Malignant PEComa is insensitive to standard chemotherapy and radiotherapy and radical surgical resection is the key to cure (18). The efficacy of adjuvant or neoadjuvant radiotherapy in PEComa has only been reported in case reports and has not been clinically proven. Due to the importance of surgical treatment for long-term survival, patients with initially diagnosed advanced or metastatic PEComa have a poor prognosis. However, due to the limited response to chemotherapy and radiotherapy, there is a lack of data on cytoreductive surgery with non-R0 resection for advanced PEComa in the presence of potentially resectable and resectable metastases, with reference to other sarcomas, the likelihood as well as the risks and benefits of surgery need to be assessed, and some patients may benefit from neoadjuvant therapy. MDT discussions should be held before treatment and clinical trials are encouraged.

Commonly used chemotherapeutic agents for malignant PEComa include gemcitabine, docetaxel, adriamycin, isocyclophosphamide. Wagner (6) et al. reported partial remission of gemcitabine in combination with docetaxel in patients with metastatic PEComa. Adriamycin and isocyclophosphamide are standard chemotherapeutic agents for soft tissue sarcoma, but have limited efficacy in malignant PEComa.

Longer-term therapeutic responses with significantly improved efficacy over chemotherapy can be achieved with mTOR inhibitors in malignant PEcoma, especially in patients with mutations in the TSC1/TSC2 genes that result in aberrant activation of the mTOR pathway. mTOR inhibitors block cell proliferation, metabolism and angiogenesis signaling pathways by inhibiting the activity of the mTORC1 complex. mTOR inhibitors include everolimus, sirolimus, temsirolimus, and others. Albumin-bound sirolimus is a novel mTOR inhibitor that improves drug delivery efficiency and tumor targeting via an albumin carrier. The AMPECT trial (6) evaluated the significant anti-tumor activity of nab-sirolimus in patients with advanced or metastatic malignant PEComa carrying mutations in the TSC1/TSC2 genes or activation of the mTOR pathway. An objective remission rate (ORR) of 39% was achieved, with 2 patients achieving complete remission after long-term follow-up, 58% of patients sustained remission for more than 2 years, and the median progression-free survival (PFS) was 10.6 months and the median duration of response was 39.7 months. There was durable disease control and survival. Accordingly in November 2021 the US Food and Drug Administration (FDA) approved the marketing of Fyarro (Albumin-bound sirolimus) for the treatment of locally advanced unresectable or metastatic, which is the first FDA-approved drug for the treatment of advanced malignant PEComa in adults and is now considered a standard first-line treatment option. Patients with PEComa harboring TSC2 mutations who are treated with mTOR inhibitors have a better objective response rate and progression-free survival than patients with TSC1 mutations. Other mTOR inhibitors, including everolimus, temsirolimus, and sirolimus, have shown similar efficacy in retrospective studies.

Recently, a class of PEComa subtypes carrying TFE3 gene rearrangements has been identified (19). About 50 cases have been reported to date. These TFE3-rearranged PEComas predominantly consist of alveolar and epithelioid cells with low immunoreactivity for muscle markers and high immunoreactivity for TFE3 (3+) (20). Patients tend to be younger and have no association with tuberous sclerosis. TFE3-translocated PEComas are less responsive to mTOR inhibitors (21), and the low response rate is associated with MET pathway activation, which is one of the mechanisms of mTOR inhibitor resistance. However, there is a lack of clinical studies evaluating mTOR inhibitors in PEComas with or without TFE3 translocation. TFE3 fusion has been found to activate MET signaling through transcriptional upregulation. Therefore, c-MET inhibitors may be more effective in TFE3-altered PEComas (18). Therefore, it has been proposed that PEComas can be subdivided into two molecular subgroups: type 1, which is responsive to mTOR inhibitors, and type 2, which is responsive to c-MET inhibitors. However, there is still a lack of supporting data. While it is generally accepted that TFE3 rearrangements and TSC1/2 mutations are mutually exclusive, our PEComa patient had a TSC2 mutation and TFE3 phenotypic alteration.

