AIDS-Related Lymphomas

Updated: Aug 14, 2019
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

AIDS-related lymphoma (ARL) is usually an AIDS-defining malignancy in patients infected with human immunodeficiency virus (HIV). ARLs comprise a narrow spectrum of histologic types consisting almost exclusively of aggressive B-cell tumors. The most common variants are diffuse large B-cell lymphoma (DLBCL) and small noncleaved cell lymphoma, including Burkitt and Burkitt-like lymphoma. [1, 2]

ARLs, both AIDS-defining and non-AIDS-defining, consist of the following [3] :

  • Aggressive B-cell lymphoma
  • Primary central nervous system lymphoma (PCNSL)
  • Primary effusion lymphoma (PEL)
  • Plasmablastic multicentric Castleman disease (MCD)
  • Hodgkin lymphoma (HL)

Non-Hodgkin lymphoma (NHL) accounts for 2%-3% of new acquired immunodeficiency syndrome (AIDS) cases. [3]  Since the advent of combined antiretroviral therapy (cART), the overall incidence of AIDS-related NHL has declined. [4, 5]  

Higher CD4-positive T-lymphocyte (CD4+) counts in the cART era have been associated with a shift in histologic diagnoses. There has been a trend away from ARLs that develop at low CD4+ counts (eg, PCNSLs, which tend to occur at CD4+ counts of less than 50/μL [6] ) and toward HL and AIDS-related Burkitt lymphoma, which develop in the presence of relatively higher sustained CD4+ counts, NHL develops later in the course of illness and in patients who have lower CD4+ counts. [7]  

As with lymphoma in HIV-negative patients, the appropriate treatment regimen for ARL is determined by stage, performance status, comorbidities, and histological subtype. A large body of evidence indicates that HIV-infected patients who are treated with standard therapies and cART for DLBCL, Burkitt lymphoma, and HL have outcomes similar to those of their uninfected counterparts. [8] However, optimal therapies for entities such as plasmablastic lymphoma or high-risk DLBCL have yet to be defined. [9]

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Etiology and Pathophysiology

The etiology of NHL is largely unknown; however, several factors play an important role in the development of the disease. These include infections with viruses, namely, Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8); continuous B-cell stimulation; and  immunodeficiency.

Different clinicopathologic categories of AIDS-related lymphomas (ARLs) arise from distinct B-cell subtypes, and the factors mentioned above interplay in varying proportions to give rise to different varieties of NHL.

Systemic NHL

Systemically arising NHL constitutes about 80% of all ARLs. [10] These lymphomas are of the following varieties [11, 12, 13, 14, 2] :

  • Burkitt lymphoma and Burkitt-like lymphoma

  • Diffuse large cell lymphoma, including centroblastic lymphoma, immunoblastic lymphoma, and plasmablastic lymphoma of the oral cavity

NHLs are heterogeneous in their molecular pathogenesis. Activation of c-Myc occurs in all AIDS patients with Burkitt lymphoma. [15, 16, 17]  Inactivation of p53 is found in 50-60% [18, 19] of patients, and EBV infection in 30-50%. [16, 20]

In centroblastic NHL, EBV infection is found in 30% of affected individuals. [16] BCL-6 proto-oncogene is positive in 20% of patients. [16, 21]

EBV is positive in 90% of patients with immunoblastic lymphoma, [16] and latent membrane protein 1 (LMP-1) (EBV-encoded protein) is expressed in 65-75% of patients. EBV-positive lymphomas express LMP1, suggesting a pathogenic role of the virus in development of lymphomas. LMP-1 is positive only in immunoblastic lymphomas. [22, 23]

In plasmablastic lymphoma of the oral cavity, the malignant cells tend to grow in a cohesive manner. The cells are usually large, monomorphic, and have abundant cytoplasm with a peripherally placed nucleus. There is a single prominent nucleolus. [24]

Differentiating plasmablastic lymphoma from immunoblastic lymphoma is possible by appreciating the differences in morphology, with the immunoblastic variety being polymorphic and more heterogeneous. [22] EBV infection is present in 50% of the patients with plasmablastic lymphoma of the oral cavity. [25, 26]

Primary effusion lymphoma

HHV-8 is present in all patients with primary effusion lymphoma. [24, 26] Coinfection with EBV is present in 90-100% of cases. [27, 28] c-Myc activation is not present, and rearrangements in the coding region of BCL proto-oncogenes are not found. [12, 27, 29]

Primary CNS lymphoma

PCNSLs generally have immunoblastic histology. [30, 31]  EBV infection of the tumor cells is consistently found, with 90% expressing LMP-1, suggesting the importance of the virus in the pathogenesis of the tumor. [11, 18] Most of the patients have mutations of BCL-6, and they also express high levels of the BCL-2 protein.

