Gene Summary

Gene:IGH; immunoglobulin heavy locus
Summary:Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. This region represents the germline organization of the heavy chain locus. The locus includes V (variable), D (diversity), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single D segment with a J segment; this partially rearranged D-J gene is then joined to a V segment. The rearranged V-D-J is then transcribed with the IGHM constant region; this transcript encodes a mu heavy chain. Later in development B cells generate V-D-J-Cmu-Cdelta pre-messenger RNA, which is alternatively spliced to encode either a mu or a delta heavy chain. Mature B cells in the lymph nodes undergo switch recombination, so that the V-D-J gene is brought in proximity to one of the IGHG, IGHA, or IGHE genes and each cell expresses either the gamma, alpha, or epsilon heavy chain. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Due to polymorphism, the numbers of functional V, J, and D genes differ among individuals and some V, D, J, and C segments may be pseudogenes. [provided by RefSeq, Oct 2013]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 11 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (13)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lymphoma, Mantle-Cellt(11;14)(q13;q32) in Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is characterised by a t(11;14)(q13;q32) translocation. This juxtaposes the CCND1 (bcl-1) locus to the immunoglobulin (IgH) gene sequences and leads to deregulation of cyclin D1. See Espinet B, et al, 1999 and Stamatopoulos K, et al, 1999.
View Publications433
Multiple MyelomaIGH and Multiple Myeloma View Publications282
Acute Lymphocytic Leukaemia (ALL)IGH and Acute Lymphocytic Leukaemia View Publications237
Chronic Lymphocytic LeukemiaIGH and Chronic Lymphocytic Leukemia View Publications162
MALT LymphomaIGH and MALT Lymphoma View Publications128
Lymphoma, Mantle-CellIGH and Mantle-Cell Lymphoma
In a GWAS study Bea et al (2013) reported IGHV mutations in 41% (12/29) of MTC cases.
View Publications68
Lymphomat(6;14)(p25,q32) in Lymphomas
This translocation is seen in some B-cell non Hodgkin lymphomas, particular in diffuse large B-cell lymphoma.
View Publications43
Waldenstrom's MacroglobulinemiaIGH and Waldenstrom's Macroglobulinemia View Publications22
-IGH and Splenic Neoplasms View Publications17
Non-Hodgkin Lymphomat(1;14)(q21;q32) and MUC1 Overexpression in NHL
Dyomin et al (2000) and Gilles et al (2000) reported that MUC1 is activated in Non-Hodgkin's lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphomas.
View Publications13
Multiple Myelomat(6;14)(p25;q32) in Myeloma
This translocation juxtaposes the IgH locus to the IRF4 gene resulting in overexpressed of IRF4, which is thought to contribute to tumorigenesis in Myeloma.
View Publications12
-t(11;14)(q23;q32) IGH-DDX6 Translocations in Hematologic Cancers View Publications1
Non-Hodgkin Lymphomat(1;14)(q21;q32) BCL9/IGH

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IGH (cancer-related)

Cicenas J, Tamosaitis L, Kvederaviciute K, et al.
KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma.
Med Oncol. 2017; 34(2):26 [PubMed] Related Publications
Cancers are the group of diseases, which arise because of the uncontrolled behavior of some of the genes in our cells. There are possibilities of gene amplifications, overexpressions, deletions and other anomalies which might lead to the development and spread of cancer. One of the most dangerous ways to the cancers is the mutations of the genes. The mutated genes can start unstoppable proliferation of cells, their uncontrolled motility, protection from apoptosis, the DNA mutation enhancement as well as other anomalies, leading to the cancer. This review focuses on the genes, which are frequently mutated in various cancers and are known to be important in the advance and progression of colorectal cancer and melanoma, namely KRAS, NRAS and BRAF.

