Our study found that the preoperative splenic area measured by CT can serve as an independent predictor of OS in early-stage NSCLC patients, as confirmed by publicly available data. These results suggest that the splenic area reflects cancer-related mechanisms and may merit being integrated into lung cancer treatment algorithms. In this study, we included patients independent of stage and histological subtypes as a reflection of the inhomogeneous lung cancer population. By doing so, we could test the true value of this potential prognostic marker in an everyday clinical setting.
Previous studies have established a potential link between splenic volume and treatment response in NSCLC patients receiving immunotherapy [16,17,18,19]. For example, in metastatic NSCLC, where systemic therapies such as immunotherapy are predominant, the evidence suggesting splenic volume as a surrogate marker for the efficacy of immune checkpoint inhibitors is compelling [18]. This correlation might be attributed to the spleen’s integral role in immune modulation and response to systemic therapies. However, translating these findings to a surgical context presents challenges due to the distinct nature of the treatment and disease progression. Additionally, the intriguing findings from studies on patients with sepsis, where preoperative splenic volume was shown to be an independent predictor of OS, add another layer of complexity [28]. These studies highlight the potential of spleen metrics as a prognostic tool, yet their applicability to NSCLC patients undergoing surgery remains to be explored. In this uncharted territory, our study makes a novel contribution by evaluating the prognostic value of the preoperative splenic area, measured by CT, in early-stage NSCLC patients who had undergone radical lung cancer resection. This focus on a surgical cohort is crucial, as it may uncover different dynamics in the prognostic value of spleen metrics compared to those observed in patients undergoing immunotherapy. Our findings suggest that the preoperative splenic area is indeed a significant predictor of overall survival in early-stage NSCLC patients. This observation not only adds a new dimension to the literature on splenic metrics in cancer but also raises questions about the underlying mechanisms that might govern this relationship in the context of surgical treatment for NSCLC. In light of these insights, future research should aim to unravel the complex interactions between splenic metrics and cancer outcomes in various treatment modalities, including surgery. Such studies will be instrumental in refining prognostic tools and potentially tailoring treatment strategies based on spleen metrics in NSCLC patients.
A study retrospectively investigated 232 patients with sepsis [28] and showed that the splenic volume of patients with sepsis appeared to be associated with mortality. They found that patients with a smaller splenic volume had a significantly higher risk of mortality than those with a normal splenic volume. However, we found a U-shaped association between splenic area and mortality. That is, patients in larger and smaller splenic areas both had worse outcomes. We did not perform stratified analysis in the abnormal splenic area group due to numerical limitations but confirmed our findings in subgroup analyses of different pathological stages, tissue types, etc. More prospective and multicenter cohort studies with large samples are needed to confirm the “U” association between the splenic area and prognosis of NSCLC.
Most of the studies investigated the relationship between the spleen and cancer outcome based on splenic volume [16,17,18,19]. The reason why we used the splenic area as a prognostic biomarker has important strengths. First, the splenic area is based on the largest cross-sectional area of the spleen and is independent of the shape or location of the spleen, thus reflecting the size of the splenic parenchyma more stably and consistently. In volumetric analysis, several factors can introduce errors and variability. The shape of the spleen, its position within the body, potential rotation, and deformation all contribute to challenges in accurately determining the volume. These factors can lead to inconsistencies in volumetric measurements across different patients or even in the same patient over time. In contrast, the splenic area is measured on a single axial CT slice that displays the spleen’s largest cross-sectional area. This approach minimizes the influence of shape and positional variations. By focusing on the maximum cross-sectional area, we reduce the potential for measurement variability that can arise from the aforementioned factors. The result is a more consistent and reproducible measurement, which is crucial in a clinical research setting. Additionally, splenic area measurement is simpler and faster. It only requires selecting one slice on CT, instead of measuring and summing multiple slices.
