Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist

Abstract

Peripheral T-cell lymphomas (PTCLs) are functionally and morphologically complex. Epstein-Barr virus (EBV)-positive B cells have been reported in angioimmunoblastic T-cell lymphoma (AITL) and other PTCLs and may mimic Hodgkin/Reed-Sternberg (HRS) cells, but EBV-negative HRS-like B cells have not been described. We wished to assess the nature of the PTCL associated with HRS-like cells and to determine whether EBV-negative HRS-like cells may be seen. We identified 57 PTCL cases reported as containing HRS-like cells. These included 32 AITL, 19 PTCL, not otherwise specified (NOS), 3 PTCL-NOS, follicular variant, 1 PTCL-NOS, T-zone variant, and 2 adult T-cell leukemia/lymphoma cases. All patients were adults with a median age of 63 and presented with lymphadenopathy. The male:female ratio was 31:26 (1.2:1). Clonal TRG rearrangement was detected in 46/53 cases. Six of 38 cases had a concomitant clonal immunoglobulin gene rearrangement. In 52/57 cases the HRS cells were positive for EBV. Five cases, 3 classified as AITL and 2 as PTCL-NOS, follicular variant, contained HRS-like cells negative for EBV. All PTCLs with EBV-negative HRS cells had a T follicular helper cell immunophenotype. The neoplastic T cells expressed CD3, CD4, and PD-1 and formed rosettes around the HRS-like cells. The HRS-like cells were positive for CD20 (variable intensity), PAX5, CD30, and CD15 (4/5). We conclude that both EBV-positive and EBV-negative HRS-like B cells may occur in the background of PTCL; caution is needed to avoid misdiagnosis as classical Hodgkin lymphoma. The close interaction between the HRS-like cells and the rosetting PD-1-positive T cells suggests a possible pathogenetic role in this phenomenon and provides new insights into the abnormal B-cell proliferations that occur in the context of TFH malignancies.

Figure 1

Angioimmunoblastic T-cell lymphoma with EBV-positive Hodgkin-Reed Sternberg-like cells. A. A large multinucleate cell is seen in a background of atypical lymphoid cells. B. CD3 highlights the cytologic atypia in the T-cells and presence of rosettes around Hodgkin-Reed Sternberg-like cell (upper left corner). C. T-cell rosettes are positive for CD10. D. Expanded CD21-positive follicular dendritic meshworks surround multinucleated cells (upper left corner). The Hodgkin-Reed Sternberg-like cells show strong membrane positivity for CD30 (E), CD15 (F), weak nuclear staining for PAX5 (G) and EBER positivity (H).

Figure 2

Angioimmunoblastic T-cell lymphoma with EBV-negative Hodgkin-Reed Sternberg-like cells (cases 1 and 2). A. Effaced lymph node with paracortical expansion and preserved and dilated peripheral cortical sinus. B. Polymorphous infiltrate composed of pleomorphic cells with uni or multilobated nuclei and prominent nucleoli, resembling Hodgkin-Reed Sternberg cells admixed with medium sized atypical lymphocytes. C. Dilated subcapsular sinus with atypical Hodgkin-Reed Sternberg-like cells (detail in inset) D. Hodgkin-Reed Sternberg-like cells (detail in inset) are embedded in expanded CD21-positive follicular dendritic cell meshworks. They are positive for CD30 (E), CD15 (F), variably positive for CD20 (G inset), weakly positive for PAX5 (H), but negative for EBER (I). G. CD20 stain shows also marginalized B-cell areas in the far cortex. The Hodgkin-Reed Sternberg-like cells are rosetted by neoplastic T-cells positive for CD3 (J), PD-1 (K), CD10 (L). M. HRS-cells are negative for Bcl-6, which stains some background T-cells. (A, B, C, F, G, H, K, L M – case 1; D, E I, J –case 2)

Figure 3

Peripheral T-cell lymphoma not otherwise specified, follicular variant, with Hodgkin-Reed Sternberg-like cells, EBV negative (case 4 and 5). A. The nodal architecture is altered by multiple irregular, disrupted follicles. B. Pale cluster of small-medium sized T-lymphocytes within the large nodule. C. Pleomorphic mono or binucleate Hodgkin-Reed Sternberg-like cells are seen amidst atypical T-cells (detail in inset). Hodgkin-Reed Sternberg-like cells strongly express CD30 (Da), CD15 (Db), weakly CD20 (Dc) and are negative for EBER (Dd). They are also weak positive for PAX5 (E inset). PAX5 (E) and CD21 (F) show the moth eaten appearance of nodules created by the atypical T-cell clusters positive for CD3 (G) and CD4 (H). Hodgkin-Reed Sternberg-like cells are rosetted by CD3 (G) and CD4 (H inset) positive T-cells. (A, B, C, E, F – case 4; D, G, H - case 5).

Figure 4

Features of neoplastic T-cells in cases of PTCL, follicular variant, with EBV-negative HRS-like cells. A. CD3 immunostain highlights a large aggregate of atypical T-cells showing variation in nuclear size and shape. B. Several nodules of atypical T-cells are highlighted by PD-1 immunostain. Two nodules on right contain HRS-like cells. C. Many of the atypical T-cells are positive for CD10, with some rosetting HRS-like cells. D. Similarly, the atypical T-cells are positive for Bcl-6, while HRS-like cell is negative. The large size of the T-cell aggregates, and the atypical immunophenotype (CD10-posiitve, Bcl-6-positive, strong and uniform PD-1) are clues against the diagnosis of lymphocyte-rich CHL. (A, B, C – case 4; D – case 5).

Figure 5

PCR studies of PTCL-NOS, follicular variant, containing HRS-like cells (Case 5). TRG PCR identifies two identical peaks, consistent with a clonal rearrangement in all three specimens tested: soft tissue 2011 (A), inguinal lymph nodes 2006 (B) and 2004 (C). This confirms that the same disease process is present in different sites and at different time points at molecular level. Color code of interrogated joining segments of TCR locus: black – J1/2; green – JP1/2 and blue – JP.