The pathogenesis and therapeutic management of rare pulmonary sarcomatoid carcinoma: a narrative review

Introduction

A rare subtype of non-small cell lung cancer (NSCLC), pulmonary sarcomatoid carcinoma (PSC) is a biphasic tumor with both epithelial and mesenchymal components, in which at least 10% of the area is composed of spindle cells and/or giant cells (1). According to the World Health Organization (WHO) classification, PSC can be divided into three main categories: carcinosarcoma (CS), pulmonary blastoma (PB), and pleomorphic carcinoma (PCC). Among these subtypes, PCC can be further subdivided into PCC, giant cell carcinoma (GCC), and spindle cell carcinoma (SpCC) (2). PSC accounts for approximately 0.5% of NSCLC cases (3), occurs more frequently in older men with a history of smoking (4), and is characterized by aggressiveness, rapid progression, and poor prognosis. The clinical manifestations of PSC are often nonspecific and commonly include cough, dyspnea, hemoptysis, chest pain, and weight loss (5). Radiologically, PSC typically presents as a solitary mass with homogeneous density and smooth margins, demonstrating rapid growth with or without enhancement (6,7). Its glucose metabolic activity is significantly higher than that of other types of NSCLC (8,9). Currently, its definitive diagnosis is primarily dependent on pathological findings. The cohort data from the Surveillance, Epidemiology, and End Results (SEER) database indicated that the median overall survival (OS) of patients with mainly advanced-stage PSC, is approximately 7 months, while the 5-year OS rate is only about 19.5% (10).

However, investigations into the pathogenesis of PSC remain limited, and comprehensive summaries on the efficacy of various treatment methods are generally lacking. This narrative review provides a necessary discussion of the pathogenic mechanisms and therapeutic approaches related to PSC, offering insights that may advance the precision diagnosis and treatment of this disease. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-886/rc).

Methods

We systematically searched the PubMed database for English-language literature published as of May, 2025 using the keywords “pulmonary sarcomatoid carcinoma”, “angiogenesis”, “metastasis”, “targeted therapy”, “immunotherapy”, and their synonyms. Relevant clinical study information was also collected from ClinicalTrials.gov, the Chinese Clinical Trial Registry (ChiCTR), and the University Hospital Medical Information Network (UMIN), along with data from major conference proceedings, including the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference on Lung Cancer (WCLC), and the European Lung Cancer Congress (ELCC). Two authors (Q.W. and H.G.) independently screened the titles and abstracts of all retrieved records according to predefined inclusion and exclusion criteria. English-language articles, including original research, reviews, clinical trials, and case reports focusing on PSC, were included, while non-English language articles and non-full text articles were excluded. The full texts of potentially eligible articles were then obtained and assessed independently by the two aforementioned authors. Any discrepancies regarding the inclusion of studies were resolved through discussion. In addition, the reference lists of the retrieved articles were searched to identify further relevant studies and supplement the data. All included articles are reported in the References section. The full search strategy is detailed in Table 1.

Pathogenesis of PSC

According to the WHO diagnostic criteria, PSC carcinoma should be diagnosed when the sarcomatoid component constitutes ≥10% of the tumor (11). Thus, PSC is a class of poorly differentiated NSCLC with biphasic differentiation, and its core pathogenesis is the formation of invasive sarcomatoid components from epithelial cells via epithelial-mesenchymal transition (EMT) (12). The two components originate from a common ancestor, with sarcomatoid transformation occurring relatively late in the process (13,14). This transformation is accompanied by significant microenvironment remodeling, with 90% of PSCs exhibiting active vascular invasion (6); moreover, the extracellular matrix undergoes a significant increase in fiber deposition due to the abnormal activation of the transcription factor (TF) Snail family transcriptional repressor 2 (SLUG) via integrin-linked kinase (ILK), which results in a significant increase in fibronectin (FN) in the extracellular matrix, forming a physical barrier that hinders drug penetration (15,16).

Studies have demonstrated that the occurrence of EMT is triggered by the activation of certain pathways under stress within the tumor microenvironment (TME), with tobacco exposure, hypoxia, and low pH being potential contributors to this process (17). A history of heavy smoking has been identified as a major risk factor for PSC (18-20). Tobacco carcinogens, as potent mutagens, directly cause DNA damage and are associated with a characteristic prevalence of smoking-related genomic alterations. For instance, smokers with PSC exhibit higher frequencies of Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor protein p53 (TP53) mutations, whereas epidermal growth factor receptor (EGFR) mutations—which are more common in nonsmokers—are relatively rare among smokers (21-23). Additionally, a milieu of chronic inflammatory and oxidative stress induced by smoking fosters a tumor-promoting microenvironment, potentially facilitating EMT in PSC.

