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The Oncologist, Vol. 3, No. 2, 119-123, April 1998
© 1998 AlphaMed Press

AIDS-Related Malignancies

David T. Scadden, Walter W. Howard

AIDS Oncology Center, Massachusetts General Hospital, Dana-Farber/Partners Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: David T. Scadden, M.D., AIDS Oncology Center, Massachusetts General Hospital, Dana-Farber/Partners Cancer Center, Harvard Medical School, 149 13th Street, Room 5212, Boston, Massachusetts 02129, USA. Telephone: 617-726-5615; Fax: 617-726-4691; e-mail: scadden.david{at}mgh.harvard.edu


   Abstract
Top
 Abstract
Epidemiology
 Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
 Other Malignancies
 Conclusion
 References
 
The changing face of the AIDS epidemic since the introduction of protease inhibitors has had a significant impact on AIDS-related malignancies. These issues, emerging concepts regarding pathophysiology and current treatment strategies, are the subject of this review.

Key Words. AIDS • Non-Hodgkin's lymphoma • Kaposi's sarcoma • HIV-1 • AIDS-related lymphoma • Immunodeficiency


   Epidemiology
Top
 Abstract
 Epidemiology
Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
 Other Malignancies
 Conclusion
 References
 
The spectrum of neoplasia seen in the context of HIV infection is listed in Table 1Go and is, in part, remarkable for its relative brevity. In general, the epithelial tumors commonly seen outside the context of HIV infection are not increased in incidence within the context of the AIDS epidemic. However, a relatively narrow spectrum of malignancies occurs with increased frequency and the unifying theme among these is the association with secondary infectious processes. In particular, Kaposi's sarcoma (KS) has recently been linked to a member of the gamma herpes virus family, KS-associated herpes virus (KSHV) [1]. This virus, also known as human herpes virus-8 (HHV-8), is also seen in a small subset of non-Hodgkin's lymphomas. A far larger proportion of the AIDS-related lymphomas (ARL) are associated with Epstein-Barr virus (EBV). The squamous cell neoplasia seen in AIDS is almost exclusively due to human papillomavirus (HPV) infection [2, 3].


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  		Table 1. AIDS-associated neoplasms
 
Several tumors are suspected to be of increased incidence, and accumulating evidence supports this view; these tumors include Hodgkin's disease (which is EBV-related in most cases of AIDS). Leiomyosarcomas are seen with increased frequency in children with HIV infection and are uniformly noted to have EBV present within them [4]. Interestingly, this tumor is not noted with increased frequency in adults with AIDS, and sporadic leiomyosarcomas are not EBV-related. Plasmacytoma appears to occur with increased frequency and has a number of interesting features in AIDS; it is the malignant transformation of a cell population that is commonly perturbed in HIV infection. Plasma cell overproduction of immunoglobulin is the most common serologic abnormality associated with HIV infection. Malignant plasmacytoma is occasionally seen and may be associated with anti-HIV-specific immunoglobulin-secreting tumors. Of note, there are also recent data that suggest that KSHV might participate in plasma cell dyscrasias [5], but it is unclear how that virus is involved in the plasmacytomas seen in AIDS.

The incidence of AIDS-related malignancies appears to be altered in the era of protease inhibitor therapy for HIV-1. This is particularly notable in KS, where the number of patients requiring systemic therapy for this disease has markedly diminished. Similar observations have been made regarding the incidence of primary CNS lymphoma, which is generally a manifestation of end-stage AIDS. However, the frequency of systemic lymphoma in AIDS appears to be far more subtly modulated. Definitive epidemiologic data regarding these changes are still in evolution.


