Comparison of Systemic EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases of Childhood Based on Classification Evolution: New Classification, Old Problems.

Systemic Epstein-Barr virus-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases of childhood are a group of lethal diseases mostly affecting children and young adults. The Ohshima Grading System and the 2017 World Health Organization (WHO) classification have been used for classifying this spectrum, but these systems have not been validated externally and compared. Therefore, we examined 36 cases of systemic Epstein-Barr virus-positive T-cell and NK-cell lymphoproliferative diseases of childhood with long-term follow-up, from Southwest China, to systematically summarize the clinicopathologic features and to validate and compare the Ohshima Grading System and the 2017 WHO classification in discrimination ability, predictive accuracy, concordance indices, and explained variation. Clinically, our cohort showed severe manifestations and poor prognoses. Morphologically, the hematopoietic and lymphoid specimens showed proliferation of small-sized to medium-sized bland-looking lymphocytes that might mask disease severity, whereas other extranodal lesions showed a disorganized to obliterated architecture infiltrated by medium-sized to large-sized, subtle to obvious atypical cells, which may mimic extranodal NK/T-cell lymphoma. Immunophenotypically, our cases mainly originate from CD8 αß T cells. Therefore, clinical and pathologic features should be equally considered to avoid missed diagnosis or misdiagnosis. In addition, the 2017 WHO classification shows a flexible grasp of pathologic features, thus classifying some cases (polymorphic and monoclonal cases with fulminant course) more reasonably; thereby, it showed statistically improved results compared with the Ohshima Grading System. However, underestimating the risk of some polyclonal cases and imprecisely discriminating monoclonal cases at diagnosis are common dilemmas in both systems. Therefore, the construction of a comprehensive grading algorithm for improved prognostic value and precise diagnosis requires additional studies.

Update on the classification of T-cell lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms.

Introduction: The classification of lymphomas is based on the postulated normal counterparts of lymphoid neoplasms and currently constitutes over 100 definite or provisional entities. As this number of entities implies, lymphomas show marked pathological, genetic, and clinical heterogeneity. Recent molecular findings have significantly advanced our understanding of lymphomas. Areas covered: The World Health Organization (WHO) classification of lymphoid neoplasms was updated in 2017. The present review summarizes the new findings that have been gained in the areas of mature T-cell neoplasms, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms since the publication of the 2017 WHO classification. Expert opinion: Although formal revisions to the WHO classification are published only periodically, our understanding of the pathologic, genetic, and clinical features of lymphoid neoplasms is constantly evolving, particularly in the age of -omics technologies and targeted therapeutics. Even in the relatively short time since the publication of the 2017 WHO classification, many significant findings have been identified in the entities covered in this review.

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.

Differences in the Epstein-Barr Virus gp350 IgA Antibody Response Are Associated With Increased Risk for Coinfection With a Second Strain of Epstein-Barr Virus.

BACKGROUND: The Epstein-Barr virus (EBV) viral glycoprotein gp350 has been proposed as a candidate antigen for an EBV vaccine. However, the proposed formulations of these vaccines have not taken into account the presence of 2 unique EBV strains (EBV-1 and EBV-2) present in areas of high incidence of the EBV-associated cancer, Burkitt lymphoma. METHODS: In this study, we analyze the kinetics of EBV-1 and EBV-2 infection in an asymptomatic infant cohort from Kisumu, Kenya. We also analyzed the kinetics of the antibody response against 5 EBV antigens, gp350 (IgG and IgA), VCA (IgG), EBNA-1 (IgG), EAd (IgG), and Zta (IgG). RESULTS: We observed a high frequency of coinfection with both EBV types over time, with the only observable defect in the antibody response in infants coinfected being a significantly lower level of anti-gp350 IgA at peak response. Gp350 IgA levels were also significantly lower in coinfected infants 2.5 months postinfection and at the time of coinfection. CONCLUSIONS: These results suggest that anti-gp350 IgA antibodies may be important for sterilizing immunity against secondary infection. These findings have implications for the development of an efficacious EBV vaccine to prevent both EBV-1 and EBV-2 infection in a population at high risk for Burkitt lymphoma.

