Tumor Spread Through Air Spaces Research Articles

The effect of spread through air spaces on postoperative recurrence-free survival in patients with multiple primary lung cancers

PurposeThe purpose of the study was to investigate the effect of spread through air spaces (STAS) on the postoperative prognosis of patients with multiple primary lung cancers staged from IA to IB based on tumor size.MethodsClinicopathological and follow-up data of 122 patients with multiple primary lung cancers diagnosed at stages IA-IB and surgically treated at the Department of Thoracic Surgery, Shenzhen people’s Hospital from January 2019 to December 2021 were retrospectively analyzed. The study involved 42 males and 80 females. STAS status was used to divide them into two groups (87 cases in STAS (-) and 35 cases in STAS (+)). A logistic regression analysis, univariate and multivariate Cox regression analysis, and Kaplan-Meier curves (K-M) were used to determine how STAS affected recurrence-free survival (RFS) in patients.ResultsSTAS (+) had a significantly higher recurrence rate than STAS (-). STAS was predicted by smoking history (P = 0.044), main tumor diameter (P = 0.02), and solid nodules on chest CT (P = 0.02). STAS incidence was not significantly different between lobectomy and sublobar resection groups (P = 0.17). Solid nodules on CT, tumor diameter, vascular invasion, pleural invasion, and STAS were significant predictors of recurrence in the univariate Cox regression analysis. Tumor diameter, pleural invasion and STAS were significant prognostic factors for recurrence in the multivariate Cox regression analysis. Furthermore, STAS (+) group was at greater risk of recurrence than STAS (-) group (34% vs. 0%, P < 0.05)。.ConclusionStage IA-IB multiple primary lung cancer patients with STAS (+) had a higher recurrence rate and a shorter overall survival rate.

MMP-7 expression is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas

ObjectivesThe spread through air spaces (STAS) of adenocarcinoma (ADC) is a unique pattern for local invasion, which comprises the spread of tumor cells within air spaces beyond the tumor edge without a direct connection with the primary tumor. Matrix metalloproteinase-7 (MMP-7), a secreted proteolytic enzyme that degrades various extracellular matrix components and other substrates, regulates several pathophysiological processes as well as the occurrence and development of cancers in humans. Here, we retrospectively analyzed a cohort of Japanese patients with treatment-naive, surgically-resected lung ADC to assess whether MMP-7 is associated with STAS development and if it could be used as a predictor of STAS. Materials and methodsWe performed histological evaluation using hematoxylin and eosin staining and immunohistochemical analysis using microarrays. Thereafter, we scored the examined tissues for immune markers to identify significant tumor STAS predictors. ResultsWe identified that high MMP-7 expression is an independent predictor of a high STAS incidence. Multivariate analysis revealed that MMP-7 expression was correlated with tumor behavior and poor prognosis. Furthermore, STAS remained significantly associated with a higher risk of ADC recurrence. ConclusionThe development of tumor STAS could be promoted by the functioning of MMP-7. This study could be a crucial basis for future investigations on the detection of tumor STAS.

P56.01 Semiquantitative Assessment of Tumor Spread Through Air Spaces in a Historic Cohort of Lung Adenocarcinomas Following Open Surgical Resection

