapse (P=0.04). Our findings suggest that some cases of NLPHL, occurring predominantly in younger patients, contain prominent populations of morphologically atypical T cells that may raise the possibility of concurrent nodal involvement by PTCL-NOS, a rare diagnosis in children. The clinical behavior of these cases appears similar to that of NLPHL with T-cell-rich diffuse areas, with a higher risk of disease recurrence and no difference in overall survival; however, this finding warrants confirmation in studies of larger numbers of patients.
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MicroRNA profiles of t(14;18)-negative follicular lymphoma support a late germinal center B-cell phenotype.
Blood
PUBLISHED: 09-29-2011
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A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.
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BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab.
Clin. Cancer Res.
PUBLISHED: 09-20-2011
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We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported.
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Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations.
Mod. Pathol.
PUBLISHED: 08-05-2011
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The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkins lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkins lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkins lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations.
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Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma.
Blood
PUBLISHED: 07-18-2011
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Follicular lymphoma in situ (FLIS) was first described nearly a decade ago, but its clinical significance remains uncertain. We reevaluated our original series and more recently diagnosed cases to develop criteria for the distinction of FLIS from partial involvement by follicular lymphoma (PFL). A total of 34 cases of FLIS were identified, most often as an incidental finding in a reactive lymph node. Six of 34 patients had prior or concurrent FL, and 5 of 34 had FLIS composite with another lymphoma. Of patients with negative staging at diagnosis and available follow-up (21 patients), only one (5%) developed FL (follow-up: median, 41 months; range, 10-118 months). Follow-up was not available in 2 cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was positive in all 17 cases tested. PFL patients were more likely to develop FL, diagnosed in 9 of 17 (53%) who were untreated. Six patients with PFL were treated with local radiation therapy (4) or rituximab (2) and remained with no evidence of disease. FLIS can be reliably distinguished from PFL and has a very low rate of progression to clinically significant FL. FLIS may represent the tissue counterpart of circulating t(14;18)-positive B cells.
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Nonhepatosplenic ?? T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation.
Am. J. Surg. Pathol.
PUBLISHED: 07-15-2011
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?? T cells represent a minor T-cell subset that is mainly distributed in mucosal surfaces. Two distinct lymphomas derived from these cells have been recognized: hepatosplenic ?? T-cell lymphoma (HSTL) and primary cutaneous ?? T-cell lymphoma (PCGD-TCL). However, whether other anatomic sites may also be involved and whether they represent a spectrum of the same disease are not well studied. The lack of T-cell receptor (TCR)? expression has been used to infer a ?? origin when other methods are not available. We studied 35 T-cell tumors suspected to be ?? TCL using monoclonal antibodies reactive with TCR ? or ? in paraffin sections. We were able to confirm ?? chain expression in 22 of 35 cases. We identified 8 PCGD-TCLs, 6 HSTLs, and 8 ?? TCLs without hepatosplenic or cutaneous involvement involving mainly extranodal sites. Two such cases were classified as enteropathy-associated T-cell lymphoma, type II. The other ?? TCL presented in the intestine, lung, tongue, orbit, and lymph node. In addition, we observed 13 cases with mainly extranodal involvement that lacked any TCR expression ("TCR silent"). In all cases, a natural killer cell origin was excluded. In conclusion, the lack of TCR? expression does not always predict ??-T-cell derivation, as TCR silent cases may be found. The recognition of ?? TCL presenting in extranodal sites other than skin and liver/spleen expands the clinical spectrum of these tumors. However, non-HSTL ?? TCL do not seem to represent a single entity. The relationship of these tumors with either HSTL or PCGD-TCL requires further study.
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Phase I trial of 7-hydroxystaurosporine and fludararbine phosphate: in vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia.
Leuk. Lymphoma
PUBLISHED: 07-12-2011
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This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.
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Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases.
Mod. Pathol.
