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Hossein Sadrzadeh

Infectious Pathogens and Hematologic Malignancy

Abstract: Infectious pathogens have been linked to the genesis of malignancy in a variety of different settings. Initial studies in virology led to the important discovery of key genetic alterations underlying common malignancies, and further, lent support to the notion that malignancy can be promoted by the process of viral infection and cellular transformation. In this review, we summarize a series of hematologic malignancies with derivations from and associations with infectious organisms. Among these are a variety of lymphomas, including Hodgkin's Disease, Burkitt lymphoma, and a host of other non-Hodgkin's lymphomas. Through innovative and ground-breaking studies, some of these malignancies have been directly linked to viral infection, such as the Epstein-Barr virus (EBV), while others have been merely associated with infection through epidemiologic studies and case-reports. Some malignancies have been demonstrated to be caused by viral infection, such as adult T-cell leukemia and lymphoma (ATLL), which is caused by the human T cell lymphotropic virus type I (HTLV-I), in certain endemic area. In the future, additional malignant states may be found to be associated with infectious etiology, which could allow for novel approaches to prevention and treatment.


In 1908, in Copenhagen, Ellermann and Bang (1908) transmitted leukemia in chickens through use of cell-free, filtered extracts and suggested thereby that the myelocytic leukemia of chickens can be of infectious etiology. Three years later, Peyton Rous (Rous, 1911) in the United States similarly transmitted chicken sarcoma, a solid tumor, by use of filtrates. Within the first half of last century, a variety of malignancies in different animal species, including cows, dogs, and rabbits (Shope and Hurst, 1933) were found to be similarly transmissible (Eddy et al., 1961; Gibbs et al., 1968; Gross, 1978; Sumi et al., 1992).

In 1973, Diamandopoulos et al. (1973) demonstrated that, under certain experimental conditions, the SV40 (a simian virus) can also induce leukemias and lymphosarcomas. Others (Melendez et al., 1969) demonstrated that Herpesvirus saimiri, a DNA virus indigenous in a squirrel monkey, might induce lymphosarcoma or leukemia when inoculated into owl monkeys or marmoset monkeys. Other supporting data soon followed (Lapin, 1975; Snyder et al., 1973). It became apparent that oncogenic viruses can promote malignancies, including leukemias and lymphomas, in many animal species.

Important studies in the field of virology in the 1960s and 1970s actually led to the discovery of oncogenes, the genes responsible for the transformation of the cell into a cancerous state (Varmus, 1983). These studies on the association between viral infections and oncogenesis, revealed how proto-oncogenes, the term applied to the normal variants of oncogenes, regulate cell metabolism and growth in the normal setting. In addition, the studies led to groundbreaking findings of how these mechanisms go awry in a cancer cells as a result of the alterations caused by oncogenes through a variety of pathways, including the production of oncoproteins, which mediate malignant pathogenesis. Studies had demonstrated that microorganisms, specifically viruses, are integrally linked to certain oncogenes and to the process of oncogenesis.

Different mechanisms of cell transformation have been described, with viruses acting through “direct” and “indirect” actions. Direct-acting viruses act on proto-oncogenes, directly altering them into their oncogenic variants. An example is the Rous sarcoma virus responsible for transforming infected non-tumorigenic cells, with the oncogene labeled as src. However, viral pathogens can also promote oncogenesis through indirect fashion. The diversity of discovered oncogenic mechanisms by viruses emphasizes that there is no single mode of transformation (Butel, 2000). For example, some viruses can integrate a provirus next to normal cellular proto-oncogenes and activate their expression. This mechanism is called “proviral insertional mutagenesis” (Varmus, 1983). In addition to the above mechanisms, further studies of small DNA tumor viruses (polyomaviruses, papillomaviruses, adenoviruses) helped lead to the important discovery of tumor suppressor genes, such as the p53 and pRb genes, which like oncogenes, are critically important in human cancer development. Studies revealed that oncogenic DNA viruses produce viral oncoproteins, which bind to specific host proteins, called tumor suppressor proteins, products of tumor suppressor genes. This interaction is fundamental to their oncogenic effect (Finlay et al., 1989; Whyte et al., 1988). Even though the majority of alterations leading to oncogenes and tumor suppressor genes, in patients with cancer, they have not been associated with an infectious link; these important initial studies in virology led to the discovery of many of these important alterations that cause cancer and made the suggestion that viral infection in some settings can promote the genesis of malignancy.

In the field of hematologic malignancies, a number of human cancers have been directly linked to or associated with infectious etiologies, which the majority of these being identified as viruses. In this review, we attempt to summarize these diseases and the related infectious pathogens, some of which appear to play key roles in cancer pathogenesis.


Lymphoma is defined as a cancer of lymphocytes, typically presenting as a solid tumor, with malignant cells often originating in and involving lymph nodes. Lymphomas can be broadly categorized as Hodgkin’s lymphomas, first described by Thomas Hodgkin in 1832 and characterized by Reed-Sternberg cells, and non-Hodgkin’s lymphomas (NHL) which consists of a large number of diseases. The recent classification of lymphomas, according to the World Health Organization (WHO), categorizes lymphomas into Precursor (immature cell) lymphoid neoplasms, Mature B-cell neoplasms, T-cell and NK-cell neoplasms, Hodgkin lymphoma, and Post-transplant lymphoproliferative disorders (PTLD) (Jaffe, 2009).

Non-Hodgkin’s Lymphoma (NHL)

Non-Hodgkin’s lymphoma accounts for about 90% of all lymphomas. NHLs have a wide range of histological appearances, clinical manifestations, and etiologies (Shankland et al., 2012).

Intriguingly, various viruses have been associated with or linked to the development of lymphomatous neoplasms. Three viruses in particular have been associated with specific NHL subtypes (Uckun et al., 1998):

Epstein-Barr virus (EBV)
-  Human T-cell lymphotropic virus I (HTLV-I)
-  Human Herpesvirus-8 (HHV-8)

Additionally, HIV infection increases the risk of lymphoma likely due to its immunosuppressive nature, but has not been definitively linked to oncogenesis.

Epstein-Barr virus (EBV)

In 1958, Denis Burkitt described a specific form of childhood lymphoma among children in Uganda, and initially suspected that viruses, closely associated with malaria, were the main etiology of this B-cell malignancy (now known as Burkitt’s lymphoma) (Burkitt, 1962). In 1965, herpesvirus particles were identified by Tony Epstein and Yvonne Barr through electron microscopy of Burkitt’s lymphoma cells (Epstein and Barr, 1965). As this virus was significantly different from other herpesviridae, it was named the Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4). Since that time, associations between EBV and multiple human malignancies such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin’s lymphoma and various non-Hodgkin’s lymphomas, including B-cell lymphoma in immunocompromised patients, have been described.

EBV is a ubiquitous double-stranded DNA virus of the herpesviridae family. Most individuals are infected with EBV during the first three years of life, at which time it is typically an asymptomatic process. However, infection in older age is frequently symptomatic and can manifest as infectious mononucleosis (IM), a disease which can rarely mimic lymphoid malignancy clinically (Bedo et al., 1992; Javier and Butel, 2008; Parkin, 2006). Means of transmission for EBV is through saliva, and therefore the primary site of infection is oropharyngeal epithelial cell. After the primary infection and binding to the C21 receptor, EBV enters the cell and remains latent, or in some, can in time induce cell growth, transformation, and immortalization (Arvanitakis et al., 1995; Liebowitz, 1998; Sixbey et al., 1984; Su and Chen, 1997).

