EBV+ high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a multi-institutional study.

AIMS: It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double- or triple-hit lymphoma (DHL/THL). METHODS AND RESULTS: Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: eight MYC and BCL2 DHL, six MYC and BCL6 DHL and two THL. There were eight men and eight women, with a median age of 65 years (range = 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B cell lymphoma morphology. Using immunohistochemistry, the lymphoma cells were positive for MYC (n = 14 of 16), BCL2 (n = 12 of 16), BCL6 (n = 14 of 16), CD10 (n = 13 of 16) and MUM1 (n = six of 14). Using Hans' algorithm, 13 cases were classified as germinal centre B cell (GCB) and three as non-GCB. The lymphomas frequently showed an EBV latency Type I with a median EBV-encoded small RNAs of 80% positive cells (range = 20-100%). After a median follow-up of 36.3 months (range = 2.0-41.6), seven patients died, with a median survival of 15.4 months (range = 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of six patients with MYC and BCL6 DHL were alive, including four in complete remission. In contrast, only four of 10 patients with MYC and BCL2 DHL or THL were alive, including two in complete remission. The median survival in patients with MYC and BCL6 DHL was unreached and was 21.6 months in patients with MYC and BCL2 DHL or THL. CONCLUSIONS: EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV- counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B cell lymphomas currently recognised in the World Health Organisation classification and suggest differences between EBV+ MYC and BCL2 DHL versus EBV+MYC and BCL6 DHL that may have therapeutic implications.

DNA Methylation-Based Classification of Small B-Cell Lymphomas: A Proof-of-Principle Study.

Although most small B-cell lymphomas (SBCLs) can be diagnosed using routine methods, challenges exist. For example, marginal zone lymphomas (MZLs) can be difficult to rule-in, in large part because no widely-used, sensitive, and specific biomarker is available for the marginal zone cell of origin. In this study, it was hypothesized that DNA methylation array profiling can assist with the classification of SBCLs, including MZLs. Extramedullary SBCLs, including challenging cases, were reviewed internally for pathology consensus and profiled. By combining the resulting array data set with data sets from other groups, a set of 26 informative probes was selected and used to train machine learning models to classify 4 common SBCLs: chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, mantle cell lymphoma, and MZL. Prediction probability cutoff was used to separate classifiable from unclassifiable cases, and show that the trained model was able to classify 95% of independent test cases (n = 264/279). The concordance between model predictions and pathology diagnoses was 99.6% (n = 262/263) among classifiable test cases. One validation reference test case was reclassified based on model prediction. The model was also used to predict the diagnoses of two challenging SBCLs. Although the differential examined and data on difficult cases are limited, these results support accurate methylation-based classification of SBCLs. Furthermore, high specificities of predictions suggest that methylation signatures can be used to rule-in MZLs.

Management of primary cutaneous lymphomas during the COVID-19 pandemic.

Primary cutaneous lymphomas are defined as a heterogenic group of T- and B-cell non-Hodgkin lymphomas that present initially in the skin. Patients with primary cutaneous lymphomas are at a higher risk for developing complications in case of infection with the novel coronavirus severe acute respiratory syndrome coronavirus 2. The coronavirus disease 2019 (COVID-19) pandemic has affected the established diagnostic approach, staging, and therapeutic guidelines in patients with primary cutaneous lymphomas. In the light of the current global health crisis, management of primary cutaneous lymphomas needs to be adjusted. The key to achieving this is to balance the optimal control of the lymphoma, with a minimal increase of the personal risk for COVID-19 exposure and complications.

The bidirectional increased risk of B-cell lymphoma and T-cell lymphoma.

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were <5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.

New developments in non-Hodgkin lymphoid malignancies.

