While CAEBV was first described as a persistent EBV infection targeting B cells, over the years the syndrome has been primarily associated with EBV infection of T cells and less often NK cells [2
]. The minimal diagnostic criteria for CAEBV are summarized above, all of which must be met. It has a strong racial predisposition, with most cases occurring in Japan and Korea and some cases in Native American populations in the Western Hemisphere from Mexico, Peru, and Central America. It is rare in Caucasians and African-Americans. The term T/NK cell CAEBV has been used in the literature to encompass a very broad spectrum of diseases, including a systemic form which may be polyclonal, fulminant and systemic EBV-positive T-cell LPDs that are clonal, hydroa vacciniforme (HV) of T-cell derivation, and severe mosquito bite allergy (usually of NK cell origin). The 2008 WHO classification has recognized the following disease entities that are considered neoplasms: systemic EBV-positive T-cell LPD of childhood (a clonal T-cell LPD) and HV-like T-cell lymphoma [10
HK (Nagoya) carried out a nation-wide survey of T/NK–CAEBV in Japan in 2001 and identified 82 cases (42 males and 40 females). The mean age of onset of the disease was 11.3 years with a range of 9 months to 53 years and all patients had elevated levels of EBV DNA in the blood [29
]. The majority of patients had evidence of systemic disease, presenting with fever (93% of patients), hepatomegaly (79%), splenomegaly (73%), thrombocytopenia (45%), anemia (44%), and lymphadenopathy (40%). Cutaneous manifestations were common and included hypersensitivity to mosquito bites (33%), skin rash (26%), and HV (10%). Patients with only cutaneous disease had a better prognosis, although the criteria to distinguish HV, which may be clonal, from HV-like T-cell lymphoma are not well delineated [31
]. It has been controversial as to whether CAEBV is a type of T-cell or NK cell malignancy or a progressive infectious disease; of the patients in whom clonality could be analyzed, the proliferation was monoclonal in 76%, oligoclonal in 13%, and polyclonal in 11% [30
]. The EBV-infected cells were shown to be T cells in 46% of patients, NK cells in 33%, T/NK cells in 4%, B cells in 2%, and unclassified or not studied in the remaining 15%.
Patients with T-cell CAEBV often presented with high fever, lymphadenopathy, hepatosplenomegaly, high titer of EBV-specific antibodies, and had rapid progression of their disease. Patients with NK cell disease, in contrast, often had hypersensitivity to mosquito bites, rash, high levels of IgE, and did not necessarily have elevated EBV-specific antibody titers. The 5-year survival rate of patients with T-cell CAEBV was 59%, while that for NK cell disease was 87% [30
]. However, uncomplicated HV (of clonal T-cell derivation) had a better prognosis. Life-threatening complications of T/NK cell CAEBV included HPS (24% of patients), disseminated intravascular coagulation (16%), hepatic failure (15%), peptic ulcer disease/perforation (11%), coronary artery aneurysms (9%), central nervous system complications (9%), myocarditis (6%), and interstitial pneumonitis (5%).
The pathogenesis of T-cell and NK cell CAEBV is uncertain. EBV-positive T/NK cells have been identified in the tonsils and peripheral blood from patients with infectious mononucleosis [33
], and the virus has been shown to infect NK cells in vitro
]. NK cells can acquire the EBV receptor, CD21, by synaptic transfer from B cells [35
], allowing EBV binding to NK cells. T and NK cells from patients with CAEBV often have latency 2 phenotype with expression of EBV EBNA-1, LMP1, and LMP2 [36
]. There is evidence that defective T-cell and NK cell responses to EBV may play a role in the pathogenesis [29
While a number of therapies have been tried for CAEBV including antiviral agents (acyclovir, ganciclovir), immunomodulators (IFN-α, IL-2), chemotherapy (etoposide, corticosteroids), cyclosporine, and EBV-specific cytotoxic T cells (CTLs), recently more promising results have been obtained with hematopoietic cell transplantation [38
]. Since the first report of successful allogeneic bone marrow transplantation for the disease [40
], many successful cases have been reported using related or unrelated bone marrow transplants, with myeloablative or nonmyeloablative transplantation or with cord blood transplantation [41
]. Hematopoietic stem-cell transplantation can eliminate EBV-infected cells, reconstitute EBV-specific cellular immunity, and have a graft-versus-tumor effect. However, the procedure carries a high risk of transplantation-related complications and the 5-year survival rate was only 53% (Japanese Association for Research on EBV Study Group, unpublished data). Poor prognostic factors that argue for early intervention and transplant are (i) age at onset >8 years, (ii) platelet count <120
000/μl, and (iii) T-cell- rather than NK cell-associated disease [30
]. Patients with HV have a better prognosis and may be followed conservatively, if there are no systemic symptoms. Measurement of the viral load after transplantation was helpful in determining the response to transplantation.
