Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma

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1 Interactive CardioVascular and Thoracic Surgery 23 (2016) doi: /icvts/ivw211 Advance Access publication 26 June 2016 ORIGINAL ARTICLE THORACIC Cite this article as: Shiono S, Yanagawa N. Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma. Interact CardioVasc Thorac Surg 2016;23: Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma a b Satoshi Shiono a, * and Naoki Yanagawa b Department of Thoracic Surgery, Yamagata refectural Central Hospital, Yamagata, Japan Department of athology, Yamagata refectural Central Hospital, Yamagata, Japan * Corresponding author. Department of Thoracic Surgery, Yamagata refectural Central Hospital, 1800, Oazaaoyagi, Yamagata , Japan. Tel: ; fax: ; sshiono@ypch.gr.jp (S. Shiono). Received 23 February 2016; received in revised form 18 May 2016; accepted 25 May 2016 Abstract 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 ( < 0.001), smoking ( < 0.001), solid nodules ( < 0.001), stage IB disease ( = 0.006), epidermal growth factor receptor mutation negativity ( < 0.001), and lymphovascular ( < 0.001) and pleural invasion ( = 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 ( < 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 ( < 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 ( < 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. Keywords: Lung cancer Lung pathology Lung cancer surgery INTRODUCTION With the advent of radiological examinations, small-sized lung cancer is now detected more frequently. The prognosis of these small-sized lung cancers, which are classified as stage T1, has been favourable, according to recent studies [1]. According to the recent lung cancer classification, revision of sublobar resection is needed, and randomized control trials comparing lobectomy with sublobar resection are ongoing in Japan and the United States [2, 3]. Although the prognosis of small-sized lung cancer has improved, a portion of patients continue to have a dismal prognosis even after curative surgery. ostoperative prognostic factors for adenocarcinoma include solid tumour size [4], proportion of groundglass opacity (GGO) [5 7], pleural invasion [8 10], lymphovascular These findings were presented at the 16th World Conference on Lung Cancer, Denver, 6 9 September invasion [9, 10], serum carcinoembryonic antigen (CEA) level [11] and positron emission tomography (ET)/computed tomography (CT) findings [12]. Among lung cancers, adenocarcinoma has been investigated in detail and is classified by new pathological criteria [13 16]. In a new statement regarding invasiveness, spread through air spaces (STAS) has been recognized as an additional pattern of tumour invasiveness, described as STAS consists of micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma [14]. Kadota et al. showed that STAS is a risk factor for recurrence of small adenocarcinomas [17]. However, a study from 2005 on pulmonary metastasis from colorectal cancer revealed aerogenous spread with floating cancer cell clusters (ASFC) as a prognostic factor significantly related to local recurrence at the surgical margin [18, 19]. Since 2004, we have paid attention to this phenomenon in resected lung cancer specimens and collected data prospectively. According to recent studies [13 16], ASFC is the ORIGINAL ARTICLE The Author ublished by Oxford University ress on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 568 S. Shiono and N. Yanagawa / Interactive CardioVascular and Thoracic Surgery same as STAS. STAS in surgically resected lung cancer has not been well investigated. We believe that the role of STAS in the prognosis and local recurrence of stage I lung adenocarcinoma cases should be explored. The objectives of this study were to access our established prospectively collected database and to investigate the relationships between STAS and clinical findings including outcomes. ATIENTS AND METHODS The ethics committees of our institution approved