Human T-Cell Lymphotropic Virus 1

 

In 1978, human T-cell lymphotropic virus 1 (HTLV-1) was identified as the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). This retrovirus produces slow, progressive infection, is transmitted through blood and breast milk, and is known to precipitate immunosuppression. HTLV-1 is endemic in Japan, the Caribbean, and parts of central Africa; carriers have a cumulative lifetime risk of ATLL of 1–5%. In endemic regions, ATLL accounts for 50% of all lymphoid malignancies. Exposure usually occurs during infancy, but due to its long latency period the median age of development of ATLL is 55 years. The leukemogenic potential of the virus is thought to arise from the infected cells’ expression of viral oncoproteins, which promotes genetic mutation and clonal proliferation. Public health strategies such as blood donor screening, protective sexual practices, and accessibility of nutritious alternatives to breast-feeding are primary prevention measures that may limit HTLV-1 transmission in countries of high viral prevalence.
Helicobacter Pylori
Helicobacter pylori (HP), a gastric pathogen, has been shown to play a pivotal role in extranodal gastric lymphoma, particularly mucous-associated lymphoid tissue (MALT) types, of which the majority are HP-positive. This association is now well-established based upon the presence of HP infection in primary gastric lymphoma, confirmation of the importance of HP in the pathogenesis of gastric lymphoma by in vitro studies, and demonstration of complete remission of the lymphoma following antibiotic eradication of HP. Chronic antigenic stimulation and inflammation due to the pathogen may represent the mechanism of lymphomagenesis in these tumors.
Human Herpes Virus 8
Some rare infectious pathogens have been linked to the development of lymphoma. Human herpes virus 8 (HHV8), primarily associated with Kaposi sarcoma, has been detected in most subjects with primary effusion lymphoma, a body-cavity-based lymphoma seen almost exclusively in HIV-positive patients. Cases often present with dual EBV and HHV8 infection; therefore, delineation of the etiologic role of each virus is difficult. These neoplasms have been demonstrated to be monoclonal expansions of a single infected cell, suggesting that the viral infection precedes tumor growth.
Hepatitis C
Approximately 180 million people, or 3% of the world population, are infected with hepatitis C virus (HCV). Although not known to be oncogenic, HCV is lymphotropic and replicates in peripheral blood mononuclear cells. In Italy, reports have suggested that up to 32% of NHL cases are HCV-positive, compared to only 1.3% of normal controls. Japanese studies have reported similar findings. In the United States, however, where HCV prevalence is less than 2%, a population-based study demonstrated a relative risk of NHL of only 2.0 with HCV positivity. Studies from Canada and several other countries have been negative. While there may be a role of HCV in NHL, this virus may only be relevant in geographic areas with the highest prevalence of infection. While the exact mechanism of lymphomagenesis is unclear, the increased risk may be due to chronic antigenic stimulation.
Simian Virus 40
In the past decade there has been considerable controversy regarding the potential role of simian virus 40 (SV40), a polyomavirus indigenous to African green monkeys, in lymphomagenesis. Confirmed as a viable contaminant of the Salk polio vaccine, SV40 has demonstrated oncogenic potential in animals and may be transmissible from person to person and from mother to infant during childbirth. In 2002, reports by two investigative teams, Vilchez et al. and Shivapurkar et al., that demonstrated detection of SV40 in 40% of NHL specimens drew significant attention to this virus as an etiologic factor in lymphoma. While additional studies have provided evidence of an association between SV40 and lymphoma, other investigations from Spain, Australia, and Germany have failed to detect SV40 DNA in any lymphoma specimen. Dissemination of the virus via contaminated vaccine in these countries has not been confirmed. Given the high prevalence of SV40 detected in lymphoma specimens in early reports, further research in this area is warranted.
Other Pathogens
A plethora of data has recently emerged linking lymphoma risk to various other infections. Recent studies suggest that Chlamydia psittaci (CP) may be associated with ocular lymphomas of the orbital adnexal type. CP is an obligate intracellular bacterium that causes psittacosis, a human lung infection associated with exposure to infected birds, cats, and other pets. Ferreri and colleagues (2004) demonstrated CP DNA in 80% of tumor biopsies from 40 Italian patients with ocular lymphomas. Of those positive, 66% were marginal zone lymphomas. Other studies have not consistently supported this finding. Genetic and phenotypic variations in CP strains present in Europe and southeastern United States may account for some of these differences.

