Enhanced PD-L1 expression on tumor cells in primary CD30-positive cutaneous large T-cell lymphoma: a report of lymph node lesions of four cases

Abstract

Scarce data are available regarding neoplastic PD-L1 (nPD-L1, clone SP142) expression in cutaneous T-cell lymphoma. We recently documented a possible association of increased nPD-L1 expression with tumor progression to secondary nodal involvement in two cases of CD30-positive primary cutaneous large T-cell lymphoma (PC-LTCL) (Pathol Int 2020;70:804). Notably, the nodal sites exhibited classic Hodgkin lymphoma (CHL) mimicry related to both morphology and tumor microenvironment (TME), i.e., abundant PD-L1-positive tumor-associated macrophages and low-level PD-1 expression on T-cells. Immunohistochemistry highlighted distinctly different nPD-L1 positivity between the cutaneous and nodal lesions. In the present study, we aimed to validate this unique phenomenon in a larger series of four cases with FISH and targeted-capture sequencing (targeted-seq) analysis. We retrospectively identified two more cases of CD30-positive PC-LTCL with secondary nodal involvement among all patients consecutively diagnosed between 2001-2021. All cases immunohistochemically exhibited elevated nPD-L1 expression on ≥50% of lymphoma cells in nodal tumors, clearly contrasting with the scarce nPD-L1 positivity (≤1%) in cutaneous tumors. Moreover, all nodal lesions exhibited CHL-like TME, with abundant PD-L1-positive tumor-associated macrophages and low-level PD-1 expression on T cells, although the CHL-like morphology was limited in the two original cases. None showed CD274/PD-L1 copy number alteration by FISH analysis, or structural variations of PD-L1 3'-UTR by targeted-seq analysis. These findings indicated that nPD-L1 expression is linked with tumor progression and CHL-like TME in nodal involvement of PC-LTCL. Interestingly, one autopsied case exhibited heterogeneity of nPD-L1 expression at different disease sites.

Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art

“…These findings support the concept that neoplastic PD-L1 expression in CTCL increases with lymphoma progression. In addition, Takahashi et al noted that the nodal lesions of PC-ALCL had a tumor microenvironment rich in PD-L1-positive TAMs with scarce PD-1 expression on T-cells very similar to that observed in cHL [ 102 ]. Although further studies are required to understand the mechanisms underlying PD-L1 expression in PC-ALCL and other CTCLs, the findings of high PD-L1 expression in tumor cells and TAMs of PC-ALCL with nodal involvement may have therapeutic implications for the use of ICIs in this setting of patients.…”

“…Kentekure et al reported increased PD-L1 expression in tumor cells in MF showing disease progression and large cell transformation [ 100 ]. Recently Takahashi et al, identified four cases of PC-ALCL that developed secondary nodal involvement and interestingly found that PD-L1 expression in neoplastic cells greatly increased with tumor progression to nodal involvement [ 101 , 102 ]. PD-L1 expression was =/>50% of lymphoma cells in nodal disease, whereas it was rarely detectable or very low (=/<1%) when the disease was limited to the skin [ 101 , 102 ].…”

“…Recently Takahashi et al, identified four cases of PC-ALCL that developed secondary nodal involvement and interestingly found that PD-L1 expression in neoplastic cells greatly increased with tumor progression to nodal involvement [ 101 , 102 ]. PD-L1 expression was =/>50% of lymphoma cells in nodal disease, whereas it was rarely detectable or very low (=/<1%) when the disease was limited to the skin [ 101 , 102 ]. These findings support the concept that neoplastic PD-L1 expression in CTCL increases with lymphoma progression.…”