Incidence and management of AIDS-related lymphoma

Over time, the spectrum of the acquired immune deficiency syndrome (AIDS) epidemic has changed, especially with the advent of highly active antiretroviral therapy (HAART). The goal of this article is to delineate changes occurring in the incidence and management of lymphoma over the course of the AIDS epidemic. Lymphoma usually occurs rather late in the course of human immunodeficiency virus (HIV) infection and is the cause of death in up to 20% of HIV-infected individuals. It is seen in all population groups at risk for HIV and is more common in men than in women. It is usually diagnosed in patients with markedly decreased CD4 cell counts, consistent with prolonged periods of HIV infection and subsequent immunosuppression. Recent data from several large series have demonstrated a substantial decline in the median CD4 cell count among patients with newly diagnosed AIDS-related lymphoma despite the recent widespread use of HAART. While still somewhat controversial, use of HAART has generally not produced a significant decline in the incidence of AIDS-related lymphoma. Patients treated with low-dose vs standard-dose chemotherapy for AIDS-related lymphoma have achieved similar response and survival rates, although standard-dose therapy is associated with greater toxicity. Adapting therapy to prognostic factors has not produced a significant improvement in survival. Use of antiretroviral therapy along with chemotherapy appears safe, and may be associated with longer survival. An infusional regimen called EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin HCl) shows promise in the future management of AIDS-related lymphoma. No regimen is currently considered the standard of therapy for patients with relapsed AIDS-related lymphoma, and survival is short in this setting.     

Clinical aspects and management of AIDS-related lymphoma

The incidence of non-Hodgkin's lymphoma (NHL) is increased by approximately 100-fold in patients with advanced HIV infection. Clinical presentations may include systemic lymphoma, primary central nervous system (CNS) lymphoma, and primary effusion lymphoma. Systemic lymphoma is the most common presentation, is almost always of intermediate or high-grade histology and B-cell phenotype, and usually involves extranodal sites. The disease is potentially curable with combination chemotherapy used for immunocompetent patients with lymphoma, although cure is achieved in only approximately 10–35% of patients. Primary CNS lymphoma may be difficult to distinguish from cerebral infection. The prognosis is very poor, although approximately 10% of patients selected for therapy may survive beyond 1 year with brain irradiation. Attention to infection prophylaxis and antiretroviral therapy is important. Evidence suggests that highly active antiretroviral therapy (HAART) has resulted in a decreased incidence of lymphoma, and that patients with systemic lymphoma treated in the post-HAART era have a better prognosis.     

Epidemiology and management of lymphoma in low-income countries

Our current knowledge of the epidemiology and treatment outcome of lymphoma in low-income countries is very limited. In the poorest countries only a small proportion of patients have access to treatment while clinical research is almost non-existent. In order to address these problems and discuss potential solutions a Workshop on 'Epidemiology and Management of Lymphoma in Developing Countries: Challenges and Opportunities for International Collaborations' was held during the 10th International Conference on Malignant lymphoma in Lugano, Switzerland in June 2008 under the sponsorship of UICC, ESMO and ESO. We report here a summary of the discussed issues with some reflections on this workshop.     

Impact of HAART on the clinical management of AIDS-related cancers

The development of HIV-related disease has changed dramatically since the introduction of highly active antiretroviral therapy (HAART) into clinical practice. Since the use of protease inhibitors became widespread, a 30–50% reduction in Kaposi's sarcoma (KS) has been observed. The results of recent studies indicate that HAART may be a useful alternative both to immune response modifiers during less aggressive stages of KS disease and to systemic cytotoxic drugs in the long-term maintenance therapy of advanced KS. The impact of HAART regimens on the incidence of systemic lymphoma (NHL-HIV) remains unclear, but it can be hypothesised that patients treated with HAART may survive longer with continued B cell stimulation and dysregulation resulting in an increased incidence of lymphoma over time. The impact of HAART on survival in patients affected by NHL-HIV has recently been evaluated and a positive correlation between HAART and outcome in these patients has been found. The spectrum of cancers in patients with HIV infection may develop further since these patients survive longer with HAART and with a better control of opportunistic infections. With the increasing use of HAART, the dilemma is whether to institute or continue protease inhibitors use during chemotherapy. Based on the advances in our understanding of HIV-related disease and the availability of new antiretroviral therapies, the choice for anti-HIV agents in patients receiving chemotherapy is important.     

Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma

The incidence of NHL is greatly increased in HIV-infected individuals; malignant lymphoma is the second most common neoplasm that occurs in association with AIDS. The vast majority of neoplasms are clinically aggressive, monoclonal B-cell neoplasms that exhibit Burkitt's, immunoblastic, large cell, or transitional histopathology. Approximately 80% arise systemically (nodal or extranodal) and 20% arise as primary CNS lymphomas. A small proportion of neoplasms are body cavity-based, primary effusion lymphomas that are uniquely associated with KSHV infection. Recently, HIV-associated polymorphic lymphoproliferative disorders have been described as well. AIDS-related NHLs appear to exhibit distinctive clinical characteristics according to their histopathology and anatomic site of origin. Factors that contribute to lymphoma development include HIV-induced immunosuppression, impaired immune surveillance, cytokine release and deregulation, and chronic antigenic stimulation. This environment is associated with the development of oligoclonal B-cell expansions. The appearance of NHL is characterized by the presence of a monoclonal B-cell population that displays a variety of genetic lesions, including, for example, EBV infection, MYC gene rearrangement, BCL6 gene rearrangement, P53 mutations and deletions, and RAS gene mutations. The number and type of genetic lesions vary somewhat among AIDS-related NHLs according to their histopathologic category and anatomic site of origin. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of AIDS-related NHLs. Further work is necessary to develop a complete understanding of the etiology and pathogenesis of NHL in the setting of HIV infection. AIDS-related NHL is an important biologic model for investigating the development and progression of high-grade NHLs and NHLs that develop in immunedeficient hosts.     

Multidrug resistance in AIDS-related lymphoma

PURPOSE OF REVIEW: AIDS-related lymphoma has a decreased response rate and poorer prognosis to standard chemotherapy when compared with lymphoma in the non-HIV population. In addition to the known HIV-related and lymphoma-related poor prognostic factors, this review discusses another factor, MDR-1 expression and its impact on response to therapy in patients with AIDS-related lymphoma. RECENT FINDINGS: There is an increased incidence of de-novo MDR-1 expression in AIDS-related lymphoma compared with lymphoma in the non-HIV settings. MDR-1 expression in AIDS-related lymphoma is associated with poor response to conventional combination chemotherapy. Liposomal encapsulation of doxorubicin when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) seems to overcome P-glycoprotein-mediated drug resistance in AIDS-related lymphoma. SUMMARY: The overexpression of MDR-1 gene product P-glycoprotein is an adverse prognostic factor in AIDS-related lymphoma. Treatment with liposomal encapsulated doxorubicin seems to overcome the P-glycoprotein-related drug resistance. This and other strategies to modulate MDR-1 should be further explored in order to improve success rates in the treatment of AIDS-related lymphoma.     

Epidemiology of AIDS-related malignancies an international perspective

Patients with HIV infection are at increased risk for developing Kaposi's sarcoma, non-Hodgkin's lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population--lung, breast, colon/rectum, stomach, liver, and prostate--are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkin's lymphoma, cervical carcinoma in situ (CIS), other anogenital neoplasms (invasive cancer and CIS), leiomyosarcoma, and conjunctival squamous cell carcinoma. There is inconclusive evidence, however, with regard to HIV infection being associated with invasive cervical cancer, testicular seminoma, or hepatocellular carcinoma. Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk.     

Autopsy findings in AIDS-related lymphoma

Autopsies in 20 patients with the acquired immune deficiency syndrome (AIDS)-related lymphoma were studied retrospectively to ascertain the precise cause of death and the extent of lymphomatous disease. Eight patients had primary central nervous system (CNS) lymphoma: two of them were diagnosed antemortem; CNS lymphoma was suspected in three others by computerized tomographic (CT) scan and was confirmed at autopsy. The remaining three were diagnosed incidentally at autopsy. All had concurrent infections at autopsy, including opportunistic infection in six and pyogenic infections in two. Opportunistic infections at autopsy in these patients outnumbered those diagnosed clinically. Twelve patients had systemic lymphoma. Three were diagnosed only at autopsy, two of whom had extensive Kaposi's sarcoma (KS) as well. Eight patients were treated with chemotherapy, but died with disseminated disease. Opportunistic infections were found at autopsy in five patients. Secondary involvement of the CNS by lymphoma was frequent (66%) and was not related to previous bone marrow involvement. The authors conclude that the incidence of lymphoma occurring in AIDS may be more frequent than diagnosed clinically. Similarly, multiple opportunistic infections occur in these patients which are not diagnosed premortem and may contribute to early death.     