The revised fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2017) reflects significant advances in understanding the biology, genetic basis and behaviour of haematopoietic neoplasms. This review focuses on some of the major changes in B-cell and T-cell non-Hodgkin lymphomas in the 2017 WHO and includes more recent updates. The 2017 WHO saw a shift towards conservatism in the classification of precursor lesions of small B-cell lymphomas such as monoclonal B-cell lymphocytosis, in situ follicular and in situ mantle cell neoplasms. With more widespread use of next generation sequencing (NGS), special entities within follicular lymphoma and mantle cell lymphoma were recognised with recurrent genetic aberrations and unique clinicopathological features. The diagnostic workup of lymphoplasmacytic lymphoma and hairy cell leukaemia has been refined with the discovery of MYD88 L265P and BRAF V600E mutations, respectively, in these entities. Recommendations in the immunohistochemical evaluation of diffuse large B-cell lymphoma include determining cell of origin and expression of MYC and BCL2, so called 'double-expressor' phenotype. EBV-positive large B-cell lymphoma of the elderly has been renamed to recognise its occurrence amongst a wider age group. EBV-positive mucocutaneous ulcer is a newly recognised entity with indolent clinical behaviour that occurs in the setting of immunosuppression. Two lymphomas with recurrent genetic aberrations are newly included provisional entities: Burkitt-like lymphoma with 11q aberration and large B-cell lymphoma with IRF4 rearrangement. Aggressive B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements, so called 'double-hit/triple-hit' lymphomas are now a distinct entity. Much progress has been made in understanding intestinal T-cell lymphomas. Enteropathy-associated T-cell lymphoma, type II, is now known to not be associated with coeliac disease and is hence renamed monomorphic epitheliotropic T-cell lymphoma. An indolent clonal T-cell lymphoproliferative disorder of the GI tract is a newly included provisional entity. Angioimmunoblastic T-cell lymphoma and nodal T-cell lymphomas with T-follicular helper phenotype are included in a single broad category, emphasising their shared genetic and phenotypic features. Anaplastic large cell lymphoma, ALK- is upgraded to a definitive entity with subsets carrying recurrent rearrangements in DUSP22 or TP63. Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.

Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells.

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.

RNA-Based next generation sequencing complements but does not replace fluorescence in situ hybridization studies for the classification of aggressive B-Cell lymphomas.

Aggressive B-cell lymphomas are currently classified based in part upon the presence or absence of translocations involving BCL2, BCL6, and MYC. Most clinical laboratories employ fluorescence in situ hybridization (FISH) analysis for the detection of these rearrangements. The potential role of RNA-based sequencing approaches in the evaluation of malignant lymphoma is currently unclear. In this study, we performed RNA sequencing (RNAseq) in 37 cases of aggressive B-cell lymphomas using a commercially available next generation sequencing assay and compared results to previously performed FISH studies. RNAseq detected 1/7 MYC (14%), 3/8 BCL2 (38%) and 4/8 BCL6 (50%) translocations identified by FISH. RNAseq also detected 1 MYC/IGH fusion in a case not initially tested by FISH due to low MYC protein expression and 2 BCL6 translocations that were not detected by FISH. RNAseq identified the partner gene in each detected rearrangement, including a novel EIF4G1-BCL6 rearrangement. In summary, RNAseq complements FISH for the detection of rearrangements of BCL2, BCL6 and MYC in the evaluation and classification of aggressive B-cell lymphomas by detecting rearrangements that may be cryptic by FISH methods and by identifying the rearrangement partner genes. Detection of these clinically important translocations may be optimized by combined use of FISH and RNAseq.

Histopathological and immunophenotypical characterization of canine multicentric lymphoma in Brazil: a study of 203 cases / Caracterização histopatológica e imunofenotípica do linfoma multicêntrico canino no Brasil: um estudo de 203 casos

The immunophenotype is regarded as an independent prognostic factor in high-grade lymphomas, seeing that lymphomas of T-cell origin are associated with shorter survival time. Although a number of studies have evaluated the immunophenotypical profile of lymphoma in the USA and Europe, Brazilian research on the matter remains scarce. Exact characterization of the histopathological type is crucial to establish proper treatment and prognosis. This study evaluated the database of immunohistochemistry laboratories that perform immunophenotyping of canine lymphoma in Brazil. A total of 203 cases of multicentric lymphoma were classified according to the WHO classification. Immunophenotyping was able to identify 71.4% lymphomas of B-cell line, 27.1% of T-cell line and 1.5% of non-B cells and non-T cell lines. Diffuse large B-cell lymphoma was the most common with 59.1% of the cases. Among T-cell lymphomas, lymphoblastic was the most common (11.33% of the cases). Even though canine lymphomas tend to be high-grade, indolent lymphomas comprised 11.82% of the cases and T-zone lymphoma was the most prevalent (8.86%). The immunophenotype of multicentric lymphoma in Brazil is similar to those in other parts of the world, which suggests similar etiologic factors to the development of this disease.(AU)