Cho BB, Kelting SM, Gru AA, et al.
Cyclin D1 expression and polysomy in lymphocyte-predominant cells of nodular lymphocyte-predominant Hodgkin lymphoma.
Ann Diagn Pathol. 2017; 26:10-15 [PubMed] Related Publications
Cyclin D1 protein expression in lymphocytes is classically associated with mantle cell lymphoma. Although increasingly recognized in other lymphoproliferative disorders, cyclin D1 expression and CCND1 gene abnormalities have not been well studied in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Using a double stain for CD20/cyclin D1, we quantified cyclin D1 expression in 10 cases of NLPHL and correlated those findings with SOX11 expression, CCND1 gene abnormalities, and clinical data. For comparison, we examined 5 cases of T cell-/histiocyte-rich large B-cell lymphoma (THRLBCL). All cases of NLPHL stained for cyclin D1 showed at least rare positivity in lymphocyte-predominant (LP) cells. In 4 cases, at least 20% of LP cells were positive for CD20/cyclin D1. Neither SOX11 expression nor CCND1 gene rearrangement was found in any of the cases, but fluorescence in situ hybridization showed a proportion of the large cells with 3 to 4 copies of nonfused IGH and CCND1 signals or 3 intact CCND1 break-apart signals. Further study with CCND1/CEP11 showed polysomy in 6 of 9 cases with cyclin D1 expression and 5 of 16 NLPHL not examined for cyclin D1. Two of 5 cases of THRLBCL showed rare positive staining for CD20/cyclin D1; 1 case showed polysomy with CCND1/CEP11. Results show that cyclin D1 may be expressed in LP cells without SOX11 expression or CCND1 translocation. Polysomy with increased copies of CCND1 may account for cyclin D1 expression in some cases. Cyclin D1 expression is not useful for distinguishing NLPHL from THRLBCL and has no apparent clinical significance in NLPHL.

Miao Y, Lin P, Wang W, et al.
CCND1-IGH Fusion-Amplification and MYC Copy Number Gain in a Case of Pleomorphic Variant Mantle Cell Lymphoma.
Am J Clin Pathol. 2016; 146(6):747-752 [PubMed] Related Publications
OBJECTIVES: Mantle cell lymphoma (MCL) may present de novo or undergo progression to a clinically aggressive variant, known as a blastoid or pleomorphic variant. We report an unusual case of classic MCL in a 78-year-old man with a typical immunophenotype, including CD5 positivity, who subsequently relapsed with CD5-negative pleomorphic variant MCL.
METHODS: Biopsy specimens were evaluated using Wright-Giemsa-stained or H&E-stained sections, flow cytometry, immunohistochemistry, conventional cytogenetic, next-generation sequencing, and fluorescence in situ hybridization.
RESULTS: The patient continued to be refractory to intensive chemotherapy and radiation therapy. Initial conventional cytogenetic analysis showed a complex karyotype with amplification of the CCND1-IGH fusion gene on the der(14): 44, Y, t(X;2)(p22.3;q21), del(2)(p21), del(6)(p23), add(7)(p22),-9, del(9)(p22), add(11)(q13),-13, add(14)(p11.2), der(14)t(11;14)(q13;q32)hsr(14)(q32), add(18)(q23), add(21)(p11.1),-22,+mar[12]. A repeat biopsy revealed MCL, pleomorphic variant, with loss of CD5 expression and extra copies of the MYC CONCLUSIONS: CCND1-IGH fusion-amplification with MYC copy number gain is extremely rare and may play a role in disease progression in a subset of MCL cases.

Besbes S, Hamadou WS, Boulland ML, et al.
Combined IKZF1 and IG markers as new tools for diagnosis and minimal residual disease assessment in Tunisian B-ALL.
Bull Cancer. 2016; 103(10):822-828 [PubMed] Related Publications
INTRODUCTION: The monitoring of minimal residual disease (MRD) approach in patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) allows an early detection of residual clones inducing relapses and therefore appropriate therapy strategy. The molecular markers may identify and quantify the residual blasts in B-ALL with normal cytology. In this study, we aimed to use combined IKZF1, IGH and IGK immunoglobulin genes for diagnosis and MRD monitoring in B-ALL sample using MLPA, multiplex PCR and real-time quantitative PCR.
MATERIAL: We showed that multiplex PCR and MLPA are necessary and complementary to detect IKZF1 deletions.
RESULTS: We have identified at the diagnosis clonal IGH rearrangement (VH3-JH5) and IKZF1 deletion (Δ4-7), which we have used it for MRD evaluation after induction chemotherapy. Despite the absence of chromosome abnormality, the patient may be classified in high-risk group with a relapse rate of residual blasts>10(-4) and sensitivity up to 10(-5). This molecular approach enabled the patient's stratification, which was overlooked by classical methods.
CONCLUSION: The combined IKZF1 and immunoglobulin genes will be used as appropriate molecular tools for diagnosis and MRD assessment of B-lineage leukemias and introduced as a routine tests in Tunisian clinical laboratories. They will be useful to stratify patients into risk groups leading to better treatment strategy.

