EPSTEIN-BARR VIRUS EPIDEMIOLOGY

Epidemiology of primary Epstein-Barr virus infection

Epstein-Barr virus (EBV) is an ancient virus, and has probably coevolved with its different hosts over the last 90–100 million years (McGeoch et al., 1995). With the ability to establish lifelong latency and intermittent reactivation after primary infection and with limited clinical symptoms in the majority of infected individuals, EBV has become ubiquitous in all human populations

Age at primary infection

Children in developing countries acquire the infection in the first few years of life, and universal seroconversion is often seen by ages 3–4 years, whereas infection in developed countries often is delayed until adolescence (de The et al., 1975; Haahr et al., 2004; Henle and Henle, 1967; Melbye et al., 1984a,b) (Figure 53.1). In some developed countries a bimodal infection rate, with peaks in children below 5 years and again after 10 years of age, has been described (Edwards and Woodroof, 1979; Henle and Henle, 1967; Lai et al., 1975). Oral EBV excretion between parents and infants, and from intimate partners in adolescence and early adulthood is the likely explanation for the observed bimodality (Crawford et al., 2002; Fleisher et al., 1979).

Fig. 53.1

Age-specific distribution of EBV antibody positive individuals in four populations. Reproduced from de The et al., 1975; Henle and Henle, 1967; Melbye et al., 1984.

EBV antibody titers in seropositive individuals vary according to age following a U-shaped pattern, with high titers among infants and in the elderly (above 50 years) (Glaser et al., 1985; Venkitaraman et al., 1985). High antibody titers in infants probably reflect primary infection, whereas in the elderly it may be due to an age-dependent reactivation due to a reduced cellular immune response (Wick and Grubeck-Loebenstein, 1997).

Geographic variation

EBV has been detected in all populations and all areas of the world (IARC, 1997), but with noticeable geographical variation in the distribution of EBV genotypes. Two major types of EBV, type 1 and 2, have been described in humans, varying in the genes that encode some of the nuclear proteins in latently infected cells (Sample et al., 1990). Both types are detected all over the world, with type 1 being the most prevalent. However, in some regions (e.g. central Africa, Papua New Guinea and Alaska) type 2 is more prevalent (Table 53.1) (Gratama and Ernberg, 1995; Zimber et al., 1986). It is assumed that the geographical distribution of the two types in EBV-associated diseases reflects the general prevalence in the areas involved (Gratama and Ernberg, 1995). Thus, there seems to be no clear association between the two types and specific diseases.

Table 53.1

Distribution of EBV types 1 and 2 in various clinical conditions and among healthy patients. (Partly reproduced from Gratama and Ernberg, 1995 with permission from Elsevier.).

In most areas recovery of type 2 is unusual, except in immunodeficient (HIV+ individuals and transplant recipients) carriers. The increased detection in immunodeficent individuals has been explained by an increased exposure to exogenous virus combined with deficient EBV-specific cellular immunity, leading to long-term carriage of multiple EBV genotypes (Gratama and Ernberg, 1995). The frequency of the type 2 genotype in HIV-positive haemophiliacs is comparable to the frequency in healthy individuals, which indicates that the immunodefiency per se is not responsible for increased type 2 detection (Yao et al., 1998).

The distribution of specific DNA sequence polymorphisms also shows geographic variation, with the epidemiology of the EBV-encoded oncogene LMP-1 being the most thoroughly studied. Numerous sequence variations have been identified in LMP-1 genes from different EBV isolates, some of which have been associated with an increased risk of nasopharyngeal carcinoma (Jeng et al., 1994). Studies indicate that LMP-1 sequence variants from nasopharyngeal carcinoma high-incidence areas in Southeast Asia have evolved distinct from LMP-1 variants in nasopharyngeal carcinoma low-incidence areas such as areas of Australia, Papua New Guinea, and Africa (Burrows et al., 2004) suggesting that positive selection pressure on the LMP-1 sequences may enhance the oncogenic potential of virus isolates from nasopharyngeal carcinoma endemic areas.

EBV viral load epidemiology

During the recent decade, methods for detecting and quantifying cellular and extracellular EBV in peripheral blood have improved significantly. Initially applicable only to small series of patients, modern techniques such as real-time PCR have now made large studies feasible. However, the majority of these have been performed to investigate EBV viral loads in specific diseases, and knowledge on EBV viral load in healthy individuals has mainly been generated from the control groups, rarely selected randomly from the population.

EBV viral load in peripheral blood mononuclear cells (PBMCs) is the combined result of the number of infected B cells and the number of EBV genomes per B-cell. A roughly constant number of infected B cells (1–50 per 1,000,000) is present in peripheral blood in the healthy latently infected host, but the number seems to vary considerably between individuals (Khan et al., 1996). Differences in detection methods, sample preparation and measurement units make comparisons of EBV viral loads from different studies difficult. But the EBV viral load appears to be transiently elevated at the time of primary EBV infection (Fan and Gulley, 2001). In general, the viral load observed in PBMCs from healthy individuals is low (<100 DNA genome copies per ug DNA) compared to the high EBV loads observed in some EBV-associated diseases (ex. post-transplant lymphoproliferative disease (PTLD)) (Stevens et al., 2002a,b). The low EBV viral loads in most healthy EBV-infected individuals reflect the low frequency of EBV-positive B cells in the circulation, whereas the high EBV loads observed during PTLD and immune suppression are the result of increased numbers of EBV infected B cells (Babcock et al., 1999; Yang et al., 2000), together with an increased number of EBV genomes in some of the infected B cells (Rose et al., 2002). However, EBV viral load in PBMCs in the single healthy individual does not appear to be static. As healthy individuals are followed over time, short episodes of increased viral load can be observed, suggestive of EBV reactivation (Maurmann et al., 2003), and measurement of EBV viral load in PBMCs and plasma seem to detect episodes of EBV reactivation earlier and with greater sensitivity than the traditional serological methods (Figure 53.2). EBV detection in whole blood and serum/plasma is becoming the ‘gold standard’ and most commonly utilized test, as it is less laborious and more reproducible than PBMCs.

Fig. 53.2

Healthy individuals with serological evidence of EBV reactivation during 15 months of follow-up. -_- viral load (PBMC), -Δ- Viremia (plasma), ♦ EBV IgG (IU/ml). Partly reproduced from Maurmann et al., 2003.

The correlation between EBV viral load in PBMCs and serological response is not obvious (Gartner et al., 2000). Increased anti-p18-VCA, suggestive of lytic viral replication, and decreased anti-EBNA-1 IgG levels has been associated with high EBV loads in HIV carriers (Stevens et al., 2002a,b).

EBV in plasma or serum, which is frequently detected in patients with nasopharyngeal carcinoma or PTLD, is only rarely detected in healthy individuals, although EBV viremia can be detected in association to episodes of EBV reactivation (Lechowicz et al., 2002;).

Infectious mononucleosis

Primary EBV infection is usually considered asymptomatic when occurring in infants and small children, and most of the knowledge on primary infection is derived from studies of adolescent patients with infectious mononucleosis. However, the assumption that primary EBV infection in childhood is always subclinical is probably fallacious, as when looked for, infectious mononucleosis symptoms may also occur in infants in association with primary EBV infection (Chan et al., 2003). Although symptoms may be milder, primary infection in infants is not presumed to be fundamentally different from the characteristic picture of infectious mononucleosis (IARC, 1997).

Primary EBV infection in adolescence causes infectious mononucleosis in more than half of the infected individuals. Symptoms of infectious mononucleosis (glandular fever) commence after an incubation period of 4–7 weeks, and typically (in more than 50%) include fever, lymphadenopathy and pharyngitis (Chang, 1980).

Confirmation of the diagnosis has traditionally been based on the detection of heterophil antibodies, which are present in 86% of adolescents and adults with infectious mononucleosis (Fleisher et al., 1983), but less frequently in acutely infected small children (Chan et al., 1998). However, positive detection of heterophil antibodies can occur in other conditions, including HIV infection, Systemic Lupus Erythematosus, and other viral diseases (Hendry and Longmore, 1993; Horwitz et al., 1979; Macsween and Crawford 2003). Detection of IgM to the viral capsid antigen (VCA) is both more sensitive and specific, and is present at time of onset of clinical symptoms. Both heterophil antibodies and anti-VCA IgM are transient and disappears within months, and detection of EBV-DNA in serum might be useful as a supplement to serology for the diagnosis (Chan et al., 2001).

Epidemiology

The majority of infectious mononucleosis patients are not hospitalized, but reliable data on the population incidence is available from sentinel systems, centralized laboratories or from areas where infectious mononucleosis is a reportable disease. Incidence rates between 60–100 per 100,000 person-years in Caucasian populations seem consistent (Evans et al., 1997; Morris and Edmunds, 2002; Rosdahl et al., 1973). In these populations the incidence of infectious mononucleosis increases from the age of 2–4 years to reach a maximum in adolescence and early adulthood, after which the disease incidence decreases, to become rare after 40 years of age (Figure 53.3) (Auwaerter, 1999; Rosdahl et al., 1973). The age-specific distribution of cases reflects the clinical disease ratio of primary EBV infection which is low in children, and may reach 74% among college students (Sawyer et al., 1971). The low incidence among older adults reflects the low number of EBV-uninfected individuals. There seems to be no seasonal variation in incidence rates.

Fig. 53.3

Age-and sex-specific distribution of positive Paul–Bunnell reactions at Statens Serum Institut in Denmark 1965–1969. Reproduced from Rosdahl et al., 1973 with permission from Taylor & Francis Scandinavia.

The difference in infectious mononucleosis incidence rates between ethnic groups within the same region, probably reflects variation in social and economic factors, influencing age at primary infection (Heath et al., 1972; Melbye et al., 1984a,b), and there is no evidence of racial differences in infectious mononucleosis susceptibility.

Risk factors for infectious mononucleosis

The factors influencing clinical disease are summarized in Table 53.2.

Table 53.2

Factors influencing the development of infectious mononucleosis.

The marked difference in infectious mononucleosis incidence in comparable settings with an equal number of susceptible individuals, indicates that determinants other than immune status and age at infection are involved. As intimate contact appears to account for most cases of infectious mononucleosis (Crawford et al., 2002), age-specific incidence of infectious mononucleosis in otherwise comparable settings can differ due to behavioural differences.

In children, carriage of the ATA haplotype in the promoter of interleukin (IL)-10, is associated with high levels of spontaneous IL-10 and a late age of primary EBV infection. Thus, the ATA haplotype may increase the age at primary infection and perhaps also the risk of symptomatic disease (Helminen et al., 2001).

Studies on HLA-alleles and infectious mononucleosis have produced conflicting results. A higher frequency of HLA-B-3501 among infectious mononucleosis cases compared to controls has been reported, however, the association between infectious mononucleosis, HLA-B-3501 and other HLA-alleles has not been reproduced in other populations (Chang, 1980).

Viral factors, including EBV strain variation, have not been associated with a different ability to cause infectious mononucleosis.

EBV dynamics during infectious mononucleosis

In healthy seropositive individuals EBV DNA in serum is only occasionally detected, but in the acute phase of infectious mononucleosis high loads of EBV DNA in serum is present in most patients (Fig. 53.4) (Berger et al., 2001). The peak in serum viral load is observed in the first seven days of disease, thereafter viral load decreases with resolution of symptoms, although there seem to be considerable inter-individual differences in the decline (Berger et al., 2001). Parallel with the increase in serum viral load, the EBV viral load in peripheral blood mononuclear cells (PBMC) increase to a maximum within the first weeks of the disease, and thereafter declines (Kimura et al., 1999). However, sustained high levels of EBV DNA is found in saliva for at least 6 months after onset of clinical disease, associated with persistent infectivity of saliva (Fafi-Kremer et al., 2005).

Fig. 53.4

EBV DNA levels in sera from individuals with different EBV-antibody patterns. A: sero-negative, B:sero-positive, C: acute EBV-infection. Reproduced from Berger et al., 2001 with permission from John Wiley & Sons, Inc.

Despite the lack of massive expansion in numbers of T lymphocytes in asymptomatic primary EBV infection, both patients with IM and asymptomatic primary infection have similar high EBV viral loads in PBMC. Thus the large T cell expansion seen in IM patients may represent an overreaction, not associated with the control of the primary EBV infection (Silins et al., 2001).

Studies on EBV viral load in primary infection have focused on the time around the infection, and the importance of early versus delayed primary EBV infection on long-term EBV viral load is unknown.

Chronic active EBV infection

Chronic active EBV infection (CAEBV) was first described in the late 1970s, and is characterized by chronic or recurrent infectious mononucleosis-like symptoms and by an unusual pattern of EBV antibodies. Criteria’s for diagnosing CAEBV has been suggested earlier, and recently a new set of guidelines has been proposed (Table 53.3) (Okano, et al., 2005; Straus, 1988).

Table 53.3

Proposed guidelines for diagnosing CAEBV (all conditions must be fulfilled). Adapted from Okano et al., 2005 with permission from John Wiley & Sons, Inc.

The antibody pattern resembles acute infection and is characterized by high titers of IgG-VCA and IgG-EA, and absence of EBNA antibodies. Patients with CAEBV also have lower frequencies of EBV-specific CD8⁺ T-cells, compared to infectious mononucleosis patients and healthy individuals (Sugaya et al., 2004). Methods for measuring EBV viral load can be included, as high EBV viral loads in peripheral blood lymphocytes and serum are present (Kimura et al., 2001). There is no known hereditary background, and CAEBV is not associated with mutations in the gene responsible for X-linked lymphoproliferative syndrome (Sumazaki et al., 2001).

CAEBV seem to constitute a disease spectrum with unusual EBV activation, from chronic symptomatic EBV infections with moderately elevated EBV antibodies and a generally good prognosis, to severe chronic active EBV infection with extraordinarily elevated EBV antibodies, clonal expansion of EBV-infected T cells and NK cells, severe clinical and hematological findings, and a generally poor prognosis with high mortality from pancytopenia, lymphoma and hepatic failure (Fig. 53.5) (Kimura et al., 2001; Okano, 2002).

Fig. 53.5

Survival after onset of severe CAEBV. All patients (A), and according to age (B), platelet count (C) and T/NK cell-type of disease (D). Reproduced from (Kimura et al., 2001) with permission from The University of Chicago Press.

Thrombocytopenia and age> = 8 years at onset of disease are associated with a poorer outcome (Kimura et al., 2003).

X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP) or Duncan’s disease is a rare, primary immunodeficiency that was first described as a familial disorder affecting males with a rapidly fatal course in response to EBV infection (Purtilo et al., 1975). XLP is characterized by three major phenotypes (Table 53.4): fulminant infectious mononucleosis, B cell lymphoma and dysgammaglobulinemia. Occasionally aplastic anemia, vasculitis and pulmonary lymphomatoid granulomatosis are seen (Engel et al., 2003). A patient can develop more than one phenotype.

Table 53.4

Phenotypes of X-linked lymphoproliferative syndrome. Adapted from Engel et al., 2003 with permission from Nature Publishing Group.

A lack of immune surveillance of EBV in patients with the infectious mononucleosis phenotype of XLP is assumed, however, the phenotypes with B-cell lymphoma and dysgammaglobulinaemia can be observed in patients with or without signs of previous infection with EBV, suggesting other antigenic stimuli are also involved in the development of XLP (Table 53.5) (Engel et al., 2003; Sumegi et al., 2000).

Table 53.5

Effect of EBV infection on clinical phenotype in XLP. Adapted from (Sumegi, et al. 2000) with permission from the American Society of Hematology.

Treatment is difficult, haematopoietic stem cell transplantation for fulminant infectious mononucleosis and B-cell lymphomas, and immunoglobulin treatment for agammaglobulinemia has been suggested, but the mortality by the age of 40 years is nearly 100% (Gross et al., 1996; Morra et al., 2001).