Possible explanations for these results are as follows. First, multiple studies have demonstrated a connection between certain types of cancer and chronic inflammation. This inflammation may weaken the immune system and help cancer grow by causing immunological inversion. It may be caused by aberrant myelopoiesis, a disease that causes myeloid-derived suppressor cells (MDSCs) to accumulate in the body [29, 30]. Similar to neutrophils, these cells are populations of immature myeloid cells that circulate in cancer patients. They suppress immune responses that are made against cancer. MDSCs inhibit the immune response by increasing tumor cell survival, invasion into healthy tissue, angiogenesis, and metastasis to promote cancer [31,32,33,34,35]. Second, in animal models, splenomegaly (enlarged spleen) is connected with MDSC accumulation. This association with hepatocellular cancer was discovered [36]. Third, in mouse models of lung cancer, the spleen is also a source of increased splenic myeloid progenitor cells, which can significantly boost the host response and affect tumor progression [37]. Finally, splenectomy increases liver metastases in colorectal cancer mouse models, highlighting the importance of the spleen in activating an immune response against the tumor [37]. This could be the cause of the worsening prognosis for NSCLC patients as the area of the spleen increases and decreases.
The findings of our study also support the idea that sex-related differences in spleen size may impact immune function and tumor malignancy in NSCLC patients. We found that male patients had a significantly higher splenic area than female patients, which is consistent with previous literature [38]. One factor that may contribute to the sex-related differences in spleen size is body size and weight [39]. Male patients are generally larger and heavier than female patients, which may result in a larger spleen size. In addition, hormones such as testosterone, which are present in higher levels in male patients, can stimulate red blood cell production, which can also lead to an increase in splenic size [40]. Our study also showed that the preoperative splenic area in the abnormal group was associated with significantly higher mortality in males (HR, 2.73; 95% CI, 54–4.82), although it was not a risk factor in females. This may be due to differences in the immune response between male and female patients. Specifically, studies have shown that female patients generally have a stronger immune response than male patients, which may play a role in their ability to fight off cancer cells [41]. This suggests that the splenic area may be a more useful prognostic marker in male NSCLC patients than in female patients. More research is needed to fully understand the relationship between sex-related differences in spleen size, immune function, and tumor malignancy in NSCLC patients.
One of the implications of our study is that the preoperative splenic area could serve as a simple, inexpensive, and noninvasive prognostic biomarker that could help screen high-risk patients with early-stage NSCLC and guide surgical treatment decisions. However, it is important to note that optimal cut-off values for the splenic areas depend on the sex of the patients in my study, as shown by our curve-fitting analysis. To effectively apply these findings in another clinical setting, we suggest that further research is warranted to validate our findings across different patient populations and healthcare settings. Such research could explore the application of preoperative splenic area measurements in various clinical scenarios, including their potential role in monitoring disease progression and response to treatment. Additionally, it would be beneficial to investigate the integration of this marker into existing clinical workflows and decision-making processes. This could involve developing guidelines for the interpretation of splenic area measurements, as well as training programs for radiologists and clinicians to enhance their understanding and utilization of this tool. Moreover, future studies should consider the interplay of the splenic area with other clinical parameters and biomarkers to develop a more comprehensive prognostic model for early-stage NSCLC. This holistic approach could lead to more personalized and effective treatment strategies, ultimately improving patient outcomes.
The large population and externally validated results of this study ensure the robustness of the findings under multiple conditions and the significant benefits of our study. However, one limitation is that due to the small number of patients with large and small spleens in our cohort, we cannot know whether large or small splenic areas are independently associated with poor prognosis in NSCLC patients. Second, we did not perform a randomized exposure analysis, so retrospective studies may suffer from issues such as confounding and selection bias. Therefore, prospective multicenter randomized controlled trials are needed to verify our results. Third, we did not collect immune parameters associated with splenic size and postoperative splenic area, so we could not determine the correlation between splenic area and related immune parameters or whether changes in splenic area would affect patient outcomes. Fourth, several major survival factors, such as surgeon experience and patient functional status, were not included in the data. These factors may have an impact on patients’ postsurgery survival times. Furthermore, we did not adjust for potential confounding factors that may affect the splenic area or NSCLC prognosis, such as comorbidities, medications, and lifestyle factors. Moreover, there was no information on the incidence and cause of death, as well as cancer specificity, recurrence-free survival, and disease-free survival. Finally, we did not compare the splenic area with other radiologic markers of spleen size or function, such as splenic density or perfusion, which may also have prognostic value. Therefore, our results should be interpreted with caution, and further prospective multicenter randomized controlled trials are needed to confirm our findings and elucidate the underlying mechanisms.
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