B-Cell and Classical Hodgkin Lymphomas Associated With Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 2

Abstract

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency.

Methods: Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings.

Results: Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings.

Conclusions: Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints.

Keywords: 9p24; Autoimmunity; Classical Hodgkin lymphoma; Iatrogenic immunodeficiency; Large B-cell lymphoma; Marginal zone lymphoma; PD-L1; Posttransplant lymphoproliferative disorder; Primary immunodeficiency; T-cell/histiocyte-rich B-cell lymphoma.

Image 1

Primary cutaneous extranodal marginal zone lymphoma. Case SH2015-116 (Dr Gong, National Cancer Institute) of a 70-year-old male patient with multiple skin lesions exemplifies a primary cutaneous extranodal marginal zone lymphoma in the immunodeficiency setting (immune senescence related) with a spectrum of small lymphocytes to plasma cell differentiation (A-C, CD79a; A, x4; B and C, x10). EBV-encoded small RNA (EBER) is positive in up to 50% of neoplastic cells (D, EBER, x10).

Image 1

Primary cutaneous extranodal marginal zone lymphoma. Case SH2015-116 (Dr Gong, National Cancer Institute) of a 70-year-old male patient with multiple skin lesions exemplifies a primary cutaneous extranodal marginal zone lymphoma in the immunodeficiency setting (immune senescence related) with a spectrum of small lymphocytes to plasma cell differentiation (A-C, CD79a; A, x4; B and C, x10). EBV-encoded small RNA (EBER) is positive in up to 50% of neoplastic cells (D, EBER, x10).

Image 2

The morphologic spectrum of nodal B-cell lymphomas with plasma cell differentiation. Case SH2015-6 (Dr Wang, Cincinnati Children’s Hospital Medical Center) illustrates the spectrum of indolent B-cell proliferations with plasmacytic differentiation. In a 17-year-old male patient with iatrogenic immunodeficiency, a gastric lesion shows features consistent with extranodal marginal zone lymphoma (A, B, CD79a; C, EBV-encoded small RNA [EBER]).

Image 2

The morphologic spectrum of nodal B-cell lymphomas with plasma cell differentiation. Case SH2015-6 (Dr Wang, Cincinnati Children’s Hospital Medical Center) illustrates the spectrum of indolent B-cell proliferations with plasmacytic differentiation. In a 17-year-old male patient with iatrogenic immunodeficiency, a gastric lesion shows features consistent with extranodal marginal zone lymphoma (A, B, CD79a; C, EBV-encoded small RNA [EBER]).

Image 3

The morphological spectrum of large B-cell proliferations. Case SH2015-116 (Dr Thibodeaux, University of Pennsylvania) of an 83-year-old female patient shows a lesion with morphology of Hodgkin-type tumor cells in a Hodgkin-type background (A-C). The tumor cells express a complete B-cell phenotype but also CD15 (D) and fascin (E).

Image 3

The morphological spectrum of large B-cell proliferations. Case SH2015-116 (Dr Thibodeaux, University of Pennsylvania) of an 83-year-old female patient shows a lesion with morphology of Hodgkin-type tumor cells in a Hodgkin-type background (A-C). The tumor cells express a complete B-cell phenotype but also CD15 (D) and fascin (E).

Image 4

Examples of PD-L1 and PD-L2 protein expression and 9p24.1 genetic alterations by fluorescent in situ hybridization analysis. Low-level copy gain (polysomy; A) in a case of diffuse large B-cell lymphoma (DLBCL), immune senescence–related, Epstein-Barr virus (EBV)–positive (SH2015-192) expression of PD-L1 protein (B) and lack of PD-L2 protein (C) by immunohistochemistry. High-level copy gain (D) in a case of DLBCL, posttransplant, EBV+ (SH2015-286) expression of PD-L1 protein in a subset of PAX5+ large atypical B cells (PD-L1, brown; PAX5, pink; E) and expression of PD-L2 protein (F) by immunohistochemistry.

Image 4

Examples of PD-L1 and PD-L2 protein expression and 9p24.1 genetic alterations by fluorescent in situ hybridization analysis. Low-level copy gain (polysomy; A) in a case of diffuse large B-cell lymphoma (DLBCL), immune senescence–related, Epstein-Barr virus (EBV)–positive (SH2015-192) expression of PD-L1 protein (B) and lack of PD-L2 protein (C) by immunohistochemistry. High-level copy gain (D) in a case of DLBCL, posttransplant, EBV+ (SH2015-286) expression of PD-L1 protein in a subset of PAX5+ large atypical B cells (PD-L1, brown; PAX5, pink; E) and expression of PD-L2 protein (F) by immunohistochemistry.

Figure 1

Overlapping morphologic and immunohistochemical features of nodal polymorphic B-cell lymphoproliferative disorder (B-LPD) (as discussed in Part 1 of the workshop report) and nodal marginal zone lymphoma (MZL), listing examples across all immunodeficiency settings.

Figure 2

Large B-cell lymphomas in immunodeficiency states form a spectrum with arbitrary boundaries. The figure illustrates the overlapping features between diffuse large B-cell lymphoma (DLBCL), T-cell–rich B-cell lymphoma (TCRBCL), and classical Hodgkin lymphoma (CHL). While at the extremes of the spectrum, the morphology and immunophenotype of the tumor cells and the composition of the reactive infiltrate may be typical and comparable to the corresponding entities in immunocompetent patients; however, frequently, discordant features are present in immunodeficient patients, precluding unequivocal classification.