Elsevier

Human Pathology

Volume 33, Issue 4, April 2002, Pages 392-404
Human Pathology

Original Contributions
AIDS-related non-Hodgkin's lymphomas: From pathology and molecular pathogenesis to treatment*,**

https://doi.org/10.1053/hupa.2002.124723Get rights and content

Abstract

In the highly active antiretroviral therapy (HAART) era, AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) and their treatment still represent an open issue, because HAART may not be sufficient to prevent the development of NHL. The present spectrum of AIDS-NHL includes systemic lymphomas, primary central nervous system lymphomas, and 2 rare entities, primary effusion lymphomas (PEL) and plasmablastic lymphomas of the oral cavity. The vast majority of systemic AIDS-NHL belongs to 3 high-grade B-cell lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and large-cell lymphoma (LCL). The pathologic heterogeneity of AIDS-NHL is correlated with the heterogeneity of the molecular lesions associated with these lymphomas. The molecular lesions associated with AIDS-BL involve activation of c-MYC inactivation of p53, and infection by Epstein-Barr virus (EBV). EBV infection occurs in 40% of LCL cases and in 90% of IBL cases. Rearrangements of BCL-6 are detected in 20% of AIDS-LCL cases. In the presence of EBV infection, BCL-6 expressing AIDS-LCL fails to express the latent membrane protein 1 (LMP1) antigen. Conversely, AIDS-IBL are characterized by absent BCL-6 expression, absence of BCL-6 rearrangements, and frequent expression of LMP1. Consistently, the molecular pathways of viral infection and lesions of cancer-related genes associated with AIDS-NHL vary substantially in different clinicopathologic categories of the disease. The marked degree of biologic heterogeneity of AIDS-NHL is highlighted by their histogenetic differences, because AIDS-NHL are related to distinct B cell subsets (ie, germinal center [GC] or post-GC B cells). The phenotypic pattern of AIDS-BL and systemic AIDS-LCL closely reflects B cells residing in the GC, namely centroblasts and centrocytes. Conversely, the phenotype of AIDS-IBL, either systemic or localized primarily to the central nervous system, and AIDS-PEL reflects post-GC B cells in all cases. New information on the molecular and virologic pathogenesis of AIDS-NHL may serve as a point of attack for pathogenic-driven therapies. Moreover, a greater knowledge of other biologic features of these tumors may help investigators identify new potential targets for “intelligent” therapies. HUM PATHOL 33:392-404. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

General features of AIDS-related non-Hodgkin's lymphomas

The incidence of AIDS-NHL is about 100-fold above expected rates. The overall incidence of NHL in AIDS is estimated at between 4% and 10%.1, 4, 15 About 10% of all NHL cases in the United States and Europe are AIDS-related.12, 14, 15

AIDS-NHL display several features that differ from those exhibited by corresponding NHL in the general population. From a clinical standpoint, AIDS-NHL have frequent extranodal presentation, an aggressive clinical course, and poor outcome.3, 4 From a pathologic

Systemic AIDS-related non-Hodgkin's lymphomas

About 80% of all AIDS-NHL cases arise systemically (ie, systemic AIDS-NHL). Common sites of extranodal involvement at presentation are the gastrointestinal tract, liver, and bone marrow.19 The vast majority of systemic AIDS-NHL belongs to 3 high-grade B cell lymphomas: Burkitt's lymphoma (BL), immunoblastic lymphoma (IBL), and large-cell lymphoma (LCL). Low-grade B cell and T cell NHL, which may occasionally develop in the HIV-infected population, are not considered AIDS-related tumors because

Primary central nervous system lymphomas

Before the introduction of HAART, about 20% of all AIDS-NHL were PCNSL, and the relative risk of these lymphomas among HIV-infected hosts was about 1,000 greater than in the HIV-negative population.18, 19 Most of those patients were profoundly immunocompromised young men who had far-advanced HIV disease. However, since the introduction of HAART, several reports have demonstrated a lower incidence of primary brain lymphomas.12, 13, 14

Lineage and clonality

The vast majority of systemic AIDS-NHL and PCNSL express monotypic surface immunoglobulin (Ig) and/or B cell lineage-associated antigens and exhibit clonal Ig gene rearrangements, confirming their monoclonal nature.4, 16, 17, 19, 33 The sole exceptions to the general literature experience are the studies by McGrath and colleagues,37 who reported that one-third of all AIDS-NHL occurring in the San Francisco Bay area are polyclonal. Their conclusion is based on their inability to detect clonal Ig

AIDS-related Burkitt's lymphomas

AIDS-BL may be the first manifestation of AIDS in a significant fraction of cases, because it also may develop in the presence of relatively sustained peripheral blood CD4 levels38, 39, 40, 41, 42, 43, 44, 45 (Table 1).The molecular pathway associated with AIDS-BL involves activation of c-MYC, inactivation of p53, and infection by EBV (Fig. 3, Table 1).