In NSCLC, upstream pathways that activate EMT, such as transforming growth factor-β (TGF-β), Wnt, Notch, phosphatidylinositol 3-kinase-Ak strain transforming (PI3K-AKT), and Janus kinase-signal transducer and activator of transcription (JAK-STAT), further directly or indirectly induce the expression of TFs or related gene programs (17). For instance, TGF-β phosphorylates small mothers against decapentaplegic homolog 2/3 (SMAD2/3), which then forms a complex with SMAD4, leading to the upregulation of key EMT TFs such as Snail family transcriptional repressor 1 (SNAIL1), SLUG, and zinc finger E-box binding homeobox (ZEB). These factors bind to E-box elements and recruit corepressors to inhibit E-cadherin transcription while simultaneously maintaining the EMT state through a positive feedback autocrine mechanism (24,25). Upon Wnt activation, β-catenin, which antagonizes E-cadherin, translocates into the nucleus and forms a TF complex, contributing to SNAIL activation and the suppression of epithelial genes (24,26). Similarly, the Notch signaling pathway regulates target genes through the translocation of its intracellular domain into the nucleus, and its products are coexpressed with EMT markers at the tumor periphery, collectively promoting phenotypic transformation (27).

The dynamic switching of certain TF networks has also been confirmed in PSC. Manzotti et al. (28) found that the deletion of epithelial-related TF ovo-like zinc finger 2 (OVOL2) and grainyhead-like TF 2 (GRHL2) directly triggers the upregulation of stromal-related TF twist family BHLH TF (TWIST), ZEB family, and membrane kinase discoidin domain receptor tyrosine kinase 2 (DDR2). Yang et al. (13) further confirmed that ZEB1 is highly expressed in the sarcomatoid region as it binds to the cadherin 1 (CDH1) gene promoter to inhibit its transcription. Moreover, the high methylation of the CDH1 promoter at the epigenetic level also synergistically leads to the loss of E-cadherin protein expression. This dual-level regulation of transcription and epigenetics disrupts cell adhesion and drives the upregulation of vimentin expression, resulting in a transition of cell morphology from a cuboidal epithelium to a spindle-shaped stroma.

Notably, the EMT mechanism also exhibits subtype specificity in PCC of PSC. Roma et al. found that lung squamous cell carcinoma (LUSC)-like PSC was associated with the significant upregulation of the sarcomatoid region, which forms neural cell adhesion molecule 1 (NCAM1), a signaling complex consisting of fibroblast growth factor receptor (FGFR), to activate the rat sarcoma viral oncogene homolog/mitogen-activated protein kinase (Ras/MAPK) pathway and promote cell migration. Also, the expression level of NCAM1 was significantly negatively correlated with that of CDH1. In lung adenocarcinoma (LUAD)-like PSC, the sarcomatoid region demonstrates enrichment of immune-related pathways, accompanied by a high expression of programmed death-ligand 1 (PD-L1) and increased infiltration of CD8⁺ T cells (14).

The decreased expression of ubiquitin-specific peptidase 9X (USP9X) also has important pathological significance in PSC and is closely associated with tumor metastasis and a poor prognosis. In terms of mechanism, the low expression of USP9X reduces the inhibition of matrix metalloproteinase 9 (MMP9), which upregulates vascular endothelial growth factor (VEGF), promotes angiogenesis, reduces immune infiltration of CD4⁺/CD8⁺T cells, and results in a decrease in E-cadherin expression and an increase in vimentin expression (29). This multilevel regulatory network involving TFs, epigenetics, membrane signaling, and immune microenvironment jointly promotes the transformation of PSC into a highly invasive sarcomatoid phenotype (a visual summary of this mechanism is provided in Figure 1).

Figure 1 Mechanisms associated with EMT in PSC (figure was created in Figdraw; https://www.figdraw.com). Abnormal activation of ILK further activates SLUG, leading to the upregulation of fibronectin and vimentin expression. The absence of OVOL2 and GRHL2 triggers the upregulation of TWIST, ZEB, and membrane kinase DDR2 expression. The direct inhibition effect of ZEB1 and the high methylation of CDH1 promoter synergistically inhibit the expression of E-cadherin and promote the expression of vimentin. In LUSC-like PCC, NCAM1 is highly expressed and forms a signaling complex with FGFR to activate the Ras/MAPK pathway. In LUAD-like PCC, PD-L1 is highly expressed. The decreased expression of USP9X reduces the inhibition of MMP9, thereby promoting angiogenesis, reducing immune infiltration of CD4⁺/CD8⁺ T cells, and leading to a decrease in E-cadherin expression and an increase in vimentin expression. CDH1, cadherin 1; DDR2, discoidin domain receptor tyrosine kinase 2; E-cadherin, epithelial cadherin; EMT, epithelial-mesenchymal transition; FGFR, fibroblast growth factor receptor; GRHL2, grainyhead-like transcription factor 2; ILK, integrin-linked kinase; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MMP9, matrix metallopeptidase 9; NCAM1, neural cell adhesion molecule 1; OVOL2, ovo-like zinc finger 2; PCC, pleomorphic carcinoma; PD-L1, programmed death-ligand 1; PSC, pulmonary sarcomatoid carcinoma; Ras/MAPK, rat sarcoma viral oncogene homolog/mitogen-activated protein kinase; SLUG, Snail family transcriptional repressor 2; TWIST, Twist family BHLH transcription factor; USP9X, ubiquitin-specific peptidase 9 X-linked; ZEB, zinc finger E-box binding homeobox.

