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Review Article
EBV-Associated Lymphoproliferative Disorders.
Clin Pediatr Hematol Oncol 2021;28:14-27.
Published online April 30, 2021
© 2021 Korean Society of Pediatric Hematology-Oncology

Young Hyeh Ko1,2

Department of Pathology, 1Korea University Guro Hospital and 2Hanyang University Hospital, Seoul, Korea
Correspondence to: Young Hyeh Ko
Department of Pathology, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea
Tel: +82-2-2626-1482
Fax: +82-2-2626-1486
E-mail: yhko310@skku.edu
ORCID ID: orcid.org/0000-0002-4383-0579
Received October 5, 2020; Revised December 11, 2020; Accepted December 31, 2020.
Abstract
Epstein Barr virus (EBV) is associated with a wide range of human lymphoproliferative disorders (LPD) of B, T, and natural killer (NK)-cell lineage. In children, abnormal immune response to primary EBV infection can cause peculiar forms of T/NK- cell LPD of childhood, such as the systemic form of chronic active EBV infection, hydroa vacciniforme-like LPD, severe mosquito bite allergy and systemic T cell lymphoma of childhood. In adults, dysregulation of the immune response to EBV infection, immunosenescence caused by aging, chronic inflammation in a closed space, and iatrogenic immune suppression can lead to EBV-positive LPD of diverse types involving B, T, and NK cells with unique clinical and pathological presentations. This review describes the clinical, pathological, and genetic findings of EBV-positive LPD listed in the revised 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue.
Keywords: Epstein-Barr virus, Lymphoma, Lymphoproliferative disorder
Introduction

Epstein–Barr virus (EBV) was the first virus shown to cause cancer in humans and is associated with a wide range of human lymphoproliferative diseases (LPDs). EBV infects primarily B cells via the EBV receptor on the B-cell surface, although EBV infrequently also infects T or NK cells. Depending on host immunity and viral factors, viral persistence in host cells can induce lymphoproliferation with a diverse clinical spectrum ranging from simple reactive hyperplasia to aggressive lymphoma/leukemia with unique clinical and pathological presentations. In children, EBV infection in T or NK cells causes peculiar forms of T/NK-cell LPDs, such as the systemic form of chronic active EBV infection (CAEBV), hydroa vacciniforme (HV)-like LPD, severe mosquito bite allergy and systemic T cell lymphoma of childhood as listed in the recent WHO classification [1]. This review describes the clinical, pathological, and genetic findings related to EBV-positive LPD, in which EBV positivity is an essential component for diagnosis. The Burkitt and Hodgkin lymphomas, in which EBV is found in a subset of tumors, are not included (Table 1).

Table 1 . Classification of EBV-positive lymphoproliferative disorders.

DiagnosisMain age groupPathogenesisEBV infected cellClinical course
Chronic active EBV infection, B, systemicChildren and young adultsGenetic defect in host immune response to EBVB-cellsVariable from indolent to aggressive
Chronic active EBV infection, T & NK, systemicChildren and young adultsGenetic defect in host immune response to EBVT or NK cellsVariable from indolent to aggressive
Severe mosquito-bite allergyChildren and young adultsGenetic defect in host immune response to EBVMainly NK cellsVariable from indolent to aggressive
Hydroa-vacciniforme-like LPDChildren and young adultsGenetic defect in host immune response to EBVT cellsVariable from indolent to aggressive
Systemic EBV-positive T cell lymphoma of childhoodChildrenGenetic defect in host immune response to EBVT cellsFulminant
EBV-positive DLBCL, NOSElderly and young adultsAge-related immune deficiency in the elderlyB-cellsDepends on age; aggressive in the elderly
EBV-positive mucocutaneous ulcerElderlyIatrogenic or age-related immune deficiencyB-cellsMostly benign
DLBCL associated with chronic inflammationAdultsLocal immunodeficiency in a closed spaceB-cellsAggressive
Fibrin-associated DLBCLAdultsLocal immunodeficiency in a closed spaceB-cellsMostly benign
Lymphomatoid granulomatosisAdultsUnderlying immunodeficiencyB-cellsVariable depending on grade
Extranodal NK/T cell lymphoma, nasal-typeAdultsOncogenic potential of EBVNK or T cellsAggressive
Aggressive NK cell leukemiaAdultsOncogenic potential of EBVNK cellsFulminant
PTCL, NOS, EBV-positiveAdultsImmune deficiencyT cellsAggressive
Oncogenic potential of EBV

LPD, lymphoproliferative disorders; DLBCL, diffuse large B cell lymphoma; PTCL, peripheral T cell lymphoma; NOS, not otherwise specified..


