Publications by authors named "Elaine S Jaffe"

379 Publications

Multicentric Castleman disease and the evolution of the concept.

Pathologica 2021 Oct;113(5):339-353

Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

The term multicentric Castleman disease (MCD) encompasses a spectrum of conditions that share some overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity, causing systemic inflammatory symptoms as well as lymphadenopathy. Some of the histological changes in lymph nodes resemble the histology of unicentric Castleman disease (UCD). However, based on current knowledge, the use of this shared nomenclature is unfortunate, since these disorders differ in pathogenesis and prognosis. In Kaposi sarcoma-associated herpesvirus (KSHV)-associated MCD, cytokine overactivity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. The authors review the evolving concepts and definitions of the various conditions under the eponym of multicentric Castleman disease.
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http://dx.doi.org/10.32074/1591-951X-351DOI Listing
October 2021

Neutrophil and Eosinophil Extracellular Traps in Hodgkin Lymphoma.

Hemasphere 2021 Sep 1;5(9):e633. Epub 2021 Sep 1.

Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

Classic Hodgkin lymphoma (cHL), nodular sclerosis (NS) subtype, is characterized by the presence of Hodgkin/Reed-Sternberg (HRS) cells in an inflammatory background containing neutrophils and/or eosinophils. Both types of granulocytes release extracellular traps (ETs), web-like DNA structures decorated with histones, enzymes, and coagulation factors that promote inflammation, thrombosis, and tumor growth. We investigated whether ETs from neutrophils (NETs) or eosinophils (EETs) are detected in cHL, and evaluated their association with fibrosis. We also studied expression of protease-activated receptor-2 (PAR-2) and phospho-extracellular signal-related kinase (p-ERK), potential targets/effectors of ETs-associated elastase, in HRS cells. Expression of tissue factor (TF) was evaluated, given the procoagulant properties of ETs. We analyzed 32 HL cases, subclassified as 12 NS, 5 mixed-cellularity, 5 lymphocyte-rich, 1 lymphocyte-depleted, 4 nodular lymphocyte-predominant HL (NLPHL), and 5 reactive nodes. Notably, a majority of NS cHL cases exhibited NET formation by immunohistochemistry for citrullinated histones, with 1 case revealing abundant EETs. All other cHL subtypes as well as NLPHL were negative. Immunofluorescence microscopy confirmed NETs with filamentous/delobulated morphology. Moreover, ETs formation correlates with concurrent fibrosis ( = 0.7999; 95% CI, 0.6192-0.9002; ≤ 0.0001). Results also showed that HRS cells in NS cHL expressed PAR-2 with nuclear p-ERK staining, indicating a neoplastic or inflammatory phenotype. Remarkably, TF was consistently detected in the endothelium of NS cHL cases compared with other subtypes, in keeping with a procoagulant status. A picture emerges whereby the release of ETs and resultant immunothrombosis contribute to the inflammatory tumor microenvironment of NS cHL. This is the first description of NETs in cHL.
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http://dx.doi.org/10.1097/HS9.0000000000000633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410234PMC
September 2021

Next-generation sequencing-based monitoring of circulating tumor DNA reveals clonotypic heterogeneity in untreated PTCL.

Blood Adv 2021 10;5(20):4198-4210

Lymphoid Malignancies Branch.

