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Epidemiology and Pathogenesis of AIDS-Related Lymphomas

Epidemiology and Pathogenesis of AIDS-Related Lymphomas

This review by Dr. Aboulafia presents aspects of the epidemiology of acquired immunodeficiency (AIDS)-related lymphomas and their pathogenesis. The author’s main focus is in the molecular area, and the summary of epidemiology is well known to those interested in this field.

The article contains a few minor mistakes. For example, it was not involvement of the central nervous system, but rather, the high grade and distribution to extranodal sites, including the brain, that first drew attention to lymphomas in the AIDS setting.

Perhaps of more substance, the estimate that 10% to 20% of AIDS patients ultimately develop lymphomas is exaggerated; 5% to 6% is more likely, based on current data.[1,2] This figure could change if large numbers of HIV-infected persons were to live for years with partial immunodysfunction because of new, highly active therapies to control human immunodeficiency virus (HIV). Presumably, if therapies were so successful that the immune system were completely restored, this population would not be at excess risk of developing lymphoma.

Role of c-myc

The author then discusses selected recent reports about lymphoma clonality, the roles of Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8), the function of oncogene translocation, and the place of HIV-related immuno-suppression. The role of c-myc is a central focus of this discussion.

Several points made in the author’s presentation can be questioned. For example, the translocation that places c-myc adjacent to the immunoglobin switch gene areas probably occurs before mutations of c-myc, rather than after these mutations, as the author’s phrasing suggests. Furthermore, although Pelicci et al find c-myc rearrangements only after lymphoma develops, their finding conflicts with reports[3,4] not cited in this review. These other reports indicate that c-myc translocations are not infrequent in the peripheral blood mononuclear cells of HIV-infected (or even uninfected) homosexual men, and that the risk of lymphoma is not significantly higher in individuals with detectable c-myc (15%) than in those without this gene rearrangement (12%).

A Thesis--Clonality is Central to Understanding Pathogenesis

A review of a field of research is useful for those who seek a synthesis of recent reports in that area. Accurate facts are essential, and one role of such a review is to present and critique the published observations to ensure that the presented results are valid and to compare the consistency among studies. Facts, even if accurate, do not provide insights into the nature of the problem, however. Another role of a review is to synthesize these facts into a thesis--right or wrong--in order to stimulate responses that can move the field forward.

I propose such a thesis: Clonality is central to understanding the pathogenesis of lymphomas and other cancers. Underlying the emergence of a malignant clone is proliferation. The clonality of lymphomas is well accepted, even though an occasional tumor can be demonstrated to have more than a single clone. The contention, described in this review, that the frequency of clonality in East and West Coast non-Hodgkin’s lymphomas differs must be a matter of definition, assuming that the quality of the work in both areas is adequate. For me, true polyclonal expansions are proliferations, not cancer, even when they can kill, as in the X-linked fatal EBV syndrome.[5]

Distinguishing Between Proliferation and Cancer

This distinction between proliferation and cancer is essential because it permits a differentiation of the mechanisms for each and probably has practical applications as well. Proliferations are physiologically mediated expansions of cells that are potentially reversible. Because proliferation is a "normal" process, studies of it will lead to reproducible results.

Furthermore, I hypothesize that proliferations increase cancer risk through introducing genetic errors--a point of view that I think Dr. Aboulafia would accept. If so, then control of proliferation will reduce cancer risk. Since some proliferation is essential, it can never be eliminated entirely, but it can be minimized by the prevention of avoidable proliferation. Thus, understanding proliferation may yield crucial insights into practical means to prevent at least some cancers.

Cancer, in contrast, is beyond physiologic control, except perhaps in the very earliest phases. Although clonal, cancer is an unstable entity. In normal cells, there must be constellations of events controlling the checkpoints of replication, and these will differ by cell type and even within the same cell type, by the level of differentiation.[6] In cancer, by definition, these differing checkpoints must have been bypassed. This can happen when genes that inhibit replication are mutated or deleted (eg, TP53, bcl-6) or when genes that enhance replication are turned on (eg,c-myc translocated to the immunoglobinswitch gene areas) or amplified (eg, by trisomy).

