Immunophenotypic and molecular analyses of acquired immune deficiency syndrome-related and Epstein-Barr virus-associated lymphomas: A comparative study

doi:10.1016/S0046-8177(96)90366-4

Human Pathology

Volume 27, Issue 2, February 1996, Pages 133-146

https://doi.org/10.1016/S0046-8177(96)90366-4 Get rights and content

Abstract

Limited information is currently available on the molecular and immunophenogenotypic characteristics of CD30-positive anaplastic large cell (ALC) lymphomas occurring in human immunodeficiency virus (HIV)—infected individuals. To address this issue, the authors have undertaken a combined analysis of these lymphomas in comparison with other Epstein-Barr virus (EBV)-associated tumors in the setting of HIV infection. Twenty-one AIDS-related lymphomas, including five CD30-positive ALC and 11 small noncleaved cell (SNCC) lymphomas, and five Hodgkin's disease (HD) specimens were characterized regarding the immunophenogenotypic features, the frequency and subtype distribution of EBV (as defined by in situ hybridization [ISH], Southern blot, and a polymerase chain reaction [PCR] amplification of the EBV nuclear antigen-2 [EBNA-2] region), and viral antigen expression (latent membrane protein-1 [LMP-1], EBNA-2, and Bam HI Z fragment, Epstein-Barr virus replication activator [ZEBRA]). The same series of samples was also investigated for the presence of DNA sequences of the human herpesvirus-6 (HHV-6), and for alterations of the tumor suppressor gene p53. Combined immunophenotypic and immunogenotypic analyses showed a derivation from anomalously matured B cells in four of five CD30-positive ALC lymphomas, whereas SNCC showed features of mature B cells; no evidence of immunoglobulin or TCR gene rearrangement could be obtained in HD cases. Combined ISH and Southern blot analyses revealed that EBV was more strictly associated with HD (five of five) and CD30-positive ALC lymphomas (four of five) than with SNCC lymphomas (four of 11). EBV-positive samples from CD30-positive ALC lymphomas carried type 1 EBV (two of two specimens tested), whereas both EBV subtypes were observed in SNCC lymphomas and HD samples. All three forms of viral latent gene expression were found in the EBV positive CD30-positive ALC lymphomas. SNCC specimens did not express LMP-1 or EBNA-2, whereas HD specimens expressed LMP-1 (four of five tested) but no EBNA-2. Immunostaining for ZEBRA was consistently negative. HHV-6 DNA sequences were detected by PCR in one SNCC of the 19 specimens analyzed. Three out of five CD30-positive ALC lymphoma specimens and six of 10 SNCC showed nuclear staining for p53. No mutation was detected in any of the three CD30-positive ALC lymphomas analyzed, whereas an aberrant SSCP pattern was found in all the four SNCC samples tested. At variance with SNCC lymphomas, AIDS-related B-cell CD30-positive ALC lymphomas are strictly associated with EBV infection and may also express the broad lymphoblastoid cell line-like (LMP1-positive, EBNA-2-positive) pattern, and lack p53 genetic lesions. Unlike EBV, HHV-6 probably does not represent a relevant factor involved in the pathogenesis of CD30-positive ALC and other HIV related lymphomas.

