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.