No doubt, we are only just beginning to understand how checkpoints are bypassed. Even within a cancer from the same clone in a patient, however, early tumors may have different cellular mechanisms, since later cancer cells will accumulate genomic changes that permit more efficient means of replication, losing inhibitors and augmenting genes that increase growth potential. This hypothesis, for which there are already some data at both the chromosomal[7] and gene[8] levels, can be examined in serial samples from cancers in individual patients. These samples should show progressive simplification, with genes that inhibit tumor growth being lost and genes that enhance growth being duplicated (eg, by trisomies).

Thus, cancers, even of the same cell type, should not be expected to have identical genetic make-up. This hypothesis could be tested by examining the same tumors (including stratification by stage and site) to determine whether they have the same basic genetic construct. Analyzing cancer cells may be of limited value in developing preventive strategies. This is not to imply that such research is unimportant. It is essential to gaining an understanding of the basics of cell replication because inhibition of the mechanisms will limit replication of already existing cancer cells. However, the insights gained from this understanding can then be applied appropriately to cancer chemotherapy, not prevention.

Resolving Some of the Confusion in This Field

Separating proliferation and cancer biology may resolve some of the confusion that currently attends this field. All viruses associated with cancers, for example, are proliferative influences. The human immunodeficiency virus acts indirectly, not being present in the cancers that occur in AIDS patients. However, even those viruses implicated as being directly involved appear to be acting as proliferative stimuli, because all infected cells (and there are millions if not billions of them) harbor the virus, but only a single cell emerges as a cancer.

Even c-myc translocations do not, themselves, cause cancer, as they can be present in persons without cancer and also may not be present in every cancer in which they are expected. According to this hypothesis, c-myc translocations would not be expected to be present in every cell and could be present in cells that have not yet escaped regulatory control. Furthermore, there is no single point at which cells become malignant, and even clonal expansions in their earliest stages can be reversed if the proliferating stimulus is removed.

Is this thesis correct? At least it clarifies why there are divergent findings in the studies presented by Dr. Aboulafia, and supplements his report by offering a vision that may challenge readers to either confirm or refute the concepts. That is what science is about.


1. Biggar RJ, Rosenberg PS, Cote TR: Kaposi’s sarcoma and non-Hodgkin’s lymphoma following the diagnosis of AIDS: The Multistate AIDS/Cancer Match Study Group. Int J Cancer 68:754-758, 1996.

2. Cote TR, Biggar RJ, Rosenberg PS, et al: Non-Hodgkin’s lymphoma among people with AIDS: Incidence, presentation, and public health burden. Int J Cancer 73:645-650, 1997.

3. Müller JR, Janz S, Goedert JJ, et al: Persistence of immunoglobulin heavy chain/c-myc recombination-positive lymphocyte clones in the blood of human immunodeficiency virus-infected homosexual men. Proc Natl Acad Sci USA 92:6577-6581, 1995.

4. Rabkin CS, Müller J, Goedert JJ: Residual clones in childhood leukemia (letter). N Engl J Med 33750-33751, 1997.

5. Seemayer TA, Gross TG, Egeler RM, et al: X-linked lymphoproliferative disease: Twenty five years after the discovery. Pediatr Res 38:471-478, 1995.

6. Orr-Weaver T, Weinberg RA: A checkpoint on the road to cancer. Nature 392:223-224, 1998.

7. Biggar RJ, Lee EG, Nkrumah FK, et al: Direct cytogenic studies by needle aspiration of Burkitt’s lymphoma in Ghana, West Africa. J Natl Cancer Inst 67:769-776, 1981.

8. Gutierrez MI, Bhatia K, Cherney B, et al: Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt’s lymphoma. Ann Oncol 8:987-994, 1997.

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