Peripheral T-cell lymphomas (PTCLs) have marked biologic and clinical heterogeneity, which confounds treatment decisions. Advances in circulating tumor DNA (ctDNA) assays using next-generation sequencing (NGS) have improved the detection of molecular relapse and driver mutations in diffuse large B-cell lymphoma and show the potential utility of ctDNA across lymphomas. We investigated NGS-based monitoring of T-cell receptor (TCR) sequences in patients with PTCL undergoing frontline treatment. Of 45 patients, 34 (76%) had tumor-specific clonotypes of the TCRβ or TCRγ genes identified, which included 18 (86%) from baseline tissue and 16 (67%) from baseline serum. Twenty-five (74%) patients had both TCRβ and TCRγ clonotypes, 23 (68%) had more than 1 TCRγ clonotype, and 4 (9%) had multiple TCRβ or TCRγ clonotypes, demonstrating significant intrapatient clonotypic heterogeneity. Among 24 patients with available serial serum samples during treatment, 9 (38%) cleared ctDNA after 2 cycles of therapy, and 11 (46%) had detectable ctDNA at the end of treatment. Patients with detectable ctDNA after therapy showed a trend toward worse survival. Notably, 2 patients with persistently detectable ctDNA after therapy remained in remission with 10 years of follow-up. Clonotypic heterogeneity in tumors and persistence, despite long-term remission, suggests variability in oncological potential. This trial was registered at www.clinicaltrials.gov as #NCT00001337.
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http://dx.doi.org/10.1182/bloodadvances.2020003679DOI Listing
October 2021

How I Diagnose Angioimmunoblastic T-Cell Lymphoma.

Am J Clin Pathol 2021 06;156(1):1-14

Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma derived from T-follicular helper cells. For pathologists, diagnosing AITL may be challenging due to its wide clinical and histopathologic spectrum, which can mimic a variety of reactive and neoplastic processes.

Methods: We summarize and discuss the clinicopathologic features of AITL, emphasizing diagnostic tools available to the practicing pathologist. Common diagnostic dilemmas are discussed.

Results: AITL exhibits various histologic patterns and is often associated with a prominent microenvironment that can obscure the neoplastic cells. Atypical B-cell proliferations, which can take a number of forms, are common in AITL, and clonal B-cell expansion can be seen. The atypical B cells can closely resemble Hodgkin/Reed-Sternberg cells, leading to misdiagnosis as classic Hodgkin lymphoma. Molecular studies have revealed recurrent genetic alterations, which can aid in differential diagnosis, particularly in problematic cases.

Conclusions: Given the complex diagnostic challenges in AITL, an integrated approach, incorporating clinical, morphologic, immunophenotypic, and molecular findings, is helpful to reach an accurate diagnosis.
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http://dx.doi.org/10.1093/ajcp/aqab090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209595PMC
June 2021

MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma.

Haematologica 2021 10 1;106(10):2682-2693. Epub 2021 Oct 1.

Hematopathology Unit, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid.

Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large-cell morphology and terminal B-cell differentiation. The differential diagnosis from Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging because of the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated 34 cases of PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma-related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2- q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, Epstein-Barr virus (EBV)-negative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors in relation to EBV infection.
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http://dx.doi.org/10.3324/haematol.2020.271957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485662PMC
October 2021

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases.

Blood Adv 2021 03;5(6):1660-1670

HIV & AIDS Malignancy Branch and.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.
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http://dx.doi.org/10.1182/bloodadvances.2020004058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993110PMC
March 2021

Genomic Rearrangement as a Secondary Event in High Grade B-Cell Lymphoma.

Hemasphere 2021 Jan 9;5(1):e505. Epub 2020 Dec 9.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1097/HS9.0000000000000505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732336PMC
January 2021

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.

Blood Adv 2020 11;4(22):5652-5665

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen-Comprehensive Cancer Center, University Hospital Tübingen, Tübingen, Germany.

Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.
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http://dx.doi.org/10.1182/bloodadvances.2020002944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686888PMC
November 2020

A Cyclin D1-Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma.

Clin Cancer Res 2021 01 12;27(1):213-225. Epub 2020 Oct 12.

Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1-mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1-dependent gene expression program and analyze its prognostic value.

Experimental Design: We integrated genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1-dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples ( = 53) and lymphoid tissues ( = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples ( = 81) by NanoString gene expression profiling to validate our findings.

Results: We identified a cyclin D1-dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1-dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1-dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression.

Conclusions: We identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051616PMC
January 2021

The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy.