“Aerogenous” spread of lung cancer has been noted since 1980. The equivalent "spread through air spaces (STAS)” was introduced in the 2015 World Health Organization (WHO) Classification of Lung Tumors as a new concept of invasion. Previous studies have shown that STAS occurred in 34-51.4% of resected lung tumors (across all stages) and is associated with poor outcomes. However, some evidence suggests that STAS represents ex vivo artifact. For example, retrieval of the specimen through a small port during video-assisted thoracic surgery (VATS) could detach tumor cell clusters via mechanical force. This study examines the STAS status of lung cancer before VATS was widely used. Invasive lung adenocarcinomas surgically resected via thoracotomy at our institution between 1990 and 1992 were analyzed semi-quantitatively as "no STAS", "low STAS” (1–4 single cells or clusters), or "high STAS” (≥5 single cells or clusters) on hematoxylin and eosin stained slides. The distance between the farthest STAS focus lying within the alveolar space and the edge of the main tumor (Maximal Spread Distance, MSD) was measured. We excluded cases with multiple foci of tumor, preoperative radiation and/or chemotherapy, positive surgical margins, or distant metastasis from the study population. Stage-matched invasive lung adenocarcinomas resected by VATS in 2020 were retrieved with the same criteria and compared. A chi-squared test or Fisher's exact test was performed on Prism 5 (GraphPad) to determine the impact of clinicopathologic parameters on STAS. P values were considered statistically significant at less than 0.05. Between 1990 and 1992, 56 lung resections met criteria for inclusion. The mean age of the study cohort was 64.4 years (range 37–83), and 51.8% were male. Thirty-two cases (57.1%) underwent lobectomy, 21 cases (37.5%) sublobar resection, 3 cases (5.4%) pneumonectomy. The mean size of tumor was 3.0 cm (range 0.8 - 10 cm). Among the histologic subtypes, 23 cases (41.1%) were acinar predominant, followed by solid (26.8%), papillary (21.4%), micropapillary (8.9%) and lepidic (1.8%) subtypes. Of these, we found STAS present in 42/56 cases (75%) and no STAS in the remaining 14 cases (25%). In the group with STAS, 10 cases (17.9%) had low STAS and 32 cases (57.1%) had high STAS. The MSD was greater than 0.5 cm in 35 cases (83.3% of STAS cases). There were no statistically significant associations between STAS and gender, age, operation, predominant subtypes of adenocarcinoma, tumor size, pleural invasion, lymphovascular invasion, or tumor stage. In comparison, STAS was identified in 54 of 88 cases resected in 2020 (61.4%). The incidence of STAS was higher in 1990-92 than in 2020 (P= 0.045). The lower rates of STAS in contemporary cohorts may reflect shifts in lung cancer biology and disease management over the last 30 years. These findings suggest that VATS does not contribute significantly to generation of artifactual tumor STAS.

Preoperative bronchial cytology for the assessment of tumor spread through air spaces in lung adenocarcinoma resection specimens

Tumor spread through air spaces (STAS), a significant prognostic indicator, has been described recently as a pattern of invasion in pulmonary carcinomas. However, questions remain regarding preoperative identification of STAS and whether it represents an in vivo phenomenon versus an ex vivo artifact. We retrospectively reviewed 67 paired preoperative bronchoalveolar lavage (BAL) or bronchial washing (BW) cytology specimens with the subsequent lung adenocarcinoma surgical resection specimen to determine whether preoperative cytology could predict STAS. Other clinical, radiologic, and pathologic features of the resected lesions were also correlated with preoperative bronchial cytology results. Positive bronchial cytology was observed in 28 cases (41.8%), 24 of which had STAS (85.7%); however, negative BAL/BW cytology was observed in 39 cases (58.2%), 29 of which had STAS (74.4%) (x2 =1.27, P=.26, not significant). High-STAS burden was observed in 44 cases (83.0%), 21 (47.7%) with negative BAL/BW and 23 (52.3%) with positive BAL/BW. Low-STAS burden was observed in 9 cases (17.0%), 8 (88.9%) with negative BAL/BW and only 1 (11.1%) with positive BAL/BW (x2 =5.11, P=.024, significant). For tumors with STAS, a statistically significant difference was identified in the maximal STAS distance from the main tumor edge between BAL/BW-positive and BAL/BW-negative groups (P=.007). Of the remaining clinicopathologic and radiologic features, only visceral pleural invasion was significantly associated with BAL/BW positivity. Presurgical bronchial cytology alone cannot adequately predict tumor STAS; however, it may provide useful information regarding the extent and overall burden of STAS on the subsequent resection specimen.

Relationship between Twist, Slug with Tumor Spread Through Air Spaces in Lung Adenocarcinoma