Komatsu K, Sakai T, Kaburaki T, et al.
Atypical presentation of primary intraocular lymphoma.
BMC Ophthalmol. 2016; 16(1):171 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In 2014, Pang et al. reported three cases with vitelliform submaculopathy as a preceding lesion of primary intraocular lymphoma (PIOL). Here, we report a case with an atypical presentation of PIOL who initially presented with vitelliform submaculopathy, vitreous haze and preripheral retinal focus.
CASE PRESENTATION: A 73-year-old female initially visited another hospital with a chief complaint of acute reduced vision in the right eye. Funduscopic examination of the right eye showed a yellowish retinal lesion at the fovea with vitreous haze and retinal foci scattered in the peripheral region. Spectral-domain optic coherence tomography (SD-OCT) revealed a hyperreflective subretinal debris above the retinal pigment epithelium (RPE) at the fovea, suggesting vitelliform submaculopathy. Vitrectomy was performed to improve visualization of the retinal lesions and for examination of PIOL. Vitreous cytology was class III and cytokine analysis of vitreous fluid showed increased IL-10 and an IL-10/IL-6 ratio >1, suggesting PIOL. Thereafter, there was a sub-RPE infiltration of presumed lymphoma in the nasal retina, and PCR analysis of anterior chamber fluid indicated IgH gene rearrangement, leading to diagnosis of PIOL. Three months later, there was complete disappearance of the vitelliform submacular lesion, with resultant disruption and thinning of the outer retinal layers on SD-OCT images.
CONCLUSIONS: Clinicians should be aware of atypical manifestations of PIOL such as vitelliform submaculopathy and peripheral retinal foci with vitreous haze. The patient's unusual funduscopic changes are findings that have not reported in patients with PIOL.

Peluso AL, Ieni A, Mignogna C, Zeppa P
Lymph Node Fine-Needle Cytology: Beyond Flow Cytometry.
Acta Cytol. 2016; 60(4):372-384 [PubMed] Related Publications
Lymph node (LN) fine-needle cytology (FNC) coupled with flow cytometry immunophenotyping provides relevant information for the diagnosis of non-Hodgkin lymphoma (NHL). Numerous studies have shown FNC samples to be suitable for different molecular procedures; in this review, some of the molecular procedures most commonly employed for NHL are briefly described and evaluated in this perspective. Fluorescence in situ hybridization and chromogenic in situ hybridization are briefly described. Polymerase chain reaction (PCR)-based assays are used to identify and quantify mutations and translocations, namely immunoglobulin (IGH) and T-cell receptor rearrangements by clonality testing and IGVH somatic hypermutations either by Sanger sequencing, single-strand conformational polymorphisms or RT-PCR strategies. High-throughput technologies (HTT) encompass numerous and different diagnostic tools that share the capacity of multiple molecular investigation and sample processing in a fast and reproducible manner. HTT includes gene expression profiling, comparative genomic hybridization, single-nucleotide polymorphism arrays and next-generation sequencing technologies. A brief description of these tools and their potential application to LN FNC is reported. The challenge for FNC will be to achieve new knowledge and apply new technologies to FNC, exploiting its own basic qualities.

Villegas Gracia R, Franco Alzate C, Rendón Henao J, et al.
Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia.
Colomb Med (Cali). 2016; 47(2):81-6 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x10(9)/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined.
METHODS: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed.
RESULTS: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x10(9)/L and a B lymphocyte count of 0.124x10(9)/L; from these, 0.04x10(9)/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found.
CONCLUSION: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population.

Brégnard C, Guerra J, Déjardin S, et al.
Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.
EBioMedicine. 2016; 8:184-94 [PubMed] Free Access to Full Article Related Publications
Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis.