EBV-Positive Lymphoproliferative Disorders in Childhood

1) Chronic active EBV infection, systemic form

Primary EBV infection usually regresses spontaneously but often results in infectious mononucleosis, which is usually resolved within 2 weeks after onset but can persist for a month or, in rare cases, even longer. Rarely, patients who have primary EBV infection or, less commonly, EBV reactivation, develop CAEBV, a form of EBV-positive LPD. CAEBV, systemic form is characterized by fever, persistent hepatitis, hepatosplenomegaly, and lymphadenopathy, which show varying degrees of severity depending on the host immune response and EBV viral load [2]. The diagnostic criteria for CAEBV include chronic illness lasting at least 3 months, increased EBV DNA in either the tissue or blood mononuclear cells (>102.5 copies/mg), and lack of evidence of a known underlying immunodeficiency according to the recent WHO classification [1].

CAEBV is a rare disease and has strong racial predisposition. It is reported more often in Asian countries, such as Japan, Korea, and China, and in Latin America, including South and Central America, and Mexico, than in Europe and North America (Canada and the United States). The disease develops in children and adolescents but can also develop in young adults and elderly patients, although with a lower frequency [3].

CAEBV in Asia and Latin America affects T or NK cells, and B-cell CAEBV accounts only for 3% of CAEBV in Asia [4]. CAEBV is much rarer in Western populations than in Eastern populations. In the largest series of CAEBV reported in the United States, nine of 10 patients, excluding Hispanics and Asians, had CAEBV of the B-cell type, while only one patient had T-cell type CAEBV [5]. Most patients with CAEBV T/NK-cell-type LPD have no consistent immunological abnormality, although B-cell CAEBV most often involves a progressive loss of B cells and hypogammaglobulinemia [5]. Reduced NK activity [6] and impaired EBV-specific CTL activity [7] have been reported in CAEBV-T and NK.

The higher prevalence of CAEBV-T/NK in Asians or indigenous Central and South Americans suggests that genetic factors that control the immune response to EBV infection underlie the susceptibility to the development of EBV-positive T/NK-cell LPD in young children and adolescents. Recent comprehensive genetic analysis using whole-exome sequencing has shown that the EBV genome in patients with CAEBV T/NK-cell or EBV-associated lymphoma harbor frequent intragenic deletions, which suggests a unique role of these mutations in the neoplastic proliferation of EBV-infected cells. In addition, somatic driver mutations are frequently found in DDX3X, KMT2D, BCOR, BCORL1, TET2, and KDM6A. These mutations were also observed in extranodal NK/T cell lymphoma, a prototype of EBV-positive T/NK cell lymphoma, suggesting that a common molecular mechanism acts in the process of clonal evolutions of EBV-infected T or NK cells [8].

Abnormal activation and replication of EBV together with the proliferation and clonal expansion of infected cells play a key role in the pathogenesis of CAEBV. The proliferating cells lack histological evidence of malignancy and may be polyclonal, oligoclonal, or monoclonal according to the stage of transformation [1,3]. Clonality does not necessarily indicate a worse prognosis.

The clinical manifestations of CAEBV vary. In addition to fever, chronic hepatitis, and lymphadenopathy, patients frequently show NK lymphocytosis and, less commonly, bowel perforation, coronary artery aneurysms, immunoglobulin A nephropathy, choreic movement, brain infarction, mosquito bite hypersensitivity, or HV-like eruption [3,4]. CAEBV is diagnosed based on the clinical and laboratory findings. Pathological changes are nonspecific except for identification of EBV-infected T or NK cells in the biopsy tissue (Fig. 1) [1]. CAEBV has significant overlap in clinical manifestation with EBV-HLH and systemic EBV-positive T cell lymphoma. Patients with CAEBV are often complicated by EBV-associated hemophgocytic syndrome and may progress to systemic T cell lymphoma during the course of disease.

Figure 1. (A) Chronic active EBV infection, T/NK cell. Liver biopsy shows minimal histologic change. (B) EBER in situ hybridization highlights EBV infected lymphocytes in hepatic sinusoids.

