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Background
Spread through air spaces (STAS) is a spreading phenomenon of lung cancers, which is defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. To date, several articles have reviewed the studies concerning the significance of STAS; however, most articles focused on the prognosis without summarizin...
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Citations
... Genetic mutations are crucial factors that contribute to tumorigenesis and play vital roles in cellular signal transduction. They have significant regulatory effects on cell cycle processes such as growth, proliferation, differentiation, and apoptosis of tumor cells [18,19] . Recently, molecular events such as EGFR and KRAS gene mutations and ALK gene rearrangements have emerged as the most important focus in lung cancer treatment and prognosis research [20,21] . ...
Objective: Lung adenocarcinoma exhibits diverse genetic and morphological backgrounds, in addition to considerable differences in clinical pathology and molecular biological characteristics. Among these, the phenomenon of spread through air space (STAS), a distinct mode of lung cancer infiltration, has rarely been reported. Therefore, this study aimed to explore the relationship between STAS tumor cells and the clinical and molecular characteristics of patients with lung adenocarcinoma, as well as their impact on prognosis. Methods: This study included 147 patients who were diagnosed with lung adenocarcinoma at the Inner Mongolia Autonomous Region Cancer Institute between January 2014 and December 2017. Surgical resection specimens were retrospectively analyzed. Using univar-iate and multivariate Cox analyses, we assessed the association between STAS and the clinicopathological features and molecular characteristics of patients with lung adenocarcinoma. Furthermore, we investigated the effects on patient prognosis. In addition, we developed a column-line plot prediction model and performed internal validation. Results: Patients with positive STAS had a significantly higher proportion of tumors with a diameter ≥2 cm, with infiltration around the pleura, blood vessels, and nerves, and a pathological stage >IIB than in STAS-negative patients (P < 0.05). Cox multivariate survival analysis revealed that clinical stage, STAS status, tumor size, and visceral pleural invasion were independent prognostic factors influencing the 5-year progression-free survival in patients with lung adenocarcinoma. The predictive values and P values from the Hosmer-Lemeshow test were 0.8 and 0.2, respectively, indicating no statistical difference. Receiver operating characteristic curve analysis demonstrated areas under the curve of 0.884 and 0.872 for the training and validation groups, respectively. The nomogram model exhibited the best fit with a value of 192.09. Conclusions: Clinical stage, pleural invasion, vascular invasion, peripheral nerve invasion, tumor size, and necrosis are independent prognostic factors for patients with STAS-positive lung adenocarcinoma. The nomogram based on the clinical stage, pleural invasion, vas-cular invasion, peripheral nerve invasion, tumor size, and necrosis showed good accuracy, differentiation, and clinical practicality.
... The existence of isolated tumor cells floating among alveolar spaces separate from the main lesion has been observed for over two decades and has been referred to using different nomenclature in various types of cancers [1]. Two representative studies have established this in lung adenocarcinoma, denoted as tumor spread through air spaces (STAS) [2,3]. ...
... The differences in clinical results from early studies dealing with the correlation between negative prognosis and STAS could be due to the lack of quantitative or qualitative analysis on the morphology of STAS. Several subtypes exist: (1) single cells, (2) micropapillary or ring-like clusters, and (3) solid nests or tumor islands [1,18]. Quantitative differences considering the distance from the edge of the tumor margin or the amount of each STAS could be evaluated. ...
... Quantitative differences considering the distance from the edge of the tumor margin or the amount of each STAS could be evaluated. The diversity of STAS seems to be related to recurrence rates and survival among small pathological stage I adenocarcinoma [1,19,20]; therefore, the grading of STAS should be considered in predicting the risk of recurrence. ...
Simple Summary
This study explored how lung cancer spreads through air spaces in small tumors (up to 2 cm) and its impact on patient outcomes. Focusing on small-size and early-stage lung adenocarcinomas, the researchers analyzed medical records of patients treated between 2012 and 2022. We measured the distance of floating cancer cells spread from the main tumor through alveolar spaces and categorized patients based on whether this spread was present and its extent. Interestingly, while overall survival rates were similar across groups, patients with more extensive spread (2 mm or more) experienced a higher chance of cancer recurrence even in this very early cancer. This suggests that understanding the extent of spread through air spaces is crucial in predicting cancer recurrence in small lung tumors. Further research with a larger group of patients is needed to confirm these risk factors and improve treatment strategies.