Liu YF, Wang BY, Zhang WN, et al.
Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.
EBioMedicine. 2016; 8:173-83 [PubMed] Free Access to Full Article Related Publications
Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

Testo N, Olson LC, Subramaniyam S, et al.
Primary Cutaneous Diffuse Large B-Cell Lymphoma With a MYC-IGH Rearrangement and Gain of BCL2: Expanding the Spectrum of MYC/BCL2 Double-Hit Lymphomas.
Am J Dermatopathol. 2016; 38(10):769-74 [PubMed] Related Publications
Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

Sirivisoot S, Techangamsuwan S, Tangkawattana S, Rungsipipat A
Application of Immunophenotyping and Heteroduplex Polymerase Chain Reaction (hPARR) for Diagnosis of Canine Lymphomas.
Asian Pac J Cancer Prev. 2016; 17(6):2909-16 [PubMed] Related Publications
BACKGROUND: Canine malignant lymphoma is classified into B- or T-cell origin, as in the human case. Due to differences in prognosis, a suitable method needs to be developed for lineage identification.
AIMS: To determine the accuracy of immunophenotypic and molecular information between three methods: immunocytochemistry (ICC), immunohistochemistry (IHC) and heteroduplex polymerase chain reaction for antigen receptor rearrangements (hPARR) in spontaneous canine lymphomas.
MATERIALS AND METHODS: Peripheral blood, fine needle aspiration and tissue biopsies from enlarged peripheral lymph nodes prior to treatment of 28 multicentric lymphoma patients were collected. Cytopathology and histopathology were examined and classified using the updated Kiel and WHO classifications, respectively. Anti-Pax5 and anti-CD3 antibodies as B- and T-cell markers were applied for immunophenotyping by ICC and IHC. Neoplastic lymphocytes from lymph node and white blood cell pellets from peripheral blood were evaluated by hPARR.
RESULTS: In this study, low grade B-cell lymphoma accounted for 25% (7/28), high grade B-cell lymphoma for 64.3% (18/28) and high grade T-cell lymphoma for 10.7% (3/28). According to the WHO classification, 50% of all cases were classified as diffuse large B-cell lymphoma. In addition, ICC showed concordant results with IHC; all B-cell lymphomas showed Pax5+/CD3, and all T-cell lymphomas exhibited Pax5-/CD3+. In contrast to hPARR, 12 B-cell lymphomas featured the IgH gene; seven presented the TCRγ gene; five cases showed both IgH and TCRγ genes, and one case were indeterminate. Three T-cell lymphomas showed the TCRγ gene. The percentage agreement between hPARR and ICC/IHC was 60%.
CONCLUSIONS: Immunophenotyping should not rely on a single method. ICC or IHC with hPARR should be used concurrently for immunophenotypic diagnosis in canine lymphomas.

Kiaei A, Onsori H, Alijani A, et al.
Detection of t(8;14) c-myc/IgH gene rearrangement by long-distance polymerase chain reaction in patients with diffuse large B-cell lymphoma.
Hematol Oncol Stem Cell Ther. 2016; 9(4):141-146 [PubMed] Related Publications
OBJECTIVE/BACKGROUND: Specific chromosomal translocations are found in human leukemias and lymphomas. These translocations are closely related to particular histological and immunological phenotypes. In Burkitt's lymphoma, translocation t(8;14)(q24;q32), which involves the c-myc gene (8q24) and the immunoglobulin heavy-chain (IgH) locus (14q32), accounts for 90-95% of all chromosomal translocations. This translocation can be found in 2-5% of diffuse large B-cell lymphoma (DLBCL). Long-distance polymerase chain reaction (LD-PCR) assays, which can identify oncogene/Ig gene rearrangement, can detect these fusion genes. The objective of this study was to detect t(8;14) c-myc/IgH gene rearrangement by LD-PCR in patients with DLBCL.
METHODS: In this study, 54 DLBCL cases were tested by LD-PCR with specific primers. LD-PCR was used for two breakpoints in both the IgH gene (joining region and γ switch region) and the myc gene (Exons 2 and 3).
RESULTS: As much as 1.85% of the samples were positive for the γ constant region and Exon 2 of the myc gene.
CONCLUSION: LD-PCR can be used for the detection of t(8;14) c-myc/IgH gene rearrangement in patients with DLBCL.

Brown JR, Hallek MJ, Pagel JM
Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination?
Am Soc Clin Oncol Educ Book. 2016; 35:e387-98 [PubMed] Related Publications
During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.

