We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.

EBV-encoded microRNAs (miRNAs) have been identified and their functions are being studied. The expression pattern of these miRNAs in clinical samples of EBV-associated nonHodgkin's lymphomas is unknown. We analyzed five primary ''endemic'' pediatric Burkitt's lymphomas (BL), two acquired immunodeficiency syndrome (AIDS)-related type I latency BL lines, a type III latency line, three EBV + primary effusion lymphomas (PEL), and three AIDS-related diffuse large B-cell lymphomas (DLBCL) for expression of EBV-encoded miRNAs.

The Epstein-Barr virus (EBV) is consistently associated with undifferentiated nasopharyngeal carcinoma (NPC). There is, however, conflicting evidence as to whether squamous cell NPCs are also EBV-associated. Moreover, it has been proposed that other epithelial tumours, particularly thymomas and thymic carcinomas, should be included in the group of EBV-associated neoplasias. However, since the viral DNA in these studies was demonstrated only in extracted DNA, the cellular origin of the viral DNA is uncertain. We have therefore investigated 152 epithelial tumours from various sites for the presence of EBV-DNA by in situ hybridization with 35S-labelled probes. Sixty-eight of 77 undifferentiated NPCs showed an EBV-specific autoradiographic signal, thus confirming the strong association of this tumour type with EBV even in geographical areas where undifferentiated NPC is not endemic. None of eight squamous cell NPCs showed an EBV-specific signal. All of 15 carcinomas with a similar morphology to undifferentiated NPC but from different anatomic sites (thymus, tonsil, breast) were EBV-negative as were 9 thymomas, 26 squamous cell carcinomas of the palatine tonsil, and 14 cervical carcinomas. Our results therefore suggest a unique association of EBV with undifferentiated NPC and support concepts assigning different biological properties to undifferentiated NPC as compared with squamous cell NPC.

Vascular endothelial growth factor (VEGF) is one of the main angiogenic cytokines in human solid tumours and inhibition of VEGF‐induced angiogenesis suppresses tumour growth. Some groups of malignant lymphoma, including peripheral T‐cell lymphomas and Hodgkin's disease, are characterized by a conspicuous proliferation of small vessels. To test the hypothesis that VEGF may also be involved in the angiogenesis in lymphomas and other lesions of the lymphoid system, VEGF expression was analysed in tissues, employing in situ hybridization with a 35S‐labelled RNA probe specific for this cytokine. Significant expression of VEGF transcripts was observed in Hodgkin's disease and peripheral T‐cell lymphomas, particularly of the angioimmunoblastic type. In contrast, expression of this cytokine was minimal or absent in follicle centre lymphoma and chronic lymphocytic leukemia of B‐cell type. VEGF was mainly observed in reactive non‐lymphoid CD68‐negative cells, which probably represent fibroblasts or myofibroblasts. In normal and ulcerated tonsils, VEGF was expressed in the squamous epithelium but only rarely found in the lymphoid tissue. Although infectious mononucleosis tonsils contained high numbers of VEGF‐positive cells in the interfollicular zone, expression of this cytokine was not found in Epstein–Barr virus (EBV)‐infected cells, as determined by simultaneous in situ hybridization for VEGF and EBV‐encoded small nuclear RNAs (EBER). In 5/8 cases of Castleman's disease, germinal centres containing small vessels also showed expression of VEGF, in contrast to normal tonsillar germinal centres which are devoid of both vessels and VEGF transcripts. It is concluded that VEGF may be involved in the induction of the angiogenesis of both peripheral T‐cell lymphomas and Hodgkin's disease, but not in low‐grade B‐cell lymphomas. In contradistinction to solid tumours, in which this cytokine is commonly secreted by the tumour cells themselves, in malignant lymphoma VEGF is not a product of neoplastic cells. Vascularization of germinal centres in Castleman's disease may also be a consequence of abnormal local expression of VEGF. © 1997 by John Wiley & Sons, Ltd.

To further specify the cellular origin and nature of anaplastic large- cell lymphoma (ALCL) and its relationship to other lymphoid neoplasms, particularly Hodgkin's disease (HD), we investigated the presence of cytotoxic molecules in a large well-characterized series of these tumors. For expression of the cytotoxic molecules perforin and granzyme B, in situ hybridization (ISH) and immunohistology were used, respectively. Overall, 23 of 25 ALCLs of T/null phenotype and five (three mixed cellularity and two nodular sclerosis) of 57 HD cases showed the presence of perforin transcripts and/or granzyme B molecules in neoplastic cells. Polymerase chain reaction (PCR) analysis of ALCLs showed that most (10 of 11) cases of null-cell ALCL (null-ALCL) contained a clonal rearrangement of T-cell receptor beta-chain genes, as did T-cell ALCL (T-ALCL; 9 of 10 cases). However, both cytotoxic molecules and clonally rearranged T-cell receptor beta-chain genes were absent in seven of seven and eight of nine cases of B-cell ALCL (B-ALCL), respectively. These data show that all or nearly all T-ALCLs, irrespective of the clinical subform or the lack of T-cell-associated molecules, are derived from activated cytotoxic T cells. The same appears to be true for the neoplastic cells of rare HD cases. These findings indicate that T-ALCLs are different from B-ALCLs and the majority of HD cases, and suggest that some HD cases, especially those with T-cell antigen-positive tumor cells, may be closely related to T- ALCL, at least in terms of cellular origin.