   Kaposi's Sarcoma
Top
 Abstract
 Epidemiology
 Kaposi's Sarcoma
Non-Hodgkin's Lymphoma
 Other Malignancies
 Conclusion
 References
 
The most common neoplasm seen in HIV disease is KS. This neoplasm is increased in incidence, particularly among individuals who have been infected by HIV-1 due to men having sex with men. The estimated excess risk of the AIDS population is approximately 100,000-fold compared with age-matched controls. Due to the relatively restricted subset of HIV-infected patients who suffer this complication, it has long been hypothesized that an infectious cofactor is involved in the pathogenesis of KS. A number of microbiologic agents have been implicated over the years, but the KSHV link now appears to be firmly established [6]. This virus is found in KS tissue regardless of whether the KS is classic, endemic, or associated with HIV-1 infection. The association with KS includes evidence for the presence of the virus in KS but not in other vascular proliferative lesions, and that seroconversion to KSHV precedes the development of the tumor. The risk of developing KS if seropositivity to KSHV is found is, at present, still unknown and remains a key question in counseling. KSHV has been shown to respond to some herpes virus medications (foscarnet, ganciclovir) in the laboratory, but whether or not these agents can be useful in preventing early KS is yet to be determined. There have been anecdotal reports of responses to ganciclovir, but, in general, these agents fail to have any significant impact on the natural history of established disease.

Patients may present with indolent KS evident by a relatively small number of lesions. There are data that suggest that lesions may be polyclonal with multifocal outgrowths, yet other data suggest that some lesions do represent metastases from monoclonal tumors [7]. For some patients, lesions are not particularly cosmetically troublesome, whereas others develop highly disfiguring lesions that may accumulate at a very brisk pace. In addition, complications are common if there is involvement of lymphatics or other viscera. The most common morbidity is that of edema induced by KS. This may be due to the increased permeability of the vasculature that composes the KS lesion and elaboration of permeability factors such as vascular endothelial growth factor (VEGF) by KS tissue, both of which are often augmented by infiltration of tumor into lymph vessels and nodes. Other sites of frequent involvement are mucosal surfaces, which can result in problems in the oral cavity due to gingival swelling or pain and difficulty in swallowing. Mucosal lesions within the GI tract are often asymptomatic, but may occasionally be the cause of bleeding or intussusception. Lung involvement can take several forms, including pleural-, bronchial-, or parenchymal-based lesions. Pleural infusions in KS are relatively common and are often hemorrhagic in nature, with no definable tumor cells in the fluid. Involvement of the airways can occasionally be the cause of chronic cough or hemoptysis. However, parenchymal lung involvement is the most significant and life-threatening complication of KS. It is often a rapidly progressive process and commonly fatal unless aggressively treated. Pulmonary infiltrates in a patient with KS should always be assessed for underlying opportunistic infections, but in the absence of evidence for these, infiltrates should be regarded as highly suspicious for KS involvement and aggressively pursued.

Treatment of patients with KS needs to be tailored to the individual. For patients with a small number of cutaneous lesions that are not particularly troublesome, local approaches may be appropriate. These have traditionally been either cryotherapy, local radiation therapy, or intralesional injection (vinblastine 0.01-0.03 mg per lesion). Newer approaches have included the topical use of 9-cis-retinoic acid, which has been tested extensively in a clinical trial currently undergoing FDA review.

Patients with more extensive lesions are candidates for systemic therapies. For patients who are not symptomatic, interferon-alpha may be useful. However, this is effective only if CD4 counts are >100 cells/mm3 and is often associated with intolerable toxicities. Time to response is often slow, generally requiring a 6- to 10-week period. A number of new approaches are being investigated in this patient population and include encouraging results with both oral 9-cis-retinoic acid and angiogenesis inhibitors such as IM862, with the latter currently in clinical trial. This compound has shown tumor regression in patients with minimal toxicity and has the advantage of being administered as a single daily-dose nasal inhalation. Other angiogenesis inhibitors are being tested, and thalidomide is also among those having encouraging preliminary data.