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There may be a higher frequency of association between Epstein-Barr virus (EBV) and HD in HIV-infected persons (80% to 100%) in contrast to 50% in non-HIV infected patients.10,38,40-42 This is further supported by data showing that at least some EBV-transforming proteins, namely EBV-encoded latent membrane protein-1 (LMP-L), are expressed in EBV-positive cases of HD.39,43 The fact that LMP-1 is expressed in virtually all HIV-associated HD cases suggests that EBV does play an etiologic role in HIV-associated HD.38
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NHL displaying the features of the established high-grade NHL types, namely pleomorphic IBL or LCL with centroblastic-large noncleaved cell morphology, can be differentiated on the basis of CD30 positivity, which is expressed by only a fraction of tumor cells in these lymphomas. CD30-positive ALCL cases express B cell or indeterminate immunophenotypes, and most of them contain EBV.32,33 Such cases have generally been included among the large cell (ie, LCL) and immunoblastic (ie, IBL) categories by most pathologists.19
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.
Epstein-Barr virus detection in non-Hodgkin's lymphoma of the oral cavity: An immunocytochemical and in situ hybridization study
2001, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics
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The infection rate of AIDS-related oral lymphomas in the study by Green and Eversole35 was 78%, a figure which may have been higher had a more sensitive detection method than DNA in situ hybridization been used. The association of EBV with AIDS-related lymphomas has been reported to vary with respect to histologic subtype, being highest in the immunoblastic types and lower in the Burkitt’s type of lymphomas.5,9,53 In this study, the uniform association of EBV with the immunosuppression-related NHL may (1) reflect the high tendency of EBV infection of T-cell lymphomas, (2) be because of the more sensitive detection techniques used in this investigation than were used in older studies, or (3) be because of increased EBV replication and shedding in immunosuppressed persons, resulting in superinfection of the existing tumor.
Objective: The purpose of this study was to histologically characterize a series of oral non-Hodgkin’s lymphomas (NHLs) and to investigate latent and lytic Epstein-Barr virus (EBV) infection in these. Study Design: The revised European-American Lymphoma classification system⁴¹ was used to categorize 58 cases of oral NHL, which included 9 immunosuppression-related NHLs. EBV infection was determined by in situ hybridization for Epstein-Barr virus–encoded RNA and by immunohistochemistry for the EBV antigens latency membrane protein, Epstein-Barr nuclear antigen-2 (EBNA2) and Z EBV replication activator protein. Results: Most tumors were B-cell lymphomas (78%), but the proportion of T-cell lymphomas was surprisingly high (22%). The most common histologic subtypes were diffuse large B-cell lymphomas (45%), peripheral T-cell lymphomas (19%), and follicle center lymphomas (14%). Two thirds of the known immunosuppression-related NHLs were T-cell lymphomas. All of the immunosuppression-related tumors were EBV-infected, whereas the EBV infection rate in the NHLs of the remaining patients presumed to be immunocompetent was only 9%. Most EBV-positive tumors expressed neither of the latent antigens (ie, latency membrane protein and Epstein-Barr nuclear antigen-2), and coexpression of the 2 was observed only in immunosuppressed patients. Z EBV replication activator protein expression, which is indicative of replicative infection, occurred only in immunosuppressed individuals. Conclusions: Diffuse large B-cell lymphomas were the most common histologic subtype of oral NHLs, but T-cell lymphomas were relatively common and frequently occurred in states of immunosuppression. EBV may play a limited role in the initiation of lymphoma in the immunocompetent patient, but the virus may be of importance in progression of the disease in those patients with more aggressive tumors, as immunosuppression occurs. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:184-93)
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^☆: Supported in part by the Istituto Superiore di Sanità, AIDS Project, 1994–1995, Rome; and by the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy.

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Original contributionImmunophenotypic and molecular analyses of acquired immune deficiency syndrome-related and Epstein-Barr virus-associated lymphomas: A comparative study☆

Abstract

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Cell

J Biol Chem

Blood

Blood

Blood

Blood

Acquired immunodeficiency syndrome and non-Hodgkin's lymphomas

Cancer Res

AIDS-related malignancies: The emerging epidemic

J Natl Cancer Inst

Pathogenesis of AIDS lymphomas

AIDS

A clinicopathologic study of lymphoid neoplasias associated with human immunodeficiency virus infection in Italy

Cancer

CD30 (Ki-1) positive anaplastic large cell lymphomas in individuals infected with the human immunodeficiency virus

Cancer

Anatomic and histologic distribution of 448 cases of AIDS-related non-Hodgkin's lymphomas

Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression

J Clin Oncol

Immunophenotypic and genotypic analysis of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas: Correlation with histologic features in 36 cases

Am J Clin Pathol

High incidence of monoclonal EBV episomes in Hodgkin's disease and anaplastic large-cell Ki-1-positive lymphomas in HIV-1-positive patients

Int J Cancer

Demonstration of Epstein-Barr viral genomes by in situ hybridization in acquired immune deficiency syndrome-related high grade and anaplastic large cell CD30+ lymphomas

Am J Clin Pathol

High frequency of Epstein-Barr virus latent membrane protein-1 expression in AIDS-related Ki-1 (CD30)-positive anaplastic large cell lymphomas

Am J Clin Pathol

Human herpesvirus 6: A survey of presence and variant distribution in normal and peripheral lymphocytes and lymphoproliferative disorders

J Infect Dis

Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS

Science

Original contribution
Immunophenotypic and molecular analyses of acquired immune deficiency syndrome-related and Epstein-Barr virus-associated lymphomas: A comparative study☆

Demonstration of Epstein-Barr viral genomes by in situ hybridization in acquired immune deficiency syndrome-related high grade and anaplastic large cell CD30⁺ lymphomas