Immune checkpoint inhibitors for unresectable or metastatic pleomorphic dermal sarcomas

Abstract

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.

Keywords: Immune checkpoint inhibitor; PD-1; PD-L1; metastasized; pleomorphic dermal sarcoma (PDS); unresectable.

Figure 1

High mutational burden and most common mutations of PDS: The dotted line represents the average of variants per megabase. The mutational frequency of pleomorphic dermal sarcoma (PDS) is compared to cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma (CM), where the bars indicate their relative prevalence (percentage, right panel). Cross entity comparison of mutational signatures shown below the right panel of mutational frequencies. Clinically, locally or systemically progressed tumors are indicated with a black bar (2).