Immune-phenotyping of pleomorphic dermal sarcomas suggests this entity as a potential candidate for immunotherapy.

BACKGROUND: Pleomorphic dermal sarcomas (PDS) are sarcomas of the skin with local recurrences in up to 28% of cases, and distant metastases in up to 20%. Although recent evidence provides a strong rational to explore immunotherapeutics in solid tumors, nothing is known about the immune environment of PDS. METHODS: In the current study, a comprehensive immune-phenotyping of 14 PDS using RNA and protein expression analyses, as well as quantitative assessment of immune cells using an image-analysis tool was performed. RESULTS: Three out of 14 PDS revealed high levels of CD8-positive tumor-infiltrating T-lymphocytes (TILs), also showing elevated levels of immune-related cytokines such as IL1A, IL2, as well as markers that were very recently linked to enhanced response of immunotherapy in malignant melanoma, including CD27, and CD40L. Using a multivariate analysis, we found a number of differentially expressed genes in the CD8-high group including: CD74, LYZ and HLA-B, while the remaining cases revealed enhanced levels of immune-suppressive cytokines including CXCL14. The "CD8-high" PDS showed strong MHC-I expression and revealed infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. Tumor-associated macrophages (TAMs) predominantly consisted of CD68 + , CD163 + , and CD204 + M2 macrophages showing an accentuation at the tumor invasion front. CONCLUSIONS: Together, we provide first explorative evidence about the immune-environment of PDS tumors that may guide future decisions whether individuals presenting with advanced PDS could qualify for immunotherapeutic options.

Immunohistochemical expression of melanocytic and myofibroblastic markers and their molecular correlation in atypical fibroxanthomas and pleomorphic dermal sarcomas.

BACKGROUND: Atypical fibroxanthomas (AFXs) and pleomorphic dermal sarcomas (PDSs) are UV-induced pleomorphic skin tumors with a non-specific immunoprofile. For that reason, exclusion of other dedifferentiated tumor entities by immunohistochemistry is still mandatory to avoid misdiagnosis. METHODS: We determined the expression frequency of several melanocytic and myofibroblastic markers investigating 50 AFXs and PDSs.. Next-generation-sequencing (NGS) was performed in microphthalmia-associated transcription factor (MiTF)-expressing cases. RESULTS: We identified one MiTF-expressing AFX and PDS, and two PDSs harboring single S100-positive dendritic cells whereas Melan A, HMB45, and SOX10 were negative. Calponin was moderately expressed by tumor giant cells in one PDS whereas h-caldesmon, desmin, and myogenin were not expressed in any of the AFXs or PDSs. The MiTF-positive AFX presented CDKN2A, OXA1L, and PDGFRA mutations whereas the PDS harbored a typical TP53 mutation. Both patients have not shown any tumor progression over the last 16 and 30 months. CONCLUSION: Rarely, AFX and PDS express the melanocytic marker MiTF and/or the myofibroblastic marker calponin. In doubtful cases, using a panel of immunohistochemical markers helps to avoid misdiagnosis.

Immune checkpoint inhibitors for unresectable or metastatic pleomorphic dermal sarcomas.

Pleomorphic dermal sarcomas (PDS) are rare neoplasms of the skin that occur in UV-exposed sites in the elderly, but represent the most common cutaneous sarcomas. Although the majority of PDS can be surgically removed, local recurrences occur in up to 28%, usually occurring within the first two years after primary excision. Metastases are diagnosed in up to 20% of cases, mainly observed in the skin, lymph nodes and lungs, preferentially affecting patients with underlying hemato-oncologic diseases. Similar to other UV-induced tumors, PDS are inflammatory and immunogenic tumors (with a high number of CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and checkpoint molecule expression such as PD-L1, LAG-3, TIGIT) with a very high mutational burden. The most common genetic alterations include UV-induced TP53 loss of function mutations, followed by alterations in the CDKN2A/B gene. Rarely, targetable genetic alterations can be detected. Compelling experimental data and clinical reports about PD-1/PD-L1-blocking antibodies in patients with PDS suggest its use as first line treatment in unresectable or metastatic tumor stages. However, individual ("off-line") patient management should be discussed in an interdisciplinary tumor board based on molecular genetic testing, mutational burden, PD-L1 expression, and evidence of tumor-infiltrating lymphocytes in addition to comorbities of the individual patient.

Hemato-Oncological Diseases as Risk Factor for Recurrence or Metastasis of Pleomorphic Dermal Sarcoma.

Background: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are increasingly common sarcomas of the skin with a genetic UV signature. Immunosuppression is a known risk factor for developing other UV-induced skin cancers such as cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma with increased mortality. In case reports or small case series of AFX/PDS patients, immunosuppression has been hypothesized as a risk factor for the development of distant metastases. The aim of the present study was to analyze immunosuppression as a risk factor for AFX/PDS in a large patient cohort. Methods: A cohort of 164 patients with AFX/PDS (47 AFX and 117 PDS) was collected between 2003 and 2021 and analyzed for clinicopathological data with a special focus on immunosuppression. Results: Of all patients, 29.9% had any kind of immunosuppression; 6.4% of the AFX and 12.0% of the PDS patients had underlying hemato-oncological diseases. Patients with immunosuppression due to an underlying hemato-oncological disease had a significantly increased risk of progressing to (p = 0.010) and developing distant organ metastases (p = 0.000). Conclusions: Immunosuppression seems to be a risk factor for developing AFX/PDS with worse clinical outcomes. Therefore, immunosuppression, especially underlying hemato-oncological diseases, should be considered in the treatment and follow-up care of patients with AFX/PDS.

First report on two cases of pleomorphic dermal sarcoma successfully treated with immune checkpoint inhibitors.

Pleomorphic dermal sarcoma (PDS) is one of the most common sarcoma of the skin. Currently, limited treatment options exist for advanced stages of the disease. While immune checkpoint inhibitors (CPIs) have revolutionized cancer treatment options-their efficacy in PDS has not been explored yet. Here, we present two advanced PDS cases that showed response to anti-PD-1 therapy. Patient A had a locally metastasized PDS and reached a complete remission of the disease after eight cycles of Pembrolizumab. Patient B developed an inoperable relapse of PDS with a complete remission of the disease 4 months after treatment with Pembrolizumab in combination with radiotherapy. To our knowledge, this is the first report of two individuals with advanced PDS that successfully underwent anti-PD1 treatment. By comparing the immune micromilieu to a previously published cohort, we show that the two cases are representative for PDS tumors - potentially making these results more generalizable.