Article

Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread Through Air Spaces (STAS)–Positive T1 Lung Adenocarcinoma: A Propensity Score–Matched Analysis1

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Abstract

Introduction: Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (a) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (b) effect of surgical margin/tumor diameter ratio in STAS-positive patients, and (c) potential utility of frozen section (FS) for detecting STAS intraoperatively. Methods: We investigated 1497 patients who underwent lobectomy (n=970) or sublobar resection (n=527) for T1N0M0 lung ADC, following propensity-score matching. Outcomes were analyzed using a competing-risks approach. The effect of margin/tumor ratio on recurrence pattern (locoregional and distant) was investigated in sublobar patients. Five pathologists evaluated the feasibility of intraoperatively identifying STAS using FS (sensitivity, specificity, interrater reliability). Results: On multivariable analysis following propensity-score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio, 2.84; P<0.001) and lung cancer-specific death (subhazard ratio, 2.63; P=0.021) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin/tumor ratio (margin/tumor ratio ≥1 vs. <1: 5-year cumulative incidence of recurrence [CIR], 16% and 25%); among patients without STAS, locoregional recurrences occurred in patients with margin/tumor ratio <1 (5-year CIR, 7%). Sensitivity and specificity for detecting STAS by FS were 71% and 92%, with substantial interrater reliability (Gwet's AC1, 0.67). Conclusions: In T1 lung ADC patients with STAS, lobectomy was associated with better outcomes than sublobar resection. Pathologists can recognize STAS on FS.

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... Currently, the clinical significance of STAS has garnered increasing attention. Numerous studies have investigated the association between STAS and the clinicopathological characteristics and semantic features of lung cancer, as well as its prognostic implications for patients with early-stage lung cancer treated with various surgical approaches (3,4). An increasing body of evidence demonstrated that the presence of STAS substantially diminishes the overall survival (OS) and recurrence-free survival (RFS) rates in lung cancer, particularly in stage I lung adenocarcinoma (5)(6)(7). ...
... However, STAS is linked to locoregional recurrence in patients undergoing sub-lobar resection for lung cancer (10). Studies have reported a heightened risk of distant and local recurrence following sub-lobar resection of STAS-positive tumors, a risk not observed in patients undergoing lobectomy (1,3). Hence, preoperative identification of STAS aids in selecting the most suitable surgical approach. ...
... These research findings suggest that the inclusion of clinical features in the combined model does not significantly enhance its performance, emphasizing the potential of radiomics features as valuable biomarkers for preoperative CT-based prediction of STAS. Several studies have consistently shown that limited resection in stage IA lung adenocarcinoma patients with STAS leads to significantly lower rates of RFS and OS compared to lobectomy (3). Notably, STAS in stage IA lung cancer patients treated with lobectomy no longer poses a significant risk for recurrence and overall survival (33). ...
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Background To accurately identify spread through air spaces (STAS) in clinical stage IA lung adenocarcinoma, our study developed a non-invasive and interpretable biomarker combining clinical and radiomics features using preoperative CT. Methods The study included a cohort of 1,325 lung adenocarcinoma patients from three centers, which was divided into four groups: a training cohort (n = 930), a testing cohort (n = 238), an external validation 1 cohort (n = 93), and 2 cohort (n = 64). We collected clinical characteristics and semantic features, and extracted radiomics features. We utilized the LightGBM algorithm to construct prediction models using the selected features. Quantifying the contribution of radiomics features of CT to prediction model using Shapley additive explanations (SHAP) method. The models' performance was evaluated using metrics such as the area under the receiver operating characteristic curve (AUC), negative predictive value (NPV), positive predictive value (PPV), sensitivity, specificity, calibration curve, and decision curve analysis (DCA). Results In the training cohort, the clinical model achieved an AUC value of 0.775, the radiomics model achieved an AUC value of 0.836, and the combined model achieved an AUC value of 0.837. In the testing cohort, the AUC values of the models were 0.743, 0.755, and 0.768. In the external validation 1 cohort, the AUC values of the models were 0.717, 0.758, and 0.765, while in the external validation 2 cohort, 0.725, 0.726 and 0.746. The DeLong test results indicated that the combined model outperformed the clinical model (p < 0.05). DCA indicated that the models provided a net benefit in predicting STAS. The SHAP algorithm explains the contribution of each feature in the model, visually demonstrating the impact of each feature on the model's decisions. Conclusion The combined model has the potential to serve as a biomarker for predicting STAS using preoperative CT scans, determining the appropriate surgical strategy, and guiding the extent of resection.
... These data are presented in a confusion matrix in Table 1. Five previous studies have also compared intraoperative frozen section examination with definitive paraffinbased histopathology, (12,(17)(18)(19)(20) as detailed in Table 2. ...
... Year N AUC Sensitivity Specificity Accuracy Walts et al. (12) 2018 48 -48% 100% -Eguchi et al. (17) 2019 48 -71% 92% -Villalba et al. (18) 2021 100 0.67 44% 91% 71% Zhou et al. (19) 2021 163 -55% 80% 74% Ding et al. (20) 2023 294 -55% 85% 74% This study 2024 38 0.85 70% 100% 92% Table 1. Confusion matrix of the results of the intraoperative frozen section examination and the histopathological analysis. ...
... However, the authors did not clearly describe a standardized protocol for the frozen section pathology technique and obtained limited samples of normal lung parenchyma adjacent to the lesion. (12) The following year, Eguchi et al. (17) analyzed a sample of 48 T1N0 adenocarcinomas, evaluated by 5 different pathologists, who achieved a sensitivity of 71%, specificity of 92%, and 75% agreement among them. The authors did not describe the frozen section methodology, using only the criterion of the resected non-neoplastic adjacent parenchyma being at least one third the size of the main tumor. ...
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Objective: To establish the accuracy of frozen section examination in identifying tumor spread through air spaces (STAS), as well as to propose a reproducible technical methodology for frozen section analysis. We also aim to propose a method to be incorporated into the decision making about the need for conversion to lobectomy during sublobar resection. Methods: This was a nonrandomized prospective study of 38 patients with lung cancer who underwent surgical resection. The findings regarding STAS in the frozen section were compared with the definitive histopathological study of paraffin-embedded sections. We calculated a confusion matrix to obtain the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and accuracy. Results: The intraoperative frozen section analysis identified 7 STAS-positive cases that were also positive in the histopathological examination, as well as 3 STAS-negative cases that were positive in the in the histopathological examination. Therefore, frozen section analysis was determined to have a sensitivity of 70%, specificity of 100%, PPV of 100%, NPV of 90.3%, and accuracy of 92% for identifying STAS. Conclusions: Frozen section analysis is capable of identifying STAS during resection in patients with lung cancer. The PPV, NPV, sensitivity, and specificity showed that the technique proposed could be incorporated at other centers and would allow advances directly linked to prognosis. In addition, given the high accuracy of the technique, it could inform intraoperative decisions regarding sublobar versus lobar resection.
... The presence of spread through air spaces (STASs) in early-stage lung adenocarcinoma is a significant prognostic factor associated with disease recurrence and poor outcomes [1,2]. STAS has been reported to be a significant risk factor for recurrence in small-sized NSCLCs treated with limited resection [3,4]. Among patients with STAS-positive T1 lung adenocarcinoma, those treated with lobectomy have been shown to have better outcomes than those treated with sublobar resection [3]. ...
... STAS has been reported to be a significant risk factor for recurrence in small-sized NSCLCs treated with limited resection [3,4]. Among patients with STAS-positive T1 lung adenocarcinoma, those treated with lobectomy have been shown to have better outcomes than those treated with sublobar resection [3]. Traditionally, STAS detection relies on pathological examinations by experienced pathologists. ...
... Our cohort also demonstrated similar results, as STAS was a significant factor associated with shorter disease-free survival (p = 0.01) but did not affect overall survival. Again, in agreement with previous research [3], our study showed that STAS was a significant factor for ...
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Simple Summary This study included 227 patients, among whom 27.7% (63/227) were diagnosed with tumors spread through air spaces (STASs), which have been shown to be associated with shorter recurrence-free survival and poor prognosis. A prediction model was developed to forecast tumor STAS in early-stage lung adenocarcinoma pathology images. The radiomics prediction model demonstrated good performance, with an AUC value of 0.83. This prediction model can assist pathologists in the diagnostic processes of clinical practice. Abstract The presence of spread through air spaces (STASs) in early-stage lung adenocarcinoma is a significant prognostic factor associated with disease recurrence and poor outcomes. Although current STAS detection methods rely on pathological examinations, the advent of artificial intelligence (AI) offers opportunities for automated histopathological image analysis. This study developed a deep learning (DL) model for STAS prediction and investigated the correlation between the prediction results and patient outcomes. To develop the DL-based STAS prediction model, 1053 digital pathology whole-slide images (WSIs) from the competition dataset were enrolled in the training set, and 227 WSIs from the National Taiwan University Hospital were enrolled for external validation. A YOLOv5-based framework comprising preprocessing, candidate detection, false-positive reduction, and patient-based prediction was proposed for STAS prediction. The model achieved an area under the curve (AUC) of 0.83 in predicting STAS presence, with 72% accuracy, 81% sensitivity, and 63% specificity. Additionally, the DL model demonstrated a prognostic value in disease-free survival compared to that of pathological evaluation. These findings suggest that DL-based STAS prediction could serve as an adjunctive screening tool and facilitate clinical decision-making in patients with early-stage lung adenocarcinoma.
... STAS consists of micropapillary clusters, solid nests, or single cancer cells that invade the surrounding lung parenchyma's air spaces 4 . Research groups worldwide have published data on over 3500 patients, finding that 15-69% of lung adenocarcinoma patients exhibit STAS, strongly correlating with lower survival rates and higher recurrence [5][6][7][8][9][10][11] . Specifically, Hassan A Khalil's team analyzed the pathology and clinical characteristics of 787 lung cancer surgical specimens and found that overall survival and recurrence-free survival were significantly lower in the STAS group compared to the non-STAS group, while the incidences of locoregional and distant recurrence nearly doubled. ...
... Intraoperative frozen section (FS) diagnosis assists clinicians in making decisions during surgery, including adjusting the scope and methods of surgery and promptly assessing surgical margins. Clinical studies have shown that lung cancer patients with STAS in stage T1 might have better survival outcomes with lobectomy compared to sublobar resection 5 . Paraffin-embedded sections (PSs) are also a fundamental method in pathological examinations, used to study the pathogenesis, pathophysiology, and molecular biology characteristics of diseases, providing a scientific basis for disease prevention, treatment, and control 17,18 . ...
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Spread through air spaces (STAS) is a distinct invasion pattern in lung cancer, crucial for prognosis assessment and guiding surgical decisions. Histopathology is the gold standard for STAS detection, yet traditional methods are subjective, time-consuming, and prone to misdiagnosis, limiting large-scale applications. We present VERN, an image analysis model utilizing a feature-interactive Siamese graph encoder to predict STAS from lung cancer histopathological images. VERN captures spatial topological features with feature sharing and skip connections to enhance model training. Using 1,546 histopathology slides, we built a large single-cohort STAS lung cancer dataset. VERN achieved an AUC of 0.9215 in internal validation and AUCs of 0.8275 and 0.8829 in frozen and paraffin-embedded test sections, respectively, demonstrating clinical-grade performance. Validated on a single-cohort and three external datasets, VERN showed robust predictive performance and generalizability, providing an open platform (http://plr.20210706.xyz:5000/) to enhance STAS diagnosis efficiency and accuracy.
... STAS consists of micropapillary clusters, solid nests, or single cancer cells that invade the surrounding lung parenchyma's air spaces [4]. Research groups worldwide have published data on over 3,500 patients, finding that 15% to 69% of lung adenocarcinoma patients exhibit STAS, strongly correlating with lower survival rates and higher recurrence [5], [6], [7], [8], [9], [10], [11]. Specifically, Hassan A Khalil's team analyzed the pathology and clinical characteristics of 787 lung cancer surgical specimens and found that overall survival and recurrence-free survival were significantly lower in the STAS group compared to the non-STAS group, while the incidences of locoregional and distant recurrence nearly doubled. ...
