Pulmonary sarcomatoid carcinoma (PSC) is a group of non-small cell lung cancers (NSCLC) that contain components of spindle or giant cells. According to the 2015 World Health Organization (WHO) classification, it can be classified into five subgroups: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma [1]. The prevalence of PSC is very low. Recent population-based studies in the United States revealed that 0.4% of patients with lung cancer had PSC, and in Korea, 2.35% of patients with NSCLC who underwent curative surgery had PSC [2,3]. Because of its rarity, there are limited data regarding its clinical manifestation, treatment, and prognosis of PSC. Unfavorable prognosis is anticipated owing to its pathological feature of poorly differentiated tumors. Some authors reported that PSC patients had worse clinical outcomes than ordinary lung cancer patients [2,4]; however, others found that there was no significant survival difference between PSC and ordinary NSCLC [5,6]. Currently, tyrosine kinase inhibitor (TKI) is recommended in treatment of NSCLC patients who have epidermal growth factor receptor (EGFR) mutation, and novel immune checkpoint inhibitors are also recommended as first-line therapy in selected patients [7]; however, their efficacy has not been well studied in PSC. This study aimed to investigate the clinicopathological characteristics, treatment modalities and responses, and prognostic factors of PSC in Korea.

In this study, we examined clinical characteristics, macro- and microscopic features, treatment response, and prognostic factors of PSC. With regard to microscopic features, we paid special attention to EGFR mutation and PD-L1 expression because TKI and immune check point inhibitor have recently replaced conventional cytotoxic chemotherapy. In patients tested, the proportions of EGFR mutation and high PD-L1 expression were 18.2% and 61.5%, respectively. Approximately 46% of patients were primarily treated with chemotherapeutic agents, and they showed fair treatment response. Although age and time from symptom onset to diagnosis were statistically significant, their clinical relevance was unclear.

The baseline demographics were similar to the findings from previous studies. PSC was more prevalent in males, smokers, and the elderly [11]. Respiratory symptoms were the most common chief complaint [12]. However, tumors were detected incidentally in about onefourths of our patients, reflecting the popularity and usefulness of routine health examinations.

The primary lesion typically presented in the right lobe and the upper lobe. It is well known that PSC presents more frequently in upper lobes [11]. However, we could identify neither the clinical significance nor any underlying mechanism. Interestingly, none of the patients had a primary lesion in the right middle lobe despite the result of right lobe dominancy. The primary lesion was located peripherally more than twice as frequently as being centrally located. In regards to centricity, there have been mixed results regarding the predominant location of primary lesions. Fishback et al. [13] reported that 60% of lesions were peripherally located. In contrast, Koss et al. [14] reported that 38% of lesions were peripherally located. It is important to note that both studies did not provide the definition of central or peripheral lesion. The proportion of central or peripheral lesion may change per the selected definition used in the particular study.

Pleomorphic carcinoma was the most common subtype, followed by spindle cell carcinoma. Other studies also demonstrated that pleomorphic carcinoma was most common. These results may be due to a pathologic definition of pleomorphic carcinoma that encompasses the widest range of cellular components. For a similar reason, spindle or giant cell carcinomas were rare because they consist almost entirely of spindle cells or giant cells [1,3,13]. Interestingly, spindle cell carcinoma presented in more than one-thirds of patients in our study. In contrast to other studies that analyzed surgical specimens only, our study included needle biopsy specimens. This explains why spindle cell carcinomas were relatively common. All three surgical specimens were pleomorphic carcinoma.