PUBLISHED: 06-10-2011
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Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow-derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of seven cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in six of seven patients, and one patient had both tumors diagnosed at the same time. The tumors included four interdigitating dendritic cell sarcomas: one Langerhans cell sarcoma, one histiocytic sarcoma and one immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V-D-J gene rearrangement. By fluorescence in situ hybridization (FISH) analysis, two cases showed deletion 17p in both components, whereas four cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in five of six cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBP?. Our study provides evidence for transdifferentiation of CLL/SLL B cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon.
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Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma.
J. Clin. Oncol.
PUBLISHED: 05-31-2011
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Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) -specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial.
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Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do?
Curr Hematol Malig Rep
PUBLISHED: 05-19-2011
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In recent years, an overlap in biologic and clinical features has been identified between classic Hodgkin lymphoma (CHL) and primary mediastinal large B-cell lymphoma (PMBL). Further strengthening this relationship is the identification of lymphomas with clinical and morphologic features transitional between the two, known as gray zone lymphomas (GZL). However, this diagnostic gray zone is not just of theoretical interest: it presents a practical problem, as the treatment approaches for CHL traditionally differ from those for aggressive B-cell lymphomas. This article reviews the treatment approach for mediastinal lymphomas, including CHL of the nodular sclerosis subtype (CHL-NS), PMBL, and mediastinal GZL. Though several trials have evaluated different regimens with or without radiation in PMBL and CHL-NS, there is a lack of prospective experience in treating GZL because of the rarity of these tumors. Historical data indicate that they have done poorly with traditional approaches developed for the treatment of either CHL or diffuse large B-cell lymphoma.
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Why is it crucial to reintegrate pathology into cancer research?
Bioessays
PUBLISHED: 05-17-2011
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The integration of pathology with molecular biology is vital if we are to enhance the translational value of cancer research. Pathology represents a bridge between medicine and basic biology, it remains the gold standard for cancer diagnosis, and it plays an important role in discovery studies. In the past, pathology and cancer research were closely associated; however, the molecular biology revolution has shifted the focus of investigators toward the molecular alterations of tumors. The reductionist approach taken in molecular studies is producing great insight into the inner workings of neoplasia, but it can also minimize the importance of histopathology and of understanding the disease as a whole. In turn, pathologists can underestimate the role of molecular studies in developing new ancillary techniques for clinical diagnosis. A multidisciplinary approach that integrates pathology and molecular biology within a translational research system is needed. This process will require overcoming cultural barriers and can be achieved through education, a more effective incorporation of pathology into biological research, and conversely an integration of biological research into the pathology laboratory.
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Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project.
Blood
PUBLISHED: 05-12-2011
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Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.
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High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy.
Haematologica
PUBLISHED: 05-05-2011
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Diffuse large B-cell lymphoma is a clinically and molecularly heterogeneous disease. Gene expression profiling studies have shown that the tumor microenvironment affects survival and that the angiogenesis-related signature is prognostically unfavorable. The contribution of histopathological microvessel density to survival in diffuse large B-cell lymphomas treated with immunochemotherapy remains unknown. The purpose of this study is to assess the prognostic impact of histopathological microvessel density in two independent series of patients with diffuse large B-cell lymphoma treated with immunochemotherapy.
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Coexisting and clonally identical classic hodgkin lymphoma and nodular lymphocyte predominant hodgkin lymphoma.
Am. J. Surg. Pathol.
PUBLISHED: 04-15-2011
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We report a case of concurrent nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic Hodgkin lymphoma (cHL), of nodular sclerosis subtype, in an otherwise healthy 24-year-old man with a strong family history of cHL. The patient was found to have a parotid mass, which was diagnosed as NLPHL, and a thymic mass diagnosed as cHL, of nodular sclerosis subtype concurrently. The lesion in the parotid showed features typical of NLPHL by morphology and immunophenotype. The LP cells were positive for PAX5, CD20, Oct2, weakly positive for CD30, and negative for CD15. The thymic lesion, diagnosed as cHL, of nodular sclerosis subtype, showed prominent bands of fibrosis and Hodgkin/Reed-Sternberg and lacunar cells positive for CD30 and CD15. These cells were variably positive for CD20 and negative for Oct2. PAX5 was weakly positive. Immunoglobulin gene rearrangement studies by polymerase chain reaction were carried out on microdissected Hodgkin/Reed-Sternberg and LP cells, which were shown to have identically sized peaks. NLPHL and cHL are 2 distinct diseases and are almost never seen concurrently. We present a case in which polymerase chain reaction analysis indicated that the tumor cells of these 2 distinct entities were clonally identical.