this study (ethical committee approval number 10) and, since the patient data remained anonymous, waived the need for informed consent from the patients. Database This was a retrospective study based on our prospectively collected institutional database established in May Staging was based on the clinical and pathological TNM stage (International Union Against Cancer staging system, 7th edition) [1]. The following parameters were collected in the database: (i) patient characteristics (age, sex, smoking status, tumour markers including the serum CEA level, comorbidities, spirometry values and blood gas analysis results); (ii) information regarding the diagnosis (method used to make the diagnosis, radiological findings of thin-section chest CT and ET/CT); (iii) surgical procedure ( pneumonectomy, lobectomy, segmentectomy or wedge resection); (iv) pathological findings (grading, size, lymph node metastasis, lymphovascular invasion, pleural invasion, ASFC/STAS); (v) epidermal growth factor receptor (EGFR) mutations; (vi) outcomes (site of recurrence, death and follow-up). reoperative examination reoperative chest CT was performed routinely, and reconstructed thin-section CT images with a 0.5-mm slice thickness at 0.5-mm reconstruction intervals were obtained. Depending on the aircontaining spaces, nodules were divided into solid or non-solid nodules based on CT findings, as we reported previously [12]. Solid nodules were defined as those that completely obscured the lung parenchyma. Non-solid nodules included both GGO and solid components [12]. For the ET/CT protocol, a standard dose of F-18 fluorodeoxyglucose (FDG; 3.75 MBq/kg) was administered intravenously, and ET and CT images were scanned 60 min later. Eight patients could not undergo ET/CT due to diabetes, and CT findings were insufficient in 15 patients. In the preoperative diagnosis, transbronchial lung biopsy or CT-guided biopsy was not performed routinely. In the case of undiagnosed lung nodules, intraoperative frozen sections were used to determine the diagnosis. Lung resections were performed using a standard technique. atients with a poor performance status, impaired respiratory function and/or severe comorbidities underwent segmentectomy or wedge resection. The selection of segmentectomy or wedge resection depended on the tumour location. In the case of ct1a lung cancer, we performed segmentectomy based on results from a Japanese clinical trial that evaluated the feasibility of segmentectomy ( JCOG0804/ WJOG4507L) [2]. Lymph node dissection was performed routinely during segmentectomy but not during wedge resection. We usually perform lobectomy or segmentectomy via a thoracotomy 12 cm in size. Of the 318 cases, 37 (11.6%) underwent videoassisted thoracic surgery. The follow-up schedule consisted of a visit 1 or 2 weeks after surgery and every month thereafter for up to 3 months. If the patients did not experience any issues, follow-up was performed every 3 4 months for 5 years. Regular outpatient clinic checkups, including physical examination, blood chemistry analysis, serum tumour marker measurements and chest radiography, were performed 3 4 times yearly for 5 years. During the follow-up period, the patients underwent annual chest and brain CT imaging. athological examination The surgically resected specimens were fixed in 10% formalin, sectioned into slices of 5 10 mm thickness and stained with haematoxylin and eosin (HE). We also routinely examined the presence of pleural, lymphatic and vascular invasion. leural and vascular invasion was evaluated by Verhoeff s elastic stain. Since we had begun examination of the pathological findings and data collection before the concept of STAS [14 17], we called this phenomenon ASFC and used a definition determined previously. ASFC was defined as the presence of tumour clusters lying freely Figure 1: resence of isolated tumour clusters (arrow) within the alveolar space at a distance of at least 0.5 mm from the main metastatic lesion (A, low-power view, B, high-power view).