K. Oshima (Kurume) presented a proposed categorization of CAEBV from the CAEBV study group [42
]. They divided cases into four categories: A1 (polymorphic and polyclonal), A2 (polymorphic and generally monoclonal), A3 (monomorphic and monoclonal proliferation of T-cell or NK cell origin, and B (monomorphic and monoclonal T-cell LPD with fulminant clinical course). The clinical course in groups A1–A3 was generally protracted with most patients surviving for several years. Group B was defined as equivalent to fulminant EBV-positive LPD of childhood [43
]; patients were under the age of five, had a fulminant clinical course that emerged soon after EBV infection, and morphology and phenotype that overlapped with group A3. Patients with the clinical syndromes of mosquito bite allergy and HV were distributed in groups A2 and A3. All patients had very high viral loads at presentation. Anti-EBV antibody titers were highest in A1 (VCA IgG 2560) and lowest in B (VCA IgG 160). Interestingly, antibody titers to EBV also were reported to be low in fulminant EBV-positive LPD of childhood [43
] (now designated ‘systemic EBV-positive T-cell LPD of childhood’ in the WHO classification of 2008 [10
]). It will be of interest to apply this classification system prospectively to CAEBV cases to determine its applicability as a diagnostic and prognostic system.
The perspective of EBV-related T-cell and NK cell disease in Korea was presented by Y-HK (Seoul) [44
]. Cases of systemic EBV-positive T-cell LPD and related entities were compared with more well-defined diseases such as extranodal NK/T-cell lymphoma and aggressive NK cell leukemia. Systemic EBV-positive T-cell LPD patients were mainly children and young adults and presented with acute illness with a fulminant clinical course, similar to aggressive NK cell leukemia, with death in a matter of weeks. These cases were comparable in behavior to those reported in the literature as ‘fatal infectious mononucleosis’ with HPS [45
]. There was a subset of children and young adults with CAEBV and a somewhat more protracted clinical course. Some of these patients had cutaneous manifestations, such as HV, but the median survival was still <1 year. Y-HK also identified a subset of patients presenting in adult life, who were often coinfected with hepatitis B or C virus, leading to reactivation of EBV [46
The perspective of systemic T-cell LPD of childhood (CAEBV) in the Western hemisphere was presented by L. Quintanilla-Martinez (Tübingen). There is evidence of a strong racial predisposition, as nearly all patients were of Native American ethnic origin from Mexico or Central America [43
]. Previously healthy patients presented with acute onset of fever suggestive of an acute viral respiratory illness. Within a period of weeks patients developed hepatosplenomegaly and liver failure, sometimes accompanied by lymphadenopathy. Laboratory tests showed pancytopenia, abnormal liver function tests, and often an abnormal EBV serology with low or absent anti-VCA IgM antibodies. The disease was usually complicated by HPS, coagulopathy, multiorgan failure, and sepsis [43
]. The clinical course was aggressive, with a median survival of <1 year. The value of morphological subtyping was felt to be questionable, as in most cases the EBV-positive T cells lacked cytological atypia. The immunophenotype was of cytotoxic T-cell origin, CD8 > CD4. All cases studied were monoclonal for TCR
gamma genes, and on this basis as well as the poor clinical outcome, the process has been considered to represent a form of mature T-cell malignancy in the 2008 WHO classification [10
X-linked lymphoproliferative disease (XLPD), which is caused by mutations in the SAP
gene, and CAEBV share many clinical features in common. Acute infection usually results in a fulminant disease with infiltration of multiple organs by EBV-infected B cells and activated T cells with HPS and tissue necrosis. Survivors often have hypogammaglobulemia and may develop B-cell lymphomas. Other complications include aplastic anemia, necrotizing vasculitis, or LYG. Based on data derived from a SAP
