Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XIV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France

Abstract

The term "gray-zone" lymphoma has been used to denote a group of lymphomas with overlapping histological, biological, and clinical features between various types of lymphomas. It has been used in the context of Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL), including classical HL (CHL), and primary mediastinal large B cell lymphoma, cases with overlapping features between nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B cell lymphoma, CHL, and Epstein-Barr-virus-positive lymphoproliferative disorders, and peripheral T cell lymphomas simulating CHL. A second group of gray-zone lymphomas includes B cell NHL with intermediate features between diffuse large B cell lymphoma and classical Burkitt lymphoma. In order to review controversial issues in gray-zone lymphomas, a joint Workshop of the European Association for Hematopathology and the Society for Hematopathology was held in Bordeaux, France, in September 2008. The panel members reviewed and discussed 145 submitted cases and reached consensus diagnoses. This Workshop summary is focused on the most controversial aspects of gray-zone lymphomas and describes the panel's proposals regarding diagnostic criteria, terminology, and new prognostic and diagnostic parameters.

Keywords: European Association for Hematopathology; Gray zone lymphoma; Society for Hematopathology; Workshop.

Fig. 1

a Burkitt lymphoma. Note the typical morphology of BL cells and the starry-sky pattern. b DLBCL. The morphology of this case is consistent with a diagnosis of DLBCL. In case of an appropriate immunophenotype and genetic background, a diagnosis of (atypical) Burkitt lymphoma with plasmacytoid differentiation may be considered. The case illustrates the morphological overlap between BL and DLBCL. c–g Cytological features and immunophenotype of BL. Note the strong positivity of the tumor cells for CD10 (c) and BCL6 (d). The proliferation rate is almost 100% as demonstrated by MIB-1 staining (e). The cytological features are characteristic of BL (f). BCL2 is negative on tumor cells in the presence of positive T cells as internal control (g). h In contrast, note the strong BCL2 positivity, suspicious of dual translocation (double hit). i Session 1, interphase FISH showing MYC trisomy and possibly amplification (IGH green, MYC red). j Session 1, BCL6 dual-color break apart FISH showing a BCL6 break. k Session 1, complex karyotype with multiple structural alterations, amplifications, and deletions. l Session 1, simple karyotype, only showing t(8;14) and trisomy 12

Fig. 2

a–d Session 2, case 38: A typical example of a primary mediastinal large B cell lymphoma arising from the thymus (a). Session 2, case 27 illustrates a primary mediastinal B cell lymphoma with large pleomorphic cells embedded within a background of sclerosis (b) that expresses CD20 (c) and CD30 (d) but lacks expression of CD15. e–i Session 2, case 1 shows a mediastinal “gray-zone” lymphoma demonstrating histologic features typical of primary mediastinal large B cell lymphoma (e) but with an atypical immunophenotype with expression of weak CD30 (f) and moderate to strong CD15 (g). The lack of CD20 among the large atypical cells (h) favors classical Hodgkin lymphoma whereas strong expression of PAX5 (i) favors a large B cell lymphoma

Fig. 3

a, b Session 2, case 11 represents an example of a composite lymphoma and illustrates distinct areas resembling classical Hodgkin lymphoma and primary mediastinal B cell lymphoma. The classical Hodgkin-like areas exhibit large atypical cells with Reed-Sternberg cell morphology (a), whereas the primary mediastinal B cell lymphoma-like areas show sheets of large atypical cells embedded in a fibrotic stroma (b). c–i Session 2, case 20 shows an example of classical Hodgkin lymphoma with aberrant T cell marker expression. The large Reed-Sternberg-like cells (c) express multiple T-lineage markers including CD3 (d), CD5 (e), and CD4 (f), in addition to weak expression of the B cell transcription factor PAX5 (g)