3 S. Shiono and N. Yanagawa / Interactive CardioVascular and Thoracic Surgery 569 within the alveolar space [18, 19], at a distance of at least 0.5 mm from the main tumour (Fig. 1). In this article, we followed the WHO guidelines [14] and used the term STAS instead of ASFC. STAS was evaluated microscopically by two of the authors within the tumour section of largest diameter. USA). A value of < 0.05 was considered to indicate statistical significance. RESULTS atients From July 2004 to November 2014, a total of 877 lung cancer patients underwent lung cancer surgery. Among them, 341 patients had pathological stage ( p-stage) I adenocarcinoma. After excluding 10 patients who received induction therapy and 13 patients with metachronous multiple lung cancers, 318 patients were reviewed. We investigated the characteristics of STAS and analysed the relationship between STAS and surgical outcomes. Statistical analysis The χ 2 test was used to evaluate the associations between categorical variables and various factors, and Student s t-test was used to evaluate the continuous variables. Since CEA level, maximum standardized uptake value (SUV) and tumour size were non-parametric variables, the Wilcoxon rank-sum test was used. Logistic regression analysis was used to identify predictive factors for STAS. The follow-up period was defined as the time from the date of surgery to the date of the last hospital visit or death from any cause. Overall and recurrence-free survival rates were estimated using the Kaplan Meier method. Overall survival was measured from the date of lung cancer surgery to either the date of death from any cause or the patient s last hospital visit. Recurrence-free survival was measured from the date of surgery to the date of detection of recurrence. Survival differences were assessed by the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were used to identify prognostic factors for overall and recurrence-free survival. Data were analysed using JM software, version 5.0.1J (SAS Institute Inc., Cary, NC, Table 1: atient characteristics a STAS (+) n = 47 (14.8) The median age of the patients at the time of surgery was 70 (range, 41 89) years. Of the 318 patients, 149 (46.9%) were male and 169 (53.1%) female. The median serum CEA level was 2.6 ng/ ml (range, ng/ml). There were 171 (53.8%) non-smokers, 101 (31.8%) past smokers and 46 (14.5%) current smokers among the patients. The median max SUV on ET/CT was 2.6 (0 22.8). Of the 318 cases, 33 (10.4%) exhibited no uptake on ET/CT. The p-stage was IA in 242 (76.1%) and IB in 76 (23.9%) patients. The median tumour size was 18 (range, 6 50) mm. EGFR mutations were detected in 169 (53.1%) patients. The number of patients with lymphovascular invasion was 16 (5.0%) and that with pleural invasion, 43 (13.5%). STAS was found in 47 (14.8%) patients. Table 1 summarizes the characteristics of the patients according to the presence of STAS. Among patients with STAS, the proportions of patients who were male, current or past smokers, p-stage IB, EGFR mutation-negative and who had a high CEA level, solid nodules on chest CT, and lymphovascular and pleural invasion were significantly higher compared with patients without STAS. The SUV was also significantly higher in the STAS-positive patients. Multivariate analysis was performed to investigate the preoperative factors of STAS (Table 2). Solid nodules on CT were an independent predictive factor of STAS ( = 0.032). We examined the rate of STAS according to the diagnostic procedure performed. Because of the difficulties with diagnosing lung cancer preoperatively, 123 of the 318 patients (38.7%) underwent lobectomy or segmentectomy initially. Among the remaining patients, 98 (30.8%) underwent wedge resection, 89 (28.0%) preoperative transbronchial biopsy and 8 (2.5%) preoperative needle biopsy to determine a diagnosis. When the rate of STAS was compared between the patients who underwent initial lobectomy or segmentectomy and those who underwent other procedures, there was no significant difference ( = 0.477). Moreover, among the surgical procedures, STAS was detected in 32 of 202 lobectomies STAS ( ) n = 271 (85.2) Male/female 33 (70.2)/14 (29.8) 116 (42.8)/155 (57.2) Median age (years), IQR 68 (60 76) 71 (63 77) Median CEA level (ng/ml), IQR 3.3 ( ) 2.4 ( ) Non-smoker/smoker 13 (27.6)/34 (72.3) 158 (58.3)/113 (41.7) <0.001 Median maxsuv on ET/CT, IQR 4.7 ( ) 2.4 ( ) <0.001 Non-solid/solid nodules on CT 10 (21.3)/31 (78.7) 148 (54.6)/114 (45.4) <0.001 Lobectomy/segmentectomy/wedge resection 32 (68.1)/9 (19.2)/6 (12.8) 170 (62.7)/68 (25.1)/33 (12.1) p-stage IA/IB 28 (59.6)/19 (40.4) 214 (79.0)/57 (21.0) Median tumour size (cm), IQR 2.1 ( ) 1.8 ( ) EGFR mutation (+/ ) 9 (19.1)/38 (80.9) 160 (59.0)/111 (41.0) <0.001 LV invasion (+/ ) 8 (17.0)/39 (83.0) 8 (3.0)/263 (97.0) <0.001 leural invasion (+/ ) 14 (29.8)/33 (70.2) 29 (10.7)/242 (89.3) ORIGINAL ARTICLE Numbers in parentheses are percentages. IQR: interquartile range; STAS: spread through air spaces; CEA: carcinoembryonic antigen; SUV: standardized uptake value; ET: positron emission tomography; CT: computed tomography; EGFR: epidermal growth factor receptor; LV: lymphovascular. a The χ 2 test was used for categorical data. Student s t-test or the Wilcoxon rank-sum test was used for continuous data.