O imunofenótipo é considerado um fator prognóstico independente em linfomas de alto grau, visto que os linfomas de origem de células T estão associados a menor tempo de sobrevida. Apesar de vários estudos terem avaliado o perfil imunofenotípico do linfoma nos EUA e na Europa, a pesquisa brasileira sobre o assunto ainda é escassa. A caracterização exata do tipo histopatológico é crucial para estabelecer o tratamento e o prognóstico adequados. Este estudo avaliou a base de dados de laboratórios de imuno-histoquímica que realizam imunofenotipagem do linfoma canino no Brasil. Um total de 203 casos de linfoma multicêntrico foi classificado de acordo com a classificação da OMS. A imunofenotipagem foi capaz de identificar 71,4% dos linfomas da linhagem de células B, 27,1% da linhagem de células T e 1,5% das linhagens de células não B e não T. O linfoma difuso de grandes células B foi o mais comum em 59,1% dos casos. Entre os linfomas de células T, o linfoblástico foi o mais comum (11, 33% dos casos). Embora os linfomas caninos tendam a ser de alto grau, os linfomas indolentes representaram 11,82% dos casos e o linfoma da zona T foi o mais prevalente (8,86%). O imunofenótipo do linfoma multicêntrico no Brasil é semelhante ao de outras partes do mundo, o que sugere fatores etiológicos semelhantes ao desenvolvimento dessa doença.(AU)

Combining gene expression profiling and machine learning to diagnose B-cell non-Hodgkin lymphoma.

Non-Hodgkin B-cell lymphomas (B-NHLs) are a highly heterogeneous group of mature B-cell malignancies. Their classification thus requires skillful evaluation by expert hematopathologists, but the risk of error remains higher in these tumors than in many other areas of pathology. To facilitate diagnosis, we have thus developed a gene expression assay able to discriminate the seven most frequent B-cell NHL categories. This assay relies on the combination of ligation-dependent RT-PCR and next-generation sequencing, and addresses the expression of more than 130 genetic markers. It was designed to retrieve the main gene expression signatures of B-NHL cells and their microenvironment. The classification is handled by a random forest algorithm which we trained and validated on a large cohort of more than 400 annotated cases of different histology. Its clinical relevance was verified through its capacity to prevent important misclassification in low grade lymphomas and to retrieve clinically important characteristics in high grade lymphomas including the cell-of-origin signatures and the MYC and BCL2 expression levels. This accurate pan-B-NHL predictor, which allows a systematic evaluation of numerous diagnostic and prognostic markers, could thus be proposed as a complement to conventional histology to guide the management of patients and facilitate their stratification into clinical trials.

Clinicopathologic features and prognostic analysis of Waldeyer ring B-cell lymphoma.

This retrospective study is to explore the clinicopathologic, immunophenotypic, and molecular genetic features of Waldeyer ring B-cell lymphoma (WR-BCL).Tissue arrays from 65 WR-BCL cases were subjected to pathologic and immunophenotypic detections. Expression of Epstein-Barr virus-encoded small RNA (EBER) was detected by in situ hybridization. Interferon regulatory factor 4 (IRF4), BCL-2, BCL-6, and C-myelocytomatosis viral oncogeneav (MYC) gene abnormalities were investigated using interphase fluorescence in situ hybridization.Among the 65 patients, there were 12 nasopharynx cases, 49 tonsil cases, and 4 tongue root cases. Moreover, there were 49 cases of diffuse large BCL (DLBCL) and 16 cases of follicular lymphoma (FL). More than 60% of the patients had Ann Arbor stage III/IV disease, with infiltrated neighboring organs, invaded spleens, and increased lactate dehydrogenase (LDH) levels. Tumor cells were positive for multiple myeloma antigen 1 (MUM1), BCL-2, BCL-6, and C-MYC. EBER expression was detected in lymphoma cells of 2 cases. Alteration frequencies of IRF4, BCL-2, BCL-6, and C-MYC were 24.6%, 32.3%, 27.7%, and 30.7%, respectively. Approximately 67.69% cases had stages 0 to II disease, while 32.31% cases had stage III disease. Five-year overall survival rate was 65.12%. Eastern Cooperative Oncology Group performance status (ECOG) score ≥2 was the only adverse factor for overall survival. IRF4/MUM1, C-MYC, and CD10 expressions were related to poor disease prognosis. WR-BCLs were largely dependent on ECOG, LDH, and bone marrow involvement. WR-DLBCL was associated with poor survival outcomes compared with WR-FL.The WR-DLBCLs have distinct clinicopathologic features, with correlations between the IRF4/MUM1, C-MYC and CD10 expressions, ECOG, LDH, bone marrow involvement, and the disease prognosis.