Mod Pathol 2021 02 14;34(2):336-347. Epub 2020 Sep 14.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Histiocytic sarcoma and tumors with dendritic cell differentiation (HDT) are uncommon neoplasms often with an aggressive clinical course that may occur in association with another hematologic malignancy or mediastinal germ cell tumor (secondary HDT, sHDT). Previous studies have shown mutations in the RAS/MAPK pathway in HDT and have demonstrated a clonal relationship between HDT and associated lymphoid malignancies through common translocations or identical immunoglobulin or T-cell receptor gene rearrangements. We performed whole exome sequencing on 16 cases of sHDT to further evaluate the spectrum of mutations that occur in sHDT in the context of an associated lymphoid malignancy, including cases associated with follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma, B- and T-cell acute lymphoblastic leukemia/lymphoma and peripheral T-cell lymphoma, NOS. In addition, we assessed the clonal relationship between the HDT and the associated lymphoid malignancy in three cases for which matched samples were available. We found mutations in RAS/MAPK pathway genes in 14/16 cases of sHDT associated with diverse mature and precursor B-cell and T-cell neoplasms, involving KRAS (8/16), BRAF (2/16), NRAS (2/16), MAP2K1 (1/16), and NF1 (1/16). In addition, we note that FL-associated sHDT frequently shares a similar mutational profile to the associated malignancy, identifying mutations in CREBBP or KMT2D in all cases and "aberrant" somatic hypermutation in 5/6 cases. Our study confirms the role of the RAS/MAPK pathway in the pathogenesis of sHDT, provides further evidence of a common neoplastic precursor and, in the case of FL, gives additional insight into the stage in lymphomagenesis at which transdifferentiation may occur.
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http://dx.doi.org/10.1038/s41379-020-00673-xDOI Listing
February 2021

Gene Expression Profiling of Mediastinal Gray Zone Lymphoma and Its Relationship to Primary Mediastinal B-cell Lymphoma and Classical Hodgkin Lymphoma.

Blood Cancer Discov 2020 Sep 30;1(2):155-161. Epub 2020 Mar 30.

Lymphoid Malignancies Branch, NCI, Bethesda, Maryland.

Mediastinal gray zone lymphoma (MGZL) has immunopathologic features between classical Hodgkin lymphoma (cHL) and primary mediastinal thymic B-cell lymphoma (PMBL), leading to uncertainty regarding its biological relationship to these entities. We performed gene expression profiling from patients with MGZL (20), cHL (18), and PMBL (17) and show MGZL clusters between cHL and PMBL. Expression signatures reveal germinal B-cell and IFN regulatory factor 4 (IRF4) signatures were relatively low in MGZL and cHL compared with PMBL, indicating downregulation of the B-cell program in MGZL, a hallmark of cHL. T-cell and macrophage signatures were higher in MGZL and cHL compared with PMBL, consistent with infiltrating immune cells, which are found in cHL. The NFκB signature was higher in MGZL than PMBL, and like cHL, MGZL and PMBL express NFκB inducing kinase (NIK), indicating noncanonical signaling. These findings indicate that while MGZL has distinctive clustering, it is biologically closer to cHL.
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478163PMC
September 2020

T-cell and NK-cell neoplasms of the gastrointestinal tract - recurrent themes, but clinical and biological distinctions exist.

Authors:
Elaine S Jaffe

Haematologica 2020 07;105(7):1760-1762

Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.3324/haematol.2020.252924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327655PMC
July 2020

CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma.

Blood Cancer J 2020 06 17;10(6):69. Epub 2020 Jun 17.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.
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http://dx.doi.org/10.1038/s41408-020-0335-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299932PMC
June 2020

Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder.

Am J Surg Pathol 2020 10;44(10):1340-1352

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.
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http://dx.doi.org/10.1097/PAS.0000000000001514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492423PMC
October 2020

Reply to M. Romero et al.

J Clin Oncol 2020 08 17;38(24):2819-2820. Epub 2020 Jun 17.

Elaine S. Jaffe, MD, Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Andrew L. Feldman, MD, Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN; Philippe Gaulard, MD, PhD, Departement de Pathologie, Hôpital Henri Mondor, Inserm U955, Université Paris-Est, Créteil, France; Roberto N. Miranda, MD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX; and Aliyah R. Sohani, MD, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.20.00931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430216PMC
August 2020

Lymphoma Classification.