Recently, infection with Borrelia burgdorferri has been linked to primary cutaneous B cell lymphoma. The majority of these observations have come from European countries, with little evidence of such an association in North America.

Mediterranean lymphoma is an unusual form of lymphoma that arises in small-intestinal-mucosa-associated lymphoid tissue. Early-stage disease regresses with antibiotic treatment, suggesting a bacterial etiology. The bacteria Campylobacter jejunei has been identified in these tumors. Although research has been quite limited due to the unusual nature of these lymphomas, these observations raise the possibility of a role for other, yet to be recognized, pathogens in lymphomagenesis.
Other Environmental Exposures
Numerous other environmental exposures have been studied related to lymphoma; however, results have been somewhat inconsistent and at times contradictory. Many of these studies have been limited by inadequate sample size, poor methodologic designs, and difficulties in measuring exposure.
Ultraviolet Radiation
The impact of exposure to ultraviolet radiation (UVR) on the risk of developing lymphoma remains controversial. Increasing recreational time, changing fashions leading to more skin exposure, and the cosmetic desirability of tanning have contributed to increasing UVR exposure in recent years, and the increasing incidence of NHL parallels the escalating incidence of skin cancer. NHL and skin cancer occur more frequently than expected in the same individuals, and some studies suggest that sun sensitivity is related to an increased risk of NHL. Such disease pairing may provide etiologic clues to disease causation. In humans, sunlight exposure in susceptible individuals produces acute UV injury, resulting in both inflammatory and immunomodulatory responses. Evidence suggests that it is the absorption of UVR by these cells and the resulting DNA damage that trigger the biochemical cascade of immunosuppression, and may alter the balance of the host–disease relationship in favor of pathogens. Some studies have implicated UVR in risk of lymphoma, but data remain inconclusive. A moderate international geographic correlation of UVR levels and NHL incidence among Caucasians has been reported. Similarly, findings of a higher risk of NHL among farmers may be attributed to the increased UVR exposure that accompanies their outdoor activities. On the other hand, Smedby and colleagues (2005) conducted a large, population-based study of 3740 patients and 3187 controls in Sweden and Denmark that yielded opposing results. The study found that higher amounts of UVR exposure were associated with decreased lymphoma risk, contrary to what was previously indicated. Protective effects of vitamin D are a possible explanation that would support an inverse association between UVR and lymphoma risk. Given the ubiquitous nature of UVR, this exposure warrants careful consideration as an etiologic factor in lymphoma. The conflicting results of published studies suggest that further investigation is, indeed, indicated.
Chemical/Agricultural Exposure
Given the excess mortality from cancer observed in rural areas, particularly those in which farming is common, and the concurrent rise in the use of pesticides, agriculture related environmental exposures have been ambitiously investigated. These studies are challenging to conduct because of the difficulty in developing high-quality assessments of exposure. While many studies have demonstrated a high rate of lymphoma among agricultural workers, few provide information on the specific agricultural exposures that might be involved, such as individual pesticides, animal pathogens, or even UVR exposure.