... Intraoperative frozen section (FS) diagnosis assists clinicians in making decisions during surgery, including adjusting the scope and methods of surgery and promptly assessing surgical margins. Clinical studies have shown that lung cancer patients with STAS in stage T1 might have better survival outcomes with lobectomy compared to sublobar resection [5]. Paraffin-embedded sections (PSs) are also a fundamental method in pathological examinations, used to study the pathogenesis, pathophysiology, and molecular biology characteristics of diseases, providing a scientific basis for disease prevention, treatment, and control [17] [18]. ...
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Spread through air spaces (STAS) is a distinct invasion pattern in lung cancer, crucial for prognosis assessment and guiding surgical decisions. Histopathology is the gold standard for STAS detection, yet traditional methods are subjective, time-consuming, and prone to misdiagnosis, limiting large-scale applications. We present VERN, an image analysis model utilizing a feature-interactive Siamese graph encoder to predict STAS from lung cancer histopathological images. VERN captures spatial topological features with feature sharing and skip connections to enhance model training. Using 1,546 histopathology slides, we built a large single-cohort STAS lung cancer dataset. VERN achieved an AUC of 0.9215 in internal validation and AUCs of 0.8275 and 0.8829 in frozen and paraffin-embedded test sections, respectively, demonstrating clinical-grade performance. Validated on a single-cohort and three external datasets, VERN showed robust predictive performance and generalizability, providing an open platform (http://plr.20210706.xyz:5000/) to enhance STAS diagnosis efficiency and accuracy.
... However, research suggests that patients with STAS-positive status experience a notably reduced recurrence-free survival (RFS) rate when undergoing sublobectomy compared to lobectomy. [11][12][13][14] In clinicalstage T1N0 lung adenocarcinoma, the STAS positivity rate ranges from 11.6% to 39.5%. 12,[15][16][17][18][19] Preoperative or intraoperative identification of STAS can optimize the surgical modality and improve the prognosis for affected patients. ...
... [11][12][13][14] In clinicalstage T1N0 lung adenocarcinoma, the STAS positivity rate ranges from 11.6% to 39.5%. 12,[15][16][17][18][19] Preoperative or intraoperative identification of STAS can optimize the surgical modality and improve the prognosis for affected patients. Although intraoperative frozen section detection of STAS has limitations owing to its low sensitivity, 20 the pathologic diagnosis of STAS remains vital. ...
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Objectives To develop computed tomography (CT)-based models to increase the prediction accuracy of spread through air spaces (STAS) in clinical-stage T1N0 lung adenocarcinoma. Methods Three cohorts of patients with stage T1N0 lung adenocarcinoma (n = 1258) were analyzed retrospectively. Two models using radiomics and deep neural networks (DNNs) were established to predict the lung adenocarcinoma STAS status. For the radiomic models, features were extracted using PyRadiomics, and 10 features with nonzero coefficients were selected using least absolute shrinkage and selection operator regression to construct the models. For the DNN models, a 2-stage (supervised contrastive learning and fine-tuning) deep-learning model, MultiCL, was constructed using CT images and the STAS status as training data. The area under the curve (AUC) was used to verify the predictive ability of both model types for the STAS status. Results Among the radiomic models, the linear discriminant analysis model exhibited the best performance, with AUC values of 0.8944 (95% confidence interval [CI], 0.8241-0.9502) and 0.7796 (95% CI, 0.7089-0.8448) for predicting the STAS status on the test and external validation cohorts, respectively. Among the DNN models, MultiCL exhibited the best performance, with AUC values of 0.8434 (95% CI, 0.7580-0.9154) for the test cohort and 0.7686 (95% CI, 0.6991-0.8316) for the external validation cohort. Conclusions CT-based imaging models (radiomics and DNNs) can accurately identify the STAS status of clinical-stage T1N0 lung adenocarcinoma, potentially guiding surgical decision making and improving patient outcomes.
... Poorly differentiated histology is classified as the highest grade in the 2021 World Health Organization classification [9], and though it is not included in the tumor grading system, spread-through-air-space (STAS) also correlates with high recurrence and low survival rates [15][16][17]. Patients with those high-grade histologic patterns are known to show different responses to treatment than those without them [18] and to benefit from aggressive surgical resection [19,20]. A high proportion of high-grade patterns within a tumor correlates with a high tumor mutational burden. ...
... Although not included in the final model of the new IASLC pathologic grading approach, STAS alone showed good correlation with poor prognosis, with an AUC value of 0.752 for recurrence and 0.765 for survival [13]. In addition, compared with lobectomy, limited resection was associated with recurrence and lung cancer-specific death in patients with STAS [19,45,46]. STAS is also related to occult lymph node metastasis in clinical stage IA patients [47]. ...
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Purpose: To develop an MRI-based radiomics model to predict high-risk pathologic features for lung adenocarcinoma: micropapillary and solid pattern (MPsol), spread through air space (STAS), and poorly differentiated patterns. Materials and methods: As a prospective study, we screened clinical N0 lung cancer patients who were surgical candidates and had undergone both 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET/CT) and chest CT from August 2018 to January 2020. We recruited patients meeting our proposed imaging criteria indicating high-risk, that is, poorer prognosis of lung adenocarcinoma, using CT and FDG PET/CT. If possible, these patients underwent an MRI examination from which we extracted 77 radiomics features from T1-contrast-enhanced and T2-weighted images. Additionally, patient demographics, SUVmax (maximum standardized uptake value) on FDG PET/CT, and the mean ADC value on DWI, were considered together to build prediction models for high-risk pathologic features. Results: Among 616 patients, 72 patients met the imaging criteria for high-risk lung cancer and underwent lung MRI. The MR-eligible group showed a higher prevalence of nodal upstaging (29.2% vs. 4.2%, p<0.001), vascular invasion (6.5% vs. 2.1%, p=0.011), high-grade pathologic features (p<0.001), worse 4-year disease free survival (p<0.001) compared with non-MR-eligible group. The prediction power for MR-based radiomics model predicting high-risk pathologic features was good, with mean area under the receiver operating curve (AUC) value measuring 0.751-0.886 in test sets. Adding clinical variables increased the predictive performance for MPsol and the poorly differentiated pattern using the 2021 grading system (AUC 0.860 and 0.907, respectively). Conclusion: Our imaging criteria can effectively screen high-risk lung cancer patients and predict high-risk pathologic features by our MR-based prediction model using radiomics.
... [8][9][10] STAS also provides crucial information for determining the appropriate extent of surgical resection in the early stage of lung cancer since its presence indicates the presence of potential residual tumor cells in the surgical margins of patients who undergo limited resection, resulting in a worse prognosis than in those who undergo lobectomy. 11,12 Despite the importance of STAS in the treatment of earlystage lung cancer, its detection is limited to preoperative sampling in small biopsied tissues. Even intraoperative frozen sections show limited accuracy, with a sensitivity, specificity, and negative predictive value of 71%, 92%, and 8%, respectively. ...
... Even intraoperative frozen sections show limited accuracy, with a sensitivity, specificity, and negative predictive value of 71%, 92%, and 8%, respectively. [12][13][14] As a result, several studies have attempted to predict STAS preoperatively using non-invasive imaging, such as computed tomography (CT) or positron emission tomography. [15][16][17][18] However, most previous studies have focused on qualitative analysis, which could be affected by subjectivity; therefore, quantitative information would be more valuable for clinical utility. ...
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Purpose To assess the added value of radiomics models from preoperative chest CT in predicting the presence of spread through air spaces (STAS) in the early stage of surgically resected lung adenocarcinomas using multiple validation datasets. Materials and Methods This retrospective study included 550 early-stage surgically resected lung adenocarcinomas in 521 patients, classified into training, test, internal validation, and temporal validation sets (n=211, 90, 91, and 158, respectively). Radiomics features were extracted from the segmented tumors on preoperative chest CT, and a radiomics score (Rad-score) was calculated to predict the presence of STAS. Diagnostic performance of the conventional model and the combined model, based on a combination of conventional and radiomics features, for the diagnosis of the presence of STAS were compared using the area under the curve (AUC) of the receiver operating characteristic curve. Results Rad-score was significantly higher in the STAS-positive group compared to the STAS-negative group in the training, test, internal, and temporal validation sets. The performance of the combined model was significantly higher than that of the conventional model in the training set {AUC: 0.784 [95% confidence interval (CI): 0.722–0.846] vs. AUC: 0.815 (95% CI: 0.759–0.872), p=0.042}. In the temporal validation set, the combined model showed a significantly higher AUC than that of the conventional model (p=0.001). The combined model showed a higher AUC than the conventional model in the test and internal validation sets, albeit with no statistical significance. Conclusion A quantitative CT radiomics model can assist in the non-invasive prediction of the presence of STAS in the early stage of lung adenocarcinomas.
... However, according to a study, patients with STAS are at a greater risk of recurrence after sublobar resection [21]. Therefore, the STAS status of patients with stage I LAC affects the choice of surgical approach. ...
... The likelihood of recurrence can be reduced by judging the STAS status of the tumor preoperatively and performing lobectomy in patients with suspected positivity when conditions permit. Perhaps due to the limited scope of materials and other reasons, presurgical bronchial cytology is not sufficient to accurately predict tumor STAS [22], and the diagnostic efficacy of intraoperative frozen pathology is also controversial [21,23,24]. By using a simple and reliable method to predict the STAS status of lung cancer, patients could be stratified effectively, and surgical Table 2 Univariate and multivariate logistic regression analysis of the independent association between risk factors and STAS STAS tumor spread through air spaces, OR odds ratio, SUV max the maximum standardized uptake value * Statistically significant, P < 0.05; ** Statistically significant, P < 0.001; a The pure ground-glass group was considered the reference plans could be developed appropriately, which could potentially improve the prognosis of patients. ...
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Objectives Tumor spread through air spaces (STAS) is associated with poor prognosis and impacts surgical options. We aimed to develop a user-friendly model based on 2-[ ¹⁸ F] FDG PET/CT to predict STAS in stage I lung adenocarcinoma (LAC). Materials and methods A total of 466 stage I LAC patients who underwent 2-[ ¹⁸ F] FDG PET/CT examination and resection surgery were retrospectively enrolled. They were split into a training cohort ( n = 232, 20.3% STAS-positive), a validation cohort ( n = 122, 27.0% STAS-positive), and a test cohort ( n = 112, 29.5% STAS-positive) according to chronological order. Some commonly used clinical data, visualized CT features, and SUV max were analyzed to identify independent predictors of STAS. A prediction model was built using the independent predictors and validated using the three chronologically separated cohorts. Model performance was assessed using ROC curves and calculations of AUC. Results The differences in age ( P = 0.009), lesion density subtype ( P < 0.001), spiculation sign ( P < 0.001), bronchus truncation sign ( P = 0.001), and SUV max ( P < 0.001) between the positive and negative groups were statistically significant. Age ≥ 56 years [ OR (95% CI ):3.310(1.150–9.530), P = 0.027], lesion density subtype ( P = 0.004) and SUV max ≥ 2.5 g/ml [ OR (95% CI ):3.268(1.021–1.356), P = 0.005] were the independent factors predicting STAS. Logistic regression was used to build the A-D-S (Age-Density-SUV max ) prediction model, and the AUCs were 0.808, 0.786 and 0.806 in the training, validation, and test cohorts, respectively. Conclusions STAS was more likely to occur in older patients, in solid lesions and higher SUV max in stage I LAC. The PET/CT-based A-D-S prediction model is easy to use and has a high level of reliability in diagnosing.
... Previous studies have shown that sublobectomy is feasible when the tumor diameter ≤ 3 cm [3,4]. However, in patients with STAS-positive, sublobectomy would cause higher postoperative recurrence rate and poorer prognosis than lobectomy [5,6]. Therefore, for tumors with diameter ≤ 3 cm, accurate preoperative prediction of STAS status is particularly important for developing surgical plans and improving prognosis. ...