Navigating the cutaneous B-cell lymphomas: avoiding the rocky shoals.

In recent years great progress has been made in understanding the classification of lymphomas. The integration of morphologic, clinical, immunophenotypic, and molecular features provides a rational basis for defining disease entities and has led to worldwide consensus. Hematopathologists and dermatopathologists have worked together to define those lymphomas that are present most commonly in the skin. Some cutaneous lymphomas have distinctive features and differ from their nodal counterparts. This is most evident in the delineation of primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma. Both are very indolent, with low risk to spread beyond the skin. Primary cutaneous marginal zone lymphoma shows evidence of immunoglobulin class switching, as distinct from involvement by other extranodal marginal zone lymphomas of MALT type, which may involve the skin secondarily. Some have suggested that primary cutaneous marginal zone lymphoma may be considered a benign clonal expansion, probably driven by antigen. Many cutaneous lymphomas share biological and clinical features with their systemic counterparts. For example, primary cutaneous large B-cell lymphoma, leg type, exhibits a similar gene expression and molecular profile as diffuse large B-cell lymphoma of the activated B-cell type, especially for those cases arising in other extranodal sites. In addition, Epstein-Barr virus plays a role in many cutaneous lesions including mucocutaneous ulcer, plasmablastic lymphoma, and even some cases of marginal zone lymphoma. These EBV-driven conditions may present primarily in the skin, but also involve other mainly extranodal sites. Thus, it is evident that some cutaneous and systemic lymphomas are driven by common pathogenetic mechanisms, necessitating an integrated approach for the classification of lymphoma in all sites.

The clinico-pathological spectrum of primary cutaneous lymphoma other than mycosis fungoides/Sezary syndrome.

The major aim of Session 1 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop was to collect examples of cutaneous lymphomas, excluding mycosis fungoides/Sezary syndrome, as defined in the current WHO classification of tumours of the haemetopoietic and lymphoid tissues. Overall 42 cases were submitted. These were considered in four main categories: primary cutaneous B cell lymphomas (12 cases), primary cutaneous T cell lymphomas/lymphoproliferations with CD8+/cytotoxic phenotype (12 cases), primary cutaneous CD30-positive lymphoproliferative disorders (15 cases) and primary cutaneous T cell lymphomas/leukaemias with CD4+ phenotype (4 cases). Using these cases as examples, we were able to present the full spectrum of cutaneous lymphoproliferations (excluding mycosis fungoides/Sezary syndrome), including examples of rare, provisional and new entities as listed in the 2017 update of the WHO classification. The findings are summarized in this report with emphasis on differential diagnostic considerations and the importance of clinico-pathological correlation for final subtyping. In presenting these findings we hope to raise awareness of this enigmatic group of neoplasms and to further our understanding of these rare disease entities.

Diffuse Large B-Cell Lymphoma and High-Grade B-Cell Lymphoma: Genetic Classification and Its Implications for Prognosis and Treatment.

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is characterized by both clinical and molecular heterogeneity. Despite efforts to tailor therapy for individual patients, treatment remains uniform and a subset of patients have poor outcomes. The past decade has witnessed a dramatic expansion of our understanding of the genomic underpinnings of this disease, especially with the application of next-generation sequencing. In this review, the authors highlight the current genomic landscape of DLBCL and how this information provides a potential molecular framework for precision medicine-based strategies in this disease.

The broad and challenging landscape of extranodal lymphoproliferations.