The genetic basis for XLP has been identified as an alteration or deletion of the gene SH2D1A, that codes for a cytoplasmatic protein, SAP (SLAM-associated protein, where SLAM is ‘signalling lymphocytic activation molecule’) (Coffey et al., 1998; Nichols et al., 1998). SAP interacts with several signaling molecules of the SLAM (CD150) family, and is expressed by all T and NK cells. Defective SAP causes selective alterations of the T-/NK-cell function that compromise the ability of these cells to control infection with EBV (Benoit et al., 2000; Engel et al., 2003). Elevated EBV antibody titers are observed in mothers to boys with XLP, although, normal levels of circulating EBV-DNA in XLP patients surviving the initial phase suggest that SAP function is not essential for proper control of EBV replication after primary infection (Sumazaki et al., 2001).

Mutations of SH2D1A are detected in nearly all cases of XLP with a previous family history of XLP, however, mutations of SH2D1A are frequently missing in XLP cases without a family history (Sumegi et al., 2000), although de novo mutations can occur (Sumazaki et al., 2001).

Epstein–barr virus and malignant neoplasms

EBV has been implicated in the development of a wide variety of benign and malignant diseases (Table 53.6). In the following, only the virus’ association with malignant diseases will be described. Accordingly, the association between EBV and autoimmune conditions such as multiple sclerosis (Wekerle and Hohlfeld, 2003) or systemic lupus erythematosus (Kang et al., 2004), or immune deficiency-related conditions, such as oral hairy leukoplakia (Niedobitek et al., 1991) and lymphoid interstitial pneumonitis (Swigris et al., 2002) will not be discussed. Focus will be on the main characteristics of EBV-associated cancers and on the evidence linking them with the virus. Nasopharyngeal carcinoma, Burkitt’s lymphoma, and Hodgkin’s lymphoma will be described in some detail, whereas the association between EBV and other malignant disorders are described more cursorily.

Table 53.6

Evidence for an association between different types of cancer and EBV. Adapted from Hsu and Glaser, 2000.

Epidemiology

The occurrence of nasopharyngeal carcinoma is characterized by a remarkable geographical and ethnic variation as reflected in the combined occurrence of all types of cancer in the nusopharynx (Table 53.7). (Yu and Yuan, 2002). The tumor is quite rare in most Western countries with incidence rates less than 1 per 100 000 persons per year, as is it indeed in most parts of the world, but high incidence rates are observed in certain ethnic populations in South-East Asia and North Africa and in the circumpolar indigenous populations (Table 53.7). Common to both low-and high incidence areas, nasopharyngeal carcinoma is seen two-to-three times more often in men than in women (Table 53.7). Different age-specific incidence patterns are observed in endemic and non-endemic regions (Parkin et al., 2002; Lee et al., 2003; Yu and Yuan, 2002): In non-endemic regions nasopharyngeal carcinoma occurrence increases continuously with age, whereas in endemic regions the incidence increases with age to peak around the age of 50 years and decrease thereafter. A third bimodal age pattern with a minor incidence peak in adolescents and young adults has been described in some populations with low to intermediate nasopharyngeal carcinoma incidence (Yu and Yuan, 2002; Daoud et al., 2003).

Table 53.7

Incidence rates for nasopharyngeal cancer (all types combined) in different regions. Adapted from Yu and Yuan, 2002 and updated from Parkin, et al., 2002. Data for Greenland from Friborg et al., 2003.

Even within regions where nasopharyngeal carcinoma is endemic considerable variation in disease occurrence can be observed between different ethnic subpopulations. For instance, in the Chinese province of Guangdong the incidence of nasopharyngeal carcinoma is twice as high in Cantonese as in other ethnic groups (Li et al., 1985; Yu et al., 1981; Yu and Yuan, 2002). Familial clustering of nasopharyngeal carcinoma and other cancers is well-established from a plethora of case-reports (Zeng and Jia, 2002). The familial accumulation in turn translates into increased risks for nasopharyngeal carcinomas, e.g., first degree-relatives of Greenlandic Inuits with nasopharyngeal carcinoma have an eight-fold higher risk of the tumor than the general population (Friborg et al., 2005). Epidemiologically, these observations may indicate a genetic predisposition to nasopharyngeal carcinoma, a suspicion that has been supported by genetic studies. Specifically, a meta-analysis of published data for Chinese patients showed increased risk for HLA alleles A2, B14, B46, and decreased risks for HLA alleles A11, B13 and B22 (Goldsmith et al., 2002). Moreover, susceptibility loci have been reported on chromosomes 3 (Xiong et al., 2004), 4 (Feng et al., 2002), 14 [Diehl et al., unpublished observations quoted in (Pickard et al., 2004)] and near the HLA-locus (Lu et al., 1990). Polymorphisms in genes coding for certain enzymes involved in nitrosamine metabolism [Gluthathione S-transferase M1 and cytochrome P450 2E1] also have been reported to correlate with risk for nasopharyngeal carcinoma [reviewed by (Zeng and Jia, 2002; Hildesheim et al., 1997)].

There is good evidence, however, that environmental factors are also significant to the risk of nasopharyngeal carcinoma. Accordingly studies of families emigrating from high to low risk regions have shown that the risk of nasopharyngeal carcinomas decreases between successive generations (IARC, 1997). Among environmental factors, the evidence is particularly strong against certain diets including Cantonese-style salted fish and other preserved foods (for review, see IARC, 1997). Accordingly, a high intake of preserved foods is a common characteristic of the populations where nasopharyngeal carcinoma is endemic, and case-control studies in endemic as well as non-endemic regions have demonstrated an association between intake of such food items and nasopharyngeal carcinoma risk. Moreover, the risk for nasopharyngeal carcinomas seems to be inversely correlated with the age of first exposure. Consistent with the role of diet, the incidence of nasopharyngeal carcinoma in Hong Kong has decreased over the last decades concomitantly with changes in lifestyle towards a western-world pattern (Lee et al., 2003). Other suggested risk factors have included low socioeconomic status (possibly correlated with high intake of preserved food items), tobacco, and alcohol, and occupational exposure to formaldehyde and wood dust (Hildesheim et al., 2001; IARC, 1997).

It is noteworthy that the association between preserved food and risk for nasopharyngeal carcinoma gains biological plausibility in the context of the familial accumulation of the tumor and its association with EBV. Accordingly, the preserved foods contain carcinogenic nitrosamines, as well as EBV-activating substances (IARC, 1997).

Evidence of association with EBV

Infection with EBV has been implicated in the development of nasopharyngeal carcinoma by several different lines of evidence (Table 53.6). Historically, the first indication was the observation that sera from African and American patients with nasopharyngeal carcihoma were often more positive for precipitating antibodies to antigens prepared from cultured Burkitt’s lymphoma cells than controls (Old et al., 1966). This observation has since been confirmed in serological studies showing elevated titers of IgG and in particular IgA antibodies against EBV viral capsid, early and nuclear antigens in nasopharyngeal carcinoma patients data being less compelling for type Ⅰ than types Ⅱ and Ⅲ, manifesting as apparent ethnic variations (IARC, 1997; Raab-Traub, 2000). Antibody titers correlate with stage of disease and has been shown to return to normal levels in long-term disease-free survivors (Yu and Henderson, 2004). More compelling than the sero-prevalence surveys in patients are, however, the results of a prospective study of 9699 persons which showed that presence of IgA anti-EBV viral capsid antigen antibodies or neutralising EBV specific anti-DNase antibodies correlated with subsequent risk for nasopharyngeal carcinoma (Fig. 53.6) (Chien et al., 2001).

Fig. 53.6

Cumulative incidence of nasopharyngeal carcinoma in persons testing positive or negative for either IgA anti-Epstein– Barr virus viral capsid or neutralizing anti-Epstein–Barr virus DNase antibodies. Reproduced from Chien et al., 2001 (more...)

The serological findings are corroborated by the demonstration of monoclonal EBV in the malignant nasopharyngeal carcinoma cells (Raab-Traub and Flynn, 1986). This line of evidence is most consistent for nasopharyngeal carcinoma types Ⅱ and Ⅲ, but the virus has also been demonstrated in type Ⅰ carcinomas (Nicholls et al., 1997; Raab-Traub, 2000). Consistent with the assumption of a causal role for the virus in development of the tumor, monoclonal EBV has also been demonstrated in pre-invasive dysplastic and carcinoma in situ lesions (Pathmanathan et al., 1995) as has the virus been demonstrated in nasopharyngeal carcinoma metastases (Lee et al., 2000).

More recently, the detection and quantification of circulating EBV DNA have attracted interest. In one study, such DNA was demonstrated in 96% of patients with nasopharyngeal carcinoma as compared with only in 7% of controls, and levels of DNA moreover correlated with disease stage (Figure 53.7) (Lo et al., 1999) and, independently hereof, also with prognosis (Lo et al., 2000; Lin et al., 2004).

Fig. 53.7

Comparison of plasma cell-free EBV DNA in NPC patients and control subjects. The categories (NPC patients and control subjects) are plotted on the X-axis. The Y-axis denotes the concentration of cell-free EBV DNA (copies of EBV DNA/ml of plasma) detected (more...)

Tumors of the lymphoid tissues

The tumors of the lymphoid tissues constitute a clinically and epidemiologically heterogeneous group of malignancies with the common characteristic that they are derived from cells belonging to the lymphoid lineage. Three major categories of lymphoid malignancies are recognized today, i.e. B-cell lymphomas, T and NK-cell lymphomas, and Hodgkin’s lymphomas (Harris et al., 2001a,b). Within each of these categories, distinct disease entities are recognised based on morphologic, immunophenotypic, genetic and clinical characteristics.

The occurrence of non-Hodgkin’s lymphoma generally increases with age and overall lymphomas are more often seen in men than in women with a male: female incidence ratio of 1.5–2:1 (Parkin et al., 2002). Incidence rates vary internationally, age-standardized (world) rates ranging from typically 3–8 and 2–6 per 100 000 Asian men and women to 10–15 and 5–10 per 100 000 in European men and women (IARC, 2002). An as yet unexplained remarkable increase in the incidence of all types of non-Hodgkin’ lymphomas combined was apparent in the latter half of the twentieth century in most regions of the world, amounting to 3%–4% increase annually (Devesa and Fears, 1992). Recent data from Scandinavia suggest that the increase has just as inexplicably begun to subside (Sandin et al., 2006).

Relatively few risk factors have been established for non-Hodgkin’s lymphomas (Scherr and Mueller, 1996; Grulich and Vajdic, 2005; Ekstrom-Smedby, 2006). In part, this may reflects that the composite nature of the malignant lymphomas including possible etiological heterogeneity has not always been taken into consideration previously. The most consistently observed risk factor is immune suppression, primary as well as acquired. Other risk factors include familial aggregation (Chang et al., 2005; Goldin et al., 2005), autoimmune conditions (Zintzaras et al., 2005) and exposure to certain hair dyes (Takkouche et al., 2005) and herbicides (Fritschi et al., 2005; Scherr and Mueller, 1996). Several infectious organisms are known or suspected to be etiologically linked to lymphoma development including both bacteria, e.g., Helicobacter pylori (Wotherspoon et al., 1991), Borrelia burgdorferi (Cerroni et al., 1997), Campylobacter jejuni (Lecuit et al., 2004), Chlamydia psittaci (Ferreri et al., 2004) and viruses, e.g., human herpesvirus-8 (Cesarman et al., 1995), human T-cell lymphotropic virus type Ⅰ (Hinuma et al., 1981), hepatis C virus (Pozzato et al., 1994), and EBV (Epstein et al., 1964).

The evidence for an association with EBV infection is the strongest for Burkitt’s lymphomas, NK/T-cell lymphomas of the nasal cavity, for malignant lymphomas in immune incompetent patients, and for a subset of Hodgkin’s lymphomas. The virus may, however, also be encountered in other types of malignant lymphomas, though less regularly (IARC, 1997). It is noteworthy, therefore, that in a prospective serological investigation elevated IgG (≧ 1:320) and IgM (≧ 1:5) titres of anti-viral capsid antigen antibodies were associated with 2.5-(IgG)and 3.2-fold (IgM) increased risks for non-Hodgkin’s lymphoma overall with no apparent difference between different lymphoma subtypes (Mueller et al., 1991).

Burkitt’s lymphoma/leukemia

Burkitt’s lymphoma is a highly aggressive lymphoma that often presents extranodally or as acute leukemia (Diebold et al., 2001). The presumed cell of origin is a germinal centre B-cell. Based on clinical and epidemiological characteristics, three variants of Burkitt’s lymphoma are recognized, i.e., endemic, sporadic, and immunodeficiency-associated Burkitt’s lymphoma. Histologically, the tumor is generally characterized by monomorphic cytoarchitecture composed of medium-sized B cells with basophilic cytoplasm and numerous mitotic figures with variations between the tumor variants. A constant feature shared by all Burkitt’s lymphoma variants is chromosomal translocations involving the MYC oncogene on chromosome 8 (i.e., either t(8:14), t(2:8) or t(8:22) (Diebold et al., 2001)).

Epidemiology of endemic Burkitt’s lymphoma

The endemic variant of Burkitt’s lymphoma is primarily a childhood malignancy seen in Papua, New Guinea and in equatorial Africa, where in certain areas it is the most common childhood cancer (van den Bosch, 2004). The tumor occurs two-to-three times as often in boys as in girls and in both genders the incidence of endemic Burkitt’s lymphoma peaks at ages 5–9 years (Diebold et al., 2001). Precise incidence rates are difficult to obtain, but data suggest crude incidence rates of 4.6 and 2.9 per 100 000 in Ugandan boys and girls < 15 years (IARC, 2002).

One of the most striking characteristics of endemic Burkitt’s lymphoma is the correspondence between its geographical distribution and measures of prevalence of malaria infection, a correlation that is apparent both between and within regions and over time (IARC, 1997). Moreover, the peak ages for endemic Burkitt’s lymphoma is also the age interval during which anti-malarial antibodies peak (IARC, 1997). These ecological similarities have been interpreted as reflecting a role for malarial infection in development of endemic Burkitt’s lymphoma, as discussed below. Other suspected risk factors, the effects of which are also related to EBV infection, are certain groups of plants used in traditional medicine that may stimulate viral replication. The direct evidence of the role of such is, however, limited (IARC, 1997).

Epidemiology of sporadic Burkitt’s lymphoma

Sporadic Burkitt’s lymphoma occurs predominantly in children and young adults, and is seen throughout the world (Diebold et al., 2001). The tumor make up a few percent of all lymphomas in industrialized countries, but constitutes up to 50% of all lymphomas in children (Diebold et al., 2001). Like the endemic variant, sporadic Burkitt’s lymphoma is seen two-to-three times as often in males as in females. Generally, the incidence of sporadic Burkitt’s lymphoma is much lower than that of the endemic variant, e.g., rates of 0.38 and 0.08 per 100 000 are observed in white US boys and girls <15 years (Parkin, 2002). Familial accumulation of the lymphoma has been reported in a few instances, but otherwise few risk factors have been established (IARC, 1997).

Epidemiology of AIDS-related Burkitt’s lymphoma

Burkitt’s lymphoma frequently is the AIDS defining malignancy in HIV-infected patients (Diebold et al., 2001). The tumor and its association with EBV are described later. Burkitt’s lymphoma is also seen in organ transplant recipients.

Evidence of association with EBV

EBV was originally identified in an endemic Burkitt’s lymphoma cell culture (Epstein et al., 1964), and of the three lymphoma variants, the endemic type has remained the most strongly associated with the virus. The evidence of an association between Burkitt’s lymphoma and EBV includes both serological and molecular biological studies (Table 53.6).

An early classical paper describes a prospective serological investigation set in the Uganda West Nile District, where Burkitt’s lymphoma is endemic. Based on an initial collection of blood samples from nearly 42 000 healthy children, children who subsequently developed Burkitt’s lymphoma displayed statistically significantly higher titres of antiviral capsid antigen antibodies than their peers, who remained healthy (geometric mean titre 425.5 vs. 125.8). No differences were observed between the two groups of children for anti-early antigen or anti-EBV nuclear antigen antibodies (de-Thé et al., 1978). In a later update of the study, each twofold dilution of antiviral capsid antigen antibody titer was associated with a five-fold in Burkitt’s lymphoma risk overall and a nine-fold increased risk of EBV-positive lymphomas (Geser et al., 1982).