The EBV genome contains genes that encode six proteins termed Epstein-Barr nuclear antigens: EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, and EBNA-LP (EBNA leader protein). It also encodes latent membrane proteins, LMP-1, LMP-2A, LMP-2B, and the Epstein-Barr non-polyadenylated early RNAs (EBERs) (Carrillo-Infante et al., 2007), which are useful markers to detect EBV in diagnostic tests and are abundant in latent infection (Camilleri-Broet et al., 2000).

These antigens have variable functions. For example, EBNA-1 is expressed in all EBV-associated malignances and is essential for viral replication (Levitskaya et al., 1995; Wilson et al., 1996). Immortalization of B-lymphocytes is highly associated with EBNA-3C (Zhao and Sample, 2000). LMP-1 has several functions. It activates NF-κB transcription factor in B cells and regulates epidermal growth factor receptor in epithelial cells (Carrillo-Infante et al., 2007; Eliopoulos et al., 1997; Mosialos et al., 1995). Additionally, it activates the anti-apoptotic proteins in the infected cell and can lead to immortalization of B-cells (Camilleri-Broet et al., 2000; Gregory et al., 1991; Laherty et al., 1992). LMP-1 is also involved in other regulatory pathways, which mediates apoptosis and proliferation, such as Janus kinase (JAK)-STAT, c-Jun N-terminal kinase (JNK)-AP-1, mitogen activated protein kinase (MAP-Kinase), among others (Eliopoulos and Young, 1998; Gires et al., 1999).

Interestingly LMP-1 is not expressed in Burkitt’s lymphoma and post-transplant lymphoproliferative disease, but EBNA-1 and EBERs are expressed (Martin and Gutkind, 2008). LMP-1, LMP-2, EBNA-1, and EBERs are in turn expressed in Hodgkin’s disease (Cen et al., 1993).

We now know that EBV is the causative factor of African Burkitt’s lymphoma, and is closely associated with Hodgkin’s lymphoma (Pallesen et al., 1991; Wu et al., 1990). However, more than 90% of adults are seropositive for EBV worldwide. The difference between the epidemiology of EBV-induced cancer and EBV exposure strongly suggests involvement of other genetic or environmental factors (Epstein et al., 2001; Lombardi et al., 1987; Young and Rickinson, 2004).

Primary Effusion Lymphoma (PEL)

Kaposi’s sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), has been recently associated with the pathogenesis of Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman disease (Cai et al., 2010). The mechanism on oncogenesis is not completely understood but may involve viral protein D-type cyclin homologues (Schulz, 2001).

PEL, also known as body cavity-based lymphoma (BCBL), is a rare, fatal lymphoma. It is usually found in HIV positive patients and manifests as pleural or pericardial effusions without mass lesions, although variants exist (Carbone and Gaidano, 1997; Cesarman, 2002).

PEL is a monoclonal B-cell tumor with late stage B cell differentiation, often expressing CD30 and CD138 (Arvanitakis et al., 1996; Carbone and Gaidano, 1997; Gaidano et al., 1996). PEL cells are usually co-infected with EBV and KSHV with a high replication rate of the KSHV genome (Cai et al., 2010; Renne et al., 1996).

AIDS-related Lymphomas

HIV infection impairs cellular immunity, therefore to predispose the host to the development of neoplasms, including lymphomas (Conant, 1995; Levine, 1994; Rabkin, 1994). AIDS-related non-Hodgkin’s lymphoma (NHL) can include:

-  Burkitt lymphoma (approximately 25%)
Diffuse large B-cell lymphoma (DLBCL, approximately 75%)
-  Plasmablastic lymphoma (less than 5%)
T-cell lymphoma (1-3%)
-  Primary central nervous system (CNS) lymphoma (15%)
– Primary effusion (or body cavity) lymphoma (less than 1%) (Cote et al., 1997; Long et al., 2008; Simonelli et al., 2003).

The major risk factors for AIDS-related NHL include low CD4 count, increased HIV viral load, and co-existent EBV infection.

The pathobiology of AIDS-related B-cell lymphoma may be partially related to dendritic cell impairment with increased production of interleukin-6 and interleukin-10, and functional disorganization of lymph nodes (D’Apuzzo et al., 1997; Dean et al., 1999; Rabkin et al., 1999).

Mucosa-associated Lymphoid Tissue (MALT) NHLs

MALT lymphomas can arise in the context of pre-existing and prolonged lymphoid proliferation in the mucosa. MALT lymphoma has been associated with chronic gastritis caused by Helicobacter pylori. Indeed, the seroprevalence of H. pylori has been reported to be significantly higher among those with gastric MALT lymphoma than among controls. Intriguingly, antibacterial therapy against H. pylori has caused remission of lymphoma in such settings (Jarrett, 2006; Parsonnet et al., 1994; Stathis et al., 2009; Wotherspoon et al., 1993; 1991).

Other bacterial infections have been associated with MALT NHLs; small intestine NHL with Campylobacter jejuni (Al-Saleem and Al-Mondhiry, 2005; Lecuit et al., 2004), lung MALT lymphoma and Sézary syndrome with Chlamydia pneumonia (Abrams et al., 2001; Chang and Parsonnet, 2010; Chanudet et al., 2007), ocular adnexa NHL with Chlamydia psittaci (de Cremoux et al., 2006; Ferreri et al., 2012; Ferreri et al., 2004), and cutaneous NHL with Borrelia afzelii and Borrelia burgdorferi (Chang and Parsonnet, 2010; Goodlad et al., 2000a; Jelic and Filipovic-Ljeskovic, 1999) (Table 1).

Hepatitis C Virus (HCV)

The role of HCV in the development of non-Hodgkin’s lymphomas is controversial. Studies from Italy, France, and the U.S. have reported an association between prior infection with HCV and subsequent development of B-cell lymphoma, with a latent period of up to decades (Silvestri et al., 1996; Zuckerman et al., 1997). Different types of B-cell lymphoma have been noted in HCV-infected patients, with interestingly one case of mantle cell lymphoma treated successfully with antiviral therapy consisting of pegylated interferon-alpha and ribavirin (Levine et al., 2003). In two other studies, the majority of patients with HCV-associated marginal zone lymphoma achieved complete remission concomitant with antiviral response (Hermine et al., 2002; Vallisa et al., 2005). Intriguingly, in HCV-infected patients, development of B-cell gene rearrangements has been reported prior to the diagnosis of malignant lymphoma, and these rearrangements have resolved upon successful antiviral therapy.

