Prognostic significance of B-cell differentiation genes encoding proteins in diffuse large B-cell lymphoma and follicular lymphoma grade 3

Aim

To define prognostic significance of B-cell differentiation genes encoding proteins and BCL2 and BCL6 gene abnormalities in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern.

Methods

In 53 patients with diffuse large B-cell lymphoma and 20 patients with follicular lymphoma grade 3 with >75% follicular growth pattern the following was performed: 1) determination of protein expression of BCL6, CD10, MUM1/IRF4, CD138, and BCL2 by immunohistochemistry; 2) subclassification into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) groups according to the results of protein expression; 3) detection of t(14;18)(q32;q21)/IgH-BCL2 and BCL6 abnormalities by fluorescent in situ hybridization in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern as well as in GCB and ABC groups; and 4) assessment of the influence of the analyzed characteristics and clinical prognostic factors on overall survival.

Results

Isolated BCL6 expression was more frequently found in follicular lymphoma grade 3 with >75% follicular growth pattern than in diffuse large B-cell lymphoma (P = 0.030). There were no differences in BCL2 and BCL6 gene abnormalities between diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern. Diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients were equally distributed in GCB and ABC groups. t(14;18)(q32;q21) was more frequently recorded in GCB group, and t(14;18)(q32;q21) with BCL2 additional signals or only BCL2 and IgH additional signals in ABC group (P = 0.004). The GCB and ABC groups showed no difference in BCL6 gene abnormalities. There was no overall survival difference between the patients with diffuse large B-cell lymphoma or follicular lymphoma grade 3 with >75% follicular growth pattern, however, GCB group had longer overall survival than ABC group (P = 0.047). Multivariate analysis showed that BCL6, CD10, and BCL2 expression, BCL2 and BCL6 abnormalities, and International Prognostic Index were not significantly related to overall survival.

Conclusion

Patients with diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern have very similar characteristics and their prognosis is more influenced by protein expression of B-cell differentiation stage genes than by tumor cells growth pattern, BCL2 and BCL6 abnormalities, and International Prognostic Index.The World Health Organization (WHO) classification defines diffuse large B-cell lymphoma as a specific type of mature B-cell neoplasm (1). However, diffuse large B-cell lymphoma types show clinical, morphological, immunophenotypic, and cytogenetic heterogeneity (2-7). Clinical heterogeneity of diffuse large B-cell lymphoma is a consequence of the expression of B-cell differentiation stage genes. The gene expression analysis has identified three prognostically significant molecular subtypes of diffuse large B-cell lymphoma as follows: germinal center B-cell-like (GCB), activated B-cell-like (ABC), and type 3 diffuse large B-cell lymphoma, which express neither genes of normal GCB-cells nor genes that are normally induced during in vitro activation of peripheral blood B-cells (8-10).Immunohistochemical subclassification of diffuse large B-cell lymphoma showed that GCB and ABC groups greatly differ (11-19). Immunohistochemical GCB and ABC groups are not always considered to be prognostically significant predictors (16-19).Cytogenetic analysis showed t(14;18)(q32;q21)/IgH-BCL2 to be more common in GCB than in ABC (20-24).Follicular lymphoma is the second most common non-Hodgkin B-cell lymphoma (B NHL) (1,25). Follicular lymphoma grade 3, in contrast to indolent follicular lymphoma grade 1 and follicular lymphoma grade 2, is clinically aggressive and has more in common with diffuse large B-cell lymphoma (5).The morphological subtypes of follicular lymphoma grade 3, follicular lymphoma grade 3A, and follicular lymphoma grade 3B show morphological, immunohistochemical, and cytogenetic characteristics of variable clinical importance (1). Clinicopathologic evaluation revealed no differences in survival between follicular lymphoma grade 3A and follicular lymphoma grade 3B patients, yet follicular lymphoma grade 3 cases with a predominant diffuse component (>50%) had a significantly worse survival (25-27).Follicular lymphoma grade 3 is characterized by variable CD10 and BCL2 protein expression and cytogenetic abnormalities, ie, rearrangements of BCL6 gene, BCL2 gene amplification, and less common t(14;18)(q32;q21) (28). Both t(14;18)(q32;q21) and BCL2 protein expression are more common in follicular lymphoma grade 3A, while BCL6 gene rearrangements are more common in follicular lymphoma grade 3B (29-32).Therapy and prognosis of patients with diffuse large B-cell lymphoma and follicular lymphoma are defined according to their morphological characteristics, clinical stage, and clinical prognostic factors included in the International Prognostic Index (IPI) (33,34).The aim of this study was to determine whether follicular lymphoma grade 3 with >75% follicular growth pattern is part of the morphological, immunophenotypic, and cytogenetic spectrum of diffuse large B-cell lymphoma. For that purpose, we determined the following parameters: 1) protein expression of B-cell differentiation stage genes BCL6, CD10, MUM1/IRF4, CD138, and BCL2 expression in patients with diffuse large B-cell lymphoma and lymphoma grade 3; 2) subclassification into GCB and ABC groups according to the results of protein expression profile; 3) t(14;18)(q32;q21)/IgH-BCL2 and abnormalities of BCL6 gene in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern, as well as in GCB and ABC groups; and 4) the influence of protein expression, cytogenetic abnormalities, and clinical prognostic factors of age, sex, Ann Arbor clinical stage, and IPI risk group on overall survival (35,36).     