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Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkins lymphoma and primary mediastinal large B-cell lymphoma.
Haematologica
PUBLISHED: 04-02-2011
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Mediastinal gray zone lymphoma is a newly recognized entity with transitional morphological and immunophenotypic features between the nodular sclerosis subtype of Hodgkins lymphoma and primary mediastinal large B-cell lymphoma. Diagnostic criteria for mediastinal gray zone lymphoma are still challenging, and the optimal therapy is as yet undetermined. Epigenetic changes have been implicated in the loss of the B-cell program in classical Hodgkins lymphoma, and might provide a basis for the immunophenotypic alterations seen in mediastinal gray zone lymphoma.
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Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States.
Blood
PUBLISHED: 03-31-2011
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Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.
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Bexarotene is active against subcutaneous panniculitis-like T-cell lymphoma in adult and pediatric populations.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 03-27-2011
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Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses. There is no standard treatment, although chemotherapy and hematopoietic stem cell transplantation are commonly used. We describe results using bexarotene for children and adults with these disorders.
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Hairy cell leukemia diagnostic criteria and differential diagnosis.
Leuk. Lymphoma
PUBLISHED: 03-21-2011
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Hairy cell leukemia (HCL) is a disease with distinctive clinical findings, as well as a unique morphology and immunophenotype. These features typically allow for a reliable and reproducible diagnosis in nearly all situations. However, certain morphological features of HCL, such as villous cytoplasmic projections or characteristic tissue specific infiltrative patterns, including red pulp expansion with pseudosinuses, may be seen in other B-cell lymphoproliferative disorders. A methodical and thorough approach evaluating the clinical, cytological, histological, architectural, and immunophenotypic features is described and will aid in rendering the appropriate diagnosis. This is paramount as current data indicate that hairy cell leukemia - variant and other splenic B-cell lymphomas must be distinguished from HCL, as the response to therapy differs in these disorders.
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Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma.
Blood
PUBLISHED: 03-08-2011
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We investigated age-related EBV(+) B-cell lymphoproliferations in the Western population. The clinical features, histology, immunophenotype, EBV-encoded RNA in situ hybridization, and clonality by PCR of T-cell receptor gamma and immunoglobulin genes were categorized in 122 EBV(+) lesions as follows: (1) reactive lymphoid hyperplasia; (2) polymorphic extranodal or (3) polymorphic nodal lymphoproliferative disease (LPD); and (4) diffuse large B-cell lymphoma (DLBCL). Interphase FISH for IG and PAX5 gene rearrangements was performed on 17 cases of DLBCL. The overall median age was 75 years (range, 45-101 years; 67 men, 55 women), and 67, 79, 73, and 77 years, respectively, for groups 1 through 4. Sixteen of 21 cases of polymorphic extranodal LPD were classified as EBV(+) mucocutaneous ulcer. PCR for immunoglobulin genes was polyclonal in reactive lymphoid hyperplasia (84%) and monoclonal in 33%, 63%, and 56% of polymorphic extranodal and nodal LPD cases and DLBCL, respectively. All groups showed restricted/clonal T-cell receptor responses (27%-70%). By FISH, 19% of DLBCLs showed IGH@ rearrangements, but PAX5 was unaffected. Disease-specific 5-year survival was 100%, 93%, 57%, and 25% for groups 1-4, respectively, and 100% for patients with EBV(+) mucocutaneous ulcer. Disease volume was predictive of therapy response (P = .0002), and pathologic subtype was predictive of overall outcome (P = .001). Age-related EBV(+) B-cell LPD encompasses a wider disease spectrum than previously recognized and includes both reactive and neoplastic conditions. Reduction in the T-cell repertoire may contribute to decreased immune surveillance.