In addition, it should be noted that treatment pressure may become an accelerator for sarcomatoid transformation. It has been reported that EGFR/anaplastic lymphoma kinase (ALK) driver gene-positive LUAD may activate an EMT-related pathway through a drug-resistance mechanism after treatment with corresponding tyrosine kinase inhibitors (TKIs), which ultimately leads to the formation of a sarcomatoid phenotype (30,31).

Therapeutic management of PSC

Similar to that for other types of NSCLC, the therapeutic management of PSC has undergone a significant paradigm shift, moving away from a historical reliance on surgery and chemotherapy toward a precision medicine approach guided by molecular profiling. Given the aggressive nature and high metastatic potential of PSC, the initial treatment focus in the majority of patients, particularly those with advanced disease, is systemic therapy, with growing number of new drugs being gradually applied in treatment. Table 2 lists the clinical studies on the treatment of PSC.

Immunotherapy

The TME of PSC is characterized by significant immune cell infiltration, and it is thus considered to be a “hot tumor” (40). Moreover, the bulk of PSCs express at least one immune checkpoint, such as PD-L1, B7 homolog x (B7x), B7 homolog 3 (B7-H3), and HERV-H LTR-associating protein 2 (HHLA2) (41). Notably, PD-L1 has been reported in several studies to be expressed at a frequency of 53–82.1% in PSC—which is approximately 40% higher than that of other NSCLC types—and at a greater frequency of high expression (41-45). In addition, the majority of PSC cases exhibit a high tumor mutational burden (TMB) (>10 mutations/Mb), with a median TMB of 8.6 mutations per megabase. Notably, TP53-mutant tumors demonstrate a significantly higher TMB as compared to wild-type tumors (4,46,47). These comprehensive immunological characteristics indicate that a considerable proportion of patients with PSC may potentially benefit from immune checkpoint inhibitor (ICI) treatment.

The National Comprehensive Cancer Network guidelines indicate that PD-L1 expression can serve as a biomarker for predicting the efficacy of PD-1/PD-L1 blockade in patients with NSCLC (48), which is also applicable to those with PSC. A higher PD-L1 expression level is associated with improved response to ICIs (49). In a study by Lee et al. (50), a tumor proportion score (TPS) ≥50% was found to function as an independent predictor of progression-free survival (PFS) and OS in patients subjected to PD-1/PD-L1 inhibitor therapy. Similarly, Wu et al. reported that patients with TPS ≥80% exhibited superior PFS and OS following ICI treatment (51). Subtype analysis based on immune infiltration patterns further revealed that immune-inflamed and adaptive immune-resistant (PD-L1⁺/CD8⁺) subtypes are associated with higher response rates to ICIs (52). However, PD-L1 expression exhibits significant spatial and temporal heterogeneity. For instance, in a study by Wang et al. (41), PD-L1 expression was significantly higher in the carcinomatous areas of PSC than in the sarcomatoid regions. In contrast, Kim et al. (53) reported the opposite pattern in PCC, where PD-L1 expression was markedly elevated in sarcomatoid components relative to epithelial components. This suggests that a single biopsy may not fully capture the tumor immune landscape, and thus the accuracy of PD-L1 as a predictive biomarker may be limited.

Furthermore, it has been suggested that high PD-L1 expression alone is not an independent predictor of ICI efficacy and must be combined with high TMB to form a more effective predictive criterion (54). TP53 mutations may also potentially predict the efficacy of ICIs in the treatment of advanced patients with PSC (51). High microsatellite instability (MSI-H) has been confirmed as a pan-cancer biomarker for immunotherapy—although it is generally rare in PSC (approximately 7%)—and has been reported to be predictor of survival benefit from ICI treatment (47). In summary, although ICIs are effective in the majority of patients with PSC, due to the high heterogeneity of the disease, the accuracy of predicting immunotherapy response based on a single biomarker remains limited. There are also certain patients with high PD-L1 expression or high TMB who do not respond to ICI treatment (55). This can be attributed to the highly complex interactions that occur within the tumor immune microenvironment. Future directions in research should include the construction of multidimensional models for predicting treatment efficacy, which could aid in more effectively identify the patient population that would derive the greatest benefit. This could include, for example, combining indicators such as PD-L1, TMB, and tumor-infiltrating lymphocytes (TILs) and integrating information on the density and spatial distribution of TILs, the activity of key immune-related signaling pathways, and the assessment of other immunosuppressive mechanisms.

There is also an abundance of clinical data related to the efficacy of ICIs in patients with PSC, with anti-PD-1 antibody being the most prominent, along with pembrolizumab, toripalimab, sintilimab, nivolumab, atezolizumab, camrelizumab, and tislelizumab, among others.