To determine the naturally occurring immunological responses to the Schistosoma mansoni antigens paramyosin, IrV-5, Sm-23 (MAP-3), and triose phosphate isomerase (MAP-4), a total of 119 subjects from an area of endemicity for schistosomiasis, including "resistant" subjects (n ‫؍‬ 17) were evaluated. Specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, and IgA levels for each of the antigens and the cytokine profile in culture supernatants from antigen-stimulated peripheral blood mononuclear cells (PBMC) were determined. Although all the subjects had a high degree of contaminated water exposure, their infection levels were variable (0 to 1,128 eggs/g of stool). There were direct correlations between infection levels and levels of SWAP-and paramyosin-specific IgG1 and IgG4 (P < 0.05). However, an inverse correlation between infection levels and specific IgG2 to IrV-5 (P < 0.01) was observed. The evaluation of the cytokine profile (interleukin 5 [IL-5], IL-10, gamma interferon [IFN-␥], and tumor necrosis factor alpha) in response to these antigens showed inverse correlations between the degree of infection and IFN-␥ levels in PBMC supernatants stimulated with paramyosin (P < 0.05) and IrV-5 (P < 0.01). Additionally, inverse correlations between the degree of infection and IL-5 levels in MAP-3-and MAP-4-stimulated PBMC supernatants (P < 0.01) were found. Logistic regression analysis was performed to adjust the results of cytokine profile by age. IL-5 production in MAP-3-stimulated PBMC supernatants was associated with lower infection levels (odds ratio ‫؍‬ 11.2 [95% confidence interval, 2.7 to 45.8]).Schistosomiasis is a chronic parasitic infection that affects 200 million people in Africa, South America, and Asia (35). Although treatment of infected people with schistosomicidal drugs has in part controlled the morbidity of the disease, transmission is largely unaltered (3,5,24). The possibility of a schistosomiasis vaccine as an additional measure to control the disease arose from the fact that the parasite does not multiply in human beings and that reduction of infection levels by schistosomicidal drugs reduces the prevalence of severe forms of the disease. Moreover, in experimental models, partial immunity can be induced by vaccination with irradiated cercariae or specific antigens (2,11,14,26,36,37,58,59). Immunological studies of subjects from areas of endemicity have demonstrated a naturally occurring resistance to reinfection (4, 19, 22-25, 27, 28). Both high levels of specific immunoglobulin E (IgE) in sera and gamma interferon (IFN-␥) in antigen-stimulated peripheral blood mononuclear cell (PBMC) cultures were associated with resistance to reinfection (1,22,24,25,27,28,56,57). These data suggest the participation of immunological mechanisms in human resistance to Schistosoma mansoni infection, with mixed cellular and humoral responses.Several S. mansoni antigens have been identified and tested in experimental models, with the induction of variable levels of protection against infection (11,32,49,59,61,(68)...

Tumor cells of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) express the viral protein, latent infection membrane protein-1 (LMP1), but evade cytotoxic responses normally directed at this antigen. We tested whether local production of the immunoregulatory interleukins (IL)-4 and -10 may have a role in this process. IL-4 RNA was not detectable in any of the HD cases. By contrast, isotopic in situ hybridization and correlation with the presence of EBV gene products showed significantly higher proportions of cases with IL-10 expressing tumor cells in LMP1-positive (17 of 26, 66%) as compared with LMP1-negative HD cases (six of 37, 16%). Absence of EBV BCRF1 RNA indicated that the transcripts originated from the cellular IL-10 gene. Similarly, an association between IL-10 expression and EBV-infection of tumor cells was found in AIDS-related malignant non-Hodgkin lymphomas (ARL). Very small proportions of EBV-infected cells, mainly blasts, expressed IL-10 in infectious mononucleosis tonsils. Thus, although not entirely exclusive to EBV-positive cases, IL-10 expression is frequently associated with EBV-infection in HD and ARL and appears to be upregulated by EBV, most likely through LMP1. In view of the established inhibitory effects of IL-10 on cell mediated immunity, it is suggested that IL-10 expression may contribute to evasion of LMP1- positive cells from cytotoxicity directed at viral antigens.

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a consistent MYC translocation. Epstein-Barr virus (EBV) has been associated with BL at different frequencies, depending on the clinical variant and geographic regions. This is a large-scale study of BL in Brazil, including 234 patients from 5 geographic regions that are widely disparate socioeconomically, including pediatric (61.1%) and adult (37.6%) populations. EBV was present in 52.6% of all BL cases, varying from 29% (12/42) in the South to 76% (13/17) in the North. Most of the cases were EBV type A. The frequency was higher in the pediatric group, and EBV association within this age range predominated in all regions except the South. Expression of p53 protein was observed in 16.2%, and only rare cases showed p63 expression. BL in Brazil is regionally distinct and has a low incidence of p53 overexpression and a higher-than-expected association with EBV in sporadic cases.