Employing different serological techniques, studies have suggested that African Burkitt’s lymphoma patients are more often infected with EBV than their peers and also display higher anti-EBV antibody titres (IARC, 1997). Similar patterns have also been observed in sporadic Burkitt’s lymphoma patients, in particular children, though with less striking differences vis à vis controls (IARC, 1997).

Large case-series have since the original observation confirmed the presence of EBV in endemic Burkitt’s lymphoma cells. Accordingly, virus has been demonstrated in more than 95% of investigated endemic Burkitt’s lymphoma cases (IARC, 1997). In contrast, the prevalence of EBV in sporadic Burkitt’s lymphoma in general appears to be less than 30% (IARC, 1997; Diebold et al., 2001), albeit with considerable variation in reported estimates ranging between 15 and 88% (Hsu and Glaser, 2000). In AIDS-related Burkitt’s lymphoma, the prevalence of EBV is 25 to 50% (Diebold et al., 2001; Raphael et al., 2001).

The mechanism by which EBV contributes to the development of Burkitt’s lymphoma is not entirely understood, but the virus’s absence in many cases either suggests that it is neither sufficient nor necessary for the tumor to develop or, alternatively, that EBV-positive and -negative tumors are different biological entities (Bellan et al., 2005). For EBV positive tumors, age at infection with the virus and the ability to control infected cells seem critical (Mueller et al., 1996). For endemic Burkitt’s lymphoma it has been suggested that early EBV infection may lead to transformation and replication of a large subset of B-lymphocytes. This process in turn may be augmented by recurrent malaria infections that act both as B-cell mitogen and T-cell suppressant. Translocation involving chromosome 8 may then result from the increased cell replication (Klein, 1979; de The, 2000). Some support for the interaction between malaria and EBV comes from studies showing that the number of EBV infected cells is higher during acute malaria than after recovery (Lam et al., 1991) and that the number of EBV infected cells correlate with the intensity of malaria transmission in the area of residence (Moormann et al., 2005). It is noteworthy, however, that in the aforementioned prospective serological investigation, the children who developed endemic Burkitt’s lymphoma and children who remained healthy had similar rates of malaria parasitemia before tumor development (de-Thé et al., 1978). Accordingly, other models for the role of EBV in Burkitt’s lymphoma development have also been proposed (Hecht and Aster, 2000; van den Bosch, 2004). The occurrence of EBV-positive Burkitt’s lymphoma in AIDS patients and in organ transplant recipients would also be consistent with a critical role for immunological control of EBV-infected cells in the lymphoma development, as would an inverse correlation between socioeconomic status and Burkitt’s lymphoma occurrence (Hsu and Glaser, 2000).

NK/T-cell lymphomas

EBV is associated with certain types of NK/T-cell lymphomas. These include in particular the extranodal NK/T-cell lymphoma of the nasal type, but also aggressive NK-cell leukemia (Nava and Jaffe, 2005) and possibly angioimmunoblastic T-cell lymphoma (Anagnostopoulos et al., 1992; Chan et al., 1999; Huh et al., 1999; Weiss et al., 1992) and extranodal enteropathy-type T-cell lymphoma (Huh et al., 1999; Quintanilla-Martinez et al., 1997; Zhang et al., 2005). Histologically, extranodal NK/T-cell lymphomas of the nasal type are characterized by a broad morphological spectrum, but an angiodestructive pattern with frequent necrosis and apoptosis is a characteristic finding (Chan et al., 2001; Nava and Jaffe, 2005). As signaled by the name the malignant cells are either of NK-cell (the majority) or T-cell origin. The nasal region is the most frequent site of involvement, but the tumor may also present at other extranodal sites such as skin testis, kidney, upper gastrointestinal tract, and the orbit (Chan et al., 2001; Rizvi et al., 2006).

Epidemiology of mature T- and NK-cell lymphomas

Mature T- and NK-cell tumors are generally rare tumors, and NK/T cell lymphomas of the nasal type even more so. In an international series comprising lymphoma patients from the US, Europe, Asia and South Africa peripheral T-cell lymphoma made up 9.4% of all non-Hodgkin’s lymphomas, however, with considerable geographic variation, ranging from 1.5% in Vancouver, Canada to 18.3% in Hong Kong (Rudiger et al., 2002). In the same series, NK/T-cell lymphomas of the nasal type constituted a mere 1.4% of the all investigated lymphomas (Rudiger et al., 2002), all cases except three diagnosed in Hong Kong. Thus, NK/T-cell lymphomas of the nasal type are rare in the Western world, and is more commonly seen in Asia, Mexico and in Central and South America countries (Hsu and Glaser, 2000). In a recent Chinese case series from Hong Kong, NK/T-cell lymphomas of the nasal type made up 6.3% of all non-Hodgkin’s lymphomas (Au et al., 2005), and similar proportions have been reported from Peru (Quintanilla-Martinez et al., 1999). Generally, the incidence is held to be higher in men than in women (Hsu and Glaser, 2000). Besides the ethnic variation little is known about risk factors for this small group of lymphomas, but the entity has been described in immune dysfunctional individuals (Stadlmann, 2001).

Evidence of association with EBV

EBV has been incriminated in NK/T-cell lymphoma development exclusively by the demonstration of the virus in the tumor cells (Table 53.6). Accordingly, patient series have shown that the NK/T-cell lymphomas of the nasal type almost invariably (90%) harbor EBV, irrespective of the patient’s ethnicity (Chan et al., 2001a,b; Kanavaros et al., 1993; Miyazato et al., 2004; Quintanilla-Martinez et al., 1997); in Asians also when presenting outside the nasal cavity (Chan et al., 1997).

Hodgkin’s lymphoma

Hodgkin’s lymphoma develops from germinal center B-lymphocytes in the vast majority (> 98%) of all cases, and in rare instances from post-thymic T-cells (Stein et al., 2001). Histologically, the tumor typically contains a small number of malignant cells, which are large mono- and multinucleated cells (Hodgkin’s or Reed–Sternberg cells), surrounded by T-lymphocytes in a rosette-like pattern and dispersed in an abundant mixture of reactive inflammatory and accessory cells (Stein, 2001). Based on clinical and biological criteria, two main types of Hodgkin’s lymphoma are recognized, i.e., nodular lymphocyte predominant (5%) and classical (95%) Hodgkin’s lymphoma, the latter being further divided into four histological subtypes [nodular sclerosing (70%), mixed cellular (20–25%), lymphocyte rich (∼ 5%) and lymphocyte depleted (<5%) classical Hodgkin’s lymphoma (Stein, 2001).

Epidemiology

Hodgkin’s lymphomas constitute 10%–15% of all malignant lymphomas [slighty more when chronic lymphocytic leukemia is disregarded] (Parkin et al., 2002). In Western countries, age-standardized (world) incidence rates are typically in the range of 2–4 per 100 000 in men and 1.5–3 per 100 000 in women, whereas incidence rates < 1 per 100 000 in both men and women are typical for Asia (Parkin et al., 2002). Geographical differences also exist with respect to age-specific incidence rates. In industrialized countries a conspicuous bimodal age distribution with cases accumulating in young adults and the elderly has become one of the lymphomas distinguishing characteristics (Fig. 53.8). In Hodgkin’s lymphoma epidemiology literature, this pattern has been referred to as Pattern Ⅲ, implying the existence of Patterns I and Ⅱ (Correa and O’Conor, 1971). Of these, Pattern I was seen in developing countries and was characterized by relatively high incidence of Hodgkin’s lymphoma in children, low incidence in the third decade and high incidence in the elderly. Pattern Ⅱ was perceived as an intermediate between Pattern I and Ⅲ. A Pattern IV describing a general paucity of Hodgkin’s lymphoma in all age groups was also suggested based on data originally reported from Asian countries (Correa and O’Conor, 1971). A more recent survey of register data indicate that, with the possible exception of Asian countries, these archetypical incidence patterns may no longer be as clearly distributed geographically (Macfarlane et al., 1995).

Fig. 53.8

Age-specific incidence of Hodgkin’s lymphoma in the white population of Brooklyn, U.S., 1943–52. Reproduced from MacMahon, 1957 with permission from John Wiley & Sons, Inc.

The bi-modal age distribution in Pattern Ⅲ reflects the age-related distributions of the different subtypes of Hodgkin’s lymphoma with the nodular sclerosis subtype making up the bulk of the young adult age peak, and mixed cellularity subtype increasing in frequency with age, but has nevertheless also been used to define epidemiologically (meaningful) disease entities (MacMahon, 1957; MacMahon, 1966). Accordingly, studies of risk factors for Hodgkin’s lymphoma have often focused on specific age-groups, i.e., children [<15 years], young adults [15–ca. 44 years], and elderly [≧ca. 45 years], rather than specific Hodgkin’s lymphoma subtypes. Presumably reflecting the age distribution of cases, most epidemiological studies have concentrated on Hodgkin’s lymphoma in young adults, the risk of which has been associated with an affluent childhood social environment, as measured by long maternal education, small sibling size and housing (Mueller, 1996). In contrast, Hodgkin’s lymphoma in children appears to be associated with low socioeconomic status, whereas it plays little if any role for the risk for Hodgkin’s lymphoma in the elderly (Mueller, 1996). It has long been suspected that the association with childhood environment in young adults cases reflects a surrogate for loads of infectious diseases in childhood, and that, in young adults, the lymphoma might arise as an untoward reaction to delayed exposure to a common childhood infectious agent (Gutensohn and Cole, 1977). Consistent with this notion, attendance of nursery school or day care for more than 1 year was associated with a reduced risk (odds ratio = 0.64; 95% confidence interval 0.45 to 0.92) for Hodgkin’s lymphoma at ages 15–54 years in a recent investigation (Chang et al., 2004). Patients suffering from immune incompetence, whether acquired or inherited, are at increased risk for Hodgkin’s lymphoma. In AIDS patients, for instance, the increase in the order of 10-fold (Frisch et al., 2001). Hodgkin’s lymphoma is also known to cluster within families suggesting a genetic predisposition to the disease (Goldin et al., 2004). Also, smoking has recently been incriminated in two large case-control studies, suggesting relative risks of around two for current smokers (Briggs et al., 2002; Chang et al., 2004), although previous studies have yielded conflicting results (for review see Briggs et al., 2002). Among investigated occupational exposures, wood working and formaldehyde exposure have frequently been associated with risk for Hodgkin’s lymphoma (Mueller, 1996).

Evidence of association with EBV

Epidemiological, serological, and molecular biological studies have all suggested that EBV is involved in the development of at least a proportion of Hodgkin’s lymphomas (Table 53.6). Consistent with suspected mechanisms underlying the association with affluence in childhood, history of infectious mononucleosis has been associated with an increased risk for Hodgkin’s lymphoma in cohort as well as case-control studies, relative risks typically in the order of two-to-threefold increased (Alexander et al., 2003; Hjalgrim et al., 2000; IARC. 1997). The risk increase seems to be specific to Hodgkin’s lymphoma and inversely correlated with time since infectious mononucleosis, in practice restricting it to the young adult age group (Hjalgrim et al., 2000). Serological investigations have also pointed to a role for EBV in Hodgkin’s lymphoma pathogenesis. Specifically, though patients with Hodgkin’s lymphoma appear not to be more frequently infected with the viruses (as measured by prevalence of antiviral capsid antigen IgG antibodies at diagnosis) than comparable controls, the patients have higher mean titres of these antibodies (IARC, 1997). In case-control studies the patients also demonstrate antibodies against the early antigen complex and at higher titres more often than normal persons (IARC, 1997). Perhaps the most compelling evidence, however, comes from a prospective serological investigation, in which prediagnostic elevated titres of antiviral capsid antigen IgG antibodies (relative risk = 2.6; 90% CI 1.1 to 6.1), anti-diffuse early antigen antibodies (relative risk = 2.6; 90% CI 1.1 to 6.1) and anti-restricted early antigen (1.9; 90% CI 0.90–4.0) were all associated with risk of Hodgkin’s lymphoma (adjusted for IgM). In multivariate analyses including all types of anti-EBV antibodies, risk for Hodgkin’s lymphoma was associated with high titers of anti-EBV nuclear antigen antibodies (relative risk = 6.7; 90% CI 1.8 to 25) and inversely associated with IgM antibodies (relative risk = 0.07; 90% CI 0.01 to 0.53) (Mueller et al., 1989). The third line of evidence of an association between EBV and Hodgkin’s lymphoma is the demonstration of the virus in the malignant cells (Weiss et al., 1987). Importantly, however, the virus is not invariably present in the malignant cells, and the proportion of EBV-positive tumors varies by histological subtype (more common in mixed cellularity than nodular sclerosis Hodgkin’s lymphoma), age (less common in young adults than other age groups), sex (more common in men than in women), and geography (more common in developing than developed countries) (Figures 53.9 and 53.10) (Cartwright and Watkins, 2004; Glaser et al., 1997).

Fig. 53.9

Percentage of Hodgkin’s lymphomas positive for EBV by five-year age group (Reproduced from (Glaser et al., 1997)) with permission from John Wiley & Sons, Inc.

Fig. 53.10

Distribution of EBV positive tumors by histological subtype (Reproduced from (Glaser et al., 1997)) with permission from John Wiley & Sons, Inc.

The role of EBV in Hodgkin’s lymphoma pathogenesis remains uncertain from epidemiological evidence, but there is some evidence to suggest that risk factors may differ between virus-positive and -negative tumors. Accordingly, in some investigations the increased risk for Hodgkin’s lymphoma following infectious mononucleosis may be restricted to virus-positive subtypes (Alexander et al., 2000; Hjalgrim et al., 2003), although other investigations have reported no particular predilection for virus-positive tumors after infectious mononucleosis (Alexander et al., 2003; Sleckman et al., 1998).

It has been speculated that the Hodgkin’s lymphoma-mononucleosis association may merely reflect the significance of high socioeconomic status. This speculation is, however, not easily compatible with observations showing that first-degree relatives of mononucleosis patients either have no increased Hodgkin’s lymphoma risk (Hjalgrim et al., 2002), or an increased risk for only for virus-positive tumors (Alexander et al., 2003). Also, titres of antiviral capsid antigen antibodies have recently been found to correlate with Hodgkin’s lymphoma virus status in both case-control (Alexander et al., 2003; Chang et al., 2004a,b) and prospective studies (Levin et al., 2002). There is also evidence to suggest that smoking is particularly associated with an increased risk for EBV-positive Hodgkin’s lymphoma (Briggs et al., 2002; Chang et al., 2004a,b; Glaser et al., 2004), as is low socioeconomic status and race for Hodgkin’s lymphoma in childhood (Flavell et al., 2001) and immune-incompetence (Audouin et al., 1992). Finally, inherited susceptibility to EBV-positive Hodgkin’s lymphoma has also recently been proposed (Diepstra et al., 2005). None of these different lines of evidence can, however, rule out the simple explanation that the proportion of virus-positive lymphomas merely reflect the number of circulating EBV-infected cells at initiation of lymphoma development (Thorley-Lawson and Gross, 2004).

Lymphoproliferative disease associated with immunodeficiency

The recent WHO classification for tumors of the hematopoietic and lymphatic tissues recognizes four broad clinical settings of immune deficiency that are associated with an increased risk for malignant lymphomas and other lympoproliferative disorders. These are (1) primary immune disorders and deficiencies (Borisch et al., 2001), (2) infection with human immunodeficiency virus (HIV) (Raphael et al., 2001), (3) iatrogenic immune suppression in organ or bone marrow transplant recipients (Harris et al., 2001a,b), and (4) iatrogenic immune suppression associated with methotrexate treatment (Harris and Swerdlow, 2001), typically for auto-immune conditions. With the exception of post-transplant lymphoproliferative disorder, the malignancies observed in these settings are largely similar to sporadic occurring neoplasms.

