DISCUSSION
PSC is a rare subtype of NSCLC, accounting for less than 1% of all lung cancers, with a poor prognosis7,8. It can metastasize through the lymph nodes and even to the bones, adrenal glands, liver, and brain. Despite the progress of imaging, the use of CT, MRI, and even PET-CT examination methods are helpful in the diagnosis of PSC, but puncture biopsy is the best strategy to obtain pathological and genetic testing, whilst biopsy-specific can provide the pathological basis for the immune checkpoint at the same time9. This PSC patient’s genetic testing (NGS) revealed ROS1 positivity, which inhibited nodule growth and improved symptoms after treatment with a ROS1 inhibitor (Crizotinib)10, allowing the patient to undergo surgery. However, when this patient discovered a small pulmonary nodule first two years ago, he did not insist on follow-up and review, resulting in the loss of the best opportunity for surgery11. Sincerely, despite receiving chemotherapy, antiangiogenetic, and immunochemical therapy, as well as having undergone two operations, the patient’s condition rapidly deteriorated due to postoperative recurrence and metastasis. Our team once questioned whether the patient needed surgery after receiving chemotherapy, antiangiogenetic therapy, and immunochemotherapy as well as whether it was a mistake to stop taking Anlotinib and Crizotinib during the time leading up to surgery.
As previously reported that adjuvant chemotherapy was significantly associated with overall survival (OS) in resectable PSC patients2, a 5-year survival rate may be increased by approximately 5%12. However, for advanced stage-PSC(IVa), non-squamous, the effect of radiotherapy and chemotherapy is not so sensitive10, making the treatment difficult. The operation was not the first line of treatment for PSC in stage IVa11,13. The NCCN NSCLC Panel recommended atezolizumab in combination with bevacizumab/carboplatin (or cisplatin)/paclitaxel (ABCP) as first-line therapy options for some patients with metastatic non-squamous NSCLC in contrast to bevacizumab/chemotherapy based on phase III randomized trial11. Apealea and Cisplatin were selected for chemotherapy. Together, since ROS1 was overexpressed in this patient, a combination of chemotherapy, targeted angiogenesis, and precise targeted-ROS1 immunochemotherapy prevented the progress of this PSC preoperational, while the operation exacerbated deterioration. Therefore, extensive panel-based genetic testing may deeper affect the efficacy in prognosis for PSC patients.
In NSCLC, KRAS mutations, especially transversion mutations, were often found in smokers, while EGFR , ALK , ROS1 , andRET mutations or translocations might be more common in light smokers or non-smokers, other alterations such as TP53 ,NRAS, and MAP2K1 are also more common in smokers1. This contradicts the fact that our patient has smoked for a long time, but the overexpression of ROS1 rather than TP53 or NRAS may be a plausible explanation for the early success of the patient’s chemotherapy, antiangiogenic therapy, and targeted therapy.
Previous research suggested that TTF-1 and Napsin A, both of which had a sensitivity of about 80% and were more easily evaluated as a nuclear stain, were well-established markers for the identification of adenocarcinoma differentiation1,14,15. This patient’s IHC results were negative because Syn was not well expressed (Figure S2, G ) (Figure S3, J ). P40 has been reported as the most specific and sensitive marker for diagnosing squamous cell differentiation14. This patient’s classification of PSC was in line with 2021 WHO Classification of Lung Tumors1, TTF-1 is positive (Figure 2, C )(Figure S3, K) , but Napsin A (Figure S2, E )(Figure S3, G) and p40 are negative (Figure S2, F )(Figure S3, H) , suggested that PSC was poorly differentiated NSCLC, favor adenocarcinoma1. Although the Ki 67 proliferation index is not an essential criterion in the 2021 WHO classification, for PSC, it can be introduced as an ideal criterion and included in the pathological report with better diagnostic and therapeutic value, which may also be closely related to cancer metastasis1,16. However, all of the positive results are based on new-generation detection methods, including NGS and biomarker of immuno-checkpoint, etc., which are significant clinically for patients with advanced NSCLC and can be targeted more for neoadjuvant chemotherapy or immunotherapy17. At one cancer center, tissue-based NGS and liquid biopsy testing for patients with advanced NSCLC to improve the diagnostic process. Combining these two techniques has greater clinical value for patient diagnosis and the detection of complete biomarkers during disease progression18.
Although tumor types change over time, most of them depend on accurately distinguishing subtypes of NSCLC, such as squamous cell carcinoma and non-squamous cell non-small cell carcinoma. Although classical genes like epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) have few targeted mutations in PSC, PD-L1 overexpression was frequently observed19. Therefore, reasonable and effective molecular testing, including molecular typing selection of corresponding genes and PD-L1 detection, could be helpful for the treatment of PSC patients1,6. As previously stated, this patient’s TPS and CPS (PD-L1) expression levels were 50% and 55%, respectively. In NSCLC, in most cases, only PD-L1 expression on tumor cells (fraction of tumor proportion; percentage of positive cells expressing membrane staining) was associated with a predictive biomarker of immune checkpoint inhibitor therapy20. Moreover, although PD-L1 detection is an imperfect predictor of the clinical efficacy of immune checkpoint inhibitors, currently, it is still the most important predictor of first-line immuno-targeted therapy21.
A recent study from one of China’s larger medical centers found that neoadjuvant chemotherapy was significantly associated with better survival and that it should be recommended for surgically treated PSC patients, particularly those with advanced cancer, younger age, or a higher BMI2. Additionally, Abdallah et al.22 conducted a retrospective study using the National Cancer Database. The results showed that neoadjuvant chemotherapy had long-term survival advantages for PSC patients with stage II and III, but did not benefit patients with stage I. While Chaft23 reported that neoadjuvant chemotherapy is only effective in relatively advanced PSC (stage IIb-IIIa vs Ib-IIa). As a result, when combined with the current patient’s condition, we have enough evidence to continue giving this patient neoadjuvant chemotherapy and immuno-targeted therapy to improve his survival.