It is well known that PSC has a worse prognosis than does ordinary NSCLC, and this was partly true in our study, but studies present contradictory outcomes for PSC and ordinary NSCLC. Pelosi et al. [5] demonstrated that PFS and OS of pleomorphic carcinoma were not significantly different from those of ordinary NSCLC. Nakajima et al. [6] also reported that there was no statistically significant difference in prognosis between PSC and ordinary NSCLC. However, these results should be interpreted with caution; the former included patients with stage I and pleomorphic carcinoma subtype only; the latter encompassed various stages and subtypes of PSC, but did not provide exact data such as 5-year survival rate or median OS. In our study, the median OS of the patients who underwent surgical resection was about 17 months, which was very similar to the data presented by Martin et al. [15]. These authors compared the survival time of PSC and ordinary NSCLC by propensity score matching, and demonstrated that PSC patients had shortened survival times with more rapid disease recurrence. Previous studies usually focused on patients who had been initially treated with surgical resection. Notably, our study collected more patients who had received palliative chemotherapy as their primary treatment rather than receiving surgery. Outcomes of chemotherapy against PSC is also known to be unfavorable. Vieira et al. [4] demonstrated that 69% of patients showed progressive disease (PD), and only 16.5% of patients showed PR. Median PFS and OS were 2.0 and 6.3 months, respectively. Bae et al. [16] reported that median OS was only 5 months and no patients responded to first-line chemotherapy. In our study, 25% of all patients receiving chemotherapy showed PR, and only 16.7% showed PD. The median PFS and OS were about 2.8 and 8.6 months, respectively. These results were better than findings from previous reports even though median PFS and OS of NSCLC were about 5.0 and 11.0 months in recent studies [17].

The occurrence of EGFR mutation was 18.2% in the patients who had been tested for, and Chang et al. [18] published a similar result in 2011. However, the actual proportion was difficult to estimate in our study because 15 patients had not been tested. Patients with EGFR mutation had been initially treated with EGFR TKI; mean OS in these patients was longer than in patients treated with platinum-based doublet therapy. However, their outcomes were at extreme ends of the spectrum: one died 54 days after diagnosis, and the other, showing PR, died 736 days after diagnosis. Efficacy of EGFR TKI for PSC was described in previous studies with promising results. In one patient harboring EGFR mutation who received TKI as first line treatment, complete response was maintained for 35 months [19]. EGFR TKI was also effective in a patient possessing EGFR mutation whose primary lesion was wild type and recurring [20]. EGFR mutation test should be performed in all PSC patients considering the frequent occurrence of EGFR mutation and the efficacy of EGFR TKIs.

Half of patients’ specimens were available for examination of PD-L1 expression. 61.5% of patients showed high expression based on TPS. Earlier studies demonstrated that PSC had higher expression of PD-L1 than ordinary NSCLC [21,22]. Although the reason why PD-L1 expression is higher in PSC is not understood, some authors hypothesized that epithelial-mesenchymal transition may have a role [23,24], and others suggested associations with K-ras mutation [22,25]. The association between K-ras mutation and PD-L1 expression could be explained by heavier smoking in PSC patients, a conclusion supported by Dix Junqueira Pinto et al. [26], who showed that patients with smoking history were more likely to express PD-L1 than patients who never smoked. However, there was no significant correlation between PD-L1 expression and smoking dose (p = 0.713) or PD-L1 expression and smoking status (p = 0.308) in our study. PD-L1 expression had a positive prognostic value on OS in univariate analysis but was insignificant in multivariate analysis. This result is consistent with other studies regarding PSC [22,23]. The PD-L1 expression seems to have limitations in predicting prognosis of PSC. Despite this, examination of PD-L1 expression is recommended because PSC patients generally show higher PD-L1 expression, and it could affect treatment planning and strategy.

There are some limitations in our study. This study was retrospective and with only a small number of patients. Therefore, our results may not be appropriate for generalization. However, these problems are inevitable to some degree because of the rarity of PSC. A multicenter collaborative project should be undertaken to overcome these issues. Additionally, it should be noted that the shortage of surgical specimens likely contributes to the high proportion of spindle cell carcinoma cases and this presents a risk of bias by distorting the ratio of PSC case components.

PSC is a rare tumor with discouraging prognosis even after complete resection. Moreover, it is known to be refractory to chemotherapy. However, our study suggests that PSC patients had a comparatively fair response to chemotherapy. The prevalence of EGFR mutation was not infrequent, and the outcome of EGFR TKI was noticeable. The introduction of PD-1/PD-L1 pathway blockade and high PD-L1 expression in PSC would provide broader treatment options. Extensive workups of biomarkers on target agents, as well as active treatment with cytotoxic chemotherapy, EGFR TKIs, or immune checkpoint inhibitors are necessary to achieve better results and more data regarding PSC management.