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Rethinking the elusive boundaries of EBV-associated T/NK-cell lymphoproliferative disorders

With great interest we read the article published in Haematologica by Dr. Fernandez-Pol and colleagues entitled “Defining the elusive boundaries of chronic active EpsteinBarr virus infection”. EBV-associated T/NK-cell lymphoproliferative disorders (EBV-T/NK-LPDs) is a spectrum of diseases from infection to malignancy, and all patients suffering these diseases (except infectious mononucleosis (IM)) are in danger. Studying this spectrum from diagnosis to clinical management is extremely urgent. The authors reviewed the recent progress of chronic active EBV infection (CAEBV), in particluar adult onset CAEBV, and discussed other entities of EBV-T/NK-LPDs. They summarized the characteristics of different EBV-T/NKLPDs types and proposed many burning issues that we confront in daily practice: 1) the overlapped histological features and immunophenotype, 2) inconsistent association with hemophagocytic lymphohistiocytosis (HLH), 3) insufficient indicators of malignancy (such as monoclonality), 4) lack of effective markers to predict the biological behavior of the diseases. We highly appreciated this work which inspired us to rethink the elusive boundaries of EBV-T/NK-LPDs; herein, we would like to propose two suggestions regarding the diagnosis of EBV-T/NK-LPDs. Within the current framework of this spectrum, IM is considered a self-limiting disease which occurs most often in children and young adults. Although IM is often regarded as a proliferation of B cells, T/NK-cell IM has also recently been reported. The pathological features of T/NK-cell IM share many similarities with other entities of EBV-positive T/NK-cell lymphoproliferative diseases in biopsy. Especially in the early stage, it is extremely difficult to identify which patients may resolve spontaneously or proceed to chronic stage or recurrent in a short time, even progress rapidly to death. Even many experienced hematopathologists cannot make a precise diagnosis. Besides, EBV-associated HLH (EBV-HLH), which has been proposed as a separate diagnosis, is currently also a challenge for pathologists. The conspicuous morphologic clue is erythrophagocytosis which is not specific and insufficient for diagnosing HLH. Additionally, EBV-HLH is an exclusive diagnosis after ruling out other entities of EBV-T/NK-LPDs accompanied by HLH and familial HLH; nearly all entities in this spectrum could be associated with HLH. It is often the underlying EBV-T/NKLPDs rather than the HLH that confuses the diagnosis. Therefore, how to define EBV-HLH is worthy of consideration. We therefore modified the current framework of the EBV-T/NK-LPDs spectrum, from two aspects (Figure 1). Corresponding to CAEBV, we proposed systemic acute EBV infection (SAEBV) which is defined as non-neoplastic lesions with systemic symptoms of EBV infection within 3 months, including IM and other acute EBV