A number of case reports have indicated that pembrolizumab monotherapy demonstrates favorable efficacy in patients with advanced pulmonary PCC, GCC, and SpCC, particularly among older adults. Pembrolizumab facilitates primary tumor resolution, with patients achieving partial response (PR) or complete response (CR) and responses lasting over 17 months in some cases (56-63). This also represents a potential treatment option following resistance to durvalumab or after failure of EGFR-TKI therapy (64,65). However, a few case reports have suggested that pembrolizumab monotherapy lacks efficacy, which may be attributed to extensive metastasis, including rare duodenal involvement (66-69). Additionally, vigilance for adverse reactions such as agranulocytosis and interstitial lung disease (ILD) may be required during pembrolizumab monotherapy (70). In one case of pulmonary SpCC, pembrolizumab monotherapy induced excessive granulocyte colony-stimulating factor (G-CSF) production, which promoted the expression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)-positive M2 macrophages, thereby contributing to resistance to PD-1 inhibition (71). Nivolumab monotherapy has also demonstrated significant efficacy against pulmonary PCC, particularly as a second-line treatment following radiotherapy. It induces rapid response, improves both metastatic and primary lesions, and is associated with prolonged response duration, with the duration of remission being reported to extend beyond 22 months (45,50,54,72). However, case reports have indicated the progression of brain and bone metastases during nivolumab monotherapy (73). Additionally, attention should be paid to potential adverse events such as ILD, nodular granulomatosis, and purpura fulminans (74-76). Patients with nivolumab should also be monitored for pseudoprogression, which may present as increased metastases and aggravated symptoms. Serum tumor marker testing may assist in distinguishing pseudoprogression from true disease progression (77,78). Durvalumab monotherapy is primarily used as consolidation therapy following chemoradiotherapy. It has demonstrated efficacy in achieving remission and improving prognosis, particularly in patients with PCC, with some patients achieving an OS exceeding 30 months (62,79-81). Similarly, toripalimab monotherapy has shown favorable efficacy in patients with PSC, exhibiting PD-L1 overexpression. Even after disease progression, patients may benefit from the combination of toripalimab and local radiotherapy (82). Meanwhile, sintilimab monotherapy has proven to be effective as a second-line treatment after chemoradiotherapy. In one case of PB, the patient achieved a PFS of over 27 months (62,83).

In addition to immune monotherapy, treatment modalities also include immunotherapy combined with chemotherapy and immunotherapy combined with targeted therapy, among others (51).

Immunotherapy as a first-line treatment has been shown to be an independent predictor for improvement in patients with advanced PSC, with two studies reporting a median PFS of 12.5 and 9.2 months and a median OS of 16.0 and 22.8 months, respectively (51,62). Patients with PSC who benefit from ICIs have more active immune-related pathways, such as chemokine signaling pathways and glycolysis (4). When ICIs are used as second-line or above treatment, objective response rate (ORR) can reach 40.5%, the disease control rate (DCR) is 64.8%, and the median OS is 12.7 months in patients with PSC (54). In a cohort of patients who received immunotherapy as either first- or second-line treatment, the PFS also reached 9.6 months, and the 1-year OS rate was estimated to be approximately 50.1% (81). In addition, due to the presence of memory T cells, immunotherapy is also accompanied by a unique tail effect phenomenon, in which the therapeutic effect can be observed even after treatment is stopped (84). Fu et al. (85) reported a case of a patient who received a combination therapy of cetuximab and anlotinib for 3 weeks. After discontinuation, the presence of tail effects manifested as sustained tumor regression, stable low levels of serum carcinoembryonic antigen (CEA), and further improvement in clinical symptoms. This further demonstrates that immunotherapy can provide significant survival benefits for patients with advanced PSC. However, immune-related adverse events (irAEs) inevitably occur during the course of immunotherapy. Studies have shown that approximately 56.5% of patients with PSC will experience irAEs during the course of immunotherapy, with mild irAEs (grades 1 to 2) typically occurring over a longer period of time (86). The consistency between the results from different regions suggests that immunotherapy has good and stable efficacy in patients with PSC and an acceptable safety profile, making it a suitable treatment option.

Immunotherapy is most widely used in combination with chemotherapy. Chemotherapy drugs can induce the death of immunogenic cells, thereby increasing antigen release and enhancing the efficacy of immunotherapy. This strategy has been proven to be effective in NSCLC regardless of PD-L1 expression status (87,88). In a real-world multicenter study, 34 patients with locally advanced or metastatic PSC had good results with first-line chemotherapy and immunotherapy, with an ORR of 70.6%, a median PFS of 10.3 months, and a 2-year survival rate of 57.8%, and two of them with transformation to PSC from LUAD also responded favorably to this treatment regimen (89). Inomata et al. (81), Shimamura et al. (80), and Yorozuya et al. (79) found that patients receiving radiotherapy, chemotherapy, and durvalumab treatment had expected long-term remission, with an OS period of even more than 30 months. Similarly, in a cohort of patients with metastatic PSC, the combination of pembrolizumab with paclitaxel or pemetrexed was superior to immunotherapy alone and was thus indicated to be a viable first-line treatment option (90). In addition to this, immunotherapy combined with chemotherapy can also be used as a neoadjuvant treatment option before surgery (91). However, a few studies reported that ICIs combined with chemotherapy did not provide significantly better efficacy compared with ICIs alone (62,86), which may be due to the fact that patients treated with combination therapy have a more advanced stage of disease.