Abstract
This study aimed to identify the clinical manifestation and implications according to the grading of tumor spread through air spaces in early-stage small (≤2 cm) pathological stage I non-mucinous lung adenocarcinomas. Medical records of patients with pathological stage I tumors sized ≤2 cm were retrospectively reviewed and analyzed. The furthest distance of the spread through air spaces from the tumor margin was measured on a standard-length scale (mm). Enrolled patients were categorized into spread through air spaces (STAS) (−) and STAS (+), and STAS (+) was subdivided according to its furthest distance as follows: STAS (+)-L (<2 mm) and STAS (+)-H (≥2 mm). Risk factors for STAS (+) included papillary predominant subtype (p = 0.027), presence of micropapillary patterns (p < 0.001), and EGFR (p = 0.039). The overall survival of the three groups did not differ significantly (p = 0.565). The recurrence-free survival of STAS (+)-H groups was significantly lower than those of STAS (−) and STAS (+)-L (p < 0.001 and p = 0.039, respectively). A number of alveolar spaces were definite risk factors for STAS (+)-H groups (p < 0.001), and male gender could be one (p = 0.054). In the patient group with small (≤2 cm) pathological stage I lung adenocarcinomas, the presence of STAS ≥ 2 mm was related to significantly lower recurrence-free survival. For identifying definite risk factors for the presence of farther STAS, more precise analysis from a larger study population should be undertaken.
... Consistent with these aforementioned findings, our study revealed that patients who underwent sublobectomy exhibited a similar prognosis to those who underwent lobectomy. Previous research has identified STAS as a risk factor influencing postoperative prognosis in stage I NSCLC patients [18,[29][30][31], but no significant difference in prognosis was observed in this study. This may be due to the fact that the concept of STAS was only recently introduced in 2015 [15]. ...
Background: The objective of the present study was to identify patients with pathologic stage I lung adenocarcinoma (LUAD) who are at high risk of recurrence and assess the efficacy of adjuvant chemotherapy (ACT) in these individuals.
Methods: A retrospective study was conducted on 1504 patients with pathologic stage I LUAD who underwent surgical resection at Shanghai Pulmonary Hospital and Sun Yat-sen University Cancer Center. Cox proportional hazard regression analyses were performed to identify indicators associated with a high risk of recurrence, while the Kaplan-Meier method and Log-rank test were employed to compare recurrence-free survival (RFS) and overall survival (OS) between patients with ACT and those without
it.
Results: Four independent indicators, including age (≥ 62 years), visceral pleural invasion (VPI), predominant pattern (micropapillary/solid), and lymphovascular invasion (LVI), were identified to be significantly related with RFS. Subsequently,
patients were classified into high-risk and low-risk groups by LVI, VPI, and predominant pattern. The administration of ACT significantly increased both RFS (P < 0.001) and OS (P = 0.03) in the high-risk group (n = 250). Conversely, no significant difference
was observed in either RFS (P = 0.45) or OS (P = 0.063) between ACT and non-ACT patients in the low-risk group (n = 1254).
Conclusions: Postoperative patients with stage I LUAD with factors such as LVI, VPI, and micropapillary/solid predominant pattern may benefit from ACT.
... According to the satatistics from the Department of Pathology, five cases were categorized as true artifacts which were distinguished from STAS. These cases shared the same characteristics: loose tissue fragments were seen in blocks after cutting through tumor bed [17].The mean age of included patients was 63.8 [8.8] years (Range 35-83 years). Postoperative pathological diagnosis showed that most cases were early-stage lung cancer (I + II) (n = 218, 90.5%). ...
Objective
A single-center study was conducted to explore the association between STAS and other clinical features in surgically resected adenocarcinoma to enhance our current understanding of STAS.
Methods
We retrospectively enrolled patients with lung adenocarcinoma (n = 241) who underwent curative surgeries. Patients undergoing surgery in 2019 were attributed to the training group (n = 188) and those undergoing surgery in January 2022 to June 2022 were attributed to the validation (n = 53) group. Univariate and multivariate logistic regression analyses were used to identify predictive factors for STAS, which were used to construct a simple nomogram. Furthermore, ROC and calibration curves were used to evaluate the performance of the nomogram. In addition, we conducted decision curve analysis (DCA) to assess the clinical utility of this nomogram.
Results
In our cohort, 52 patients were identified as STAS-positive (21.6%). In univariate analysis, STAS was significantly associated with age, surgical approach, CEA, CTR (Consolidation Tumor Ratio), TNM stage, tumor grade, gross tumor size, resection margin, vessel cancer embolus, pleural invasion, lymph node metastasis, high ki67 and positive PD-L1 staining (P < 0.05). Lower age, CTR > 0.75, vessel cancer embolus, high Ki67 and PD-L1 stain positive were significant predictors for STAS during multivariate logistics analysis. A simple nomogram was successfully constructed based on these five predictors. The AUC values of our nomogram for the probability of tumor STAS were 0.860 in the training group and 0.919 in the validation group. In addition, the calibration curve and DCA validated the good performance of this model.
