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Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

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Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

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Chapter 53The epidemiology of EBV and its association with malignant disease

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Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S. Denmark

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.

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.).

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.

Sex differences

There is no consistent difference in EBV seroprevalence by sex in children (Golubjatnikov 1973; Lang et al., 1977; Sumaya et al., 1975). In developed countries, this similarity continues into early adolescence, when a higher seroprevalence and an earlier occurrence of infectious mononucleosis among girls indicate earlier exposure to the virus (Crawford et al., 2002).

Generally, antibody titers seem to be higher in females than in males (Biggar et al., 1981; Levine et al., 1982; Wagner et al., 1994). This difference, which also has been observed for other viruses, is in accordance with the notion that women in general mount more vigorous antibody- and cell-mediated immune response following infection or vaccination than men (Beagley and Gockel, 2003).

Socioeconomic factors

Poor socioeconomic conditions have been associated with early primary EBV infection, whereas late primary EBV infection is seen in populations of high socioeconomic status. Based on father’s education and the family’s living conditions, Henle and colleagues documented a seroprevalence of 60% among young American school children (aged 5 to 10 years) of low socioeconomic status compared to less than 20% in children with high socioeconomic level (Henle et al., 1969). Low income and crowded family conditions have also been found to increase the likelihood of being EBV seropositive in children from other geographical locales, such as Thailand (Mekmullica et al., 2003), Turkey (Ozkan et al., 2003), Ghana (Biggar et al., 1978) and Denmark (Hesse et al., 1983). In an early work by Lang and colleagues (Lang et al., 1977) three genetically different Melanesian populations with differences in living conditions and social patterns were found to have similar patterns of early EBV infection. In all three populations the mothers chew the food before feeding the children. Thus, exposure to saliva either directly or via for example unclean toys are believed to explain differences in socioeconomic conditions. This is in line with the observation that socioeconomic associated differences in sero-prevalence are greatly diminished in age groups who have become sexually active.

Genetic and racial factors

Differences in prevalence and more generally the infection patterns have never been clearly associated with race, but merely seen as differences in socioeconomic, hygienic, and cultural behavior. The high prevalence of EBV infection in populations around the world would indicate that the influence of host-specific characteristics on natural resistance to EBV infection is limited. Yet, the distinct distribution of nasopharyngeal carcinoma (NPC) with high incidence figures observed in Inuits from the Arctic and in South-East Asian populations suggests the existence of a particular immunologic control of EBV in these ethnicities, though the exact mechanism remains to be described (Hildesheim et al., 2002; Yu and Yuan, 2002). Supportive of a genetically determined response to the EBV carrier state is the finding among Greenlandic Inuits of remarkably high titers throughout life of IgG antibodies to EBV-VCA (Melbye et al., 1984a,b).

Transmission

Most frequently, EBV transmission takes place through oropharyngeal secretion. In adolescent and adult cases of IM intimate kissing has been the main route of transmission whereas saliva on, for example, toys and fingers is believed to be major routes of transmission among smaller children. However, 40 years into the discovery of EBV we still need data to better explain the exact determinants of infection. Among EBV seronegative adults, close contact with IM cases (Sawyer et al., 1971), or longer stays together with seropositive persons in a restricted space (Storrie and Sphar, 1976) only infrequently leads to secondary cases. On the contrary, EBV infection frequently takes place among smaller children of low socioeconomic status, in nurseries (Chang et al., 1981) and when sharing a room (Crawford et al., 2002).

Shedding of EBV in saliva among seropositive individuals ranges from 22% to 90% (Apolloni and Sculley, 1994; Haque and Crawford, 1997; Ikuta et al., 2000; Sixbey et al., 1984;Yao et al., 1991). Ling and colleagues observed that shedding of EBV in saliva among adults at any given time over a 12 months period varies between 32% and 73% (Ling et al., 2003). These and other authors were unable to detect any correlation between viral shedding frequency or viral load in saliva and the presence of EBV in PBMCs (Haque and Crawford, 1997; Ling et al., 2003), suggesting that the factors responsible for EBV reactivation in the oropharynx are different from those governing viral load in the blood.

EBV has been detected in cervical secretions in between 8 and 28% of teenage girls and adult women, and in semen samples and samples scraped from the penile sulcus of men (Enbom et al., 2001; Israele et al., 1991; Kapranos et al., 2003; Naher et al., 1992), but evidence on whether EBV is transmitted through genital contact is limited. A recent study found EBV type 2 among homosexual men to be significantly more prevalent than among heterosexual men and to be correlated with the number of sexual partners (van B. D. et al., 2000). However, the exact mode of transmission in these studies remains unknown since it is difficult to distinguish between genital transmission, orogenital contact and kissing.