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Purpose The aim of this study was to explore and develop a preoperative and noninvasive model for predicting spread through air spaces (STAS) status in lung adenocarcinoma (LUAD) with diameter ≤ 3 cm. Methods This multicenter retrospective study included 640 LUAD patients. Center I included 525 patients (368 in the training cohort and 157 in the validation cohort); center II included 115 patients (the test cohort). We extracted radiomics features from the intratumor, extended tumor and peritumor regions. Multivariate logistic regression and boruta algorithm were used to select clinical independent risk factors and radiomics features, respectively. We developed a clinical model and four radiomics models (the intratumor model, extended tumor model, peritumor model and fusion model). A nomogram based on prediction probability value of the optimal radiomics model and clinical independent risk factors was developed to predict STAS status. Results Maximum diameter and nodule type were clinical independent risk factors. The extended tumor model achieved satisfactory STAS status discrimination performance with the AUC of 0.74, 0.71 and 0.80 in the three cohorts, respectively, performed better than other radiomics models. The integrated discrimination improvement value revealed that the nomogram outperformed compared to the clinical model with the value of 12 %. Patients with high nomogram score (≥ 77.31) will be identified as STAS-positive. Conclusions Peritumoral information is significant to predict STAS status. The nomogram based on the extended tumor model and clinical independent risk factors provided good preoperative prediction of STAS status in LUAD with diameter ≤ 3 cm, aiding surgical decision-making.
... Ren's study indicated that STAS is an independent risk factor for recurrence following sublobar resection (5). Eguchi's findings show that stage I LUAD patients with positive STAS indications benefit more from lobectomy than sublobar resection (6). This evidence suggests that the presence of STAS should contraindicate sublobar resection due to its strong association with decreased disease-free survival (hazard ratio =1.975, 95% confidence interval: 1.691-2.307), ...
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Background Sublobar resection is suitable for peripheral stage I lung adenocarcinoma (LUAD). However, if tumor spread through air spaces (STAS) present, the lobectomy will be considered for a survival benefit. Therefore, STAS status guide peripheral stage I LUAD surgical approach. This study aimed to identify radiological features associated with STAS in peripheral stage I LUAD and to develop a predictive machine learning (ML) model using radiomics to improve surgical decision-making for thoracic surgeons. Methods We conducted a retrospective analysis of patients who underwent surgical treatment for lung tumors from January 2022 to December 2023, focusing on clinical peripheral stage I LUAD. High-resolution computed tomography (CT) scans were used to extract 1,581 radiomics features. Least absolute shrinkage and selection operator (LASSO) regression was applied to select the most relevant features for predicting STAS, reducing model overfitting and enhancing predictability. Ten ML algorithms were evaluated using performance metrics such as area under the receiver operating characteristic curve (AUROC), accuracy, recall, F1-score, and Matthews Correlation Coefficient (MCC) after a 10-fold cross-validation process. SHapley Additive exPlanations (SHAP) values were calculated to provide interpretability and illustrate the contribution of individual features to the model’s predictions. Additionally, a user-friendly web application was developed to enable clinicians to use these predictive models in real-time for assessing the risk of STAS. Results The study identified significant associations between STAS and radiological features, including the longest diameter, consolidation-to-tumor ratio (CTR), and the presence of spiculation. The Random Forest (RF) model for 3-mm peritumoral extensions demonstrated strong predictive performance, with a Recall_Mean of 0.717, Accuracy_Mean of 0.891, F1-Score_Mean of 0.758, MCC_Mean of 0.708, and an AUROC_Mean of 0.944. SHAP analyses highlighted the influential radiomics features, enhancing our understanding of the model’s decision-making process. Conclusions The RF model, employing specific intratumoral and 3-mm peritumoral radiomics features, was highly effective in predicting STAS in peripheral stage I LUAD. This model is recommended for clinical use to optimize surgical strategies for LUAD patients, supported by a real-time web application for STAS risk assessment.
... Our findings are consistent with previous studies that have highlighted the potential of imaging and inflammatory markers as predictors of STAS in lung cancer [18,19]. However, this study offers several advantages over prior work, including a larger sample size, a more comprehensive analysis that integrates both imaging and inflammatory parameters, and the development of a combined predictive model and nomogram. ...
... The 2021 WHO classification explicitly denotes STAS as a histological feature bearing prognostic significance. Studies propose that patients with STASpositive early stage NSCLC who undergo lobectomy exhibit a more favorable prognosis than those treated with sublobectomy [5,6]. Consequently, many surgeons advocate for lobectomy in such cases. ...
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Spread through air spaces (STAS) is a recognized aggressive pattern in lung cancer, serving as a crucial risk factor for postoperative recurrence. However, its phenotype and related spatial structure have remained elusive. To address these limitations, we conducted a comprehensive study based on spatial data, analyzing over 30,000 spots from 14 non-STAS samples and one STAS sample. We observed increased proliferation activities and angiogenesis in STAS, identifying S100P as a potential biomarker for STAS. Furthermore, our investigation into the heterogeneity of STAS tumor cells revealed a subset identified as S100P + TFF1 +, exhibiting a negative impact on patients' survival in public datasets. This subtype exhibited the highest activities in the TGFb and hypoxia, suggesting its potential pro-tumor role within the tumor microenvironment. To assess the role of S100P + TFF1 + tumor cells in therapy response, we included data from two clinical trial cohorts (BPI-7711 for EGFR-TKI therapy and ORIENT-3 for immunotherapy). The presence of S100P + TFF1 + tumor cells correlated with worse responses to both EGFR-TKI therapy and immunotherapy. Notably, TFF1 emerged as a serum marker for predicting EGFR-TKI response. Cell–cell communication analysis revealed that the TGFb signaling pathway was the most activated in S100P + TFF1 + tumor cells, with TGFB2-TGFBR2 identified as the main ligand-receptor pair. This was further validated by multiplex immunofluorescence performed on twenty NSCLC samples. In summary, our study identified S100P as the biomarker for STAS and highlighted the adverse role of S100P + TFF1 + tumor cells in survival outcomes.
... Recent studies have identified spread through air spaces (STAS) as an independent prognostic factor associated with worse outcomes after lung resection [5]. STAS is a form of tumor invasion whereby tumor cells extend beyond the tumor edge into the surrounding lung parenchyma. ...
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Objectives Spread through air spaces (STAS) is a form of lung cancer invasion that extends beyond the tumor edge and is associated with a worse prognosis. Recent advances in immunotherapy highlight the importance of understanding the tumor microenvironment. This study aimed to investigate the prognostic significance of immune-cell distribution in lung cancer, focusing on the association with STAS. Materials and methods We retrospectively analyzed 283 patients who underwent curative-intent lung resection for primary lung cancer. Multiplex immunofluorescence staining/phenotyping was performed on tissue microarrays to assess the distribution of CD4, CD8, CD20, CD68, and FoxP3 immune cells within the center and tumor edge. We defined the delta-Edge value (Δ) as the difference in the number of immune cells between the tumor edge and center. Recurrence-free probability (RFP) was analyzed using Kaplan–Meier and Cox proportional hazard models. Results High ΔCD4 and ΔCD8 values were significantly associated with worse RFP. In stage I adenocarcinoma patients, STAS, and high ΔCD8 were independent risk factors for recurrence. Effect modification analysis revealed that high ΔFoxP3 was significantly associated with worse RFP in patients with STAS, but not in those without STAS. Patients with STAS and high Δimmune cell values had the lowest RFP among all groups. Conclusion Immune-cell distribution, particularly CD4, CD8, and FoxP3, is a crucial prognostic factor in lung cancer. STAS and specific immune cell distribution patterns can be used to further stratify patient prognosis. Understanding these interactions may provide insights into potential therapeutic targets for personalized lung cancer treatment.
... Subsequent studies have con rmed that STAS is an independent risk factor for recurrence in patients with stage I lung adenocarcinoma (LUAD) who undergo sublobar resection [2]. Eguchi [3] suggested that for patients with T1 stage LUAD who are STAS-positive, lobectomy offers greater survival bene ts compared to sublobar resection. Furthermore, STAS is also an independent adverse prognostic factor for patients with stage I LUAD [4][5], signi cantly associated with recurrence-free survival[6] (HR=1.975, ...
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Purpose: To evaluate the clinical applicability of deep learning (DL) models based on automatic segmentation in preoperatively predicting tumor spread through air spaces (STAS) in peripheral stage I lung adenocarcinoma (LUAD). Methods: This retrospective study analyzed data from patients who underwent surgical treatment for lung tumors from January 2022 to December 2023. An external validation set was introduced to assess the model's generalizability. The study utilized conventional radiomic features and DL models for comparison. ROI segmentation was performed using the VNet architecture, and DL models were developed with transfer learning and optimization techniques. We assessed the diagnostic accuracy of our models via calibration curves, decision curve analysis, and ROC curves. Results: The DL model based on automatic segmentation achieved an AUC of 0.880 (95% CI 0.780-0.979), outperforming the conventional radiomics model with an AUC of 0.833 (95% CI 0.707-0.960). The DL model demonstrated superior performance in both internal validation and external testing cohorts. Calibration curves, decision curve analysis, and ROC curves confirmed the enhanced diagnostic accuracy and clinical utility of the DL approach. Conclusion: The DL model based on automatic segmentation technology shows significant promise in preoperatively predicting STAS in peripheral stage I LUAD, surpassing traditional radiomics models in diagnostic accuracy and clinical applicability.
... It was described by the World Health Organization in 2015 as an invasion pattern showing tumor foci spreading through air spaces at the border of the primary tumor [19]. It is estimated that 15-60% of STAS lung cancer patients are positive [20]. From a clinical and pathological perspective, the presence of STAS is more often seen in individuals who have lymphatic and pleural invasion, poorly differentiated tumors bigger than 1 cm, a history of smoking, and advanced stages of the disease [21]. ...
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Background and Objectives: Lung cancer is the leading cause of cancer-related deaths. Spread through air spaces (STAS) is an adverse prognostic factor that has become increasingly known in recent years. This study aims to investigate the impact of STAS presence on overall survival (OS) and disease-free survival (DFS) in patients with surgically resected stage IA-IIIA lung cancer and to identify clinicopathological features associated with STAS. Materials and Methods: This research involved 311 lung cancer surgery patients. The relationship between the presence of STAS in the patients’ surgical pathology and OS and DFS values was examined. Clinicopathological features associated with the presence of STAS were determined. Results: There were 103 (33%) STAS-positive patients. Adenocarcinoma histological subtype, perineural invasion (PNI), and lymphovascular invasion (LVI) were significantly correlated with being STAS positive. STAS significantly predicted DFS and OS. One-year and five-year DFS rates were significantly lower in the STAS-positive group compared to the STAS-negative group (65% vs. 88%, 29% vs. 62%, respectively, p ≤ 0.001). Similarly, one-year and five-year OS rates were significantly lower in the STAS-positive group compared to the STAS-negative group (92% vs. 94%, 54% vs. 88%, respectively, p ≤ 0.001). In multivariate analysis, STAS was found to be an independent prognostic factor for both DFS and OS (HR: 3.2 (95%CI: 2.1–4.8) and 3.1 (95%CI: 1.7–5.5), p < 0.001 and <0.001, respectively). Conclusions: In our study, STAS was found to be an independent prognostic biomarker in operated stage IA-IIIA lung cancer patients. It may be a beneficial pathological biomarker in predicting the survival of patients and managing their treatments.
... Eguchi T et al. found that in patients with lung adenocarcinoma who developed STAS, undergoing lobectomy had a better outcome than sublobar resection [17]. Therefore, accurate preoperative prediction of STAS status is important for the selection of surgical options for lung cancer patients. ...
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OBJECTIVE: The aim of this study was to develop a machine learning model that can predict spread through air space (STAS) of lung adenocarcinoma preoperatively. STAS is associated with poor prognosis in invasive lung adenocarcinoma. Therefore non-invasive and accurate pre-surgical prediction of STAS in patients with lung adenocarcinoma is essential for individualised patient management. METHODS:We included 138 patients with invasive lung adenocarcinoma who underwent lobectomy, collected their preoperative imaging data and clinical features, built a model for predicting STAS using machine learning and deep learning methods, and validated the efficacy of the model. Finally a nomogram was created based on logistic regression (LR). RESULTS:Imaging histology features showed good model efficacy in both the training set (LR AUC=0.764) and the test set (LR AUC=0.776), and we combined the imaging histology and clinical features to jointly build a nomogram graph (AUC=0.878), extracted the deep learning features, and built a machine learning model based on the ResNET50 algorithm, where the LR AUC=0.918 CONCLUSIONS:This presented radiomics model can be served as a non-invasive for predicting STAS in Infiltrating lung adenocarcinoma.