Conclusion
A nomogram was successfully constructed to identify the presence of STAS in surgically resected lung adenocarcinoma patients.
... However, STAS was reportedly associated with the poor prognosis of other types of lung cancer, such as lung squamous cell carcinoma, 20 lung pleomorphic carcinoma, 21 and lung neuroendocrine tumors. 22 Jia et al. 23 also showed that clinical characteristics such as age, gender, and the carcinoembryonic antigen (CEA), were predictors of STAS in lung cancer. To the best of the present authors' knowledge, studies focusing on clinical stage IA NSCLC [excluding pure GG nodules (pGGNs)] and incorporating the relevant CT radiological features and valuable clinical information for predicting the STAS status are rare. ...
Purpose:
To investigate the value of clinical characteristics and radiological features for predicting spread through air spaces (STAS) in patients with clinical stage IA non-small cell lung cancer (NSCLC).
Methods:
A total of 336 patients with NSCLC from our hospital were randomly divided into two groups, i.e., the training cohort (n = 236) and the internal validation cohort (n = 100) (7:3 ratio). Furthermore, 69 patients from two other hospitals were collected as the external validation cohort. Eight clinical patient characteristics were recorded, and 20 tumor radiological features were quantitatively measured and qualitatively analyzed. In the training cohort, the differences in clinical characteristics and radiological features were compared using univariate and multivariate analysis. A nomogram was created, and the predictive efficacy of the model was evaluated in the validation cohorts. The receiver operating characteristic curve and area under the curve (AUC) value were used to evaluate the discriminative ability of the model. In addition, the Hosmer-Lemeshow test and calibration curve were used to evaluate the goodness-of-fit of the model, and the decision curve was used to analyze the model's clinical application value.
Results:
The best predictors included gender, the carcinoembryonic antigen (CEA), consolidation-to-tumor ratio (CTR), density type, and distal ribbon sign. Among these, the tumor density type [odds ratio (OR): 6.738] and distal ribbon sign (OR: 5.141) were independent risk factors for predicting the STAS status. Moreover, three different STAS prediction models were constructed, i.e., a clinical, radiological, and combined model. The clinical model comprised gender and the CEA, the radiological model included the CTR, density type, and distal ribbon sign, and the combined model comprised the above two models. A DeLong test results revealed that the combined model was superior to the clinical model in all three cohorts and superior to the radiological model in the external validation cohort; the cohort AUC values were 0.874, 0.822, and 0.810, respectively. The results also showed that the combined model had the highest diagnostic efficacy among the models. The Hosmer-Lemeshow test showed that the combined model showed a good fit in all three cohorts, and the calibration curve showed that the predicted probability value of the combined model was in good agreement with the actual STAS status. Finally, the decision curve showed that the combined model had a better clinical application value than the clinical and radiological models.
Conclusion:
The nomogram created in this study, based on clinical characteristics and radiological features, has a high diagnostic efficiency for predicting the STAS status in patients with clinical stage IA NSCLC and may support the creation of personalized treatment strategies before surgery.
... It refers to the presence of tumor cells that extend into air spaces around the tumor without continuity with the primary tumor itself [16]. In recent years, STAS has been widely identi ed as a novel and reliable prognostic risk factor in lung cancer and is closely associated with invasive characteristics such as pleural invasion, vascular invasion, lymphatic invasion and greater tumor diameter [17][18][19][20]. In addition, it serves as an independent predictive indicator for poor survival in intermediate and advanced lung cancer [19,21,22]. ...
Purpose
Spread through air spaces (STAS) is an independent predictive indicator of poor survival in intermediate and advanced non-small cell lung cancer (NSCLC). However, whether the presence of STAS is significantly related to worse prognosis in early-stage NSCLC, especially in IA stage NSCLC, remains unclear. Thus, this study was designed to explore the role of STAS in predicting postoperative long-term survival of pathological IA stage NSCLC patients based on current evidence.
Methods
Several databases were searched up to January 16, 2023, for relevant studies. The primary and secondary outcomes were recurrence-free survival (RFS) and overall survival (OS)/cancer-specific survival (CSS). The hazard ratios (HRs) and 95% confidence intervals (CIs) were combined, and all statistical analyses were conducted by STATA 15.0 software.
