Differentiating HIV-associated non-Hodgkin's lymphomas with similar plasmacellular differentiation.

AuthorPantanowitz, Liron
PositionLEADING ARTICLE - Report

INTRODUCTION

AIDS-related lymphomas (ARL) are divided by the World Health Organization (WHO) [1] into three main categories:

* Lymphomas also occurring in immunocompetent patients e.g. Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL);

* Lymphomas occurring more specifically in HIV-infected patients e.g. primary efFusion lymphoma (PEL), plasmablastic lymphoma and lymphoma arising in HHV8-associated multicentric Castleman's disease;

* Lymphomas also occurring in other immunodeficiency states e.g. polymorphic B-cell lymphomas.

ARL display clinical, phenotypic and molecular heterogeneity [2-8]. However, many show evidence of similar plasmacellular differentiation [4,9]. ARL that take on a plasmacytoid appearance contain lymphoma cells with moderate amounts of basophilic cytoplasm, have eccentric nucleolated nuclei, and occasionally an identifiable perinuclear hof. Plasmacytoid lymphoma cells characteristically lose their B-cell (or T-cell) markers and acquire plasma cell markers. The ensuing difficulty in accurately diagnosing this group of similar ARL frequently translates into management difficulties. Moreover, because of these similarities there has been much confusion in the literature, especially with the emergence of new entities such as plasmablastic lymphoma, extracavitary (solid) variant of PEL, and polyclonal lymphoma [10, 11]. The new WHO classification (of tumours of haematopoietic and lymphoid tissues) divides DLBCL into: (a) those lymphomas not otherwise specified (NOS), such as immunoblastic lymphoma (IBL); (b) specific lymphoma subtypes, like primary DLBCL of the central nervous system (CNS); (c) other variant lymphomas with large B-cells, including plasmablastic lymphoma and PEL; and (d) borderline (unclassifiable) B-cell lymphoma cases, like those that have features intermediate between DLBCL and Burkitt's lymphoma (previously classified as Burkitt-like lymphoma) [12]. New concepts have also materialised, such as the development of microlymphomas from Castleman's disease into frank plasmablastic lymphomas. This article reviews the literature pertaining ro those ARL that share a common plasmacellular differentiation, and underscores the diagnostic clinicopathological features (Table 1) that can be used to help distinguish between them.

LYMPHOMAGENESIS

Plasma cells are a cellular product of the germinal centre cell reaction and central to humoral immunity. Plasma cells typically mature from antigen-stimulated naive B-cells (CD45+, CD20+) after passing through a germinal centre (Figure 1). When naive B-cells (BCL6-, MUM1-, CD 138-) enter the germinal centre, they become centroblasts (BCL6+, MUM1-, CD138-) that subsequently mature into centrocytes (BCL6+, MUM1-, CD138+) as they undergo immunoglobulin class switching, somatic hypermutation of the immunoglobulin variable genes and mutations of the proto-oncogene BCL6. B-cells that exit the germinal centre begin to differentiate into memory B-cells or plasma cells (BCL6-, MUM1+, CD138+). As BCL6 and PAX5 (master regulators of the germinal centre cell reaction and the B-cell transcriptional programmes, respectively) expression declines, the synthesis of other markers indicative of plasmacellular differentiation including multiple myeloma oncogene-1 (MUM1 or interferon regulatory Factor 4), VS38c, CD38 and CD138 (syndecan-1) increases [5], There is also a concomitant change from surface to cytoplasmic immunoglobulin expression, a reduction in CD45 (leukocyte common antigen or LCA) and CD20 expression in plasma cells. Various ARL may arise from transformed B-cells at the pre-germinal centre, follicular centre, or post-germinal centre stage during this differentiation process. The expression of BCL6, MUM1 and CD138 in these lymphomas corresponds to the stage from which they are thought to develop [13,14]. For example, Burkitt's lymphoma and DLBCL develop from follicular centre B-cells while plasmablastic lymphoma and most cases of PEL arise from post-germinal centre B-cells. Superimposed on this model are molecular events (e.g. MYC activation and p53 inactivation), aberrant somatic hypermutation resulting in mutations of one or more proto-oncogenes (e.g. c-MYC, PAX5, PIM1, RhoH/TTF) [15], and co-infection with Epstein--Barr virus (EBV) and human herpesvirus 8 (HHV8). Moreover, cytokines and highly active antiretroviral therapy (HAART) may further modify lymphomagenesis.