An update on high grade B-cell lymphoma

The new WHO 2017 revised fourth edition details updates on several large B-cell entities, the most important including separation of cases of large B-cell lymphomas with the so called “double-hit” or “triple-hit” phenotype that harbor rearrangements of MYC in conjunction with rearrangements of BCL2 and/or BCL6. In addition, the knowledge of several EBV-driven B-cell lymphoproliferations has led to the firm establishment of the entity called EBV+ diffuse large B-cell lymphoma, not otherwise specified which can mimic several other Hodgkin-like lymphoproliferations including classical Hodgkin lymphoma and T-cell/histiocyte rich large B-cell lymphoma. Certain other newer provisional entities with unique molecular alterations including Burkitt-like lymphoma with 11q aberration which do not harbor MYC alterations occurring mostly in the paediatric population as well as large B-cell lymphoma with IRF4 rearrangement are also discussed in this review although these may not necessarily exhibit aggressive clinical behavior.     

Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria

The frequency of Epstein-Barr virus (EBV) in anaplastic large cell lymphoma (ALCL) has been controversial. The interpretation of previous studies is complicated by the use of nonuniform EBV detection methods and the inclusion of cases of CD30-positive diffuse large B-cell lymphoma and so-called "ALCL, Hodgkin-like," as defined in the Revised European-American Lymphoma classification scheme. In the current World Health Organization (WHO) classification system, both of these tumors are excluded from the ALCL category. Also, recently developed antibodies (eg, the antibody specific for PAX-5/B-cell-specific activator protein [BSAP]) provide new, sensitive tools for identifying neoplasms of B-cell lineage that can morphologically resemble ALCL. In this study we evaluated 64 cases of ALCL of T- or null-cell lineage, defined according to the WHO classification system, for the presence of EBV. All tumors were negative for B-cell antigens, including PAX-5/BSAP and CD20 or CD79a. The study group included 27 (42%) anaplastic lymphoma kinase (ALK)-positive (18 T-cell and 9 null-cell) and 37 (58%) ALK-negative (30 T-cell and 7 null-cell) tumors analyzed by in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemistry for EBV-latent membrane protein type 1. All 64 cases were negative for EBV. We conclude, based on the current definition of ALCL in the WHO classification, there is no role for EBV in ALCL arising in Western patients. We suggest that published reports of EBV in a small proportion of ALCL cases in Western patients can be explained by the inclusion of tumors no longer considered to be in the current classification of ALCL, such as CD30-positive anaplastic tumors of B-cell origin.     

Nodal T-cell lymphomas with a T-follicular helper cell phenotype

The discovery and characterisation of T-follicular helper (TFH) cells, a distinct functional subset of T-helper cells has led to the recognition that some peripheral T-cell lymphomas (PTCLs) have a TFH cell immunophenotype. Due to the overlap in clinical, morphological, immunophenotypic and genetic characteristics, the revised 4^th edition to the WHO classification recognises one umbrella category of ‘angioimmunoblastic T-cell lymphoma and other nodal TCLs of TFH cell origin’. This review provides a brief overview of TFH cells with special emphasis on function and phenotype and a more detailed discussion of clinical, morphologic, immunophenotypic and genotypic characteristics of AITL, follicular T-cell lymphoma and nodal PTCL with TFH phenotype which constitute nodal TCLs of TFH origin. Secondary B-cell proliferations (often EBV positive) and features that help differentiate reactive lymphoid hyperplasia and other types of lymphoma, including PTCL, NOS and secondary B-cell lymphomas and classic Hodgkin lymphoma, from nodal TCLs with a TFH phenotype are discussed.     