Transplacental transmission and transmission through breast milk have been reported in rare circumstances, but are considered non-significant modes of transmission (Fleisher and Bologonese, 1984; Kusuhara et al., 1997; Meyohas et al., 1996). EBV may be spread through blood transfusion and as a result of organ transplantation (Alfieri et al., 1996; Scheenstra et al., 2004). One transfusion unit of erythrocytes contains an average of two EBV genomes, in contrast to a whole blood unit which harbored on average 600 to 700 EBV genomes (Wagner et al., 1995). Transmission is of particular concern in association with organ transplantations where primary EBV infection is a major risk factor for post-transplant lymphoproliferative disease (PTLD) (Aguilar et al., 1999; Bodeus et al., 1999; Scheenstra et al., 2004).

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.

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.

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.

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.

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.

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.

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).

Epidemiology

Studies on CAEBV have been based on case series, and estimates of population incidences are not available. The disease is very rare, and in 2002 a national survey of severe CAEBV in Japan identified 82 patients (Kimura et al., 2003). Mean age at onset of disease in this survey was 11.3 years with men and women equally represented. Many of the studies on CAEBV have originated in Japan, but whether this reflects a true difference in incidence, or an increased awareness is unknown. However, CAEBV in different geographical areas may be of different entities, as CAEBV in Western populations appears to be milder (Savoldo et al., 2002).

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.

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.

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).

Epidemiology

XLP is estimated to affect approximately 1 in 1,000,000 males (Purtilo et al., 1975). However, this number is likely to be an underestimate, due to the similarity of disease manifestations with other clinically related disorders, such as common variable immunodefiency and the hemophagocytic syndromes (Nichols et al., 2005). The age at onset of clinical disease vary considerably from less than one year to 40 years, with a median of three to eight years (Sumegi et al., 2000). An international XLP registry was established in 1978 and contains over 300 patients from more than 80 families, with up to 17 affected males reported from a single family (Hamilton et al., 1980; Sumegi et al., 2000). XLP patients have been reported from North and South America, Europe and Japan, but it is unknown whether the geographical distribution reflects true differences in incidence or differences in awareness.

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.

Table 53.6

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

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma is derived from the epithelial lining of the nasopharynx. It typically develops in the lymphoreticular tissue rich area in the fossa of Rosenmüller, and less frequently in the roof and wall of the nasopharynx (IARC, 1997). Histopathologically, two major groups of nasopharyngeal carcinomas are recognized, i.e. keratinizing squamous cell carcinoma (WHO type I), and non-keratinizing carcinoma, the latter being further split up into differentiated (WHO type Ⅱ) and undifferentiated carcinomas (WHO type Ⅲ) (Shanmugaratnam, 1991).

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.

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.

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.

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.

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.

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.

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

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).

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.

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.

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.).

Table 53.10

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

Other malignancies associated with EBV infection

EBV has been shown, or is suspected, to be involved in the development of a series of other malignancies, much less frequently occurring than those described in the above sections. These include lymphoepithelioma-like carcinomas and soft tissue sarcomas, for which an association with EBV is compelling, and carcinomas of the breast, thymus, and liver, for which the evidence is less evident.

Lymphoepithelioma-like carcinomas

Lymphoepithelioma-like carcinomas are tumors that morphologically resemble undifferentiated carcinoma of the nasopharynx. In addition to the stomach (see above) the tumor has been described in the salivary glands, oral cavity, larynx, thymus, trachea, lungs, breast, uterine cervix, vagina, urinary bladder, skin, stomach (Iezzoni et al., 1995), thyroid (Shek et al., 1996), esophagus (Mori et al., 1994), kidney (Elzevier et al., 2002), ureter (Chalik et al., 1998), and liver (Jeng et al., 2001).

The tumor attracts interest because, in addition to the morphological similarity with nasopharyngeal carcinoma, EBV has been reportedly demonstrated in the malignant cells in some, but not all of the affected organs (Chalik et al., 1998; Elzevier et al., 2002; Iezzoni et al., 1995; Jeng et al., 2001; Mori et al., 1994; Shek et al., 1996).

Also, the prevalence of the virus in the malignant cells follows the same geographical distribution as observed nasopharyngeal carcinoma for salivary gland and lung lymphoepithelial-like carcinomas, being higher in Asian than in Western patients, thereby further underscoring the analogy between the two groups of tumors (Hsu and Glaser, 2000).

Leiomyosarcoma

Leiomyosarcomas are malignant neoplasms of smooth muscle tissues. They are exceedingly rare tumors, occurring at rates around 1 per 100 000, slightly higher in women than in men (Levi et al., 1999; Zahm et al., 1996) The connection with EBV is fairly recent and initially arose from the apparent accumulation in HIV infected children and organ transplant recipients (see for review Jenson, 2000 of cases reported until 1998). Epidemiologically, the association for HIV-infected children has been supported by surveys of cohorts of such children demonstrating excessive occurence of the tumor (Biggar et al., 2000; Granovsky 1998). The conclusive piece of evidence for the association with EBV is, however, the demonstration of the virus in the tumors of immunocompromised hosts (Jenson, 2000).

Other malignancies

In recent years, the involvement of EBV in other malignancies than those discussed above has been debated. These include breast carcinomas (Glaser et al., 2004a,b), hepatocellular carcinoma (Sugawara et al., 1999), and thymomas (Chen, 2002). As yet, however, the evidence for the association with EBV remains controversial.

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