Primary Cutaneous Large T-cell Lymphoma Research Articles

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

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.

CD8+ T cells in cutaneous T-cell lymphoma: expression of cytotoxic proteins, Fas Ligand, and killing inhibitory receptors and their relationship with clinical behavior.

We investigated the number, phenotype, and prognostic significance of CD8+ T cells in patients with mycosis fungoides (MF) and CD30- primary cutaneous large T-cell lymphoma (PCLTCL). Immunohistochemical stainings for CD8, granzyme B (GrB), T cell-restricted intracellular antigen (TIA-1), Fas ligand (FasL), and killer-cell inhibitory receptors (KIRs; CD95, CD158a, and CD158b) were performed on 83 first-diagnostic biopsy samples obtained from patients with plaque-stage MF (n = 42), tumor-stage MF (n = 20), and CD30- PCLTCL (n = 21). Serial sections and double-staining experiments showed that the large majority of CD8+ T cells in MF and CD30- PCLTCL expressed TIA-1 and FasL, whereas only a minority expressed GrB, which suggested that these CD8+ T cells were partly activated cytotoxic T lymphocytes (CTLs). These CD8+ CTLs never or rarely expressed KIRs. This phenotype was a constant feature of CD8+ CTLs and did not alter with disease progression. In contrast, the median percentage of CD8+ CTLs in plaque-stage MF (22%), tumor-stage MF (7%), and CD30- PCLTCL (3%) differed significantly (P < .0001) and was associated with a significant decrease in 5-year survival. Also within the group of tumor-stage MF, a significant relation between CD8+ CTLs and survival was found. Multivariate analysis in the total group of MF demonstrated that both skin stage and percentage of CD8+ CTLs were independent parameters of survival. Our results demonstrated that partly activated CD8+ CTLs were present in CTCL and that high proportions of these cells correlated with a better prognosis. This suggested that these CD8+ CTLs could play an important role in the antitumor response in these conditions.

Expression of Fas and Fas-ligand in primary cutaneous T-cell lymphoma (CTCL): association between lack of Fas expression and aggressive types of CTCL.

Fas (CD95; APO-1) is a transmembrane protein that mediates apoptosis upon cross-linking with Fas-ligand (Fas-L). Interaction of Fas-L expressed by cytotoxic T cells with Fas-expressing tumour cells plays an important part in antitumour immune responses. We aimed to investigate Fas and Fas-L expression in frozen and paraffin-embedded material from a large group of patients with cutaneous T-cell lymphoma (CTCL). Immunostaining with monoclonal antibodies against Fas and Fas-L was performed in material from 23 patients with mycosis fungoides (MF), 10 with lymphomatoid papulosis (LyP), 10 with CD30-positive primary cutaneous large T-cell lymphoma (LTCL) and nine with CD30-negative LTCL. The results were correlated with the type and stage of CTCL and clinical features. Expression of Fas by the large majority of the neoplastic T cells was observed in 15 of 15 cases of plaque-stage MF, 10 of 10 cases of LyP and 10 of 10 cases of CD30-positive LTCL, but only in four of 12 cases of tumour-stage MF and two of nine cases of CD30-negative LTCL. In three of four MF patients in whom both plaques and tumours could be studied, a significant decrease in Fas expression was observed with progression from plaque-stage to tumour-stage disease. Fas-L was expressed by > 50% of the neoplastic T cells in 46 of 56 biopsies, and no clear relationship with type of CTCL and clinical behaviour was observed. This study demonstrates loss of Fas expression in aggressive types of CTCL, but not in indolent types of CTCL. These data suggest that loss of Fas receptor expression may be one of the mechanisms that allow tumour cells to escape an effective immune response, and may contribute to the unfavourable prognosis of some types of CTCL.

Multidrug resistance related proteins in primary cutaneous lymphomas.

In patients with primary cutaneous B-cell lymphomas (CBCL) and primary cutaneous T-cell lymphomas (CTCL), extracutaneous sites may become involved and then polychemotherapy is indicated. Multi-agent chemotherapy may induce long lasting complete remissions in CBCL's. Most CTCL's, especially mycosis fungoides (MF), and CD30 negative primary cutaneous large T-cell lymphoma (PCLTCL) respond poorly or partially to Multi-agent Chemotherapy. We have studied whether cutaneous lymphomas express the following multidrug resistance (MDR) related proteins: multidrug resistance protein (MRP), lung resistance protein (LRP) and P-glycoprotein (Pgp). From the files of the Dutch Cutaneous Lymphoma Working Group we selected pretreatment punch biopsy specimens of the skin from 14 patients with MF, 10 patients with a PCLTCL and 8 patients with a CBCL. In several patients with a clinical relapse of their disease after multi-agent chemotherapy, punch biopsy specimens of cutaneous lesions were available (6 MF, 3 PCLTCL, 1 CBCL). Benign dermatoses with a dense lymphoid infiltrate were included as a control. Immunohistochemistry was done on formalin fixed, paraffin-embedded punch biopsy specimens with monoclonal antibodies MRPrl (anti-MRP); LRP-56 (anti-LRP); C219 (anti-Pgp). Staining was performed by the biotin-streptavidin immunoperoxidase method. MRPrl staining was found in the cytoplasm of > or = 5%-50% of lymphoid cells in 13 out of 14 cases of MF and in 6 out of 10 patients with a PCLTCL. In 2 out of 8 cases of CBCL > or = 5%-50% positive tumorcells were found. Strong staining (> or = 50% of the cells positive) was found in 10 out of the total of 24 CTCL cases. LRP56 staining of lymphoid cells was found in 1 out of 14 cases of MF and in 1 out of 10 cases of PCLTCL and in 1 out of 8 cases of CBCL. C219 expression was found in 4 out of 10 cases of PCLTCL and in 2 out of 8 cases of CBCL. After chemotherapy both a higher staining intensity and a higher number of positive cells were found with MRPrl especially in patients with MF. The present study shows that lymphoid cells in both primary cutaneous lymphomas and benign skin disorders may express MDR related proteins and that the expression profile of these proteins is roughly related to the tumor cell phenotype. However, the functional role of these proteins in clinical drug resistance in primary cutaneous lymphomas has to be proven.