UCSF RESEARCHERS REPORT NEW RISK FACTORS FOR NON-HODGKIN'S LYMPHOMA

By Abby Sinnott on August 12, 1999

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.