Hall JM, Meyers N, Andrews J
Hemophagocytosis-Related (Asian Variant) Intravascular Large B-Cell Lymphoma in a Hispanic Patient:  A Case Report Highlighting a Micronodular Pattern in the Spleen.
Am J Clin Pathol. 2016; 145(5):727-35 [PubMed] Related Publications
OBJECTIVES: We report a case of hemophagocytosis-related (Asian variant) intravascular large B-cell lymphoma (IVLBCL) in a patient of Western origin initially diagnosed by splenectomy with diffuse large B-cell lymphoma (DLBCL) with a micronodular pattern. The clonal relationship between these two DLBCL subtypes is also investigated.
METHODS: Hemophagocytosis-related (Asian variant) IVLBCL was identified at autopsy in a 62-year-old Hispanic woman, in North America, following an antemortem diagnosis of massive splenic involvement by DLBCL with a micronodular pattern, a feature not expected of IVLBCL.
RESULTS: These two apparently distinct lymphoma types demonstrated similar immunophenotypic profiles and IgH gene rearrangements of identical size suggesting a clonal relationship. The 2008 WHO classification system describes IVLBCL in the spleen as having a sinusoidal pattern.
CONCLUSIONS: Our observations provide the first molecular genetic support for a seemingly underrecognized micronodular pattern of IVLBCL in the spleen and further support the proposal of a "mixed variant" of IVLBCL with concomitant "intravascular" and "solid" phases of disease.

Roepman P, Boots CM, Scheidel KC, et al.
Molecular clonality assessment shows high performance to predict malignant B-cell non-Hodgkin's lymphoma using cytological smears.
J Clin Pathol. 2016; 69(12):1109-1115 [PubMed] Related Publications
AIMS: Molecular PCR-based clonality analysis is helpful for identification of monoclonal B-cell or T-cell populations and to distinguish malignant lymphoma from reactive lymphoid hyperplasia. Typically, clonality assessment on fine-needle aspiration cytology (FNAC) requires freshly obtained aspirates, but the collection and processing of these samples are often challenging in daily practice. In this study, we assessed the routine diagnostic value of the EuroClonality/BIOMED-2 assay for B-cell clonality on air-dried archived Giemsa-stained smears.
METHODS: This study comprised a retrospective analysis of a consecutive diagnostic cohort of 192 FNAC samples from 184 patients with at least 2-year follow-up. The results from the clonality assay were integrated with cytomorphological assessment and evaluated for their accuracy in detecting malignant disease. EuroClonality expert re-evaluation was performed for all cases with ambiguous results and for cases in which the diagnosis did not match the follow-up data.
RESULTS: The clonality assay showed a high accuracy of 93% for detection of malignancy, with a sensitivity of 93% and a specificity of 92%. All 64 cases with monoclonal Ig heavy chain (IGH)/Ig kappa chain (IGK) rearrangements were confirmed malignant by histology or clinical follow-up. Expert re-evaluation changed the definite diagnosis for five cases (3%), mainly because of low signals or no proper duplicate results. We discuss and elucidate all cases for which the clonality results did not match the disease follow-up.
CONCLUSIONS: This study showed that EuroClonality/BIOMED-2 assay can successfully be performed on cytological Giemsa-stained smears and inclusion in daily practice can assist in better identification of malignant lymphoma.

Parikh SA, Shanafelt TD
Prognostic factors and risk stratification in chronic lymphocytic leukemia.
Semin Oncol. 2016; 43(2):233-40 [PubMed] Related Publications
There is considerable heterogeneity in the clinical outcome of patients with chronic lymphocytic leukemia (CLL). While some patients live for decades without any therapy, others die within years of diagnosis despite multiple treatments. To better counsel newly diagnosed CLL patients about their disease course, the Rai and Binet staging systems were developed four decades ago. A deeper understanding of the biologic and molecular aberrations contributing to the pathogenesis of CLL led to identification of novel prognostic markers such as immunoglobulin heavy-chain variable gene (IGHV) mutation status, leukemia-cell expression of CD38, ZAP-70, and CD49d, and cytogenetic abnormalities detected by fluorescent in situ hybridization (FISH). The advent of next-generation sequencing has provided unprecedented insights into the subclonal architecture of CLL and its impact on disease progression and survival. More recently, integrated prognostic scoring systems that incorporate clinical, biologic and genetic characteristics into a single risk score have been developed and appear to improve the accuracy of prognostication for individual patients. This review summarizes the state-of-the-art prognostic factors and will guide the practicing clinician in their care of patients with CLL.