For patients with symptomatic disease, systemic chemotherapy is generally appropriate. A number of regimens have been tested, and recently several drugs have become available which are highly potent and well tolerated. Liposomal anthracyclines (Doxil or DaunoXome) are often first-line therapies, while some centers employ bleomycin (15 units) and vincristine (1.4 mg/mm2 up to 2 mg) as initial treatment. In Phase III randomized trials, the liposomal anthracycline drugs were shown to have advantageous toxicity profiles compared with combination doxorubicin/bleomycin/vincristine [8, 9]. Liposomal doxorubicin (Doxil) also has been shown to have a better response rate than doxorubicin/bleomycin/vincristine, whereas liposomal daunorubicin (DaunoXome)showed tumor control equivalent to the combination regimen. Whether there are substantial differences between the two liposomal agents remains somewhat ambiguous, however, as a head-to-head clinical comparison has never been undertaken. Clinical evaluation of responses to treatments are generally difficult secondary to a lack of uniform, standard criteria. The NCI and the AIDS Malignancy Consortium are in the process of trying to define and standardize these criteria.

While the frequency of response with the use of liposomal anthracyclines is quite high, patients often relapse and fail to maintain control beyond a three-month period. In the past, the options beyond these agents have until recently been quite limited. Paclitaxel has recently come on the scene as perhaps the most potent agent yet tested against KS. This drug can be used at low-dose intensity (100 mg/m2 over three h every two weeks) with extremely effective and highly durable tumor control. There are now patients at our center who have received over 65 cycles of this medication without significant adverse effects and with continued excellent control of otherwise devastatingly severe KS. The major drawbacks to use of the medication are alopecia and the inconvenience and expense of its use. Therefore, we typically reserve this as a second-line regimen in patients who have failed liposomal anthracyclines.


   Non-Hodgkin's Lymphoma
Top
 Abstract
 Epidemiology
 Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
Other Malignancies
 Conclusion
 References
 
Non-Hodgkin's lymphoma (NHL) is the most lethal complication of HIV disease [10]. Its incidence is increased in the setting of HIV infection and is a manifestation of other types of immunodeficiency as well. Patients with congenital immunodeficiency or immunosuppression due to medication for organ transplant also have a markedly increased incidence of NHL. While there are similarities between these syndromes, there are a number of distinct differences [11]. For example, Epstein-Barr virus is uniformly present in the post-transplant lymphoproliferative disease and yet occurs in only one-third to two-thirds of ARL. In addition, the small non-cleaved cell or Burkitt's-like histology is an extreme rarity in the post-transplant setting, but accounts for almost one-third of ARL. c-myc rearrangements are common in ARL, but rare in the other contexts. These features highlight the unique aspects of ARL and suggest a complex pathophysiology that is in the process of being evaluated.

Unlike KS, lymphoma occurs across the spectrum of HIV risk groups. There are subtle differences between these groups, with a slight increase among hemophiliacs and a decrease among i.v. drug users or those of Caribbean descent [12]. The interpretation of these data is complex, and it is not clear to what extent these reflect true biologic differences. The incidence of lymphoma among patients with HIV disease is estimated at 1.6%-8% per year [13]. This is generally higher among patients with more advanced immune suppression, but ARL can occur at any time during the course of HIV disease. It may be the presenting symptom in approximately 4% of HIV-infected individuals.

The clinical presentation of ARL can be broken down into two basic categories: there are those that present with a parenchymal lesion of the brain (primary CNS lymphoma), and those with systemic involvement with or without concurrent CNS involvement. Among the systemic lymphomas, there is a small subset that has recently been identified and termed primary effusion lymphomas (PEL). The PEL patients represent a particularly unique group with several unusual characteristics [14, 15].

The features of PEL include involvement of a body cavity, generally without the presence of any mass lesion. These are often difficult to classify because of the absence of B- or T-cell markers on their surface. DNA analysis does indicate that they have rearranged immunoglobulin and are therefore of B-cell origin. Quite interestingly, they are all positive for the presence of KSHV. Many also have EBV present, but the ubiquitous finding is that of KSHV.