... Numerous retrospective clinical studies have reported that STAS is associated with poorer prognosis, higher recurrence risk, and more advanced clinicopathological staging [7][8][9][10] . Although STAS is considered an independent high-risk factor for LUAD, its impact on the need for adjuvant therapy in surgically treated early-stage LUAD patients remains uncertain. ...
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Tumor spread through air spaces (STAS) is a distinctive metastatic pattern affecting prognosis in lung adenocarcinoma (LUAD) patients. Several challenges are associated with STAS detection, including misdetection, low interobserver agreement, and lack of quantitative analysis. In this research, a total of 489 digital whole slide images (WSIs) were collected. The deep learning-based STAS detection model, named STASNet, was constructed to calculate semi-quantitative parameters associated with STAS density and distance. STASNet demonstrated an accuracy of 0.93 for STAS detection at the tiles level and had an AUC of 0.72-0.78 for determining the STAS status at the WSI level. Among the semi-quantitative parameters, T10S, combined with the spatial location information, significantly stratified stage I LUAD patients on disease-free survival. Additionally, STASNet was deployed into a real-time pathological diagnostic environment, which boosted the STAS detection rate and led to the identification of three easily misidentified types of occult STAS.
... Furthermore, there is no data included on margin status, PET-avidity, and presence of STAS, which we know may affect recurrence and survival. [11][12][13][14] Nonetheless, this important work exhibits the need for a multidimensional analysis of individual tumor characteristics beyond size that may inform surgical decision making about early-stage NSCLC. While the exact size at which outcomes for a given tumor grade treated by one surgical approach may prove to be somewhat of a moving target, the visual representation of survival curves used here enables clinicians to include interpretations of more obvious inflection points in their decision making on individual cases. ...
... STAS positivity rates ranging from 30.3% to 72% at different stages of lung adenocarcinoma have been reported. [15][16][17] Analysis of the correlations between STAS and clinical and pathological parameters revealed no significant associations with patient age, sex, or smoking history. However, a close relationship exists between STAS and factors indicating tumor invasion and metastasis, such as tumor diameter ≥2 cm, pleural, vascular, and neural invasion, and pathological stage >IIB. ...
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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 univariate 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, vascular invasion, peripheral nerve invasion, tumor size, and necrosis showed good accuracy, differentiation, and clinical practicality.
... Surgery recommendations for non-invasive and invasive adenocarcinoma are different, patients who undergo lobectomy have superior overall and cancer-specific survival rates, regardless of tumor size [8][9][10][11][12][13]. In clinical practice, intraoperative frozen sections will determine the specific mode of operation, thus the accuracy of intraoperative frozen sections will directly influence the patient's prognosis [14], however, pathological upstages occur for various reasons [15], research findings found that complementary treatment is encouraged in AIS/MIA upstaged to invasive adenocarcinoma by final pathology after sublobectomy [16]. ...
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Background Sublobar resection for ground-glass opacity became a recommend surgery choice supported by the JCOG0804/JCOG0802/JCOG1211 results. Sublobar resection includes segmentectomy and wedge resection, wedge resection is suitable for non-invasive lesions, but in clinical practice, when pathologists are uncertain about the intraoperative frozen diagnosis of invasive lesions, difficulty in choosing the appropriate operation occurs. The purpose of this study was to analyze how to select invasive lesions with clinic-pathological characters. Methods A retrospective study was conducted on 134 cases of pulmonary nodules diagnosed with minimally invasive adenocarcinoma by intraoperative freezing examination. The patients were divided into two groups according to intraoperative frozen results: the minimally invasive adenocarcinoma group and the at least minimally invasive adenocarcinoma group. A variety of clinical features were collected. Chi-square tests and multiple regression logistic analysis were used to screen out independent risk factors related to pathological upstage, and then ROC curves were established. In addition, an independent validation set included 1164 cases was collected. Results Independent risk factors related to pathological upstage were CT value, maximum tumor diameter, and frozen result of AL-MIA. The AUC of diagnostic mode was 71.1% [95%CI: 60.8-81.3%]. The independent validation included 1164 patients, 417 (35.8%) patients had paraffin-based pathology of invasive adenocarcinoma. The AUC of diagnostic mode was 75.7% [95%CI: 72.9-78.4%]. Conclusions The intraoperative frozen diagnosis was AL-MIA, maximum tumor diameter larger than 15 mm and CT value is more than − 450Hu, highly suggesting that the lung GGO was invasive adenocarcinoma which represent a higher risk to recurrence. For these patients, sublobectomy would be insufficient, lobectomy or complementary treatment is encouraged.
... can be observed in other type of NSCLC, such as squamous cell carcinoma, lung pleomorphic carcinoma, and lung neuroendocrine tumors (Lu et al. 2017;Yokoyama et al. 2018;Aly et al. 2019). The presence of STAS indicated the presence of potential residual tumor cells in the surgical margins of patients who underwent limited resection such as segmentectomy or wedge resection, resulting in a poorer prognosis (Kadota et al. 2015;Eguchi et al. 2019;Bains et al. 2019;Huang et al. 2022;Ren et al. 2019). More recently, in a meta-analysis to compare prognostic outcomes between lobectomy and sublobar resection in stage I NSCLC patients with STAS, the results indicated that sublobar resection resulted in worse outcomes than lobectomy in stage I NSCLC patients with STAS (Li et al. 2022a, b). ...
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Purpose This study aims to assess the predictive value of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) radiological features and the maximum standardized uptake value (SUVmax) in determining the presence of spread through air spaces (STAS) in clinical-stage IA non-small cell lung cancer (NSCLC). Methods A retrospective analysis was conducted on 180 cases of NSCLC with postoperative pathological assessment of STAS status, spanning from September 2019 to September 2023. Of these, 116 cases from hospital one comprised the training set, while 64 cases from hospital two formed the testing set. The clinical information, tumor SUVmax, and 13 related CT features were analyzed. Subgroup analysis was carried out based on tumor density type. In the training set, univariable and multivariable logistic regression analyses were employed to identify the most significant variables. A multivariable logistic regression model was constructed and the corresponding nomogram was developed to predict STAS in NSCLC, and its diagnostic efficacy was evaluated in the testing set. Results SUVmax, consolidation-to-tumor ratio (CTR), and lobulation sign emerged as the best combination of variables for predicting STAS in NSCLC. Among these, SUVmax and CTR were identified as independent predictors for STAS prediction. The constructed prediction model demonstrated area under the curve (AUC) values of 0.796 and 0.821 in the training and testing sets, respectively. Subgroup analysis revealed a 2.69 times higher STAS-positive rate in solid nodules compared to part-solid nodules. SUVmax was an independent predictor for predicting STAS in solid nodular NSCLC, while CTR and an emphysema background were independent predictors for STAS in part-solid nodular NSCLC. Conclusion Our nomogram based on preoperative ¹⁸F-FDG PET/CT radiological features and SUVmax effectively predicts STAS status in clinical-stage IA NSCLC. Furthermore, our study highlights that metabolic parameters and CT variables associated with STAS differ between solid and part-solid nodular NSCLC.
... Studies have increasingly reported that patients with solid or micropapillary patterns have a poorer prognosis even if their patterns are not predominant (21)(22)(23)(24). Wedge resection is one type of limited resection or sublobar resection that may affect the survival of patients due to an insufficient resection range caused by tumor spread through air spaces (STAS) (25)(26)(27). VPI is widely recognized as a risk factor for the prognosis of lung cancer patients and is included in the TNM classification (1). The presence of VPI is a significant predictive factor in pathologic stage I NSCLC after resection (28)(29)(30). ...
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Background: Surgical resection is the main treatment for early-stage non-small cell lung cancer (NSCLC), but recurrence remains a concern. Adjuvant chemotherapy has been shown to have survival benefits for resected stage II and III NSCLC, but debate continues regarding its use in stage I NSCLC. High-risk features, such as tumor size and stage, are considered in deciding whether to administer adjuvant chemotherapy. Methods: The data of 666,689 patients diagnosed with lung cancer from 2004 to 2016 were collected from the Surveillance, Epidemiology, and End Results database. Ultimately, 26,160 patients diagnosed with stage I NSCLC were included in the study based on a screening procedure. Results: After matching, 4,285 patients were identified, of whom 1,440 (33.6%) received chemotherapy. High-risk clinicopathologic features, including a high histologic grade, visceral pleural invasion (VPI), the examination of an insufficient number of lymph nodes (LNs), and limited resection, were independent risk factors for a poor prognosis. Chemotherapy significantly improved lung cancer-specific survival (LCSS) and overall survival (OS) in stage I patients with VPI [LCSS: hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.706-0.998, P=0.047; OS: HR: 0.711, 95% CI: 0.612-0.826, P<0.001], regardless of whether or not the patient had fewer than 11 LNs (LCSS: HR: 0.809, 95% CI: 0.664-0.986, P=0.04; OS: HR: 0.677, 95% CI: 0.570-0.803, P<0.001). Chemotherapy was only observed to improve OS for stage IB patients with a high histologic grade when combined with either or both of the following high-risk factors: the presence of VPI and fewer than 11 LNs examined. Conclusions: The presence of VPI was the dominant predictor and the examination of an insufficient number of LNs was the secondary indicator, and a high histologic grade was a potential indicator of the need to administer chemotherapy in the treatment of stage I NSCLC.
... Spread through air spaces (STAS) has been verified not only as an independent prognostic factor but also as a predictor for locoregional recurrence after sublobar resection. 11,12 Recently, Gross and colleagues 13 reported the presence of STAS in the completion lobectomy specimen after wedge resection despite a negative resection margin. Both prognostic inferiority and capability in spreading beyond resection margins provided preliminary evidence to reevaluate STAS status in the R classification. ...
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BACKGROUND: We aimed to validate the prognostic implication of uncertain resection, R(un), proposed by International Association for the Study of Lung Cancer (IASLC) and evaluate the prognostic value of spread through air spaces (STAS) in reclassifying the R classification among patients with lung adenocarcinoma after segmentectomy. METHODS: We enrolled 1007 patients who underwent segmentectomy for c-stage IA lung adenocarcinoma between 2014 and 2017. Recurrence-free survival (RFS) and overall survival (OS) were compared to evaluate the prognostic value of IASLC-R(un) and STAS. Whether STAS would skip into complementary lobectomy was evaluated in a prospective cohort. RESULTS: The current IASLC-R(un) failed to significantly stratify the RFS (P[ .078) in segmentectomy, and STAS was a stronger risk factor of poor prognosis for both RFS and OS (P < .001). Moreover, the presence of STAS was associated with increased locoregional recurrence in patients undergoing segmentectomy (P < .001) but not in those treated with lobectomy (P [ .187), indicating that only STAS-positive segmentectomy was consistent with the concept of R(un) in relapse pattern. After reclassifying STAS-positive segmentectomy into the R(un) category, the proposed R(un) showed an improvement in prognosis stratification. In addition, 2 of 30 patients (6.2%) in the prospective cohort who underwent initial segmentectomy and complementary lobectomy had STAS clusters in the complementary lobectomy specimens. CONCLUSIONS: Unfavorable prognosis, relapse patterns consistent with R(un), and pathologic verification that saltatory spread of STAS observed in complementary lobectomy specimens supported reclassifying STAS-positive segmentectomy as R(un). STAS is a critical concern for the surgical completeness evaluation after segmentectomy.
... 28 STAS can be identified in both paraffin tissue and frozen sections. 29 As a powerful indicator for identifying high-risk patients, STAS has been employed by several grading systems, including those proposed by Kadota et al. and Sica et al. 7 In addition, our model employs a quantitative cutoff of 10% for the selected variable. This cutoff is utilized to evaluate the solid subtype, which is more straightforward to recognize than the high-grade structures containing micropapillary, cribriform, or complex glandular patterns. ...