Cutaneous EBV-related lymphoproliferative disorders

This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cell-EBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B-cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBV-DLBCL) of the elderly, has been changed to EBV-DLBCL with ‘not otherwise specified’ as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites.     

Epstein-Barr virus positive anaplastic large cell lymphoma: myth or reality?

The World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissue, 2008 edition, states that anaplastic large cell lymphoma (ALCL) is "consistently negative for Epstein-Barr virus (EBV)". The statement made by the WHO has led to the widespread belief that EBV can have no pathogenic role in ALCL. Herein we report a case of an immunocompetent 35-year-old male who presented with hemophagocytic syndrome secondary to lymphoma for which diagnostic material consisted solely of a bone marrow biopsy. The biopsy demonstrated large anaplastic cells which were uniformly positive for surface CD3, CD30 (strong membranous and Golgi expression), CD45, TIA-1 and Granzyme B but negative for ALK-1. In-situ hybridization was strongly positive for EBER in the large neoplastic cells. The uniformity of CD30 expression and positivity for cytotoxic markers on the anaplastic tumor cells raised the diagnostic possibility of an EBV-associated ALCL, ALK-. Discussion of this case as well as a retrospective review of 64 cases of reported of EBV+ ALCL are presented.     

Overview of lymphoid neoplasms in the fourth edition of the WHO classification

The fourth edition of the "WHO Classification of Tumours of Haematopoietic and Lymphoid tissues" was published in 2008 as an updated version of the third edition published in 2001. In this review, the revised points in the lymphoid neoplasms in the fourth edition were summarized from the viewpoint of doctors and medical technologists in clinical laboratories in hospitals. The diseases are classified based on information about morphology, immunophenotype, genetic features, and clinical features. B lymphoblastic leukemia/lymphoma with 7 recurrent genetic abnormalities is individually classified as a provisional entity. Anaplastic large cell lymphoma is divided into two entities, ALK positive and ALK-negative. The pathogenesis of the former is involved with ALK gene rearrangement with several partner genes. Two borderline categories between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, and between DLBCL and classical Hodgkin lymphoma are newly recognized as a distinct disease entity based on the overlapping morphological and genetic features. In the diagnosis of lymphoid neoplasms, understanding the morphological features is fundamental. On the other hand, the importance of immunohistochemistry and flow cytometry to clarify the immunophenotype, and chromosomal analysis and genetic examination to clarify the genetic features has been raised.     

The World Health Organization classification of malignant lymphoma: incidence and clinical prognosis in HTLV-1-endemic area of Fukuoka