Results
A total of eight retrospective studies were included. The pooled results demonstrated that the presence of STAS was significantly associated with worse RFS (HR = 1.84, 95% CI: 1.52–2.23, P < 0.001), OS (HR = 1.87, 95% CI: 1.47–2.39, P < 0.001) and CSS (HR = 2.03, 95% CI: 1.05–3.94, P = 0.035) in pathological IA stage NSCLC. In addition, subgroup analysis based on country showed similar results.
Conclusion
The presence of STAS is predictive of poor long-term survival of pathological IA stage NSCLC patients. However, more prospective high-quality studies are still needed to verify the above results.
... Lung tumors can spread through a process known as spread through air spaces (STAS), which is characterized by the presence of tumor cells in the lung parenchyma that extend past the margin of the primary tumor [25]. Although it may also be present in other primary lung cancers, it has primarily been characterized in lung adenocarcinoma [26]. ...
Aim:
Tumor budding is a significant prognostic parameter that has been related to aggressive behavior in early-stage tumors of various origins. The aim of this study was to evaluate the clinicopathological significance of tumor budding in pathologic stage (pStage) I lung adenocarcinomas.
Methods:
This study comprised 107 patients who underwent curative resection for pStage I lung adenocarcinomas at our hospital between December 2010 and January 2016. We examined tumor budding on routine hematoxylin and eosin (H&E) slides from resected specimens. Tumors were categorized into two groups based on the degree of tumor budding: low grade (grade 0-1) and high grade (grade 2-3). We evaluated the relationship between tumor budding and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters.
Results:
There is a significant difference (p = 0.002) between the 5-year DFS rates of the high-grade and the low-grade tumor budding group, which were 70 % and 90 %, respectively. High-grade tumor budding positive patients from the same pathological stage (p < 0.001; HR = 2.93 [1.51-5.68]) and clinical stage (p = 0.002) had poorer cumulative survival rates than low grade tumor budding positive patients. High grade tumor budding was positively associated with spread through air spaces (STAS) (p < 0 0.001), lymphovascular invasion (LVI) (p < 0.001), tumor necrosis (p < 0.001), high SUVmax value (SUVmax>3.0) (p < 0.001), and tumor size >20 mm (p = 0.024). High-grade tumor budding was significant prognostic factor of OS (p < 0.006) and DFS (p < 0.001) on univariate Cox regression hazard model analysis. However, it did not show significance in the multivariate analysis (p > 0.05).
Conclusions:
High-grade tumor budding is an independent prognostic factor and associated with adverse clinicopathological features and poor survival rates. We proposed that high-grade tumor budding should be recognized as a new prognostic parameter and will be beneficial in predicting the clinical course in pStage I lung adenocarcinomas.
... However, this phenomenon is rarely seen in patients with early-stage NSCLC. STAS has also previously been shown to be a risk factor for the postoperative prognosis of patients with stage I NSCLC [38][39][40][41], but no significant difference in survival was observed in this study. This may be due to the fact that STAS could be easily confused with artifacts such as loose tumor tissue fragments, which led to a bias toward the diagnosis [42,43]. ...
Simple Summary
A retrospective study was performed on 955 eligible patients with stage I lung adenocarcinoma (LUAD) after surgery. The systematic oxidative stress score (SOS) was established based on three biochemical indicators, including serum creatinine (CRE), lactate dehydrogenase (LDH), and uric acid (UA). SOS is an independent prognostic indicator for stage I LUAD. In addition, the constructed nomogram based on SOS could accurately predict the survival of those patients.
Abstract
This study aimed to construct an effective nomogram based on the clinical and oxidative stress-related characteristics to predict the prognosis of stage I lung adenocarcinoma (LUAD). A retrospective study was performed on 955 eligible patients with stage I LUAD after surgery at our hospital. The relationship between systematic-oxidative-stress biomarkers and the prognosis was analyzed. The systematic oxidative stress score (SOS) was established based on three biochemical indicators, including serum creatinine (CRE), lactate dehydrogenase (LDH), and uric acid (UA). SOS was an independent prognostic factor for stage I LUADs, and the nomogram based on SOS and clinical characteristics could accurately predict the prognosis of these patients. The nomogram had a high concordance index (C-index) (0.684, 95% CI, 0.656–0.712), and the calibration curves for recurrence-free survival (RFS) probabilities showed a strong agreement between the nomogram prediction and actual observation. Additionally, the patients were divided into two groups according to the cut-off value of risk points based on the nomogram, and a significant difference in RFS was observed between the high-risk and low-risk groups (p < 0.0001). SOS is an independent prognostic indicator for stage I LUAD. These things considered, the constructed nomogram based on SOS could accurately predict the survival of those patients.