Table 53.8Distribution of tumors by primary immunodeficiency syndrome in a combined series of patients with inherited immune deficiencies (Reproduced from Filipovich et al., 1992; Mueller, 1999.) The table is not exhaustive with respect to immune deficiencies carrying increased cancer risk

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Immunodeficiency	Total tumors	NHL	Hodgkin’s disease	Leukemia	Other tumors
Severe combined immunodeficiency	42	31 (73.8)a	4 (9.5)	5 (11.9)	2 (4.8)
Hypogammaglobulinemia	21	7 (33.3)	3 (14.3)	7 (33.3)	4 (19.0)
Common variable immunodeficiency	120	55 (45.8)	8 (6.7)	8 (6.7)	49 (40.8)
IgA deficiency	38	6 (15.8)	3 (7.9)	0 (0)	29 (76.3)
Hyper-UgM syndrome	16	9 (56.3)	4 (25.0)	0 (0)	3 (18.8)
Wiskott-Aldrich syndrome	78	59 (75.6)	3 (3.8)	7 (9.0)	9 (11.5)
Ataxia telangiectasia	150	69 (46.0)	16 (10.7)	32 (21.3)	33 (22.0)
Other immunodeficiencies	25	12 (48.0)	1 (4.0)	4 (16.0)	8 (32.0)
Total immunodeficiency categories	500	252 (50.4)	43 (8.6)	63 (16.0)	142 (28.4)

a

Percentage of total tumors.

b

NHL, non-Hodgkin’s lymphoma.

Primary immune disorders

Primary immune disorders are associated with a substantial risk for malignant disease, reported absolute risks ranging from 12%–25% in patients with Wiskott-Aldrich syndrome, ataxia telangiectasia, and common variable immunodeficiency (Filipovich et al., 1992). Hematopoietic malignancies make up nearly 70% of the observed tumors, clearly different from the normal 8% (Mueller, 1999). Onset of disease is typically in childhood (Borisch et al., 2001). EBV infection plays a significant role in many, though not all, of the malignant lymphomas occurring in patients with primary immune deficiencies (Filipovich et al., 1992) Specifically, loss of immunological control of EBV-infected lymphocytes allows their continued proliferation and malignant transformation, possibly promoted by defective immune regulation and chronic immune stimulation (Filipovich et al., 1992).

Post-transplant lymphoproliferative disease

“Post-transplant lymphoproliferative disorder” (PTLD) in reality defines a spectrum of lymphoid hyperproliferative states that may be observed in solid organ and bone marrow transplant recipients (Loren et al., 2003). PTLDs are most often but not invariably of B-lymphocyte origin, and manifest heterogeneously, possibly reflecting serial development of the disorder (Harris et al., 2001a,b) (Table 53.9). Histologically, it has been suggested that EBV-associated PTLD should include two of the following three features: disruption of underlying architecture by a lymphoproliferative process, presence of monoclonal or polyclonal cell populations, and evidence (typically by in situ hybridization for virus-encoded RNA) of EBV in many of the cells (Paya et al., 1999). Although it also includes reactive hyperplasia, the term PTLD is normally used in reference to the malignant end of the PTLD spectrum unless otherwise specified (Green, 2001; Loren et al., 2003).

Table 53.9

Post-transplant lymphoproliferative disorders (reproduced from Harris et al., 2001 with permission from IARC).

In solid organ transplant recipients, PTLD is typically of recipient origin (>90%), whereas in hematopoietic stem cell transplant recipients it is most often of donor origin (Harris et al., 2001a,b). The organ graft is frequently involved in PTLD (e.g., in 80% of lung transplanted, 33% of liver transplants, and 32% of kidney transplants in children) (Holmes and Sokol, 2002).

Epidemiology

The epidemiology of PTLD remains scantily characterized. Occurrence varies by type of transplantation, ranging from a few percent or less in renal transplant recipients to ∼20% in recipients of HLA mismatched, T-cell depleted bone marrow, and even 33% of child-recipients of combined liver-kidney transplants (Curtis et al., 1999; Harris et al., 2001a,b; Holmes and Sokol, 2002; Loren et al., 2003).

PTLD may develop as soon as the first week or as late as 9 years after transplantation, but the median latency period is around 6 months in solid organ recipients and 70–90 days in hematopoietic stem cell recipients (Loren et al., 2003). PTLD occurs in all age groups, but is seen in more men than women, which could, however, reflect gender differences in transplantation frequency (Hsu and Glaser, 2000). Inadequate T-cell control of EBV-infected B-lymphocytes is thought to be critical to the development of EBV-positive PTLDs. Consistent with this theory, established risk factors for PTLD include recipient EBV seronegativity (in particular if the donor is EBV-seropositive), primary or reactivated EBV infection following transplantation, high levels of immune suppression (cyclosporine, tacrolimus, antithymocyte globulin, or antilymphocyte antibodies), cytomegalovirus infection, transplanted organ (renal < non-renal) and – less certain – younger age (Aguilar et al., 1999; Loren et al., 2003; Swinnen, 2000).

Evidence of association with EBV

The significance of EBV to PTLD development is implied first and foremost by demonstration of the virus in approximately 80% of cases (Harris et al., 2001a,b). EBV-negative PTLDs have been described, and tend to occur with longer latency periods than their virus-positive counterparts (Nalesnik, 2002).

Because early recognition of developing PTLD may affect prognosis, attempts have been made to develop techniques for monitoring EBV infection activity. Decreased anti-EBV nuclear antigen antibody levels have been associated with an increased risk for PTLD (Cen et al., 1993; Riddler et al., 1994). A more useful measure of EBV activity is, however, the assessment of the burden of virus infection in peripheral blood mononuclear cells and serum which, by a wide variety of different assays, have been found to correlate with risk for PTLD (Stevens et al., 2002a,b).

Lymphomas in HIV

EBV infection is involved in different diseases in HIV-infected individuals, in particular malignant lymphomas and leiomyosarcomas.

Malignant lymphoma in people with HIV

The risk for malignant lymphomas is increased massively in patients with acquired immune deficiency syndrome (AIDS). Accordingly, aggressive B-cell non-Hodgkin’s lymphoma has been an AIDS-defining condition almost since the recognition of the HIV epidemic and is the second most common tumor associated with HIV (Dal Maso and Franceschi, 2003; Lim and Levine, 2005).

The magnitude of reported increases in risk for non-Hodgkin’s lymphoma in persons with AIDS have varied somewhat, but generally have been in the order of 100-fold for all types of non-Hodgkin’s lymphoma combined in the period before the introduction of Highly Active Anti-Retroviral Therapy (HAART) (Dal Maso and Franceschi, 2003), relative risks possibly being more increased in children (Biggar et al., 2000) and less increased in elderly (Biggar et al., 2004). Particularly elevated relative risks have been reported for high grade diffuse immunoblastic (652-fold increased) and Burkitt’s lymphoma (261-fold increased)(Cote et al., 1997). While some uncertainty has existed for Hodgkin’s lymphoma, recent data have suggested that the risk for this lymphoma is also increased in HIV-infected persons, although to a much lesser extent, i.e., around 10-fold (Frisch et al., 2001; IARC, 1996).

The risk of non-Hodgkin’s lymphoma varies by level of immune suppression as measured by CD4 count and typically is a late manifestation of HIV infection (IARC, 1996). Consistent with this, the introduction of HAART seems to have accompanied by a decrease in AIDS-malignant lymphoma occurrence, notably of the subtypes most strongly associated with EBV (see below) (International Collaboration on HIV and Cancer, 2000; Lim and Levine, 2005) (Fig. 53.11).

Fig. 53.11

Incidence rates of certain types of non-Hodgkin’s lymphoma in 1992 through 1996 (before HAART) and in 1997 through 1999 [after HAART] and rate ratios (RRs) of incidence rates in 1992 through 1996 compared with 1997 through 1999. Reproduced from (more...)

In contrast to AIDS-related Kaposi’s sarcoma, a human herpesvirus 8-associated malignancy that occurs predominantly in homo- or bisexual men, the occurrence of malignant lymphomas show no predilection for mode of HIV acquisition (IARC, 1996).

HIV itself appears not to be directly involved in the lymphoma development as illustrated by its absence in the malignant cells. Rather, through chronic antigenic stimulation causing B-cell proliferation, and through cytokine dysregulation, the virus may create an environment conducive for the development of malignant lymphomas (Levine, 2000; Knowles, 2001).

The range of different types of malignant lymphomas in HIV-infected persons is wide, but can be categorized according to whether they also occur in immune-competent individuals (Burkitt’s lymphoma, diffuse large B-cell lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma), peripheral T-cell lymphomas and classical Hodgkin’s lymphoma), whether they are seen in other immune dysfunctional conditions (polymorphic B-cell lymphoma) or whether they are more specific to HIV infected individuals (primary effusion lymphoma, plasmablastic lymphoma of the oral cavity) (Raphael et al., 2001). However, the various lymphoma subtypes are not equally frequent and a few of these make up the vast majority of cases in AIDS, i.e., Burkitt’s lymphoma (50%–60% of all HIV-related lymphomas) and diffuse large B-cell lymphomas (25% of all HIV-related lymphomas many of which present in the central nervous system), primary effusion lymphoma (less than 5% of all HIV-related lymphoma) and plasmablastic lymphoma of the oral cavity (Raphael et al., 2001).

Evidence of association with EBV

As for other lymphomas, the primary evidence of EBV involvement in development of HIV-related lymphomas is the demonstration of monoclonal virus in the tumors (Table 53.6). Overall, EBV is present in approximately 60% of HIV-related lymphomas, but the proportion of virus-positive tumors varies considerably with site of presentation and histological subtype. Thus, EBV is almost invariably present in Hodgkin’s lymphomas, in (primary) central nervous system lymphomas and in primary effusion lymphomas (so-called PEL), in 80% of diffuse large cell lymphomas with immunoblastic features, in more than 50% of plasmablastic lymphomas of the oral cavity, in 30%–50% of AIDS-related Burkitt’s lymphomas, and in 30% of diffuse large B-cell lymphomas of the centroblastic variant (Raphael et al., 2001). As the risk of the various types of non-Hodgkin’s lymphoma correlating with level of immune deficiency, a similar correlation arises with respect to prevalence of EBV in the lymphoma (Carbone and Gloghini, 2005).

Gastric carcinoma

Gastric carcinomas are tumors derived from the epithelium of the stomach mucosa with glandular differentiation (Fenoglio-Preiser et al., 2000). Histologically, the tumors either are gland-forming with tubular, acinary, or papillary structures or display a complex mixture of dis-cohesive, isolated cells with variable morphologies, sometimes in combination with glandular, trabecular, or alveolar solid structures (Fenoglio-Preiser et al., 2000). The current WHO classification of tumor of the digestive system distinguishes between tumors occurring at the junction between esophagus and the stomach, many of which would previously have been classified as cancers of the gastric cardia, and gastric cancer differing epidemiologically.

Epidemiology

The incidence of gastric cancer has been decreasing world-wide for several decades (Parkin et al., 2002), yet with an estimated 876 000 incident cases annually it remains the fourth most common cancer worldwide, and because of its relatively poor prognosis the second most common cancer-specific cause of death attributed 647 000 deaths annually (Parkin et al., 2000). There is considerable (more than 10-fold) geographical variation in the incidence of gastric cancer, with high rates in the Andean regions of South America, Eastern Europe, and Eastern Asia, and low rates in Northern Europe, most African countries, and North American whites (Fenoglio-Preiser et al., 2006). For instance, world standardized incidence rates of 6.6 per 100 000 are observed in white American men as compared with rates between 60 and 90 per 100 000 observed in Japanese men (IARC, 2002). Irrespective of this geographical variation, the cancer is twice as common in men as in women (Parkin et al., 2002; Nyren and Adami, 2002). In contrast to decreasing occurrence of gastric cancer, there is evidence to suggest that cancer of the esophageal–gastric junction may be increasing (Newnham et al., 2003; Wijnhoven et al., 2002), although this is still debated (Ekstrom et al., 1999).

Both gastric cancer and cancers of the esophageal–gastric junction are rare before the age of 30 years, but increase with older age (Parkin et al., 2002). Besides age, established risk factors for gastric cancer include familial occurrence, tobacco smoking, certain diets, alcohol, and infection with Helicobacter pylori (Nyren and Adami, 2002). With respect to familial occurrence of gastric carcinoma, it has been estimated that familial clustering of gastric cancer occurs in approximately 1% of patients (Shinmura et al., 1999). Increased gastric cancer risk has been described in a number of hereditary conditions, notably the Li–Fraumeni syndrome and hereditary non-polyposis colorectal cancer, but other syndromes may exist (Nyren and Adami, 2002). Familial clustering of gastric cancer may reflect shared genetic or environmental factors, or both. Accordingly, in a study of more than 44 000 Scandinavian twins, compared to men whose twin did not have stomach cancer 7- and 10-fold increased risks for gastric cancer were observed in dizygotic and monozygotic male twins, whose twin had stomach cance. For women, the corresponding relative risk estimates were 6 and 20 respectively (Lichtenstein et al., 2000). This corresponded to inherited factors accounting for 28%, shared environmental factors 10%, and non-shared environmental factors to 62% of the overall gastric cancer risk.

Smoking is associated with stomach cancer risk, in cohort studies amounting to 1.5 to 2-fold increased risk (Tredaniel et al., 1997). Certain dietary items are suspected to be of importance for gastric cancer risk. Accordingly, salt intake and, in some populations, smoked or cured meats have been associated with increased risk of gastric cancer, whereas intake of fresh fruit and vegetables have been associated with a reduced gastric cancer risk (Nyren and Adami, 2002). Finally, several studies have shown that infection with Helicobacter pylori carries an increased risk of gastric cancer. Thus, in a Japanese cohort study, 36 cases of gastric carcinoma was observed during follow-up in 1246 Helicobacter pylori infected persons compared with no cases among 280 uninfected men (Uemura et al., 2001). Analogously, a meta-analysis of 42 studies showed Helicobacter pylori infection to be associated with a two-fold increased risk of gastric cancer (Eslick et al., 1999).

Evidence of an association with EBV

The scientific evidence incriminating EBV in development of gastric carcinoma encompasses the demonstration of monoclonal virus in the malignant cells and aberrant anti-virus antibody patterns before and at diagnosis (Table 53.6).

The first suggestion of an involvement of EBV in gastric carcinoma development came in the early 1990s by the demonstration of the virus in lymphoepithelioma-like carcinomas of the stomach (Burke et al., 1990). Subsequent investigations indicate that the virus is present in the vast majority of this specific subgroup of gastric carcinomas, i.e., 80+% (Fukayama et al., 1998). Importantly, however, the association with EBV is not restricted to lymphoepithelioma-like gastric carcinomas as the virus can also be demonstrated in varying proportions (typically less than 10%) of carcinomas of more common histologies (Fukayama et al., 1998; Imai et al., 1994; Koriyama et al., 2004; Shibata and Weiss, 1992; van Beek et al., 2004).

EBV has also been implicated in gastric carcinoma development by serological studies. Specifically, elevated seroprevalence of anti-viral capsid antigen IgA and IgGy and elevated anti-early antigen antibies and (elevated IgG viral capsid antigen antibody titers) have been described at and before diagnosis of EBV-associated gastric carcinomas (Imai et al., 1994; Levine et al., 1995).

Besides, by histology the proportion of EBV-positive gastric carcinomas appears to vary by gender, age, tumor location, and possibly geography. EBV-positive gastric carcinomas seem to be more common in men than in women. In a large Japanese investigation of 1918 cases, EBV was demonstrated in 83 (6.8%) of 1212 male and in 17 (2.4%) of 706 female cases (Koriyama et al., 2004). Likewise, in a recent Dutch series 38 (11.7%) of 324 gastric carcinomas in men and 3 (1.2%) of 242 carcinoma in women harbored EBV (van Beek et al., 2004), and from smaller US series EBV prevalence of 15%–21% and 3%–5% are reported for gastric carcinomas in men and women, respectively (Shibata, 1998). Overall, the proportion of EBV-positive tumors seems to correlate inversely with age, but the age pattern may differ between gastric carcinoma subtypes (Koriyama et al., 2004; van Beek et al., 2004).