Hodgkin’s Lymphoma (HL)

Hodgkin’s lymphoma was first described by the British pathologist Thomas Hodgkin in 1832 as a primary disorder of the lymphatic glands (Hodgkin, 1832). The majority of patients with Hodgkin’s lymphoma are currently cured with multi-agent intensive chemotherapy (Armitage, 2010). HL has unique clinicopathologic features, with the characteristic Reed-Sternberg cells and its variants being the specific neoplastic cells in HL. The epidemiology and pathobiology of this disease have proven to be complex. Epidemiologic data appears to support a role for delayed exposure to a ubiquitous infection, with EBV being the leading candidate, in the pathogenesis of HL (Flavell et al., 2001; Gutensohn and Cole, 1981; Jarrett and MacKenzie, 1999). Also, HL case clustering has been reported (Grufferman et al., 1979; Vianna et al., 1972; Vianna and Polan, 1973).

Case-control studies have also revealed that an elevated EBV antibody titer is found in patients with Hodgkin’s disease (Alexander et al., 2000; Lehtinen et al., 1993; Mueller et al., 1989). An increased risk of HL has also been reported in those with a history of infectious mononucleosis (IM), an infectious state caused by EBV (Hjalgrim et al., 2003). Intriguingly, a population-based cohort study of young adults with IM reported no significant increased risk of developing EBV-negative HL after IM, but the risk of developing EBV-positive HL was significantly increased (relative risk 4.0, 95% CI 3.4-4.5), with a median incubation time from IM to EBV-positive HL of approximately four years. They concluded that the absolute risk of developing HL after IM was approximately 1 in 1,000 (Hjalgrim et al., 2003).

Studies have also reported the presence of EBV DNA in the tumor biopsies of Hodgkin’s lymphoma. EBV is found in the malignant cells of Hodgkin’s disease (Reed-Sternberg cells), and their monoclonality suggests that the EBV infection occurs prior to the malignant transformation of the cell clone (Anagnostopoulos et al., 1989; Boiocchi et al., 1989; Uccini et al., 1989; Weiss et al., 1987).

However, additional case examinations have revealed that EBV is not found in all malignant cells of Hodgkin’s lymphomas. Rather, as shown by pooled analysis of 1,546 Hodgkin’s lymphoma cases, factors such as age, gender, race, and histological subtype are linked to the prevalence of EBV. The co-presence of EBV is higher among children and older adults in comparison to younger adults, and appears to be more prevalent in the mixed cellularity subtype (Glaser et al., 1997).

Moreover, HIV infection has also been associated with an increased risk of HL. Several studies reported 10-15 fold higher risk of developing HL in comparison to the general population (Biggar et al., 2006; Franceschi et al., 1998; Goedert et al., 1998; Herida et al., 2003; Hessol et al., 1992). HL, occurring in the setting of HIV infection, tends to be more aggressive, and more commonly presents with advanced stage, frequent constitutional symptoms, less favorable histology, and a poorer prognosis (Biggar et al., 2006).

HTLV-I-associated Adult T-cell Leukemia-Lymphoma

Adult T-cell leukemia-lymphoma (ATLL) was first described as a distinct clinical entity in 1977 based on its unique demographic distribution and clinicopathologic features (Takatsuki et al., 1976; Uchiyama et al., 1977). ATLL, associated with an infection with the human T-cell lymphotropic virus type I (HTLV-I), is geographically clustered, involving populations in the Caribbean, Japan, western Africa, and parts of South America and Central Asia, mirroring areas where HTLV-I infection is endemic.

When HTLV-I was identified as the causative agent in the pathogenesis of ATLL (Poiesz et al., 1980; Yoshida et al., 1982), it was indeed the first retrovirus shown to cause a human malignancy. HTLV-I, a member of the delta retrovirus family, appears to impart its leukemogenic role through the Tax protein, encoded in the virus’s genome (Franchini, 1995; Yoshida, 2001). Tax potently increases the expression of viral genes through the viral long terminal repeat (LTR) and also increases the transcription of cellular genes through cellular signaling pathways. It also promotes release of cytokines, which in turn leads to arrest in differentiation and cell proliferation (Azimi et al., 1998; Ballard et al., 1988; Himes et al., 1993; Wano et al., 1988). It interacts with cellular proteins such as NF-κB, CREB, SRF, and AP-1 that act as transcriptional factors or modulators of cellular function. There is often a long latency period from initial infection to onset of disease, suggesting that a multistep leukemogenic process is involved (Okamoto et al., 1989) (Figure 1). It is speculated that Tax leads to persistent proliferation of HTLV-I-infected cells during a latency period, and a subsequent accumulation of genetic and epigenetic changes can eventually lead to Tax-independent proliferation and disease manifestation (Kibler and Jeang, 1999).

Figure 1.The progression of leukemogenesis from HTLV-1 infection to onset of ATLL. After infection, HTLV-I promotes clonal proliferation of infected cells. Proliferation of HTLV-I-infected cells is controlled by cytotoxic T cells. Alternatively, alternations in the host genome accumulate during the latent period, finally leading to the onset of ATL (Adapted from Matsuoka, 2003).

Figure 1. The progression of leukemogenesis from HTLV-1 infection to onset of ATLL. After infection, HTLV-I promotes clonal proliferation of infected cells. Proliferation of HTLV-I-infected cells is controlled by cytotoxic T cells. Alternatively, alternations in the host genome accumulate during the latent period, finally leading to the onset of ATL. (Adapted from Matsuoka, 2003; with permission.)

Interestingly, although as many as 20 million people worldwide are infected with HTLV-I, ATLL impacts a small minority. For example, in Japan, approximately 1.2 million individuals were estimated to be infected by HTLV-I, and more than 800 cases of ATLL are diagnosed each year. The cumulative risk of ATLL among HTLV-I carriers in Japan was estimated at about 6.6% for men and 2.1% for women. Indeed, most infected by HTLV-I are carriers and asymptomatic for the duration of life (Arisawa et al., 2000). The average age of those with ATLL at the time of diagnosis is 40 years. In most, transmission is thought to occur through breast-feeding, although the virus is transmissible by sexual contact, exchange of contaminated needles, or blood transfusions (Sato and Okochi, 1986; Yara et al., 2009).

There are four described variants of ATLL: chronic, smoldering, acute, and lymphoma subtypes. The chronic and smoldering variants are generally more indolent, and exhibit overall survival rates at 4 years of approximately 50%. Unfortunately, the outcomes for the acute and lymphomatous forms are significantly worse. Although various chemotherapeutic regimens have been studied, results remain quite poor and median survival is in the range of 12 months (Tsukasaki et al., 2003; 2007; Yamada et al., 2001). Unfortunately, successful therapy for most patients with ATLL remains elusive.

Parvovirus B19 and Hematologic Malignancies

Parvovirus B19 has also been linked with hematologic malignancy. B19 infection, linked to aplastic crises and pure red cell aplasia in susceptible patient populations, has been reported as a preceding factor to ALL. More than 20 studies have reported persistent B19 infection in cases of acute lymphoblastic leukemia (ALL). (Barah et al., 2001; Garcia-Tapia et al., 1995; Heegaard et al., 1999; Sinclair et al., 1999). Indeed, acute parvoviral infection is associated with a significant cytokine cascade, leading to a degree of disturbed hematopoiesis and/or suppression of normal marrow function (Gerard and Rollins, 2001), although a definitive role in leukemogenesis has not been found.

Childhood Leukemia

Infectious associations with childhood acute leukemia have been described in three distinct areas of study: exposure to the infectious agent in utero or in the peripartum period, delayed exposure beyond the first year of life to common infections, and population mixing of various types during childhood (Greaves, 1999; Kinlen, 1988; 1995).