Epstein-Barr virus and skin

Abstract: Epstein-Barr virus is a DNA virus infecting human beings and could affect 90% of human population. It is crucial to take in account that in Latin America, unlike what happens in developed countries, the exposure to the virus is very early and therefore people have a much longer interaction with the virus. The virus is related to many diseases, mainly the oncological ones, and when the onset is in cutaneous tissue, it can present many clinical variants, as well acute as chronic ones. Among the acute ones are infectious mononucleosis rash and Lipschutz ulcers; the chronic presentations are hypersensivity to mosquito bites, hydroa vacciniforme, hydroa vacciniforme-like lymphoma, its atypical variants and finally nasal and extra-nasal NK/T-cell lymphoma. Although they are not frequent conditions, it is crucial for the dermatologist to know them in order to achieve a correct diagnosis.

Epstein-Barr virus and skin.

Epstein-Barr virus is a DNA virus infecting human beings and could affect 90% of human population. It is crucial to take in account that in Latin America, unlike what happens in developed countries, the exposure to the virus is very early and therefore people have a much longer interaction with the virus. The virus is related to many diseases, mainly the oncological ones, and when the onset is in cutaneous tissue, it can present many clinical variants, as well acute as chronic ones. Among the acute ones are infectious mononucleosis rash and Lipschutz ulcers; the chronic presentations are hypersensivity to mosquito bites, hydroa vacciniforme, hydroa vacciniforme-like lymphoma, its atypical variants and finally nasal and extra-nasal NK/T-cell lymphoma. Although they are not frequent conditions, it is crucial for the dermatologist to know them in order to achieve a correct diagnosis.

Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?

Epstein-Barr virus (EBV)-related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade.

Reexamining post-transplant lymphoproliferative disorders: Newly recognized and enigmatic types.

Post-transplant lymphoproliferative disorders (PTLD) are a known risk for both solid organ transplant and stem cell transplant recipients. Overall transplant recipients have a six fold increase in risk for developing any kind of non-Hodgkin lymphoma and PTLDs occur in up to 10% of SOT recipients. Several new entities have been accepted or renamed in the 2018 update of the WHO classification of tumors of hematopoietic and lymphoid neoplasms, including florid follicular hyperplasia and extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT-lymphoma) (excluding common locations such as stomach and salivary gland). Other more rare types of PTLD have been reclassified including EBV-positive mucocutaneous ulcer, which is now a recognized diagnosis in its own right and should not be considered polymorphous PTLD. In this paper newly recognized PTLD entities and more unusual PTLDs will be examined.

[Atypical profile problem in serological diagnosis of EBV]. / EBV serolojik tanisinda atipik profil sorunu.

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis. Burkitt's lymphoma, nasopharyngeal carcinoma and post-transplant lymphoproliferative diseases are also associated with EBV. Diagnosis is frequently based on detection of specific antibodies. Using three parameters (anti VCA-IgM, anti VCA-IgG and anti EBNA-1 IgG), it is possible to define infection status and diagnose acute or past infection. However, sometimes the detection of atypical serological profiles makes it difficult to interpret these results. This study aims to evaluate the serological profiles of patient sera suspected of EBV infection and to determine atypical profiles. Sera of 2749 patients were analyzed between January 2014 and August 2016, in the Dokuz Eylul University Hospital Central Laboratory and evaluated retrospectively. Serum samples were tested for EBV VCA IgM and EBV VCA IgG antibodies with immunofluorescence test (Euroimmun, Germany), EBNA-1 IgG antibodies with enzyme immunoassay (Euroimmun, Germany). Medical files of the patients with two or more samples and have an atypical profile were reviewed. Patients were grouped as no EBV infection, acute infection, past infection and atypical serologic profile according to three routine laboratory assays (VCA IgG, VCA IgM and EBNA-1 IgG). Out of 2794 subjects 1334 (48.5%) were female and 1415 (51.5%) were male, with mean age 30 (< 1-89 years, median value: 27). The distribution of the results was; 72.5% past infection, 10.9% absence of EBV infection and 5.2% acute infection and 11.4% showed atypical serologic profile. Among the atypical profiles, isolated VCA-IgG positivity was the most frequent pattern detected in 7.9% which is followed by 2.7% of the cases with all three markers positive and 0.8% with isolated EBNA-1 IgG positivity. Off the patients, 72.5% were seropositive for EBV and this result is consistent with the seroprevalence studies previously conducted in Turkey. The rate of atypical profiles was 11.4% which is close to the result (15%) of another study performed in Izmir. Nearly one third of the patients with atypical serological profile had an immune disorder and it was possible to reach a conclusion only among half of the patients during serological follow-up. This study points out that clinical diagnosis and serologic follow-up is important for the interpretation of the atypical profiles.

[Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities]. / Aggressive primär kutane B-Zell-Lymphome und neue EBV-positive Entitäten.

Primary cutaneous large B­cell lymphomas (PCBLT), EBV-positive large B­cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B­cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B­cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R­CHOP, has led to significant improvements in prognosis, especially in diffuse large B­cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy.

Molecular classification of gastric cancer.

INTRODUCTION: Gastric cancer is among the most common cancers worldwide. Despite declining incidences, the prognosis remains dismal in Western countries and is better in Asian countries with national cancer screening programs. Complete endoscopic or surgical resection of the primary tumor with or without lymphadenectomy offers the only chance of cure in the early stage of the disease. Survival of more locally advanced gastric cancers was improved by the introduction of perioperative, adjuvant and palliative chemotherapy. However, the identification and usage of novel predictive and diagnostic targets is urgently needed. Areas covered: Recent comprehensive molecular profiling of gastric cancer proposed four molecular subtypes, i.e. Epstein-Barr virus-associated, microsatellite instable, chromosomal instable and genomically stable carcinomas. The new molecular classification will spur clinical trials exploring novel targeted therapeutics. This review summarizes recent advancements of the molecular classification, and based on that, putative pitfalls for the development of tissue-based companion diagnostics, i.e. prevalence of actionable targets and therapeutic efficacy, tumor heterogeneity and tumor evolution, impact of ethnicity on gastric cancer biology, and standards of care in the East and West. Expert commentary: The overall low prevalence of actionable targets and tumor heterogeneity are the two main obstacles of precision medicine for gastric cancer.

[Cutaneous lymphomas: new entities and rare variants]. / Kutane Lymphome: Neue Entitäten und seltene Varianten.

Primary cutaneous lymphomas are the second most common group of extranodal non-Hodgkin lymphomas. Recently several new variants and entities have been described but have not yet become part of the World Health Organization (WHO) classification. These forms include the granulomatous form of mycosis fungoides, which is associated with a poorer prognosis, as well as indolent CD8+ lymphoproliferations on the head and at acral localizations. Within the group of cutaneous CD30+ lymphoproliferative disorders, new histological types of lymphomatoid papulosis have been identified, such as type D (CD8+ epidermotropic) and type E (angioinvasive) which simulate aggressive lymphomas. Cutaneous peripheral T-cell lymphomas are a prognostically heterogeneous group of cutaneous lymphomas. The cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are very aggressive neoplasms, whereas cutaneous CD4+ small to medium-sized T-cell lymphoma in its solitary or localized form represents an indolent lymphoproliferation: the terminology, histogenesis and differentiation from nodular T-cell pseudolymphoma are still a matter of debate. Among B-cell lymphomas, disorders associated with Epstein-Barr virus (EBV) are discussed focusing on EBV diffuse large B-cell lymphoma of the elderly and EBV-associated mucocutaneous ulcer. This review describes the clinical, histological and immunophenotypic features of new and rare entities and variants of cutaneous lymphomas and highlights the impact of the clinicopathological correlation in the diagnostic process.

EBV associated lymphomas in 2008 WHO classification.

Epstein-Barr virus (EBV) is a ubiquitous γ-herpes virus that asymptomatically infects more than 90% of the world's population. The exact mechanism of EBV in oncogenesis is an area of active debate. However, EBV has been implicated in the pathogenesis of several kinds of lymphomas and lymphoproliferative disorders, including B-, T- and NK-cell derived. Subsequent studies have proven that the EBV gene expression product plays an activating and/or promoting role on lymphomagenesis, and paves the way for novel cellular therapies of EBV-associated lymphomas. This review concentrates on the pathology, morphology, treatment and prognosis of EBV-associated lymphomas in the 2008 WHO classification of tumors of hematopoietic and lymphoma tissues.

Cutaneous EBV-positive γδ T-cell lymphoma vs. extranodal NK/T-cell lymphoma: a case report and literature review.

