Intratumoural programmed cell death protein expression in 92 patients with atypical fibroxanthoma and pleomorphic dermal sarcoma

The expression of PD-1/PD-L1 has rarely been explored in AFX/PDS (atypical fibroxanthoma/pleomorphic dermal sarcoma), although these cancers are good candidates for anti-PD-1/PD-L1 therapy.1-10 We aimed to investigate PD-1/PD-L1 and CD8 protein expression in AFX/PDS. We studied FFPE tissue of primary AFX and PDS of patients (Table 1), for which complete clinical work-up and follow-up was performed according to the current national S1-guideline for AFX/PDS.4 Histopathologically, AFX and PDS were defined as outlined in the aforementioned guideline.4 Microscopic evaluation of immunoreactivity was carried out using the H-score (range: 0–300).7 The tumour proportion score (TPS) was calculated by the percentage of viable tumour cells showing partial or complete membrane staining at any intensity. Data analysis was performed using the statistical package MedCalc Software (Ostend, Belgium). Data were analysed using the Mann–Whitney test, Chi2 test, Spearman correlation procedure, ROC analysis, Kaplan–Meier statistics and Cox proportional-hazards model. Age Median (range) years Gender f/m TPSb > 1% (no/yes) Relapse-free survival r = −0.31, p = 0.026 PD-L1 expression r = 0.33, p = 0.044 PD-1 expression r = 0.47, p = 0.0035 CD8 peritumoural r = 0.38, p = 0.031 CD8 intratumoural r = 0.39, p = 0.0030 CD8 intratumoural r = 0.34, p = 0.049 Clinical basic data are listed in Table 1. We observed significantly more male (n = 75) than female (n = 17) patients (81.5% vs. 18.5%, p < 0.0001). There was a trend for disease relapse (p = 0.070) in female AFX patients. Compared to AFX [3.5 mm (0.7–15)] tumour thickness (TT) was significantly (p = 0.005) higher in PDS [5 mm (1.1–14)]. Data of rank correlation is shown in Table 1. As shown in Figure 1, PD-L1 expression was significantly (p = 0.016) higher in PDS [5 (0–177.5)] than in AFX tumours [1.2 (0–168.3)]. 24/55 (45.5%) of AFX and 25/37 (64.9%) of PDS had a TPS >1%. PD-1 and CD8 expression did not significantly differ between AFX and PDS (p > 0.10, Table 1). Kaplan–Meier statistics showed a trend for worse relapse-free survival (p = 0.076, hazard ratio 2.3, 95% confidence interval 0.92 to 5.78, Figure 1) but not overall survival (p = 0.13) of patients with PDS. AFX and PDS TT >4.2 was significantly associated with disease relapse (p = 0.0054, AUC 0.77 and p = 0.010, AUC 0.73, respectively). Low H-score (≤ 54) of peritumoural lymphocytes was associated with disease relapse of PDS patients (p = 0.033, AUC 0.77). We did not observe significant predictors of overall survival, except for higher TT in AFX patients (p = 0.0049, AUC 0.71). On separate Cox regression analysis of AFX and PDS patients, however, none of the aforementioned significant parameters remained significant in the model. The research group of Helbig et al.2-4 showed that the majority of PDS are inflammatory and immunogenic tumours with a high number of CD8+ tumour-infiltrating lymphocytes and expression of diverse checkpoint molecules such as PD-L1 and CTLA-4. Similar to other ultraviolet-induced tumours, AFX/PDS are immunogenic tumours with a very high mutational burden. We confirm that the frequency of PD-L1-positive (>1%) tumours is high with 64.9% of PDS cases studied. Accordingly, TT of PDS correlated with PD-L1 and PD-1 expression. In line with the data recently reported by Ríos-Viñuela et al.10 and Ørholt et al.,1 PDS is the more relevant tumour in this context because of its higher rate of metastases and thus need for immunotherapeutic interventions. Moreover, low presence of peritumoural lymphocytes in PDS is associated with disease relapse. PD-L1 expression in AFX as well as PDS correlated with presence of intratumoural lymphocytes. We showed that TT of AFX as well as PDS is associated with disease relapse and relapse-free survival, respectively. Since the vertical TT measurement is not routinely performed in AFX/PDS, our data represent a novel information on these tumours. Conclusively, accumulating data indicate that anti-PD-1/PD-L1 inhibitors can be used as first choice treatment in unresectable or metastatic tumour stages of AFX/PDS. This work is part of the doctoral thesis of Emilia Sorescu. None. None to declare. The study was approved by the ethics review board of the Ruhr-University Bochum (#16-5985) and conducted according to the Declaration of Helsinki principles. The data that support the findings of this study are available from the corresponding author upon reasonable request.