Antoro EL, Dwianingsih EK, Indrawati, et al.
The Polymerase Chain Reaction in Diagnosis of Small B-Cell Non-Hodgkin Lymphomas.
Asian Pac J Cancer Prev. 2016; 17(2):491-5 [PubMed] Related Publications
BACKGROUND: Small B-cell non-Hodgkins lymphoma (NHL) is difficult to be distinguished from non-neoplastic reactive processes using conventional haematoxylin-eosin (HE) staining due to different interpretations among pathologists with diagnosis based on morphologic features. Ancillary examinations such as immunohistochemical (IHC) staining are essential. However, negative or doubtful results are still sometimes obtained due to unsatisfactory tissue processing or IHC technique. The polymerase chain reaction (PCR) as a molecular diagnostic technique is very sensitive and specific. Clonality detection of heavy chain immunoglobulin (IgH) gene rearrangement has been widely used to establish diagnosis of B-cell NHL.
AIMS: To elaborate interobserver variation in small B-cell NHL diagnosis based on morphologic features only and to confirm sensitivity and specificity of the PCR technique as an ancillary method.
MATERIALS AND METHODS: A toptal of 28 samples of small B cell NHL and suspicious lymphoma were interpreted by 3 pathologists in Sardjito General Hospital based on their morphology only. The reliability of assessment and the coefficient of interobserver agreement were calculated by Fleiss kappa statistics. Interpretation results were confirmed with IHC staining (CD20, CD3, Bcl2). PCR was performed to analyze the clonality of IgH gene rearrangement.
RESULTS: Interobserver agreement in morphologic evalution of small B cell NHL and chronic lymphadenitis revealed kappa coefficient 0.69 included in the substantial agreement category. The cases were divided into 3 groups based on morphology and IHC results; lymphoma, reactive process and undetermined group. PCR analysis showed 90% sensitivity and 60% specificity.
CONCLUSIONS: The present study revealed a substantial agreement among pathologists in small B-cell NHL diagnosis. For difficult cases, PCR is useful as complementary method to morphologic and IHC examinations to establish definitive diagnosis.

Rombout A, Lust S, Offner F, et al.
Mimicking the tumour microenvironment of chronic lymphocytic leukaemia in vitro critically depends on the type of B-cell receptor stimulation.
Br J Cancer. 2016; 114(6):704-12 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
BACKGROUND: The B-cell receptor (BCR) has a key role in the cross-talk between chronic lymphocytic leukaemia (CLL) cells and the tissue microenvironment, which favours disease progression by promoting proliferation and drug resistance. In vitro studies on downstream signalling and functional effects of CLL BCR ligation often report contradictory results, in part owing to the lack of a standardised stimulation protocol. Our aim was to define a biologically relevant and robust in vitro stimulation method with regard to cellular phenotypic and transcriptional responses.
METHODS: We evaluated mRNA (FOS, MYC, LPL) and protein (CD54, CD19, CD62L, CD184) expression of genes modulated by BCR triggering in immunoglobulin heavy-chain variable region genes (IGHV)-mutated and -unmutated CLL cells, after stimulation using soluble or immobilised anti-IgM antibodies from different suppliers.
RESULTS: The effect of BCR stimulation on gene and protein expression was comparable in all CLL patients, irrespective of IGHV mutation status. However, immobilised anti-IgM stimulation elicited clear and robust changes in gene and protein expression, whereas the response to soluble anti-IgM was far less obvious.
CONCLUSIONS: These data indicate that the method of BCR stimulation is of major importance regarding responsiveness of CLL cells in the context of the tumour microenvironment, whereas genetic differences in the BCR pathway are less critical.

Tausch E, Mertens D, Stilgenbauer S
Genomic Features: Impact on Pathogenesis and Treatment of Chronic Lymphocytic Leukemia.
Oncol Res Treat. 2016; 39(1-2):34-40 [PubMed] Related Publications
Genomic markers are among the strongest prognostic factors in chronic lymphocytic leukemia (CLL). Chromosomal aberrations, IGHV and TP53 mutation status are well-established and essential to discriminate between a more indolent course of disease and a high-risk CLL, which requires an alternative treatment regimen. In addition, a variety of gene mutations with unclear prognostic value have been identified: SF3B1, ATM, and BIRC3 may describe CLL with adverse outcome, whereas NOTCH1 is predictive for resistance against CD20 antibodies. Integration of novel drivers into a small set of key pathways forms the basis for future pathogenetic and therapeutic implications.

