AIDS-Related Lymphomas

Updated: Dec 01, 2015
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Individuals infected with human immunodeficiency virus (HIV) have a high risk of developing lymphomas. Approximately 4% of people with acquired immunodeficiency syndrome (AIDS) have non-Hodgkin Lymphoma (NHL) at diagnosis and at least the same proportion develop NHL during the course of illness. [1, 2]

AIDS-related lymphoma (ARL) can be divided into the following three types on the basis of areas of involvement:

  • Systemic NHL
  • Primary central nervous system lymphoma (PCNSL)
  • Primary effusion lymphomas ("body cavity lymphoma")

Systemic NHL is the most common variety of ARL, followed by PCNSL, which is less common but not rare, and primary effusion lymphoma, which is a rare disease. Histologically, the most common variants are diffuse, large B-cell lymphoma and small, noncleaved cell lymphoma, including Burkitt and/or Burkitt-like lymphoma (see the images below). [3, 4]

Burkitt lymphoma under low magnification showing s Burkitt lymphoma under low magnification showing sheets of atypical mononuclear cells. Scattered macrophages can be seen (as demonstrated by the green arrows) giving rise to classical "starry-sky" pattern.
Burkitt lymphoma under high magnification showing Burkitt lymphoma under high magnification showing sheets of atypical mononuclear cells. The cells are intermediate to large in size with scant cytoplasm, round to irregular nuclear contour, smudged chromatin and some with nucleoli. Mitosis and apoptosis are frequent with scattered macrophages giving focal "starry-sky" pattern. Green arrows = macrophages; yellow arrows = mitosis.
Diffuse large B cell lymphoma under low magnificat Diffuse large B cell lymphoma under low magnification showing diffuse proliferation of large atypical lymphoid cells in this lymph node specimen.
Diffuse large B cell lymphoma under high power sho Diffuse large B cell lymphoma under high power showing cells that have moderate to abundant cytoplasm, round to irregular nuclear contour, vesicular nuclear chromatin and one to multiple nucleoli. Scattered small mature lymphocytes are seen. Green arrows = atypical lymphocytes; yellow arrows = small lymphocytes.

AIDS-related Burkitt lymphoma may develop in the presence of relatively sustained CD4+ counts. [5] In contrast, diffuse large B-cell lymphoma usually develops later in the course of illness and in patients who have lower CD4+ counts. [6] PCNSLs tend to occur at CD4 counts of less than 50/μL. [7]

Studies in England found that the incidence of AIDS-related NHL has not changed significantly over the years, but lymphoma has become more common as the initial AIDS-defining condition. Some French and Swiss studies have shown a reduction in the overall incidence of AIDS-related NHL and higher CD4+ cell counts at presentation, presumably due to the effect of highly active antiretroviral therapy (HAART) therapy. [8, 9] In the era of HAART therapy and effective treatment of opportunistic infections both leading to longer life expectancy, the burden of NHL might be altered. [10]

The treatment options in these patients have unique challenges, and although the prognosis is improving, it still remains poor.

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Pathophysiology

Since the start of AIDS pandemic in early 1980s, the disease has been a focus of researchers worldwide. Most ARLs are high-grade, aggressive NHLs.

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Etiology

The etiology of NHL is largely unknown; however, several factors play an important role in development of the disease. These include infections with viruses, namely, Epstein-Barr virus (EBV) infection and human herpesvirus 8 (HHV-8) infection; continuous B-cell stimulation; and last, but not least, 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 AIDS-related lymphomas (ARLs). [10] These lymphomas are of the following varieties [11, 12, 13, 14, 4] :

  • 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, 18] Inactivation of p53 is found in 50-60% [19, 20] of patients and EBV infection in 30-50%. [16, 21]

In centroblastic NHL, EBV infection is found in 30% of affected individuals. [16] BCL-6 proto-oncogene is positive in 20% of patients. [16, 22]

EBV is positive in 90% of patients with immunoblastic lymphoma, [16] and latent membrane protein (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. LMP1 is positive only in immunoblastic lymphomas. [23, 24]

