Non-Hodgkin's Lymphoma Sheila Zahm, Ph.D.*	Lymphomas are cancers that affect the white blood cells of the immune system. They are characterized by the abnormal growth of lymphocytes, the infection-fighting cells in the lymph nodes, spleen, and thymus. The tonsils, stomach, small intestine, and skin may also be affected. Primary lymphomas of the skin such as mycosis fungoides and Sezary's disease are extremely rare. Burkitt's lymphoma, rare in most of the world, is the most common childhood cancer in Central Africa, and is one of the most aggressive of all human cancers. Lymphomas are usually classified as Hodgkin's disease or non-Hodgkin's lymphoma. An estimated 45,000 new cases of non-Hodgkin's lymphoma were diagnosed in the United States in 1994 (Boring et al., 1994). Incidence per 100,000 is 18.6 among white males, 12.0 among white females, 12.8 among black males, and 8.1 among black females. In the United States, five-year survival is 53 percent for white patients and 45 percent for black patients. The highest incidence rates internationally for non-Hodgkin's lymphoma were observed for the United States and Canada (Parkin et al., 1992), although comparing incidence, survival, and mortality statistics among countries may be difficult because of differing classification systems used for these diseases. Between 1973 and 1991, the 73 percent increase in the incidence of non-Hodgkin's lymphoma was one of the largest among the major cancer sites in the United States (Ries et al., 1994). Part of the increase in incidence of non-Hodgkin's lymphoma in recent years has been related to AIDS. Non-Hodgkin's lymphoma is about 60 times more common in AIDS patients than in the general U.S. population (Beral et al., 1991). Gail et al. (1991) estimated that between 8 and 27 percent of all non-Hodgkin's lymphoma cases that occurred in the United States in 1992 were a direct consequence of infection with human immunodeficiency virus (HIV). AIDS, however, cannot explain the increase in non-Hodgkin's lymphoma observed over a period that began years before the AIDS epidemic surfaced, and continues to be observed in the absence of HIV infection. Other immunodeficiency states, both genetic and induced by medications or illness, are also associated with extremely high risks of non-Hodgkin's lymphoma (Filipovich et al., 1992; Kinlen, 1992). Kidney transplant patients, whose immune systems are suppressed with medications, develop non-Hodgkin's lymphomas 40 to 100 times more frequently than expected (Fraumeni and Hoover, 1977; Kinlen et al., 1979). As an alternative mechanism, immunostimulation may play a role in the high risks observed in some groups with immune abnormalities (Hoover, 1992). Viruses other than HIV have also been linked to non-Hodgkin's lymphoma (Mueller et al., 1992). Human T-lymphotropic virus, type I (HTLV-I) has been linked to certain types of adult T-cell leukemias and lymphomas found mostly in southern Japan, parts of the Caribbean and Africa, and the southeastern United States (Mueller, 1991), but is not a likely factor in the widespread increase in non-Hodgkin's lymphoma. On the other hand, Epstein-Barr virus (EBV) is ubiquitous--by adulthood almost everyone has been exposed to it and has developed antibodies against it. EBV has been linked to Burkitt's lymphoma in African children (Ziegler, 1981) and is linked to non-Hodgkin's lymphoma in persons with acquired or genetic immunosuppression (Mueller et al., 1992). Its role in non-Hodgkin's lymphoma in the general population is under investigation. Pesticides have been associated with non-Hodgkin's lymphoma in studies of farmers, other pesticide applicators, manufacturing workers and other exposed populations (Zahm and Blair, 1992). One study, conducted in Kansas, revealed a striking association between non-Hodgkin's lymphoma and the use of herbicides, particularly 2,4-D (Hoar et al., 1986). The risk of non-Hodgkin's lymphoma rose with increasing frequency of use of herbicides, rising almost eight-fold among 2,4-D-using farmers who handled herbicides 20 or more days per year. Another study conducted in Nebraska also found a significantly increasing risk of non-Hodgkin's lymphoma with increasing use of 2,4-D, although the risks were lower than observed in Kansas (Zahm et al., 1990). Associations between non-Hodgkin's lymphoma and herbicides were also found in Sweden (Hardell et al., 1981) and Canada (Wigle et al., 1990) and with chlorophenols in Sweden (Hardell et al., 1979). Canine malignant lymphoma has also been associated with dog owner use of 2,4-D and commercial pesticide lawn treatments (Hayes et al., 1991). Grain handlers exposed to pesticides, grain dusts, and organic solvents have been found to have a five-fold risk of nonHodgkin's lymphoma (Alavanja et al., 1990). Exposure to organophosphate insecticides may also play a role in the development of non-Hodgkin's lymphoma (Zahm et al., 1990; Cantor et al., 1992). Risks to the general population, who are exposed at much lower levels than occupationally exposed groups, have not been well studied. Occupations other than agriculture that have been associated with nonHodgkin's lymphoma include rubber workers (Monson and Nakano, 1976; Wilcosky et al., 1984), petroleum refining workers (Delzell et al., 1988), vinyl chloride workers (Chiazze et al., 1977), chemists (Li et al., 1969; Searle, 1978; Olin and Ahlbom, 1980), dry cleaners (Blair et al., 1990), and aircraft maintenance workers (Spirtas et al., 1991). The etiologic agents responsible for these excesses have not been identified definitively, but the occupations have in common exposure to organic solvents. Hair dye use, particularly long-term use of dark-color products, and occupational exposure to hair coloring products were associated with lymphatic and hematopoietic malignancies, including non-Hodgkin's lymphoma, in several recent studies (Cantor et al., 1988; Zahm et al., 1992; Thun et al., 1994; Linos et al., 1994; Giles et al., 1984). Hair-coloring products contain compounds that are mutagenic, carcinogenic, and teratogenic in animals. While there was no or little increased risk reported for overall use of hair coloring products, long-term dark-product users experienced two- to four-fold increased risk in some studies. The role of hair coloring products in the etiology of these malignancies, however, remains controversial (Zahm et al., 1994; Colditz 1994; Thun et al., 1994). The studies that reported the excesses were not conducted to investigate hair-coloring products as their primary focus, and so the questionnaires lack detail that is critical to judging causality. It is important to resolve the questions about the possible carcinogenicity of hair-coloring products. Approximately 35 to 60 percent of women and 10 percent of men use hair-coloring products (Zahm et al., 1994; Zahm et al., 1992), and use appears to be rising in young people (Sturgeon and Hartge, submitted). In summary, the incidence of non-Hodgkin's lymphoma has been rising inexplicably. A continued, perhaps even larger, increase is anticipated because of AIDS-related cases. The cofactors that predispose AIDS cases to lymphoma need elucidation and research is needed into other possible causes of non-Hodgkin's lymphoma, such as hair-coloring products, pesticides, nitrates, solvents, other industrial chemicals, and viruses other than HIV.
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* From the Environmental Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland