Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology

Abstract

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed. The second half of the session focused on mediastinal and non-mediastinal gray zone lymphomas (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). Several cases illustrating the current challenges in separating this entity from PMBL/DLBCL and CHL were presented. There was discussion regarding the clinical and genetic differences between mediastinal and non-mediastinal GZLs. Rare cases of PMBL and GZL associated with EBV or follicular lymphoma were reviewed. Finally, several cases included in the session highlighted composite or sequential CHL and PMBL/DLBCL and/or GZL, highlighting challenges in separating such cases from GZL.

Keywords: B cell lymphoma, Unclassifiable, with features intermediate between diffuse large B cell lymphoma and classic Hodgkin lymphoma; Classic Hodgkin lymphoma; Composite lymphoma; Gray zone lymphoma; Mediastinal gray zone lymphoma; Primary mediastinal large B cell lymphoma.

Fig. 1

Immunophenotype and Lymph3Cx analysis of 10 Workshop cases with features of classic PMBL. The figure illustrates the immunophenotype of each classic PMBL case, as well as the results of Lymph3Cx analysis. Abbreviations: No., number; PMBL-sig, primary mediastinal large B-cell lymphoma gene expression signature; Unclear-sig, unclear diffuse large B-cell lymphoma versus primary mediastinal large B-cell lymphoma gene expression signature

Fig. 2

Mediastinal B-cell lymphomas challenging the diagnostic border between PMBL and DLBCL (cases 489, 162, and 264). Case 489 showed centroblastic cytology (A), extensive necrosis (B), and only focal CD30 (C) and CD23 (D) expression. Case 162 demonstrated features reminiscent of a T cell/histiocyte-rich LBCL (E–F), with expression of CD79a (G) and CD30 (H). Case 264 showed immunoblastic and plasmacytoid cytology (I). The neoplastic cells were positive for CD20 (J), with kappa light chain restriction (K), rare CD30 expression (L), and showed diffuse Golgi/dot-like staining for CD15 (M)

Fig. 3

Extramediastinal transformed FL with a PMBL gene expression signature (case 193). Grade 3A of 3 FL (A) with a component of LBCL (B). The large B cells expressed CD10 (C), CD23 (D), and MAL (E)

Fig. 4

Immunophenotype and Lymph3Cx analysis of 20 Workshop cases submitted as GZL. Sixteen MGZLs (15 EBV negative and one (case 654) EBV positive) (A) and four EBV-negative non-mediastinal cases (B) are illustrated. The morphologic classification of these cases into CHL-like/LYSA groups 0–1 or LBCL-like/LYSA groups 2–3 is included. Abbreviations: DLBCL-sig, diffuse large B-cell lymphoma gene expression signature; No., number; PMBL-sig, primary mediastinal large B-cell lymphoma gene expression signature; Unclear-sig, unclear diffuse large B-cell lymphoma versus primary mediastinal large B-cell lymphoma gene expression signature

Fig. 5

Next-generation sequencing analysis of 16 workshop cases submitted as GZL. Alterations found in 12 MGZLs [11 EBV negative and one (case 654) EBV positive] and four non-mediastinal cases are included. The 20 most common genes with alterations are illustrated. Abbreviations: CHL, classic Hodgkin lymphoma; LBCL, large B-cell lymphoma; No., number; TMB, tumor mutational burden

Fig. 6

EBV-negative MGZLs with CHL-like features (cases 701, 317, and 751). Case 701 showed a vaguely nodular proliferation with focal fibrotic bands (A) reminiscent of CHL (B). The neoplastic cells demonstrated strong expression of CD20 (C) and CD79a (D), with moderate expression of OCT2 (E). Rearrangements of BCL2 and BCL6 genes were not detected by FISH in this case and Lymph3Cx analysis provided an unclear GE. Case 317 demonstrated a vaguely nodular proliferation of pleomorphic large cells, with some areas more closely resembling CHL (F), LBCL (G), or with transitional features. The neoplastic cells showed strong CD30 (H) and PAX5 (I) expression, and positivity for CD20 (J) and OCT2 (K). Lymph3Cx analysis showed a PMBL GE signature. Case 751 showed a diffuse growth (L), with some areas more closely resembling CHL (M), and other areas resembling LBCL, including clearly centroblast-like cells (N). The lymphoma demonstrated strong positivity for CD30 (O) and CD15 (P). Lymph3Cx analysis provided a PMBL GE signature

Fig. 7

EBV-negative GZLs with LBCL-like features (cases 332 and 774). Case 332 showed a vaguely nodular (A) proliferation of predominantly large mononuclear cells that had pale/clear cytoplasm (B). The neoplastic cells were diffusely positive for CD45 (C), CD30 (D), and PAX5 (E), while few were positive for CD15 (F), and they were negative for OCT2 (G) and CD20 (H). Lymph3Cx analysis showed a DLBCL GE signature and sequencing demonstrated mutations in BCL2 and TP53. FISH studies showed no rearrangements of MYC, BCL2, or BCL6. Case 774 demonstrated a diffuse infiltrate of predominantly large mononuclear cells (I), with some showing HRS features (J). The neoplastic cells were strongly positive for CD30 (K) and CD15 (L), PAX5, at moderate to strong intensity (M), and were negative for OCT2 (N). RT-MLPA analysis was consistent with a PMBL GE signature, while Lymph3Cx analysis showed an unclear result

Fig. 8

EBV-positive MGZL (case 654) and PMBL (case 452). Case 654 showed GZL-like morphology (A), strong positivity for CD20 (B) and CD30 (C), negativity for CD15 (D), and diffuse EBER positivity (E). Case 452 demonstrated a morphology (F) and immunophenotype compatible with PMBL, showing expression of CD30 (G), CD23 (H), and PDL1 (I), in addition to diffuse EBER (J) staining