Anti-angiogenic therapy blocks the process of tumor angiogenesis by inhibiting the activity of tumor angiogenic factors, thereby cutting off the nutrient supply to the tumor and inhibiting tumor growth and metastasis. The main targets include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). In the VEGF/VEGFR pathway VEGF-A is a core regulator of angiogenesis and promotes endothelial cell proliferation and angiogenesis through the VEGFR-2 signaling pathway. Small molecule tyrosinase inhibitors such as Sorafenib, Sunitinib and Pazopanib are multi-targeted inhibitors that exert anti-angiogenic effects by inhibiting VEGFR, PDGFR and other pathways, and have achieved partial remission in several PEComa patients (22, 23). The therapeutic efficacy of single-agent angiogenesis inhibitors for advanced PEcoma is often limited, and the therapeutic strategy of VEGFR inhibitors combined with mTOR inhibitors exerts a synergistic effect, blocking the survival and proliferation signals of tumor cells from different angles and reducing the possibility of tumor cells to develop drug resistance through activation of other bypass signaling pathways, thus delaying the emergence of drug resistance (24). The incidence of ILD caused by m-TOR inhibitors has been reported to be approximately 0.4% to 10%, and the mechanism may involve direct cytotoxicity, immune-mediated inflammatory response, and vascular endothelial damage (25, 26). In this case, the patient was discontinued after everolimus therapy due to intolerable interstitial pneumonitis, and the disease progressed after restarting therapy at a reduced dose. Subsequent combination of antiangiogenic therapy with VEGFR inhibitors (amlotinib) maintained disease stabilization for 10 months without further exacerbation of interstitial pneumonitis. There is no conclusive evidence that VEGFR inhibitors may have an effect on m-TOR inhibitor-induced interstitial lung disease. VEGFR inhibitors may attenuate m-TOR inhibitor-induced lung injury by inhibiting angiogenesis and inflammatory responses in an animal model of pulmonary fibrosis. Some clinical studies have also reported the effectiveness of nidanib, a VEGFR inhibitor, in slowing the progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) (27).

Malignant PEComa is a rare and aggressive subtype of soft tissue sarcoma with a low response rate to conventional chemotherapy, while immune checkpoint inhibitors (ICIs) have received attention for their potential efficacy in tumors with high tumor mutation load (TMB) or high PD-L1 expression. There are case reports of objective remission rates (ORR) of 17%-50% for ICIs alone in malignant PEComa with high TMB-H or PD-L1 expression (28, 29). In patients carrying patients carrying TSC1/2 mutations everolimus combined with pembrolizumab synergistically inhibits tumor growth and enhances immune response. Theoretically, ICIs combined with anti-angiogenic drugs can improve the tumor microenvironment and enhance the efficacy of ICIs through “vascular normalization”. In this case, the patient obtained 11-month disease control after multiple lines of therapy with amlotinib in combination with teraplizumab. Local radiotherapy or selective internal radiation therapy (SIRT) can enhance the immune-activating effect of ICIs and provide new ideas for combination therapy. Currently, there are relatively few cases of immunotherapy application in malignant PEcoma, and more clinical trials and basic research are still needed to further clarify the predictive markers of immunotherapy efficacy, explore the optimal combination therapy regimen, and thoroughly study the resistance mechanism of immunotherapy, in order to improve the therapeutic efficacy of malignant PEcoma and improve the prognosis of patients.

Although the current standard first-line drug, albumin-conjugated sirolimus, improves the efficacy of PEComa significantly, it is not satisfactory. Combination therapy may save more patients.Anti-PD-1 immunotherapy combined with radiotherapy benefits patients who are not eligible for radical resection, providing relief from cancer-related pain and bleeding. Sanfilippo et al. (30) evaluated the efficacy of adding anti-estrogen therapy to the treatment of female patients who were resistant to mTOR inhibitors. The study found an ORR of 43% and a DCR of 86%. Combination anti-angiogenic agents, such as pazopanib and sunitinib, are also under study (31). A targeted or immune combination with gemcitabine and/or albumin nanopaclitaxel-based chemotherapy could also be a second-line option (18). Known mechanisms of resistance to mTOR inhibitors from studies of other tumors include mutations in the structural domains of TSC1/TSC2 kinases; activation of PI3K/AKT or MAPK/ERK pathways; overexpression of ABC transporter proteins; activation of METs; and changes in the microenvironment. Future strategies to overcome resistance, such as using dual PI3K/AKT inhibitors or C-MET inhibitors in combination with anti-vascular therapies, deserve further investigation (32).