The management and therapy of patients with HIV infection has improved in the past few years as a result of major advances in antiretroviral therapy. However, despite these advances and perhaps as a result of longer survival, some of the oncologic complications of HIV infection remain important. Indeed HIV-associated cancers have already emerged as a leading cause of death among patients with AIDS.¹

Kaposi's Sarcoma (KS) and Non-Hodgkin's Lymphoma (NHL) are the two most prominent AIDS-associated malignancies. Earlier in the AIDS epidemic, the incidence of both cancers had been increasing. However, recent reports have indicated discrepant trends in the incidence of KS and NHL in the HIV-infected population since the introduction of potent antiretroviral therapy. Data suggest that there is a persistence of NHL risk as compared to reductions in opportunistic infections and KS.^2-6

This article reviews the characteristics of systemic NHL in persons with HIV infection and the impact of potent antiretroviral therapy on this opportunistic disease.

Epidemiology

The first cases of NHL occurring in patients with HIV infection were reported in 1982. NHL was subsequently added to the AIDS case definition after cancer registry data demonstrated a significantly increased incidence of such neoplasms in this same patient population. NHL is a relatively late manifestation of HIV infection, occurring after years of HIV-induced B lymphoid stimulation and proliferation. NHL incidence increases markedly with progression of HIV infection, although the association with level of CD4 lymphopenia is less pronounced than with other opportunistic infections.⁷ The overall incidence of NHL is 60 times higher in persons with HIV infection than in the general population. Moreover, NHL is the initial AIDS-defining diagnosis in approximately 4% of patients, although 12%-16% of HIV-infected individuals will eventually die of the disease.7 All population groups at risk for HIV are also at risk for the development of lymphoma, in contrast to Kaposi's sarcoma, which is diagnosed primarily in homosexual or bisexual men. .⁷

The NHL that occurs in HIV-infected patients can be divided into two categories: systemic and primary central nervous system (CNS) lymphoma. Table 1 shows the characteristics of these 2 types of lymphomas. Furthermore, recent studies of lymphomas during potent antiretroviral therapy have revealed differences in the incidence of these 2 categories of NHL. A report of AIDS cases from 17 countries in Europe examined the incidence of systemic and primary brain lymphoma from 1988 to 1997. The overall number of NHL cases among all AIDS-defining illnesses rose steadily from 1988 to 1996, but then declined in 1997. As a percentage of all AIDS-defining illnesses, however, systemic lymphoma actually increased from 3.6% in 1994 to 4.9% in 1997.⁵ In the CDC-sponsored Spectrum of Disease Study, based upon case records from 89 hospitals and clinics in 9 US cities, the incidence of primary brain lymphoma decreased from 8.5 cases/1000 person years (PYs) in 1994 to 0.9 cases/1000 PYs in 1996 (p<0.04). In contrast, no such decrease was apparent in the incidence of systemic lymphoma.³ Our analysis⁶ of the incidence of AIDS-related malignancies from 1992 to 1999 at the Harris County Hospital District indicated no significant decrease in systemic NHL during the years of potent antiretroviral therapy (1996-99). However, an increasing trend for systemic lymphoma over time was found during the study period (p=0.001).

While further follow-up will be required to determine the precise incidence of systemic NHL during the era of potent antiretroviral therapy, it does appear that this malignancy is becoming a major cause of illness in HIV-infected patients.

Etiology and pathogenesis

In HIV-infected patients, lymphomagenesis is a complex phenomenon not yet completely understood. However, the molecular characteristics of NHL in HIV-infected patients exhibit a great deal of heterogeneity, suggesting that the development of lymphomas may occur by a variety of different mechanisms. Possible mechanisms include viral cofactors, chronic antigenic stimulation and cytokine dysregulation.

Viral Cofactors. Epstein-Barr virus (EBV) is suspected of playing a role in causing some cases of AIDS-associated NHL. In fact, EBV DNA has been detected in monoclonal tumor tissue, especially in tumors localized to the CNS. However, EBV has been detected less frequently in systemic lymphomas, leading investigators to suggest that the role of other common latent or chronic viral infections should be considered in these tumors, in view of the increasing incidence of this type of cancer in HIV-infected patients.^8-10

Chronic Antigen Stimulation and Cytokine Dysregulation. It is believed that AIDS-related lymphoma arises as a consequence of long-term stimulation and proliferation of B lymphocytes. HIV may cause these effects through the induction of a number of inflammatory cytokines, such as interleukin 6 and interleukin 10. These cytokines have been associated with proliferation, stimulation and activation of B lymphocytes.¹¹ This persistent stimulation is thought to increase the accumulation of genetic errors and chromosomal alterations (translocations), which in turn lead to aberrant expression of certain oncogenes and/or tumor suppressor genes. Indeed, various genetic lesions are present in many of these tumors, causing activation of the c-myc (especially in Burkitt's type lymphomas), bcl-6 and ras proto-oncogenes and inactivation of the p53 tumor suppressor gene.¹² These multiple genetic events accumulate within a few years time and are considered one of the major pathogenic mechanisms in AIDS-related lymphomas.