The histology of the tumors is generally of a Burkitt's-like, immunoblastic or large-cell lymphoma. Unlike lymphomas outside the context of HIV, AIDS-related lymphoma often involves extranodal tissue. Indeed, involvement of extranodal tissue is the rule rather than the exception and is often the site sampled for diagnosis [16-30]. Favored extranodal sites include CNS, bone marrow, GI tract, and liver.

The evaluation of patients with ARL should include standard complete blood count, chemistries, and bone marrow sampling. We also generally send the bone marrow for acid-fast bacilli (AFB) and fungal culture and ask that special stains be performed to exclude such opportunistic infections. Among patients who have "B" symptoms of fever, night sweats, weight loss or anorexia, it is particularly important and it is incumbent upon the physician to exclude coincident opportunistic infection. Bacterial and fungal cultures, CMV antigen, cryptococcal antigen, toxoplasma titer and sputum for Pneumocystis carinii pneumonia are often analyzed. Routine CT scanning is performed, with a gallium scan added for those who have mediastinal or retroperitoneal adenopathy that would be difficult to assess by CT alone. Unique to this patient population is a high incidence of CNS involvement. It is therefore our practice to image the brain and sample CSF. In patients with Burkitt's-like histology, perinasal, testicular, or bone marrow involvement, we administer intrathecal cytarabine (ara-C) on a weekly basis x 4 with the initiation of chemotherapy, regardless of the CSF cytology.

Systemic chemotherapy has been evaluated in a number of trials. Due to the toxicities seen with chemotherapy early in the AIDS epidemic, efforts to use minimally toxic treatments emerged. One of these (low-dose m-BACOD) was tested in a phase III randomized, prospective clinical trial [29]. The study demonstrated that overall survival, disease-free survival, and response rates were all equivalent whether the half-dose or full-dose m-BACOD regimen was used. Toxicity profiles were, as expected, better in the low-dose arm. The results of this trial have led to an adoption of a low-dose approach in patients with advanced immunodeficiency. It is important to realize that these data were generated in an era prior to the use of highly active antiretroviral therapy and improved prophylaxis regimens. The applicability of this study to patients who have attained viral control is unclear. Among patients who have good performance status, full-dose regimens such as CHOP are generally reasonably well tolerated. It is our practice when clinical trials are not available to use full-dose CHOP in patients who have a CD4 count of >100 and/or good performance status as well as good viral control. Other centers are also achieving good results with infusional regimens using cyclophosphamide, doxorubicin, and etoposide [31].

For patients who present with primary CNS lymphoma, the outcome remains quite bleak. In general, therapy is restricted to steroids and radiation [32]. Ongoing clinical trials are testing whether new biologic approaches can result in meaningful benefit. There are a number of theoretic approaches which can be tried, focusing on the EBV that is present uniformly in primary CNS lymphomas in AIDS; however, these remain the subject of clinical investigation.


   Other Malignancies
Top
 Abstract
 Epidemiology
 Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
 Other Malignancies
Conclusion
 References
 
Papillomavirus-related tumors of squamous cell surfaces are being seen with increased frequency [33]. The guidelines for approaching these patients are generally similar to those for the non-HIV infected population. The same can be said for Hodgkin's disease, where treatment for stage therapies should be applied. In the latter case, dose compromise should not be considered unless patients have been shown to be intolerant of standard regimens or have far-advanced AIDS [16, 34].


   Conclusion
Top
 Abstract
 Epidemiology
 Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
 Other Malignancies
 Conclusion
References
 
The area of AIDS-related malignancies represents the unique interplay of immunology and neoplasia. Better understanding of the relationships between tumorigenic viruses and underlying immune function will yield more pathophysiologically directed therapies that are just entering the clinical realm. Ongoing clinical investigation in AIDS-related tumors is directed at immune modulating or antiviral approaches that hold considerable promise for more specific therapy in the future.


   References
Top
 Abstract
 Epidemiology
 Kaposi's Sarcoma
 Non-Hodgkin's Lymphoma
 Other Malignancies
 Conclusion
 References
 

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accepted for publication March 3, 1998.





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