Architectural Grade Combined With Spread Through Air Spaces (STAS) Predicts Recurrence and is Suitable for Stratifying Patients Who Might Be Eligible for Lung Sparing Surgery for Stage I Adenocarcinomas

Pathology & Oncology Research https://doi.org/10.1007/s12253-020-00855-7 ORIGINAL ARTICLE Architectural Grade Combined With Spread Through Air Spaces (STAS) Predicts Recurrence and is Suitable for Stratifying Patients Who Might Be Eligible for Lung Sparing Surgery for Stage I Adenocarcinomas Tamás Zombori 1 1 1 & Anita Sejben & László Tiszlavicz & Gábor Cserni 1,2 3 3 & Regina Pálföldi & Edit Csada & József Furák 4 Received: 28 May 2020 / Accepted: 11 June 2020 # The Author(s) 2020 Abstract The spread through air spaces (STAS) has a main role in local recurrence of stage I lung adenocarcinomas (LAs), therefore its presence might question sublobar resection as a therapeutic option. The aim of our study was to evaluate the distribution of STAS in stage I LAs, to stratify patients according to local recurrence and to identify a group of patients who might be suitable for sublobar surgery. Patients resected with LA were included. The presence of STAS was recorded on hematoxylin eosin stained slides and clinicopathological data were obtained from medical charts. Overall survival (OS) and disease-free survival (DFS) were registered. Statistical methods included Kruskal-Wallis tests, Kaplan-Meier analyses, log-rank tests and Cox-regressions. 292 patients were included. STAS was identified in 38.7% and 95.7% of micropapillary carcinomas showed STAS. Significant correlation was found between STAS and high-grade patterns. Significant differences were found between OS and DFS estimates of STAS0 and STAS1 cases (5-y-OS: 80.0% vs. 68.4%; 5-y-DFS: 71.1% vs. 57.1%). The presence of STAS was associated with unfavorable prognosis in low and intermediate architectural grades, but not in high-grade. Multivariate analysis revealed that architectural grade (HR(OS):2.09; HR(DFS):1.52) and STAS (HR(OS):1.51; HR(DFS):1.48) were independent prognostic markers in stage I LA. Architectural grade combined with STAS was superior to other prognostic grades. The combination of architectural grade and STAS proved to be a prognostic factor that is superior to previously introduced grading systems. Patients having low and intermediate grade LAs without STAS might be eligible for sublobar resection. Keywords Lung adenocarcinoma . Spread through airspaces (STAS) . Architectural grade . Lung sparing surgery . Sublobar resection Background Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12253-020-00855-7) contains supplementary material, which is available to authorized users. * Tamás Zombori 1 Department of Pathology, Faculty of Medicine, University of Szeged, Állomás u. 1., H6725 Szeged, Hungary 2 Department of Pathology, Bács-Kiskun County Teaching Hospital, Nyíri út 38, Kecskemét H6000, Hungary 3 Csongrád County Hospital of Chest Diseases, Alkotmány u. 36. , Deszk H6772, Hungary 4 Department of Surgery, University of Szeged, Semmelweis u. 8., Szeged H6720, Hungary Despite the development of molecular targeted therapies and immune checkpoint inhibitors for the treatment of pulmonary adenocarcinoma, its outcome is still unfavorable [1]. Lobar resection with lymph node dissection remains the most common curative therapy in stage I disease [2, 3]. There are several studies in progress aiming to validate the utility of lung sparing or sublobar resection for early stage lung adenocarcinoma and to answer whether lung sparing resection for this disease is only a function preserving or a curative treatment option as well [4]. These ongoing Japanese trials have suggested, that sublobar resection achieves local control and recurrence-free survival in patients with radiologically noninvasive lung cancer, with a maximum tumor diameter of ≤ 2 cm and a solid tumor ratio of ≤ 0.25 defined with CT [4, 5]. Zombori et al. Spread through air spaces (STAS) is a recently described pattern of invasion of lung neoplasms [6]. STAS represents micropapillary clusters, solid nests or single cells beyond the edge of the tumor invading into air spaces [7, 8]. STAS was implemented in the 2015 World Health Organization Classification of Lung Tumors, and in the 8th edition of the Cancer Staging Manual of the American Joint Committee on Cancer (AJCC), resulting in the refining of the definition of tumor invasion and furthermore the criteria of in situ, minimally invasive and invasive adenocarcinoma, as well [9, 10]. Although STAS is extensively studied nowadays, the pathomechanism is yet unknown. Cellular dedifferentiation, loss of cell membrane cohesion and mechanical impact by the surgeon have been proposed in the etiology of STAS [11]. Though the development of STAS is debated, an unfavorable prognostic impact on survival was demonstrated in lung adenocarcinomas with STAS by several reports [7, 12–16]. STAS has been associated with adverse prognosis in early stage lung adenocarcinomas in patients, who underwent sublobar resections [7, 17]. In contrast to these results, Uruga and coworkers have not found such an impact in cases of sublobar surgery. Even though, lobectomy is the standard therapy for lung adenocarcinoma in early stage, the process itself might be high-risk for patients with comorbidities, namely chronic obstructive lung diseases, bronchiectasis or severe cardiovascular diseases. Sublobectomy may be a treatment option for these patients, in selected cases of lung adenocarcinoma lacking STAS. The aim of our study was to evaluate the distribution of STAS among different subtypes of stage I lung adenocarcinoma; to analyze the impact of morphologic features and prognostic systems on survival; to stratify patients according to local recurrence and to identify a group of patients who are suitable for lung sparing surgery. Methods Patients operated on at the Department of Surgery, University of Szeged between 2004 and 2013 with stage I lung adenocarcinoma were included in our retrospective, consecutive series. Exclusion criteria were multicentric, metachronous or metastatic tumors, variants of adenocarcinoma (namely invasive mucinous, mixed invasive mucinous/non-mucinous, colloid, fetal, enteric adenocarcinoma and sarcomatoid carcinoma), patients who underwent lung cancer surgery in the previous 2 years, positive surgical margins, perioperative death, metastasis to lymph nodes and vascular invasion. All hematoxylin eosin slides of the patients included were evaluated and revised if needed, according to the WHO Classification of Lung Tumors [9]. The presence of STAS was recorded by two pathologists (TZ, LT), who were blinded to patients’ clinical outcome and discrepancies were discussed at a multi-headed microscope (Olympus BX43, Tokyo, Japan). STAS was defined as micropapillary structures or solid nests that were present in the air spaces beyond the edge of the tumor, even if in the first alveoli from tumor edge [7]. Figure 1 presents a micropapillary adenocarcinoma with STAS. The intraalveolar tumor clusters found distant from the tumor without alveola (...truncated)