New insights into the pathogenesis of lymphoid malignancies have been gained through novel genetic, molecular and immunological techniques. A new classification system for lymphoid malignancies, known as the new World Health Organization (WHO) classification, has been proposed recently based on these findings. The relative incidence of the subtypes of malignant lymphoma is known to differ according to geographic location. Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukemia virus type 1 (HTLV-1), and the Kyushu islands are an HTLV-1 endemic area. To clarify the relationship between the histological classification and prognosis of lymphoid malignancies, we reclassified previous cases in our department and summarized our previous reports using the WHO classification. Of 933 cases of lymphoid malignancies, 471 (50%) were B-cell lymphoma, 396 (42%) T/natural killer (NK)-cell lymphoma and 41 (4%) Hodgkin lymphoma (HL). Analysis of clinical outcome showed favorable prognosis for HL, intermediate for B-cell lymphoma and poor prognosis for T-cell lymphoma. Among B-cell lymphomas, the commonest type was diffuse large B-cell lymphoma (n = 281; 60%). Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) was diagnosed in 82 cases (17%), follicular lymphoma in 52 (11%) and mantle cell lymphoma in 24 (5%). Other less common lymphomas were Burkitt lymphoma (n = 9; 2%) and lymphoblastic lymphoma (n = 5; 1%). Using overall survival rates, the various B-cell lymphoma types could be divided into three broad groups for prognostic purposes: (i) low-risk group comprising follicular lymphoma and MALT; (ii) intermediate-risk group comprising diffuse large B-cell lymphoma and Burkitt lymphoma; and (iii) high-risk group comprising mantle cell lymphoma and lymphoblastic lymphoma. Among the T/NK-cell lymphomas, the commonest type was ATLL (n = 191; 48%), followed by peripheral T-cell lymphoma, unspecified (n = 83; 21%), angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) (n = 38; 10%), anaplastic large cell lymphoma (ALCL) (n = 22; 6%). Less common types were lymphoblastic lymphoma (n = 17; 4%), nasal and nasal-type NK/T-cell lymphoma (n = 17; 4%), mycosis fungoides (MF) (n = 9; 2%) and other rare types. With respect to clinical prognosis, T/NK-cell lymphomas fell into three groups: (i) relative low-risk group comprising ALCL, AILD, MF and lymphoblastic lymphoma; (ii) relative intermediate-risk group comprising NK/T-cell lymphoma and unspecified lymphoma; and (iii) extremely high-risk group comprising ATLL. Among the lymphoblastic lymphomas, B-cell type and T-cell type lymphomas exhibited different clinical outcomes. We conclude that the histological, phenotypic and genotypic classification of the new WHO system should be beneficial for the clinical approach to these tumors.     

Grauzonenlymphome

Grey zone lymphomas are lymphatic tumors that cannot be assigned to a defined lymphoma entity due to morphological, clinical or genetic reasons. As a defining criterion they present with features of two overlapping entities or features that are intermediate. Such lymphomas may represent a grey zone in the differentiation between indolent and aggressive lymphomas. Often they may show morphological features of one entity but be more related to another entity with respect to the immunophenotype and/or genetic constitution, such as lymphomas in the grey zone between primary mediastinal large B-cell lymphoma and primary nodal diffuse large B-cell lymphoma. The B-cell lymphoma, unclassified, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma has recently been recognized as a provisional category in the updated WHO 2008 classification of malignant lymphomas. This corresponds to a practical lymphoma category that obviously contains several entities with a Burkitt-like appearance and aggressive clinical behavior. Genetically, tumors in this category are frequently characterized by an atypical MYC translocation and complex karyotypic alterations. As yet, no adequate therapy concept exists.     

The spectrum of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma: a description of 10 cases

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, is a diagnostic provisional category in the World Health Organization (WHO) 2008 classification of lymphomas. This category was designed as a measure to accommodate borderline cases that cannot be reliably classified into a single distinct disease entity after all available morphological, immunophenotypical and molecular studies have been performed. Typically, these cases share features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, or include characteristics of both lymphomas. The rarity of such cases poses a tremendous challenge to both pathologists and oncologists because its differential diagnosis has direct implications for management strategies. In this study, we present 10 cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma and have organized the criteria described by the WHO into four patterns along with detailed clinical, morphological and immunophenotypic characterization and outcome data. Our findings show a male preponderance, median age of 37 years and a mediastinal presentation in 80% of cases. All cases expressed at least two markers associated with B-cell lineage and good response to combination chemotherapy currently employed for non-Hodgkin lymphomas.     

Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.     

非霍奇金B细胞淋巴瘤369例病理形态观察--2001年世界卫生组织淋巴组织肿瘤新分类应用体会

目的探讨非霍奇金B细胞淋巴瘤(B—NHL)的病理形态和免疫表型在B—NHL诊断中的价值,评价2001版世界卫生组织(WHO)淋巴瘤分类的可行性。方法依据2001版WHO淋巴瘤分类,应用HE、免疫组织化学(LSAB法)和原位杂交技术对369例B—NHL重新诊断分型。结果369例B—NHL确定了11个类型,未观察到毛细胞白血病和B-前淋巴细胞白血病,其中最常见的3个类型依次是：弥漫大B细胞淋巴瘤(189例,51．2％),黏膜相关淋巴组织结外边缘区细胞淋巴瘤(55例,14．9％),滤泡淋巴瘤(39例,10．6％)。发生于淋巴结者占42．8％(158例),结外为57．2％(211例)。单纯HE形态诊断对比形态结合免疫表型的诊断结果,符合率达80％,免疫组织化学可将B—NHI。的诊断正确率提高近20％。结论病理形态是淋巴瘤诊断的基础,免疫表型在诊断和分型中起重要作用,二者与临床特征结合可使绝大多数淋巴瘤得到明确诊断。2001版WHO淋巴瘤分类具有较强的实用性。     