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Background Several studies have proposed grading systems for risk stratification of early‐stage lung adenocarcinoma based on histological patterns. However, the reproducibility of these systems is poor in clinical practice, indicating the need to develop a new grading system which is easy to apply and has high accuracy in prognostic stratification of patients. Methods Patients with stage I invasive nonmucinous lung adenocarcinoma were retrospectively collected from pathology archives between 2009 and 2016. The patients were divided into a training and validation set at a 6:4 ratio. Histological features associated with patient outcomes (overall survival [OS] and progression‐free survival [PFS]) identified in the training set were used to construct a new grading system. The newly proposed system was validated using the validation set. Survival differences between subgroups were assessed using the log‐rank test. The prognostic performance of the novel grading system was compared with two previously proposed systems using the concordance index. Results A total of 539 patients were included in this study. Using a multioutcome decision tree model, four pathological factors, including the presence of tumor spread through air space (STAS) and the percentage of lepidic, micropapillary and solid subtype components, were selected for the proposed grading system. Patients were accordingly classified into three groups: low, medium, and high risk. The high‐risk group showed a 5‐year OS of 52.4% compared to 89.9% and 97.5% in the medium and low‐risk groups, respectively. The 5‐year PFS of patients in the high‐risk group was 38.1% compared to 61.7% and 90.9% in the medium and low‐risk groups, respectively. Similar results were observed in the subgroup analysis. Additionally, our proposed grading system provided superior prognostic stratification compared to the other two systems with a higher concordance index. Conclusion The newly proposed grading system based on four pathological factors (presence of STAS, and percentage of lepidic, micropapillary, and solid subtypes) exhibits high accuracy and good reproducibility in the prognostic stratification of stage I lung adenocarcinoma patients.
... Therefore, identification of STAS can provide key information for the clinical treatment of patients with LUAD (6,7). Reports indicate a significant risk of local and distant recurrence in STAS-positive cases treated with sublobar resection (3,8), whereas patients who undergo lobectomy have no increased recurrence risk. Thus, early detection of STAS is of clinical importance. ...
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Spread Through Air Spaces (STAS) is involved in lung adenocarcinoma (LUAD) recurrence, where cancer cells spread into adjacent lung tissue, impacting surgical planning and prognosis assessment. Radiomics-based models show promise in predicting STAS preoperatively, enhancing surgical precision and prognostic evaluations. The present study performed network meta-analysis to assess the predictive efficacy of imaging models for STAS in LUAD. Data were systematically sourced from PubMed, Embase, Scopus, Wiley and Web of Science, according to the Cochrane Handbook for Systematic Reviews of Interventions) and A Measurement Tool to Assess systematic Reviews 2. Using Stata software v17.0 for meta-analysis, surface under the cumulative ranking area (SUCRA) was applied to identify the most effective diagnostic method. Quality assessments were performed using Cochrane Collaboration's risk-of-bias tool and publication bias was assessed using Deeks' funnel plot. The analysis encompassed 14 articles, involving 3,734 patients, and assessed 17 predictive models for STAS in LUAD. According to comprehensive analysis of SUCRA, the machine learning (ML)_Peri_tumour model had the highest accuracy (56.5), the Features_computed tomography (CT) model had the highest sensitivity (51.9) and the positron emission tomography (pet)_CT model had the highest specificity (53.9). ML_Peri_tumour model had the highest predictive performance. The accuracy was as follows: ML_Peri_tumour vs. Features_CT [relative risk (RR)=1.14; 95% confidence interval (CI), 0.99–1.32]; ML_Peri_tumour vs. ML_Tumour (RR=1.04; 95% CI, 0.83–1.30) and ML_Peri_tumour vs. pet_CT (RR=1.04; 95% CI, 0.84–1.29). Comparative analyses revealed heightened predictive accuracy of the ML_Peri_tumour compared with other models. Nonetheless, the field of radiological feature analysis for STAS prediction remains nascent, necessitating improvements in technical reproducibility and comprehensive model evaluation.
... STAS not only affects patient prognosis but also influences the choice of surgical approach. Previous studies [22,23] have shown that, in stage I lung adenocarcinoma patients who undergo limited resection, compared to those who undergo lobectomy, the prognosis is worse when STAS is present. Therefore, assessing the risk of STAS in the primary tumor through preoperative CT imaging can provide diagnostic information in selecting surgical approaches, and can impact patient prognosis. ...
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Background The consolidation tumor ratio (CTR) is a predictor of invasiveness in peripheral T1N0M0 lung adenocarcinoma. However, its association with spread through air spaces (STAS) remains largely unexplored. We aimed to explore the correlation between the CTR of primary tumors and STAS in peripheral T1N0M0 lung adenocarcinoma. Methods We collected data from patients who underwent surgery for malignant lung neoplasms between January and November 2022. Univariate and multivariate analyses following propensity-score matching with sex, age, BMI, were performed to identify the independent risk factors for STAS. The incidence of STAS was compared based on pulmonary nodule type. A smooth fitting curve between CTR and STAS was produced by the generalized additive model (GAM) and a multiple regression model was established using CTR and STAS to determine the dose-response relationship and calculate the odds ratio (OR) and 95% confidence interval (CI). Results 17 (14.5%) were diagnosed with STAS. The univariate analysis demonstrated that the history of the diabetes, size of solid components, spiculation, pleural indentation, pulmonary nodule type, consolidation/tumor ratio of the primary tumor were statistically significant between the STAS-positive and STAS-negative groups following propensity-score matching(p = 0.047, 0.049, 0.030, 0.006, 0.026, and < 0.001, respectively), and multivariate analysis showed that the pleural indentation was independent risk factors for STAS (with p-value and 95% CI of 0.043, (8.543–68.222)). Moreover, the incidence of STAS in the partially solid nodule was significantly different from that in the solid nodule and ground-glass nodule (Pearson Chi-Square = 7.49, p = 0.024). Finally, the smooth fitting curve showed that CTR tended to be linearly associated with STAS by GAM, and the multivariate regression model based on CTR showed an OR value of 1.24 and a p-value of 0.015. Conclusions In peripheral stage IA lung adenocarcinoma, the risk of STAS was increased with the solid component of the primary tumor. The pleural indentation of the primary tumor could be used as a predictor in evaluating the risk of the STAS.
Article
For small lung carcinomas, sublobar resections allow the preservation of a greater pulmonary reserve than after lobectomy. It was unclear for a long time to what extent this would jeopardize the goal of curative, radical tumor removal. Current studies show under what conditions a sublobar resection should be carried out and under which circumstances lobectomy continues to be the required standard.
Article
Background Spread through air spaces (STAS) is a well-established factor associated with poor oncological outcomes in patients undergoing surgery for solid lung adenocarcinoma. There could potentially be a disparity in iodine uptake between patients with positive and negative airway spread of solid lung adenocarcinoma. Purpose To explore the associations and find correlations of iodine uptake with STAS status in patients who underwent surgery for solid lung adenocarcinoma. Material and Methods Patients who underwent solid lung adenocarcinoma resection between January and June 2022 were included in this retrospective study. Iodine concentration and CT features were assessed using contrast-enhanced dual-energy computed tomography (DECT) scans, and these were compared with the status of STAS. Results Of 52 patients included, 25 (48%) were STAS-positive and 27 (52%) were STAS-negative. There were no statistically significant differences in CT features between the two groups ( P > 0.05). STAS-positive was significantly associated with low arterial phase iodine concentration (ICA), normalized arterial phase iodine concentration (NICA), and venous phase iodine concentration (ICV), with a cutoff established at 1.15 mg/mL, 0.11, and 1.35 mg/mL, respectively ( P < 0.05). The AUCs for ICA, NICA, and ICV in predicting STAS in solid lung adenocarcinoma were 0.82, 0.83, and 0.73, respectively. ICA and NICA were identified as independent risk factors for STAS in solid lung adenocarcinoma, with a combined AUC of 0.89. Conclusion This study suggests that solid lung adenocarcinoma patients with low ICA, NICA, and ICVA were associated with STAS-positive, as well as a worse survival outcomes.
Article
Objective To investigate the value of intraoperative assessment of spread through air spaces (STAS) on frozen sections (FS) in peripheral small-sized lung adenocarcinoma. Background Surgical decision-making based on FS diagnosis of STAS may be useful to prevent local control failure after sublobar resection. Methods We conducted a multicenter prospective observational study of consecutive patients with cT1N0M0 invasive lung adenocarcinoma to evaluate the accuracy of FS for the intraoperative detection of STAS. The final pathology (FP) diagnosis of STAS was based on corresponding permanent paraffin sections. Results This study included 878 patients with cT1N0M0 invasive lung adenocarcinoma. A total of 833 cases (95%) were assessable for STAS on FS. 26.4% of the cases evaluated positive for STAS on FP, whereas 18.2% on FS. The accuracy, sensitivity, and specificity of FS diagnosis of STAS were 85.1%, 56.4%, and 95.4%, respectively, with moderate agreement (κ=0.575). Inter-observer agreement was substantial (κ=0.756) among the three pathologists. Subgroup analysis based on tumor size or consolidation-to-tumor ratio all showed moderate agreement for concordance. After rigorous reassessment of false-positive cases, the presence of artifacts may be the main cause of interpretation errors. Additionally, true positive cases showed more high-grade histological patterns and more advanced p-TNM stages than false negative cases. Conclusions This is the largest prospective observational study to evaluate STAS on FS in patients with cT1N0M0 invasive lung adenocarcinoma. FS is highly specific with moderate agreement, but is not sensitive for STAS detection. While appropriately reporting STAS on FS may provide surgeons with valuable information for intraoperative decision-making, better approaches are needed.
Article
Spread through air spaces (STAS) represents a relatively novel concept in the pathology of lung cancer, and it specifically refers to the dissemination of tumour cells into the parenchymal air spaces adjacent to the primary tumour. In 2015, the World Health Organization (WHO) classified STAS as a new invasive form of lung adenocarcinoma (LUAD). Many studies investigated the role of STAS and revealed its association with the prognosis of LUAD and its influence on the outcomes of other malignant pulmonary neoplasms. Additionally, the underlying mechanisms and predictive models of STAS have received considerable attention in recent years. This paper provides a comprehensive overview of the research advancements and prospects of STAS by examining it from multiple perspectives.
Article
The purpose of this study was to investigate the effect of tumor size and differentiation grade on long term survival in patients with early-stage lung adenocarcinoma (LUAD) after lobectomy and segmentectomy. Patients with stage T1–2N0M0 LUAD who underwent lobectomy and segmentectomy were identified from the Surveillance, Epidemiology, and End Results database. Patients were stratified as grade I (well differentiated), grade II (moderately differentiated), and grade III/IV (poorly differentiated/undifferentiated) carcinomas. The effect of tumor size on overall survival (OS) and lung cancer-specific survival (LCSS) was evaluated using the multivariate Cox regression model, including the interaction between tumor size, type of surgery, and tumor differentiation grade. The inverse probability of treatment weighting method was used to adjust for bias between the groups. A total of 19,857 patients were identified, including 18,759 (94.4%) who underwent lobectomy and 1098 (5.5%) who underwent segmentectomy. A three-way interaction among tumor size, differentiation grade, and type of surgery was observed in the overall cohort. After stratifying by differentiation grade, plots of interaction revealed that lobectomy was associated with improved survival compared with segmentectomy when the tumor size exceeded 23 mm for grade I LUAD and 14 mm for grade II LUAD. No interaction was observed between the studied factors in grade III/IV carcinomas. This study interpreted the interaction between tumor size and type of surgery on long-term survival in patients with early stage LUAD and established a tumor size threshold beyond which lobectomy provided survival benefits compared with segmentectomy.
Article
The clinical significance of lung tumor spread through air spaces (STAS) has been extensively studied, and is recognized as a unique pattern of invasion. Previous studies of STAS have focused primarily on STAS in alveolar spaces, whereas STAS in the bronchiolar spaces (bronchiolar STAS) has been described in only a few case reports only. Here, we examined 306 cases of primary lung adenocarcinoma and found that bronchiolar STAS was present in 18%. Bronchiolar STAS was associated with an inferior prognosis, more advanced stage, and higher histologic grade. No significant difference in clinicopathological factors or prognosis was observed between cases with bronchiolar STAS and those with alveolar STAS alone. Notably, bronchiolar STAS often occurred simultaneously with alveolar STAS and endobronchial spread of adenocarcinoma, particularly when bronchiolar STAS was present outside the main tumor. We also identified cases where bronchiolar STAS and endobronchial spread of adenocarcinoma occurred simultaneously in the same bronchi or bronchioles located outside the main tumor, as well as cases with bronchiolar STAS adjacent to intrapulmonary metastatic nodules. Our results highlight the significant role of bronchiolar STAS in the aerogenous spread of adenocarcinoma cells. Bronchiolar STAS can be regarded as a histologic variant of alveolar STAS. This study also supports the idea that STAS is not a tissue processing artifact, but a true biological process with clinical implications, offering histologic evidence of aerogenous spread in lung adenocarcinoma.