Some have hypothesized that the process leading to the onset of childhood leukemia consists of at least two events or series of events. The initial processes may be spontaneous, involving germline or somatic alterations, but later events perhaps may involve an “environmental” trigger and may lead to the phenotypic manifestation of the disease (Greaves, 1988). Both series of events would involve genetic alterations and/or the proliferation of premalignant clones. Infections have been considered as possible candidates for playing the role of such environmental triggers.

Although direct causality and role in leukemogenesis has not been established, various associations of childhood leukemia with preceding viral infection have been described. A number of studies have reported on maternal infections, childhood infections, and vaccinations and the subsequent risk of childhood leukemia. Some have found a significantly increased risk for childhood leukemia associated with maternal infection during pregnancy (Table 2). Specifically, maternal infection with the Epstein-Barr virus (EBV) had an odds ratio (OR) of 2.9 (95% CI: 1.5-5.8) (Lehtinen et al., 2003) of subsequent childhood malignancy. Interestingly, this study also described an association of maternal lower genital tract infection and subsequent acute leukemia in the child, with an OR of 1.8 (95% CI: 1.2-2.7) (Naumburg et al., 2002).

In individuals younger than 30, increased risk of acute lymphocytic leukemia (ALL) with preceding non-specific viral infection (OR =6.0; 95% CI: 1.2-29.7) has been reported (Roman et al., 1997). A non-significantly raised OR for varicella (Till et al., 1979) and influenza infections during pregnancy and subsequent childhood leukemia has also been reported (Hakulinen et al., 1973; Randolph and Heath, 1974). Additionally, high levels of HHV-6 antibodies were reported in ALL patients compared with healthy controls (Ablashi et al., 1988) but subsequent studies (Levine et al., 1992; Schlehofer et al., 1996) have found no such association.

It is important to note that others have reported an opposite association, a specifically protective effect of preceding infections. Petridou et al. (2001) studied 94 incident cases of ALL and 94 matched controls in Greece, and found no association of ALL with specific infectious agents amongst children aged 0-4 years, and for children aged 5 years or more, an inverse association with seropositivity to EBV, HHV-6, Mycoplasma pneumoniae, and Parvovirus B19 (Table 2).

In terms of studies looking at instances of population mixing, one group reported an increased onset of childhood leukemia and NHL at two isolated sites in England. The investigators proposed the occurrence of an unusual pattern of population mixing with a high level of inward and outward migration. They further proposed that this may have led to greater prevalence of infection and subsequent increase in leukemias. Subsequent studies by the same investigators appeared to support this notion (Kinlen, 1988; 1992; 1990; Kinlen and Hudson, 1991).

There has also been some other supportive evidence for an infectious etiology, provided by the findings of space-time clustering and seasonal variation (Higgins et al., 2001; Karimi and Yarmohammadi, 2003; Kinlen, 1992; Sorensen et al., 2001). For example some groups have reported a significant monthly peak in childhood ALL diagnosis (November) and seasonal variation in childhood AML diagnosis (winter) in Iran (Higgins et al., 2001; Karimi and Yarmohammadi, 2003; Sorensen et al., 2001).


In summary, a variety of microbiological pathogens have been either associated with or found to directly mediate the pathogenesis of hematologic malignancies. These discoveries have shed new light on the stepwise process of malignant transformation in these tumors. Some malignancies have even been successfully treated with antimicrobial therapy. In time, infectious pathogens may be linked to other malignancies and provide greater insight into the genesis of cancers. Most importantly, perhaps, such discoveries may allow opportunities for novel and effective preventive and therapeutic strategies.


The authors report no conflicts of interest.

Corresponding Author

Amir T. Fathi, M.D., Center for Leukemia and the Bone Marrow Transplant Unit, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.


Ablashi DV, Josephs SF, Buchbinder A, Hellman K, Nakamura S, Llana T, Lusso P, Kaplan M, Dahlberg J, Memon S, et al. Human B-lymphotropic virus (human herpesvirus-6). J Virol Methods 21(1-4):29-48, 1988.

Abrams JT, Balin BJ, Vonderheid EC. Association between Sezary T cell-activating factor, Chlamydia pneumoniae, and cutaneous T cell lymphoma. Ann N Y Acad Sci 941:69-85, 2001.

Al-Saleem T, Al-Mondhiry H. Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. Blood 105(6):2274-2280, 2005.

Alexander FE. Is Mycoplasma Pneumonia associated with childhood acute lymphoblastic leukemia? Cancer Causes Control 8(5):803-811, 1997.

Alexander FE, Jarrett RF, Lawrence D, Armstrong AA, Freeland J, Gokhale DA, Kane E, Taylor GM, Wright DH, Cartwright RA. Risk factors for Hodgkin’s disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer 82(5):1117-1121, 2000.

Anagnostopoulos I, Herbst H, Niedobitek G, Stein H. Demonstration of monoclonal EBV genomes in Hodgkin’s disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood 74(2):810-816, 1989.

Arisawa K, Soda M, Endo S, Kurokawa K, Katamine S, Shimokawa I, Koba T, Takahashi T, Saito H, Doi H, Shirahama S. Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer 85(3):319-324, 2000.

Armitage JO. Early-stage Hodgkin’s lymphoma. N Engl J Med 363(7):653-662, 2010.

Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385(6614):347-350, 1997.

Arvanitakis L, Mesri EA, Nador RG, Said JW, Asch AS, Knowles DM, Cesarman E. Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus. Blood 88(7):2648-2654, 1996.

Arvanitakis L, Yaseen N, Sharma S. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. J Immunol 155(3):1047-1056, 1995.

Azimi N, Brown K, Bamford RN, Tagaya Y, Siebenlist U, Waldmann TA. Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. Proc Natl Acad Sci U S A 95(5):2452-2457, 1998.

Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS, Asch AS, Cesarman E, Gershengorn MC, Mesri EA. G-protein-coupled receptor of Kaposi’s sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391(6662):86-89, 1998.

Ballard DW, Bohnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science 241(4873):1652-1655, 1988.

Barah F, Vallely PJ, Chiswick ML, Cleator GM, Kerr JR. Association of human parvovirus B19 infection with acute meningoencephalitis. Lancet 358(9283):729-730, 2001.

Bedo S, Mezes M, Barcsak Toth G. Blood glutathione peroxidase enzyme activity as an index of selenium release from Permasel in ewes. Acta Vet Hung 40(3):151-154, 1992.

Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108(12):3786-3791, 2006.

Boiocchi M, Carbone A, De Re V, Dolcetti R. Is the Epstein-Barr virus involved in Hodgkin’s disease? Tumori 75(4):345-350, 1989.

Boshoff C, Chang Y. Kaposi’s sarcoma-associated herpesvirus: a new DNA tumor virus. Annu Rev Med 52:453-470, 2001.

Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y, Weiss RA. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278(5336):290-294, 1997.

Burkitt D. A lymphoma syndrome in African children. Ann R Coll Surg Engl 30:211-219, 1962.

Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 21(3):405-426, 2000.

Byard SD, Chowdhury HR, Lee RM, Hyer J, Hart-George AL. Unilateral isolated extraocular muscle lymphoma. BMJ Case Rep 2012, 2012.