Interestingly, the EBV-positive tumors are not evenly distributed topographically in the stomach. Accordingly, the virus can more often be demonstrated in carcinomas of the cardia and the middle stomach than in the antrum, proportions varying 3–4 fold or more (Koriyama et al., 2004; Takada, 2000; van Beek et al., 2004). Of interest, EBV-positive tumors have been reported to make up a relatively large proportion of gastric carcinomas after partial gastrectomy for non-malignant diseases, published estimates ranging between 27% and 42% (Baas et al., 1998; Chang et al., 2000; Koriyama et al., 2004; Nishikawa et al., 2002; Yamamoto et al., 1994). It has been suggested that this distribution of the EBV-positive tumors reflect that the non-neoplastic mucosa of the proximal stomach may be conditioned to develop EBV-related tumors (Fukayama et al., 1998).

As illustrated in Fig. 53.12 the proportion of EBV-positive gastric carcinomas appears to differ between countries and may even vary within countries (Tashiro et al., 1998). However, so far it has been difficult to define a clear geographic pattern in the distribution of EBV-related gastric carcinomas like those known for nasopharyngeal carcinoma and Burkitt’s lymphoma. The precise siginificance of variation in referral patterns, case selection or possible variation in other risk factors for gastric carcinomas is difficult to evaluate in this context (Hsu and Glaser, 2000; Levin and Levine, 1998).

Fig. 53.12

World distribution of proportions of gastric cancers that are EBV-related. Reproduced from Tashiro et al., 1998.

Lymphoepithelioma-like carcinomas may have a better prognosis than other gastric lymphomas, and recently, it has been suggested that other types of EBV-positive gastric carcinomas may also have better prognosis than virus-negative tumors (van Beek et al., 2004).

Given the high incidence of gastric adenocarcinoma worldwide [around 870 000 incident cases annually (Parkin et al., 2001), EBV-related gastric carcinoma, estimated to amount to at least 50 000 cases per year may be the most common of all EBV-associated malignancies (Takada, 2000) (Table 53.10).

Table 53.10

Estimated number of neoplasms associated with EBV (reproduced from Levin and Levine, 1998.).