4 570 S. Shiono and N. Yanagawa / Interactive CardioVascular and Thoracic Surgery Table 2: redictive factors for STAS a Table 3: rognostic factors for overall survival a reoperative variables Odds ratio Female 0.92 ( ) Age 0.57 ( ) CEA level 1.46 ( ) Smoker 3.01 ( ) maxsuv on ET/CT 4.32 ( ) Solid nodules on CT 2.50 ( ) Tumour size 0.95 ( ) STAS: spread through air spaces; CI: confidence interval; CEA: carcinoembryonic antigen; SUV: standardized uptake value; ET: positron emission tomography; CT: computed tomography. a Logistic regression analysis. (15.8%), 9 of 77 segmentectomies (11.7%) and 6 of 39 wedge resections (14.8%), with no significant difference ( = 0.667). After lung cancer surgery, recurrence developed in 30 of the 318 (9.4%) patients. Recurrence developed in 9.9% of the lobectomy, 9.1% of the segmentectomy and 7.7% of the wedge resection cases, with no significant difference among the surgical procedures ( = 0.090). The sites of recurrence were as follows: pleural dissemination (8), lungs (6), surgical stump (4), brain (4), bone (4), lymph nodes (3) and a case of meningitis carcinomatosa (1). When the local recurrence was pleural dissemination or at the lungs, surgical stump or lymph nodes, patients positive for STAS showed a higher rate of recurrence [7 of 47 (14.9%) patients] compared with those negative for STAS [8 of 271 (3.0%) patients] ( = 0.002). Furthermore, all cases of surgical stump recurrence had STAS. No deaths occurred within 90 days of surgery. The Kaplan Meyer estimate of the median length of follow-up was 30 months (95% confidence interval, months). The overall 5-year survival rate in all cases was 85.1%. Univariate analysis revealed that age, smoking, a high max SUV, solid nodules, pleural invasion and STAS positivity were significant prognostic factors for poor overall survival (Table 3). Figure 2 shows the Kaplan Meier curve for overall survival according to the presence of STAS; the overall 5-year survival rate of patients with STAS was 62.7%, and that of those without STAS was 91.1% ( < 0.001). Multivariate analysis showed that age, pleural invasion and STAS were significant prognostic factors for poor survival (Table 3). To determine the predictive factors for recurrence, we investigated recurrence-free survival. The recurrence-free survival rate after surgery was 75.8% for all cases. Univariate analysis revealed that a high CEA level, high max SUV, solid nodules, larger tumour size, lymphovascular invasion, pleural invasion and STAS were significant predictive factors for recurrence (Table 4). Figure 3 shows the Kaplan Meier curve for the recurrence-free survival rate according to the presence of STAS; the 5-year recurrence-free survival rate of patients with STAS was 54.4%, and that of those without STAS was 87.8% ( < 0.001). Multivariate analysis showed that age, tumour size, pleural invasion and STAS were significant prognostic factors for recurrence (Table 4). DISCUSSION In 2015, the concept of STAS, which is a characteristic of lung cancer invasiveness, was defined in the WHO guidelines [14, 15]. Variables Univariate analysis Multivariate analysis Kadota et al. [17] showed that lymphovascular invasion and highgrade morphological patterns are closely related to STAS. A few studies evaluated this finding by other expressions [18 21]. Onozato et al. [20] reported the isolation of tumour islands, which are large clusters of tumour cells, within alveolar spaces. The prognosis was significantly worse for patients with lung adenocarcinomas with versus without tumour islands on multivariate analysis. As mentioned above, before the proposal of the term STAS, we focused on tumour cell spreading in air spaces and, following our definition of ASFC, have collected data on resected lung cancer cases prospectively since Since the WHO guideline was set forth and other studies on the subject have appeared, we