Background: Tumor spread through air spaces (STAS) was recently reported as a novel risk factor for the prognosis of patients with resected lung adenocarcinoma that indicates invasive tumor behavior. The purpose of this study was to investigated the relationship between Twist, Slug with STAS in surgically resected lung adenocarcinoma and aimed to characterize the potential connection between epithelial-mesenchymal transition (EMT) and STAS. Methods: A total of 115 patients with resected lung adenocarcinomas were analyzed retrospectively to evaluate the relationship between Twist, Slug with STAS. Findings: STAS was observed in 56 (48.7%) patients. There were significant correlations between the presence of tumor STAS with Twist / Slug overexpression. The logistic model further revealed that pathological stage, Twist / Slug overexpression were independent risk factors for STAS. A multivariate analysis contained pathologic stage, STAS, Twist / Slug overexpression, showed that pathologic stage and STAS were independent prognostic factors for poor RFS/OS. The other multivariate model contained pathologic stage, Twist / Slug overexpression, showed that pathologic stage and Twist / Slug overexpression were independent prognostic factors for poor RFS/OS. Interpretation: STAS was correlated with overexpression of Twist / Slug, which could potentially provide information on the mechanism of STAS. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interest: The authors have no conflicts of interest to declare. Ethical Approval: The Institutional Review Board of Affiliated Hospital of Qingdao University approved this retrospective study (IRB#QYFYKY 2018-10-11-2). Informed consent was waived by the institutional review board because this was a retrospective study.

Tumor Spread Through Air Spaces Is a Survival Predictor in Non–Small-Cell Lung Cancer

BackgroundTumor spread through air spaces (STAS) is a newly recognized invasion pattern in non–small-cell lung cancer (NSCLC). However, the clinical application value of STAS in NSCLC remains to be clarified. We aimed to comprehensively explore the potential role of STAS as a prognostic indicator in NSCLC. Patients and MethodsA systematic search was performed in PubMed, Embase, Cochrane Library, and Web of Science until April 15, 2018. A quantitative meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ResultsA total of 3231 patients from 8 studies were included. STAS was observed in 1204 cases (37.3%). A significant association was found between STAS and poor progression-free survival (PFS) (hazard ratio [HR], 1.789; P < .001) and overall survival (OS; HR, 1.488; P < .001). STAS was also an independent prognostic factor for PFS (HR, 1.632; P < .001) and OS (HR, 1.475; P < .001) without obvious heterogeneity. Subgroup analyses and meta-regression showed histology type, tumor, node, metastases (TNM) stage, publication year, sample size, region, and quality score did not alter prognostic value of STAS. Tumor STAS was associated with male sex (P < .001), history of smoking (P < .001), tumor budding (P = .038), vascular invasion (P < .001), lymphatic invasion (P < .001), pleural invasion (P < .001), T stage (P < .001), N stage (P < .001), and TNM stage (P < .001). The publication bias was observed. After adjustment using a nonparametric “trim-and-fill” method, corrected HRs had no significant change. ConclusionTumor STAS is associated with clinicopathologically aggressive features and could be exploited as a novel prognostic predictor in NSCLC.

Erratum: Spread through air spaces predicts a worse survival in patients with stage I adenocarcinomas >2 cm after radical lobectomy.

[This corrects the article DOI: 10.21037/jtd.2018.09.22.].

Relationship between stromal cells and tumor spread through air spaces in lung adenocarcinoma.

BackgroundThe mechanism underlying tumor spread through air spaces (STAS) has not been well studied. We investigated the role of tumor stromal cells in the pathogenesis of STAS from a pathological perspective and evaluated the prognostic significance of tumor stromal cells and STAS in postoperative patients with lung adenocarcinoma.MethodsWe retrospectively analyzed 208 postsurgical patients with stage I–IIIA lung adenocarcinoma. The presence of STAS was evaluated by hematoxylin and eosin staining. The expression of α‐smooth muscle actin (SMA)‐positive cancer‐associated fibroblasts (CAFs) and CD204‐positive tumor‐associated macrophages (TAMs) was analyzed by immunohistochemistry. A logistic regression model was applied to confirm the predictive factors of STAS. Survival analysis was performed to evaluate the effect of α‐SMA‐positive CAFs, CD204‐positive TAMs, and STAS on prognosis. A nomogram was generated to evaluate the prognosis of postoperative patients.ResultsLogistic regression suggested that the expression of α‐SMA‐positive CAFs (P < 0.001) and the number of CD204‐positive TAMs (P < 0.001) were related to the presence of STAS. The multivariate Cox proportional hazards model suggested that STAS (P = 0.004), α‐SMA‐positive CAFs (P < 0.001), and CD204‐positive TAMs (P < 0.001) were independent risk factors for prognosis. Harrell's c‐indexes for overall and recurrence‐free survival prediction based on nomograms were 0.84 (95% confidence interval 0.76–0.91) and 0.82 (95% confidence interval 0.76–0.89), respectively.ConclusionsThe presence of STAS was associated with high expression of α‐SMA and CD204 in lung adenocarcinoma. Nomograms including STAS and stromal cells as variables are recommended as practical models to evaluate the prognosis of lung adenocarcinoma patients.