Cai Q, Verma SC, Lu J, Robertson ES. Molecular biology of Kaposi’s sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res 78:87-142, 2010.

Camilleri-Broet S, Camparo P, Mokhtari K, Hoang-Xuan KH, Martin A, Arborio M, Hauw JJ, Raphael M. Overexpression of BCL-2, BCL-X, and BAX in primary central nervous system lymphomas that occur in immunosuppressed patients. Mod Pathol 13(2):158-165, 2000.

Carbone A, Gaidano G. HHV-8-positive body-cavity-based lymphoma: a novel lymphoma entity. Br J Haematol 97(3):515-522, 1997.

Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A. Viral infections as a cause of cancer (review). Int J Oncol 30(6):1521-1528, 2007.

Cen H, Williams PA, Mcwilliams HP, Breinig MC, Ho M, McKnight JL. Evidence for restricted Epstein-Barr virus latent gene expression and anti-EBNA antibody response in solid organ transplant recipients with posttransplant lymphoproliferative disorders. Blood 81(5):1393-1403, 1993.

Cesarman E. The role of Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) in lymphoproliferative diseases. Recent Results Cancer Res 159:27-37, 2002.

Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332(18):1186-1191, 1995.

Chan LC, Lam TH, Li CK, Lau YL, Yuen HL, Lee CW, Ha SY, Yuen PM, Leung NK, Patheal SL, Greaves MF, Alexander FE. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol 16(2):154-165, 2002.

Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clin Microbiol Rev 23(4):837-857, 2010.

Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266(5192):1865-1869, 1994.

Chanudet E, Adam P, Nicholson AG, Wotherspoon AC, Ranaldi R, Goteri G, Pileri SA, Ye H, Muller-Hermelink HK, Du MQ. Chlamydiae and Mycoplasma infections in pulmonary MALT lymphoma. Br J Cancer 97(7):949-951, 2007.

Choung HK, Kim YA, Lee MJ, Kim N, Khwarg SI. Multigene methylation analysis of ocular adnexal MALT lymphoma and their relationship to Chlamydophila psittaci infection and clinical characteristics in South Korea. Invest Ophthalmol Vis Sci 53(4):1928-1935, 2012.

Collot S, Petit B, Bordessoule D, Alain S, Touati M, Denis F, Ranger-Rogez S. Real-time PCR for quantification of human herpesvirus 6 DNA from lymph nodes and saliva. J Clin Microbiol 40(7):2445-2451, 2002.

Conant MA. Management of human immunodeficiency virus-associated malignancies. Recent Results Cancer Res 139:423-432, 1995.

Cote TR, Biggar RJ, Rosenberg PS, Devesa SS, Percy C, Yellin FJ, Lemp G, Hardy C, Geodert JJ, Blattner WA. Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 73(5):645-650, 1997.

D’Apuzzo M, Rolink A, Loetscher M, Hoxie JA, Clark-Lewis I, Melchers F, Baggiolini M, Moser B. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol 27(7):1788-1793, 1997.

De Cremoux P, Subtil A, Ferreri AJ, Vincent-Salomon A, Ponzoni M, Chaoui D, Arnaud P, Lumbroso-Le Rouic L, Sacchetti F, Dendale R, Thioux M, Escande MC, Stern MH, Dolcetti R, Decaudin D. Re: Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 98(5):365-366, 2006.

Dean M, Jacobson LP, Mcfarlane G, Margolick JB, Jenkins FJ, Howard OM, Dong HF, Goedert JJ, Buchbinder S, Gomperts E, Vlahov D, Oppenheim JJ, O’Brien SJ, Carrington M. Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-delta32 mutation. Cancer Res 59(15):3561-3564, 1999.

Diamandopoulos GT. Induction of lymphocytic leukemia, lymphosarcoma, reticulum cell sarcoma, and osteogenic sarcoma in the Syrian golden hamster by oncogenic DNA simian virus 40. J Natl Cancer Inst 50(5):1347-1365, 1973.

Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer 80(9):1483-1489, 1999.

Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoff C. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 95(4):1406-1412, 2000.

Eddy BE, Borman GS, Berkeley WH, Young RD. Tumors induced in hamsters by injection of rhesus monkey kidney cell extracts. Proc Soc Exp Biol Med 107:191-197, 1961.

Eliopoulos AG, Stack M, Dawson CW, Kaye KM, Hodgkin L, Sihota S, Rowe M, Young LS. Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor-associated factors. Oncogene 14(24):2899-2916, 1997.

Eliopoulos AG, Young LS. Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1). Oncogene 16(13):1731-1742, 1998.

Ellermann V, Bang O. Experimentelle Leukämie bei Hühnern. Zentralbl Bakteriol Parasitenkd Infectionskr Hyg Abt Orig 46:595-609, 1908.

Engels EA. Infectious agents as causes of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 16(3):401-404, 2007.

Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics of oral and paraoral malignant lymphoma: a population-based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92(5):519-525, 2001.

Epstein MA, Barr YM. Characteristics and mode of growth of tissue culture strain (Eb1) of human lymphoblasts from Burkitt’s lymphoma. J Natl Cancer Inst 34:231-240, 1965.

Ferreri AJ, Govi S, Pasini E, Mappa S, Bertoni F, Zaja F, Montalban C, Stelitano C, Cabrera ME, Giordano Resti A, Politi LS, Doglioni C, Cavalli F, Zucca E, Ponzoni M, Dolcetti R. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J Clin Oncol 30(24):2988-2994, 2012.

Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell’oro S, Fleischhauer K, Caggiari L, Lettini AA, Dal Cin E, Ieri R, Freschi M, Villa E, Boiocchi M, Dolcetti R. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96(8):586-594, 2004.

Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene can act as a suppressor of transformation. Cell 57(7):1083-1093, 1989.

Flavell KJ, Biddulph JP, Powell JE, Parkes SE, Redfern D, Weinreb M, Nelson P, Mann JR, Young LS, Murray PG. South Asian ethnicity and material deprivation increase the risk of Epstein-Barr virus infection in childhood Hodgkin’s disease. Br J Cancer 85(3):350-356, 2001.

Franceschi S, La Vecchia C, Dal Maso L, Serraino D, Rezza G. Spectrum of AIDS-associated malignant disorders. Lancet 352(9131):906-907; author reply 907, 1998.

Franchini G. Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection. Blood 86(10):3619-3639, 1995.

Gaidano G, Cechova K, Chang Y, Moore PS, Knowles DM, Dalla-Favera R. Establishment of AIDS-related lymphoma cell lines from lymphomatous effusions. Leukemia 10(7):1237-1240, 1996.

Garcia-Tapia AM, Fernandez-Gutierrez Del Alamo C, Giron JA, Mira J, De La Rubia F, Martinez-Rodriguez A, Martin-Reina MV, Lopez-Caparros R, Caliz R, Caballero MS, et al. Spectrum of parvovirus B19 infection: analysis of an outbreak of 43 cases in Cadiz, Spain. Clin Infect Dis 21(6):1424-1430, 1995.

Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2(2):108-115, 2001.

Gibbs CJ, Jr, Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM, Matthews WB. Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science 161(3839):388-389, 1968.

Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffing M, Hammerschmidt W. Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J 18(11):3064-3073, 1999.

Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P, Pallesen G, Gulley ML, Khan G, O’Grady J, Hummel M, Preciado MV, Knecht H, Chan JK, Claviez A. Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70(4):375-382, 1997.

Goedert JJ, Cote TR, Virgo P, Scoppa SM, Kingma DW, Gail MH, Jaffe ES, Biggar RJ. Spectrum of AIDS-associated malignant disorders. Lancet 351(9119):1833-1839, 1998.

Goodlad JR, Davidson MM, Hollowood K, Batstone P, Ho-Yen DO. Borrelia burgdorferi-associated cutaneous marginal zone lymphoma: a clinicopathological study of two cases illustrating the temporal progression of B. burgdorferi-associated B-cell proliferation in the skin. Histopathology 37(6):501-508, 2000a.

Goodlad JR, Davidson MM, Hollowood K, Ling C, Mackenzie C, Christie I, Batstone PJ, Ho-Yen DO. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am J Surg Pathol 24(9):1279-1285, 2000b.

Greaves M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur J Cancer 35(14):1941-1953, 1999.

Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 2(2):120-125, 1988.

Gregory CD, Dive C, Henderson S, Smith CA, Williams GT, Gordon J, Rickinson AB. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature 349(6310):612-614, 1991.

Gross L. Viral etiology of cancer and leukemia: a look into the past, present and future — G.H.A. Clowes Memorial Lecture. Cancer Res 38(3):485-493, 1978.

Grufferman S, Cole P, Levitan TR. Evidence against transmission of Hodgkin’s disease in high schools. N Engl J Med 300(18):1006-1011, 1979.

Gutensohn N, Cole P. Childhood social environment and Hodgkin’s disease. N Engl J Med 304(3):135-140, 1981.

Hakulinen T, Hovi L, Karkinen J, Penttinen K, Saxen L. Association between influenza during pregnancy and childhood leukaemia. Br Med J 4(5887):265-267, 1973.

Heegaard ED, Jensen L, Hornsleth A, Schmiegelow K. The role of parvovirus B19 infection in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 16(4):329-334, 1999.

Herida M, Mary-Krause M, Kaphan R, Cadranel J, Poizot-Martin I, Rabaud C, Plaisance N, Tissot-Dupont H, Boue F, Lang JM, Costagliola D. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 21(18):3447-3453, 2003.

Hermine O, Lefrere F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347(2):89-94, 2002.

Hernandez-Losa J, Fedele CG, Pozo F, Tenorio A, Fernandez V, Castellvi J, Parada C, Ramon Y, Cajal S. Lack of association of polyomavirus and herpesvirus types 6 and 7 in human lymphomas. Cancer 103(2):293-298, 2005.

Hessol NA, Katz MH, Liu JY, Buchbinder SP, Rubino CJ, Holmberg SD. Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Intern Med 117(4):309-311, 1992.

Higgins CD, Dos-Santos-Silva I, Stiller CA, Swerdlow AJ. Season of birth and diagnosis of children with leukaemia: an analysis of over 15 000 UK cases occurring from 1953-95. Br J Cancer 84(3):406-412, 2001.

Himes SR, Coles LS, Katsikeros R, Lang RK, Shannon MF. HTLV-1 tax activation of the GM-CSF and G-CSF promoters requires the interaction of NF-kB with other transcription factor families. Oncogene 8(12):3189-3197, 1993.

Hjalgrim H, Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, Zhang JS, Madsen M, Rosdahl N, Konradsen HB, Storm HH, Melbye M. Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349(14):1324-1332, 2003.

Hodgkin. On some morbid appearances of the absorbent glands and spleen. Med Chir Trans 17:68-114, 1832.

Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer 83(11):1559-1564, 2000.

Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523-531, 2009.

Jarrett RF. Viruses and lymphoma/leukaemia. J Pathol 208(2):176-186, 2006.

Jarrett RF, MacKenzie J. Epstein-Barr virus and other candidate viruses in the pathogenesis of Hodgkin’s disease. Semin Hematol 36(3):260-269, 1999.

Javier RT, Butel JS. The history of tumor virology. Cancer Res 68(19):7693-7706, 2008.

Jelic S, Filipovic-Ljeskovic I. Positive serology for Lyme disease borrelias in primary cutaneous B-cell lymphoma: a study in 22 patients; is it a fortuitous finding? Hematol Oncol 17(3):107-116, 1999.

Karimi M, Yarmohammadi H. Seasonal variations in the onset of childhood leukemia/lymphoma: April 1996 to March 2000, Shiraz, Iran. Hematol Oncol 21(2):51-55, 2003.

Kerr JR, Barah F, Cunniffe VS, Smith J, Vallely PJ, Will AM, Wynn RF, Stevens RF, Taylor GM, Cleator GM, Eden OB. Association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia. J Clin Pathol 56(11):873-875, 2003.

Kibler KV, Jeang KT. Taxing the cellular capacity for repair: human T-cell leukemia virus type 1, DNA damage, and adult T-cell leukemia. J Natl Cancer Inst 91(11):903-904, 1999.

Kinlen L. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain. Lancet 2(8624):1323-1327, 1988.

Kinlen LJ. Childhood leukaemia on Greek islands. Lancet 339(8787):252-253, 1992.

Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 71(1):1-5, 1995.

Kinlen LJ, Clarke K, Hudson C. Evidence from population mixing in British New Towns 1946-85 of an infective basis for childhood leukaemia. Lancet 336(8715):577-582, 1990.

Kinlen LJ, Hudson C. Childhood leukaemia and poliomyelitis in relation to military encampments in England and Wales in the period of national military service, 1950-63. BMJ 303(6814):1357-1362, 1991.

Lacroix A, Jaccard A, Rouzioux C, Piguet C, Petit B, Bordessoule D, Ranger-Rogez S. HHV-6 and EBV DNA quantitation in lymph nodes of 86 patients with Hodgkin’s lymphoma. J Med Virol 79(9):1349-1356, 2007.

Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem 267(34):24157-24160, 1992.

Lapin BA. Epidemiology of leukemia among baboons of Sukhumi monkey colony. Bibl Haematol (43):212-215, 1975.

Lecuit M, Abachin E, Martin A, Poyart C, Pochart P, Suarez F, Bengoufa D, Feuillard J, Lavergne A, Gordon JI, Berche P, Guillevin L, Lortholary O. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 350(3):239-248, 2004.

Lehtinen M, Koskela P, Ogmundsdottir HM, Bloigu A, Dillner J, Gudnadottir M, Hakulinen T, Kjartansdottir A, Kvarnung M, Pukkala E, Tulinius H, Lehtinen T. Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring. Am J Epidemiol 158(3):207-213, 2003.

Lehtinen T, Lumio J, Dillner J, Hakama M, Knekt P, Lehtinen M, Teppo L, Leinikki P. Increased risk of malignant lymphoma indicated by elevated Epstein-Barr virus antibodies–a prospective study. Cancer Causes Control 4(3):187-193, 1993.

Levine AM. AIDS-related malignancies. Curr Opin Oncol 6(5):489-491, 1994.