are convinced that ASFC is the same entity as STAS. Although STAS was observed in 14.8% of our cases, it was observed previously in 38% of stage I cases [17] and in 50.6% of overall lung adenocarcinoma cases [21]. The lower rate of STAS detected in this study was likely due to the proportion of noninvasive lung cancers. Because our Female 0.67 ( ) ( ) Age 1.06 ( ) ( ) CEA level 1.07 ( ) ( ) Smoker 1.58 ( ) ( ) maxsuv 1.12 ( ) ( ) Solid nodule 1.87 ( ) ( ) Lobectomy 1.36 ( ) ( ) Tumour size 1.29 ( ) ( ) EGFR 0.77 ( ) ( ) mutation+ LV invasion ( ) ( ) leural 2.38 ( ) < ( ) invasion+ STAS ( ) ( ) CI: confidence interval; CEA: carcinoembryonic antigen; SUV: standardized uptake value; EGFR: epidermal growth factor receptor; LV: lymphovascular; STAS: spread through air spaces. a Cox proportional hazards model. Figure 2: Overall survival according to the presence of spread through air spaces. Survival differences were assessed by the log-rank test.

5 S. Shiono and N. Yanagawa / Interactive CardioVascular and Thoracic Surgery 571 Table 4: rognostic factors for recurrence-free survival a Variables Univariate analysis Multivariate analysis Figure 3: Recurrence-free survival according to the presence of spread through air spaces. Survival differences were assessed by the log-rank test. Female 0.72 ( ) ( ) Age 1.03 ( ) ( ) CEA level 1.09 ( ) ( ) Smoker 1.37 ( ) ( ) maxsuv 1.19 ( ) < ( ) Solid nodule 2.66 ( ) < ( ) Lobectomy 1.05 ( ) ( ) Tumour size 1.79 ( ) ( ) EGFR 0.79 ( ) ( ) mutation+ LV invasion ( ) ( ) leural 2.90 ( ) < ( ) invasion+ STAS ( ) < ( ) CI: confidence interval; CEA: carcinoembryonic antigen; SUV: standardized uptake value; EGFR: epidermal growth factor receptor; LV: lymphovascular; STAS: spread through air spaces. a Cox proportional hazards model. present data included cases of adenocarcinoma in situ (38; 11.9%) and of minimally invasive adenocarcinoma (57; 17.9%), our data showed a lower rate of STAS than that reported in other studies. When these preinvasive lesions were excluded from the analysis, STAS was identified as a prognostic factor for overall ( < 0.001) and recurrence-free ( = 0.022) survival on multivariate analysis. Our prospectively collected data validated STAS as a significant risk factor for recurrence and a prognostic factor after lung cancer surgery. We included cases of wedge resection without lymph node dissection in this study, even though wedge resection should be excluded in prognostic evaluations. However, even after excluding wedge resection cases, STAS was still a significant factor for recurrence risk and prognosis (data not shown). Warth et al. [21] showed that STAS was detected at high rates in men and in patients with wild-type EGFR status, lymph node positivity, distant metastasis and advanced-stage lung cancer. However, smoking was not associated with STAS. Our data supported these previous results and showed that male sex, a high SUV, solid nodules, wildtype EGFR, lymphovascular invasion and pleural invasion are significantly related to STAS. Because these factors are generally considered prognosticators of poor survival, STAS may be a surrogate factor for the aggressive behaviour of lung cancers. Because lung cancers with STAS are considered to have poor outcomes, we can further concentrate interest on adjuvant chemotherapy or local stump radiation therapy. Four patients developed surgical stump recurrence in this study. Two of these patients underwent segmentectomy, while the other two underwent wedge resection, and all four had STAS. A previous report investigating colorectal lung metastasis revealed that the number of STAS events was significantly related to surgical stump recurrence [20]. Onozato et al.