PD-L1 status in refractory lymphomas

Abstract

Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (!5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/ JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL.

Immunohistochemical assessment of the diagnostic utility of PD‐L1: a preliminary analysis of anti‐PD‐L1 antibody (SP142) for lymphoproliferative diseases with tumour and non‐malignant Hodgkin–Reed‐Sternberg (HRS)‐like cells

“…In concordance with previous reports . robust PD‐L1 expression was found in the large tumour cells in many (70%) CHL cases, including all (100%) EBV‐negative NSCHL and EBV + CHL.…”

“…A case was considered to have a microenvironment positive for PD‐L1 if ≥20% of the total tissue cellularity showed moderate or strong membrane or cytoplasmic staining in malignant and/or non‐malignant cells. The threshold used here is comparable to that from a prior publication involving the same clone antibody . To assess reproducibility, four pathologists (authors A.S., K.K., A.S. and S.N.)…”

“…In lymphoid malignancies, PD‐L1 expression is detected variably not only in lymphoma cells but also in the immune cells of the microenvironment, best exemplified by tissue macrophages . Of note, previous studies have shown that PD‐L1 was expressed frequently in classical (C) Hodgkin lymphoma (HL), primary mediastinal large B cell lymphoma and Epstein–Barr virus (EBV)‐associated lymphomas, including EBV + diffuse large B cell lymphoma (DLBCL) of not otherwise specified (NOS) type and extranodal natural killer (NK)/T cell lymphoma of nasal type (EBV + ) in the World Health Organisation (WHO) 2016 classification .…”

“…Thus, these three diseases often pose a differential diagnostic problem for pathologists because of their shared tumour and non‐malignant Hodgkin–Reed‐Sternberg (HRS)‐like large B cells, which are now regarded as a diagnostic hallmark and also a pitfall in routine practice. We recently documented that non‐malignant HRS‐like large B cells in nodal PTCL‐TFH lack PD‐L1 expression, which appear to contrast with its high‐frequency expression in tumour cells of CHL and EBV + DLBCL–NOS . This finding led us to investigate the usefulness and applicability of PD‐L1 immunohistochemistry in malignant lymphomas/lymphoproliferative disorders (LPDs) sharing HRS‐like large cells with and without EBV association.…”

Autopsy case report of intravascular large B-cell lymphoma with neoplastic PD-L1 expression

“…In parallel, studies have focused on analyzing of the PD1/ PD-L1 axis for prognostic relevance and prediction of treatment response. 4,[6][7][8][9][10] With regards to lymphoid malignancies, tumor cell PD-L1 expression is frequently reported in classic Hodgkin lymphoma (CHL), primary mediastinal large B-cell lymphoma, and Epstein-Barr virus (EBV)-associated lymphomas, including EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) type, and extranodal NK/T-cell lymphoma, nasal type 11 according to the WHO 2017 classification. 1 Moreover, a recent report describes a higher incidence of neoplastic PD-L1 overexpression in primary DLBCL of the CNS (PCNS-DLBCL) compared to systemic ordinal cases.…”