Primary cutaneous γδ T-cell lymphoma and extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type are two distinct lymphoma entities in the World Health Organization (WHO) classification. We report the case of an aggressive cutaneous lymphoma of γδ T-cell origin showing overlapping features of both lymphomas. A 78-year-old female presented with confluent erythematous plaques with ulcerations over her right thigh. Microscopically, section of the skin showed a diffuse dermal and subcutaneous lymphocytic infiltration with tumor necrosis and angioinvasion. The medium- to large-sized tumor cells expressed CD3, CD8, cytotoxic molecules and T-cell receptor (TCR)-γ but not CD4, CD20, CD30, CD56 or ßF1. In situ hybridization for Epstein-Barr virus-encoded mRNA (EBER) was diffusely positive. Polymerase chain reaction-based clonality assay showed a clonal TCR-γ chain gene rearrangement. The features compatible with γδ T-cell lymphoma include dermal and subcutaneous involvements, cytotoxic phenotype, expression of TCR-γ, as well as an aggressive course. On the other hand, the diffuse EBER positivity, angioinvasion, tumor necrosis and cytotoxic phenotype may also fit in the diagnosis of an ENKTL of T-cell lineage. We review the literature on EBER-positive γδ T-cell lymphoma and discuss the diagnostic dilemma using the current WHO classification system.

Epstein-Barr virus in lymphoproliferative processes: an update for the diagnostic pathologist.

The Epstein-Barr virus is an orally transmitted herpesvirus that is widespread in human populations and exhibits marked B-cell tropism. It is associated with more human neoplasms than any other known virus, and its role in the pathogenesis of such neoplasms has been the subject of intense investigation. This review presents an overview and update of the biology of Epstein-Barr virus and the diagnostic features of lymphoproliferative disorders associated with this intriguing human pathogen.

[Analysis of Epstein-Barr virus BamH I "f" variant in nodal metastasis of nasopharyngeal carcinoma].

OBJECTIVE: To investigate the Epstein-Barr virus (EBV) BamH I "f" variant in primary nasopharyngeal carcinoma (NPC) and its metastases in lymph nodes (LN). METHODS: In situ hybridization was used to detect EBV-encoded small RNA (EBER) expression in 21 paired paraffin-embedded tissue from primary NPC and their lymph node metastases and 22 primary NPC without lymph node metastasis. PCR and restriction fragment length polymorphism (RFLP) assay were used to detect EBV BamH I "f" variant in all cases of NPCs, lymph node metastases and 50 cases of chronic inflammation of nasopharynx from Canton. RESULTS: All cases of NPCs and their lymph node metastases showed EBER expression, indicating a high EBV-positive rate in Cantonese NPC patients. EBV BamH I "f" variant was found in 11 cases (52.4%, 11/21) of primary NPCs with LN metastasis, 12 cases (57.1%, 12/21) of the LN metastases, and 18 cases (81.8%, 18/22) of primary NPCs without LN metastasis. However, of the 50 cases of chronic inflammation of nasopharynx, only one case (2.1%, 1/47) demonstrated BamH I "f" variant. The frequency of BamH I "f" variant in NPC was therefore dramatically higher than that in chronic inflammation of nasopharynx. It is of note that atypical hyperplasia was observed in a few epithelial cells from the case of chronic inflammation of nasopharynx expressing BamH I "f" variant. CONCLUSIONS: The frequency of EBV BamH I "f" variant in NPC is significantly higher than that in chronic inflammation of nasopharynx. It is the first demonstration that the BamH I "f" variant is also present in the LN metastases of NPC. The frequency of BamH I "f" variant in metastatic NPC of the lymph node is almost equal to that of primary NPCs.

[Current problems of hepatitis]. / Aktuelle Probleme der Hepatitis.

New findings have been made in recent years on the various forms of the hepatitis virus in terms of disease course, its etiopathogenetic link with comorbidities and the definition of new forms in Central Europe. Epstein-Barr virus (EBV)- and cytomegalovirus (CMV)-induced hepatitis may occur in the so-called sero-negative group of hepatitis and direct demonstration of the viral genome in paraffin liver tissues is required to confirm the diagnosis. Since diagnosis of autoimmune hepatitis in daily practice may be difficult, a scoring system with simplified criteria has recently been developed.

EBV-associated lymphoproliferative disorders: classification and treatment.

Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt's lymphoma, classic Hodgkin's lymphoma, and lymphomas arising in immunocompromised individuals (post-transplant and HIV-associated lymphoproliferative disorders). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal type natural killer/T-cell lymphoma, and other rare histotypes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation. However, the exact mechanism by which EBV promotes oncogenesis is an area of active debate. The focus of this review is on the pathology, diagnosis, classification, and pathogenesis of EBV-associated lymphomas. Recent advances in EBV cell-based immunotherapy, which is beginning to show promise in the treatment of EBV-related disorders, are discussed.