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GAMMA-HERPESVIRUSES

EBV and Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) are members of the gamma-herpes virus subfamily. As is the case with all herpesviruses, their life cycle includes both latent and lytic phases. Both viruses establish persistent latent infection in lymphocytes, which contributes to the transformation process, and helps drive cell proliferation and escape from immune attack [16-22]. Latency is characterised by persistence of the viral genome, restricted virus expression of latent gene products that alter cell growth and proliferation, and retained potential for reactivation to lytic replication. The percentage of ARL cases with these viral infections is variable (Table 1). The 172-kbp EBV genome encodes approximately 100 genes, 10 of which ale expressed during latency including six nuclear proteins (EBNAs 1, 2, 3A, 3B, 3C and LP), two latent membrane proteins (LMP1 and -2), and two EBV-encoded RNAs (EBERs 1 and 2). HHV8, a rhadinovirus, has a 165-kbp genome with more than 80 open reading frames. HHV8 genes encode numerous proteins that are homologous to cell-signalling and regulatory-pathway proteins, such as viral interleukin-6 (vIL-6) and D-type cyclin homologue (vcyc). While in latency, HHV8 exists as circular episomal DNA and expresses limited gene products, including LANA-1 (or LNA-1).

BURKITT'S LYMPHOMA

Burkitt's lymphoma accounts for up to 30% of HIV-associated lymphomas [10]. It typically develops in the setting of mild immunodeficiency (CD4+ T-cell count > 200 cells/[mm.sup.3]). HIV-positive persons may develop classical and less frequently atypical Burkitt's lymphoma, as well as Burkitt's lymphoma with plasmacytoid differentiation (Figure 2), which is relatively unique to patients with AIDS [1], Those Burkitt's lymphomas with predominantly plasmacytoid features account for up to two-thirds of ARL [1]. These lymphomas frequently involve the leptomeninges (Figure 3), bone marrow (Figure 4) and peripheral blood. In Africa, HIV-related Burkitt's lymphoma presents with usual facial as well as extrafacial (mainly lymphadenopathy) tumours [23]. A high proliferation index is typical, with >90% of cells staining positive for Ki-67 (Mib-1). Lymphoma cells are medium-sized, non-cleaved lymphocytes that have a deeply basophilic cytoplasm, lipid vacuoles and several nucleoli. In the plasmacytoid variant, lymphoma cells have a more basophilic cytoplasm with an eccentric nucleus and single central nucleolus. They are positive for B-cell-associated antigens (CD19, CD20), CD10 and BCL6, in keeping with a germinal centre stage of differentiation. Frequently, there is also CD38 coexpression [24] and monotypic cytoplasmic immunoglobulin present. Cases with absent immunoglobulins have been noted [25]. All cases have MYC activation and p53 inactivation. ebv genomes can be demonstrated in 30% of classical, 30-50% of atypical, and 50-70% of plasmacytoid Burkitt's lymphomas [26]. EBV protein LMP1 is not expressed in Burkitt's lymphoma, but EBNA-1, which is necessary for the replication and maintenance of the latent viral episomal DNA, is found consistently in Burkitt cells [27]. No association has been found between Burkitt's lymphoma and HHV8 by immunohistochemical analysis, in situ hybridisation and PCRm[28].

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DIFFUSE LARGE B-CELL LYMPHOMA

Morphological variants of DLBCL (NOS) include:

(a) centroblastic lymphomas (comprising centroblasts with several nuclear membrane-bound nucleoli);

(b) immunoblastic lymphomas (IBL) that, by convention, must contain at least 90% immunoblasts (which have single, central, prominent nucleoli); and (c) CD30+ LBCL with anaplastic features (or histology). Centroblastic lymphomas represent 25-30% of ARL, whereas IBL constitute 10% of ARL [26]. While IBL typically present with advanced HIV disease (CD4+ T-cell count

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PLASMABLASTIC LYMPHOMA

Plasmablastic lymphoma is a unique ARL that was first described in the jaws and oral cavity (Figure 6) of HIV-infected persons [32-35]- Since then, it has been reported to occur in several other extranodal sites such as the lung [36], mediastinum [37], oesophagus [38], anorectum [39,40], nose and paranasal sinuses [41], skin [42-44], orbit [45], testes and bone [46], breast [47], as well as within long-standing sacrococcygeal cysts [48] in HIV-positive individuals. Nodal involvement occurs but is uncommon [49]. Sinister presentations like spinal cord compression as a result of widespread lymphoma have been reported [50]. While this lymphoma arises mainly in adult HIV-infected males, rare cases involving children has been reported [51,52]. Reactive lymphoid infiltrates in HIV-positive individuals that mimic plasmablastic lymphoma have also been described [53]. Like Burkitt's lymphoma, plasmablastic lymphoma is a rapidly growing destructive tumour [54-56]. The proliferation index ranges from >60% to 95% [57]. They may also evolve into plasmablastic leukaemia in HIV-infected individuals [58]. Only a few cases have been reported with good outcomes after the use of HAART [37,52,59]. Microscopically, they consist of plasmablasts (Figure 7) that have abundant basophilic cytoplasm, eccentrically placed nuclei and occasional perinuclear clearing [60]. Tingible-body macrophages (akin to the 'starry sky' appearance seen with Burkitt's lymphoma) and mitotic figures indicative of a high-grade lymphoma are readily seen [39,61,62]. Based upon data from a recent review of 112 cases [52] of...

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