Immunotherapy in combination with targeted therapy, usually in conjunction with antiangiogenic therapy, has emerged as a means to circumventing the side effects associated with chemotherapy. In a study on patients with PSC and chemotherapy-resistant or multitarget mutations (92), ICIs in combination with antiangiogenic therapy were found to be highly efficacious, significantly prolonging PFS and improving the ORR and DCR (4). The combination of pembrolizumab and anlotinib is an excellent chemotherapy-free option for treatment-naive patients with advanced PSC (high TMB, high PD-L1 expression, and TP53 mutations) (93). A number of studies have examined a regimen consisting of tislelizumab in combination with anlotinib, which may be the preferred strategy for patients with PSC and TP53 mutations. In one case report, a patient achieved clinical complete remission with a PFS of more than 20 months after treatment (94). A female patient who received this regimen for 2 years also achieved significant results and was then treated with localized radiotherapy, which prolonged survival by more than 10 months (95). One patient was switched to this regimen after chemotherapy failed and also had a PFS of more than 1 year (96). However, Pu et al. also reported a patient who developed symptoms of fatal hemoptysis with this regimen, suggesting that clinicians should be more alert to this potential complication (97). In addition to the two combinations mentioned above, sintilimab in combination with anlotinib has also shown promising clinical performance and has been demonstrated to be effective in patients with advanced metastatic NSCLC with rare EGFR mutations, squamous cell carcinoma of the thyroid, or metastatic uroepithelial bladder cancer, among other conditions (98-101). Dai et al. (102) reported a favorable outcome with tolerable adverse effects in an older adult male patient with PSC, 60% TPS, and KRAS and TP53 mutations treated with sintilimab and anlotinib. Bao et al. (103) reported the first case of a patient with PSC and bone metastases who responded well to sintilimab in combination with anlotinib. In addition, in a phase II study, camrelizumab in combination with famitinib demonstrated good efficacy and safety in the treatment of advanced urologic and gynecologic tumors (104). Chu et al. (39) conducted a prospective, multicenter, single-arm study on locally advanced or metastatic PSC and found that camrelizumab in combination with famitinib provided promising activity and acceptable safety.

In conclusion, as precision medicine continues to advance rapidly, innovations are being achieved in combination immunotherapy. Immunotherapy in combination with chemotherapy tends to be more effective when patients have rapidly progressing tumors or extensive metastases that require urgent reduction of tumor load. This strategy also represents a treatment option for patients with low or as-yet-unknown levels of PD-L1 expression. In contrast, for patients with chemotherapy-resistant disease, immunotherapy in combination with antiangiogenic therapy is a more suitable option.

Targeted therapy

Following immunotherapy, targeted therapy is a critical precision medicine approach for patients with PSC harboring certain actionable genetic alterations. Similar to NSCLC, PSC can involve a multitude of genetic mutations. Reports derived from the Catalogue of Somatic Mutations in Cancer (COSMIC) indicated that the top three mutations detectable in patients with PSC are TP53, AT-rich interaction domain 1A (ARID1A), and neurofibromin 1 (NF1), observed in 31%, 23%, and 17% of cases, respectively. TP53 mutations include missense, deletion, and nonsense mutations, which are often mutually exclusive to mesenchymal-epithelial transition (MET) factor exon 14 skipping mutations (12). Nonetheless, the incidence of MET exon 14 skipping mutations is significantly higher in patients with PSC than in those with conventional NSCLC, while the incidence of EGFR activating mutations is lower (51,105). In addition to this, ALK fusion and KRAS mutations are also more common in PSC, and EGFR, KRAS, and ALK mutations are more common in thyroid TF 1 (TTF-1)-positive patients with PSC (1). A series of targeted drugs have been to be proven effective for other types of NSCLC (44,46,51), some of which can be used in patients with PSC with genomic changes, but there remains an urgent need to confirm the efficacy of other drugs. The findings from studies on targeted therapies for common biomarkers in PSC are summarized in Table 3.

Antiangiogenesis

Vascular infiltration is an important cause of poor prognosis, making it a potential indication for antiangiogenic therapy. Bevacizumab is a large-molecule monoclonal antibody and the first antiangiogenic drug approved for first-line treatment of nonsquamous NSCLC (147). One case report described symptom improvement in a patient with PSC patient when this regimen was combined with ICIs (148). However, due to the higher fibrotic content in the TME of PSC, small-molecule inhibitors are often more effective. For example, anlotinib is a new multitarget kinase inhibitor that inhibits tumor angiogenesis and proliferation signaling, with its primary targets including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, FGFR-1, FGFR-2, FGFR-3, FGFR-4, platelet-derived growth factor receptor α/β (PDGFRα/β) and others (82,149). Ma et al. (150) found that anlotinib alone or in combination with immunotherapy was effective in treating PSC, both improving symptoms and prolonging PFS in patients with high Eastern Cooperative Oncology Group performance status (ECOG PS) scores and that the PFS in patients treated with a single agent was longer. Li et al. (94) reported on a patient with a TP53 mutation with poor tolerance to chemotherapy who showed significant improvement in severe anemia after treatment with anlotinib. In another three cases of advanced unresectable PSC, apatinib, an antiangiogenic drug that also targets VEGFR-2, demonstrated short-term efficacy, with two of the patients achieving PR (151). A phase II clinical study also confirmed the efficacy and safety of apatinib, as 96.1% of patients responded to treatment, the short-term efficacy improved, and 25.49% of patients experienced PR, with some attaining long-term remission (152).