Patients with CAEBV die of infection, hemophagocytic syndrome, or progressive lymphoproliferation. The only proven effective treatment for this disease is hematopoietic stem cell transplantation (HSCT). In a Japanese study of patients with T or NK cell CAEBV, the 3-year overall survival rates in patients treated with chemotherapy only, chemotherapy followed by allogeneic HSCT, or allo-HSCT only were 0%, 65%, and 82%, respectively [9]. Factors indicating a poor prognosis include late onset of disease, thrombocytopenia, and T cell CAEBV [4]. The prognosis of patients with B-cell CAEBV is similar to that of patients with T/NK-cell CAEBV, and only two of five patients with B-cell CAEBV were alive after HSCT [5].

2) Severe mosquito bite allergy

Mosquito bite reaction is common in the general population and usually raises no specific medical problems. Severe mosquito bite allergy, also known as mosquito bite hypersensitivity, is defined as an EBV-positive NK-cell LPD with peculiar cutaneous manifestations characterized by intense local skin symptoms, including erythema, bullae, ulcers, and skin necrosis following a mosquito bite. This condition may also have other symptoms such as fever, malaise, hematuria, NK lymphocytosis, and abdominal cramps [1,10,11]. Mosquito bite allergy is not a simple allergic reaction but a cutaneous manifestation of underlying EBV-positive NK-cell proliferative disease [12]. EBV-infected NK cells are monoclonal or oligoclonal according to EBV terminal repeat analysis, which suggests that patients with severe mosquito bite allergy have clonal NK cell proliferation [13].

The geographic distribution of mosquito bite allergy is similar to that of other EBV-positive T/NK-cell lymphoproliferative diseases. Most patients are in the first two decades of life, with a median age of 6.7 years (range 0-18 years) [13]. Patients usually experience repeated episodes of severe symptoms induced by mosquito bites. Skin lesions of severe mosquito bite allergy can be triggered by injection of mosquito saliva, which results in prominent infiltration of CD4+ T cells. In vitro studies have suggested that CD4+ T cells stimulated by mosquito bites play a key role in the development of the skin lesions and that NK cell oncogenesis occurs via reactivation of EBV in latently infected NK cells and EBV oncogene expression [14,15]

Patients have a high serum IgE level and high EBV load in the peripheral blood. The skin at the mosquito bite site shows epidermal necrosis and ulceration (Fig. 2). Predominant infiltration in the skin is CD4+ T cells with some CD8+ T cells and EBV-positive NK cells [1]. Al-though NK-cell lymphocytosis is common in the peripheral blood, EBV-positive NK cells comprise a minor population of the cells in the skin infiltrate [16].

Figure 2. (A, B) Severe mosquito bite allergy. Skin biopsy shows epi-dermal necrosis with perivascular cellular infiltration in the dermis. (C) EBER in situ hybridization re-veals EBV infected lymphocytes.

The clinical course of mosquito bite allergy is variable. Some patients have a prolonged and indolent disease course, which may be complicated by T/NK-cell CAEBV or HV-like eruptions. Half of patients die of hemophagocytic syndrome or aggressive NK-cell leukemia (ANKL) [13,16,17].

3) Hydroa vacciniforme-like LPD

HV-like LPD is a peculiar cutaneous form of chronic EBV-positive LPD of polyclonal or monoclonal T cells and displays a broad spectrum of clinical aggressiveness and usually a long clinical course [1]. This disease has been reported under various names including angiocentric cutaneous T cell lymphoma of childhood [18], edematous scarring, vasculitic panniculitis [19], EBV-associated lymphoproliferative lesion with HV-like eruption [20], classic HV and severe HV [21], or HV-like lymphoma [22], depending on severity of the cutaneous manifest-ations. The revised 2016 WHO classification proposed the term “HV-like LPD” to include the full spectrum of HV-like eruption because of the broad clinical spectrum of the disease and the lack of reliable morphological and molecular criteria for predicting its clinical behavior [1].

The geographic distribution of this disease is similar to that of other EBV-positive T/NK-cell LPD and is more common in children in Asia and Latin America. The median patient age at diagnosis is 8 years [1]. HV-like LPD can develop in adults, but the frequency is low [23,24].