References

• Abdel-Hamid M., Chen J. J., Constantine N., Massoud M., Raab-Traub N. EBV strain variation: geographical distribution and relation to disease state. Virology. 1992;190:168–175. [PubMed: 1356286]
• Aguilar L. K., Rooney C. M., Heslop H. E. Lymphoproliferative disorders involving Epstein-Barr virus after hemopoietic stem cell transplantation. Curr. Opin. Oncol. 1999;11(2):96–101. [PubMed: 10188073]
• Aitken C., Sengupta S. K., Aedes C., Moss D. J., Sculley T. B. 1994Heterogeneity within the Epstein-Barr virus nuclear antigen 2 gene in different strains of Epstein-Barr virus J. Gen. Virol. 75(Pt 1):95–100. [PubMed: 8113744]
• Alexander F. E., Jarrett R. F., Lawrence D., et al. Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br. J. Cancer. 2000;82(5):1117–1121. [PMC free article: PMC2374437] [PubMed: 10737396]
• Alexander F. E., Lawrence D. J., Freeland J., et al. An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin’s disease (HD): evidence for a specific association with EBV+ve HD in young adults. Int. J. Cancer. 2003;107(2):298–302. [PubMed: 12949811]
• Alfieri C., Tanner J., Carpentier L., et al. Epstein-Barr virus transmission from a blood donor to an organ transplant recipient with recovery of the same virus strain from the recipient’s blood and oropharynx. Blood. 1996;87(2):812–817. [PubMed: 8555507]
• Anagnostopoulos I., Hummel M., Finn T., et al. Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood. 1992;80(7):1804–1812. [PubMed: 1327284]
• Apolloni A., Sculley T. B. Detection of A-type and B-type Epstein-Barr virus in throat washings and lymphocytes. Virology. 1994;202(2):978–981. [PubMed: 8030259]
• Au W. Y., Ma S. Y., Chim C. S., et al. Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of, 10 years. Ann. Oncol. 2005;16(2):206–214. [PubMed: 15668271]
• Audouin J., Diebold J., Pallesen G. Frequent expression of Epstein-Barr virus latent membrane protein-1 in tumour cells of Hodgkin’s disease in HIV-positive patients. J. Pathol. 1992;167(4):381–384. [PubMed: 1328576]
• Auwaerter P. G. Infectious mononucleosis in middle age. JAMA. 1999;281(5):454–459. [PubMed: 9952206]
• Baas I. O., Rees, Musler A., et al. Helicobacter pylori and Epstein-Barr virus infection and the p53 tumour suppressor pathway in gastric stump cancer compared with carcinoma in the non-operated stomach. J. Clin. Pathol. 1998;51(9):662–666. [PMC free article: PMC500902] [PubMed: 9930069]
• Babcock G. J., Decker L. L., Freeman R. B., Thorley-Lawson D. A. Epstein-barr virus-infected resting memory B cells, not proliferating lymphoblasts, accumulate in the peripheral blood of immunosuppressed patients. J. Exp. Med. 1999;190(4):567–576. [PMC free article: PMC2195601] [PubMed: 10449527]
• Beagley K. W., Gockel C. M. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol. Med. Microbiol. 2003;38(1):13–22. [PubMed: 12900050]
• Bellan C., Lazzi S., Hummel M., et al. Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. Blood. 2005;106(3):1031–1036. [PubMed: 15840698]
• Benoit L., Wang X., Pabst H. F., Dutz J., Tan R. Defective NK cell activation in X-linked lymphoproliferative disease. J. Immunol. 2000;165(7):3549–3553. [PubMed: 11034354]
• Berger C., Day P., Meier G., Zingg W., Bossart W., Nadal D. Dynamics of Epstein-Barr virus DNA levels in serum during EBV-associated disease. J. Med. Virol. 2001;64(4):505–512. [PubMed: 11468736]
• Biggar R. J., Frisch M., Goedert J. J. Risk of cancer in children with AIDS. AIDS-Cancer Match Registry Study Group. JAMA. 2000;284(2):205–209. [PubMed: 10889594]
• Biggar R. J., Gardiner C., Lennette E. T., Collins W. E., Nkrumah F. K., Henle W. Malaria, sex, and place of residence as factors in antibody response to Epstein-Barr virus in Ghana, West Africa. Lancet. 1981;2(8238):115–118. [PubMed: 6113482]
• Biggar R. J., Henle W., Fleisher G., Bocker J., Lennette E. T., Henle G. Primary Epstein-Barr virus infections in African infants. I. Decline of maternal antibodies and time of infection. Int. J. Cancer. 1978;22(3):239–243. [PubMed: 212369]
• Biggar R. J., Kirby K. A., Atkinson J., McNeel T. S., Engels E. Cancer risk in elderly persons with HIV/AIDS. J. Acquir. Immune. Defic. Syndr. 2004;36(3):861–868. [PubMed: 15213571]
• Bodeus M., Smets F., Reding R., et al. Epstein-Barr virus infection in sixty pediatric liver graft recipients: diagnosis of primary infection and virologic follow-up. Pediatr. Infect. Dis. J. 1999;18(8):698–702. [PubMed: 10462339]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Borisch, B., Raphael, M., Swerdlow, S. H., and Jaffe, E. S. (2001). Lymphoproliferative diseases associated with primary immune disorders. In: , editors. Tumours of Haematopoietic and lymphoid tissues Lyon: IARC, 257–271.
• Briggs N. C., Hall H. I., Brann E. A., Moriarty C. J., Levine R. S. Cigarette smoking and risk of Hodgkin’s disease: a population-based case-control study. Am. J. Epidemiol. 2002;156(11):1011–1020. [PubMed: 12446257]
• Burke A. P., Yen T. S., Shekitka K. M., Sobin L. H. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod. Pathol. 1990;3(3):377–380. [PubMed: 2163534]
• Burrows J. M., Bromham L., Woolfit M., et al. Selection pressure-driven evolution of the Epstein-Barr virus-encoded oncogene LMP1 in virus isolates from Southeast Asia. J. Virol. 2004;78(13):7131–7137. [PMC free article: PMC421669] [PubMed: 15194789]
• Carbone A., Gloghini A. AIDS-related lymphomas: from pathogenesis to pathology. Br. J. Haematol. 2005;130(5):662–670. [PubMed: 16115121]
• Cartwright R. A., Watkins G. Epidemiology of Hodgkin’s disease: a review. Hematol. Oncol. 2004;22(1):11–26. [PubMed: 15152367]
• Cen H., Williams P. A., McWilliams H. P., Breinig M. C., Ho M., McKnight J. L. Evidence for restricted Epstein-Barr virus latent gene expression and anti-EBNA antibody response in solid organ transplant recipients with posttransplant lymphoproliferative disorders. Blood. 1993;81(5):1393–1403. [PubMed: 8382973]
• Cerroni L., Zochling N., Putz B., Kerl H. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J. Cutan. Pathol. 1997;24:457–461. [PubMed: 9331890]
• Cesarman E., Chang Y., Moore P. S., Said J. W., Knowles D. M. Kaposi’s sarcoma-associated Herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 1995;332:1186–1191. [PubMed: 7700311]
• Chalik Y. N., Wieczorek R., Grasso M. Lymphoepithelioma-like carcinoma of the ureter. J. Urol. 1998;159(2):503–504. [PubMed: 9649274]
• Chan A. C., Ho J. W., Chiang A. K., Srivastava G. Phenotypic and cytotoxic characteristics of peripheral T-cell and NK-cell lymphomas in relation to Epstein-Barr virus association. Histopathology. 1999;34(1):16–24. [PubMed: 9934580]
• Chan C. W., Chiang A. K., Chan K. H., Lau A. S. Epstein-Barr virus-associated infectious mononucleosis in Chinese children. Pediatr. Infect. Dis. J. 2003;22(11):974–978. [PubMed: 14614370]
• Chan J. K., Sin V. C., Wong K. F., et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997;89:4501–4513. [PubMed: 9192774]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Chan, J. K. C, Jaffe, E. S., and Ralfkiaer, E. (2001). Ekstranodal, NK/T-cell lymphoma, nasal type. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 204–207.
• Chan K. H., Luo R. X., Chen H. L., Ng M. H., Seto W. H., Peiris J. S. Development and evaluation of an Epstein-Barr virus (EBV) immunoglobulin M enzyme-linked immunosorbent assay based on the 18-kilodalton matrix protein for diagnosis of primary EBV infection. J. Clin. Microbiol. 1998;36(11):3359–3361. [PMC free article: PMC105330] [PubMed: 9774594]
• Chan K. H., Ng M. H., Seto W. H., Peiris J. S. Epstein-Barr virus (EBV) DNA in sera of patients with primary EBV infection. J. Clin. Microbiol. 2001;39(11):4152–4154. [PMC free article: PMC88503] [PubMed: 11682546]
• Chang E. T., Smedby K. E., Hjalgrim H., et al. Family history of hematopoietic malignancy and risk of lymphoma. J. Natl. Cancer Inst. 2005;97(19):1466–1474. [PubMed: 16204696]
• Chang E. T., Zheng T., Lennette E. T., et al. Heterogeneity of risk factors and antibody profiles in epstein-barr virus genome-positive and -negative hodgkin lymphoma. J. Infect Dis. 2004;189(12):2271–2281. [PubMed: 15181575]
• Chang E. T., Zheng T., Weir E. G., et al. Childhood Social Environment and Hodgkin’s Lymphoma: New Findings from a Population-Based Case-Control Study. Cancer Epidemiol Biomarkers Prev. 2004;13(8):1361–1370. [PubMed: 15298959]
• Chang M. S., Lee J. H., Kim J. P., et al. Microsatellite instability and Epstein-Barr virus infection in gastric remnant cancers. Pathol. Int. 2000;50(6):486–492. [PubMed: 10886725]
• Chang, R. S. (1980Infectious mononucleosis Boston: G. K. Hall medical Publishers;
• Chang R. S., Rosen L., Kapikian A. Z. Epstein-Barr virus infections in a nursery. Am. J. Epidemiol. 1981;113(1):22–29. [PubMed: 6257109]
• Chen P. C., Pan C. C., Yang A. H., Wang L. S., Chiang H. Detection of Epstein-Barr virus genome within thymic epithelial tumours in Taiwanese patients by nested PCR, PCR in situ hybridization, and RNA in situ hybridization. J. Pathol. 2002;197(5):684–688. [PubMed: 12210090]
• Chien Y. C., Chen J. Y., Liu M. Y., et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N. Engl. J. Med. 2001;345(26):1877–1882. [PubMed: 11756578]
• Coffey A. J., Brooksbank R. A., Brandau O., et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 1998;20(2):129–135. [PubMed: 9771704]
• Correa P., O’Conor G. T. Epidemiologic patterns of Hodgkin’s disease. Int. J. Cancer. 1971;8:192–201. [PubMed: 5133848]
• Correa R. M., Fellner M. D., Alonio L. V., Durand K., Teyssie A. R., Picconi M. A. Epstein-barr virus (EBV) in healthy carriers: Distribution of genotypes and, 30 bp deletion in latent membrane protein-1 (LMP-1) oncogene. J. Med. Virol. 2004;73(4):583–588. [PubMed: 15221903]
• Cote T. R., Biggar R. J., Rosenberg P. S., et al. Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int. J. Cancer. 1997;73:645–650. [PubMed: 9398040]
• Crawford D. H., Swerdlow A. J., Higgins C., et al. Sexual history and Epstein-Barr virus infection. J. Infect Dis. 2002;186(6):731–736. [PubMed: 12198605]
• Curtis R. E., Travis L. B., Rowlings P. A., et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood. 1999;94(7):2208–2216. [PubMed: 10498590]
• Maso, Franceschi S. Epidemiology of non-Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet Oncol. 2003;4(2):110–119. [PubMed: 12573353]
• Daoud J., Toumi N., Bouaziz M., et al. Nasopharyngeal carcinoma in childhood and adolescence: analysis of a series of 32 patients treated with combined chemotherapy and radiotherapy. Eur. J. Cancer. 2003;39(16):2349–2354. [PubMed: 14556927]
• Goedert J. J.de The, G. (2000). Epstein-Barr virus and Burkitt’s lymphoma. In: , editor. Infectious Causes of Cancer New Jersey: Humana Press, 77–92.
• The, Day N. E., Geser A., et al. 1975Sero-epidemiology of the Epstein-Barr virus: preliminary analysis of an international study – a review IARC Sci. Publ., (11 Pt 2), 3–16. [PubMed: 191375]
• de-Thé G., Geser A., Day N. E., et al. Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt’s lymphoma from Ugandan prospective study. Nature. 1978;274:756–761. [PubMed: 210392]
• Devesa S. S., Fears T. 1992Non-Hodgkin’s lymphoma time trends: United States and international data Cancer Res. 525432s–5440s. [PubMed: 1394149]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Diebold, J., Jaffe, E. S., Raphael, M., and Warnke, R. A. (2001). Burkitt lymphoma. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 181–184.
• Diepstra A., Niens M., Vellenga E., et al. Association with HLA class Ⅰ in Epstein-Barr-virus-positive and with HLA class Ⅲ in Epstein-Barr-virus-negative Hodgkin’s lymphoma. Lancet. 2005;365(9478):2216–2224. [PubMed: 15978930]
• Edwards J. M., Woodroof M. EB virus-specific IgA in serum of patients with infectious mononucleosis and of healthy people of different ages. J. Clin. Pathol. 1979;32(10):1036–1040. [PMC free article: PMC1145887] [PubMed: 230203]
• Ekstrom A. M., Signorello L. B., Hansson L. E., Bergstrom R., Lindgren A., Nyren O. Evaluating gastric cancer misclassification: a potential explanation for the rise in cardia cancer incidence. J. Natl. Cancer Inst. 1999;91(9):786–790. [PubMed: 10328109]
• Ekstrom-Smedby K. Epidemiology and etiology of non-Hodgkin lymphoma – a review. Acta Oncol. 2006;45(3):258–71. [PubMed: 16644568]
• Elzevier H. W., Venema P. L., Kropman R. F., Kazzaz B. A. Lymphoepithelioma-like carcinoma of the kidney. J. Urol. 2002;167(5):2127–2128. [PubMed: 11956457]
• Enbom M., Strand A., Falk K. I., Linde A. Detection of Epstein-Barr virus, but not human herpesvirus 8, DNA in cervical secretions from Swedish women by real-time polymerase chain reaction. Sex Transm. Dis. 2001;28(5):300–306. [PubMed: 11354271]
• Engel P., Eck M. J., Terhorst C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat. Rev. Immunol. 2003;3(10):813–821. [PubMed: 14523387]
• Epstein M. A., Achong B. G., Barr Y. M. Virus particles in cultured lymphoblasts from Burkitts lymphoma. Lancet. 1964;15:702–703. [PubMed: 14107961]
• Eslick G. D., Lim L. L., Byles J. E., Xia H. H., Talley N. J. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am. J. Gastroenterol. 1999;94(9):2373–2379. [PubMed: 10483994]
• Evans, A. S., Kaslow, R. A., editors. (1997). Epidemiology and control. In: Viral Infections of Humans. 4. ed. New York: Plenum Medical Book Company;
• Fafi-Kremer S., Morand P., Brion J. P., et al. Long-term shedding of infectious epstein-barr virus after infectious mononucleosis. J. Infect Dis. 2005;191(6):985–989. [PubMed: 15717276]
• Fan H., Gulley M. L. Epstein-Barr viral load measurement as a marker of EBV-related disease. Mol. Diagn. 2001;6(4):279–289. [PubMed: 11774193]
• Feng B. J., Huang W., Shugart Y. Y., et al. Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4. Nat. Genet. 2002;31(4):395–399. [PubMed: 12118254]
• Hamilton S. R., Aaltonen L. A.Fenoglio-Preiser, C., Carneiro, F., Correa, P. et al2000). Gastric carcinoma. In: , editors. Tumours of the Digestive System Lyon: IARC, 37–68.
• Ferreri A. J., Guidoboni M., Ponzoni M., et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J. Natl. Cancer Inst. 2004;96(8):586–594. [PubMed: 15100336]
• Filipovich A. H., Mathur A., Kamat D., Shapiro R. S. 1992Primary immunodeficiencies: genetic risk factors for lymphoma Cancer Res. 525465s-5467s. [PubMed: 1327508]
• Flavell K. J., Biddulph J. P., Powell J. E., et al. South Asian ethnicity and material deprivation increase the risk of Epstein-Barr virus infection in childhood Hodgkin’s disease. Br. J. Cancer. 2001;85(3):350–356. [PMC free article: PMC2364082] [PubMed: 11487264]
• Fleisher G., Bologonese R. Infectious mononucleosis during gestation: report of three women and their infants studied prospectively. Pediatr. Infect Dis. 1984;3(4):308–311. [PubMed: 6473132]
• Fleisher G., Henle W., Henle G., Lennette E. T., Biggar R. J. Primary infection with Epstein-Barr virus in infants in the United States: clinical and serologic observations. J. Infect Dis. 1979;139(5):553–558. [PubMed: 220340]
• Fleisher G. R., Collins M., Fager S. Limitations of available tests for diagnosis of infectious mononucleosis. J. Clin. Microbiol. 1983;17(4):619–624. [PMC free article: PMC272704] [PubMed: 6304142]
• Frank D., Cesarman E., Liu Y. F., Michler R. E., Knowles D. M. Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus. Blood. 1995;85(5):1396–1403. [PubMed: 7858270]
• Friborg J., Koch A., Wohlfarht J., Storm H. H., Melbye M. Cancer in Greenlandic Inuit 1973–1997: a cohort study. Int. J. Cancer. 2003;107(6):1017–1022. [PubMed: 14601064]
• Friborg J., Wohlfahrt J., Koch A., Storm H., Olsen O. R., Melbye M. Cancer susceptibility in nasopharyngeal carcinoma families–a population-based cohort study. Cancer Res. 2005;65(18):8567–8572. [PubMed: 16166338]
• Frisch M., Biggar R. J., Engels E. A., Goedert J. J. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001;285(13):1736–1745. [PubMed: 11277828]
• Fritschi L., Benke G., Hughes A. M., et al. Occupational exposure to pesticides and risk of non-Hodgkin’s lymphoma. Am. J. Epidemiol. 2005;162(9):849–857. [PubMed: 16177143]
• Fukayama M., Chong J. M., Kaizaki Y. Epstein-Barr virus and gastric carcinoma. Gastric Cancer. 1998;1(2):104–114. [PubMed: 11957053]
• Gartner B. C., Kortmann K., Schafer M., et al. No correlation in Epstein-Barr virus reactivation between serological parameters and viral load. J. Clin. Microbiol. 2000;38(6):2458. [PMC free article: PMC86846] [PubMed: 10917775]
• Geser A., The, Lenoir G., Day N. E., Williams E. H. Final case reporting from the Ugandan prospective study of the relationship between EBV and Burkitt’s lymphoma. Int. J. Cancer. 1982;29(4):397–400. [PubMed: 6282763]
• Glaser R., Strain E. C., Tarr K. L., Holliday J. E., Donnerberg R. L., Kiecolt-Glaser J. K. Changes in Epstein-Barr virus antibody titers associated with aging. Proc. Soc. Exp. Biol. Med. 1985;179(3):352–355. [PubMed: 2987972]
• Glaser S. L., Hsu J. L., Gulley M. L. Epstein-Barr virus and breast cancer: state of the evidence for viral carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2004;13(5):688–697. [PubMed: 15159298]
• Glaser S. L., Keegan T. H., Clarke C. A., et al. Smoking and Hodgkin lymphoma risk in women United States. Cancer Causes Control. 2004;15(4):387–397. [PubMed: 15141139]
• Glaser S. L., Lin R. J., Stewart S. L., et al. Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int. J. Cancer. 1997;70:375–382. [PubMed: 9033642]
• Goldin L. R., Landgren O., McMaster M. L., et al. Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples. Cancer Epidemiol. Biomarkers Prev. 2005;14(10):2402–2406. [PubMed: 16214923]
• Goldin L. R., Pfeiffer R. M., Gridley G., et al. Familial aggregation of Hodgkin lymphoma and related tumors. Cancer. 2004;100(9):1902–1908. [PubMed: 15112271]
• Goldschmidts W. L., Bhatia K., Johnson J. F., et al. Epstein-Barr virus genotypes in AIDS-associated lymphomas are similar to those in endemic Burkitt’s lymphomas. Leukemia. 1992;6(9):875–878. [PubMed: 1325581]
