UCSF Researchers Report New Risk Factors For Non-Hodgkin's Lymphoma

The two-part study included a total of 4100 participants, and results for 3376of the population are published in the August 15 issue of the American Journalof Epidemiology.

"These findings are important because although there has been a steady increasein the incidence of non-Hodgkin's lymphoma, there are very few established riskfactors," says Elizabeth Holly, PhD, MPH, UCSF professor in the department ofEpidemiology and Biostatistics and lead author of the study. "They also areimportant because much of the data generated in this study is consistent withthe role of activated macrophages in the pathogenesis of lymphoma."

Despite the lack of known risk factors for non-Hodgkin's lymphoma, its annualincrease of nearly four percent among men and three percent among women hasexceeded that of all other cancers except melanoma of the skin. The AmericanCancer Society estimates that 25,700 people will die of non-Hodgkin's lymphomaand 56,800 new cases will be diagnosed this year.

Lymphomas are an overexpression of B cells that are stimulated by activated Tcells and activated macrophages, both components of the immune system.Macrophages stimulate the production and replication of B cells by driving Tcell activation. Therefore, anything that affects this activation process mightinfluence the rate of overproduction.

The researchers reported that factors associated with an increased risk ofnon-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 andhistamine H2-receptor antagonists, which are medications for stomach ulcers(2.5-fold). Holly says that the increased risk associated with cimetidine andhistamine H2 antagonists is probably related to underlying conditions ofstomach 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-foldincreased risk, whereas a person with a BMI of 30 or more had a 2.5-foldincreased 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 27or more is defined as overweight for both sexes.

"This may be relevant for the more than 50 percent of Americans who areoverweight," Holly says.

Conversely, researchers found that factors associated with a decreased risk ofnon-Hodgkin's lymphoma include allergy to plants (40 percent reduction inrisk), bee and wasp stings (26 percent reduction), five or more vaccinations(21 percent reduction), drugs to lower blood cholesterol (43 percentreduction), and nonsteroidal anti-inflammatory drugs (28 percent reduction).

Further, an increased number of sexual partners in both men and women andincreased use of marijuana among men was associated with a decreased risk ofdeveloping non-Hodgkin's lymphoma. Holly reports that a person's B cells may bemildly suppressed by these immunologic stresses and by other behavior patternsassociated with mild immunosuppression.

In addition, Holly says that a person with a history of allergies is likely tohave an immune system that fully utilizes, rather than accumulates B cells, andtherefore is at a reduced risk of developing non-Hodgkin's lymphoma. Allergieshave been associated with reduced risks for other cancers as well.

The researchers also report that the reduction of the risk of developingnon-Hodgkin's lymphoma was strongly associated with the use of nonsteroidalanti-inflammatory drugs (NSAIDS) and cholesterol-lowering drugs.

"These data are very exciting because they suggest that NSAIDS and perhapscholesterol-lowering drugs may reduce the risk for non-Hodgkin's lymphoma,"Holly says. "People using these medications for other conditions may have theadded bonus of lower risk for some forms of cancer."

These drugs decrease the activation of macrophages and, therefore, theproduction and replication of B cells. Normally, macrophages become activatedupon ingestion of fat and cholesterol. Like NSAIDS, cholesterol-lowering drugshave anti-inflammatory properties. They also decrease fat uptake in the gut,thereby decreasing activation of macrophages, which in turn inhibits theproduction 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 celllymphomas. Antigen-driven B cells function as part of the immune system bysecreting antibodies that fight off foreign substances in the body. B cells canaccumulate if they do not function properly, leading to the development ofnon-Hodgkin's lymphoma.

During the study, which was conducted between 1988 and 1995 in the SanFrancisco Bay Area, a total of 1,600 non-Hodgkin's lymphoma patients (casegroup) and 2,500 men and women without non-Hodgkin's lymphoma (control group)were interviewed and tested for viruses and lymphocyte subsets. Questionsfocused on medical and personal history, history of immunizations and viralinfections, legal and illicit drug use, exposure to chemicals, travel toforeign countries, sexual history and demographic characteristics.

People in the control group were identified using random-digit dialing and werematched to patients in the case group by sex, county of residence and age.

The current study includes information on 580 women and 701 heterosexual menfrom the case group with lymphoma, and 838 women and 1,257 heterosexual menfrom the control group without lymphoma. The remaining individuals in both thecase and control group who were interviewed identified themselves as homosexualand were part of previous papers on HIV-related lymphomas. Holly says that thecurrent study's findings are consistent with those of the previous study onHIV-related lymphomas.

The study was funded by the National Cancer Institute. Other authors includePaige M. Bracci, MS, MPH, Department of Epidemiology and Biostatics, UCSFSchool of Medicine; Chitra Lele, PhD, Department of Mathematics, IndianInstitute of Technology, Bombay, India; and Michael McGrath, MD, PhD,Department of Laboratory Medicine, UCSF School of Medicine.