Cancer J 2020 May/Jun;26(3):176-185

Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Twenty-five years after the Revised European American Classification of Lymphoid Neoplasms classification was published, its principle of an integrative approach to disease definition based on several parameters still prevails and has been adopted and expanded in the following World Health Organization classifications of tumors of the hematopoietic organs. The latest World Health Organization classification revised in 2017 comprises more than 80 entities of mature lymphoid neoplasms (B-cell, T-cell, and Hodgkin lymphomas), which are defined according to their morphology, immunophenotype, genetic lesions and molecular profiles, clinical features, and cellular derivation. The classification also recognizes both incipient and indolent lymphoid neoplasms with a low potential of progression. In this review, we highlight some of the new data and recent modifications introduced in the 2017 classification.
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http://dx.doi.org/10.1097/PPO.0000000000000451DOI Listing
May 2021

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

J Clin Oncol 2020 08 26;38(22):2519-2529. Epub 2020 May 26.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.

Purpose: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.

Methods: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).

Results: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.

Conclusion: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
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http://dx.doi.org/10.1200/JCO.20.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392744PMC
August 2020

Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder.

Blood 2020 04;135(16):1344-1352

Lymphoid Malignancies Branch, Center for Cancer Research and.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment. In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune modulation and combination immunochemotherapy, are discussed.
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http://dx.doi.org/10.1182/blood.2019000933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162687PMC
April 2020

Best Practices Guideline for the Pathologic Diagnosis of Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

J Clin Oncol 2020 04 11;38(10):1102-1111. Epub 2020 Feb 11.

Office of Surgical and Infection Control Devices, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD.

Purpose: To provide guidelines for the accurate pathologic diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), the preoperative evaluation of the patient with suspected BIA-ALCL, and the pathologic evaluation of the capsulectomy specimen.

Methods: To better inform patients and healthcare providers about BIA-ALCL, we convened to review diagnostic procedures used in the evaluation of patients with suspected BIA-ALCL. We focused on the processing of the seroma fluid/effusion surrounding the implant, the handling of capsulectomy specimens following removal of implant(s), and the preoperative evaluation of the patient with suspected BIA-ALCL. Recommendations were based on the published literature and our experience to optimize procedures to obtain an accurate diagnosis and assess for tumor invasion and the extent of the disease.

Recommendations: Early diagnosis of BIA-ALCL is important as the disease can progress and deaths have been reported. Because the most common presentation of BIA-ALCL is swelling of the breast with fluid collection, an accurate diagnosis requires cytologic evaluation of the effusion fluid surrounding the affected implant. The first priority is cytocentrifugation and filtration of fresh, unfixed effusion fluid to produce air-dried smears that are stained with Wright-Giemsa or other Romanowsky-type stains. Preparation of a cell block is desirable to allow for hematoxylin and eosin staining and immunohistochemical analysis of formalin-fixed, paraffin-embedded histologic sections. Cell block sections can be used for polymerase chain reaction-based investigation of T-cell receptor gene rearrangement to detect clonality. Fixation and mapping of the capsulectomy specimen to select multiple representative sections are advised to assess for microscopic tumor involvement and capsular invasion. It is appropriate to assess lymph node involvement by excisional biopsy material rather than fine needle aspiration, due to propensity for focal involvement.
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http://dx.doi.org/10.1200/JCO.19.02778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106983PMC
April 2020

Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting.

Leuk Lymphoma 2020 04 13;61(4):808-819. Epub 2019 Dec 13.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV.
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http://dx.doi.org/10.1080/10428194.2019.1699080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189159PMC
April 2020

Diagnostic utility of STAT6 expression in classical Hodgkin lymphoma and related entities.

Mod Pathol 2020 05 10;33(5):834-845. Epub 2019 Dec 10.

Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6 although no underlying STAT6 mutations were observed in either sample examined. STAT6 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.
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http://dx.doi.org/10.1038/s41379-019-0428-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191386PMC
May 2020

Expansion of PD1-positive T Cells in Nodal Marginal Zone Lymphoma: A Potential Diagnostic Pitfall.

Am J Surg Pathol 2020 05;44(5):657-664

National Institutes of Health, Bethesda, MD.

The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.
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http://dx.doi.org/10.1097/PAS.0000000000001414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189156PMC
May 2020

Distinct molecular profile of IRF4-rearranged large B-cell lymphoma.

Blood 2020 01;135(4):274-286

Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.
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http://dx.doi.org/10.1182/blood.2019002699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978155PMC
January 2020

18F-FDG PET Imaging Features of Patients With Autoimmune Lymphoproliferative Syndrome.

Clin Nucl Med 2019 Dec;44(12):949-955

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases.

Introduction: Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory condition, usually presenting in childhood with massive lymphadenopathy, splenomegaly, and an increased incidence of lymphoma. Methods to differentiate between benign ALPS adenopathy and lymphoma are needed. To this end, we evaluated the usefulness of FDG PET.

Methods: We prospectively evaluated 76 ALPS/ALPS-like patients including FS-7-associated surface antigen (FAS) germline mutation with (n = 4) and without lymphoma (n = 50), FAS-somatic (n = 6), ALPS-unknown (n = 6), and others (n = 10) who underwent FDG PET. Uptakes in 14 nodal sites, liver, and spleen were determined.

Results: In 76 ALPS patients, FDG PET showed uptake in multiple nodal sites in all but 1 patient. The highest SUVmax values in FAS mutation without lymphoma, FAS mutation with lymphoma, FAS somatic, ALPS-unknown, and other genetic mutations were a median (range) 9.2 (4.3-25), 16.2 (10.7-37.2), 7.6 (4.6-18.1), 11.5 (4.8-17.2), and 5.5 (0-15.3), respectively. Differences between uptake in the FAS group with and without lymphoma were statistically significant, but overlapped, making discrimination between individuals with/without lymphoma impossible. The spleen:liver uptake ratio was greater than 1 in 82% of patients.

Conclusions: While statistically significant differences were observed in FAS mutation ALPS with and without lymphoma, the significant overlap in FDG uptake and visual appearance in many patients prevents discrimination between patients with and without lymphoma. Similar patterns of FDG biodistribution were noted between the various ALPS subgroups.
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http://dx.doi.org/10.1097/RLU.0000000000002816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189160PMC
December 2019

Novel markers in pediatric-type follicular lymphoma.

Virchows Arch 2019 Dec 4;475(6):771-779. Epub 2019 Nov 4.

Department of Pathology, University College London, London, UK.

The aim of this study was to review the histopathological, phenotypic, and molecular characteristics of pediatric-type follicular lymphoma (PTFL) and to assess the diagnostic value of novel immunohistochemical markers in distinguishing PTFL from follicular hyperplasia (FH). A total of 13 nodal PTFLs were investigated using immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR and were compared with a further 20 reactive lymph nodes showing FH. Morphologically, PTFL cases exhibited a follicular growth pattern with irregular lymphoid follicles in which the germinal centers were composed of numerous blastoid cells showing a starry-sky appearance. Immunohistochemistry highlighted preserved CD10 (13/13) and BCL6 (13/13) staining, CD20 (13/13) positivity, a K light chain predominance (7/13), and partial BCL2 expression in 6/13 cases (using antibodies 124, E17, and SP66). The germinal center (GC)-associated markers stathmin and LLT-1 were positive in most of the cases (12/13 and 12/13, respectively). Interestingly, FOXP-1 was uniformly positive in PTFL (12/13 cases) in contrast to reactive GCs in FH, where only a few isolated positive cells were observed. FISH revealed no evidence of BCL2, BCL6, or MYC rearrangements in the examined cases. By PCR, clonal immunoglobulin gene rearrangements were detected in 100% of the tested PTFL cases. Our study confirmed the unique morphological and immunophenotypic features of PTFL and suggests that FOXP-1 can represent a novel useful diagnostic marker in the differential diagnosis between PTFL and FH.
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http://dx.doi.org/10.1007/s00428-019-02681-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881426PMC
December 2019
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