Panero J, Alves-Paiva RM, Roisman A, et al.
Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma.
Am J Hematol. 2016; 91(5):481-5 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.

Van Roosbroeck K, Ferreiro JF, Tousseyn T, et al.
Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies.
Genes Chromosomes Cancer. 2016; 55(5):428-41 [PubMed] Related Publications
The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.

Davis Z, Forconi F, Parker A, et al.
The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.
Br J Haematol. 2016; 173(1):127-36 [PubMed] Related Publications
IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline.

Alsafadi S, Houy A, Battistella A, et al.
Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage.
Nat Commun. 2016; 7:10615 [PubMed] Article available free on PMC after 15/03/2017 Related Publications
Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1(R625/K666) mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss. Modelling the differential junctions in SF3B1(WT) and SF3B1(R625/K666) cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1(WT) knockdown or overexpression do not reproduce the SF3B1(R625/K666) splice pattern, qualifying SF3B1(R625/K666) as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1(R625/K666)-promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

Parikh SA, Strati P, Tsang M, et al.
Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis.
Blood. 2016; 127(14):1752-60 [PubMed] Related Publications
Since the first description of the natural history of chronic lymphocytic leukemia (CLL) by David Galton in 1966, the considerable heterogeneity in the disease course has been well recognized. The Rai and Binet staging systems described ∼40 years ago have proven to be robust prognostic tools. Over the past 2 decades, several novel biological, genetic, and molecular markers have been shown to be useful adjuncts to the Rai and Binet staging systems. In this systematic review, we examined the role of immunoglobulin heavy-chain variable region gene (IGHV) mutation status and genetic abnormalities determined by interphase fluorescence in situ hybridization (FISH) in patients with newly diagnosed CLL. The cumulative evidence presented in this systematic review is sufficient to recommend that FISH and IGHV be performed as standard clinical tests for all patients with newly diagnosed CLL in those countries with the resources to do so. In addition to clinical stage, these parameters could represent the minimal standard initial prognostic evaluation for patients with CLL. This approach will allow the application of powerful, recently developed prognostic indices (all of which are dependent on IGHV and FISH results) to all patients with newly diagnosed CLL.

Krenn PW, Hofbauer SW, Pucher S, et al.
ILK Induction in Lymphoid Organs by a TNFα-NF-κB-Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia.
Cancer Res. 2016; 76(8):2186-96 [PubMed] Related Publications
The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell-cycle progression, but is poorly characterized in hematologic malignancies. In this study, we investigated the role of ILK in the context of CLL and observed high ILK expression in patient samples, particularly in tumor cells harboring prognostic high-risk markers such as unmutated IGHV genes, high Zap70, or CD38 expression, or a signature of recent proliferation. We also found increased numbers of Ki67 (MKI67)-positive cells in regions of enhanced ILK expression in lymph nodes from CLL patients. Using coculture conditions mimicking the proliferative lymph node microenvironment, we detected a parallel induction of ILK and cyclin D1 (CCND1) expression in CLL cells that was dependent on the activation of NF-κB signaling by soluble TNFα. The newly synthesized ILK protein colocalized to centrosomal structures and was required for correct centrosome clustering and mitotic spindle organization. Furthermore, we established a mouse model of CLL in which B-cell-specific genetic ablation of ILK resulted in decelerated leukemia development due to reduced organ infiltration and proliferation of CLL cells. Collectively, our findings describe a TNFα-NF-κB-mediated mechanism by which ILK expression is induced in the lymph node microenvironment and propose that ILK promotes leukemogenesis by enabling CLL cells to cope with centrosomal defects acquired during malignant transformation. Cancer Res; 76(8); 2186-96. ©2016 AACR.