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Accurate classification of diffuse large B-cell lymphoma into germinal center and activated B-cell subtypes using a nuclease protection assay on formalin-fixed, paraffin-embedded tissues.
Clin. Cancer Res.
PUBLISHED: 03-01-2011
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Classification of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes based on gene expression profiles has well-established prognostic value. These subtypes, termed germinal center B cell (GCB) and activated B cell (ABC) also have different genetic alterations and overexpression of different pathways that may serve as therapeutic targets. Thus, accurate classification is essential for analysis of clinical trial results and planning new trials by using targeted agents. The current standard for COO classification uses gene expression profiling (GEP) of snap frozen tissues, and a Bayesian predictor algorithm. However, this is generally not feasible. In this study, we investigated whether the qNPA technique could be used for accurate classification of COO by using formalin-fixed, paraffin-embedded (FFPE) tissues. We analyzed expression levels of 14 genes in 121 cases of R-CHOP-treated DLBCL that had previously undergone GEP by using the Affymetrix U133 Plus 2.0 microarray and had matching FFPE blocks. Results were evaluated by using the previously published algorithm with a leave-one-out cross-validation approach. These results were compared with COO classification based on frozen tissue GEP profiles. For each case, a probability statistic was generated indicating the likelihood that the classification by using qNPA was accurate. When data were dichotomized into GCB or non-GCB, overall accuracy was 92%. The qNPA technique accurately categorized DLBCL into GCB and ABC subtypes, as defined by GEP. This approach is quantifiable, applicable to FFPE tissues with no technical failures, and has potential for significant impact on DLBCL research and clinical trial development.
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Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma.
Blood
PUBLISHED: 02-25-2011
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Romidepsin (depsipeptide or FK228) is a histone deacetylase inhibitor, one of a new class of agents active in T-cell lymphoma. A phase 2 trial was conducted in cutaneous (CTCL) and peripheral (PTCL) T-cell lymphoma. Major and durable responses in CTCL supported the approval of romidepsin for CTCL. Forty-seven patients with PTCL of various subtypes including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma were enrolled. All patients had received prior therapy with a median of 3 previous treatments (range 1-11); 18 (38%) had undergone stem-cell transplant. All patients were evaluated for toxicity; 2 patients discovered to be ineligible were excluded from response assessment. Common toxicities were nausea, fatigue, and transient thrombocytopenia and granulocytopenia. Complete responses were observed in 8 and partial responses in 9 of 45 patients, for an overall response rate of 38% (95% confidence interval 24%-53%). The median duration of overall response was 8.9 months (range 2-74). Responses were observed in various subtypes, with 6 responses among the 18 patients with prior stem-cell transplant. The histone deacetylase inhibitor romidepsin has single agent clinical activity associated with durable responses in patients with relapsed PTCL.
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Lymphoid proliferations of indeterminate malignant potential arising in adults with common variable immunodeficiency disorders: unusual case studies and immunohistological review in the light of possible causative events.
J. Clin. Immunol.
PUBLISHED: 02-20-2011
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Patients with common variable immunodeficiency disorders (CVIDs) who developed B cell lymphoproliferation of indeterminate malignant potential are described in order to raise a discussion of the relationship between infection and lymphoproliferation in infection prone patients. Those with CVID are at risk of developing either polyclonal or monoclonal lymphoproliferation in part due to the dysregulation of their adaptive immune systems. The aetiologies of the lymphoproliferations are unknown but intriguing; the relevance of infection being particularly problematic. The patients described here demonstrate variability in preceding infection, age at presentation, response to antibiotics and other types of therapy as well as outcome. The question of treatment is also controversial; issues include whether antibiotics or chemotherapy are the first line of therapy in all patients and whether transformation to aggressive B cell malignancy is inevitable or depends on other factors and if so, the length of time for such progression.