HV-like LPD is characterized by blistering photodermatosis in childhood that heals with vacciniform scarring. The severity of skin lesions varies according to season and UV ray exposure. The number of EBV-positive lymphocytes increases in spring and summer, but few EBV-positive cells are present during periods of remission in autumn and winter [16]. This observation suggests that EBV-infected T or NK cells are recruited to the skin and activated following sun exposure. Local production of interferon-gamma and chemokines by cellular infiltrates results in inflammation and tissue damage [25] which lead to epidermal reticular degeneration and spongiotic vesiculation (Fig. 3).

Figure 3. (A) Hydroa vacciniforme-like lymphoproliferative dis-order. Skin biopsy shows vesicular degeneration of the epi-dermis and lymphocytic infiltration in the dermis. (B) Numerous EBV infected lymphocytes present.

Histologically, the dermis contains perivascular and periappendiceal lymphocytic infiltration. Most of the infiltrating cells are CD4+ or CD8+ T cells, and NK cells are rare. Most cells express cytotoxic molecules such as TIA-1 and granzyme B. The histological changes of severe HV are similar to those of classic HV, but the dermal infiltrates tend to be more extensive and deeper, and can reach to the subcutaneous tissue [16].

As in other types of EBV-positive T/NK-cell LPD, HV-like LPD is uncommon in Caucasians. A recent series from the United States reported on the clinicopathological findings of HV-like LPD in 10 Caucasian patients. Whites with HV-like LPD were less likely to experience systemic disease and had a much better prognosis than nonwhites [26]. The higher prevalence of severe HV in persons of Asian descent may be ascribed to the influence of the genetic background and may be linked to the HLA type or environmental factors and immunological tolerance because of early exposure to EBV infection [27].

HV-like LPD is classified into two types based on the clinical features. The classic type is a self-limited form characterized by the formation of vesicles on sun-exposed areas, and the lesions heal with vacciniform scarring after photoprotection. All patients show photosensitivity either as a positive reaction to UV provocation or symptoms induced by sun exposure. These patients have a high EBV viral load in the tissue and peripheral blood, but evidence of systemic involvement is usually lacking [21]. In most patients, this condition tends to pursue a benign course, although chronic recurrent eruption can result in severe scarring and disfiguration of the face. However, one-third of patients with classic HV-like LPD can develop cutaneous or systemic T-cell lymphoma or systemic CAEBV 3-19 years after the initial presen-tation. The severe type of HV-like LPD involves more extensive skin lesions that occur on both sun-exposed and -unexposed skin. This form is associated with systemic manifestations including fever, hepatomegaly, serologic abnormalities, and peripheral NK lymphocytosis. Half of cases of the severe form progress to EBV-associated T-cell malignancy. For patients with HV-like LPD with systemic symptoms, only HSCT has been reported to be curative [28].

4) Systemic EBV-positive T cell lymphoma of childhood

Systemic T-cell lymphoma of childhood is a major category of EBV-positive T/NK cell LPD of childhood and is a life-threatening illness that occurs in children. This disease is characterized by the systemic clonal proliferation of T cells, and the characteristic clinical features including acute onset of fever, hemophagocytic syndrome, pancytopenia, and organomegaly. The clinical progression is rapid, and patients die of sepsis, intravascular coagulation, and multiorgan failure usually within days or weeks after the diagnosis [1,16,22].

Systemic T-cell lymphoma of childhood has been described under a variety of terms including fatal EBV-associated hemophagocytic syndrome [29], fulminant EBV-positive T cell proliferative disorder of childhood [30], or fatal hemophagocytic lymphohistiocytosis (HLH) [31]. This condition usually occurs in children with primary EBV infection or during the course of systemic CAEBV infection. The infection of T cells by EBV activates T cells to secrete Th1 cytokines such as tumor necrosis factor-alpha and IFN-gamma, which subsequently activate macrophages [32].

