Primary Effusion Lymphoma: A Timely Review on the Association with HIV, HHV8, and EBV

Abstract

Primary effusion lymphoma (PEL) is defined by the WHO classification as a large B-cell neoplasm without detectable tumor masses. It is universally associated with HHV8, with most cases occurring in the setting of immunodeficiency such as HIV infection, and a poor prognosis. Morphologically, the neoplastic cells range from immunoblastic, plasmablastic, to anaplastic; and phenotypically, most cases express plasma cell but not B-cell markers, i.e., plasmablastic. During the past decade, primary HHV8-negative effusion lymphoma has been reported. Such cases were considered in the WHO classification scheme as effusion-based lymphoma. We performed a systemic review of 167 HHV8-negative effusion lymphomas from the literature and found that only 42% were associated with a fluid overload state, and with low rates of HIV (6%) or EBV (21%) infection. Furthermore, most patients are old (or immunosenescent) with underlying medical conditions/comorbidities, most neoplasms are of B-cell phenotype, and the outcome is more favorable than that of HHV8-positive PEL. These distinctive findings supported our prior proposal of designating these HHV8-negative cases as type II PEL, in contrast to the classic or type I PEL as defined by the WHO. Furthermore, we propose an algorithmic approach for the diagnosis of PEL and its mimickers.

Keywords: EBV; HHV8; HIV; effusion-based lymphoma; primary effusion lymphoma.

Figure 1

A case of HIV-unrelated, HHV8-positive primary effusion lymphoma occurring in a 72-year-old immunocompetent man who presented with bilateral pleural effusions. Cytological smears show large, atypical lymphocytes with centroblastic, immunoblastic, plasmablastic, and anaplastic morphology by Liu (a) and Papanicolaou (b) stains. Cell block section shows large, atypical lymphocytes with nucleoli and occasional binucleation ((c), H&E stain). Immunohistochemically, the atypical lymphocytes express CD30 (e), CD45, HHV8-LANA1 (h) and IRF4/MUM1 (g), but not CD3, CD19, CD20 (d), CD79a, CD138 (f), PAX5 or ALK. Ki-67 proliferation index is up to 70%. EBER in situ hybridization is negative (i). Primary effusion lymphoma is diagnosed. Serum HIV test is negative. The patient does not have underlying immunodeficiency ((a–c), ×1000; (d–i), ×400 magnification).

Figure 2

An example of HIV-unrelated, HHV8-negative (type II) PEL of plasmablastic type in a 61-year-old man who presented with left pleural effusion and ascites without solid tumor by CT scans. Cytological smears of the left pleural effusion and ascites show similar features of large, atypical lymphocytes with anaplastic morphology and intracytoplasmic vacuoles by Liu stain (a) and Papanicolaou stain (b). Cell block section shows large, atypical lymphocytes with occasional Hodgkin/Reed–Sternberg-like cells ((c), H&E stain). Immunohistochemically, the atypical lymphocytes express CD138 (f), EMA and IRF4/MUM1, but not CD3, CD19, CD20 (d), CD30, CD45, CD56, CD79a, PAX5 (e), HHV8-LANA1 (h), kappa, or lambda light chains. Ki-67 proliferation index is greater than 90% (g). EBER in situ hybridization is positive (i). Interphase fluorescence in situ hybridization reveals rearrangements of BCL2 and MYC, but not BCL6. Serum HIV assay is negative ((a–c), ×1000; (d–i), ×400 magnification).

Figure 3

An example of HHV8-negative type II PEL (or effusion-based lymphoma) of indeterminate (B-cell vs. plasmablastic) phenotype in a 59-year-old woman presenting with pleural effusion without hepatosplenomegaly or lymphadenopathy by CT scans. Cytological smears show large, atypical lymphocytes by Papanicolaou stain (a). Cell block section shows anaplastic cells and occasional Hodgkin/Reed–Sternberg-like cells ((b), H&E stain). Immunohistochemically, the atypical lymphocytes express BCL2 (d), BCL6, IRF4/MUM1 and MYC (e), but not CD3, CD10, CD20 (c), CD30, CD138, cyclin D1, or HHV8-LANA1. Ki-67 proliferation index is up to 70% (f). EBER in situ hybridization is negative ((a,b), ×1000; (c–f), ×400 magnification).

Figure 4

Algorithmic approach incorporating ancillary studies for the diagnosis of PEL. The initial step is the assessment of clinical history of concurrent lymphoma or lymphadenopathy to exclude secondary effusion lymphoma. The proposed initial panel for suspicious PEL includes one marker for each of B, T, and plasma cell lineages. After determining the cellular lineages (plasmablastic vs. B-cell phenotype), HHV8 immunostain and EBER should be performed in all cases of large cell-predominant lymphomatous effusion. When encountering indeterminate examples, a large panel of B, T, and plasma cell markers, as well as clonality assay will be helpful in determining cellular lineages. Careful clinicopathological correlation, including HIV infection, history of immunodeficiency, chronic pleural effusion, other medical conditions, and additional ancillary studies, is needed for the differential diagnosis of PEL with its mimickers. Abbreviations: Y; Yes, N; No.