Some specific herbicides and pesticides have been linked to an increased risk of lymphoma. Phenoxy herbicides, which are widely utilized both in agriculture and by the general population, have most frequently been associated with higher risk of lymphoma. One of particular interest has been Agent Orange, a phenoxy herbicide formulation used as a defoliant by U.S. forces in Vietnam. Some but not all studies have reported an increased incidence of lymphoma among veterans exposed to this agent. The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) has been associated with excess risk of lymphoma; risk estimates of 3–8 times normal have been associated with the heaviest exposure levels. Additional studies have suggested some increased risk of lymphoma among persons exposed to organochlorine chemicals such as polychlorinated biphenyls, or PCBs. Although the data for occupational exposures are not entirely consistent, there is evidence that some links may exist between the development of lymphoproliferative diseases and environmental or work-related toxins. Chemical exposures have been shown to increase genetic mutations and alter cellmediated immunity. Occupations that include tobacco, leather, construction, automotive, and health-care workers have been studied, but results are inconsistent. Additional large, population-based studies are needed in order to improve our current understanding of this problem.
Hair Dyes
Hair dyes contain compounds, such as aromatic amines, that are known to be mutagenic and carcinogenic in animals. Excess hematologic malignancies have been reported in both hairdressers and men and women whose hair is dyed. It appears that darker permanent dyes pose the highest risk, but there is some evidence that this risk has greatly diminished or been eliminated since 1982, when oxidative dye products were reformulated in the United States and Europe. A recent international European study of 2302 lymphoma patients and 2417 controls examined patterns of hair dye use among men and women. This study found that 38% of study subjects reported previous use of a hair dye product, and a history of having ever used hair dye was associated with a 19% increased risk of lymphoma. The odds ratio in this study was markedly higher for those using hair dyes exclusively prior to 1980 compared with those who started dyeing their hair after that year (1.37). Although the increased risk apparently posed by hair dyes is comparatively small, the potential impact of this exposure is magnified by the prevalence of hair dye use. For this reason, the use of products currently available merits closer examination.
Tobacco And Alcohol
Tobacco has been shown to alter the immune response and contains substances known to be leukemogenic; however, minimal support for an association of HL and NHL with tobacco exists. Most studies have found no association with smoking amount or duration.

Studies regarding alcohol have been inconsistent, but several have suggested a protective effect of alcohol related to HL and NHL, implicating a cellular and humoral immune response benefit. This reduced risk appears to be independent of specific type of alcohol consumed, duration of alcohol use, and lifetime consumption.
Blood Transfusions
Several studies have demonstrated an association between history of blood transfusion and lymphoma. In patients who are diagnosed with low-grade lymphomas within months or a few years following transfusion, it is often impossible to know if the lymphoma preceded the transfusion or if the reverse is true. Potential biologic mechanisms that may have an etiologic impact include transmission of an oncogenic virus, transfusion-induced immunosuppression, and engraftment of malignant lymphoma cells from the donor. A population-based study of women in Iowa found a twofold or greater risk of lymphoma among persons receiving blood transfusions. Additional cohort studies have likewise shown a significant increase in risk of NHL in patients with a history of blood transfusion.
Diet
The Westernized diet has changed substantially over the past decades with the inclusion of more processed and refined foods. Diet has been shown as a source of mutagenic and chemopreventive agents; therefore, dietary factors may account for some of the increase in lymphoma incidence that has occurred over the past several decades. The risk of NHL has been linked to increased consumption of animal protein and saturated and animal fats. Animal products may generate chronic antigenic stimulation and/or immune unresponsiveness, or confounding by dietary absorption of pesticides and herbicides may account for the association. The roles of specific types of fats and their effects on immune function remain poorly understood. Some studies have attributed increased lymphoma risk to consumption of dairy products and eggs as well.