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n=24) or atypical Burkitt lymphoma with BCL2 expression (n=9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n=23) or more aggressive chemotherapy regimens (n=34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, ≥2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index >2 were associated with worse overall survival (P<0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n=6) or MYC rearrangement with extra BCL2 signals (n=2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.     

Differential diagnosis of aggressive neoplasms with plasmablastic and late post-follicular differentiation

Plasmablastic lymphoma (PBL) is a clinicopathological entity with a spectrum of epidemiological, clinical, morphological, phenotypic and genetic features. However, plasmablastic features (PB/F) also define other B-cell neoplasms including ALK positive large B-cell lymphoma, primary effusion lymphoma, HHV8 positive diffuse large B-cell lymphoma and plasmablastic myeloma, which, respectively, also have other characteristic clinical, and pathological determinants. In addition, late post follicular B-cell differentiation with partial plasma cell phenotypes can be variably encountered in EBV associated B-cell lymphomas and diffuse large B-cell lymphoma NOS, bringing them within differential diagnosis with the entities characterized by PB/F. While in many instances characteristics other than PB/F are crucial and result in specific diagnosis, there are considerable overlaps rendering on occasion distinction problematic, with significant management implications. Diagnostic difficulties may also emanate from conceptual issues and variable understanding as to what is a plasmablast. In this review we discuss the conceptual and definition aspects and the commonly encountered differential diagnoses surrounding entities with PB/F, providing recommendations for routine practice.     

根据WHO新分类对493例非霍奇金淋巴瘤的临床病理分析

目的探讨非霍奇金淋巴瘤(NHL)的临床病理特点,评价世界卫生组织(WHO)2001淋巴瘤新分类标准的实用性.方法复查1992-2003年500例既往经病理诊断为NHL的病例,观察其形态学、免疫学及临床特点,按WHO新分类标准进行重新定性和分类,对其中156例有随访的病例进行生存率分析.结果 500例中,493例NHL,其中B细胞肿瘤69.0%,T和NK细胞肿瘤29.8%;前六位最常见类型为弥漫大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、非特殊型周围T细胞淋巴瘤(PT-un)、T淋巴母细胞淋巴瘤(T-LBL)、MALT型结外边缘区B细胞淋巴瘤(MALT)及B-小淋巴细胞性淋巴瘤(B-SLL);青少年中最常见为LBL、DLBCL及Burkitt淋巴瘤.在本组病例中,LBL在所有患者尤其是青少年患者中的比例均明显高于国外报道,FL的比例明显高于国内报道.不同类型NHL的生存情况在总体上差异有统计学意义(P<0.001),其中边缘区B细胞淋巴瘤(MZL)与SLL的预后最佳,LBL与PT-un的预后最差,DLBCL与FL介于前两组之间.按WHO推荐的两种方法划分的FL不同级别之间,生存情况差异无统计学意义(P>0.05).结论淋巴瘤WHO2001新分类实用性强、便于掌握,各亚型的形态学、免疫学指标可靠,结合临床能较好应用于淋巴瘤的诊断和预后.但是,建议国内同行对FL的判断及分级标准进一步审定.     

Age‐related EBV‐associated B‐cell lymphoproliferative disorders and other EBV + lymphoproliferative diseases: New insights into immune escape and immunodeficiency through staining with anti‐PD‐L1 antibody clone SP142

Epstein–Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age‐related EBV‐associated B‐cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency‐associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B‐cells often have a Hodgkin/Reed‐Sternberg (HRS)‐like appearance and are shared beyond the diagnostic categories of mature B‐cell neoplasms, mature T‐cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency‐associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD‐L1). Assessing PD‐L1 positivity by staining with the anti‐PD‐L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B‐cells harboring EBV.     

