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):
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).
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).
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).
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.
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.
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