Take home messages EBV is a ubiquitous virus which establishes latent infection in 5% of the population and remains under tight immunological control of the adaptive immune response. Loss of immune control over EBV can result in EBV associated lymphoproliferations, which comprise a broad spectrum of disease with varying prognosis, ranging from indolent localized lesions to highly aggressive systemic lymphomas. Determination of pathological nature of any EBV positive lymphoproliferation relies on a complete clinico-pathological correlation; A history of congenital, acquired or iatrogenic immunosuppression should be actively sought. Hodgkin-like morphology is frequently seen in EBV positive lymphoproliferations other than classical Hodgkin lymphoma posing a difficult differential diagnosis. Introduction First isolated from endemic Burkitt's lymphoma (BL) in the 1960s, Epstein Barr virus (EBV) is now recognized as the most oncogenic viruses ever described.1,2 Approximately 95% of the population are infected.3 Following acute infection, the virus establishes lifelong latency in the host. Adaptive immune responses maintain control over the virus residing latently in the reservoir of memory B-cells.4 Transformation of lymphoid cells by EBV is primarily driven by two viral genes, LMP1 and EBNA2. However, the precise pattern of viral gene expression varies in accordance with the host immune state, reflected in 3 principal viral latency patterns. Latency III is associated with acute EBV infection in the naïve host and severe immunodeficiency, as unrestricted expression of all 9 latency genes (nuclear: EBNA1, 2, 3A–C; membrane: LMP1, LMP2A, and LMP2B) renders the infected cell highly immunogenic. Latency II is an intermediate program involving expression of most genes except EBNA2. Latency I is characterized by expression of the EBNA1, essential for maintenance and replication of the EBV genome.5▪ The differential expression of LMP1 and EBNA2 by immunohistochemistry can, therefore, be used to determine latency.3,4 EBV virus encoded small RNAs (EBERs) I and II are non-coding RNAs confined to the nucleus and are transcribed across all stages of latency. Thus, is-situ hybridization for EBERs is the most sensitive test for EBV infection in tissue.6 Pathogenesis of EBV associated lymphoproliferative entities is varied. In many instances, this knowledge is of high relevance to the choice of patient management. Some entities arise as a result of predominating oncogenic features of the EBV, but others are more impacted by patients’ inherent susceptibility. Finally, emergence of some EBV associated lymphoproliferations is impacted primarily by the state of the immune system and iatrogenic or other types of immunosuppression, or by particular anatomical settings resulting in “immune sequestration” of affected tissues. While in some lymphoproliferations EBV is positive in 100% of cases, indicating crucial pathogenetic role, others are partly positive pointing to alternative pathogenetic pathways and non-essential role of EBV (Table 1).5▪,7,8▪Table 1: Summary of EBV Associated Lymphoproliferations.The spectrum of EBV associated lymphoproliferations ranges from indolent localized diseases to aggressive systemic malignancies. Likewise, their treatment ranges from conservative measures, modulation of immunosuppression through to aggressive therapies.5▪ Current “state of the art” A number of EBV associated lymphoproliferations have been updated in the WHO 2016 lymphoma classification and new entities have been added.9▪ The features of the most common EBV associated entities, new additions to the classification and those which have undergone significant update are briefly mentioned. The recognition that some lymphoroliferations with seemingly malignant pathology show an indolent clinical course, has led to the inclusion of new diseases such as EBV positive mucocutaneous ulcer (EBVMCU) in the WHO 2016 classification of lymphoid neoplasms as a provisional entity. EBVMCU typically presents as solitary ulceration on the skin or mucous membranes in immunosuppressed individuals. Histologically, the lesions comprise shallow, well demarcated, ulcerations with polymorphous infiltrates of inflammatory cells admixed with Hodgkin/Reed Sternberg (HRS)-like cells.10 New insights have been afforded into long established entities such as EBV+ diffuse large B-cell lymphoma (EBV+DLBCL), which is no longer regarded as a disease exclusively of the elderly as it also affects young patients. It is a highly aggressive lymphoma typically presenting as bulky extranodal disease in patients with no history of