Article
Objective Accurate intraoperative diagnosis of spread through air spaces (STAS), a known poor prognostic factor in lung cancer, is crucial for guiding surgical decision-making during sublobar resections. This study aimed to evaluate the diagnostic sensitivity of STAS using frozen section (FS) slides prepared with the cryo-embedding medium inflation technique. Methods In this prospective study at Shinshu University Hospital, 99 patients undergoing lung resection for tumors <3 cm in size were included, a total of 114 lesions. FS slides were prepared with injecting diluted cryo-embedding medium into the lung parenchyma of resected specimens. The diagnostic performance of these FS slides for STAS detection was evaluated by comparing FS-STAS results with the gold-standard STAS status. Results The incidence of STAS, determined by the gold standard, was 43 (38%) of 114 lesions, including 31 (37%) of 84 primary lung cancers and 12 (40%) of 30 metastatic lung tumors. The sensitivity, specificity, positive and negative predictive values, and accuracy of FS slides for STAS detection were 81%, 89%, 81%, 89%, and 86%, respectively. Specifically, in primary lung cancers, these values were 90%, 89%, 82%, 94%, and 89%, respectively. Regarding metastatic lung tumors, the corresponding values were 58%, 89%, 78%, 76%, and 77%, respectively. Conclusions Our adapted cryo-embedding medium inflation method has demonstrated enhanced sensitivity in detecting STAS on FS slides, providing results similar to the gold-standard STAS detection. Compared with historical benchmarks, this technique could show excellent performance and be readily incorporated into clinical practice without requiring additional resources beyond those used for standard FS analysis.
Chapter
Lung cancer is the most common cause of incidence and mortality of major cancers worldwide. Lung cancer incidence was estimated at 2,093,876 cases globally in 2018, accounting for 11.6% of the total cases. Estimated mortality for lung cancer in 2018 was 1,761,007 deaths globally, constituting around 18.4% of the total cancer deaths. The incidence varies according to geographic area, with Europe and Asia having the highest incidence rates. The global distribution for lung cancer incidence in 2018 was Asia (58.5%), Europe (22.4%), North America (12.1%), Latin American (4.3%), Africa (1.9%), and Oceania (0.81%). About 58% of lung cancer cases occur in underdeveloped countries. Compared to other highly incident malignancies (breast, colorectal, prostate, skin, and stomach cancer), lung cancer displays the lowest 5 years survival rate (10%–20%) in most countries among those diagnosed during 2010 through 2014.
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Background Identification of micropapillary and solid subtypes components in small-sized (≤ 2 cm) lung adenocarcinoma plays a crucial role in determining optimal surgical procedures. This study aims to propose a straightforward prediction method utilizing preoperative available indicators. Methods From January 2019 to July 2022, 341 consecutive patients with small-sized lung adenocarcinoma who underwent curative resection in thoracic surgery department of Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The patients were divided into two groups based on whether solid or micropapillary components ≥ 5% or not (S/MP5+ and S/MP5-). Univariate analysis and multivariate logistic regression analysis were utilized to identify independent predictors of S/MP5+. Then a nomogram was constructed to intuitively show the results. Finally, the calibration curve with a 1000 bootstrap resampling and the receiver operating characteristic (ROC) curve were depicted to evaluate its performance. Results According to postoperative pathological results, 79 (23.2%) patients were confirmed as S/MP5+ while 262 (76.8%) patients were S/MP5-. Based on multivariate analysis, maximum diameter (p = 0.010), consolidation tumor ratio (CTR) (p < 0.001) and systemic immune-inflammation index (SII) (p < 0.001) were identified as three independent risk factors and incorporated into the nomogram. The calibration curve showed good concordance between the predicted and actual probability of S/MP5+. Besides, the model showed certain discrimination, with an area under ROC curve of 0.893. Conclusions The model constructed based on SII is a practical tool to predict high-grade subtypes components of small-sized lung adenocarcinoma preoperatively and contribute to determine the optimal surgical approach.
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In recent years, the concept of spread through air spaces (STAS) has been discussed as an adverse prognostic factor for lung cancer. The aim of our study is to clarify the prognostic role of STAS in relation to the main recognized prognostic factors in a retrospective cohort of 330 European patients who underwent stages I to III lung adenocarcinoma resection. On univariate analysis, the presence of STAS was related to progression-free survival (PFS; hazard ratio [HR]: 1.48; 95% CI: 1.02-2.19; P = 0.038) and overall survival (OS; HR: 1.61; 95% CI: 1.03-2.52; P = 0.50). On multivariate analysis, STAS was related to PFS (HR: 1.51; 95% CI: 1.00-2.17; P = 0.050) and to OS (HR: 1.67; 95% CI: 1.00-2.81; P = 0.050). We showed that the presence of STAS was associated with lower PFS, equivalent to the next pathologic T stage, especially the median PFS of T3 stages without STAS was at 62.8 months while the median PFS of T3 stages with STAS was at 15.7 months, closer to the median PFS of 17.4 months in T4 stages. To conclude, STAS is an independent prognostic factor of PFS in this European cohort and is close to significance for OS. We suggest that the presence of STAS might lead to an upstaging of lung adenocarcinoma.
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PURPOSES: The aim of this study was to evaluate whether sublobar resection could achieve recurrence and survival rates equivalent to lobectomy in high-risk elderly patients. METHODS: We conducted a retrospective multicenter study that including all consecutive patients (aged >75 years) who underwent operation for clinical stage I non-small cell lung cancer (NSCLC). The clinicopathological data, postoperative morbidity and mortality, recurrence rate and vital status were retrieved. The overall survival, cancer-specific survival and disease-free survival were also assessed. RESULTS: Two hundred and thirty-nine patients (median age 78 years) were enrolled. Lobectomies were performed in 149 (62.3 %) patients and sublobar resections in 90 (39 segmentectomies, 51 wedge resections). There were no differences in the recurrence rates following lobar versus sublobar resections (19 versus 23 %, respectively; p = 0.5) or the overall survival (p = 0.1), cancer-specific survival (p = 0.3) or disease-free survival (p = 0.1). After adjusting for 1:1 propensity score matching and a matched pair analysis, the results remained unchanged. A tumor size >2 cm and pN2 disease were independent negative prognostic factors in unmatched (p = 0.01 and p = 0.0003, respectively) and matched (p = 0.02 and p = 0.005, respectively) analyses. CONCLUSIONS: High-risk elderly patients may benefit from sublobar resection, which provides an equivalent long-term survival compared to lobectomy.
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Background/aim: Spread through air spaces (STAS) is a novel invasive pattern of lung cancer, especially adenocarcinoma and squamous cell carcinoma. However, its frequency and significance in patients with resected small cell lung cancer (SCLC) remains unclear. Patients and methods: A total of 30 patients with resected SCLC were analyzed for STAS. STAS was classified as either no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (≥5 single cells or clusters of STAS). We evaluated the association between STAS and clinicopathological characteristics and postoperative survivals. Results: Among 30 patients, 5 (17%), 6 (20%) and 19 (63%) were classified as having no, low and high STAS, respectively. Fisher's exact test demonstrated no significant associations between the positivity for STAS and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survival between STAS-negative/low and STAS-high patients. Conclusion: STAS was frequently observed in patients with resected SCLC.
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Purpose: Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment for early-stage lung cancer. The histologic subtype of surgically resected lung adenocarcinoma is recognized as a prognostic factor, with the presence of solid or micropapillary patterns predicting poor outcomes. We describe the outcomes after SBRT for early-stage lung adenocarcinoma stratified by histologic subtype. Methods and materials: We identified 119 consecutive patients (124 lesions) with stage I to IIA lung adenocarcinoma who had undergone definitive SBRT at our institution from August 2008 to August 2015 and had undergone core biopsy. Histologic subtyping was performed according to the 2015 World Health Organization classification. Of the 124 tumors, 37 (30%) were a high-risk subtype, defined as containing a component of solid and/or micropapillary pattern. The cumulative incidences of local, nodal, regional, and distant failure were compared between the high-risk and non-high-risk adenocarcinoma subtypes using Gray's test, and multivariable-adjusted hazard ratios (HRs) were estimated from propensity score-weighted Cox regression models. Results: The median follow-up for the entire cohort was 17 months and for surviving patients was 21 months. The 1-year cumulative incidence of and adjusted HR for local, nodal, regional, and distant failure in high-risk versus non-high-risk lesions was 7.3% versus 2.7% (HR 16.8; 95% confidence interval [CI] 3.5-81.4), 14.8% versus 2.6% (HR 3.8; 95% CI 0.95-15.0), 4.0% versus 1.2% (HR 20.9; 95% CI 2.3-192.3), and 22.7% versus 3.6% (HR 6.9; 95% CI 2.2-21.1), respectively. No significant difference was seen with regard to overall survival. Conclusions: The outcomes after SBRT for early-stage adenocarcinoma of the lung correlate highly with histologic subtype, with micropapillary and solid tumors portending significantly higher rates of locoregional and metastatic progression. In this context, the histologic subtype determined from core biopsies is a prognostic factor and could have important implications for patient selection, adjuvant treatment, biopsy methods, and clinical trial design.
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Purpose: To determine the survival following segmentectomy versus lobectomy in elderly patients with early-stage non-small cell lung cancer (NSCLC). Methods: We identified 12324 elderly (≥ 70 years) patients with stage I ≤ 3 cm NSCLC in the Surveillance, Epidemiology and End Results (SEER) database. Propensity score methods were used to balance baseline characteristics of patients undergoing segmentectomy or lobectomy. Overall survival (OS) and lung cancer-specific survival (LCSS) of patients treated with segmentectomy versus lobectomy were compared in Cox regression models after adjusting, stratifying or matching patients based on propensity scores. Results: Cox models adjusting, stratifying or matching propensity scores all showed that patients treated with segmentectomy had significantly worse OS and LCSS compared to lobectomy. Subgroup analysis of patients with tumors ≤ 2cm, aged ≥ 75 years, or had ≥ 7 lymph nodes examined also revealed survival advantage associated with lobectomy. Conclusion: Elder age alone could not justify the application of segmentectomy in early-stage lung cancer. Prospective randomized trials are warranted to validate our results.
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Background: Recent data have suggested possible oncologic equivalence of sublobar resection with lobectomy for early stage NSCLC.Our aim was to evaluate and compare short and long term survival for these surgical approaches. Methods: This retrospective cohort study utilized the National Cancer Data Base. Patients undergoing lobectomy, segmentectomy,or wedge resection for preoperative clinical T1A N0 NSCLC from 2003-2011 were identified.Overall survival (OS) and 30-day mortality were analyzed using multivariable Cox proportional hazards models,logistic regression models,and propensity score matching.Further analysis of survival stratified by tumor size, facility type, number of lymph nodes examined, and surgical margins was performed. Results: A total of 13,606 patients were identified. After propensity score matching, 987 patients remained in each group. Both segmentectomy and wedge resection were associated with significantly worse OS when compared with lobectomy (HR 1.70 and 1.45, respectively, both p < 0.001), with no difference in 30 day mortality. Median OS for lobectomy, segmentectomy, and wedge resection were 100, 74, and 68 months, respectively (p < 0.001). Finally, sublobar resection was associated with increased likelihood of positive surgical margins, lower likelihood of having more than 3 lymph nodes examined, and significantly lower rates of nodal upstaging. Conclusion: In this large national-level, clinically diverse sample of clinical T1ANSCLC patients, wedge and segmental resectionswere shown to have significantly worse OS compared tolobectomy.Further patients undergoing sublobar resection were more likely to have inadequate lymphadenectomy and positive margins. Ongoingprospective study taking into account LN upstaging and margin status is still needed.
