Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma

Abstract

We investigated age-related EBV(+) B-cell lymphoproliferations in the Western population. The clinical features, histology, immunophenotype, EBV-encoded RNA in situ hybridization, and clonality by PCR of T-cell receptor gamma and immunoglobulin genes were categorized in 122 EBV(+) lesions as follows: (1) reactive lymphoid hyperplasia; (2) polymorphic extranodal or (3) polymorphic nodal lymphoproliferative disease (LPD); and (4) diffuse large B-cell lymphoma (DLBCL). Interphase FISH for IG and PAX5 gene rearrangements was performed on 17 cases of DLBCL. The overall median age was 75 years (range, 45-101 years; 67 men, 55 women), and 67, 79, 73, and 77 years, respectively, for groups 1 through 4. Sixteen of 21 cases of polymorphic extranodal LPD were classified as EBV(+) mucocutaneous ulcer. PCR for immunoglobulin genes was polyclonal in reactive lymphoid hyperplasia (84%) and monoclonal in 33%, 63%, and 56% of polymorphic extranodal and nodal LPD cases and DLBCL, respectively. All groups showed restricted/clonal T-cell receptor responses (27%-70%). By FISH, 19% of DLBCLs showed IGH@ rearrangements, but PAX5 was unaffected. Disease-specific 5-year survival was 100%, 93%, 57%, and 25% for groups 1-4, respectively, and 100% for patients with EBV(+) mucocutaneous ulcer. Disease volume was predictive of therapy response (P = .0002), and pathologic subtype was predictive of overall outcome (P = .001). Age-related EBV(+) B-cell LPD encompasses a wider disease spectrum than previously recognized and includes both reactive and neoplastic conditions. Reduction in the T-cell repertoire may contribute to decreased immune surveillance.

Figure 1

Histologic features of AR-EBVLPD. (A) Reactive follicular hyperplasia. (B) Reactive paracortical hyperplasia. (C) Plasma cell hyperplasia: monomorphic proliferation of uniform plasma cells. (D) Poly-N: polymorphous infiltrate comprising plasma cells, lymphocytes, and immunoblasts with occasional eosinophils. Occasional atypical HRS-like cells are noted (inset). (E) Poly-E–EBVMCU: well-circumscribed ulcerated lesion in oral mucosa with polymorphous infiltrate and HRS-like cells (inset). (F) DLBCL: “conventional” histologic picture with a diffuse proliferation of large mononuclear cells with centroblastic and immunoblastic features. Occasional pleomorphic cells are noted, but an inflammatory background is absent. (G) DLBCL: large numbers of HRS-like cells are present. (H) Plasmablastic lymphoma: the cells show basophilic cytoplasm and most have prominent nuclei (H&E; original magnifications, ×20 (B,E); ×40 (A); and ×400 (C,D,F-H and insets).

Figure 2

Immunohistochemical features and EBER in situ hybridization of AR-EBVLPD. (A-F) Poly-N with prominent HRS-like cells. (A) Reduced expression of CD20. (B) The HRS-like cells are CD30⁺. There is nuclear expression of PAX5 (C), Oct.2 (D), and BOB1 (E). (F) Occasional cells are positive for CD15. (G) Reactive follicular hyperplasia. Germinal center shows intense EBER positivity. (H) Reactive paracortical hyperplasia. There is paracortical/interfollicular distribution of EBER⁺ cells. (I) EBVMCU. Note superficial distribution of EBER⁺ cells. (J) Poly-N. High concentration of EBER⁺ cells. (K) Poly-E. Arterial wall infiltrated by EBER⁺ B cells. Original magnifications, ×20 (I); ×40 (G-H); ×100 (J-K); ×400 (A-E); and ×600 (F).

Figure 3

PCR for IG and TRG@ gene rearrangements. (A) The majority of the cases of RH were polyclonal for IG gene rearrangements (84%); Poly-E, Poly-N, and DLBCL showed clonal IG gene rearrangements in 33%, 63%, and 56% of cases, respectively. (B) 27% of cases with RH had monoclonal TRG@ gene rearrangements and no restricted T-cell responses; Poly-E, Poly-N, and DLBCL showed clonal TRG@ gene rearrangements in 50%, 24%, and 15% of cases, respectively; Poly-E, Poly-N, and DLBCL showed restricted T-cell responses in 20%, 9%, and 15% of cases, respectively.

Figure 4

Examples of FISH with LSI IGH and IGL break-apart probes performed on case 18 (A) and case 42 (B), respectively. Note a split of IGH signals indicative of t(14q32/IGH) in panel A and copy number changes of IGL in panel B.

Figure 5

Kaplan-Meier survival curves. Curves are shown for (1) RH (Reactive), (2) Poly-E, (3) EBVMCU (MCU), (4) Poly-N, and (5) DLBCL. (A) Overall survival for groups 1, 2, 4, and 5. (B) Overall survival for groups 1-5. (C) Disease-related mortality for groups 1, 2, 4, and 5. (D) Disease-related mortality for groups 1-5. Plots for Reactive and MCU overlap in panel D.