Spread through air spaces predicts a worse survival in patients with stage I adenocarcinomas >2 cm after radical lobectomy.

The aim of this study was to evaluate the significance of spread through air spaces (STAS) in early lung adenocarcinomas after radical lobectomy and lymphadenectomy. A total of 242 patients with lung adenocarcinomas less than 4 cm (8th pStage I) were selected from the lung cancer patients surgically treated from January, 2009 to September, 2011. Pathological review focused on STAS as well as histological subtypes, blood vessel & neural invasion, pathological tumor size etc. Recurrence or disease-free survival (DFS) and overall survival (OS) were compared between patients as stratified by STAS and tumor size. STAS was observed in 33.47% (81/242) patients, which was significantly correlated with histological predominant subtype (χ2=25.903, P=0.093×10-3) and differentiation grade (χ2=23.986, P=0.025×10-3). Patients with STAS (+) showed a comparable PFS (P=0.268) and OS rates (P=0.100) in all stage I cases, but a significant lower PFS (P=0.029) and OS (P=0.013) in tumors within 2< tumors ≤4 cm. Multivariate analysis revealed STAS to be an independent worse prognostic factor in lung adenocarcinomas within 2< tumors ≤4 cm, both for PFS (P=0.004) and OS (P=0.002), while no significant difference was found in patients with tumors ≤2 cm (PFS, P=0.537; OS, P=0.448), after adjusting by other clinicopathological parameters as age, gender, smoking etc. Presence of STAS was a significant worse predictor for pStage I patients with lung adenocarcinoma >2 cm who underwent radical lobectomy, while it is not significant in patients with tumor ≤2 cm. These findings may be helpful in assessing postoperative therapy stratified by tumor size and STAS status.

Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces

ObjectiveThe World Health Organization Classification of Lung Tumors considers “Spread Through Air Spaces (STAS)” as a form of invasion in lung adenocarcinoma. However, its existence as an independent pathologic entity rather than an artifact caused by spreading through a knife surface is still controversial. Therefore, we performed comprehensive analyses on the genetic and clinicopathologic characteristics of lung adenocarcinoma with STAS. Materials and MethodsA total of 316 surgically resected lung adenocarcinoma cases were analyzed retrospectively. Detailed analyses were performed on clinical-histological-molecular features. Tumor STAS was defined as tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. ResultsSTAS was observed in 160 cases (50.6%). STAS was significantly related to lymphovascular invasion, lymph node metastasis, higher stage, and high-grade histologic subtype. STAS was frequently found in tumors with wild-type EGFR or ALK-rearrangement. Logistic regression analysis showed that STAS was significantly associated with absence of lepidic component, presence of micropapillary component, cribriform predominant type, lymphovascular invasion, and wild-type EGFR. Multivariate survival analysis demonstrated that STAS was independently associated with shorter recurrence-free survival. STAS was also associated with recurrences to extrathoracic sites as well as intrathoracic sites. ConclusionSTAS is associated with certain pathological and molecular subtypes. STAS might be a parameter for tumor aggressiveness in that it is strongly associated with poor prognostic factors and recurrence, including to extrathoracic sites.

Tumor Spread Through Air Spaces Identifies a Distinct Subgroup With Poor Prognosis in Surgically Resected Lung Pleomorphic Carcinoma

Tumor spread through air spaces (STAS) has recently been reported as a novel form of lung adenocarcinoma invasion that can negatively affect survival; however, its role in pleomorphic carcinoma remains unclear. The goal of this study was to characterize tumor STAS in pleomorphic carcinoma, including its association with clinicopathologic features and prognosis. Tumor specimens obtained from 35 consecutive patients with pleomorphic carcinoma who underwent surgical resection between 2009 and 2015 were reviewed. Tumor STAS was defined as tumor cells spreading within the air spaces in the surrounding lung parenchyma beyond the edge of the primary tumor. Fourteen patients (40%) had evidence of STAS-positive pleomorphic carcinomas. Three types of morphologic findings were observed: single cells, small tumor cell clusters, and tumor nests. Tumor necrosis tended to be more prevalent in STAS-positive tumors than in STAS-negative tumors (P= .094). Patients with STAS experienced significantly worse recurrence-free survival (P= .005) and overall survival (P= .002) rates than those without STAS. Moreover, multivariate analysis revealed that tumor STAS was an independent risk factor for both recurrence (P= .014) and poor overall survival (P= .042). In this first study of its kind, tumor STAS in patients with pleomorphic carcinoma was shown to be associated with high recurrence rates and poor survival after surgical resection. Hence, tumor STAS can serve as a predictor of postoperative survival; this information will enable better risk stratification and more effective clinical management of patients with this rare type of tumor.