immunosuppression. The histological features of EBV+ DLBCL are variable, but typically comprise sheets of variably large EBV+ lymphoid cells. HRS-like cells are sometimes present, mimicking classical Hodgkin lymphoma (cHL).5▪ Other notable developments in EBV associated large B-cell lymphomas include the recognition of DLBCL associated with chronic inflammation (DLBCL-CI) and the fibrin associated DLBCL (FA-DLBCL) in the 2016 WHO classification.9▪ Formerly termed pyothorax associated DLBCL, DLBCL-CI is rare and classically associated with pyothorax following therapeutic pneumothorax for tuberculosis. The recent re-classification reflects the recognition that LPDs with similar pathological features can involve other cavities and anatomically confined spaces with concurrent chronic inflammation. DLBCL-CI is highly aggressive and usually invades local structures with formation of symptomatic tumor masses. Similarly, FA-DLBCL arises in fibrin masses such as blood clots, cysts or in adjacent to prosthetic devices but shows an indolent clinical course with an excellent prognosis. Immune sequestration is common underlying pathogenetic features of CI-DLBCL, DLBCL-FA, and PEL, whereby lymphoid cells are effectively segregated from regulatory immunosurveillance which would normally eliminate transforming malignant cells. Distinguishing these large B-cell lymphomas from each other and conventional DLBCL is imperative as these entities confer widely different prognoses and warrant divergent management approaches.5▪ As the B-cell lymphoproliferations, T/NK cell lymphoproliferations associated with EBV also represent a wide pathological and clinical spectrum. It ranges from clinically mainly indolent chronic active EBV infection (CAEBV) to aggressive lymphomas (Table 1). Most of these entities show striking racial predisposition and geographical prevalence to South America and Asia, believed to be pathogenetically dependent on defective EBV responses.5▪ The classification of post-transplant lymphoproliferative disorders (PTLD) has been updated (Table 1). It represents a heterogeneous spectrum of lymphoproliferations and a setting in which the diagnosis of a “neoplasm”, as defined by genetic clonality, in many instances does not indicate necessity for upfront cancer type therapy. Understanding of pathogenesis of PTLD, and particularly the molecular mechanisms involved, is still evolving. For the EBV positive subtypes, the postulated mechanism is through depletion of EBV specific cytotoxic T-cells through immunosuppression.11 While this sequence has not been well documented, it is speculated that the initially polyclonal and reactive lymphoproliferations evolve into oligoclonal and finally clonal neoplasms.12 The pathogenesis of the increasing numbers of EBV negative PTLDs is more obscure, postulating an EBV “hit and run” scenario or an effect of antigenic overexposure.13,14 A range of other lymphomas may contain EBV positive infiltrates or be occasionally EBV positive. These include chronic lymphocytic leukemia, angioimmunoblastic T-cell lymphoma, and multiple myeloma. The EBV positive components in the former two are often characterized by Hodgkin-like morphology posing challenging differential diagnosis with classical Hodgkin lymphoma. As indicated above, Hodgkin-like morphology is also frequently observed in other EBV associated B-cell lymphoproliferations. Resolution of this important differential diagnosis relies on careful consideration of the clinical context, staging investigations and assessment of the full wealth of the pathological features, including the composition of the background inflammatory infiltrate.5▪ In the clinical workup of EBV associated lymphoproliferation it is imperative that a history of congenital, acquired or iatrogenic immunosuppression is conveyed to the reporting pathologist, a clinical feature often omitted from pathology request forms. As the definitive characterization of many of the EBV associated entities depends on the clinical context, definitive management decisions require careful multidisciplinary consideration. Future perspectives Of interest for potential therapeutic targeting, is the activity of the JAK/STAT pathway recently described in PTLDs.15 In addition, activity of the PD1-PDL1 and/or CTLA4/B7/CD28 axis are increasingly being recognized as important pathways in so-called “host response” lymphomas which include cHL and EBV+ lymphoproliferations/lymphomas, including PTLD but also T/NK cell lymphoma of nasal type.16,17,18▪,19▪ These insights provide new opportunities for checkpoint inhibition therapeutic strategies in future.