B-cell stimulation

Continuous B-cell stimulation plays an important role in development of these tumors. The role of cyclins and hypermutation in this regard is as follows:

Hypermutation

Most patients carry mutations in BCL-6 genes and immunoglobulin genes. [12, 32] Multiple genetic loci, including proto-oncogene PAX5, c-myc, RHO/TTF, and PIM1, are mutated. [26, 33, 34, 35, 36] The mutational profile of these genes in subtypes of AIDS-related NHLs showed mutations in 1 or more genes in 50% of the cases and 2 or more genes in 23% of the cases. [37]

Role of cyclins

p27K1P1 is an important inhibitor of cyclin-dependent kinase (CDK)–cyclin complex. [38] Cyclins are cell cycle regulators that form complexes with the CDKs. The regulatory step in this process is the inhibitor of the complex formation. [39, 40] There is an inverse relationship between cell proliferation and the presence of p27K1P1 expression in normal lymphoid tissue as well as in most cases of NHL. [41]

Important exceptions that feature the expression of p27K1P1 and a high proliferative index are immunoblastic lymphoma and primary effusion lymphoma. [42, 43]

In primary effusion lymphomas, HHV-8–encoded viral cyclins appear to play an important role. The cyclins produced by the virus induce progression of the cell cycle from the G1 to S phase. Although the cyclins encoded by HHV-8 are resistant to the effect of inhibitors such as p27K1P1, [43, 44] the mechanism by which immunoblastic lymphoma cells escape the inhibitory effect of p27K1P1 is not yet fully understood.

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Epidemiology

Frequency

Individual records from AIDS registries have been linked to cancer registry records in many developed countries to obtain a reliable estimate of lymphomas in HIV-infected patients. Using cancer registry data to identify AIDS-related non-Hodgkin lymphoma (NHL) is a valid research practice. [45]

Such registry-based studies provide valuable data regarding the cancer risk among people with HIV/AIDS (PWHA). They utilize the standardized incidence ratio (SIR) to estimate the relative risk (RR). However, it must be borne in mind that the SIR may underestimate the RR when the HIV/AIDS prevalence in the general population or RR is very high. [46]

United States

The incidence of systemic NHL in HIV patients is around 1.18 cases/100 person-years in parts of the United States. [47] The relative risk is elevated for all histologic types of AIDS-related lymphomas (ARLs), as noted in the following [48] :

  • Diffuse immunoblastic tumors – 652-fold
  • Burkitt lymphomas – 261-fold
  • Intermediate-grade lymphoma – 113-fold
  • Low-grade lymphoma – 14-fold
  • Hodgkin lymphoma – 19-fold [49]

The peak incidence for primary central nervous system lymphomas (PCNSLs) has varied over time and has been affected the most by introduction of highly active antiretroviral therapy (HAART). The incidence increased from early 1990s onward and reached a peak in 1995, followed by a decline. The tumor is rare in immunocompetent individuals. Primary cerebral lymphoma (PCL) comprises 4% of newly diagnosed primary CNS neoplasms and has an incidence of 30 per million person-years in immunocompetent individuals. In contrast, the incidence of PCNSLs is 1000-fold higher in AIDS patients. [50, 51]

International

Linkage between tumor registries and HIV registries in individiual countries has allowed RR estimates of developing lymphomas in HIV/AIDS patients. [52, 53]  

Africa has the highest burden of AIDS, but epidemiologic data and studies on HIV infection and lymphopoietic neoplasm are limited, if available at all, in African countries. Association between NHL and HIV infection seems to be weaker in African countries than in more developed countries. [54] The RR of NHL is 10% lower in African patients with AIDS than in AIDS patients in developed countries (eg, in Uganda, the annual incidence of NHL in 1995-1997 was reported as 6 per 100,000). [55]