MET factor

As a tyrosine kinase receptor, MET is mainly expressed in epithelial cells, and its natural ligand is hepatocyte growth factor (HGF), the aberrant activation of which can lead to the development of malignant tumors (153). MET exon 14 mutations are detected in approximately 22% to 31.8% of patients with PSC, which is much higher than the 3–5% detection rate for those with NSCLC. This mutation is more common in older patients, especially in women without a history of smoking, and the most frequent MET mutation is exon 14 skipping (106,108,109). MET inhibitors have been shown to be effective in this group of patients, with savolitinib being one of the more widely studied inhibitors, as it selectively inhibits the phosphorylation of MET kinase. A phase II clinical study of a Chinese population with locally advanced or metastatic PSC and MET exon 14 mutations demonstrated that once-daily oral administration of 600 mg of savolitinib provided good therapeutic effect, with an ORR of 50%, a DCR of 90%, a median duration of response (DOR) of 12.4 months, and an acceptable safety profile in patients whose tumor response was assessable (34,35). Han et al. (154) and Wang et al. (155) also each reported a case of advanced patients with PSC and MET exon 14 mutation who achieved rapid and durable PR with savolitinib treatment; in one case, the allele frequency of the MET ex14 mutation in plasma circulating tumor DNA was gradually reduced. In addition, other MET inhibitors such as capmatinib and tepotinib have also demonstrated efficacy in treating patients with NSCLC harboring MET mutations in clinical trials (156,157), but it remains to be determined whether they can be similarly applied to patients with PSC.

Epidermal growth factor receptor

In contrast to those with conventional NSCLC, patients with PSC exhibit a lower frequency of EGFR exon 19 deletion and exon 21 L858R mutation (with reported incidences ranging from 1.7% to 28% in across several studies), and these differences may be related to ethnicity, as there is a higher frequency in the Asian population (44,47,105,111,112). Among 15 patients with PCC treated with first-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reported across several studies, the best outcome was achieved in a patient who had a CR of about 35 months; furthermore, 10 patients achieved PR (117-123), but two of them had a PFS of only 1.3 and 1.6 months, respectively (105). Patients with rare multiple target mutations can also benefit from EGFR-TKIs; for instance, one patient with PSC and EGFR exon 21 L858R mutation accompanied by MET amplification was effectively treated with gefitinib combined with crizotinib (158). Third-generation EGFR-TKIs such as osimertinib have also been used in the treatment of patients with PSC. A patient initially diagnosed with unresectable stage III PSC harboring an EGFR mutation was treated with neoadjuvant therapy in the form of osimertinib plus chemotherapy, which resulted in radical resection of the lesion and pathologic complete response (pCR) (124). However, EGFR mutations cannot predict EGFR-TKI efficacy with high accuracy, which may be due to the temporal and spatial evolution of EGFR mutations leading to resistance; for example, threonine 790 methionine (T790M) and NK2 homeobox 4 (NKX2-4) mutations commonly lead to EGFR-TKI resistance (123,159). The heterogeneity within tumors poses an additional challenge, as EGFR-TKIs often produce better therapeutic effects in adenocarcinoma components but are generally ineffective in sarcomatoid components (122).

ALK

The incidence of ALK mutations in patients with PSC is also not high, ranging from about 3.5% to 5.9% in several retrospective studies (105,125), but it has been shown to be significantly associated with the OS of patients (160). The most common type of ALK mutation is rearrangement, which is often seen in young patients who do not smoke (125), and the second most common is fusion, with fusion partners including echinoderm microtubule-associated protein-like 4 (EML4), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), and glypican 1 (GPC1), among others (92,161,162); meanwhile other types of mutations, such as ALK amplification and polyploidy, are much less common. Both the first-generation ALK inhibitor, crizotinib, and the second-generation ALK inhibitor, alectinib, have demonstrated excellent efficacy in patients with other types of NSCLC with ALK gene mutations; for example, treatment of alectinib yielded a PFS of up to 41.6 months in a group of treatment-naïve Asian patients with advanced ALK-positive NSCLC (127). However, the efficacy of ALK inhibitors in patients with PSC has not been extensively reported on and varies widely across individuals, with better efficacy occurring in patients with ALK rearrangements and fusions and worse efficacy occurring in patients with ALK amplification. For the latter group, this poor response to ALK inhibitors makes them potential candidates for ICI therapy (163). Crizotinib treatment was first reported on by Murakami et al. in 2015; since then, six patients with ALK-rearranged PSC have benefited from this therapy, achieving PR, among whom two with PCC had better outcomes with crizotinib than with chemotherapy (125,128,129). In one study, two patients harboring ALK fusion genes had widely different outcomes after treatment with crizotinib: one experienced a PFS of only 2.1 months, and the other had a PFS of 14.0 months and further received alectinib as a second-line treatment, resulting in a PFS of 83.3 months (105). However, when patients have mutations in multiple driver genes including ALK mutations, such as cases with coexisting KRAS mutations, a worse prognosis and poor efficacy can be expected, even when treatment includes combination with chemotherapy (164). At this time, combination treatments consisting of antiangiogenic therapy can be expected to achieve a longer PFS (92).