• Goldsmith D. B., West T. M., Morton R. HLA associations with nasopharyngeal carcinoma in Southern Chinese: a meta-analysis. Clin. Otolaryngol. 2002;27(1):61–67. [PubMed: 11903375]
• Golubjatnikov R., Allen V. D., Steadman M., Pilar, Inhorn S. L. Prevalence of antibodies to Epstein-Barr virus, cytomegalovirus and Toxoplasma in a Mexican highland community. Am. J. Epidemiol. 1973;97(2):116–124. [PubMed: 4347509]
• Granovsky M. O., Mueller B. U., Nicholson H. S., Rosenberg P. S., Rabkin C. S. Cancer in human immunodeficiency virus-infected children: a case series from the Children’s Cancer Group and the National Cancer Institute. J. Clin. Oncol. 1998;16(5):1729–1735. [PubMed: 9586885]
• Gratama J. W., Ernberg I. Molecular epidemiology of Epstein-Barr virus infection. Adv. Cancer Res. 1995;67:197–255. [PubMed: 8571815]
• Green M. Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am. J. Transplant. 2001;1(2):103–108. [PubMed: 12099356]
• Gross T. G., Filipovich A. H., Conley M. E., et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant. 1996;17(5):741–744. [PubMed: 8733691]
• Grülich A. E., Vajdic C. M. The epidemiology of non-Hodgkin lymphoma. Pathology. 2005;37(6):409–19. [PubMed: 16373224]
• Gutensohn N., Cole P. Epidemiology of Hodgkin’s disease in the young. Int. J. Cancer. 1977;19:595–604. [PubMed: 863541]
• Haahr S., Plesner A. M., Vestergaard B. F., Hollsberg P. A role of late Epstein-Barr virus infection in multiple sclerosis. Acta. Neurol. Scand. 2004;109(4):270–275. [PubMed: 15016009]
• Hamilton J. K., Paquin L. A., Sullivan J. L., et al. X-linked lymphoproliferative syndrome registry report. J. Pediatr. 1980;96(4):669–673. [PubMed: 7188959]
• Haque T., Crawford D. H. 1997PCR amplification is more sensitive than tissue culture methods for Epstein-Barr virus detection in clinical material J. Gen. Virol. 78(Pt 12), 3357–3360. [PubMed: 9400988]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Harris, N. L., Jaffe, E. S., Vardiman, J. W. et al2001). WHO classification of tumours of haematopoietic and lymphoid tissues: Introduction. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 12–13.
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Harris, N. L., and Swerdlow, S. H. (2001). Methotrexate-associated lymphoproliferative disorders. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 270–271.
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Harris, N. L., Swerdlow, S. H., Frizzera, G., and Knowles, D. M. (2001). Post-transplant lymphoproliferative disorders. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 264–271.
• Heath C. W. Jr, Brodsky A. L., Potolsky A. I. Infectious mononucleosis in a general population. Am. J. Epidemiol. 1972;95(1):46–52. [PubMed: 5007364]
• Hecht J. L., Aster J. C. Molecular biology of Burkitt’s lymphoma. J. Clin. Oncol. 2000;18(21):3707–3721. [PubMed: 11054444]
• Helminen M. E., Kilpinen S., Virta M., Hurme M. Susceptibility to primary Epstein-Barr virus infection is associated with interleukin-10 gene promoter polymorphism. J. Infect Dis. 2001;184(6):777–780. [PubMed: 11517440]
• Hendry B. M., Longmore J. M. 1982Systemic lupus erythematosus presenting as infectious mononucleosis with a false positive monospot test Lancet 20;1(8269), 455. [PubMed: 6121125]
• Henle G., Henle W. Immunofluorescence, interference, and complement fixation technics in the detection of the herpes-type virus in Burkitt tumor cell lines. Cancer Res. 1967;27(12):2442–2446. [PubMed: 4295480]
• Henle G., Henle W., Clifford P., et al. Antibodies to Epstein-Barr virus in Burkitt’s lymphoma and control groups. J. Natl. Cancer Inst. 1969;43(5):1147–1157. [PubMed: 5353242]
• Hesse J., Ibsen K. K., Krabbe S., Uldall P. Prevalence of antibodies to Epstein-Barr virus (EBV) in childhood and adolescence in Denmark. Scand. J. Infect Dis. 1983;15(4):335–338. [PubMed: 6318303]
• Hildesheim A., Anderson L. M., Chen C. J., et al. CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan. J. Natl. Cancer Inst. 1997;89(16):1207–1212. [PubMed: 9274915]
• Hildesheim A., Apple R. J., Chen C. J., et al. Association of HLA class Ⅰ and Ⅱ alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan. J. Natl. Cancer Inst. 2002;94(23):1780–1789. [PubMed: 12464650]
• Hildesheim A., Dosemeci M., Chan C. C., et al. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol. Biomarkers Prev. 2001;10(11):1145–1153. [PubMed: 11700262]
• Hinuma Y., Nagata K., Hanaoka M., et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc. Natl. Acad. Sci., USA. 1981;78(10):6476–6480. [PMC free article: PMC349062] [PubMed: 7031654]
• Hjalgrim H., Askling J., Rostgaard K., et al. Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N. Engl. J. Med. 2003;349(14):1324–1332. [PubMed: 14523140]
• Hjalgrim H., Askling J., Sorensen P., et al. Risk of Hodgkin’s disease and other cancers after infectious mononucleosis. J. Natl. Cancer Inst. 2000;92(18):1522–1528. [PubMed: 10995808]
• Hjalgrim H., Rostgaard K., Askling J., et al. Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis. J. Natl. Cancer Inst. 2002;94(9):678–681. [PubMed: 11983756]
• Holmes R. D., Sokol R. J. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant. 2002;6(6):456–464. [PubMed: 12453197]
• Horwitz C. A., Henle W., Henle G., Penn G., Hoffman N., Ward P. C. Persistent falsely positive rapid tests for infectious mononucleosis. Report of five cases with four–six-year follow-up data. Am. J. Clin. Pathol. 1979;72(5):807–811. [PubMed: 228546]
• Hsu J. L., Glaser S. L. Epstein-barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit. Rev. Oncol. Hematol. 2000;34(1):27–53. [PubMed: 10781747]
• Hu L. F., Zabarovsky E. R., Chen F., et al. 1991Isolation and sequencing of the Epstein-Barr virus BNLF-1 gene (LMP1) from a Chinese nasopharyngeal carcinoma J. Gen. Virol. 72(Pt 10), 2399–2409. [PubMed: 1681026]
• Huh J., Cho K., Heo D. S., Kim J. E., Kim C. W. Detection of Epstein-Barr virus in Korean peripheral T-cell lymphoma. Am. J. Hematol. 1999;60(3):205–214. [PubMed: 10072112]
• IARC. (1996IARC Monographs on the evaluation of carcinogenic risks to humans: Human immunodeficiency viruses and human T-cell lymphotropic viruses Lyon: IARC; [PMC free article: PMC5366879] [PubMed: 9190379]
• IARC. (1997IARC Monographs on the evaluation of carcinogenic risks to humans: Epstein-Barr virus and Kaposi’s sarcoma herpesvirus/herpesvirus 8 LYON: IARC; [PMC free article: PMC5046075] [PubMed: 9705682]
• Iezzoni J. C., Gaffey M. J., Weiss L. M. The role of Epstein-Barr virus in lymphoepithelioma-like carcinomas. Am. J. Clin. Pathol. 1995;103(3):308–315. [PubMed: 7872253]
• Ikuta K., Satoh Y., Hoshikawa Y., Sairenji T. Detection of Epstein-Barr virus in salivas and throat washings in healthy adults and children. Microbes Infect. 2000;2(2):115–120. [PubMed: 10742683]
• Imai S., Koizumi S., Sugiura M., et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc. Natl. Acad. Sci., USA. 1994;91(19):9131–9135. [PMC free article: PMC44761] [PubMed: 8090780]
• International Collaboration on HIV and Cancer. (2000Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults J. Natl. Cancer Inst. 92(22):1823–1830. [PubMed: 11078759]
• Israele V., Shirley P., Sixbey J. W. Excretion of the Epstein-Barr virus from the genital tract of men. J. Infect Dis. 1991;163(6):1341–1343. [PubMed: 1645383]
• Jeng K. C., Hsu C. Y., Liu M. T., Chung T. T., Liu S. T. Prevalence of Taiwan variant of Epstein-Barr virus in throat washings from patients with head and neck tumors in Taiwan. J. Clin. Microbiol. 1994;32(1):28–31. [PMC free article: PMC262964] [PubMed: 8126200]
• Jeng Y. M., Chen C. L., Hsu H. C. Lymphoepithelioma-like cholangiocarcinoma: an Epstein-Barr virus-associated tumor. Am. J. Surg. Pathol. 2001;25(4):516–520. [PubMed: 11257627]
• Goedert J. J.Jenson, H. B. (2000). Leiomyoma and Leiomyosarcoma. In: , editor. Infectious causes of cancer: Targets for intervention Totowa, New Jersey: Humana Press, 145–159.
• Kanavaros P., Lescs M. C., Briere J., et al. Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus. Blood. 1993;81(10):2688–2695. [PubMed: 8387835]
• Kang I., Quan T., Nolasco H., et al. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J. Immunol. 2004;172(2):1287–1294. [PubMed: 14707107]
• Kapranos N., Petrakou E., Anastasiadou C., Kotronias D. 2003Detection of herpes simplex virus, cytomegalovirus, and Epstein-Barr virus in the semen of men attending an infertility clinic Fertil Steril, 79 Suppl 31566–1570. [PubMed: 12801561]
• Khan G., Miyashita E. M., Yang B., Babcock G. J., Thorley-Lawson D. A. Is EBV persistence in vivo a model for B cell homeostasis? Immunity. 1996;5(2):173–179. [PubMed: 8769480]
• Kim I., Park E. R., Park S. H., Lin Z., Kim Y. S. Characteristics of Epstein-Barr virus isolated from the malignant lymphomas in Korea. J. Med. Virol. 2002;67(1):59–66. [PubMed: 11920819]
• Kimura H., Hoshino Y., Kanegane H., et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood. 2001;98(2):280–286. [PubMed: 11435294]
• Kimura H., Morishima T., Kanegane H., et al. Prognostic factors for chronic active Epstein-Barr virus infection. J. Infect Dis. 2003;187(4):527–533. [PubMed: 12599068]
• Kimura H., Morita M., Yabuta Y., et al. Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J. Clin. Microbiol. 1999;37:132–136. [PMC free article: PMC84187] [PubMed: 9854077]
• Klein G. Lymphoma development in mice and humans: diversity of initiation is followed by convergent cytogenetic evolution. Proc. Natl. Acad. Sci., USA. 1979;76(5):2442–2446. [PMC free article: PMC383618] [PubMed: 221925]
• Klumb C. E., Hassan R., Oliveira, et al. Geographic variation in Epstein-Barr virus-associated Burkitt’s lymphoma in children from Brazil. Int. J. Cancer. 2004;108(1):66–70. [PubMed: 14618617]
• Knowles D. M. Biology of non-Hodgkin’s lymphoma. Cancer. Treat. Res. 2001;104:149–200. [PubMed: 11191126]
• Koriyama C., Akiba S., Corvalan A., et al. Histology-specific gender, age and tumor-location distributions of Epstein-Barr virus-associated gastric carcinoma in Japan. Oncol. Rep. 2004;12(3):543–547. [PubMed: 15289835]
• Kunimoto M., Tamura S., Tabata T., Yoshie O. 1992One-step typing of Epstein-Barr virus by polymerase chain reaction: predominance of type 1 virus in Japan J. Gen. Virol. 73(Pt 2), 455–461. [PubMed: 1311368]
• Kusuhara K., Takabayashi A., Ueda K., et al. Breast milk is not a significant source for early Epstein-Barr virus or human herpesvirus 6 infection in infants: a seroepidemiologic study in 2 endemic areas of human T-cell lymphotropic virus type Ⅰ in Japan. Microbiol. Immunol. 1997;41(4):309–312. [PubMed: 9159404]
• Kyaw M. T., Hurren L., Evans L., et al. Expression of B-type Epstein-Barr virus in HIV-infected patients and cardiac transplant recipients. AIDS Res. Hum. Retroviruses. 1992;8(11):1869–1874. [PubMed: 1336962]
• Lai P. K., Mackay-Scollay E. M., Alpers M. P. Epidemiological studies of Epstein-Barr herpesvirus infection in Western Australia. J. Hyg. (Lond.). 1975;74(3):329–337. [PMC free article: PMC2130598] [PubMed: 168249]
• Lam K. M., Syed N., Whittle H., Crawford D. H. Circulating Epstein-Barr virus-carrying B cells in acute malaria. Lancet. 1991;337(8746):876–878. [PubMed: 1672968]
• Lang D. J., Garruto R. M., Gajdusek D. C. Early acquisition of cytomegalovirus and Epstein-Barr virus antibody in several isolated Melanesian populations. Am. J. Epidemiol. 1977;105(5):480–487. [PubMed: 193397]
• Lechowicz M. J., Lin L., Ambinder R. F. Epstein-Barr virus DNA in body fluids. Curr. Opin. Oncol. 2002;14(5):533–537. [PubMed: 12192273]
• Lecuit M., Abachin E., Martin A., et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N. Engl. J. Med. 2004;350(3):239–248. [PubMed: 14724303]
• Lee A. W., Foo W., Mang O., et al. Changing epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year period (1980–99): an encouraging reduction in both incidence and mortality. Int. J. Cancer. 2003;103(5):680–685. [PubMed: 12494479]
• Lee W. Y., Hsiao J. R., Jin Y. T., Tsai S. T. Epstein-Barr virus detection in neck metastases by in-situ hybridization in fine-needle aspiration cytologic studies: an aid for differentiating the primary site. Head Neck. 2000;22(4):336–340. [PubMed: 10862015]
• Levi F., Vecchia, Randimbison L., Te V. C. Descriptive epidemiology of soft tissue sarcomas in Vaud, Switzerland. Eur. J. Cancer. 1999;35(12):1711–1716. [PubMed: 10674018]
• Levin, L. I., Lennette, E. T., Ambinder, R., Chang, E. T., Rubertone, M. V., and Mueller, N. (2002). Prediagnostic Epstein-Barr virus serologic patterns in EBV-positive and EBV-negative Hodgkin lymphoma. Presented at the 10th International EBV Symposium, Cairns.
• Osato T., Takada K., Tokunaga M.Levin, L. I., and Levine, P. H. (1998). The epidemiology of Epstein-Barr virus-associated human cancers. In: , editors. Epstein-Barr virus and human cancer Tokyo: Japan Scientific Societies Press, 51–74.
• Goedert J. J.Levine, A. (2000). Aids-related lymphoma. In: , editor. Infectious causes of cancer: Targets for intervention Totowa, New Jersey: Humana Press, 129–143.
• Levine P. H., Ebbesen P., Connelly R. R., Das S., Middleton M., Mestre M. Complement-fixing antibody to Epstein-Barr virus soluble antigen in populations at high and low risk for nasopharyngeal carcinoma. Int. J. Cancer. 1982;29:265–268. [PubMed: 6279526]
• Levine P. H., Stemmermann G., Lennette E. T., Hildesheim A., Shibata D., Nomura A. Elevated antibody titers to Epstein-Barr virus prior to the diagnosis of Epstein-Barr-virus-associated gastric adenocarcinoma. Int. J. Cancer. 1995;60(5):642–644. [PubMed: 7860138]
• Li C. C., Yu M. C., Henderson B. E. Some epidemiologic observations of nasopharyngeal carcinoma in Guangdong, People’s Republic of China. Natl Cancer Inst Monogr. 1985;69:49–52. [PubMed: 3834344]
• Lichtenstein P., Holm N. V., Verkasalo P. K., et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 2000;343(2):78–85. [PubMed: 10891514]
• Lim S. T., Levine A. M. Recent advances in acquired immunodeficiency syndrome (AIDS)-related lymphoma. CA Cancer J. Clin. 2005;55(4):229–241. [PubMed: 16020424]
• Lin J. C., Wang W. Y., Chen K. Y., et al. Quantification of plama Epstein–Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N. Engl. J. Med. 2004;350(24):2461–70. [PubMed: 15190138]
• Ling P. D., Lednicky J. A., Keitel W. A., et al. The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J. Infect Dis. 2003;187(10):1571–1580. [PubMed: 12721937]
• Lo Y. M., Chan A. T., Chan L. Y., et al. Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res. 2000;60(24):6878–6881. [PubMed: 11156384]
• Lo Y. M., Chan L. Y., Lo K. W., et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res. 1999;59(6):1188–1191. [PubMed: 10096545]
• Loren A. W., Porter D. L., Stadtmauer E. A., Tsai D. E. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant. 2003;31(3):145–155. [PubMed: 12621474]
• Lu S. J., Day N. E., Degos L., et al. Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region. Nature. 1990;346:470–471. [PubMed: 2377207]
• Macfarlane G. J., Evstifeeva T., Boyle P., Grufferman S. International patterns in the occurrence of Hodgkin’s disease in children and young adult males. Int. J. Cancer. 1995;61(2):165–169. [PubMed: 7705942]
• MacMahon B. Epidemiological evidence of the nature of Hodgkin’s disease. Cancer. 1957;10(5):1045–1054. [PubMed: 13472655]
• MacMahon B. Epidemiology of Hodgkin’s disease. Cancer Res. 1966;26:1189–1201. [PubMed: 5329907]
• Macsween K. F., Crawford D. H. Epstein-Barr virus-recent advances. Lancet Infect Dis. 2003;3(3):131–140. [PubMed: 12614729]
• Maurmann S., Fricke L., Wagner H. J., et al. Molecular parameters for precise diagnosis of asymptomatic Epstein-Barr virus reactivation in healthy carriers. J. Clin. Microbiol. 2003;41(12):5419–5428. [PMC free article: PMC308959] [PubMed: 14662920]
• McGeoch D. J., Cook S., Dolan A., Jamieson F. E., Telford E. A. Molecular phylogeny and evolutionary timescale for the family of mammalian herpesviruses. J. Mol. Biol. 1995;247(3):443–458. [PubMed: 7714900]
• Mekmullica J., Kritsaneepaiboon S., Pancharoen C. Risk factors for Epstein-Barr virus infection in Thai infants. Southeast Asian J. Trop. Med. Public Health. 2003;34(2):395–397. [PubMed: 12971570]
• Melbye M., Ebbesen P., Bennike T. Infectious mononucleosis in Greenland: a disease of the non-indigenous population. Scand. J. Infect Dis. 1984;16:9–15. [PubMed: 6695160]
• Melbye M., Ebbesen P., Levine P. H., Bennike T. Early primary infection and high Epstein-Barr virus antibody titers in Greenland Eskimos at high risk for nasopharyngeal carcinoma. Int. J. Cancer. 1984;34:619–623. [PubMed: 6094363]
• Meyohas M. C., Marechal V., Desire N., Bouillie J., Frottier J., Nicolas J. C. Study of mother-to-child Epstein-Barr virus transmission by means of nested PCRs. J. Virol. 1996;70(10):6816–6819. [PMC free article: PMC190727] [PubMed: 8794321]
• Miyazato H., Nakatsuka S., Dong Z., et al. NK-cell related neoplasms in Osaka, Japan. Am. J. Hematol. 2004;76(3):230–235. [PubMed: 15224357]
• Moormann A. M., Chelimo K., Sumba O. P., et al. Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children. J. Infect Dis. 2005;191(8):1233–1238. [PubMed: 15776368]
• Mori M., Watanabe M., Tanaka S., Mimori K., Kuwano H., Sugimachi K. Epstein-Barr virus-associated carcinomas of the esophagus and stomach. Arch. Pathol. Lab Med. 1994;118(10):998–1001. [PubMed: 7944903]
• Morra M., Howie D., Grande M. S., et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev Immunol. 2001;19:657–82. [PubMed: 11244050]
• Morris M. C., Edmunds W. J. The changing epidemiology of infectious mononucleosis? J. Infect. 2002;45(2):107–109. [PubMed: 12217713]
• Mueller N. 1999Overview of the epidemiology of malignancy in immune deficiency J. Acquir. Immune. Defic. Syndr., 21 Suppl 1S5–10. [PubMed: 10430211]
• Mueller N., Evans A., Harris N. L., et al. Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N. Engl. J. Med. 1989;320:689–695. [PubMed: 2537928]
• Mueller N., Mohar A., Evans A., et al. Epstein-Barr virus antibody patterns preceding the diagnosis of non- Hodgkin’s lymphoma. Int. J. Cancer. 1991;49:387–393. [PubMed: 1655660]