AIDS-related primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) can develop in the setting of profound immunosuppression, including late-stage infection with HIV. The management of such patients has yet to be defined optimally and differs substantially from that of immunocompetent patients who have PCNSL. The clinical features, diagnosis, and management of AIDS-related PCNSL are reviewed. The authors focus on commonly encountered diagnostic and therapeutic dilemmas and explore some promises and pitfalls of Epstein-Barr virus-directed therapies.     

The evidence-based treatment of AIDS-related non-Hodgkin's lymphoma

As we enter the third decade of the AIDS epidemic, it is apparent that a large number of cancers are more common in people with the human immunodeficiency virus type 1 (HIV). Non-Hodgkin's lymphoma (NHL) remains the second most common tumour in such patients. At the onset of the epidemic, dose-intense combination regimens were used but these were quickly abandoned in favour of dose-modified strategies because of difficulties in tolerating aggressive chemotherapy in the presence of underlying immunosuppression. With the improvements in supportive care including more effective anti-retroviral therapies, colony-stimulating factors and prophylaxis against opportunistic infections, we are returning to the traditional chemotherapeutic approaches similar to those utilised in the non-HIV infected individual including infusional regimens. In this review, we discuss the evidence for choosing particular therapies in patients with AIDS-related NHL.     

Clinical aspects of AIDS-related non-Hodgkin's lymphoma.

The association of malignant lymphoma with the acquired immunodeficiency syndrome (AIDS) has been recognized since early in the human immunodeficiency virus epidemic. Important clues regarding the etiology of AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) and estimates of the future incidence of AIDS-NHL have been derived from epidemiologic studies. Recent epidemiologic and cohort studies reviewed in this article have confirmed that the incidence of non-Hodgkin's lymphoma is high in patients with human immunodeficiency virus infection, and increase with the duration of severe immunodeficiency in patients receiving antiretroviral therapies. A recent retrospective analysis of clinical features associated with AIDS-NHL described two groups of patients possessing distinct prognostic features. Finally, a number of new observations relating to the molecular and pathogenic mechanism underlying the development of AIDS-NHL have recently been described. The role of Epstein-Barr virus in the pathogenesis of AIDS-NHL continues to be enigmatic, and there may be multiple mechanisms contributing to the development of lymphoma, even in an individual patient.     

Report of AIDS-related lymphoma in South Korea

Background: The prevalence of AIDS-related lymphoma (ARL) is increasingin South Korea. The aim of this study is to identify the clinicalfeatures of ARL in South Korea. Methods: From 1998 through 2006, we retrospectively analysed a totalof 23 cases of ARL from seven institutions. Results: The patients consisted of 20 males and 3 females at a medianage of 40 (range, 20–72) on diagnosis of AIDS. ARL developedat their median age of 41 (range, 24–72). The histologicaldiagnosis was aggressive B cell lymphoma in the majority, butrare T cell and NK/T cell lymphoma were also included. Ten of23 (43.5%) was receiving highly active anti-retroviral therapy(HAART) before the diagnosis of ARL. Fifteen of twenty-threepatients were given combination chemotherapy with/without radiation,four were given radiation alone, and four did not receive anytreatment against medical advice. Of 20 patients followed-up,nine were alive in remission, two alive in disease, one diedof treatment related complication, four died of progressivelymphoma, four died of AIDS related causes. The response totreatment included CR in eight (44.4%), PR in four (22.2%) andPD in three (16.7%). The response to HARRT was evaluable in13 patients based on CD4+ cell count and HIV viral load, amongwhich nine (69.2%) responded. Estimated median survival timewas 43.9 months. Conclusions: Although the population of patients is small, this is the firstclinical data analyses of Korean ARL patients. As a substantialportion of the patients remains alive disease free, the impactof HAART on the clinical course of ARL needs further follow-upand evaluation.     

Epidemiology,pathology and clinical management of multiple gastric cancers: A mini-review

The incidence of multiple gastric cancers (MGCs) has been increasing over the recent decades due to the advance in diagnostic techniques combining with the detailed pathological examinations of surgical resection specimens. Reduction of the surgical extent and trauma under the premise of radical resection improves the quality of life of patients with gastric cancer. However, MGC lesions may have been missed, which can result in adverse consequences. We carried out this systematic review of previous literatures, in order to provide deep insights into epidemiological, pathological and clinical features of MGCs and to establish an efficient way to screen the individuals with high risks. MGCs represent a special type of malignant gastric tumor and possess distinctive features compared with the solitary one. More attention should be paid to both diagnosis and treatment of MGCs. Possibility of overlooking accessory lesions must be kept in mind constantly. For the population at high risk, such as the elderly with differentiated type, strict perioperative tissue examinations and follow-up are essential.     