... 36 There is no consensus whether sublobar resection increases the risk of locoregional recurrence compared with lobectomy in patients with STAS. 20,[36][37][38][39] A few studies suggested that sublobar resection was associated with a higher risk of recurrence in patients with stage IA and presence of STAS. 20,36,37 Kagimoto et al. 40 described that prognosis after sublobar resection, however, was comparable with that of lobectomy in lung adenocarcinoma with STAS without increasing locoregional recurrence. ...
... 20,[36][37][38][39] A few studies suggested that sublobar resection was associated with a higher risk of recurrence in patients with stage IA and presence of STAS. 20,36,37 Kagimoto et al. 40 described that prognosis after sublobar resection, however, was comparable with that of lobectomy in lung adenocarcinoma with STAS without increasing locoregional recurrence. Regarding adjuvant treatment, Chen et al. 29 found that adjuvant chemotherapy improved outcomes in STAS-positive patients with stage IA who underwent sublobar resection. ...
... In the literature, it is still controversial whether sublobar resection increases the risk of locoregional recurrence compared with lobectomy in patients with STAS. 20,[37][38][39] A few studies agreed that sublobar resection was associated with higher risk of recurrence in patients with STAS, 20,36,37 whereas Kagimoto et al. 40 disagreed. Taking this into account, it is reasonable to suggest that STAS-positive patients who undergo sublobar resection may potentially benefit from a completion lobectomy or adjuvant therapy to decrease the risk of recurrence. ...
Background
Tumor spread through air spaces (STAS) in lung adenocarcinoma is a novel mechanism of invasion. STAS has been proposed as an independent predictor of poor prognosis. The aim of this study was to evaluate the correlations between STAS status and other clinicopathologic variables and to assess the prognostic implications of STAS and the distance from the edge of the tumor to the farthest STAS in patients with resected lung adenocarcinoma.
Material and methods
This is a single-institution retrospective observational study. We included all patients with resected lung adenocarcinoma from January 2017 to December 2018 at La Paz University Hospital. The cut-off for the distance from the edge of the tumor to the farthest STAS was 1.5 mm and was assessed by the area under the receiver operating characteristic curve.
Results
A total of 73 patients were included. STAS was found in 52 patients (71.2%). Histological grade 3 (P = 0.035) and absence of lepidic pattern (P = 0.022) were independently associated with the presence of STAS. The median recurrence-free survival (RFS) was 48.06 months [95% confidence interval (CI) 33.58 months to not reached]. STAS-positive patients had shorter median RFS [39.23 months (95% CI 29.34-49.12 months)] than STAS-negative patients (not reached) (P = 0.04). STAS-positive patients with a distance from the edge of the tumor to the farthest STAS ≥1.5 mm had an even shorter median RFS [37.63 months (95% CI 28.14-47.11 months)]. For every 1 mm increase in distance, the risk of mortality increased by 1.26 times (P = 0.04).
Conclusions
Histological grade 3 and absence of lepidic pattern were independently associated with the presence of STAS. STAS was associated with a higher risk of recurrence. The distance from the edge of the tumor to the farthest STAS also had an impact on overall survival.
... Fourth, our prediction model was solely based on imaging features because our main hypothesis was that the imaging features could reflect the information of the existence of STAS. However, clinical factors such as age, gender, and serum carcinoembryonic antigen are also reported to be predictors of STAS, and the addition of these factors may lead to a more predictive model 27 . Lastly, there is room to further reduce data sampling bias by applying sophisticated methods to building a prediction model, such as nested cross validation; however, we needed to leave a test cohort aside in advance for the following survival outcome analysis. ...
The spread through air spaces (STAS) is recognized as a negative prognostic factor in patients with early-stage lung adenocarcinoma. The present study aimed to develop a machine learning model for the prediction of STAS using peritumoral radiomics features extracted from preoperative CT imaging. A total of 339 patients who underwent lobectomy or limited resection for lung adenocarcinoma were included. The patients were randomly divided (3:2) into training and test cohorts. Two prediction models were created using the training cohort: a conventional model based on the tumor consolidation/tumor (C/T) ratio and a machine learning model based on peritumoral radiomics features. The areas under the curve for the two models in the testing cohort were 0.70 and 0.76, respectively (P = 0.045). The cumulative incidence of recurrence (CIR) was significantly higher in the STAS high-risk group when using the radiomics model than that in the low-risk group (44% vs. 4% at 5 years; P = 0.002) in patients who underwent limited resection in the testing cohort. In contrast, the 5-year CIR was not significantly different among patients who underwent lobectomy (17% vs. 11%; P = 0.469). In conclusion, the machine learning model for STAS prediction based on peritumoral radiomics features performed better than the C/T ratio model.
