AIDS' big question: Why so little cancer?

Rates should be sky-high if immunity plays a role

The AIDS epidemic poses an intriguing question about cancer that hardly anyone seems to have considered, says one expert: Why hasn't AIDS resulted in whopping increases in the rates of more types of cancer?

"What stands out crystal clear is the way most malignancies are not affected at all by the deterioration of the immune system we see with AIDS," says Robert Biggar, MD, senior investigator at the AIDS viral epidemiology group at the National Cancer Institute. That fact appears to undermine cancer researchers' most cherished assumptions about immunity and its role in the development of cancer, Biggar adds.

"What we have is a case of a dog that should be barking like crazy," he says. "And this dog simply doesn't bark."

Nor is it likely that the type of immunity lost in AIDS is not responsible for cancer control, says Biggar, because "cellular immunity is exactly what we think should be controlling cancer."

By the same token, cancers that do increase with AIDS deserve a closer look, says Biggar. In some instances, at least, the appearance of increasing rates may prove misleading.

Take cervical cancer and anal cancer, he says. The two are basically the same disease, linked both by the same etiologic agent - human papilloma virus - and the same lifestyle factors (namely, higher rates of sexual activity).

Before AIDS, anal cancers occurred among gay men at double the background rate; with AIDS, they've doubled again. But is that because of some immune function, Biggar asks, or because the group that gets AIDS is especially active sexually?

The factors driving cervical cancer rates are even harder to dissect. Women with HIV (or those at risk for infection) are screened frequently for low-grade cervical proliferations; treating precursor forms of the cancer obviously prevents many cases from developing. On the other hand, even without AIDS, rates are elevated among women who are especially active sexually. Again, are increases with AIDS due to immune status, or lifestyle?

For reasons not well-established, Hodgkin's disease rates are clearly elevated, perhaps as much as ten-fold, Biggar says. And testicular cancer may be slightly elevated with AIDS - but so slightly that Biggar says he's "on the fence" for that particular cancer for now.

There's no room on the fence when it comes to non-Hodgkin's lymphoma (NHL), a composite of malignancies of the lymphoid system. AIDS drives up risks for NHL 270-fold; yet the increase reflects immune proliferation, not suppression, Biggar says, and for three reasons. With AIDS, destruction of CD4 cells leaves the immune system out of balance, he notes. Also, CD4 cell destruction means the immune system must gear up to contend with an onslaught of new invaders. Finally, high viral loads associated with AIDS mean the immune system is chronically stimulated.

Kaposi's sarcoma, the malignancy most elevated with AIDS, is the toughest to interpret. AIDS pushes up relative risk for KS by 100,000-fold in the United States, yet even modest restorations to the immune system (achieved through antiretroviral therapy) have brought rates back down. What kind of cancer manifests skyrocketing rates that fall in response to so slight an improvement?

"I'm mystified," says Biggar.

Further muddying the KS picture is the absence, so far, of a test for HHV8 (the herpes virus linked to KS) that's widely accepted as being accurate. With no way to gauge the true prevalence of HHV8, it's tough to understand the etiology of the cancer, Biggar adds.

Rates of brain lymphoma, like KS, have fallen with antiretroviral therapy, maybe because the cancer was so rare initially. Then again, the malignancy may be behaving strangely, as is KS. One patient with brain lymphoma apparently has remitted spontaneously after the application of just minimal therapy, says Biggar - a truly astounding event.

In sum, a handful of cancers increase (or seem to increase) with AIDS. Many more don't; and that, says Biggar, deserves more of our attention.