Changing incidence of AIDS-related Kaposi sarcoma and non-Hodgkin lymphoma in Ontario,Canada

Objective  To examine the influence of the AIDS epidemic on the incidence of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) in Ontario. Methods  Age-standardized incidence rates for KS and NHL from 1981 to 2000 were calculated from the population-based Ontario Cancer Registry. AIDS cases were extracted from Ontario Ministry of Health and Long-Term Care reports. HIV death data were obtained from the Ontario Cancer Registry. Results  KS was a rare cancer before the 1980s; however, incidence increased sharply between 1985 and 1995 by 13.8% per year. Thereafter, incidence rates fell close to those in the early 1980s. NHL incidence in males increased steadily during the 1980s at 3.2% per year and then slowed beyond 1990. In males aged 30–44, NHL incidence rose from 1981 to 1990 (8.8% per year) and then fell (−2.5%) thereafter. NHL and KS cases represented one-third of HIV deaths. Conclusions  The AIDS epidemic, the introduction of antiretroviral therapies, and the decrease in HIV infection rates explain the rise and decline of KS incidence in Ontario. NHL incidence trends are more complex, although the AIDS epidemic explains the trends observed in younger men (in whom AIDS is more common), and for the AIDS-related subtypes.     

AIDS-related non-Hodgkin's lymphoma: etiology, epidemiology, and impact of highly active antiretroviral therapy

Lymphoproliferative disorders (LPD) occur more frequently in the immunosuppressed host compared to those who are immunocompetent. The biological and clinical characteristics of a particular LPD are specific to the underlying immune defect, though there are clear similarities in the various tumor types that occur. Immunosuppression-related LPD are more frequently associated with gamma-herpesviruses suggesting that the immunologic environment influences tumorigenesis. Clinical outcomes may be optimized when appropriate treatment strategies are based on consideration of the underlying immunodeficiency and on the tumor biology. Consistent with this observation, in AIDS-related lymphomas (ARL), tumor biology, clinical presentations, and treatment outcomes are correlated with the CD4 cell count. This review will consider the role of immune deficiency in HIV disease on ARL pathogenesis and epidemiology, and the impact that highly active antiretroviral therapy has had in this disease.     

AIDS-related malignant lymphoma: results of prospective treatment trials

Twenty-two consecutive patients with high-grade, B-cell lymphomas related to the acquired immunodeficiency syndrome (AIDS) were accrued onto two sequential phase II studies, consisting of a standard regimen (M-BACOD, group no. 1, N = 13), or a novel, intensive regimen (group no. 2, N = 9), which included high-dose cytosine arabinoside (HD-Ara-C), and high-dose methotrexate (HD-MTX), in an attempt to prevent CNS relapse and improve response rates. Stage IV disease was present in 82%. Complete remission (CR) was achieved in seven of 13 patients (54%) in group no. 1, and in three of nine (33%) group no. 2 (P = NS). By multivariate analysis, the most significant factor in predicting response was a Karnofsky performance score (KPS) greater than 60 (P = .04). Three of the ten patients who achieved CR on either regimen have relapsed; in all, five of 13 patients (31%) in group no. 1 have achieved disease-free survival for more than 1 year, compared with one of nine (11%) in group no. 2. CNS progression occurred in six patients in group no. 2, and in two patients in group no. 1. Hematologic toxicity was significantly greater in group no. 2, and these patients had an increased risk of opportunistic infection (one in group no. 1 v seven in group no. 2; P less than .01). Survival was similar, with a median of 11 months in group no. 1 and 6 months in group no. 2. We conclude that the intensive regimen of combination chemotherapy described here is associated with significant risk of early death due to opportunistic infection in patients with AIDS-related lymphoma, and that progression in the CNS remains a major problem. Trials of combination chemotherapy of a less intensive nature, perhaps in combination with immunomodulators or antiretroviral agents should be explored.     

Treatment outcome in presumed and confirmed AIDS-related primary cerebral lymphoma

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n=26) or confirmed (n=12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n=4), cerebrospinal fluid (CSF) examination for Epstein–Barr virus (EBV) by PCR (n=7) or postmortem examination (n=1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n=14) or chemotherapy (n=2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P=0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.