. Heterogeneity of the molecular lesions associated with AIDS-NHL categories. As summarized here, classic BL selectively associates with

Primary effusion lymphomas

Only after the discovery of HHV-8 in 1995 was PEL recognized as a distinct entity, thanks to its consistent association with HHV-8 infection.21 Thus PEL is a recently discovered disease that is not yet widely known. It is a tumor disease not easily recognizable because of its unusual behavior. According to clinical, pathologic, and molecular investigations, the distinguishing features of PEL are liquid growth in serous cavities, absence of solid tumor masses, and infection of the tumor clone by

Plasmablastic lymphomas of the oral cavity

PBL nearly always occur in HIV-infected individuals, in whom they preferentially localize in the oral mucosa.22 PBL are not limited to HIV-infected individuals and also can be seen in posttransplant recipients.29 Most patients present with localized disease, but the lymphoma may extend to involve the abdomen, retroperitoneum, soft tissues, and the bone marrow.22, 23 All of the reported AIDS-PBL were extranodal.22, 23, 70 The tumors were localized in the mucosa of the oral cavity, and in several

Highly active antiretroviral therapy (HAART) era

HAART has been widely used by HIV-infected people in North America, Europe, and Australia since late 1996, but its impact on the incidence of NHL in HIV-infected people is still unclear.12, 14 A recent publication from an international collaborative group studying about 48,000 HIV-seropositive individuals from the United States, Europe, and Australia reported a 42% decline in NHL incidence in the period 1997 through 1999 compared with 1992 through 1996, when HAART was not available. This

Histogenesis of AIDS-related non-Hodgkin's lymphomas

Today, pathologists have at their disposal both genotypic and phenotypic markers that allow the distinction of mature B cells into different compartments, including virgin B cells, GC B cells, and post-GC B cells. Genotypic markers of B cell histogenesis are represented by mutations of IgV genes and of BCL-6 which are somatically acquired by B cells at the time of transit through the GC.72, 73, 74 Positivity for IgV and/or BCL-6 mutations indicates that a given lymphoma derives from GC or

The variety of AIDS-related non-Hodgkin's lymphoma

It is surprising that AIDS-related NHL occur in so many clinically, histopathologically and pathogenetically distinct varieties, given that these lymphomas develop as a result of malignant transformation of GC or post-GC B cells. It is important to consider that several factors probably account for the heterogeneity of AIDS-NHL: 1. Cell derivation. Cell progenitors at distinct stages of differentiation give birth to different types of tumors. 2. The pathogenetic pathway. The tumor progenitors

Current therapy

Systemic NHL in patients with HIV infection are potentially curable diseases, although the potential for cure is lower than in immunocompetent individuals.13 In fact, combination chemotherapy regimens commonly used to treat HIV-seronegative patients with high-grade NHL have generally resulted in poor outcomes in patients with AIDS-NHL.75, 76 This has been attributed to treatment-associated toxicities and poor prognostic factors, including lymphoma-specific factors (eg, aggressive histology,

Acknowledgements

The author gives special thanks to Jeffrey Cossman for his critical reading and for his valuable suggestions and stimulating comments. The author is indebted to Gianluca Gaidano of the Division of Internal Medicine, Department of Medical Sciences, “Amedeo Avogadro” University of Eastern Piedmont, Novara-Italy, with whom he has shared all the scientific production on AIDS-related lymphomas in the specific field of molecular pathogenesis. The author is also deeply indebted to Annunziata Gloghini

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    *

    Supported by Istituto Superiore di Sanità, III Programma Nazionale di Ricerca Sull'AIDS-Progetto Patologia Clinica e Terapia Dell'AIDS, Rome, Italy; by Ministero della Sanita', RF 1999, Rome, Italy; and by the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy.

    **

    Address correspondence and reprint requests to Antonino Carbone, MD, Scientific Director, Centro di Riferimento Oncologico-IRCCS, National Cancer Institute, Via Pedemontana Occidentale 12, I-33081 Aviano, Italy.

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