Predictive value of CT and ¹⁸F-FDG PET/CT features on spread through air space in lung adenocarcinoma

Lung cancer is a highly lethal malignancy and is the leading cause of cancer-related deaths worldwide. The Overall five-year lung cancer survival is relatively low compared to other major malignancies. Early diagnosis and proper treatment of lung cancer are crucial for enhancing patient survival [1, 2]. Lung adenocarcinoma, which is the predominant form of lung cancer, is known as the most fatal cancer globally [3]. With the popularization of imaging tests, more and more lung adenocarcinomas are detected at an early stage. The standard surgery for lung adenocarcinoma is usually anatomical lobectomy and segmental resection or wedge resection can be chosen in combination with the patient's metastatic lymph node status. The spread through air space (STAS) was introduced in the 4th edition of the World Health Organization classification of thoracic tumors in 2015, and was considered as another mode of tumor spread in lung adenocarcinoma [4]. It was defined as micropapillary clusters, solid nests, or single cells that extend beyond the tumor margins into the airspace of the surrounding lung parenchyma, and tumor cells can detach from the main tumor, migrate through the air space, and then reattach to the distant alveolar wall through vascular symbiosis [5]. A study revealed that STAS was a poor prognostic predictor and an aggressive pathological characteristic [2]. STAS represented a detrimental prognostic indicator for both limited resection and radical resection of lung cancer, exerting a negative impact on patient outcomes, and is a prognostic risk factor for local recurrence [6, 7]. Therefore, predicting STAS was useful for developing clinical diagnoses, and treatment plans, and facilitating surgical decision-making for patients. A previous study found that using computed tomography(CT) features to predict STAS had a high sensitivity of 89.2% and specificity of 60.3% and identified the percentage of solid components as an independent predictive factor for STAS [8]. Another study utilized ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography(PET)/CT to predict STAS and found that maximum standardized uptake value (SUVmax) was a valuable indicator for predicting STAS in clinical stage I lung adenocarcinoma [9]. However, there is currently no research comparing the differences between ¹⁸F-FDG PET/CT and CT in predicting STAS in lung adenocarcinoma. The purpose of this retrospective study was to investigate the usefulness and difference of CT and ¹⁸F-FDG PET/CT features in predicting and evaluating the STAS status of lung adenocarcinoma, to provide predictive value for imaging in the clinical diagnosis and treatment of lung adenocarcinoma.

The Ethics Committee of The First Affiliated Hospital of Nanchang University approved this retrospective study, and the requirement for informed consent from participants was not required. The records and information of the patients were anonymized and de-identified before analysis.

Previous studies have mainly focused on using CT or ¹⁸F-FDG PET/CT alone to predict the presence of STAS. To the best of our knowledge, this is the first study to use a combination of ¹⁸F-FDG PET/CT and CT imaging features to predict STAS in lung adenocarcinoma. The nadir criteria were developed following clinical practice guidelines, and both clinicopathologic factors and multiple characterization factors of CT were combined with ¹⁸F-FDG PET/CT for multivariate analysis. Our research findings indicated that there are significant differences in CT and ¹⁸F-FDG PET/CT features between the STAS-positive and STAS-negative groups according to univariate analysis. However, multivariate analysis revealed that the maximum tumor diameter measured by CT and the SUVmax measured by PET/CT were independent predictors of STAS. Furthermore, SUVmax showed a significant superiority over the maximum tumor diameter in predicting STAS. Our results indicate that PET/CT can serve as a non-invasive preoperative method to predict STAS in lung adenocarcinoma, and has important value in treatment decision-making.

Increasing numbers of studies now show that STAS can be used as a predictor of postoperative and healing factors in lung adenocarcinoma and was significantly linked to stronger invasive behavior [14]. In both limited and radical resection groups, STAS was identified as an independent poor prognostic factor for recurrence [6]. The routine inclusion of STAS status in pathology reports can help doctors identify high-risk patients so that they can benefit from additional interventions [15]. A substantial and robust body of scientific literature consistently demonstrates a strong correlation between the presence of STAS and reduced survival rates. Moreover, these findings consistently support the notion that STAS is an independent prognostic factor, regardless of the stage of the tumor [16]. Accurately predicting the presence of STAS in preoperative noninvasive imaging studies can aid preoperative surgical decision-making, and treatment planning and provide a basis for clinical surgery planning [17]. Previous research has indicated that CT imaging features help predict the STAS phenomenon and determine the appropriate surgical strategy before operation [18]. The current research found that the presence of STAS was statistically different in the nodule type, CTR, maximum tumor diameter, maximum solid component diameter, vasculature, pleural invasion, lobulation, and spiculation. This is consistent with Hironori's results based on a semi-quantitative assessment of early STAS in lung adenocarcinomas, which demonstrated that higher STAS was more frequent in patients with small resected solid dominant adenocarcinomas, pleural and lymphovascular invasion, and larger tumor size, and was associated with poorer recurrence-free survival [19].

