Page 22 - Haematologica June

EDITORIALS & PERSPECTIVES
Defining the elusive boundaries of chronic active Epstein-Barr virus infection
Sebastian Fernandez-Pol, Oscar Silva and Yasodha Natkunam
Department of Pathology, Stanford University School of Medicine, CA, USA
E-mail: yaso@stanford.edu doi:10.3324/haematol.2018.193714
The Epstein-Barr virus (EBV) infects more than 90% of people by early adulthood. While childhood EBV infec- tion tends to be asymptomatic, adolescents and young adults often develop infectious mononucleosis (IM). With rare exceptions, IM usually resolves spontaneously. EBV is also implicated in the development of several hematolymphoid malignancies derived from B-, T- and natural killer (NK)-cells, including Burkitt lymphoma, classic Hodgkin lymphoma, extranodal NK-/T-cell lymphoma, nasal type (ENKTL), and immunodeficiency-associated lymphoproliferative disorders (LPD).1-5
Primarily because of their rarity, systemic EBV+ T-cell and NK-cell LPDs are not completely understood. Criteria to sep- arate clinical risk groups at diagnosis are confounded by sev- eral important factors: 1) non-specific histopathological and immunophenotypic features that overlap with infectious and inflammatory conditions as well as with other T- and NK-LPDs; 2) lack of markers to reliably predict clinical behavior that ranges from self-limiting proliferations to those that are rapidly fatal; 3) molecular clonality, although often detected, is not necessarily indicative of malignancy; and 4) inconsistent association with hemophagocytic lym- phohistiocytosis (HLH), whose presence is often life-threat- ening.1-3,6-11 Large, clinically well-annotated cohorts of patients offer a tremendous opportunity to investigate rare subtypes of EBV+ T- and NK-cell proliferations, define diag- nostic and prognostic criteria, and explore disease bound- aries. To that end, the paper by Kawamoto et al. in this issue of Haematologica addresses a rare type of EBV+ T- and NK-cell proliferation in adult patients with chronic active EBV-like features (adult-onset CAEBV).12
Chronic active EBV is characterized by EBV+ T- or NK-cell proliferations and includes systemic as well as cutaneous forms. Systemic CAEBV presents with fever, lym- phadenopathy and splenomegaly, and typically develops in immunocompetent patients following primary EBV infec- tion. The initial phase resembles an IM-like illness. These lymphoid proliferations may be polyclonal, oligoclonal or monoclonal, and have a propensity to evolve into a systemic EBV+ T- or NK-cell lymphoma. CAEBV most often occurs in children and adolescents without a history of immunodefi- ciency or autoimmunity. The clinical course and prognosis of CAEBV is highly variable: while some patients exhibit a pro- tracted disease course, others experience a fulminant form of the disease accompanied by HLH.1-3,8-10
Chronic active EBV of T- and NK-cell types have a strong ethnic predisposition, and are most frequent in East Asia and in indigenous populations of Central and South America.1,6-11 It is rare in Western and African populations.1,13 The etiology of CAEBV is unknown, although susceptibility is thought to result from defective cytotoxic T-cell or NK-cell activity against EBV-infected cells. In addition to a defective host
immune response, EBV viral load is a key factor that impacts the severity of the disease.1,2 Rare CAEBV cases with EBV+ B- cell proliferations have also been reported in Asia and in the United States.2,13 Although CAEBV typically affects children and adolescents, rare cases of adult-onset CAEBV have been reported; these are associated with a worse prognosis.1,2
Kawamoto et al. describe a cohort of 54 patients with adult-onset CAEBV (defined as onset >15 years of age).12 For comparison, they utilized control groups of patients includ- ing pediatric onset CAEBV (n=75), and ENKTL of nasal (n=37) and non-nasal (n=45) types. The diagnostic criteria for CAEBV as defined in the recently revised World Health Organization classification include persistent IM-like symp- toms for more than three months, increased EBV DNA (>102.5 copies/mg) in peripheral blood, histological evidence of organ disease, and EBV RNA or viral protein in affected tissues.1 All patients in the Kawamoto et al. study met these criteria. Patients with prior immunodeficiency, including HIV infection, were rigorously excluded. A median age of onset at 39 years (range 16-86 years) and the period from estimated onset to diagnosis of over one year typified this cohort. In addition, there was a bimodal age distribution for adult-onset CAEBV, a finding that had not been previously appreciated.
The EBV+ lymphoid infiltrates of CAEBV most often lack atypical features and may mimic non-specific inflammatory or infectious conditions. As such, a strong index of suspicion is necessary to perform appropriate testing for EBV DNA in peripheral blood and EBV RNA (in situ hybridization for EBER) in affected tissue to establish a diagnosis. T-cell CAEBV patients typically have high titers of IgG antibodies against EBV viral capsid antigen and early antigen, and demonstrate a worse prognosis when compared to NK-cell type CAEBV.1-3 In the Kawamoto et al. study,12 EBV DNA viral load was measured in peripheral blood as well as in tis- sue by in situ hybridization for EBER RNA. Lymphadenopathy was more frequent in patients with T-cell CAEBV, while skin involvement was more frequent in NK- cell CAEBV. There were no significant differences in out- come between the T-cell and NK-cell cases among adult- onset CAEBV patients. When patients aged over 50 years were analyzed separately, no significant differences were found in comparison to all adult-onset CAEBV cases.
Cutaneous CAEBV includes hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD), which typically occurs in children. It is most often a cytotoxic CD8+ T-cell proliferation, although CD4, CD56 and CD30 are positive in subsets of cases. The clinical course is variable, and the severity may depend on photosensitivity.1,2,9,14-16 Pathological diagnosis may be confounded by the lack of distinctive his- tological features. Clinical correlation and testing for EBV is paramount to making the diagnosis. Severe allergy to mos-
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haematologica | 2018; 103(6)