Natural killer cell subsets and natural killer-like T-cell populations in benign and neoplastic B-cell proliferations vary based on clinicopathologic features

Microenvironmental factors play a critical role in B-cell lymphomas. Most studies emphasize the role of lymphoma-infiltrating T-cells and macrophages, with few studies on natural killer cells. Natural killer cells include a less mature (CD56(bright)/CD16-) subset that is more common in lymph nodes and a more mature (CD56(dim)/CD16+) subset that is more numerous in peripheral blood. Therefore, the proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells (CD3+, CD56+, and/or CD16/57+) were determined by flow cytometry in 150 cases of tissue-based B-cell non-Hodgkin lymphoma and 89 nonneoplastic tissue biopsies. Results were correlated with the clinicopathologic findings. A higher percentage of natural killer cells was found in nonneoplastic spleen versus other nonneoplastic tissue (P < .001), in splenic-based B-cell non-Hodgkin lymphoma versus other B-cell non-Hodgkin lymphoma (P < .01), and in stage II to IV diffuse large B-cell lymphoma versus stage I diffuse large B-cell lymphoma (n = 19, P = .02). The more mature natural killer subset was increased in benign spleen (P < .001) and nonsplenic B-cell non-Hodgkin lymphoma (P < .01) versus nonsplenic, nonneoplastic tissue; in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P < .001); and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score (n = 17, P = .04). A higher proportion of natural killer-like T-cells was seen in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P = .001), whereas chronic lymphocytic leukemia/small lymphocytic lymphoma contained fewer natural killer-like T-cells (P < .001). The proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells vary with tissue site, type of B-cell non-Hodgkin lymphoma, and clinical stage in diffuse large B-cell lymphoma and follicular lymphoma. A higher proportion of CD56(dim)/CD16/57+ natural killer cells is found in spleen, in more aggressive B-cell non-Hodgkin lymphoma, and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score. This may be of importance with increasing therapeutic use of immunomodulatory agents.     

Malignant lymphoma of the spleen in Japan: A clinicopathological analysis of 115 cases

Primary splenic lymphoma is rare, but malignant lymphoma often produces a lesion in the spleen as part of systemic disease. The frequency of splenic malignant lymphoma in Japan is unknown. We classified 184 specimens of the spleen according to the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition (2008). Of the 184 specimens, 115 were determined to be lymphoid neoplasm (62.5%). The most common subtype of lymphoid neoplasm was diffuse large B-cell lymphoma (DLBCL) (46 cases), followed by splenic marginal zone lymphoma (SMZL) (28 cases), follicular lymphoma (11 cases), splenic B-cell lymphoma, unclassifiable (SBL-U) (6 cases) and peripheral T-cell lymphoma, not otherwise specified (4 cases). In the SBL-U subtype, 5 of 6 cases were splenic diffuse red pulp small B-cell lymphoma, and one case was the hairy cell leukemia variant. Analysis of clinical features revealed that patients with DLBCL had a higher age, high lactate dehydrogenase and tumor formation in the spleen. On the other hand, it was found that patients with SMZL had splenomegaly but no discrete tumor formation. Most of the patients with SBL-U presented with thrombocytopenia, bone marrow involvement, and advanced stage. Our study revealed the frequency and clinical features of splenic malignant lymphoma in Japan.     

Diagnostik kutaner B-Zell Lymphome

Skin is the second most common site of extranodal lymphoma. The significance of cutaneous B-cell lymphomas has been underestimated due to the lack of monoclonal antibodies and molecular genetics in former years. Cutaneous B-cell lymphomas represent a heterogeneous group of entities which show variation in histology, immunophenotype and in prognosis. The most common entities presenting in skin are follicular lymphomas, marginal zone B-cell lymphomas, and diffuse large B-cell lymphomas. The majority of primary cutaneous B-cell lymphomas have an excellent prognosis. Whereas in B-cell lymphomas with secondary spread to the skin the clinical course is dependent on the prognosis of the primary lymphoma. It is evident that primary cutaneous lymphomas are distinct from nodal lymphomas and not extranodal manifestations of their lymph-node-based counterparts. In the current review the morphologic spectrum of cutaneous B-cell lymphomas comprising primary and secondary cutaneous B-cell lymphomas is discussed according to the WHO classification scheme.