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To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma. © 2015 by American Society of Clinical Oncology.
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Purposes: The aim of this study was to evaluate whether sublobar resection could achieve recurrence and survival rates equivalent to lobectomy in high-risk elderly patients. Methods: We conducted a retrospective multicenter study that including all consecutive patients (aged >75 years) who underwent operation for clinical stage I non-small cell lung cancer (NSCLC). The clinicopathological data, postoperative morbidity and mortality, recurrence rate and vital status were retrieved. The overall survival, cancer-specific survival and disease-free survival were also assessed. Results: Two hundred and thirty-nine patients (median age 78 years) were enrolled. Lobectomies were performed in 149 (62.3 %) patients and sublobar resections in 90 (39 segmentectomies, 51 wedge resections). There were no differences in the recurrence rates following lobar versus sublobar resections (19 versus 23 %, respectively; p = 0.5) or the overall survival (p = 0.1), cancer-specific survival (p = 0.3) or disease-free survival (p = 0.1). After adjusting for 1:1 propensity score matching and a matched pair analysis, the results remained unchanged. A tumor size >2 cm and pN2 disease were independent negative prognostic factors in unmatched (p = 0.01 and p = 0.0003, respectively) and matched (p = 0.02 and p = 0.005, respectively) analyses. Conclusions: High-risk elderly patients may benefit from sublobar resection, which provides an equivalent long-term survival compared to lobectomy.
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Objective: Our objective was to compare the oncologic outcomes of lobectomy and segmentectomy for clinical stage IA lung adenocarcinoma. Methods: We examined 481 of 618 consecutive patients with clinical stage IA lung adenocarcinoma who underwent lobectomy or segmentectomy after preoperative high-resolution computed tomography and F-18-fluorodeoxyglucose positron emission tomography/computed tomography. Patients (n = 137) who underwent wedge resection were excluded. Lobectomy (n = 383) and segmentectomy (n = 98) as well as surgical results were analyzed for all patients and their propensity score-matched pairs. Results: Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between patients undergoing lobectomy (3-year RFS, 87.3%; 3-year OS, 94.1%) and segmentectomy (3-year RFS, 91.4%; hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.27-1.20; P = .14; 3-year OS, 96.9%; HR, 0.49; 95% CI, 0.17-1.38; P = .18). Significant differences in clinical factors such as solid tumor size (P < .001), maximum standardized uptake value (SUVmax) (P < .001), and tumor location (side, P = .005; lobe, P = .001) were observed between both treatment groups. In 81 propensity score-matched pairs including variables such as age, gender, solid tumor size, SUVmax, side, and lobe, RFS and OS were similar between patients undergoing lobectomy (3-year RFS, 92.9%, 3-year OS, 93.2%) and segmentectomy (3-year RFS, 90.9%; 3-year OS, 95.7%). Conclusions: Segmentectomy is suitable for clinical stage IA lung adenocarcinoma, with survivals equivalent to those of standard lobectomy.
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The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity. A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved. Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking. Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.
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Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12-65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92-100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.Modern Pathology advance online publication, 20 July 2012; doi:10.1038/modpathol.2012.106.
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Introduced the statistic kappa to measure nominal scale agreement between a fixed pair of raters. Kappa was generalized to the case where each of a sample of 30 patients was rated on a nominal scale by the same number of psychiatrist raters (n = 6), but where the raters rating 1 s were not necessarily the same as those rating another. Large sample standard errors were derived.
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A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (P<0.001). Among the clinicopathological factors, stage 1B versus 1A (P<0.001), male sex (P<0.008), high histological grade (P<0.001), vascular invasion (P=0.002) and necrosis (P<0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P<0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P=0.038), male gender (P=0.007), tumor invasive size (P=0.026) and necrosis (P=0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas.
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The propensity score is a subject's probability of treatment, conditional on observed baseline covariates. Conditional on the true propensity score, treated and untreated subjects have similar distributions of observed baseline covariates. Propensity-score matching is a popular method of using the propensity score in the medical literature. Using this approach, matched sets of treated and untreated subjects with similar values of the propensity score are formed. Inferences about treatment effect made using propensity-score matching are valid only if, in the matched sample, treated and untreated subjects have similar distributions of measured baseline covariates. In this paper we discuss the following methods for assessing whether the propensity score model has been correctly specified: comparing means and prevalences of baseline characteristics using standardized differences; ratios comparing the variance of continuous covariates between treated and untreated subjects; comparison of higher order moments and interactions; five-number summaries; and graphical methods such as quantile-quantile plots, side-by-side boxplots, and non-parametric density plots for comparing the distribution of baseline covariates between treatment groups. We describe methods to determine the sampling distribution of the standardized difference when the true standardized difference is equal to zero, thereby allowing one to determine the range of standardized differences that are plausible with the propensity score model having been correctly specified. We highlight the limitations of some previously used methods for assessing the adequacy of the specification of the propensity-score model. In particular, methods based on comparing the distribution of the estimated propensity score between treated and untreated subjects are uninformative.
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Background: Segmentectomy has the advantage of less complications, but might have less lymph node sampling and higher risk of recurrence. We aimed to compare treatment outcome between two surgical options, and explore the effect of regional lymph node removal on the prognostic difference. Methods: We retrospectively analyzed data of stage I non-small cell lung cancer (NSCLC) (≤3 cm in size) patients who underwent either segmentectomy, or lobectomy, collected from the Surveillance, Epidemiology and End Results (SEER) database, from 2003 to 2013. The primary endpoints were overall survival (OS) and lung cancer-specific survival (LCSS). We also collected data from Shandong Provincial Hospital as validation. Results: Ultimately 1,156 patients treated by segmentectomy and 17,748 patients treated by lobectomy from SEER database were included in the analysis. Overall, segmentectomy was inferior to lobectomy in terms of OS [hazard ratio (HR): 1.316 (1.186-1.461), P<0.001] and LCSS [HR: 1.310 (1.142-1.504), P<0.001]. When the removal of regional lymph nodes (LN) was taken into consideration, no significant difference was found in OS and LCSS, in any Scope of Regional Lymph Node Surgery layer (0, 1-3, more than 3, and biopsy/sentinel layer, all P>0.05). After propensity score matching (PSM), there was no difference between segmentectomy and lobectomy in OS [HR: 1.081 (0.937-1.248), P=0.286] and LCSS [HR: 1.039 (0.861-1.253), P=0.692]. Only sex, age, histology, summary stage, differentiation, tumor size, and radiation still remained as independent prognostic factors for both OS and LCSS. For validation part, there was no significantly prognostic difference between lobectomy and sublobectomy group in overall (P=0.132) and each regional LN removed layer (0, 1-3, more than 3 layers: all P>0.05). Conclusions: Segmentectomy with proper lymph node resection or sampling could be a good alternative to lobectomy.
Article
Context: - Tumor spread through alveolar spaces (STAS) has been correlated with unfavorable prognosis in lung adenocarcinomas treated with sublobar resection, but it is unknown whether STAS can be reliably identified in frozen section (FS) to help stratify patients for lobectomy or sublobar resection. Objective: - To evaluate STAS in FS. Design: - Tumor spread through alveolar spaces was evaluated in hematoxylin-eosin-stained FS, FS control slides, and all additional slides with lung tissue adjacent to tumor (AdLT) from 48 pT1-2 adenocarcinomas operated on using video-assisted thoracotomy (n = 25) or open thoracotomy (n = 23). The samples included lobectomies (n = 27) and sublobar resections (n = 21). The STAS incidences were compared by FS versus FS control versus AdLT, video-assisted thoracotomy versus open thoracotomy, and lobectomy versus sublobar resection. Sensitivity, specificity, positive and negative predictive values of STAS(+) findings were calculated. The literature was queried for best evidence regarding incidence and predictive value of STAS in FS. Results: - Tumor spread through alveolar spaces positivity was identified in 46 of 48 cases (95.8%), including 23 FS (47.9%), 32 FS control (66.7%), and 43 AdLT (89.6%). The STAS incidence was significantly higher in AdLT than in FS or FS control. Only 2 of the 25 cases that were STAS(-) in FS were true negatives. Frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and 8% negative predictive value. Systematic literature review identified no evidence regarding STAS identification in FS. Conclusions: - The sensitivity and negative predictive value of FS for STAS detection are unacceptably low. There are insufficient data to support intraoperative detection of STAS as a useful predictive feature to help stratify patients for lobectomy or sublobar resections.
Article
Objectives: To investigate the relationships between clinicopathological prognostic factors, including, surgical margin distance and tumor spread through air spaces (STAS), and recurrence after limited resection for primary lung cancer. Methods: We identified 508 limited resection cases (12.8%) and examined their clinicopathological features. Using Cox regression analysis, we examined the significant prognostic factors for recurrence of limited resection. Finally, we conducted a histopathological evaluation of tumor STAS. Results: Multivariate Cox analysis showed that the risk of local recurrence was significantly associated with STAS (HR 12.24, p = 0.001) and tumor margin < 1.0 cm (HR 6.36, p = 0.02). However, the presence of tumor STAS was not significantly associated with distant recurrence (p = 0.98). This lack of association of STAS with distant recurrence may be due to the small number of distant recurrences. Seventy-six cases (15.0%: 60 adenocarcinomas, 9 squamous cell carcinomas, and 7 others) were positive for STAS. The morphological STAS patterns were 12 single cells, 45 small cell clusters, and 19 large nests. There was no significant relationship between the recurrence rate and morphological STAS pattern. The STAS-positive group was associated with the presence of micropapillary (p = 0.002) and/or solid components (p = 0.008) in adenocarcinoma patients, and with lymphovascular and pleural invasion (p < 0.001). Conclusions: The presence of STAS and tumor margins < 1.0 cm are significant risk factors for local recurrence in early-stage lung cancer following limited resection. Thus, the presence of tumor STAS might be a pathologic prognostic factor for patients with lung cancer who have undergone limited resection. However, the pathological and molecular significance of STAS remain to be clarified.
Article
Tumor spread through air spaces (STAS) is a newly recognized pattern of invasion in lung adenocarcinoma. However, clinical significance of STAS has not yet been characterized in lung squamous cell carcinoma. In this study, we investigated whether STAS could determine clinical outcome in Japanese patients with lung squamous cell carcinoma. We reviewed tumor slides from surgically resected lung squamous cell carcinomas (n=216). STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. Tumors were evaluated for histologic subtypes, tumor budding, and nuclear diameter. Recurrence-free survival (RFS) was analyzed using the log-rank test and the Cox proportional hazards model. Tumor STAS was observed in 87 patients (40%), increasing incidence with lymph node metastasis (P=0.037), higher pathologic stage (P=0.026), and lymphatic invasion (P=0.033). All cases with STAS showed a solid nest pattern. The 5-year RFS for patients with STAS was significantly lower than it was for patients without STAS in all patients (P=0.001) and in stage I patients (n=134; P=0.041). On multivariate analysis, STAS was an independent prognostic factor of a worse RFS (hazard ratio=1.61; P=0.023). Patients with STAS had a significantly increased risk of developing locoregional and distant recurrences (P=0.012 and 0.001, respectively). We found that tumor STAS was an independent predictor of RFS in patients with resected lung squamous cell carcinoma, and it was associated with aggressive tumor behavior.
Article
Objectives: Tumor spread through air spaces (STAS) is a novel invasive pattern in lung adenocarcinoma (ADC). The effects of the combination of STAS and tumor size on survival have not been well studied. Methods: A total of 383 patients with ADC ≤ 3 cm (Stage IA) and 161 patients with Stage IB ADC were identified from 2009 to 2010. Recurrence-free survival (RFS) and overall survival (OS) were compared between patients as stratified by STAS and tumor size. A validation cohort was included in this study. Results: STAS was observed in 116 ADCs ≤ 3 cm (30.3%). In ADCs ≤ 3 cm, patients with STAS had worse RFS (P = 0.006) and OS (P < 0.001) than those without STAS. Furthermore, comparable RFS (P = 0.091) and OS (P = 0.443) were observed in patients with ADCs ≤ 3 cm/STAS-positive and those with Stage IB ADC. Multivariate analysis revealed STAS to be an independent prognostic factor in ADCs ≤ 3 cm (RFS, P = 0.043; OS, P = 0.009). Among patients with ADC > 2-3 cm, STAS still stratified the prognosis. Moreover, the unfavorable prognosis of patients with ADC > 2-3 cm/STAS-positive was similar to that of patients with Stage IB ADC. Among patients with ADC ≤ 2 cm, STAS failed to stratify the prognosis significantly. Similar results were obtained in the validation cohort. Conclusions: These results provide preliminary evidence that STAS could be considered as a factor in staging system to predict prognosis more precisely, especially in ADCs > 2-3 cm.