The distinction between EBV–HLH and systemic T-cell LPD is challenging in the diagnosis of EBV-positive T/NK-cell LPD [33,34]. In the revised 2016 WHO classification, EBV–HLH is included as part of the systemic form of EBV-positive T-cell LPD and is considered to be a self-limited nonneoplastic hyperimmune reaction. These two categories share similar histological and immunophenotypic findings. Excluding systemic T-cell lym-phoma arising in patients with CAEBV, most patients with EBV-positive systemic T-cell lymphoma are initially diagnosed with EBV-associated HLH [33]. Cells infiltrating into the bone marrow and tissue lack obvious atypia both in EBV–HLH and initial biopsy of systemic T-cell lymphoma (Fig. 4A). The immunophenotype of the infiltrating cells is CD8+ cytotoxic T cells in both con-ditions. Systemic T-cell lymphoma is a clonal disease by definition of the 2016 revised WHO classification. Like-wise, EBV-HLH can be clonal [35]. There are reports that patients initially diagnosed with EBV–HLH have died of systemic T-cell lymphoma after treatment with the HLH-2004 regimen [33]. In these patients, the initial biopsy tissue lacked cytological atypia, although subsequent biopsy showed atypical EBV-positive T lymphocytes infiltrated into the tissue along with necrosis (Fig. 4B-D). These overlapping clinical and pathological findings suggest that EBV–HLH and systemic T-cell lymphoma of childhood reflect a biological continuum rather than discrete entities [33,34].

Figure 4. (A) Systemic T cell lymphoma of childhood. Bone marrow biopsy shows many hemophagocytic histiocytes. (B) Lymph node biopsy shows infiltration of EBV-positive atypical T-lymphocytes with necrosis. (C) CD3. (D) EBER in situ hybridization.
EBV-Positive Lymphoproliferative Disorders in Adulthood

1) EBV-positive diffuse large B-cell lymphoma, not otherwise specified

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is an EBV-positive clonal B cell proliferation which can be diagnosed after exclusion of specific type of EBV positive B cell proliferation such as lymphomatoid granulomatosis (LYG) and DLBCL associated with chronic inflammation. It was initially defined as an aggressive large B cell lymphoma arising in patients older than 50 years [22], however, a substantial proportion of EBV-positive DLBCL can occur in young adults [36,37], therefore the restriction to elderly patients was removed in the revised 2016 WHO classification [1].

In elderly patients, senescence of immune system inherent to aging contributes to defective surveillance of EBV, is thought to play a major role in pathogenesis. Case reports have noted EBV-positive DLBCL concurrent with EBV-positive reactive hyperplasia in a same patient [38], an EBV-positive DLBCL patient with a prior history of mucocutaneous ulcer [39], and EBV-positive reactive hyperplasia that progressed to EBV-positive lymphoma after a couple of years [40]. These case studies support the idea that decreased T cell immunity induced by aging or other causes allows persistence of EBV-infected B cells which continues to proliferate and eventually proceeds to overt lymphoma. Gene expression profiling reveals that antiviral response genes, proinflammatory cytokines, and chemokines associated with the innate immune response are overexpressed in tumor tissue, indicating that a virus induced inflammatory microenvironment plays a role in oncogenesis of EBV-positive DLBCL [41].

The histologic feature is variable ranging from polymorphic case with EBV-positive Hodgkin’s lymphoma-like or T-cell/histiocyte-rich DLBCL-like histologic changes, to monomorphic lymphoma with necrosis (Fig. 5). The diagnosis is made through a careful pathological evaluation and detection of EBV-encoded RNA (EBER) in tumor cells. Although a clear cutoff for positivity has not been defined [1], virtually all tumor cells should be positive for EBV. Tumor cells exhibit mostly type II latency and fewer cases involve type III latency. Most cases exhibit an activated B cell phenotype characterized by NF-kB activation [42]. EBV-positive DLBCL is aggressive disease and prognosis depends on the age of patients. In elderly patients, EBV-positive DLBCL has a lower survival rate than EBV-negative DLBCL, while EBV positivity of DLBCL in young adults is not associated with unfavorable clinical characteristics or worse outcomes [37].

Figure 5. (A) EBV-positive diffuse large B cell lymphoma, not otherwise specified. Lymph node biopsy shows large cell lymphoma. (B) CD20. (C) EBER in situ hybridization.

2) EBV-positive mucocutaneous ulcer

EBV positive mucocutaneous ulcer is an indolent condition that shows shallow, sharply circumscribed, unifocal mucosal or cutaneous ulcers that occur in immunosuppressed patients, including those with age-associated immunosenescence, iatrogenic immunosuppres-sion, primary immune disorders, and HIV/AIDS-associated immune deficiencies. The ulcer typically has an indolent course, and spontaneous regression occurs in some cases [1,43-46]. EBV-positive mucocutaneous ulcer can appear in the oral mucosa, skin, or gastrointestinal (GI) tract, but there is no systemic involvement [43]. Patients are mostly adults, with a median age of 77 years (range 42-101 years) reported in one study [43]. The lesion is usually isolated but can be multiple lesions confined to a single anatomic area [46]. Histologically the lesion is characterized by a polymorphous infiltrate and atypical large B-cell blasts that often exhibit Hodgkin/Reed-Sternberg (HRS) cell-like morphology.