The prevalence of the diagnosis of AIDS with concurrent NHL increased from 3.6% to 5.4% between 1994 and 2000 in some European countries, then had a declining pattern. A Swiss cohort study found that the NHL incidence reached 13.6 per 1000 person years between 1993 and 1995 and then declined to 1.8 in the years 2002-2006, with the maximum decline for PCNSLs. [4] Among non-HAART users, being individuals who were men having sex with men, being aged 35 years or older, or, most notably, having low CD4 cell counts at study enrollment were significant predictors of NHL onset. The study also concluded that the beneficial effect in reduction of AIDS-related lymphomas (ARLs) remains strong up to 10 years after the initiation of HAART therapy. [4]

Race- and sex-related demographics

In the United States, the incidence rates and the proportion of NHL as an AIDS-defining illness is lower in blacks relative to whites. [56]

In the general population, the male-to-female incidence ratio for NHL is 2:1. In people with AIDS, however, systemic NHL seems to occur equally in both sexes. In contrast, primary effusion lymphomas almost always occurs in males. [57]

Age

In children and adolescents who are infected with HIV, NHL is the most common malignant disorder. As many as 2% of children have NHL as their AIDS-defining illness. Burkitt lymphoma, immunoblastic lymphoma, and PCNSLs are  common neoplasms. NHL composes 65% of all tumors reported in this patient population. [58, 59, 60]

The pattern of NHL distribution with regard to AIDS, however, is more predictable in non-HIV patients, in whom an increase in the incidence has been seen in the sixth and seventh decade. [61] This has been attributed to a major and parallel decrease in mortality from other disease processes.

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Prognosis

A unique characteristic of AIDS-related lymphoma (ARL) is that antiretroviral therapy can significantly affect the outcomes by reducing viral replication, and its use plays a pivotal role in improving the prognosis. Prognoses of patients with ARL have been associated with the following factors  [3] :

  • Stage (ie. extent of disease, extranodal involvement, lactate dehydrogenase level, and bone marrow involvement)
  • Age
  • Severity of the underlying immunodeficiency (measured by CD4 lymphocyte count in peripheral blood)
  • Performance status
  • Prior AIDS diagnosis (i.e., history of opportunistic infection or Kaposi sarcoma)

Primary effusion lymphoma (PEL) has very poor prognosis, with a median survival of 10.2 months. PEL has been demonstrated to coexist with Kaposi sarcoma in 25–100% of reported cases and MCD was shown to coexist in 9–50%. The frequent coinfection of the tumor cells by HHV‐8 and EBV appears to be very specific to this unusual subset of malignant lymphoma. However, EBV status of the tumor did not influence survival. [62]

A comparative study of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) treatment of HL in HIV-infected and non-HIV-infected patients showed that HIV infection did not adversely affect progression-free survival (PFS) or overall survival (OS) which were 94% and 89%, respectively [49] ​ 

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Patient Education

Detailed discussions regarding the disease and its management should be had with the patient, with the aim of improved understanding of the disease and compliance with therapy. Patients receiving chemotherapy are at high risk of developing febrile neutropenia and life-threatening infections. They should be instructed to monitor their temperature frequently during treatment and to report fever immediately, even if they are feeling well.

Patients who become neutropenic from chemotherapy should avoid eating the following [63] :

  • Raw and undercooked eggs
  • Unpasteurized dairy products
  • Freshly squeezed unpasteurized fruit and vegetable juices
  • Fish and seafood
  • Raw vegetables and raw fruits
  • Raw, uncooked grain products
  • Moldy and outdated food products

Patients should be instructed to inform their physicians if they develop chills, diarrhea, sore throat, shortness of breath, cough, or redness and pain at the site of the venous access.

There is a consensus among experts that these patients should avoid large crowds, people who have fever, and exposure to animal feces, as well as consensus regarding maintaining adequate oral and skin hygiene.

For patient education information, see the Cancer Center, as well as HIV/AIDS and Lymphoma.

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