Chemotherapy and radiotherapy

In the absence of targets for immunotherapy or targeted agents, conventional chemotherapy remains a fundamental treatment option, often serving as the backbone in combination regimens or as an alternative for patients ineligible for more novel therapies. For patients with PSC, chemotherapy regimens are generally aligned with the platinum-based doublet protocols established for NSCLC, such as cisplatin or carboplatin combined with gemcitabine or pemetrexed.

In a study by Wang et al. (165), 960 patients who were treated with chemotherapy alone or in combination as first-line therapy and those who had never used chemotherapy were divided into two groups, and the results showed a significantly higher OS and cancer-specific survival in the former group. Regarding adjuvant chemotherapy, a meta-analysis that included 1,835 patients found that patients who received adjuvant chemotherapy had a significantly longer OS than did those treated with surgery alone (166). This finding was corroborated by a retrospective analysis based on the US National Cancer Data Bank, which included 1,497 cases: adjuvant chemotherapy significantly improved 5-year OS for patients with stage II and III disease, but it did not improve prognosis for those with stage I PSC (167). Other studies, however, have reported contradictory results. For example, in a cohort of 148 patients examined by Lococo et al. (168), adjuvant chemotherapy did not provide a long-term survival advantage compared to surgery alone. Moreover, Gong et al. (169) found that postoperative chemotherapy did not significantly improve the disease-free survival (DFS) in 28 patients with PSC who were matched for disease staging, and the results of a retrospective analysis of 127 patients from the Mayo Clinic were similar (170). These discrepancies may be due to the differences in sample size and certain confounding factors included in different cohorts, as larger sample sizes often yield more convincing results.

Patients with PSC of different histologic subtypes respond differently to chemotherapy. Results from an SEER database study indicated that patients with CS receive the most significant prognostic benefit from perioperative chemotherapy, especially when the tumors are relatively large. In addition, although the difference in survival was not significant compared to those undergoing surgery alone, another study found a degree of benefit from perioperative chemotherapy in patients with PB and SpCC (171). Perioperative chemotherapy has also been found to have a survival benefit in patients with stage II and advanced-stage PCC in another study (172). These differences may be due to the heterogeneity of molecular features and immunophenotypes among PSC subtypes; for example, CS has a greater tendency to proliferate and metastasize, SpCC belongs to a low-proliferative subtype, and PCC is an immune-inflamed phenotype. Therefore, CS often has better response to chemotherapy (52), and this fact should be to be taken into account in clinical applications.

First-line palliative chemotherapy also has highly limited efficacy in patients with locally advanced or metastatic PSC. In related studies, the progression rate was 72%, there was significant improvement in PFS, and a slight increase in OS compared to patient groups that did not undergo chemotherapy; however, the median OS was only 5–8 months (173,174).

Similar to chemotherapy, radiotherapy, as a traditional treatment, has been used for sarcomatoid carcinomas of various organs and is generally used to achieve preoperative tumor shrinkage, postoperative reduction of local recurrence risk, or palliative care for symptomatic relief.

Overall, PSC exhibits limited sensitivity to radiotherapy. Gang et al. reported improved OS in patients with PSC who received radiotherapy (175). In addition, other studies have reported success in treating superior vena cava syndrome (SVCS) due to PSC using brachytherapy with iodine¹²⁵ particles (176). However, after radical radiotherapy in patients with PSC, although there is a low local recurrence rate (9.5%), distant metastases remain highly common (47.6%). Differences in prognosis for radical radiotherapy are also related to tumor size and radiation dose. For example, patients with >5 cm lesions have a significantly worse prognosis, while patients have a better prognosis when the radiation dose is >58 gray equivalent dose in 2 Gy per fraction (177).

Therefore, overall, the suboptimal efficacy of chemotherapy and radiotherapy and the high frequency of drug resistance can be attributed to several resistance mechanisms. As discussed previously, the pathogenesis of PSC is closely associated with EMT, a process involving the high expression of the TF ZEB1. ZEB1 can directly bind to the promoter of the ATP-binding cassette subfamily B member 1 (ABCB1) gene and enhance its expression, thereby increasing the expression of P-glycoprotein, one of the ATP-binding cassette (ABC) transporters. This leads to reduced intracellular drug accumulation and efficacy, which has been demonstrated to be associated with multidrug resistance to platinum agents and taxanes in various tumors (178-180). During EMT, the extracellular matrix of PSC undergoes extensive remodeling and becomes enriched with components such as FN, which impedes the penetration of chemotherapeutic drugs to the target cells in the tumor core (15). Additionally, radiotherapy and chemotherapeutic drugs such as platinum agents primarily induce tumor cell death by triggering DNA damage. However, in PSC, the extremely high mutation frequency of key tumor-suppressor genes (such as TP53) disrupts the core hub of the DNA damage response and repair (DDR), leading to genomic instability and DDR dysfunction (12,181). Consequently, cells subjected to therapeutic stress fail to effectively initiate apoptosis and cell cycle arrest, resulting in drug resistance.

