PSC is a rare, highly malignant tumor which accounts for approximately 0.1%–0.5% of lung malignant cancers (1). PSC exhibits features of both epithelial and mesenchymal tumors and is categorized as a subtype of poorly differentiated NSCLC contains sarcoma-like elements including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (2). The principles of the treatment for metastatic sarcomatoid lung cancer are the same as for other metastatic carcinomas. Surgery is the first choice of treatment when clinically appropriate. Conventional treatments and chemotherapy have limited efficacy in PSC, leading to a poorer prognosis than other subtypes of NSCLC. Meanwhile, reports of the potential benefit of immunotherapy and molecular targeted therapy in PSC are very rare.

Anlotinib, as an antiangiogenic inhibitor, is a novel multitarget TKI targeting the vascular endothelial growth factor receptor (VEGFR), which is effective in the palliative treatment of advanced NSCLC and some sarcomas (3). It has been shown that vascular invasion is a major factor in the poor prognosis of PSC patients (4). PD-L1 expression is associated with improved tumor response rates and prolonged progression free survival (PFS) after immunotherapy, which may still be effective even with PD-L1 levels <1% (5). Currently, the expression of PD-L1 in malignant tumors indicates a potential response to ICIs. Sintilimab is a human-derived immunoglobulin G4 (IgG4) monoclonal PD-1 antibody that blocks the binding of PD-1 to receptor (3, 6). In lung cancer patients carrying TP53 mutations, the expression of PD-L1 is significantly increased, leading to enhanced T-cell infiltration and immune sensitivity of the tumor. Therefore, patients with PD-L1 expression combined with TP53 mutations may benefit from immunotherapy. In this case, we treated metastatic PSC with the combination of anlotinib plus sintilimab which rapidly reduced the tumor volume. Although there have been anecdotal reports on the use of ICIs and TKIs in the treatment of PSC, data from clinical studies of the combination of anlotinib and sintilimab in patients with PSC are still lacking. Further, little is known about whether the combination of targeted therapy and immunotherapy can provide limb-salvage conditions for patients with metastatic tumors. We reported the dramatic response of systemic multiple metastatic PSC with comprehensive treatments including anlotinib combined with sintilimab, an antiangiogenic drug with PD-1 inhibitor. This rare case may provide for individualized treatment of patients with advanced PSC. In particular, the efficacy of immunological and antiangiogenic therapies in the preoperative treatment of limb salvage in patients with metastatic tumors can be demonstrated.

Antiangiogenic agents combined with PD-1 inhibitors have shown synergistic antitumor effects and have been proposed as an effective strategy for the treatment of NSCLC (7–10). However, the efficacy of this combination in neoadjuvant chemotherapy before tumor resection has not been reported. PSC is a rare and poorly differentiated NSCLC, which is commonly accompanied by sarcoma or sarcomatoid components, characterized by rapid proliferation, high vascular invasion and epithelial-mesenchymal transition. Many previous case reports have shown that compared with surgical resection or combined chemotherapy, combination therapy with TKIs and ICIs have promising efficacy in patients with PSC, significantly improving the progression free survival (PFS) and overall survival (OS) of patients, and some even achieve PR (8, 11).

The efficacy of immunotherapy is closely correlated to the expression of PD-L1. Immune checkpoint proteins which are involved in immune regulation of tumor, can promote antitumor immunity. Among them, PD-1 may be utilized by tumor cells expressing PD-L1 to evade immune surveillance (3). ICIs can improve the prognosis of patients with advanced NSCLC. The high expression of PD-L1 and proportion of patients with high TMB are relatively common in PSC compared with other subtypes (8). It has been reported that among PSC patients, over 50% showed positive PD-L1 expression (12). Therefore, we proposed that PSC is expected to benefit from immunotherapy.

Sintilimab is a novel highly selective humanized IgG4 monoclonal antibody that blocks the interaction between PD-1 and its ligand by binding site of programmed cell death PD-1, thereby restoring the function of endogenous T cell and eliminating tumor cells (3, 6). It has been proven to have encouraging antitumor activity and clinically beneficial in the treatment of advanced solid tumors including advanced NSCLC (13, 14).

As is consistent with data reported in other studies, the most common mutation in PSC is the TP53 gene (7, 15). The next generation sequencing (NGS) results for the patient in this study revealed the TP53 gene mutation (abundance 11.35%), which is associated with benefit from immunotherapy. We measured PD-L1 expression to determine the sensitivity of tumor cells to immunotherapy. In our patient, the PD-L1 TPS≥1% in metastatic femoral neoplasm sections indicated that the patient was likely to achieve favorable response to sintilimab.