[20] demonstrated that the presence of tumour islands was significantly related to early recurrence after wedge resection and concluded that patients with tumour islands tended to develop recurrence even with tumor-free margins. From these reports and our results, STAS is speculated to be a risk factor for surgical stump recurrence in segmentectomy or wedge resection. To prevent surgical stump recurrence, the importance of accurate intraoperative cytologic analysis [22, 23] and sufficient surgical margins has been reported [24]. Unfortunately, we did not explore surgical margin size and thus were unable to clarify whether the surgical margin also had an influence on surgical stump recurrence. Whether or not the effect of STAS on local recurrence has been investigated sufficiently, further prospective studies are needed. Before our evaluation of STAS, we did not know which preoperative factors were associated with STAS; therefore, we assessed generally known negative prognosticators following lung cancer surgery. Solid nodules on CT were closely related to STAS. Chest CT findings can provide useful information. The consolidation/tumour ratio on CT and the GGO ratio are recognized as significant methods to detect non-invasive lung adenocarcinoma [6, 7, 25]. GGO is generally defined as an area with a slight homogeneous increase in density that does not obscure the underlying vascular markings [25]. However, based on CT findings, the size of consolidation or GGO cannot be evaluated clearly, and evaluation results might differ among investigators. Hashizume et al. [5] showed that pathological invasiveness was not present in patients with air-containing type of nodule. For these reasons, we divided the lung cancers into solid and non-solid types and examined the relationships between STAS and radiological findings. Because of the possibility of STAS, lobectomy is a feasible procedure for solid lung cancers on CT to prevent locoregional recurrence. This study has some limitations. First, differentiating tumour cell clusters from macrophages is difficult in some cases. We did not use immunohistochemical or other strict criteria to show STAS as specified in a previous study [17]. However, STAS can be detected by routine HE staining without the use of immunohistochemical tests, and our criteria demonstrated the same results as those of other studies [17, 20, 21]. Second, there is the possibility that STAS is merely an artefact. Certainly, although we could not reconfirm our procedure precisely, manipulation or stapling devices could artificially cause STAS during surgery. Therefore, we compared the proportion of STAS cases after different surgical procedures, but there was no difference among surgical procedures (Table 1). However, when the rate of STAS was compared between the patients who underwent preoperative biopsy and those who underwent intraoperative diagnosis, there was a marginal difference ( = 0.052). It is possible that preoperative biopsy might contaminate tumours in the alveolar spaces. Third, this was a single-centre study and could have lacked sufficient statistical ORIGINAL ARTICLE

6 572 S. Shiono and N. Yanagawa / Interactive CardioVascular and Thoracic Surgery power. As STAS is a new concept and novel prognosticator for lung cancer, prospective data collection is needed. In conclusion, among p-stage I lung adenocarcinoma patients, STAS was frequently found among the invasive cases. Lung cancers with STAS may be associated with recurrence and a poor prognosis. Chest CT findings could provide useful radiological information to identify lung adenocarcinoma with STAS. In cases predicted to have STAS, limited resection should be carried out carefully. Routine assessment of STAS is needed for pathological diagnosis. Conflict of interest: none declared. REFERENCES [1] Goldstraw, Crowley J, Chansky K, Giroux DJ, Groome A, Rami-orta R et al. International Association for the Study of Lung Cancer International Staging Committee; articipating Institutions. 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