The relatively recent concept STAS was officially established in the 2015 World Health Organization classification of lung tumor fascicles as a novel mechanism of air space invasion that is associated with a worse prognosis [9–11]. STAS has predominantly been described in ADC, although it may also be recognized in other primary lung malignancies. To date, the exact biological mechanisms underlying the process of STAS are not well understood. Some studies suggest that the standard of care for STAS-positive patients may be lobectomy rather than segmentectomy or wedge resection in ADC due to the high risk of recurrence in STAS-positive patients [12, 21]. Therefore, more work should be performed to improve the preoperative predictive power and STAS identification. Very few studies have been conducted to date that have sought to establish the correlation between hematological and biochemical parameters and STAS in stage I ADC, although hematologic tests are generally applied during surgical resection. Our cohort research of individuals with pathological stage I ADC examined the relationship between preoperative peripheral blood parameters and the risk of STAS and survival outcomes.
In our research, STAS positivity was identified in 45.0% of patients, and STAS correlates with sex, smoking status, disease stage, predominant histological pattern and histopathological differentiation grade, which is comparable with the findings of other investigations [20, 22]. We specifically discovered that patients with increased CEA or high AMC values were more likely to be STAS-positive among regular detection indicators of hematologic testing before surgical procedures, and both characteristics were confirmed to be independent factors increasing the risk of STAS. Daily clinical practice includes peripheral blood testing, making it simple to determine CEA and AMC levels. The glycoprotein CEA, a well-known soluble tumor marker, is only expressed in tumors and not in normal tissues. CEA is frequently used to forecast the recurrence of cancers such as lung cancer and colon cancer [23]. Previous research has demonstrated that a high serum CEA level is a risk factor for lung cancer prognosis [24, 25]. Despite the lower proportion of stage I ADC patients (7.9%) with elevated CEA, our study's findings revealed a statistically significant relationship between elevated CEA levels and STAS. Therefore, it is conceivable that CEA5 g/L represents an independent preoperative predictor for identifying STAS.
Circulating monocytes quickly develop into macrophages during the body's earliest inflammatory responses in many tissues [26]. Studies have revealed that macrophages are double-edged swords with dual potential in cancer. Macrophages have the potential to kill tumour cells and mediate antibody-dependent cellular cytotoxicity and phagocytosis. In contrast, in most established tumours, macrophages contribute to cancer progression and metastasis by various mechanisms, including promotion of cancer cell survival and proliferation, angiogenesis, and suppression of innate and adaptive immune responses [27, 28]. Monocytes can increase the number of tumor-associated macrophages and contribute to tumor progression [29]. A higher density of CD68+ macrophage infiltration was shown by Kyuichi et al to be a significant predictor of STAS in resected ADC [30]. They later discovered that a larger density of M2 polarized macrophages, which exhibit highly expressed CD163+, was associated with a higher prevalence of STAS [31]. Circulating monocyte counts were related to the incidence of STAS in stage I ADC in the current investigation. We hypothesize that the invasion of monocytes or monocyte-derived macrophages—more particularly, M2-polarized macrophages—creates an immunosuppressive tumor microenvironment that promotes the onset and progression of STAS. The inherent precise mechanism of immunosuppression should be clarified in cell function experiments in vitro and animal experiments in vivo in the future. In short, AMC is the most widely available and convenient laboratory test before lung surgical procedures compared to lung macrophages, and the preoperative AMC level could serve as an independent predictor for STAS.
Early-stage NSCLC patients frequently enjoy a better prognosis than those with advanced-stage lung cancer, which has 5-year OS rates of 90 − 73% and 10-year RFS rates of 83.9% [3, 4]. Several clinicopathological variables, including population demographic characteristics, preoperative radiographic features, and postoperative histopathological findings, have been proven to be substantial risk factors for cancer recurrence and death in stage I ADC. In general, STAS was found to be an independent risk factor for NSCLC recurrence as well as mortality [20, 22]. Our study found that STAS was an independent risk factor for recurrence but not for mortality in stage I ADC, similar to results from Han et al. and Chen et al. [11, 32]. We hypothesize that the prognostic impact of STAS varies depending on the disease stage and patient subpopulations. Patients were divided into groups based on their CEA levels, and in the normal-CEA subgroup but not in the increased CEA subgroup, STAS was found to be an independent poor factor for RFS and OS. Moreover, CEA demonstrated an independent prognostic value for both recurrence and mortality in the STAS-negative subpopulation but not in the STAS-positive subpopulation after dividing the population based on the presence or absence of STAS. The AMC value was recognized as an unfavorable prognostic factor affecting RFS only in STAS-positive patients but not in STAS-negative patients. Based on these findings, it is possible to improve the prediction of cancer mortality or recurrence by combining preoperative hematological parameters and postoperative histopathological examination.
There are several limitations of this study. First, we should not ignore the inherent biases of a retrospective study since it is a retrospective, single-center analysis with a limited sample size. Second, the relatively short follow-up time for early lung cancer is another significant limitation. The longest follow-up period was 46 months in the current research. Third, given that our results are exploratory and hypothesis-generating, a larger, multicenter prospective investigation is required to further support them. In the future, it will be important to clarify the fundamental mechanism by which AMC promotes the emergence and development of STAS.
In conclusion, this study comprehensively demonstrated the correlations of preoperative peripheral blood indexes with STAS and survival outcomes in pathological stage I lung ADC. Our findings demonstrated that CEA ≥ 5 µg/L and AMC ≥ 0.38 g/L were independent risk predictors for STAS. For stage I ADC STAS positivity, CEA ≥ 5 µg/L, and AMC ≥ 0.38 G/L were poor prognostic indicators. In particular, STAS was identified as an independent poor factor for RFS and OS in the normal CEA subgroup but not in the elevated CEA subgroup. Elevated CEA levels were recognized as an independent poor factor for RFS and OS in the STAS-negative subpopulation but not in the STAS-positive subpopulation. Thus, after patient subclassification, combining preoperative hematological data with STAS can optimize the prediction of cancer mortality or recurrence.