The B cells in EBV-positive mucocutaneous ulcer show strong CD30 and EBER positivity, and some have reduced CD20 expression in a background of abundant T cells. Clonality studies have reported variable results: e.g., slightly more than one-third of cases involve clonal Ig rearrangement, one-third involve clonal T-cell rearrangement, and one-third show a restricted T-cell pattern [43,46]. About a half of cases regressed spontaneously with no treatment and 15% showed relapsing and remitting course [43]. The iatrogenic lesions respond to a reduction in immunosuppressive agents. If only histological changes are considered, EBV-associated mucocutaneous ulcer may be diagnosed as lymphoma. There-fore, careful differentiation is important for avoiding overdiagnosis and overtreatment.

3) Diffuse large B cell lymphoma associated with chronic inflammation

DLBCL associated with chronic inflammation occurs in the setting of long-standing chronic inflammation, is associated with EBV, and usually involves body cavities or narrow spaces. Pyothorax-associated lymphoma represents the prototype of this type of lymphoma [47]. Pyothorax-associated lymphoma is a non-Hodgkin lymphoma of an exclusively B-cell phenotype that develops in the pleural cavity of patients after more than 20-year history of pyothorax following an artificial pneumothorax for the treatment of pulmonary tuberculosis or tuberculous pleuritis [48,49]. Similar tumors reported in the patients with a chronic osteomyelitis and chronic skin ulcer [50], and knee prosthesis implant [51]. EBV latency type III is characteristic.

Chronic inflammation in local sites results in local immunodeficiency and provides a favorable environment for EBV-infected B cells to escape from the host immune surveillance via their secretion of IL-10 [49,52]. IL-6 produced locally within a chronic pyothorax might also promote the development of pyothorax-associated lymphoma [53]. Recently, EBV-positive pyothorax-associated lymphoma has been shown to involve expression of CCL17 and CCL22 chemokines, which attract CCR4-expressing regulatory T cells among human peripheral blood mononuclear cells [54]. DLBCL associated with chronic inflammation is responsive to chemotherapy, but the overall prognosis is poor, as shown by a 5-year survival rate of 21.6% [55].

4) Fibrin-associated diffuse large B cell lymphoma

DLBCL that develops in the setting of long-standing chronic inflammation is typically associated with EBV and usually presents as a tumor mass found in body cavities, as in pyothorax-associated lymphoma. Another unusual form of EBV-positive large B-cell lymphoma appears along with fibrin mixed with tissue debris in the wall of cysts, hematomas, hydroceles, coronary aneurysms, and cardiac myxomas [56-63]. In contrast to DLBCL associated with chronic inflammation, this lesion does not form a mass itself, but instead microscopic foci of atypical (neoplastic) large lymphoid cells are found within the contents of the cysts, curettage material, or the stroma of atrial myxoma [60]. These lymphoid cells are positive for B-cell markers and have a high Ki-67 labeling index.

The clinical course of fibrin-associated DLBCL is benign. Most cases, particularly those associated with pseudocysts, behave indolently, may be cured by surgery alone, and may represent a form of EBV-positive LPD rather than lymphoma [64]. Large B cells express LMP1 and EBNA2, belonging to EBV latency type III. As with DLBCL associated with chronic inflammation, the pathogenesis of fibrin-associated DLBCL is thought to be related to decreased immunosurveillance acquired at a local site [65]. Local immunodeficiency at closed space prevents a cytolytic response to EBV-infected cells and may favor the clonal proliferation of EBV-infected B cells.

5) Lymphomatoid granulomatosis

Lymphomatoid granulomatosis (LYG) is an EBV-positive lymphoproliferative disease with characteristic clinicopathological findings. Clinically, patients have pulmonary involvement that usually comprised of multifocal lesions with a predilection for the lower lobes [1,66]. Extra-pulmonary sites are commonly involved and include the CNS, liver, skin, and kidney. Mucosal sites including the GI tract and oral mucosa can be involved, although this is uncommon. The spleen, bone marrow, and lymph nodes are usually not involved, and caution should be exercised when diagnosing LYG in a patient with enlarged lymph nodes and splenomegaly. Histologically, the lesions show polymorphous infiltrate comprising of a variable number of large atypical cells admixed with many small T cells with an angiocentric distribution [1,66].