Levine AM, Shimodaira S, Lai MM. Treatment of HCV-related mantle-cell lymphoma with ribavirin and pegylated interferon Alfa. N Engl J Med 349(21):2078-2079, 2003.

Levine PH, Ablashi DV, Saxinger WC, Connelly RR. Antibodies to human herpes virus-6 in patients with acute lymphocytic leukemia. Leukemia 6(11):1229-1231, 1992.

Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald-Mullen PM, Klein G, Kurilla MG, Masucci MG. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375(6533):685-688, 1995.

Liebowitz D. Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients. N Engl J Med 338(20):1413-1421, 1998.

Lombardi L, Newcomb EW, Dalla-Favera R. Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell 49(2):161-170, 1987.

Long JL, Engels EA, Moore RD, Gebo KA. Incidence and outcomes of malignancy in the HAART era in an urban cohort of HIV-infected individuals. AIDS 22(4):489-496, 2008.

Luppi M, Barozzi P, Garber R, Maiorana A, Bonacorsi G, Artusi T, Trovato R, Marasca R, Torelli G. Expression of human herpesvirus-6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol 153(3):815-823, 1998.

Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene 27(Suppl 2):S31-S42, 2008.

Matsuoka M. Human T-cell leukemia virus type I and adult T-cell leukemia. Oncogene 22(33):5131-5140, 2003.

Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Pleural and peritoneal lymphoma among people with AIDS in the United States. J Acquir Immune Defic Syndr 29(4):418-421, 2002.

McKinney PA, Juszczak E, Findlay E, Smith K, Thomson CS. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study. Br J Cancer 80(11):1844-1851, 1999.

Melendez LV, Hunt RD, Daniel MD, Garcia FG, Fraser CE. Herpesvirus saimiri. II. Experimentally induced malignant lymphoma in primates. Lab Anim Care 19(3):378-386, 1969.

Mosialos G, Birkenbach M, Yalamanchili R, Vanarsdale T, Ware C, Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80(3):389-399, 1995.

Mueller N, Evans A, Harris NL, Comstock GW, Jellum E, Magnus K, Orentreich N, Polk BF, Vogelman J. Hodgkin’s disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med 320(11):689-695, 1989.

Naumburg E, Bellocco R, Cnattingius S, Jonzon A, Ekbom A. Perinatal exposure to infection and risk of childhood leukemia. Med Pediatr Oncol 38(6):391-397, 2002.

Ogata M. Human herpesvirus 6 in hematological malignancies. J Clin Exp Hematop 49(2):57-67, 2009.

Okamoto T, Ohno Y, Tsugane S, Watanabe S, Shimoyama M, Tajima K, Miwa M, Shimotohno K. Multi-step carcinogenesis model for adult T-cell leukemia. Jpn J Cancer Res 80(3):191-195, 1989.

Pallesen G, Sandvej K, Hamilton-Dutoit SJ, Rowe M, Young LS. Activation of Epstein-Barr virus replication in Hodgkin and Reed-Sternberg cells. Blood 78(5):1162-1165, 1991.

Pannekoek Y, Van Der Ende A. Chlamydia psittaci infection in nongastrointestinal MALT lymphomas and their precursor lesions. Am J Clin Pathol 136(3):480; author reply 481, 2011.

Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118(12):3030-3044, 2006.

Parravicini C, Corbellino M, Paulli M, Magrini U, Lazzarino M, Moore PS, Chang Y. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman’s disease. Am J Pathol 151(6):1517-1522, 1997.

Parsonnet J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, Jellum E, Orentreich N, Vogelman JH, Friedman GD. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 330(18):1267-1271, 1994.

Parsonnet J, Isaacson PG. Bacterial infection and MALT lymphoma. N Engl J Med 350(3):213-215, 2004.

Petridou E, Dalamaga M, Mentis A, Skalkidou A, Moustaki M, Karpathios T, Trichopoulos D. Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece). Cancer Causes Control 12(7):645-652, 2001.

Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 77(12):7415-7419, 1980.

Rabkin CS. Epidemiology of AIDS-related malignancies. Curr Opin Oncol 6(5):492-496, 1994.

Rabkin CS, Yang Q, Goedert JJ, Nguyen G, Mitsuya H, Sei S. Chemokine and chemokine receptor gene variants and risk of non-Hodgkin’s lymphoma in human immunodeficiency virus-1-infected individuals. Blood 93(6):1838-1842, 1999.

Randolph VL, Heath CW, Jr. Influenza during pregnancy in relation to subsequent childhood leukemia and lymphoma. Am J Epidemiol 100(5):399-409, 1974.

Renne R, Lagunoff M, Zhong W, Ganem D. The size and conformation of Kaposi’s sarcoma-associated herpesvirus (HHV8) DNA in infected cells and virions. J Virol 70(11):8151-8154, 1996.

Rochford R, Cannon MJ, Moormann AM. Endemic Burkitt’s lymphoma: a polymicrobial disease? Nat Rev Microbiol 3(2):182-187, 2005.

Roman E, Ansell P, Bull D. Leukaemia and non-Hodgkin’s lymphoma in children and young adults: are prenatal and neonatal factors important determinants of disease? Br J Cancer 76(3):406-415, 1997.

Rous P. A Sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med 13(4):397-411, 1911.

Sato H, Okochi K. Transmission of human T-cell leukemia virus (HTLV-I) by blood transfusion: demonstration of proviral DNA in recipients’ blood lymphocytes. Int J Cancer 37(3):395-400, 1986.

Schlehofer B, Blettner M, Geletneky K, Haaf HG, Kaatsch P, Michaelis J, Mueller-Lantzsch N, Niehoff D, Winkelspecht B, Wahrendorf J, Schlehofer JR. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer 65(5):584-590, 1996.

Schmidt CA, Oettle H, Peng R, Binder T, Wilborn F, Huhn D, Siegert W, Herbst H. Presence of human beta- and gamma-herpes virus DNA in Hodgkin’s disease. Leuk Res 24(10):865-870, 2000.

Schulz TF. KSHV/HHV8-associated lymphoproliferations in the AIDS setting. Eur J Cancer 37(10):1217-1226, 2001.

Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet 380(9844):848-857, 2012.

Shiramizu B, Chang CW, Cairo MS. Absence of human herpesvirus-6 genome by polymerase chain reaction in children with Hodgkin disease: a Children’s Cancer Group Lymphoma Biology Study. J Pediatr Hematol Oncol 23(5):282-285, 2001.

Shope RE, Hurst EW. Infectious papillomatosis of rabbits : with a note on the histopathology. J Exp Med 58(5):607-624, 1933.

Silvestri F, Pipan C, Barillari G, Zaja F, Fanin R, Infanti L, Russo D, Falasca E, Botta GA, Baccarani M. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood 87(10):4296-4301, 1996.

Simonelli C, Spina M, Cinelli R, Talamini R, Tedeschi R, Gloghini A, Vaccher E, Carbone A, Tirelli U. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 21(21):3948-3954, 2003.

Sinclair JP, Croxson MC, Thomas SM, Teague LR, Mauger DC. Chronic parvovirus B19 meningitis in a child with acute lymphocytic leukemia. Pediatr Infect Dis J 18(4):395-396, 1999.

Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano JS. Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310(19):1225-1230, 1984.