Jiang Y, Nie K, Redmond D, et al.
VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma.
J Vis Exp. 2015; (106):e53215 [PubMed] Related Publications
Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding the clonal composition changes that occur within a tumor in response to certain micro-environment or treatments may lead to the design of more sophisticated and effective approaches to eradicate tumor cells. However, tracking tumor clonal sub-populations has been challenging due to the lack of distinguishable markers. To address this problem, a VDJ-seq protocol was created to trace the clonal evolution patterns of diffuse large B cell lymphoma (DLBCL) relapse by exploiting VDJ recombination and somatic hypermutation (SHM), two unique features of B cell lymphomas. In this protocol, Next-Generation sequencing (NGS) libraries with indexing potential were constructed from amplified rearranged immunoglobulin heavy chain (IgH) VDJ region from pairs of primary diagnosis and relapse DLBCL samples. On average more than half million VDJ sequences per sample were obtained after sequencing, which contain both VDJ rearrangement and SHM information. In addition, customized bioinformatics pipelines were developed to fully utilize sequence information for the characterization of IgH-VDJ repertoire within these samples. Furthermore, the pipeline allows the reconstruction and comparison of the clonal architecture of individual tumors, which enables the examination of the clonal heterogeneity within the diagnosis tumors and deduction of clonal evolution patterns between diagnosis and relapse tumor pairs. When applying this analysis to several diagnosis-relapse pairs, we uncovered key evidence that multiple distinctive tumor evolutionary patterns could lead to DLBCL relapse. Additionally, this approach can be expanded into other clinical aspects, such as identification of minimal residual disease, monitoring relapse progress and treatment response, and investigation of immune repertoires in non-lymphoma contexts.

Markozashvili D, Pichugin A, Barat A, et al.
Histone deacetylase inhibitor abexinostat affects chromatin organization and gene transcription in normal B cells and in mantle cell lymphoma.
Gene. 2016; 580(2):134-43 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a rare lymphoma caused by the t(11:14) juxtaposing the cyclin D1 (CCND1) locus on chromosome 11 and the immunoglobulin heavy chain (IgH) locus on chromosome 14. Several new treatments are proposed for MCL, including histone deacetylase inhibitors (HDACi). We have studied gene expression and chromatin organization in the translocated 11q13 locus in MCL cells as compared to lymphoblastoid cell lines as well as the effect of HDACi abexinostat on chromatin organization and gene expression in the 11q13 locus. We have identified a cluster of genes overexpressed in the translocation region on chromosome 11 in MCL cells. Abexinostat provokes a genome-wide disaggregation of heterochromatin. The genes upregulated after the t(11;14) translocation react to the HDACi treatment by increasing their expression, but their gene promoters do not show significant alterations in H3K9Ac and H3K9me2 levels in abexinostat-treated cells.

Freedman A
Follicular lymphoma: 2015 update on diagnosis and management.
Am J Hematol. 2015; 90(12):1171-8 [PubMed] Related Publications
DISEASE OVERVIEW: Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon.
DIAGNOSIS: Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes.
RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved.
RISK-ADAPTED THERAPY: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease.

Jelic TM, Huang TW, Brenholz P, et al.
Nodal Marginal Zone Large B-Cell Lymphoma with Burkitt Translocation and Complex Chromosomal Changes Associated with Overexpression of BCL2, MYC, and BCL6.
J Clin Exp Hematop. 2015; 55(3):175-80 [PubMed] Related Publications
We report the first case of a nodal marginal zone large B-cell lymphoma and the first with MYC rearrangement. This high proliferation rate lymphoma (40% of cells) occurred in the bilateral cervical, axillary, and para-aortic lymph nodes of an 82 year old woman. It involved extensively her bone marrow, and was lethal. Malignant B-cells were CD10 negative, harbored Burkitt translocation, and multiple chromosomal changes including trisomies of chromosomes 3 and 18, and three copies of 8q with an intact q24 cytoband (in addition to MYC rearrangement), associated with overexpression of BCL6, BCL2, and MYC respectively. We suggest that in aggressive nodular marginal zone lymphomas (clinical picture or high proliferation rate of lymphoma cells), fluorescence in situ hybridization analysis for MYC rearrangement, with break-apart probe, and for MYC/IGH translocation, in addition to chromosome analysis, should be performed. MYC rearrangement associated with a more rapid progression of the neoplasia, might warrant a more aggressive treatment.

Lorenzi L, Lonardi S, Essatari MH, et al.
Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of "germinotropic" lymphoproliferative disorder.
Virchows Arch. 2016; 468(4):441-50 [PubMed] Related Publications
Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals.

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