LYG is divided into three grades according to the number of EBV-positive B cells. Grade 1 lesions contain a polymorphous lymphoid infiltrate without cytological atypia and with only infrequent EBV-positive cells (<5/HPF). Grade 2 lesions contain occasional large lymphoid cells in a polymorphous background with EBV-positive cells (5-20/HPF). Grade 3 lesions show an inflammatory background with increased EBV-positive cells (>50/HPF). EBER-positive cells can be of various sizes, and numerous small B cells are also positive for EBER. Necrosis is common [66].

Patients typically presents in the fifth decade and there is a male predominance [66]. Patients with underlying immunodeficiency are at increased risk for LYG. Most patients show no evidence of underlying known immunodeficiency however usually manifest reduced immune function in EBV surveillance in laboratory analysis [1]. The EBV latency pattern of LYG has been reported as type III latency in 70% of cases examined [66,67].

Differential diagnosis includes other EBV-positive lymphoproliferative disease including EBV-positive DLBCL, NOS. However, a uniform population of atypical EBV-positive B cells without a polymorphous background is beyond the spectrum of LYG and should be classified as diffuse large B-cell lymphoma [22]. The clinical course ranges from indolent disease to aggressive large B-cell lymphoma. The treatment is selected according to the histological grade and underlying pathobiology, and includes augmentation of the immune response to EBV for low-grade LYG and immunotherapy for high-grade disease [68].

6) Extranodal NK/T cell lymphoma, nasal-type

Extranodal NK/T-cell lymphoma, nasal-type (ENKTL) is defined as a EBV-positive NK or cytotoxic T-cell lymphoma arising in extranodal sites. The nasal cavity is the prototypic site of involvement. Necrosis of tumor tissue with angiodestructive and angiocentric infiltration of tumor cells is characteristic. EBV positivity is observed in virtually all neoplastic cells [1]. At the initial presentation, bone marrow involvement is uncommon. ENKTL accounts for 2.6-12% of non-Hodgkin lymphoma cases in East Asian countries and for 0.5-7.8% in Latin American countries, but <1% of cases in Caucasians [69].

The fact that ENKTL is clustered in East Asia and Latin America suggests that genetic and environmental factors are important in the disease development. Evidence from genetic studies, including mitochondrial DNA and Y chromosome haplotypes, indicates an Asian ancestry of the native population in Latin America, especially in countries located along the Pacific coast [70]. ENKTL affects mainly adults, and the median age is 44-50 years. Its incidence begins to increase in the third decade of life and this form is a major subtype of EBV-positive T/NK-cell lymphoproliferative disease throughout life in Asia. The disease rarely affects children. In children, NK/T-cell lymphoma may be associated with mosquito bite hypersensitivity or systemic CAEBV infection [69].

The typical immunophenotype of ENKTL is CD2+, cytoplasmic CD3+, CD4−, CD5−, CD8− and CD56+, and involves expression of cytotoxic molecules such as TIA-1, granzyme B, and perforin. While NK-cell marker CD56 is positive in more than 90% of cases, CD16 is usually negative. NK cell receptors such as CD94-NKG2 and KIRs are expressed in 75% and 30% of cases, respectively. CD30 is expressed in fewer than 50% of ENKTL cases in a subset of tumor cells. PDL-1 is commonly expressed in tumor as well as in background immune cells (Fig. 6) [50, 71].

Figure 6. (A) Extranodal NK/T cell lymphoma. Nasal biopsy shows polymorphic atypical tumor cells. (B) CD3. (C) CD56. (D) EBER in situ hybridization.

Tumors of T-cell origin account for 46% of ENKTL cases, and half of T cell ENKTL are T-cell receptor silent [72-74]. Next-generation sequencing studies have identified recurrent mutations shared by patients with ENKTL of NK- and T-cell origin, including mutations involving the RNA helicase gene DDX3X, tumor suppressors, JAK–STAT pathway molecules, and epigenetic modifiers [75-78]. The overall 5-year survival rates for localized and advanced ENKTL were reported as 70% and 24%, re-spectively. Factors indicating a poor prognosis include nonnasal tumors, advanced stage, high viral load in the blood, and an immune-silenced tumor microenviron-ment. Prognostic models based on clinicopathological parameters and EBV DNA load are useful in the stratification of patients for therapy [71,79,80].

7) Aggressive NK cell leukemia

Aggressive NK cell leukemia (ANKL) is a systemic neoplastic proliferation of NK cells that is almost always associated with EBV. It is most commonly found in the bone marrow, peripheral blood, liver, and spleen along with pancytopenia [1]. The clinical course is very aggressive, and most patients die within a few months of disseminated intravascular coagulation, hemophagocytic syndrome, and multiorgan failure [81]. ANKL is closely associated with EBV, and only 10% of ANKL cases are negative for EBV [82]. ANKL usually presents among young adults or the elderly, and the median age at presentation is 49 years. As for other EBV-positive lymphomas, the frequency is much higher in Asians than in Caucasians. The high prevalence in Asians is associated with EBV-positive disease and seems to be lower in those with EBV-negative disease [83]. EBV-negative and EBV-positive ANKL patients have similar clinical and pathological characteristics, but it is unclear whether the clinical outcomes are similar [82,84]. De novo ANKL accounts for 80% of cases, and the other 20% evolve from chronic active EBV infection, severe mosquito bite allergy, or chronic LPD of NK cells. ANKL arising from CAEBV infection or severe mosquito bite allergy tends to develop more often in younger patients than does de novo ANKL [85].

The bone marrow section shows diffuse destructive infiltration of atypical tumor cells and hemophagocytic histiocytes. The morphology of tumor cells is variable in individual patients and may range from large granular lymphocytes to large pleomorphic cells. Tumor cells express markers that delineate the NK lineage including CD16, CD56, and cCD3. sCD3 and myeloid markers are negative, and the TCR gene is in the germline confi-guration.

ANKL differs from ENKTL in both the clinical findings and the cell lineage of tumor cells. ENKTL involves tumors of NK or cytotoxic T cells, whereas ANKL involves tumors of NK cells. ENKTL usually has an extranodal involvement such as in the nasal cavity, skin, or GI tract even in cases initially diagnosed in bone marrow biopsy. ANKL may exhibit similar clinical features as systemic T-cell lymphoma of childhood, but ANKL is rare in children and involves NK cells, whereas most cases of systemic T-cell lymphoma of childhood involve CD8+ cytotoxic T cells. Genetically, ANKL is characterized by mutations of the JAK–STAT pathway, which is also recurrent in ENKTL [78,86,87].

8) Peripheral T cell lymphoma, not otherwise specified, EBV-positive

EBV can infect non-neoplastic B cells or neoplastic T cells in mature T-cell lymphoma. The patient’s prognosis worsens as the number of EBV-positive cells increases. In this situation, EBV-infected cells account for a very small fraction of infiltrating cells. Apart from such examples, rare nodal T-cell lymphomas in which virtually all tumor cells are EBV positive has been reported in Asia [88-90]. EBV-positive nodal T cell lymphoma is not a separate entity but described as a EBV-positive variant of peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) in the revised 2016 WHO classification. Median age of patients is 64 years (range, from 25 to 90 years) [89]. Patients have no definite immunodeficiency but are often older adults with a history of other viral infections such as HBV and HCV, or diabetes mellitus, which suggests that these patients have an impaired immune function that allows viral persistence [89].

Most patients showed adverse clinical features, including advanced Ann Arbor stage and high or high/intermediate international prognostic index. Biopsy shows diffusely proliferating small-medium-to large-sized atypical pleomorphic or monomorphic tumor cells with an often centroblastic morphology. Majority of tumor cells are of cytotoxic ab-T cell followed by (in decreasing order of frequency) TCR-silent cytotoxic T cell, and uncommonly gd-T cell and NK cell [90,91]. Tumor cells frequently show 14q11.2 loss which correlates with loss of TCRA loci and upregulation of PDL1 [92]. The tumors have poor treatment outcomes similar to ANKL, and the median overall survival is 1.5 months [93].

Conclusion

EBV-positive LPD shows a variety of clinical features and histological findings. To diagnose these accurately, it is important to consider the patient’s clinical findings in detail and to test for EBV for all types of lymphoproliferative diseases.

Conflict of Interest Statement

The author has no conflict of interest to declare.

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  • Young Hyeh Ko