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Epstein-Barr Virus, the CNS, and AIDS-Related Lymphomas: As Close as Flame to Smoke

Massachusetts General Hospital, Dana-Farber/Partners CancerCare, Harvard Medical School, Boston, MA

THE WORLD HAS TURNED dramatically since 1996 in the care of patients with human immunodeficiency virus (HIV) disease in regard to most but not all complications. Those complications notably lacking a clinically perceptible change since the introduction of potent antiretroviral therapy are in oncology and, in particular, systemic non-Hodgkin’s lymphoma. When combination therapies for HIV infection were introduced and the inhibitors of HIV protease made their entry onto the clinical scene in 1996, the dividend for intensive investment in AIDS research was immediately paid for North American, European, and Australian patients.

The oncologic side of AIDS was what brought the epidemic to public attention in the United States when the New York Times reported an unusual clustering of the rare tumor, Kaposi’s sarcoma (KS), in gay men in 1981. KS was among the most obvious indicators of a very unusual syndrome, and its association with other forms of immune dysfunction helped unify the conceptualization of the process eventually known as AIDS. Now that patient immune function is improving in conjunction with effective antiretroviral drugs, KS is again a harbinger of change. KS patients, formerly in every waiting room where AIDS patients were seen, are now a rarity calling for a special teaching session with those too young to have seen the pre-1996 AIDS epidemic. KS is diminishing dramatically in incidence, and the treatment of choice when KS does occur is antiretroviral therapy, not because of any direct effect on the tumor or its associated herpesvirus, KSHV, but because of the interconnection of the tumor with immune function. Although the immunobiology of KSHV is still unfolding, it is already apparent that immune function directly affects the oncologic outcome.

A similar simple calculus may apply to some of the non-Hodgkin’s lymphomas seen in AIDS and in other settings of immunodeficiency. It is apparent that a subset of AIDS lymphomas resemble posttransplantation lymphoproliferative disease (PTLD) or lymphoproliferation of congenital immune dysfunction in terms of the association with Epstein-Barr virus (EBV) infection and expression of a specific type III pattern of EBV-latent genes. PTLD is responsive to anti-EBV–specific T-cell–based immunity, and mapping of the dominant epitopes responsible for immune control of EBV-infected B cells expressing latent antigens is quite sophisticated and well defined. The subset of AIDS lymphomas with a similar expression pattern of EBV-latent genes often comprises those presenting with primary mass lesions in the brain in the setting of advanced immunosuppression. Primary CNS lymphoma in AIDS is virtually always accompanied by EBV in the tumor and a pathologic picture similar to that of PTLD. This clinical group has become an extremely rare entity in the current era of AIDS care. Primary CNS lymphoma, like KS, has become an orphan disease within the HIV-infected, at least while the current success in antiretroviral therapy is sustained.

Although primary CNS lymphoma in AIDS and PTLD can be reasonably conceived as sharing a pathophysiologic basis in EBV-driven B-cell proliferation, the relationship of PTLD and of EBV itself breaks down in the setting of the systemic AIDS-related lymphomas. Systemic lymphomas are highly heterogeneous and do not consistently share the fundamental common thread of the PTLD tumors, EBV. As Cingolani et al¹ point out in their article that appears in this issue of the Journal of Clinical Oncology, a limited proportion of large-cell and a minority of small-cell lymphomas in AIDS patients have detectable EBV present in the tumor tissue. Indeed, the very presence of a small, non–cleaved-cell subset underscores the distinction between AIDS-related versus other immune deficiency–related lymphomas. In the latter, small, non–cleaved-cell cancer (Burkitt’s or Burkitt’s-like lymphoma) is virtually nonexistent. Yet despite the heterogeneity of AIDS-related lymphomas as defined by morphologic features, by EBV infection or by molecular aberrations, a one-size-fits-all therapeutic approach has generally been applied. The data presented by Cingolani et al indicate that therapy tailored to the patient has arrived.

CNS involvement often complicates systemic AIDS-related lymphoma and has led to CNS prophylaxis in the treatment of newly diagnosed patients, a practice made controversial because of the absence of guidelines for those patients who are at greatest risk. Now Cingolani et al¹ have shown that the presence of EBV in the tumor has a strong correlation with CNS involvement, particularly when in the context of extranodal lymphoma. Notably, no patient who had or developed CNS involvement failed to have EBV detected in tumor tissue. In addition, the positive- and negative-predictive values of detecting EBV in CSF by polymerase chain reaction were virtually 100% for eventual CNS involvement by tumor. Therefore, the administration of prophylactic intrathecal therapy can now be more sparingly and more rationally applied. Those patients with EBV present in the tumor should have prophylactic intrathecal therapy as a part of their treatment program. Those with EBV detected in the CSF should at least receive prophylactic therapy and may require a more substantial course of treatment.

What this study further provokes is the question of how we can continue to refine therapeutic approaches to match specific characteristics of the patient. All lymphomas are clearly in need of such subcategorization, and molecular profiling may soon permit highly refined subgrouping to occur. Patients with AIDS-related lymphomas have a number of other variables to be considered, including the activity of the HIV infection and the overall state of immune health. Although the International Prognostic Index is a potent tool to guide the treatment of large-cell lymphomas outside the context of HIV infection, it has been less consistently useful in AIDS patients and similar tools need to be assembled. Currently limiting our ability to accomplish this is patient numbers available for clinical trial, partly driven by the nature of the epidemic and partly driven by limited referral of such patients to centers focusing on AIDS oncology.

The pessimism associated with the treatment of lymphoma patients before 1996 is no longer appropriate. A number of highly encouraging limited-scale studies have provided solid evidence of good patient tolerance and durable remissions. However, standard-in-office therapies for these patients are also not yet appropriate. We must gain a better handle on which patient populations represent unusual risk; this is possible only through analyses such as those of Cingolani et al.¹ Further, we now have unique opportunities to assess basic immunologic and virologic parameters and to apply novel cell-manipulation strategies. Bone marrow transplantation approaches to patients with relapsed or refractory disease are being applied and permit testing whether stem cells may be transduced with genes rendering them less sensitive to HIV infection or capable of developing into cells specifically targeting HIV. These represent critical contexts in which to evaluate immune restoration and in particular immune restoration capable of controlling HIV. Further, the complexity of lymphomas seen in AIDS indicates the potential lessons we may learn from these patients about lymphomas generally. Much has been learned from the less-complex PTLD setting. More can be learned from patients with HIV. The benefits to these patients from involving them in settings of intensive study are apparent in the findings of Cingolani et al; the benefit to a larger group from understanding the molecular mechanisms conferring risk to the CNS is not difficult to envision. There is a very real need to engage patients with AIDS-related malignancies in settings of intensive study. It is an investment the National Cancer Institute has made by establishing the AIDS Malignancy Consortium, and it is an investment the oncology community would well serve their patients in supporting. HIV offers a window on interaction of immune function and tumor development and an opportunity to identify links between these distinct realms that are "as close... as flame to smoke."²

REFERENCES

1. Cingolani A, Gastaldi R, Fassone L, et al: Epstein-Barr infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin’s lymphomas. J Clin Oncol 18: 3325-3330, 2000[Abstract/Free Full Text]

2. Shakespeare W: Pericles. Act I, scene I, line 149.

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