Anlotinib is a novel TKI with a broad-spectrum of targeted inhibitory effect on cell growth and angiogenesis such as vascular endothelial growth factor receptor (VEGFR) and fibroblasts growth factor receptor (FGFR) (3). VEGF not only promotes angiogenesis but also inhibits T cell differentiation and dendritic cell maturation, reduces tumor T cell infiltration and regulates immune response by increasing immune suppressor cells. It helps tumor cells evade immune surveillance and ultimately leads to an immunosuppressive tumor microenvironment (3, 16). As a novel multitarget antiangiogenic drug, anlotinib is currently approved as a third-line treatment of NSCLC by the National Medical Products Administration (NMPA) (3, 14). It can down-regulate the expression of PD-L1 on vascular endothelial cells, reducing hypoxia, increasing CD8+ T cell infiltration, inhibiting recruitment of tumor-associated macrophages and enhancing the immune surveillance on tumor cells, thereby inhibiting the tumor (14).

A growing amount of evidence describes the significantly synergistic therapeutic benefits against a variety of tumors between sintilimab and anlotinib (3, 11, 14, 17). Antiangiogenic agents plus PD-1 inhibitors showed promising activity in patients with advanced soft tissue sarcoma (STS) (18). Accordingly, we speculated the potential by which the synergistic effect of anlotinib and sintilimab plays an antitumor role in the neoadjuvant chemotherapy of metastatic sarcomatoid carcinoma.

In this case, CT-guided percutaneous femoral biopsy was performed. Spindle cells and epithelioid cells were shown microscopically. Epithelial-related markers TTF-1 (focal+), CK (+), CK8/18(+), CK7(+), EMA (+), and the mesenchymal-related marker Vimentin (+), CD34(-), Desmin (-) were shown immunohistochemically. Therefore, the final pathological report diagnosed metastatic sarcomatoid carcinoma (spindle cell carcinoma).

Sintilimab has been approved by the NMPA for patients with locally advanced or metastatic nonsquamous and squamous NSCLC. Therefore, we attempted to administrated sintilimab combined with anlotinib treatment, a PD-1 inhibitor with antiangiogenic drug, and favorable results were obtained. After one cycle of treatment, the body temperature returned to normal, the thigh circumference was significantly reduced, and the pain symptoms were relieved. Unfortunately, pathological fracture occurred. We believe that the occurrence of pathological fracture was caused by shrinkage and necrosis in the tumor during immunotherapy and targeted therapy, rather than tumor proliferation. Tumor necrosis was found in the femoral neoplasms resected during the operation, and no tumor tissue was found at the resection margin. These proved that the NACT of anlotinib and sintilimab combination therapy was effective. The efficacy of combination therapy was also confirmed by follow-up for over 1 year. There was no peripheral recurrence in the left thigh, the pulmonary cavity was reduced, and the pulmonary nodules partially disappeared after 1 year of treatment, indicating the ability of ICIs and TKIs combination therapy.

To our knowledge, this is the first case showing a favorable response to sintilimab combined with anlotinib which was used as neoadjuvant chemotherapy for metastatic bone tumor resection. In general, the combination of sintilimab plus anlotinib has exhibited encouraging efficacy, durability, and tolerability in patients with advanced NSCLC. Immunotherapy combined with antiangiogenic drug may be a promising strategy and an effective way as NACT for treating patients with PSC.

During the early phase of my disease, I experienced recurrent fever and pain in the left thigh, which was not controlled by multiple antibiotics. However, during the treatment with the combination of sintilimab and anlotinib, my fever relieved. After completing limb salvage surgery, I was able to engage in activities of daily living including performing household chores, walk up and down stairs on my own without the use of a walker. At present, my symptoms related to the disease are well-controlled and no pulmonary symptoms such as cough occur. During the regular combination therapy, I have no nausea and vomiting.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Ethics Committee of 960th Hospital of PLA Joint Service Support Force. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

ZB: Writing – original draft, Writing – review & editing. XY: Writing – original draft, Writing – review & editing. KZhe: Writing – original draft. KZha: Writing – original draft, Writing – review & editing. HC: Writing – original draft. MX: Writing – original draft, Writing – review & editing.