Higher intake of fruits, cruciferous vegetables, green leafy vegetables, and vegetables high in carotenoids have been demonstrated to have an inverse association with NHL. The relationship between fruits and vegetables and risk of NHL may be due to the antioxidants and inhibitors of nitrosation found in some foods. Fish consumption has also been associated with a decreased risk of lymphoma.
Drugs
As early as 1966, systemic ‘pseudolymphoma’ syndromes were linked to the use of anticonvulsants. These syndromes are often clinically indistinguishable from lymphoma, and they usually regress when the offending agent is withdrawn. Other drugs, such as calcium channel blockers, ACE inhibitors, statins, H2 blockers, and SSRIs, can produce cutaneous hypersensitivity reactions, which often appear to overlap histologically with cutaneous B or T cell lymphomas and occasionally progress to NHL. Factors related to the evolution of these lymphomas remain largely unknown. No consistent associations of NHL with long-term use of non-steroidal anti-inflammatory drugs, aspirin, or COX- 2 inhibitors have been observed.
Reproductive
While hormones have immunomodulatory effects, there is no convincing evidence of any influence of hormones or reproductive factors on HL or NHL. A small increase in lymphoma risk has been reported during pregnancy, but the immune dysregulation of pregnancy has been repeatedly suggested to increase the mother’s vulnerability to cancer and other diseases.
Anthropometric Parameters
While physical activity is thought to influence immune function, there are little data to suggest that there is a relation with lymphoma. Reported risk estimates of 1.6 and 1.4 for males and females, respectively, with a body mass index of greater than or equal to 30 appear in the literature. Studies have indicated that obesity can lead to impaired immune function, which can be restored if calories are restricted and physical activity is increased. Obesity may also affect the metabolism of endogenous hormones, which may interfere with cell proliferation, differentiation, and apoptosis. Taller height, also associated with availability of food and energy and greater exposure to growth-related hormones, has also been suggested as a marker of increased HL risk.
Summary
A significant step in lymphoma research has been the gradual realization that the lymphomas comprise a diverse set of diseases, which vary not only in pathology and clinical course but most likely in etiology. The improved treatment and prevention of these hematologic malignancies depend on our understanding of the etiology and pathogenesis of these diseases. The rapid increase in the occurrence of NHL between 1975 and 1995 suggests that lymphomagenesis may be influenced by environmental factors. The identification of environmental–genetic interactions that may predispose patients to develop lymphoma is an important component to the delineation of disease causation.

Although we have seen that there is an abundance of epidemiologic data in lymphoma, many questions remain unanswered. While many of these factors have been discussed, it is not certain which factor(s) may serve as an initiator of malignancy and which promote the survival of a cancer cell, perhaps at times merely by ignoring its existence. We must build on our current knowledge regarding the etiology of NHL and the mechanisms related to its progression. As knowledge is gained in these two arenas, prevention, treatment, and eventual cure will be realized. Potential strategies that may be useful include: administration of vaccines and medications (antibiotics or antivirals) to prevent or treat viral infections that are eventually demonstrated to be associated with lymphoma; development of immunotherapeutic treatments that will treat existing tumors whose growth may be dependent on viral antigenicity, or will enhance the immune response against the tumor; development of therapies that interfere with tumor survival such as antiangiogenesis drugs and biologics that interrupt critical growth-signaling pathways in the tumor; novel approaches to enhance immune function such as vitamins and nutrients that will improve immune surveillance during episodic exposure to carcinogens or during anticipated immunosuppression such as during medical procedures or high-stress events; implementation of protective practices for hazardous and mutagenic substance use, such as protective clothing, air management systems, and so forth; and development of new agricultural, industrial, and home products that are effective while carcinogen-free.

Bibliography:

 	
Askling J, Klareskog L, Hjalgrim H, Baecklund E, Bjo¨ rkholm M, and Ekbom A (2005) Do steroids increase lymphoma risk? A case-control study of lymphoma risk in polymyalgia rheumatica/giant cell arteritis. Annals of the Rheumatic Diseases 64(12): 1765–1768.
 	
Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, and Engels EA for the HIV/AIDS Cancer Match Study (2006) Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108: 3786–3791.
 	
Ferreri AJ, Guidoboni M, Ponzoni M, et al. (2004) Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. Journal of the National Cancer Institute 96(8): 586–594.
 	
Jaffe ES, Harris NL, Stein H, and Vardiman JW (2001) World Health Organization Classification of Tumours: Tumours of the Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer.
 	
Mack TM, Cozen W, Shibata DK, et al. (1995) Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. New England Journal of Medicine 332: 413–418.
 	
Opelz G and Dohler B (2004) Lymphomas after solid organ transplantation: A collaborative transplant study report. American Journal of Transplantation 4(2): 222–230.