Article
Introduction: Recent studies have suggested that segmentectomy may be an acceptable alternative treatment to lobectomy, for surgical management of smaller lung adenocarcinomas. The objective of this study was to compare survival after lobectomy and segmentectomy among patients with pathological stage IA adenocarcinoma categorized as the new T1b (>10 to ≤20 mm) according to the eighth TNM system. Methods: In total, 7,989 patients were identified from the Surveillance, Epidemiology, and End Results registry. Propensity scores, generated from logistic regression on preoperative characteristics, were used to balance the selection bias of undergoing segmentectomy. Overall and lung cancer-specific survival of patients undergoing segmentectomy and lobectomy were compared in propensity score-matched groups. Results: Overall, 564 (7.1%) patients underwent segmentectomy. Lobectomy led to better overall and lung cancer-specific survival than segmentectomy for the entire cohort (log-rank P<0.01). After 1:2 propensity score matching, segmentectomy (n=552) was no longer associated with significant worse overall (5-year survival: 74.45% versus 76.67%, hazard ratio: 1.09, 95% confidence interval: 0.90-1.33) or lung cancer-specific (5-year survival: 83.89% versus 86.11%, hazard ratio: 1.12, 95% confidence interval: 0.86-1.46) survival compared with lobectomy (n=1,085) after adjusting for age, sex, lymph node quantity, and histology. Similar negative findings were identified when stratifying patients according to sex, age, histology, and number of evaluated lymph nodes. Conclusions: Segmentectomy may have survival outcomes not different than some patients who received lobectomy for pathological stage IA adenocarcinomas that are >10 and ≤20 mm in size. These results should be further confirmed via prospective randomised trials.
Article
Introduction: Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma; however, it has not yet been characterized in squamous cell carcinoma (SCC). Methods: We reviewed 445 resected stage I to III lung SCCs and investigated the clinical significance of STAS. Cumulative incidence of recurrence and lung cancer-specific death were evaluated by competing risks analyses and overall survival by Cox models. Results: Of the total 445 patients, 336 (76%) were older than 65 years. Among the 273 patients who died, 91 (33%) died of lung cancer whereas the remaining ones died of competing events or unknown cause. STAS was observed in 132 patients (30%) and the frequency increased with stage. The cumulative incidences of any, distant, and locoregional recurrence as well as lung cancer-specific death were significantly higher in patients with STAS compared with in those without STAS, whereas there was no statistically significant difference in overall survival. In multivariable models for any recurrence and lung cancer-specific death, STAS was an independent predictor for both outcomes (p = 0.034 and 0.016, respectively). Conclusion: STAS was present in one-third of resected lung SCCs. In competing risks analysis in a cohort in which three-fourths of the patients were elderly, STAS was associated with lung cancer-specific outcomes. Our findings suggest that STAS is one of the most prognostically significant histologic findings in lung SCC.
Article
Background: This study compares long-term prognosis of intentional extended segmentectomy and lobectomy of clinical T1aN0M0 non-small cell lung cancer (NSCLC). Risk factors of local-regional recurrence are identified and segmentectomy outcomes are examined per segment. Methods: 164 intentional extended segmentectomies were compared with 73 lobectomies subcategorized by consolidation to maximum tumor diameter ratio (C/T) measured by computed tomographies. Preoperative characteristics were propensity score matched to evaluate local-regional recurrence-free survival using the log-rank test. Preoperative factors and surgical procedure were analyzed with the Cox proportional hazards regression model to identify independent predictor of local-regional recurrence. Local-regional recurrence per segment were assessed by Kaplan-Meier estimates between both groups. Results: No recurrences were observed for 46 C/T ≤0.5 segmentectomies. In 59 C/T >0.5 propensity score-matched pairs, 5-year local-regional recurrence-free survival rates of segmentectomies were 76.3%, versus 91.5% for lobectomies (p = 0.082). Multivariate analysis confirmed segmentectomies to be the only independent risk factor for local-regional recurrence-free probability (p = 0.020). Subset analysis reveals superior segmentectomies have significantly less local-regional recurrence (p = 0.029) than other segments and comparable prognosis to lower lobectomies. Left upper lobe segmentectomies also showed comparable prognosis to lobectomies. Segmentectomies in the right upper lobe and of basal segments showed significantly higher local recurrence (p = 0.001) than other segments. Basal segmentectomies showed significantly poor prognosis versus lower lobectomies (p = 0.005). Conclusions: For radiographically invasive right upper lobe or basal segment clinical T1a NSCLC, strict inclusion criteria is necessary for intentional segmentectomy. For superior and left upper lobe segments, however, segmentectomies may be preferred with prognosis comparable to lobectomies.
Article
Purpose: According to the lung cancer staging project, T1a (≤ 2 cm) non-small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. Methods: We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. Results: OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. Conclusion: Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.
Article
Objective: Pulmonary adenocarcinoma with a micropapillary component (MPC) has aggressive malignant behavior even if resectable. The aim of this study was to determine clinicopathologic features of patients who underwent surgery for pulmonary adenocarcinoma harboring MPCs, with particular focus on coexistent free tumor clusters (FTCs). Methods: We retrospectively reviewed 444 patients with pulmonary adenocarcinoma who underwent surgery from March 2007 to July 2013. An MPC was defined as a >5% micropapillary pattern. We also defined FTCs to be a group of more than 3 small clusters containing <20 nonintegrated micropapillary tumor cells that were spreading within air spaces, >3 mm apart from the main tumor. The clinicopathologic characteristics of patients with and without FTCs were retrospectively investigated in MPC-positive patients. Results: MPCs were identified in 67 patients (15.1%), 31 of whom (46.3%) were positive for FTCs. The distance between the furthest edge of FTCs and main tumors did not exceed the diameter of the main tumor in each case (average, 7.3 mm). Locoregional recurrences were frequently observed in FTC-positive patients. FTC-positive patients experienced a significantly lower 5-year recurrence-free survival rate compared with FTC-negative/MPC-positive patients (20.4% vs 52.2%, P < .001). Recurrence-free survival of FTC-negative and -positive patients was equivalent to that of patients with p-T2 and p-T3 MPC-negative adenocarcinoma, respectively. Conclusions: Coexistence of FTCs resulted in a further negative impact on postoperative prognosis among MPC-positive adenocarcinomas and should be considered for upstaging the p-T factor and during evaluation of surgical margins.
Article
OBJECTIVES Spread through air spaces (STAS) is considered a prognosticator related to local recurrence. We assessed the prognostic impact of spread through air spaces and local recurrence in stage I lung adenocarcinoma. METHODS From July 2004 to November 2014, 877 lung cancer patients underwent surgery, of whom 318 with pathological stage I adenocarcinoma were reviewed. We investigated the characteristics of spread through air spaces and analysed the relationship between spread through air spaces and prognosis. RESULTS The median follow-up was 30 months. Of the 318 patients, 47 (14.8%) had spread through air spaces. The patients with spread through air spaces were associated with male sex (P < 0.001), smoking (P < 0.001), solid nodules (P < 0.001), stage IB disease (P = 0.006), epidermal growth factor receptor mutation negativity (P < 0.001), and lymphovascular (P < 0.001) and pleural invasion (P = 0.001). Among the preoperative findings, spread through air spaces was significantly related to solid nodules on computed tomography. Local recurrence occurred in 11 of 47 (23.4%) cases with spread through air spaces and 10 of 271 (3.7%) cases without spread through air spaces (P < 0.01). Univariate analysis showed that the overall 5-year survival rates were 62.7 and 91.1% in cases with and without spread through air spaces, respectively (P < 0.01), and the recurrence-free 5-year survival rates were 54.4 and 87.8% in cases with and without spread through air spaces, respectively (P < 0.01). Multivariate analysis confirmed spread through air spaces as a significant prognosticator for overall survival and a predictive factor for recurrence after surgery. CONCLUSIONS Among stage I lung adenocarcinoma patients, spread through air spaces was found frequently in the invasive cases and was closely related to poor prognosis and recurrence.
Article
Background: The indication for limited resection of radiologically pure solid non-small cell lung cancer (NSCLC) is controversial owing to its invasive pathologic characteristics. This study was performed to compare the outcomes after lobectomy and segmentectomy in these NSCLC patients. Methods: We retrospectively reviewed 251 patients with radiologically pure solid cT1a N0 M0 NSCLC who underwent lobectomy or segmentectomy, and the preoperative characteristics of the patients treated with the two operative techniques were matched using propensity score methods. Overall survival (OS) and disease-free survival (DFS) curves were compared using the log rank test, and differences in survival were also evaluated by the McNemar test. The preoperative factors and surgical procedure were analyzed with the multivariate Cox proportional hazards regression model to identify independent predictors of poor OS and DFS. Results: In the propensity score matched lobectomy and segmentectomy groups (87 patients per group), the 5-year and 10-year OS rates were 85% versus 84% and 66% versus 63%, respectively; and the 5-year and 10-year DFS rates were 80% versus 77% and 64% versus 58%, respectively. There were no significant differences between the two groups in OS or DFS by the log rank test, and also no significant differences in 3-year, 5-year, or 7-year OS or DFS by the McNemar test. Although age, smoking status, pulmonary function, and carcinoembryonic antigen were identified as significant predictors of both OS and DFS, the surgical procedure was not identified. Conclusions: Similar oncologic outcomes after lobectomy and segmentectomy were indicated among patients with radiologically pure solid small-sized NSCLC.
Article
Background: We retrospectively compared the oncologic outcome after segmentectomy versus lobectomy in patients with clinical (c-) T1a N0 M0 non-small cell lung cancer (NSCLC) detected as a part-solid ground-glass nodule or purely solid nodule on thin-section computed tomography. Methods: From 1997 to 2010, 312 patients with c-T1a N0 M0 NSCLC were determined to require a surgical approach categorized as segmentectomy or lobectomy. Preoperatively available data were collected using logistic regression analysis, and propensity matching was performed. Factors affecting local-regional recurrence were assessed by Cox proportional hazards regression analysis and Kaplan-Meier estimates. Results: The 5-year and 10-year overall survival rates for the 80 patients who underwent segmentectomy were 97.5% and 83.5%, respectively, compared with 87.75% and 75.0%, respectively, for the 232 patients who underwent lobectomy (p = 0.019). Local-regional recurrence as the first relapse site was found in 3 the 80 segmentectomies (3.8%) of and in 15 of the 232 lobectomies (6.5%). The difference in local-regional recurrence-free survival in patients undergoing segmentectomy compared with lobectomy was not significant (p = 0.304). In 69 propensity score-matched pairs, there was no significant difference in the overall survival (p = 0.442) or local-regional recurrence-free survival (p = 0.717) between the two groups. Multivariate analysis using the Cox proportional hazards regression model identified lymphatic invasion as the only independent factor predicting local-regional recurrence (relative risk, 10.764; 95% confidence interval, 2.98 to 57.68). Conclusions: Our results suggest that the oncologic outcome of segmentectomy vs lobectomy is similar in this cohort of c-T1a N0 M0 NSCLC patients. These results will be validated by large-scale, prospective, randomized trials.
Article
With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption. Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type. In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician. The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility. Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation. However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function. In this article we propose a novel semiparametric proportional hazards model for the subdistribution. Using the partial likelihood principle and weighting techniques, we derive estimation and inference procedures for the finite-dimensional regression parameter under a variety of censoring scenarios. We give a uniformly consistent estimator for the predicted cumulative incidence for an individual with certain covariates; confidence intervals and bands can be obtained analytically or with an easy-to-implement simulation technique. To contrast the two approaches, we analyze a dataset from a breast cancer clinical trial under both models.