Furthermore, activation of specific oncogenic pathways can directly confer drug resistance. As demonstrated by Kojima et al. (182), pathogenic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are associated with poor postoperative prognosis and chemotherapy resistance in PCC. Constitutive activation of the PI3K/Akt/mTOR pathway promotes cell survival, proliferation, and inhibition of apoptosis, thereby counteracting the cytotoxic effects of chemotherapy. Additionally, certain paraneoplastic features associated with PSC may serve as indicators of chemotherapy resistance. For instance, abnormal elevation and ectopic production of β-human chorionic gonadotropin (β-HCG), a rare phenomenon documented in a case of PCC, have also been shown to correlate with a chemotherapy-refractory phenotype and poorer prognosis (183).

Surgical treatment

While the preceding sections have emphasized systemic therapies for advanced disease, surgical resection has a critical role in the management of early-stage PSC. For eligible patients with localized disease, complete surgical resection remains the cornerstone of potentially curative intent, with the specific approach (e.g., lobectomy, pneumonectomy) being determined according to tumor size, invasion, and patient fitness (93). Studies have demonstrated that surgical intervention provides prognostic benefit, with median survival times (MSTs) ranging from 11 to 23 months and 1-year OS being 42.9% to 77.3% higher than that of nonsurgical patients (20,184,185). When surgery was combined with postoperative adjuvant therapy, a therapeutic improvement was also demonstrated in stage III patients, with the MST increasing to 17.0 months, compared to 8.0 months in those who underwent surgery only (185).

Surgical treatment also entails certain risks, including complications that can lead to death in severe cases (186). Additionally, the higher postoperative recurrence rate also imposes certain limitations on the long-term benefits of surgical treatment. A multicenter study found that patients with PSC after surgery demonstrated an extremely high rate of postoperative distant recurrence of 81%, with a 62% rate of distant recurrence being observed in patients with pathologic stage I who underwent R0 resection (168). Similar results were found in another study, in which the percentage of postoperative recurrence also reached almost 60% in 22 cases treated with radical lobectomy plus mediastinal lymph node dissection (184).

Although surgical intervention remains a key component of treatment for early-stage disease, in clinical practice, a high proportion of patients are already in advanced stages (stages IIIB–IV) that are not amenable to surgical resection at the time of initial diagnosis, and therefore, the role of surgical treatment in patients with PSC remains limited (44).

Conclusions

PSC, a rare and highly aggressive subtype of NSCLC, is characterized by its unique biphasic epithelial-mesenchymal differentiation, which poses significant challenges in both diagnosis and treatment. This review systematically summarizes the core pathophysiology of PSC—EMT and the consequent remodeling of the TME—and provides a comprehensive evaluation of current therapeutic strategies. Studies indicate that although resistance to conventional radiotherapy and chemotherapy is common and surgical outcomes remain unsatisfactory, precision therapy based on molecular profiling has demonstrated transformative potential. PSC exhibits a notably high frequency of driver mutations such as MET exon 14 skipping; however, the efficacy of targeted agents in PSC is generally inferior to that observed in other NSCLC subtypes. The immunologically “hot tumor” phenotype, marked by high PD-L1 expression, suggests that immunotherapy should be prioritized for those patients with PSC. Combination strategies incorporating immunotherapy with antiangiogenic agents or chemotherapy have further expanded the therapeutic landscape. Nevertheless, the selection of patients likely to benefit requires refinement, and the development of more multidimensional predictive models for treatment response remains a critical need.

Future breakthroughs in this field will be achieved through both expanding the depth and breadth of research. In terms of mechanistic studies, it is essential to move beyond static descriptions of EMT and dynamically examine the heterogeneity, evolutionary trajectories, and bidirectional signaling communication among epithelial and sarcomatoid cellular subpopulations within tumors. This can systematically clarify the core pathways driving phenotypic transformation and immune microenvironment heterogeneity. Regarding therapeutic strategies, there is an urgent need to develop approaches that can overcome resistance to targeted agents such as MET inhibitors and to optimize the sequencing and regimens of combination immunotherapy. In the realm of clinical research, given the rarity of PSC, efforts should begin with establishing preclinical models that recapitulate the pathogenesis and therapeutic responses of PSC; moreover, there is a need to promote implementation of clinical trials, such as basket trials based on specific molecular alterations or platform trials capable of simultaneously evaluating multiple therapies, in order to efficiently generate high-level evidence. Ultimately, these endeavors will improve personalized precision therapy for patients with PSC and tangibly improve their outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-886/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-886/coif). Caicun Zhou serves as an Editor-in-Chief of Translational Lung Cancer Research. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: J. Gray)