Clinical Characteristics of Systemic NHL

Despite the fact that HIV infects T lymphocytes, AIDS-related lymphomas are of B lymphoid origin in at least 95% of all cases described. Most are intermediate or high-grade lymphomas, and mostly large cell (60%) or small, non-cleaved lymphomas (35%). Systemic NHL presents in persons with varied levels of immune function (median CD4 cell count of ~100/mm³). The vast majority of patients with AIDS-related lymphoma present with systemic "B" symptoms including unexplained fever, drenching night sweats and/or weight loss in excess of 10% of normal body weight.¹³ Consideration of this type of presentation is important, as many opportunistic infections may also produce similar symptoms. However, clinicians should recognize that these symptoms might be indicative of lymphoma, thus mandating careful physical examination, a CAT scan of chest, abdomen and pelvis, and/or bone marrow examination, in addition to a work-up for infection.

Many of these tumors present with extranodal disease, sometimes at unusual sites with bone marrow (30%), meninges (10%-20%) and gastrointestinal tract (10%-25%) being most common.¹³ One characteristic feature of the widespread extranodal involvement in HIV-infected patients with lymphoma is the extensive nature of lymphomatous disease. Therefore, it is not unusual for the patient with gastrointestinal involvement to have lymphomatous infiltration of the entire length of the gastrointestinal tract. In the setting of underlying HIV infection, systemic NHL truly behaves as an opportunistic neoplasm, overwhelming those immune mechanisms that may normally attempt to keep the cancer in check.

Treatment of Systemic NHL

Although better understanding of the pathogenesis of AIDS-related lymphomas may ultimately result in more effective treatment and/or prevention strategies for this tumor, current treatment approaches include systemic chemotherapy with support of hematopoietic growth factor. However, treatment of these tumors in HIV-infected patients with myelotoxic drugs often results in profound neutropenia. In addition, treatment is frequently complicated by the occurrence of opportunistic infection and by poor bone marrow reserves induced by HIV. Current regimens include half-dose chemotherapeutic agents such as methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) with adjunctive use of hematopoietic growth factor (granulocyte-macrophage colony stimulating factor, GM-CSF, or granulocyte colony stimulating factor, G-CSF).^14,15 However, complete response occurs in ~65% of treated patients, with relapse in ~25% of these patients within 6 months. Overall, the median survival has been 4-8 months; ~50% die of lymphoma and the other 50% die from opportunistic infection.¹⁶

In summary, as systemic NHL has become an increasingly important cause of morbidity and mortality in HIV-infected individuals and because its treatment generally requires aggressive combination chemotherapy, it is necessary to develop a better understanding of the pathogenesis of this disease. Such insights could lead to the development of more rational and less immunosuppressive approaches to the treatment of patients with NHL and HIV infection.

Table 1: Characteristics of systemic and primary CNS non-Hodgkin's lymphoma in patients with HIV infection.
Patient and Tumor Characteristics	Systemic-NHL	Primary CNS-NHL
Histology	Large cell and small noncleaved cell	Large cell
Clonality	Monoclonal or polyclonal	Monoclonal
EBV DNA in tumors	Present in minority	Almost always present
Medium CD4 cell count	~100 cells/mm3	<30 cells/mm3
Patient survival from time of diagnosis	6-8 months	3 months

Glossary

Dysregulation: impairment of the mechanisms that control production or function.

Etiology: the cause or origin of a disease.

Extranodal: outside the lymph node.

Hematopoietic: relating to the formation of blood or blood cells.

Lymphoma: a tumor of the lymphoid tissue (usually malignant).

Lymphomagenesis: the development of lymphoma.

Lymphomatous: relating to lymphoma.

Lymphopenia: a reduction in the number of circulating lymphocytes.

Monoclonal: produced by or relating to cells derived from a single cell.

Myelotoxic: destructive to bone marrow.

Neoplasm: a new growth of tissue that has no specific or relevant function, i.e. a tumor.

Neutropenia: a decrease in white blood cells where the majority lost are neutrophils (a type a cell that engulfs foreign bodies and cellular debris in the body).

Oncogene: a gene that can cause a cell to become cancerous.

Oncologic: relating to cancer.

Pathogenesis: the development of a disease.

Proto-oncogene: a gene that has the potential of becoming an oncogene.

References

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3. Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW. Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. Adult/Adolescent Spectrum of HIV Disease Project Group. J Acquir Immune Defic Syndr. 1999;21(Suppl 1):S11-S17.
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