Back in 1991, the National Cancer Institute sponsored a 2-day workshop to ponder the mysterious "emerging epidemic" of non-Hodgkins lymphoma. A decade later, the mystery persists, and NHL cases continue to rise. "Its been quite dramatic," says pathologist Dennis Weisenburger, M.D., of the University of Nebraska. "Something is clearly going on, and we dont understand it."
Since 1950, NHL has increased in frequency by about 4% a year. Overall, between 1973 and 1997, incidence grew 81%. This year 56,200 Americans will be diagnosed with NHL, which is now the fifth most common non-skin cancer in the United States. "It is remarkable how NHL has gone from being what we would consider a rare disease ... to what we consider in the moderate risk, mid-range of cancers," said Sheila Zahm, Sc.D., deputy director of the NCIs Division of Cancer Epidemiology and Genetics. "Its really a phenomenal increase compared to most other cancers."
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Causal Chain?
Something goes wrong in the immune system to cause NHL, but the causal chain remains unknown. Tumors consist of abnormal, malignant lymphoid cellseither T cells or, more commonly, B cellsoriginating in the bodys lymphatic system. Exactly how genetic and environmental factors interact to turn lymphocytes into cancer cells continues to baffle researchers.
On the genetic level, some things are known. Chromosomal translocations are a hallmark of NHL. In follicular lymphoma, for example, gene exchange between chromosomes 14 and 18 takes place, leading to the overexpression of the BCL-2 gene on 18, preventing programmed cell death (apoptosis). This allows the B cell to survive to sustain other genetic damage that eventually makes it cancerous. The breakpoint on 14 is at an immunoglobulin (Ig) gene locus, so something apparently goes wrong during Ig rearrangement in the bone marrow to cause the translocation. Similar translocations, usually involving oncogenes and antigen receptor loci, take place in other lymphomas.
That sets the stage for inevitable genetic errors. "B cells are sort of built to recombine DNA," noted Dan Longo, M.D., scientific director of the National Institute on Aging. "The follicular center [where B cells are selected for antigen response] is a mutation factory." But why repair fails to take place, and, more generally, which genetic and environmental factors predispose certain individuals to the genetic errors that cause NHL, remain unknown. "We dont know which [susceptibility] genes are mutated, unlike the clean work in colon cancer," said Longo.
Risk Factors?
And no clear risk factors have emerged for NHL in the general population. But severe immunosuppression often leads directly to NHL. Up to 25% of patients with one of the rare inherited immunodeficiencies will develop B-cell lymphomas during their lifetimes. Organ transplant patients, who receive immunosuppressive drugs, are at high risk, as are bone marrow transplant patients. Patients who receive chemotherapy or radiation for other cancers often develop NHL years later.
Most strikingly, AIDS patients run a 100- to 300-fold higher risk for NHL than the general population. (AIDS, though, accounts for a minor part of the overall rise in incidence.) Epstein-Barr virus (EBV), a ubiquitous herpesvirus that can immortalize B cells, activates in many immunosuppressed patients, leading to NHL. Reduced immune surveillance against abnormal cells, or compensatory proliferation of lymphocytes (making mistakes more likely), probably accounts for other AIDS-related cases.
But are viruses the culprit in the general population? EBV also leads to Burkitts lymphoma (common in Africa), and human T cell lymphotrophic virus-1 is closely associated with adult T-cell lymphoma, widespread in Japan but rare in the United States. But the vast majority of non-AIDS cases in western countries appear to have nothing to do with viruses. "There have been conscientious efforts made to find the footprints of viruses in lymphomas," said Longo. "It seems unlikely that a major fraction of common lymphomas will be explainable by viral activity."
Yet no other risk factor has emerged to explain the surge in NHL cases. Studies have linked NHL to hair dyes, nitrate in drinking water, dietary fat and red meat, autoimmune diseases and especially to occupational exposure to herbicides, pesticides, and organic solvents. But, except for the herbicide/pesticide connection, the links are tenuous at best. And high chemical exposure on farms cannot account for NHL in the general population.
"Something has changed in the world to lead to the huge, huge increase in lymphoma in the general population," said Patricia Hartge, Sc.D., deputy director of the NCIs Epidemiology and Statistics Program. "Im pretty mystified."
The best lead so far is immune system depression and stimulation. "There could be agents in the environment that are causing some sort of subtle immune deficiency," said Weisenburger. "[And] when you expose the whole population to it you see an increase in cancers thats fairly significant." Similarly, if the immune system is under constant challenge, B-cell and T-cell activity jump, and the likelihood of mutation rises. "The body is desperately trying to make up for the fact that its under attack," explained Zahm.
AIDS, involving both immune suppression and immune challenge, offers a possiblethough extrememodel. "Could it be that a very similar thing is going on, but at a very low level, in the population?" asked Weisenburger. "Thats a possibility. But its very hard to prove."
Thats because low-potency risk factors barely register in epidemiologic studies, if at all. Yet if almost everyone is exposed, such factors could account for the lymphoma epidemic. "Some subtle immune deficiency in conjunction with increased exposure to environmental antigens, or viruses, or other things ... could increase that risk from, say, zero to maybe twofold," said Weisenburger. "You would double the number of cases"roughly whats happened with NHL over the last 30 years.
But this theory may be simplistic. A large casecontrol study in San Francisco recently showed a protective effect associated with allergies, marijuana use, and multiple sexual partners. "A small amount of immune system stimulation may be good," concluded principal investigator Elizabeth Holly, Ph.D., of the University of California at San Francisco.
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So far, a decade after the NCI first addressed the NHL epidemic, few answers have emerged. Weisenburger, for one, does not expect a breakthrough anytime soon. Teasing out NHLs subtle risk factors "probably requires either very large epidemiologic [studies], or some special tools we dont have," he said. "We havent figured out how to look for risk factors in new ways. And so were continuing to apply the old methods, and Im not sure thats going to work."
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