Tumor spread through air spaces is a useful predictor of recurrence and prognosis in stage I lung squamous cell carcinoma, but not in stage II and III

ObjectivesTumor spread through air spaces (STAS) is a newly identified invasion pattern in lung adenocarcinoma. This study aimed to analyze and validate the clinical impact of tumor STAS in surgically resected lung squamous cell carcinoma (SQCC). Materials and methodsWe retrospectively reviewed 220 patients with lung SQCC. Tumor STAS was defined as detached tumor cells within the air spaces in the lung parenchyma beyond the edge of the main tumor. Statistical analyses were conducted to investigate the proportion of STAS and the relationship between the presence of STAS and clinicopathological factors, including clinical outcome. ResultsSTAS was identified in 42 of 220 patients (19.1%). The patients with STAS had a significantly worse 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) than those without STAS (5-year RFS: 37.4% vs. 68.4%; p = 0.0006; 5-year OS: 50.2% vs. 71.4%, p = 0.0078) in stage I, but not in stage II and III. A multivariate analysis showed that the presence of STAS was an independent predictive factor of recurrence (hazard ratio = 3.27; 95% confidence interval, 1.7–6.29; p = 0.0004) and an independent prognostic factor (hazard ratio = 3.01; 95% confidence interval, 1.54–5.89; p = 0.0013) in stage I, but not in stage II and III. ConclusionWe found that STAS was detected in 19.1% of surgical resected SQCC, and it was associated with recurrence and worse survival in stage I SQCC, but not in stage II and III SQCC. Therefore, we suggest that STAS is a useful predictor of recurrence and prognosis in stage I lung SQCC.

Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer

The aim of this study was to investigate the relationship between clinicopathological prognostic factors, including surgical margin distance and tumor spread through air spaces (STAS), and recurrence after limited resection for primary lung cancer. We identified 508 cases of limited resection (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. Multivariate Cox analysis showed that the risk for local recurrence was significantly associated with STAS (hazard ratio= 12.24, p= 0.001) and a tumor margin less than 1.0 cm (hazard ratio= 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. In all, 76 cases (15.0%) (60 adenocarcinomas, nine squamous cell carcinomas, and seven 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 patients with adenocarcinoma and with lymphovascular and pleural invasion (p < 0.001). The presence of STAS and tumor margins less than 1.0 cm are significant risk factors for local recurrence in early-stage lung cancer after limited resection. Thus, the presence of tumor STAS might be a pathological prognostic factor for patients with lung cancer who have undergone limited resection. However, the pathological and molecular significance of STAS remain to be clarified.

Tumor Spread Through Air Spaces Is an Independent Predictor of Recurrence-free Survival in Patients With Resected Lung Squamous Cell Carcinoma.

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.

MA12.09 Comparative Histological Subtype Analysis of Lung Adenocarcinoma Tumor and Metastatic Lymph Nodes and the Prognostic Impact

The goal of this study is to investigate comprehensive comparative pathological analyses of both primary tumor and metastatic lymph node (LN) and correlate with lung cancer-specific death (LC-death) in patients with LN-positive lung adenocarcinoma. PN1/2 lung adenocarcinoma patients who underwent R0 resection without induction therapy (n=402, 2000-2012) were included in the study. In primary tumor, lymphatic/vascular/pleural invasion, necrosis, tumor spread through air spaces (STAS), as well as histologic subtypes according to 2015 WHO classification were evaluated. In metastatic LN, metastatic tumor size, extracapsular invasion, histologic subtypes were evaluated. Recurrence and LC-death were analyzed by Cox model. Micropapillary and solid predominant subtypes were more frequent in LN metastases than in primary tumors (Figure). In multivariable analyses, adjuvant chemotherapy, pleural invasion, extracapsular invasion of LN metastasis, micropapillary predominant subtype in LN metastasis were independent factors for recurrence; adjuvant chemotherapy, pleural invasion, tumor STAS, and extracapsular invasion were for LC-death (Table). In lung adenocarcinoma lymph node metastases, predominant micropapillary pattern and extracapsular invasion indicate high risk for recurrence and lung cancer-specific death.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

P3.01-002 The Clinical Impact of Spread through Air Spaces (STAS) in Surgically Resected pStage I Lung Squamous Cell Carcinoma: Topic: Morphology

Spread through air spaces (STAS) is identified as a newly invasive pattern in lung adenocarcinoma. It contributes to the significantly increased recurrence rate for patients with small adenocarcinoma. But the presence of STAS and its clinical impact has remained uncertain in squamous cell carcinoma (SQCC). The purpose of this study is to analyze whether STAS happens in surgically resected pathological Stage I (pStage I) lung SQCC. We retrospectively reviewed 141 pStage I patients of SQCC (Female/Male, 13/128; Smoker/Never smoker, 135/6; pStage IA/IB, 93/48). Tumor STAS was defined as tumor cells within the air spaces in the lung parenchyma beyond the edge of the main tumor. Statistical analyses were conducted to investigate the relationship between its presence and the clinicopathological background factors, including the clinical outcome. STAS was identified in 23 of 141 patients (16.3%) with limited (7.1%) and extensive (9.2%) feature, respectively. Both disease-free survival (DFS) and overall survival (OS) were significantly worse in the patients with STAS in comparison with the patients without STAS (5-year DFS, 35.1% vs. 65.6%, p<0.01; 5-year OS, 41.7% vs. 71.2%, p<0.01, respectively). In multivariate analyses adjusting for sex, year, smoking history and pStage, the presence of STAS was found to be an independent predictive factor of both DFS (HR=3.154, 95%CI: 1.592-6.249; p=0.001) and OS (HR=3.07, 95%CI: 1.595-5.911; p=0.0008). The 141 tumors were divided into patients who underwent limited resection and those who underwent standard resection in order to examine whether the surgical procedure affected the DFS and OS of patients with and without STAS. In the standard resection group, both 5-year DFS and 5-year OS were worse in the patients with STAS in comparison with the patients without STAS (44.1% vs. 68.3%, p=0.03; 53.8% vs. 72.3%, p=0.048, respectively). In the limited resection group, both 5-year DFS and 5-year OS were worse in the patients with STAS in comparison with the patients without STAS (0% vs.57.5%, p=0.001; 0% vs. 66.4%, p=0.001, respectively). STAS happened in lung SQCC and was found to be an independent predictive factor of both DFS and OS. Both 5-year DFS and 5-year OS were worse in the patients with STAS regardless of surgical procedure.

Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas

Tumor invasion in lung adenocarcinoma is defined as infiltration of stroma, blood vessels, or pleura. Based on observation of tumor spread through air spaces (STAS), we considered whether this could represent new patterns of invasion and investigated whether it correlated with locoregional versus distant recurrence according to limited resection versus lobectomy. We reviewed resected small (less than or equal to 2 cm) stage I lung adenocarcinomas (n = 411; 1995-2006). Tumor STAS was defined as tumor cells-micropapillary structures, solid nests, or single cells-spreading within air spaces in the lung parenchyma beyond the edge of the main tumor. Competing risks methods were used to estimate risk of disease recurrence and its associations with clinicopathological risk factors. STAS was observed in 155 cases (38%). In the limited resection group (n = 120), the risk of any recurrence was significantly higher in patients with STAS-positive tumors than that of patients with STAS-negative tumors (5-year cumulative incidence of recurrence, 42.6% versus 10.9%; P < 0.001); the presence of STAS correlated with higher risk of distant (P = 0.035) and locoregional recurrence (P = 0.001). However, in the lobectomy group (n = 291), the presence of STAS was not associated with either any (P = 0.50) or distant recurrence (P = 0.76). In a multivariate analysis, the presence of tumor STAS remained independently associated with the risk of developing recurrence (hazard ratio, 3.08; P = 0.014). The presence of STAS is a significant risk factor of recurrence in small lung adenocarcinomas treated with limited resection. These findings support our proposal that STAS should formally be recognized as a pattern of invasion in lung adenocarcinoma.