Original ContributionsAIDS-related non-Hodgkin's lymphomas: From pathology and molecular pathogenesis to treatment*,**
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).
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.
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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.