• Schottenfeld D., Fraumeni J. Jr.Mueller, N. E. (1996). Hodgkin’s disease. In: , editors. Cancer Epidemiology and Prevention Oxford: Oxford University Press;
• Schottenfeld D., Fraumeni J. Jr.Mueller, N. E., Evans, A. S., and London, W. T. (1996). Viruses. In: , editors. Cancer Epidemiology and Prevention Oxford: Oxford University Press, 502–531.
• Naher H., Gissmann L., Freese U. K., Petzoldt D., Helfrich S. Subclinical Epstein-Barr virus infection of both the male and female genital tract–indication for sexual transmission. J. Invest Dermatol. 1992;98(5):791–793. [PubMed: 1314867]
• Nalesnik M. A. Clinicopathologic characteristics of post-transplant lymphoproliferative disorders. Recent Results. Cancer Res. 2002;159:9–18. [PubMed: 11785849]
• Nava V. E., Jaffe E. S. The pathology of NK-cell lymphomas and leukemias. Adv. Anat. Pathol. 2005;12(1):27–34. [PubMed: 15614162]
• Newnham A., Quinn M. J., Babb P., Kang J. Y., Majeed A. Trends in the subsite and morphology of oesophageal and Gastric Cancer in England and Wales 1971–1998. Aliment Pharmacol. Ther. 2003;17(5):665–676. [PubMed: 12641515]
• Nicholls J. M., Agathanggelou A., Fung K., Zeng X., Niedobitek G. The association of squamous cell carcinomas of the nasopharynx with Epstein-Barr virus shows geographical variation reminiscent of Burkitt’s lymphoma. J. Pathol. 1997;183(2):164–168. [PubMed: 9390028]
• Nichols K. E., Harkin D. P., Levitz S., et al. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc. Natl. Acad. Sci., USA. 1998;95(23):13765–13770. [PMC free article: PMC24894] [PubMed: 9811875]
• Nichols K. E., Ma C. S., Cannons J. L., Schwartzberg P. L., Tangye S. G. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol. Rev. 2005;203:180–99. [PubMed: 15661030]
• Niedobitek G., Young L. S., Lau R., et al. 1991Epstein-Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase J. Gen. Virol. 72(Pt 12), 3035–3046. [PubMed: 1662695]
• Nishikawa J., Yanai H., Hirano A., et al. High prevalence of Epstein-Barr virus in gastric remnant carcinoma after Billroth-Ⅱ reconstruction. Scand J. Gastroenterol. 2002;37(7):825–829. [PubMed: 12190097]
• Adami H. O., Hunter D., Trichopoulos D.Nyren, O. and Adami, H. O. (2002). Stomach cancer. In: , editors. Textbook of Cancer Epidemiology New York: Oxford University Press, 162–187.
• Okano M. Overview and problematic standpoints of severe chronic active Epstein-Barr virus infection syndrome. Crit. Rev. Oncol. Hematol. 2002;44(3):273–282. [PubMed: 12467967]
• Okano M., Kawa K., Kimura H., et al. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am. J. Hematol. 2005;80(1):64–69. [PubMed: 16138335]
• Old L. J., Boyse E. A., Oettgen H. P. Precipitating antibody in human serum to antigen present in cultured Burkitt lymphoma cell. Proc. Natl. Acad. Sci. 1966;56:1699–1704. [PMC free article: PMC220158] [PubMed: 16591407]
• Ozkan A., Kilic S. S., Kalkan A., Ozden M., Demirdag K., Ozdarendeli A. Seropositivity of Epstein-Barr virus in Eastern Anatolian Region of Turkey. Asian Pac. J. Allergy Immunol. 2003;21(1):49–53. [PubMed: 12931751]
• Parkin D. M., Bray F., Ferlay J., Pisani P. Estimating the world cancer burden: Globocan. Int. J. Cancer. 2001;94(2):153–156. [PubMed: 11668491]
• Parkin D. M., Whelan S. L., Ferlay J., Teppo L., Thomas D. B., editors. (2002Cancer Incidence in Five Continents vol VIII Lyon: IARC. IARC Scientific Publications No. 155.
• Pathmanathan R., Prasad U., Sadler R., Flynn K., Raab-Traub N. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma [see comments] N. Engl. J. Med. 1995;333:693–698. [PubMed: 7637746]
• Paya C. V., Fung J. J., Nalesnik M. A., et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation. 1999;68(10):1517–1525. [PubMed: 10589949]
• Pickard A., Chen C. J., Diehl S. R., et al. Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan. Int. J. Cancer. 2004;111(1):117–123. [PubMed: 15185352]
• Pozzato G., Mazzaro C., Crovatto M., et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood. 1994;84(9):3047–3053. [PubMed: 7949176]
• Purtilo D. T., Cassel C. K., Yang J. P., Harper R. X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet. 1975;1(7913):935–940. [PubMed: 48119]
• Quintanilla-Martinez L., Franklin J. L., Guerrero I., et al. Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high prevalence of p53 overexpression. Hum. Pathol. 1999;30(7):849–855. [PubMed: 10414505]
• Quintanilla-Martinez L., Lome-Maldonado C., Ott G., et al. Primary non-Hodgkin’s lymphoma of the intestine: high prevalence of Epstein-Barr virus in Mexican lymphomas as compared with European cases. Blood. 1997;89:644–651. [PubMed: 9002968]
• Goedert J. J.Raab-Traub, N. (2000). Epstein-Barr virus and nasopharyngeal carcinoma. In: , editor. Infectious causes of cancer: Targets for intervention Totowa, New Jersey: Humana Press, 93–111.
• Raab-Traub N., Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986;47(6):883–889. [PubMed: 3022942]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Raphael, M., Borisch, B., and Jaffe, E. (2001). Lymphomas associated with infection by the human immune deficiency virus (HIV). In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 260–263.
• Riddler S. A., Breinig M. C., McKnight J. L. Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood. 1994;84(3):972–984. [PubMed: 8043879]
• Rizvi M. A., Evens A. M., Tallman M. S., Nelson B. P., Rosen S. T. T-cell non-Hodgkin’s lymphoma. Blood. 2006;107:1255–1264. [PubMed: 16210342]
• Rosdahl N., Larsen S. O., Thamdrup A. B. Infectious mononucleosis in Denmark. Epidemiological observations based on positive Paul-Bunnell reactions from 1940–1969. Scand. J. Infect Dis. 1973;5(3):163–170. [PubMed: 4801052]
• Rose C., Green M., Webber S., et al. Detection of Epstein-Barr virus genomes in peripheral blood B cells from solid-organ transplant recipients by fluorescence in situ hybridization. J. Clin. Microbiol. 2002;40(7):2533–2544. [PMC free article: PMC120580] [PubMed: 12089275]
• Rudiger T., Weisenburger D. D., Anderson J. R., et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann. Oncol. 2002;13(1):140–149. [PubMed: 11863096]
• Sample J., Young L., Martin B., et al. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J. Virol. 1990;64(9):4084–4092. [PMC free article: PMC247870] [PubMed: 2166806]
• Sandvej K., Peh S. C., Andresen B. S., Pallesen G. Identification of potential hot spots in the carboxy-terminal part of the Epstein-Barr virus (EBV) BNLF-1 gene in both malignant and benign EBV-associated diseases: high frequency of a 30-bp deletion in Malaysian and Danish peripheral T-cell lymphomas. Blood. 1994;84(12):4053–4060. [PubMed: 7994023]
• Savoldo B., Huls M. H., Liu Z., et al. Autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood. 2002;100(12):4059–4066. [PubMed: 12393655]
• Sawyer R. N., Evans A. S., Niederman J. C., McCollum R. W. Prospective studies of a group of Yale University freshmen. I. Occurrence of infectious mononucleosis. J. Infect Dis. 1971;123(3):263–270. [PubMed: 4329526]
• Scheenstra R., Verschuuren E. A., de Haan A. et alThe value of prospective monitoring of Epstein-Barr virus DNA in blood samples of pediatric liver transplant recipients. Transpl. Infect Dis. 2004;6(1):15–22. [PubMed: 15225222]
• Schottenfeld D., Fraumeni J. F.Scherr, P. A. and Mueller, N. E. (1996). Non-Hodgkin’s lymphomas. In: , editors. Cancer Epidemiology and Prevention Oxford New York: Oxford University Press, 920–945.
• Shanmugaratnam K. Histological Typing of Tumours of the Upper Respiratory Tract and Ear. Berlin: Springer; 1991.
• Shek T. W., Luk I. S., Ng I. O., Lo C. Y. Lymphoepithelioma-like carcinoma of the thyroid gland: lack of evidence of association with Epstein-Barr virus. Hum. Pathol. 1996;27(8):851–853. [PubMed: 8760022]
• Osato T., Takada K., Tokunaga M.Shibata, D. (1998). Epstein-Barr virus-associated Gastric Cancer in the United States. In: , editors. Epstein-Barr virus and human cancer Tokyo: Japan Scientific Societies Press, 99–101.
• Shibata D., Weiss L. M. Epstein-Barr virus-associated gastric adenocarcinoma. Am. J. Pathol. 1992;140(4):769–774. [PMC free article: PMC1886378] [PubMed: 1314023]
• Shinmura K., Kohno T., Takahashi M., et al. Familial Gastric Cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. Carcinogenesis. 1999;20(6):1127–1131. [PubMed: 10357799]
• Shu C. H., Chang Y. S., Liang C. L., Liu S. T., Lin C. Z., Chang P. Distribution of type A and type B EBV in normal individuals and patients with head and neck carcinomas in Taiwan. J. Virol. Methods. 1992;38(1):123–130. [PubMed: 1322927]
• Silins S. L., Sherritt M. A., Silleri J. M., et al. Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood. 2001;98(13):3739–3744. [PubMed: 11739180]
• Sixbey J. W., Nedrud J. G., Raab-Traub N., Hanes R. A., Pagano J. S. Epstein-Barr virus replication in oropharyngeal epithelial cells. N. Engl. J. Med. 1984;310(19):1225–1230. [PubMed: 6323983]
• Sleckman B. G., Mauch P. M., Ambinder R. F., et al. Epstein-Barr virus in Hodgkin’s disease: correlation of risk factors and disease characteristics with molecular evidence of viral infection. Cancer Epidemiol Biomarkers Prev. 1998;7:1117–1121. [PubMed: 9865430]
• Smith J. L., Hodges E., Quin C. T., McCarthy K. P., Wright D. H. Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy. Am. J. Pathol. 2000;156(2):661–669. [PMC free article: PMC1850038] [PubMed: 10666395]
• Stadlmann S., Fend F., Moser P., Obrist P., Greil R., Dirnhofer S. Epstein-Barr virus-associated extranodal NK/T-cell lymphoma, nasal type of the hypopharynx, in a renal allograft recipient: case report and review of literature. Hum. Pathol. 2001;32(11):1264–1268. [PubMed: 11727268]
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Stein, H. (2001). Hodgkin lymphomas: Introduction. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 239.
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Stein, H., Delsol, G., Pileri, S. et al2001). Classical Hodgkin lymphoma. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 244–253.
• Jaffe E. S., Harris N. L., Stein H., Vardiman J. W.Stein, H., Delsol, G., Pileri, S. et al2001). Nodular lymphocyte predominant Hodgkin lymphoma. In: , editors. Tumours of haematopoietic and lymphoid tissues Lyon: IARC, 240–243.
• Stevens S. J., Blank B. S., Smits P. H., Meenhorst P. L., Middeldorp J. M. High Epstein-Barr virus (EBV) DNA loads in HIV-infected patients: correlation with antiretroviral therapy and quantitative EBV serology. AIDS. 2002a;16(7):993–1001. [PubMed: 11953465]
• Stevens S. J., Verschuuren E. A., Verkuujlen S. A., van den Brule A. J., Meijer C. J., Middeldorp J. M. Role of Epstein-Barr virus DNA load monitoring in prevention and early detection of post-transplant lymphoproliferative disease. Leuk. Lymphoma. 2002b;43(4):831–840. [PubMed: 12153173]
• Storrie M. C., Sphar R. L. Seroepidemiological studies of polaris Submarine crews. Ⅱ. Infectious mononucleosis. Mil. Med. 1976;141(1):30–32. [PubMed: 814488]
• Straus S. E. The chronic mononucleosis syndrome. J. Infect Dis. 1988;157(3):405–412. [PubMed: 2830340]
• Sugawara Y., Makuuchi M., Kato N., Shimotohno K., Takada K. Enhancement of hepatitis C virus replication by Epstein-Barr virus-encoded nuclear antigen 1. EMBO J. 1999;18(20):5755–5760. [PMC free article: PMC1171642] [PubMed: 10523318]
• Sugaya N., Kimura H., Hara S., et al. Quantitative analysis of Epstein-Barr virus (EBV)-specific CD8+ T cells in patients with chronic active EBV infection. J. Infect Dis. 2004;190(5):985–988. [PubMed: 15295706]
• Sumaya C. V., Henle W., Henle G., Smith M. H., LeBlanc D. Seroepidemiologic study of Epstein-Barr virus infections in a rural community. J. Infect Dis. 1975;131(4):403–408. [PubMed: 163869]
• Sumazaki R., Kanegane H., Osaki M., et al. SH2D1A mutations in Japanese males with severe Epstein-Barr virus–associated illnesses. Blood. 2001;98(4):1268–1270. [PubMed: 11493483]
• Sumegi J., Huang D., Lanyi A., et al. Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000;96(9):3118–3125. [PubMed: 11049992]
• Swigris J. J., Berry G. J., Raffin T. A., Kuschner W. G. Lymphoid interstitial pneumonia: a narrative review. Chest. 2002;122(6):2150–2164. [PubMed: 12475860]
• Goedert J. J.Swinnen, L. J. (2000). Posttransplant lymphoproliferative disorders. In: , editor. Infectious causes of cancer: Targets for intervention Totowa, New Jersey: Humana Press, 63–76.
• Takada K. Epstein-Barr virus and gastric carcinoma. Mol. Pathol. 2000;53(5):255–261. [PMC free article: PMC1186978] [PubMed: 11091849]
• Takkouche B., Etminan M., Montes-Martinez A. Personal use of hair dyes and risk of cancer: a meta-analysis. JAMA. 2005;293(20):2516–2525. [PubMed: 15914752]
• Osato T., Takada K., Tokunaga M.Tashiro, Y., Arikawa, J., Itoh, T., and Tokunaga, M. (1998). Clinico-pathological findings of Epstein-Barr virus-related Gastric Cancer. In: , editors. Epstein-Barr virus and human cancer Tokyo: Japan Scientific Societies Press, 87–98.
• Thorley-Lawson D. A., Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N. Engl. J. Med. 2004;350(13):1328–1337. [PubMed: 15044644]
• Tredaniel J., Boffetta P., Buiatti E., Saracci R., Hirsch A. Tobacco smoking and Gastric Cancer: review and meta-analysis. Int. J. Cancer. 1997;72(4):565–573. [PubMed: 9259392]
• Uemura N., Okamoto S., Yamamoto S., et al. Helicobacter pylori infection and the development of Gastric Cancer. N. Engl. J. Med. 2001;345(11):784–789. [PubMed: 11556297]
• Beek, zur HA, Klein K. E., et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J. Clin. Oncol. 2004;22(4):664–670. [PubMed: 14966089]
• van den Bosch C. A. Is endemic Burkitt’s lymphoma an alliance between three infections and a tumour promoter? Lancet Oncol. 2004;5(12):738–746. [PubMed: 15581545]
• van Baarle D., Hovenkamp E., Dukers N. H., et al. High prevalence of Epstein-Barr virus type 2 among homosexual men is caused by sexual transmission. J. Infect Dis. 2000;181(6):2045–2049. [PubMed: 10837190]
• Venkitaraman A. R., Lenoir G. M., John T. J. The seroepidemiology of infection due to Epstein-Barr virus in southern India. J. Med. Virol. 1985;15(1):11–16. [PubMed: 2981976]
• Wagner H. J., Hornef M., Teichert H. M., Kirchner H. 1994Sex difference in the serostatus of adults to the Epstein-Barr virus Immunobiology 190(4–5), 424–429. [PubMed: 7982725]
• Wagner H. J., Kluter H., Kruse A., Bucsky P., Hornef M., Kirchner H. Determination of the number of Epstein-Barr virus genomes in whole blood and red cell concentrates. Transfus. Med. 1995;5(4):297–302. [PubMed: 8646296]
• Weiss L. M., Jaffe E. S., Liu X. F., Chen Y. Y., Shibata D., Medeiros L. J. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood. 1992;79(7):1789–1795. [PubMed: 1373088]
• Weiss L. M., Strickler J. G., Warnke R. A., Purtilo D. T., Sklar J. Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am. J. Pathol. 1987;129(1):86–91. [PMC free article: PMC1899692] [PubMed: 2821817]
• Wekerle H., Hohlfeld R. Molecular mimicry in multiple sclerosis. N. Engl. J. Med. 2003;349(2):185–186. [PubMed: 12853593]
• Wick G., Grubeck-Loebenstein B. Primary and secondary alterations of immune reactivity in the elderly: impact of dietary factors and disease. Immunol Rev. 1997;160:171–84. [PubMed: 9476675]
• Wijnhoven B. P., Louwman M. W., Tilanus H. W., Coebergh J. W. Increased incidence of adenocarcinomas at the gastro-oesophageal junction in Dutch males since the 1990s. Eur. J. Gastroenterol. Hepatol. 2002;14(2):115–122. [PubMed: 11981334]
• Wotherspoon A. C., Ortiz-Hidalgo C., Falzon M. R., Isaacson P. G. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma [see comments] Lancet. 1991;338:1175–1176. [PubMed: 1682595]
• Xiong W., Zeng Z. Y., Xia J. H., et al. A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma. Cancer Res. 2004;64(6):1972–1974. [PubMed: 15026332]
• Yamamoto N., Tokunaga M., Uemura Y., et al. Epstein-Barr virus and gastric remnant cancer. Cancer. 1994;74(3):805–809. [PubMed: 8039108]
• Yang J., Tao Q., Flinn I. W., et al. Characterization of Epstein-Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood. 2000;96(13):4055–4063. [PubMed: 11110673]
• Yao Q. Y., Croom-Carter D. S., Tierney R. J., et al. Epidemiology of infection with Epstein-Barr virus types 1 and 2: lessons from the study of a T-cell-immunocompromised hemophilic cohort. J. Virol. 1998;72(5):4352–4363. [PMC free article: PMC109665] [PubMed: 9557725]
• Yao Q. Y., Rowe M., Martin B., Young L. S., Rickinson A. B. 1991The Epstein-Barr virus carrier state: dominance of a single growth-transforming isolate in the blood and in the oropharynx of healthy virus carriers J. Gen. Virol. 72(Pt 7), 1579–1590. [PubMed: 1649896]
• Schottenfeld D., Fraumeni J. Jr.Yu, M. C., Henderson, B. E. (1996). Nasopharyngeal cancer. In: , editors. Cancer Epidemiology and Prevention Oxford: Oxford University Press, 603–618.
• Yu M. C., Ho J. H., Ross R. K., Henderson B. E. Nasopharyngeal carcinoma in Chinese—salted fish or inhaled smoke? Prev. Med. 1981;10(1):15–24. [PubMed: 7232343]
• Yu M. C., Yuan J. M. Epidemiology of nasopharyngeal carcinoma. Semin. Cancer Biol. 2002;12(6):421–429. [PubMed: 12450728]
• Schottenfeld D., Fraumeni J. Jr.Zahm, S. H., Tucker, M. A., Fraumeni Jr., J. (1996). Soft tissue sarcomas. In: , editors. Cancer Epidemiology and Prevention Oxford: Oxford University Press, 984–999.
• Zeng Y. X., Jia W. H. Familial nasopharyngeal carcinoma. Semin. Cancer Biol. 2002;12(6):443–450. [PubMed: 12450730]
• Zhang W. Y., Li G. D., Liu W. P., et al. Features of intestinal T-cell lymphomas in Chinese population without evidence of celiac disease and their close association with Epstein-Barr virus infection. Chin. Med. J. (Engl.). 2005;118(18):1542–1548. [PubMed: 16232331]
• Zimber U., Adldinger H. K., Lenoir G. M., et al. Geographical prevalence of two types of Epstein-Barr virus. Virology. 1986;154(1):56–66. [PubMed: 3019008]
• Zintzaras E., Voulgarelis M., Moutsopoulos H. M. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch. Intern. Med. 2005;165(20):2337–2344. [PubMed: 16287762]