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

ORIGINAL ARTICLE – THORACIC Interactive CardioVascular and Thoracic Surgery 23 (2016) 567–572 doi:10.1093/icvts/ivw211 Advance Access publication 26 June 2016 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;23:567–72. Satoshi Shionoa,* and Naoki Yanagawab a b Department of Thoracic Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan Department of Pathology, Yamagata Prefectural Central Hospital, Yamagata, Japan * Corresponding author. Department of Thoracic Surgery, Yamagata Prefectural Central Hospital, 1800, Oazaaoyagi, Yamagata 990-2292, Japan. Tel: +81-23-6852626; fax: +81-23-6852608; e-mail: (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 (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. 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. Postoperative 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 2015. invasion [9, 10], serum carcinoembryonic antigen (CEA) level [11] and positron emission tomography (PET)/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 © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. ORIGINAL ARTICLE Spread through air spaces is a predictive factor of recurrence and a prognostic factor in stage I lung adenocarcinoma† 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. PATIENTS 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 2004. 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 PET/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). 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 surge (...truncated)