Two sessions in the workshop of the 19th meeting of the European Association for Haematopathology termed "challenging extranodal lymphoproliferations" and "extranodal non-site-specific lymphoproliferations", dealt with a series of heterogenous cases. These included lymphoproliferations of all cell lineages, from reactive lesions mimicking lymphomas through indolent lymphoid neoplasia and tumours with unclear biological behaviour to aggressive and transformed lymphomas. The themes addressed included cases with borderline features between hyperplastic and neoplastic lesions, the diagnostic spectrum of IgG4-related disease, T cell lymphoproliferations arising in extranodal sites with presumed indolent behaviour, diverse clinical presentations of intravascular large B cell lymphoma, diagnostic problems encountered with tumours displaying plasmablastic morphology, pitfalls concerning rare entities like adult T cell lymphoma/leukaemia (ATLL) and extranodal natural killer/T cell (NK/T) lymphomas, and unusual clinical presentations of various lymphomas. Altogether, within the frame of these two sessions, 75 cases remarkably differing in their clinical background, genetic features and overall need for a meticulous diagnostic approach were presented and discussed. In this paper, the salient points raised during the discussion of the cases, current diagnostic concepts and recommendations relevant to the diagnosis of these lymphoproliferations are described.

A large single-institution retrospective analysis of aggressive B-cell lymphomas according to the 2016/2017 WHO classification.

BACKGROUND: High-grade B-cell lymphomas (HGBLs) comprise a new entity in the revised 2016/2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. The diagnosis of HGBL encompasses histopathology and immunohistochemistry, with additional molecular examination of the BCL2/MYC or BCL6/MYC rearrangement status. OBJECTIVES: The aim of the study was to summarize our experience in the histopathological and immunohistochemical diagnosis of patients with aggressive B-cell lymphomas according to the revised 2016/2017 WHO classifications. MATERIAL AND METHODS: We reviewed our single-institution experience with accurate diagnoses of HGBL and diffuse large B-cell lymphoma (DLBCL) using the available histopathological and immunohistochemical tools. The timeframe was from January 1, 2017 to April 18, 2018. RESULTS: Out of 265 patients, 217 (81.9%) were diagnosed with DLBCL, 43 (16.2%) with HGBL/DLBCL and 5 (1.9%) with not otherwise specified HGBL (HGBL-NOS). Regarding concurrent expression of MYC and BCL2 and/or BCL6 (double expressors (DE) and triple expressors (TE)), more DE and TE cases were found in the HGBL/DLBCL group than in the DLBCL group (25.53% vs 8.47%, p < 0.001, for DE cases and 55.32% vs 6.21%, p < 0.001, for TE cases). All 48 (100.00%) of the HGBL-NOS and HGBL/DLBCL patients, and 26 (11.98%) of the DLBCL-DE/TE cases were recommended for molecular analysis. CONCLUSIONS: Our findings show that a comprehensive histopathological and immunohistochemical examination may identify potential HGBL cases. This study emphasizes the need to introduce a suitable molecular examination for patients with HGBL morphology and/or double/triple expression of BCL2/BCL6/MYC proteins.

EBV-Associated Lymphoproliferative Disorders: Update in Classification.

Although about 90% of the world's population is infected by EBV only a small subset of the related infections result in neoplastic transformation. EBV is a versatile oncogenic agent involved in a multitude of hematopoietic, epithelial, and mesenchymal neoplasms, but the precise role of EBV in the pathogenesis of many of the associated lymphoid/histiocytic proliferations remains hypothetical or not completely understood. Additional studies and use of evolving technologies such as high-throughput next-generation sequencing may help address this knowledge gap and may lead to enhanced diagnostic assessment and the development of potential therapeutic interventions.

Ontogeny, Genetics, Molecular Biology, and Classification of B- and T-Cell Non-Hodgkin Lymphoma.

Mature B- and T-cell lymphomas are diverse in their biology, etiology, genetics, clinical behavior, and response to specific therapies. Here, we review the principles of diagnostic classification for non-Hodgkin lymphomas, summarize the characteristic features of major entities, and place recent biological and molecular findings in the context of principles that are applicable across the spectrum of mature lymphoid cancers.

[B-cell lymphomas].

Among the hematologic tumors, lymphoid malignancies, especially B-cell lymphomas (BLs), are categorized according to the WHO classification into a large number of entities, which are aggregates of clinically and biologically diverse diseases. It is thought that various molecular genetic abnormalities are involved in lymphoid tumorigenesis. Recent advances in genetic analysis technology have resulted in the discovery of many novel and recurrent genetic abnormalities. In particular, those associated with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma have been identified utilizing molecular pathology techniques, which is important aspect for the future development of novel therapeutic drugs and indications for clinical trials. In this section, the possibility of patient-stratification based on genetic abnormalities of DLBCL and FL, which are particularly prevalent among mature BLs, are described. I also introduce the genetic features and clinical importance of BL and MCL identified in a small number of patients in Japan.