Snyder SP, Dungworth DL, Kawakami TG, Callaway E, Lau DT. Lymphosarcomas in two gibbons (Hylobates lar) with associated C-type virus. J Natl Cancer Inst 51(1):89-94, 1973.

Sorensen HT, Pedersen L, Olsen J, Rothman K. Seasonal variation in month of birth and diagnosis of early childhood acute lymphoblastic leukemia. JAMA 285(2):168-169, 2001.

Stathis A, Chini C, Bertoni F, Proserpio I, Capella C, Mazzucchelli L, Pedrinis E, Cavalli F, Pinotti G, Zucca E. Long-term outcome following Helicobacter pylori eradication in a retrospective study of 105 patients with localized gastric marginal zone B-cell lymphoma of MALT type. Ann Oncol 20(6):1086-1093, 2009.

Su IJ, Chen JY. The role of Epstein-Barr virus in lymphoid malignancies. Crit Rev Oncol Hematol 26(1):25-41, 1997.

Sumi Y, Ozaki Y, Amemiya K, Shirakata A, Tamamoto F, Katayama H. Re-appraisal of clinical usefulness of 67Ga-citrate scintigraphy for primary colorectal carcinoma: with evaluation of scintigram obtained from resected specimens. Ann Nucl Med 6(3):137-145, 1992.

Sumiyoshi Y, Kikuchi M, Ohshima K, Takeshita M, Eizuru Y, Minamishima Y. Analysis of human herpes virus-6 genomes in lymphoid malignancy in Japan. J Clin Pathol 46(12):1137-1138, 1993.

Takatsuki K, Uchiyama T, Sagawa K, Yodoi J. [Surface markers of malignant lymphoid cells in the classification of lymphoproliferative disorders, with special reference to adult T-cell leukemia (author's transl)]. Rinsho Ketsueki 17(4):416-421, 1976.

Till M, Rapson N, Smith PG. Family studies in acute leukaemia in childhood: a possible association with autoimmune disease. Br J Cancer 40(1):62-71, 1979.

Torelli G, Marasca R, Luppi M, Selleri L, Ferrari S, Narni F, Mariano MT, Federico M, Ceccherini-Nelli L, Bendinelli M, et al. Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin’s lymphomas by polymerase chain reaction. Blood 77(10):2251-2258, 1991.

Trovato R, Di Lollo S, Calzolari A, Torelli G, Ceccherini-Nelli L. Detection of human herpesvirus-6 and Epstein-Barr virus genome in childhood Hodgkin’s disease. Pathologica 86(5):500-503, 1994.

Tsukasaki K, Tobinai K, Shimoyama M, Kozuru M, Uike N, Yamada Y, Tomonaga M, Araki K, Kasai M, Takatsuki K, Tara M, Mikuni C, Hotta T. Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109). Int J Hematol 77(2):164-170, 2003.

Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, Ikeda S, Masuda M, Nagoshi H, Ueda R, Tamura K, Sano M, Momita S, Yamaguchi K, Kawano F, Hanada S, Tobinai K, Shimoyama M, Hotta T, Tomonaga M. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol 25(34):5458-5464, 2007.

Uccini S, Monardo F, Ruco LP, Baroni CD, Faggioni A, Agliano AM, Gradilone A, Manzari V, Vago L, Costanzi G, et al. High frequency of Epstein-Barr virus genome in HIV-positive patients with Hodgkin’s disease. Lancet 1(8652):1458, 1989.

Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50(3):481-492, 1977.

Uckun FM, Sensel MG, Sun L, Steinherz PG, Trigg ME, Heerema NA, Sather HN, Reaman GH, Gaynon PS. Biology and treatment of childhood T-lineage acute lymphoblastic leukemia. Blood 91(3):735-746, 1998.

Valente G, Secchiero P, Lusso P, Abete MC, Jemma C, Reato G, Kerim S, Gallo RC, Palestro G. Human herpesvirus 6 and Epstein-Barr virus in Hodgkin’s disease: a controlled study by polymerase chain reaction and in situ hybridization. Am J Pathol 149(5):1501-1510, 1996.

Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, Lazzaro A, Trabacchi E, Anselmi E, Arcari AL, Moroni C, Berte R, Lazzarino M, Cavanna L. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol 23(3):468-473, 2005.

Varmus HE. Using retroviruses as insertional mutagens to identify cellular oncogenes. Prog Clin Biol Res 119:23-35, 1983.

Vianna NJ, Greenwald P, Brady J, Polan AK, Dwork A, Mauro J, Davies JN. Hodgkin’s disease: cases with features of a community outbreak. Ann Intern Med 77(2):169-180, 1972.

Vianna NJ, Polan AK. Epidemiologic evidence for transmission of Hodgkin’s disease. N Engl J Med 289(10):499-502, 1973.

Wano Y, Feinberg M, Hosking JB, Bogerd H, Greene WC. Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. Proc Natl Acad Sci U S A 85(24):9733-9737, 1988.

Weiss LM, Jaffe ES, Liu XF, Chen YY, Shibata D, Medeiros LJ. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood 79(7):1789-1795, 1992.

Weiss LM, Strickler JG, Warnke RA, Purtilo DT, Sklar J. Epstein-Barr viral DNA in tissues of Hodgkin’s disease. Am J Pathol 129(1):86-91, 1987.

Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334(6178):124-129, 1988.

Wilson JB, Bell JL, Levine AJ. Expression of Epstein-Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 15(12):3117-3126, 1996.

Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, De Boni M, Isaacson PG. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342(8871):575-577, 1993.

Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338(8776):1175-1176, 1991.

Wu TC, Mann RB, Charache P, Hayward SD, Staal S, Lambe BC, Ambinder RF. Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin’s disease. Int J Cancer 46(5):801-804, 1990.

Yamada Y, Tomonaga M, Fukuda H, Hanada S, Utsunomiya A, Tara M, Sano M, Ikeda S, Takatsuki K, Kozuru M, Araki K, Kawano F, Niimi M, Tobinai K, Hotta T, Shimoyama M. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma: Japan Clinical Oncology Group Study 9303. Br J Haematol 113(2):375-382, 2001.

Yara S, Fujita J, Date H. Transmission of human T-lymphotropic virus type I by bilateral living-donor lobar lung transplantation. J Thorac Cardiovasc Surg 138(1):255-256, 2009.

Yoshida M. Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol 19:475-496, 2001.

Yoshida M, Miyoshi I, Hinuma Y. A retrovirus from human leukemia cell lines: its isolation, characterization, and implication in human adult T-cell leukemia (ATL). Princess Takamatsu Symp 12:285-294, 1982.

Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 4(10):757-768, 2004.

Zhao B, Sample CE. Epstein-barr virus nuclear antigen 3C activates the latent membrane protein 1 promoter in the presence of Epstein-Barr virus nuclear antigen 2 through sequences encompassing an spi-1/Spi-B binding site. J Virol 74(11):5151-5160, 2000.

Zuckerman E, Zuckerman T, Levine AM, Douer D, Gutekunst K, Mizokami M, Qian DG, Velankar M, Nathwani BN, Fong TL. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med 127(6):423-428, 1997.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 14(79):421-433, December 2012. Copyright © Discovery Medicine. All rights reserved.]

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