Immunotherapy in Primary Mediastinal Undifferentiated Pleomorphic Sarcoma: A Promising Approach

Soft tissue sarcomas (STSs) are a rare group of cancers originating from the connective tissue stroma, constituting approximately 1% of all cancer cases. Among them, primary mediastinal sarcomas are even rarer, accounting for 10% of primary mediastinal tumors and only 1% of all STSs. Due to their rarity and the heterogeneity in disease progression, STSs have been less frequently studied in the past, with limited data available primarily from small retrospective case series. The median overall survival for STS patients has historically been disappointing, with a reported average of 27.2 months. Undifferentiated pleomorphic sarcoma (UPS), a high-grade sarcoma with no specific differentiation direction, lacks distinctive clinical manifestations or immunohistochemical markers, making histopathological examination the gold standard for diagnosis. Vimentin positivity can enhance diagnostic specificity. For patients with advanced sarcoma, the prognosis remains dismal, and doxorubicin monotherapy has been the standard first-line chemotherapy option. However, the outcomes have been unsatisfactory, underscoring the urgent need for more effective therapies. In recent years, immunotherapy with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) pathway has shown promising results in various cancer types. Monoclonal antibodies blocking PD-1 and PD-L1 interaction can activate T lymphocytes, preventing immune evasion by tumors. The presence of tumor-infiltrating lymphocytes and PD-L1 expression in tumor and immune cells has been associated with treatment response. However, evidence on the efficacy of ICIs in UPS has been limited to small-sample studies, such as the phase II SARC028 trial, which indicated some efficacy of ICIs in UPS treatment but did not result in official approval for sarcoma treatment.

In a new study published in the Frontiers in Oncology Journal by Dr. Hujuan Yang, Dr. Zhiquan Qin, Dr. Xianglei He, Dr. Qian Xue, Dr. Hongying Zhou, Dr. Jie Sun, Dr. Xiaoyi Li and Dr. Tongwei Zhao from the Zhejiang Provincial People’s Hospital discussed a clinical case report of a patient with primary UPS characterized by high PD-L1 expression who responded well to immunotherapy, highlighting the potential of ICIs in the treatment of this rare and aggressive cancer.

The patient in question was a 61-year-old man who presented with chest pain. Imaging studies revealed a potentially malignant cardiac mass and abnormal lymph nodes in the neck region, suggestive of metastasis. Subsequent pathological analysis confirmed the presence of a malignant tumor with lymph node involvement. Further immunohistochemical staining showed that the tumor exhibited characteristics consistent with UPS, and PD-L1 expression was notably high (tumor proportion score [TPS] = 80%). According to the American Joint Committee on Cancer (AJCC) 8th edition staging, the patient was classified as cT3N1M1 (stage IV) due to tumor invasion of the pericardium, rendering surgical resection unfeasible. Consequently, the patient received a combination of epirubicin and tislelizumab chemotherapy for six cycles, which resulted in a partial response (PR) with a progression-free survival (PFS) of 8.5 months. However, during treatment, the patient experienced cardiotoxicity attributed to epirubicin, leading to its discontinuation in favor of tislelizumab monotherapy for maintenance. Subsequent imaging demonstrated stable disease, but later scans revealed disease progression with new lesions, ultimately leading to the patient’s demise from obstructive jaundice caused by tumor progression.

The new study showed that immunotherapy, specifically immune checkpoint blockade, has shown promise in the treatment of STS. Notably, UPS has been identified as a tumor type with a relatively higher incidence of PD-L1 expression. Several ongoing clinical trials are evaluating the safety and efficacy of ICIs in various STS subtypes. In the presented case, the patient exhibited high PD-L1 expression and tumor-infiltrating lymphocytes, indicative of a potential response to immunotherapy. The combination of tislelizumab and epirubicin resulted in a PR and an extended PFS, surpassing the average survival duration reported for conventional chemotherapy in UPS.

The clinical case presented by Dr. Tongwei Zhao and colleagues highlights the potential of immunotherapy, particularly immune checkpoint inhibitors, in the treatment of primary mediastinal UPS with high PD-L1 expression. While UPS is a rare and aggressive cancer, patients with high PD-L1 expression and tumor-infiltrating lymphocytes may benefit from immunotherapy. This case report provides a valuable addition to the growing body of evidence supporting the use of immunotherapy in the management of STS. However, further research, including larger clinical trials and mechanistic studies, is required to fully understand and optimize the role of immunotherapy in UPS treatment.