The presence of STAS was identified as an independent prognostic factor in patients with radiologically pure solid lung adenocarcinoma, and the proportion of solid components was regarded as an independent imaging factor for STAS [8]. In other words, STAS was more likely to be observed in lung adenocarcinomas with a solid component compared to those without [18]. Therefore, STAS is more prevalent in predominantly solid lesions than in partially solid nodules, as well as in GGN [8]. Furthermore, a correlation exists between the type of operation and STAS. Masanori et al. discovered that patients who underwent lobectomy resection had higher levels of CTR and a higher proportion of solid tumors, as well as a higher degree of malignancy in STAS than patients who underwent sublobar resection [20]. Furthermore, STAS demonstrated a poor prognostic impact only in pure solid lesions [21]. A strong correlation exists between nodule size and STAS either. It was concluded that the STAS-positive nodules appeared to have a significantly larger size than the STAS-negative lesions [17]. According to Margerie et al., subsolid pulmonary adenocarcinomas with histological evidence of STAS were found to be larger than those without [22]. Our study found that solid tumors with a CTR of 1 commonly exhibited STAS. Multivariate prediction models indicated that maximum tumor diameter was a useful independent predictor, regardless of other CT features. Therefore, the presence of STAS suggests a higher degree of malignancy in a tumor. Taken together, Our results align with these reports, which suggest that an increase in maximum tumor diameter correlates with a higher chance of STAS occurrence, and that maximum tumor diameter can not only reflect the degree of malignancy and tumor growth but also help predict the presence of STAS. An increase in maximum tumor diameter corresponds to higher amounts of solid components, lower tumor differentiation, higher tumor activity, greater invasive ability, and more aggressive malignancy. This conclusion is consistent with the findings of Zhang, whose study of stage IA lung adenocarcinoma also confirmed that higher maximum tumor diameter and maximum solid component diameter were associated with the presence of STAS [23]. While the results showed no statistically significant difference in perineural invasion, this may reflect that STAS-positive tumor cells detach from the basement membrane of the alveolar septum at the primary site, reattach through the airway, and grow following the alveolar septum distant from the primary lesion, without relying on perineural invasion [24].

The study results indicated that all ¹⁸F-FDG PET/CT metrics, Namely, SUV (SUVmax, SUVmean, SUVpeak), SUL (SULmax, SULmean, SULpeak), MTV, and TLG were significantly higher in STAS-positive lesions. Additionally, half of the qualitative parameter-SUVmax showed the best predictive performance according to multivariable logistic analysis. Consistent with previous findings, a CTR ≥ 0.25 and a SUVmax ≥ 2.5 among preoperative parameters were identified as independent predictors of STAS [25]. Tumors with poor prognoses of high activity or low differentiation show increased FDG uptake due to glucose overexpression. The STAS represents anatomical tumor spread, as reflected by FDG, which represents biological aggressiveness [26]. Measuring the SUVmax of FDG uptake allows for quantitative assessment of the malignant potential of tumor cells, reflects the maximal metabolic activity of the tumor, and helps predict its biological characteristics. A higher SUVmax may be valuable in predicting the presence of STAS [25]. According to Nishimori et al., the frequency of STAS increased significantly with higher histologic grading [9]. Once STAS tumors reach a certain stage, they begin to spread through the airspace, demonstrating not only their spread, but also the increased activity of tumor cells, accelerated growth rate, and thus increased rate of ¹⁸F-FDG/CT uptake. Therefore, the reason for the increased SUVmax in STAS-positive lung adenocarcinomas may reflect the malignant potential and metabolic activity of their tumors. According to Nishimori, STAS is primarily linked to FDG uptake, rather than MTV or TLG, which represent the metabolically active tumor volume, and these volume parameters may not truly reflect the true state of the tumor [9]. However, some scholars that SULmax prediction is an independent prognostic factor for STAS in stage I NSCLC adenocarcinoma, possibly due to the study inclusion criteria and the fact that only SUL-related metrics were calculated and SUVmax was not considered in the study [26], and the results may need to be further confirmed.

In the multivariate logistic regression modeling study cohort, SUVmax of ¹⁸F-FDG PET/CT features in model 2 showed better performance than CT features of maximum tumor diameter in all aspects. Even though both maximum tumor diameter and SUVmax could indicate tumor metabolism and activity, ¹⁸F-FDG PET/CT is a more accurate indicator of tumor activity as the solid fraction of lung adenocarcinoma increases. Therefore, greater tumor activity and higher ¹⁸F-FDG uptake are associated with increased SUVmax, suggesting that lung adenocarcinoma tends to spread through the airspace. Furthermore, the presence of STAS not only increases the risk of the disease and requires more caution during clinical surgery when choosing between lobectomy, segmental resection, or wedge resection. SUVmax can be easily measured on ¹⁸F-FDG PET/CT and may assist in the appropriate therapeutic management of lung cancer.

This study has several limitations. Firstly, this study was a retrospective single-center study with a relatively small sample size, which may have led to selection bias and requires external validation studies. Second, this study only evaluated STAS prediction for one histologic type of lung adenocarcinoma. More histologic types of lung cancer should be included in future studies. Finally, since the present results only focus on the prediction model, further validation in clinical practice may be needed. Due to the small sample size, this preliminary study was unable to evaluate CT and PET predictors within subgroups of the same tumor stage. We recognize this as an important limitation, and will validate predictors within stage-matched groups in future research to control for potential confounding by overall stage.

In conclusion, the SUVmax of ¹⁸F-FDG PET/CT is an imaging biomarker capable of accurately predicting STAS in lung adenocarcinoma. SUVmax showed satisfactory diagnostic performance in predicting STAS preoperatively and was superior to other measures. Predicting the presence of STAS based on preoperative information is critical for guiding treatment decisions. It also supports surgical decision-making and provides valuable information for patient survival and prognosis.