UCSF Researchers Report New Risk Factors for Non-Hodgkin's Lymphoma
In a large population-based study conducted on non-Hodgkin’s lymphoma, researchers at the University of California, San Francisco found that exposure to certain environmental factors that affect the immune system could decrease a person’s risk of developing the disease.
The two-part study included a total of 4100 participants, and results for 3376 of the population are published in the August 15 issue of the American Journal of Epidemiology.
“These findings are important because although there has been a steady increase in the incidence of non-Hodgkin’s lymphoma, there are very few established risk factors,” says Elizabeth Holly, PhD, MPH, UCSF professor in the department of Epidemiology and Biostatistics and lead author of the study. “They also are important because much of the data generated in this study is consistent with the role of activated macrophages in the pathogenesis of lymphoma.”
Despite the lack of known risk factors for non-Hodgkin’s lymphoma, its annual increase of nearly four percent among men and three percent among women has exceeded that of all other cancers except melanoma of the skin. The American Cancer Society estimates that 25,700 people will die of non-Hodgkin’s lymphoma and 56,800 new cases will be diagnosed this year.
Lymphomas are an overexpression of B cells that are stimulated by activated T cells and activated macrophages, both components of the immune system. Macrophages stimulate the production and replication of B cells by driving T cell activation. Therefore, anything that affects this activation process might influence the rate of overproduction.
The researchers reported that factors associated with an increased risk of non-Hodgkin’s lymphoma include a history of splenectomy (5-fold increase), gonorrhea among men (2-fold increase), polio among men (2.5-fold increase), endocrine gland disorders among women (3.3-fold increase), and cimetidine and histamine H2-receptor antagonists, which are medications for stomach ulcers (2.5-fold). Holly says that the increased risk associated with cimetidine and histamine H2 antagonists is probably related to underlying conditions of stomach ulcers rather than the drugs themselves.
In addition, an increased risk was associated with an increased body mass index (BMI). Researchers found that compared with people who had a body mass index (BMI) of less than 20, a person with a BMI of 25 to less than 30 had a 2.0-fold increased risk, whereas a person with a BMI of 30 or more had a 2.5-fold increased risk of developing non-Hodgkin’s lymphoma.
For women, a normal BMI is between 19.1-25.8 and 20.7-26.4 for men. A BMI of 27 or more is defined as overweight for both sexes.
“This may be relevant for the more than 50 percent of Americans who are overweight,” Holly says.
Conversely, researchers found that factors associated with a decreased risk of non-Hodgkin’s lymphoma include allergy to plants (40 percent reduction in risk), bee and wasp stings (26 percent reduction), five or more vaccinations (21 percent reduction), drugs to lower blood cholesterol (43 percent reduction), and nonsteroidal anti-inflammatory drugs (28 percent reduction).
Further, an increased number of sexual partners in both men and women and increased use of marijuana among men was associated with a decreased risk of developing non-Hodgkin’s lymphoma. Holly reports that a person’s B cells may be mildly suppressed by these immunologic stresses and by other behavior patterns associated with mild immunosuppression.
In addition, Holly says that a person with a history of allergies is likely to have an immune system that fully utilizes, rather than accumulates B cells, and therefore is at a reduced risk of developing non-Hodgkin’s lymphoma. Allergies have been associated with reduced risks for other cancers as well.
The researchers also report that the reduction of the risk of developing non-Hodgkin’s lymphoma was strongly associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDS) and cholesterol-lowering drugs.
“These data are very exciting because they suggest that NSAIDS and perhaps cholesterol-lowering drugs may reduce the risk for non-Hodgkin’s lymphoma,” Holly says. “People using these medications for other conditions may have the added bonus of lower risk for some forms of cancer.”
These drugs decrease the activation of macrophages and, therefore, the production and replication of B cells. Normally, macrophages become activated upon ingestion of fat and cholesterol. Like NSAIDS, cholesterol-lowering drugs have anti-inflammatory properties. They also decrease fat uptake in the gut, thereby decreasing activation of macrophages, which in turn inhibits the production of B cells. In addition to having anti-inflammatory properties, NSAIDS block activated macrophage production of B-cell growth factors.
In the United States, 85 percent of non-Hodgkin’s lymphomas are B cell lymphomas. Antigen-driven B cells function as part of the immune system by secreting antibodies that fight off foreign substances in the body. B cells can accumulate if they do not function properly, leading to the development of non-Hodgkin’s lymphoma.
During the study, which was conducted between 1988 and 1995 in the San Francisco Bay Area, a total of 1,600 non-Hodgkin’s lymphoma patients (case group) and 2,500 men and women without non-Hodgkin’s lymphoma (control group) were interviewed and tested for viruses and lymphocyte subsets. Questions focused on medical and personal history, history of immunizations and viral infections, legal and illicit drug use, exposure to chemicals, travel to foreign countries, sexual history and demographic characteristics.
People in the control group were identified using random-digit dialing and were matched to patients in the case group by sex, county of residence and age.
The current study includes information on 580 women and 701 heterosexual men from the case group with lymphoma, and 838 women and 1,257 heterosexual men from the control group without lymphoma. The remaining individuals in both the case and control group who were interviewed identified themselves as homosexual and were part of previous papers on HIV-related lymphomas. Holly says that the current study’s findings are consistent with those of the previous study on HIV-related lymphomas.
The study was funded by the National Cancer Institute. Other authors include Paige M. Bracci, MS, MPH, Department of Epidemiology and Biostatics, UCSF School of Medicine; Chitra Lele, PhD, Department of Mathematics, Indian Institute of Technology, Bombay, India; and Michael McGrath, MD, PhD, Department of Laboratory Medicine, UCSF School of Medicine.