knockout mouse model, J. Sullivan (Worcester) suggested that patients with XLPD may have defective apoptosis of CD8 T cells that predisposes them to the HPS and fatal EBV infections [47
The clinical spectrum of HV in Asia and the Western hemisphere was presented by X. Zhou (Beijing) and C. Barrionuevo (Lima). The median age of patients from China was 7 years (range 3–15 years), with an increased male-to-female ratio. All the patients presented with a papulovesicular rash, with ulceration and crusting, primarily affecting sun-exposed areas of the skin. Twenty-five percent (4 of 16) of the patients also reported hypersensitivity to mosquito bites. EBV-positive cells were abundant in the lesions during periods of active disease (spring, summer); lesions often regressed during the autumn and winter. Most of the HV patients also had evidence of systemic disease. About 80% (13 of 16) of patients presented with high fever 38°C–40°C and 38% of patients had hepatosplenomegaly and/or lymphadenopathy. Follow-up data (mean 22 months; range 4–46 months) was available for 44% (7 of 16) of cases. Two patients died of liver or multiple organ failure, and five were still alive with a stable or smoldering disease.
C. Barrionuevo (Lima) presented cases with HV-like lesions from Peru, which were categorized as HV-like T-cell lymphoma in their series based on infiltrative growth pattern, often aberrant T-cell phenotype, clonal rearrangement of TCR genes, and poor clinical outcome [48
]. The clinical and pathological features are very similar to those observed in Japan and Korea (). The mean age of patients in Peru was 11 years (range 5–17 years). Lesions most commonly involved sun-exposed areas (face and upper limbs). Lesions often showed edema, papules, blisters, crusts, ulcers, and healed as vacciniforme scars. Some patients had hypersensitivity to insect bites. Systemic symptoms were common and lymphadenopathy was present in 30% of cases and hepatosplenomegaly in 10%. Less frequent were intercurrent infections, HPS, or visceral involvement. The 2-year survival rate was 43%. Patients receiving chemotherapy or chemotherapy and radiation therapy had partial response (a decrease in the size of a tumor, or in the extent of cancer in the body in response to treatment) rates of 30%. Deaths were due to sepsis, liver failure, malignancy, or HPS.
Figure 3. Hydroa vacciniforme-like lymphoma. (A) Sun-exposed areas of the skin exhibit a papulovesicular eruption, with ulceration and crusting. (B) The infiltrate is present in the superficial dermis. (C) Lymphoid cells are positive with EBER in situ hybridization. (more ...)
The criteria for the distinction of HV from HV-like T-cell lymphoma have not been clearly delineated in the literature. Based on the published experience and reports presented at the meeting, EBV and T-cell clonality were found in both types of cases. Some patients with HV have eventual resolution of their disease in adult life, whereas other patients develop progressive disease with worsening of cutaneous symptoms and eventual systemic dissemination [31
]. In addition, some patients with HV-like symptomatology have severe CAEBV early in the course of the disease. Cases of HV lacking clonal rearrangement of TCR genes appear to have a more benign clinical course [50
]. The entity of HV-like lymphoma as included in the WHO classification stipulates an EBV-positive clonal proliferation [51
]. However, it is not clear that T-cell clonality is always predictive of a progressive clinical course, as discussed by HK. A related issue is severe mosquito bite allergy, which is usually of NK cell derivation, but shows overlap with HV [52
]. Both HV and severe mosquito bite allergy are considered part of the spectrum of CAEBV, with a broad spectrum of clinical aggressiveness.