Fig. 4

a–d Session 3, case 01: NLPHL. Lymph node with NLPHL with a characteristic nodular growth pattern (a). LP cells (a, insert) are strongly positive for CD20 and embedded in a background rich in small B cell lymphocytes (b). The LP cells are surrounded by reactive CD57⁺ (c) and PD1⁺ (d) T cells. e–g Session 3, case 03: NLPHL with diffuse areas, depletion of background B lymphocytes and IgD⁺. NLPHL with diffuse growth pattern infiltrating a lymph node (e). Note that the background infiltrate of small B lymphocytes is reduced (f); however, rosetting of PD1⁺ reactive T cells around the LP blasts is present (f, insert). The LP cells are strongly positive for IgD (g). The IgD⁺ LP cells are surrounding the nodules of reactive small B lymphocytes. h–i Session 3, case 09: NLPHL with THRLBCL-like areas. CD20 staining highlights the LP cells with areas of very reduced (h) or complete loss of CD20⁺ small B lymphocytes mimicking THRLBCL (i). j–k Session 3, case 18: NLPHL with CD15 positivity. Typical case of NLPHL with LP cells positive for CD20 (j) showing unequivocal strong expression of CD15 in the LP tumor cells (k). l–n Session 3, cases 07 and 27: NLPHL EBV⁺. CD20 staining highlights the typical characteristics of NLPHL (l) where the LP cells are EBV⁺ by EBER ISH (m). Case 27 showed in addition progression to a DLBCL. Note that the high-grade component (left), as well as the LP cells (right) are EBER⁺ (s)

Fig. 5

a–d Session 3, case 10: THRLBCL of the spleen with micronodular involvement. Micronodular involvement of the white pulp of the spleen characterized by scattered large neoplastic B cells in a background of reactive T cells (a). CD20 expression highlights the abnormal infiltrating nodules compared to the normal white pulp (b). PD1-positive T cells are scattered and T cell rosettes around the large neoplastic B cells are absent (c). THRLBCL shows areas of progression to DLBCL (d). e–j Session 3, case 17: B cell lymphoma unclassifiable with features intermediate between DLBCL and CHL. Lymph node with a diffuse infiltration (e) and numerous large cells with typical RS cell morphology (f). The RS-like cells are negative for CD15 (f, insert), strongly and uniformly positive for CD20 (g), CD79a (h), Oct 2 (i), and EBER ISH (j). k–n Session 3, case 20: B cell lymphoma unclassifiable with features intermediate between DLBCL and CHL. Lymph node with vaguely nodular infiltration reminiscent of NLPHL but with numerous large cells with typical RS cell morphology (k). The RS cells are strongly and uniformly positive for CD20 (l), Oct 2 (m), and EBER ISH (n), in addition to CD15 and CD30 positivity

Fig. 6

a-f Session 4, case 03: EBV⁺ DLBCL of the elderly. The neoplastic population—provided with some HRS-like features—is admixed with a rich reactive T cell component (a) and expresses CD30 (b), CD20 (c), PAX5/BSAP (d), OCT-2 (e), and LMP1 (f). g–i Session 4, case 09: HIV-associated plasmablastic lymphoma. The neoplasm infiltrates the lachrymal gland (g; cytological details in the inset) and shows EBV integration (h) and Ig kappa monoclonality (i) at ISH. j–n Session 4, case 29: Extracavitary PEL in the absence of immunodeficiency. Lymphomatous cells vary in size and shape (from immunoblastic to plasmablastic; j), are negative for CD45 (k), express IRF4 (l), and turn positive for HHV8 LANA (m) and EBV (n). o–r Session 4, case 14: Monomorphic PTLD. The surgical specimen (colon) is characterized by multiple ulcers (o). The tumor consists of large cells with plasmablastic features (p) and does express LMP1 (q) and EBNA2 (r)

Fig. 7

a–d Session 4, case 24: LYG grade 3. The neoplastic growth shows angiocentricity and angioinvasiveness (a). At immunohistochemistry, lymphomatous cells express CD20 (b) and partly CD30 (b, inset) and are admixed with abundant CD3⁺ T lymphocytes (c). ISH reveals EBV integration (arrowed; d). e–h Session 4, case 16: EBV⁺ LPD mimicking DLBCL, leg type. The tumor infiltrates the deep dermis and subcutaneous tissue (e) and consists of large cells with plasmablastic features (f) that display high Ki-67 rate (g) and EBV integration at ISH (h). i–l Session 4, case 23: DLBCL associated with chronic inflammation (PAL). The lymphomatous population, showing immunoblastic/plasmablastic features (i), expresses CD20 (j), CD79a (k), and EBNA2 (l). m–p Session 4, case 32: HHV6⁺ THRLBCL. Scattered neoplastic cells (m) are comprised within a reactive population consisting of small lymphocytes and histiocytes (m). At immunohistochemistry, they express CD20 (n), are surrounded by CD3⁺ T lymphocytes (n, inset) and turn positive for the virus-associated antigen HIND (o). Electron microscopy shows viral particles consistent with HHV6 (p)