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The incidence of hepatosplenic T-cell lymphoma in a large managed care organization, with reference to anti-tumor necrosis factor therapy, Northern California, 2000-2006.
Pharmacoepidemiol Drug Saf
PUBLISHED: 02-09-2011
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Hepatosplenic T-cell lymphoma (HSTCL), a rare and rapidly progressive subtype of peripheral T-cell lymphoma, has been reported following TNF-?-blocker therapy. To better understand this relationship, we conducted an epidemiologic study in the Kaiser Permanente membership.
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The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
Blood
PUBLISHED: 02-07-2011
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The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field.
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Cyclin D1 positive diffuse large B-cell lymphoma is a post-germinal center-type lymphoma without alterations in the CCND1 gene locus.
Leuk. Lymphoma
PUBLISHED: 02-01-2011
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The aims of this study were to analyze the incidence and morphology of cyclin D1+ DLBCL and cases of Richter transformation (RT), and to elucidate possible molecular mechanisms of cyclin D1 overexpression. Seventy-two cases of de novo DLBCL and 12 cases of RT were included in this study. Cyclin D1 positivity was found in 10/66 (15%) cases of unselected de novo DLBCL and in 2/11 (18%) cases of RT. Seven independently identified cases of cyclin D1+ DLBCL, including one RT, were added to the study. Centroblastic morphology was found in 17/19 (89%) cases of cyclin D1+, most with a post-germinal center phenotype (CD10-, BCL6+, MUM1+). No alterations in the CCND1 gene indicative for a translocation t(11;14) were identified by FISH. Analysis of the MYC locus yielded gene copy alterations in five cases and no disruption of the gene locus in any case, suggesting an alternative mechanism of cyclin D1 deregulation.
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Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project.
Blood
PUBLISHED: 01-26-2011
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The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (? 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.
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Marginal zone lymphomas involving meningeal dura: possible link to IgG4-related diseases.
Mod. Pathol.
PUBLISHED: 11-19-2010
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Dura-based marginal zone lymphomas represent an uncommon group of low-grade B-cell neoplasms, and literature regarding the clinical, histological and genetic profile of these tumors in the context of the newly described IgG4-related entities is lacking. We analyzed 32 dura-based marginal zone lymphomas identified in 27 females and 5 males ranging in age from 33-82 years (median 50). Morphologic examination, immunohistochemical studies and PCR for B-cell clonality were carried out in all cases. In addition, IgG4 immunohistochemistry and cytogenetic studies (either by FISH or RT-PCR) were carried out in 20 (18 primary dural; 2 with associated extradural disease) and 9 cases, respectively. Clinically, most cases presented radiologically as dura-based masses, mimicking meningioma. Histologically, the majority exhibited plasmacytoid differentiation, and were clonal either by PCR or immunohistochemical light chain analysis (28 out of 32). In the subset tested for IgG4, 6 of 18 primary dural marginal zone lymphoma (including one epidural tumor) showed numerous IgG4-positive plasma cells; all 6 were light chain restricted and clonal by PCR in 5 of 6 tested cases. Three IgG4-positive marginal zone lymphomas tested for cytogenetics did not show any cytogenetic aberrations. Across all cases, FISH and RT-PCR identified abnormalities in three out of nine cases (trisomies 3 and 18; trisomies 3 and 1; trisomy 18) without any extranodal marginal zone lymphoma specific translocations. Regardless of the treatment modality, 16 of 17 patients with follow-up are alive without evidence of disease over a period of 4-124 months (median 19.5). The expression of IgG4 in light-chain-restricted clonal plasma cells of a significant subset of dural marginal zone lymphomas, including one in an epidural location, is a novel finding and points to distinctive biology. Cytogenetic aberrations are present only in a minority of dural marginal zone lymphomas.
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