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. [25]

Differentiating plasmablastic lymphoma from immunoblastic lymphoma is possible by appreciating the differences in morphology, with the immunoblastic variety being polymorphic and more heterogeneous. [23] EBV infection is present in 50% of the patients with plasmablastic lymphoma of the oral cavity. [26, 27]

Primary effusion lymphoma

HHV-8 is present in all patients with primary effusion lymphoma. [25, 27] Coinfection with EBV is present in 90-100% of the cases. [28, 29] c-Myc activation is not present, and rearrangements in the coding region of BCL proto-oncogenes are not found. [12, 28, 30]

Primary CNS lymphoma

PCNSLs generally have immunoblastic histology. [31, 32] There is consistent infection of the tumor cells by EBV, with 90% of the patients expressing LMP-1, suggesting the importance of the virus in the pathogenesis of the tumor. [11, 19] Most of the patients have mutations of BCL-6, and they also express high levels of the BCL-2 protein.

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, 33] Multiple genetic loci, including proto-oncogene PAX5, c-myc, RHO/TTF, and PIM1, are mutated. [27, 34, 35, 36, 37] 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. [38]

Role of cyclins

p27K1P1 is an important inhibitor of cyclin-dependent kinase (CDK)–cyclin complex. [39] Cyclins are cell cycle regulators that form complexes with the CDKs. The regulatory step in this process is the inhibitor of the complex formation. [40, 41] 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. [42]

Important exceptions that feature the expression of p27K1P1 and a high proliferative index are immunoblastic lymphoma and primary effusion lymphoma. [43, 44]

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 like p27K1P1, [44, 45] the mechanism by which immunoblastic lymphoma cells escape the inhibitory effect of p27K1P1 is not yet fully understood.

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Epidemiology

Frequency

United States

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 NHL is a valid research practice. [46]

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. [47]

The incidence of systemic NHL in HIV patients is around 1.18 cases/100 person-years in parts of the United States. [48] The relative risk is elevated for all histologic types of AIDS-related lymphomas (ARLs), as noted in the following [49] :

  • Diffuse immunoblastic tumors – 652-fold
  • Burkitt lymphomas – 261-fold
  • Intermediate-grade lymphoma – 113-fold
  • Low-grade lymphoma – 14-fold

The peak incidence for PCNSLs has varied over time and has been affected the most by introduction of HAART therapy. 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 to this, the incidence of PCNSLs is increased by 1000-fold in AIDS patients. [50, 51]

International

In an attempt to estimate the lymphoma risk in HIV patients, several trials have suffered from selection bias. Registry linkage between tumor registry and HIV registry 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 and lymphopoietic neoplasm are limited if available at all in African countries. Association between NHL and HIV seems to be weaker in African countries as compared with more developed countries. [54] The RR increase of NHL in people with AIDS in Africa is 10% lower as compared with AIDS patients in developed countries (eg in Uganda, the annual incidence of NHL was reported as 6 per 100,000 between 1995 and 1997). [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. [8] 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. [8]

Race

In the United States, the incidence rates and the proportion of NHL as an AIDS-defining illness is lower in blacks relative to whites. [57]

Sex

The male-to-female incidence ratio for NHL in the general population 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. [58]

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 the common neoplasms. NHL composes 65% of all tumors reported in this patient population. [59, 60, 61]

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. [62] This has been attributed to a major and parallel decrease in mortality from other disease processes.

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Prognosis

Mortality/Morbidity

Despite recent advances in the management of AIDS and its associated lymphomas, AIDS still has a poor prognosis, especially when it comes to PCNSLs and primary effusion lymphomas. The underlying severity of the HIV infection also plays a critical role in mortality and morbidity. These factors have been discussed in detail elsewhere in the article (see Pathophysiology and Treatment, Medical Care). Generally speaking, with therapy, the median survival of primary effusion lymphomas is 2-3 months; with diffuse, large B-cell lymphoma, around 21 months; and that of PCNSLs, 3.5 months. [56]

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