Our study explored the value of several preoperative systemic inflammatory markers in predicting specific components and their association with outcomes in stage IA lung adenocarcinoma using a relatively large sample population. Only the preoperative NLR was informative for micropapillary component determination, while none of the systemic inflammatory markers were associated with CIR in stage IA lung adenocarcinoma.
As limited tumor resection is becoming an acceptable approach for small peripheral lung nodules, accurately recognizing the solid and micropapillary components preoperatively or intraoperatively, which may not be suitable for limited resection [12, 13], is extremely important for optimal surgical planning. However, the accuracy of identifying solid or micropapillary components based on preoperative needle biopsy or intraoperative frozen sections is unsatisfactory [28, 29]. Many studies have demonstrated that some CT scan image features are meaningful in the prediction of micropapillary or solid components [15, 16]. However, some of these characteristics are described subjectively and qualitatively, and reproducibility is a significant limiting factor to their widescale clinical use. Cha et al. [30] reported that solid appearance, tumor diameter extent of 2.5 cm, maximum standardized uptake value extent of 7, and tumors exceeding stage I were independent indicators for the micropapillary and solid components. However, limited resection is no longer suitable for patients with these characteristics. Moreover, owing to its high cost, positron emission tomography has not become a routine examination for early-stage lung cancer in China. Previous research has explored the association between certain genes and the microcapillary component. A higher expression of c-MET and chemokine ligand 14 are found in patients with the micropapillary component and could serve as possible biomarkers for the micropapillary component in lung adenocarcinoma [31, 17]. However, these techniques are expensive and difficult to implement.
Systemic inflammatory markers can be easily calculated using blood count analysis. We found that patients with a solid component had no significant change in preoperative NLR, PLR, or LMR compared to patients without a solid component, while patients with a micropapillary component showed an elevated preoperative NLR compared with those without a micropapillary component. Moreover, multivariate analysis verified the role of preoperative NLR as an independent indicator of the micropapillary component. To the best of our knowledge, this is the first study to clearly indicate that there is a correlation between preoperative NLR and the micropapillary component in stage IA lung adenocarcinoma. However, it must be emphasized that, as the AUC value generated from the ROC curve was relatively low, caution should still be exercised when using the preoperative NLR level or combined score based on the preoperative NLR level, CEA level, and tumor size to determine the existence of the micropapillary component in patients considered to have stage IA lung adenocarcinoma. In clinical practice, the preoperative NLR may be used as the preliminary screening method to predict whether stage IA lung adenocarcinomas contain a micropapillary component. The use of the preoperative NLR value in combination with other clinicopathological parameters should be explored to improve sensitivity and specificity in future.
The specific mechanism supporting the correlation between preoperative NLR and micropapillary components remains unclear. Previous studies have reported a higher NLR in smokers compared to that in nonsmokers [32], but this trend was not observed in our study. Our results show that the micropapillary component was more common in nonsmokers, which is consistent with a previous report [33]. Taken together, the high preoperative NLR, which is associated with stage IA adenocarcinomas with a micropapillary component, reported herein may occur independent of smoking status. Tumor tissues secrete various kinds of inflammatory factors, which could stimulate the proliferation of peripheral blood neutrophil [34]. Meanwhile, elevated neutrophil levels could contribute to cancer progression through various mechanisms [35, 36]. In contrast, lymphocytes are a key mediator of immune surveillance against tumor cells [37]. Low lymphocyte level is associated with a poorer immune response to tumors and is often observed in patients with advanced tumors [38]. Therefore, NLR is commonly recognized as an indicator of tumor progression [18, 19]. The micropapillary component was reported to be generated from the papillary component in lung adenocarcinoma, indicating that the appearance of the micropapillary component is a manifestation of lung adenocarcinoma progression [39], which may explain why preoperative NLR was increased among stage IA lung adenocarcinomas containing a micropapillary component. However, patients with another component with intense aggressive behavior, i.e., adenocarcinoma with a solid component, did not show increased preoperative NLR in our study. Mucin 1 (MUC1) gene is mainly expressed on micropapillary components [40]. As a powerful chemoattractant, previous reports have revealed that MUC1 was involved in the recruitment of neutrophils, which may also be responsible for the elevated preoperative NLR in stage IA lung adenocarcinomas containing a micropapillary component [41, 42].
Systemic inflammatory markers are believed to have prognostic potential in advanced tumors [19–21]. However, their value in early-stage lung cancer remain controversial as some studies have found that preoperative NLR does not exhibit good prognostic value in stage I lung cancer [43, 44]. Our results are consistent with these findings, and preoperative NLR, LMR, or PLR were not correlated with the CIR in stage IA lung adenocarcinoma. One possible explanation for this inconsistency may be that stage IA lung adenocarcinoma can achieve a relatively high cure rate through radical surgery, and our results showed that < 10% of patients experienced tumor recurrence events. Thus, radical surgery may weaken the value of preoperative systemic inflammatory markers in predicting the outcomes of stage IA lung adenocarcinoma. From this perspective, the serial monitoring of systemic inflammatory markers pre- and postoperatively may provide more information on outcomes than may preoperative systemic inflammatory markers, which requires further in-depth analysis [45].
This study has some limitations. First, the study was retrospective in nature, and all data were obtained from one center; thus, patient selection bias was inevitable. Validation through settings in different institutions, that is, a multicenter prospective study, should be conducted to verify our results. Second, systemic inflammation marker levels can be influenced by various factors, and, although we formulated strict exclusion criteria, there may still be unexpected factors that could influence systemic inflammation marker levels, including undiscovered comorbidities and drug usage, which may result in potential bias.