Lung Cancer 89 (2015) 38–42

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Does ground glass opacity-dominant feature have a prognostic significance even in clinical T2aN0M0 lung adenocarcinoma? Shota Nakamura ∗ , Takayuki Fukui, Koji Kawaguchi, Koichi Fukumoto, Akihiro Hirakawa, Kohei Yokoi Department of Thoracic Surgery, and Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan

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Article history: Received 11 February 2015 Received in revised form 19 April 2015 Accepted 20 April 2015 Keywords: Lung cancer Adenocarcinoma GGO-dominant tumor Ground glass opacity High-resolution computed tomography Lepidic growth pattern

a b s t r a c t Introduction: Recent studies have demonstrated that ground glass opacity (GGO)-dominant tumors correspond to pathologically low-grade adenocarcinomas and that patients with resected tumors have an excellent prognosis. However, almost all of those studies were limited to tumors measuring ≤3.0 cm. The purpose of this study was to characterize lung adenocarcinomas >3.0 cm in diameter with GGO-dominant features and evaluate the prognosis of patients with such tumors. Methods: One hundred and thirteen patients with cT2aN0M0 lung adenocarcinoma underwent surgical resection between 2005 and 2011. Twenty-five had tumors with a ≥50% GGO component (GGO-dominant group) and the remaining had solid-dominant tumors (Solid-dominant group). The clinicopathological findings and prognosis of the two groups were evaluated. Results: The tumors in the GGO-dominant group rarely exhibited pathological invasiveness, such as lymphatic (n = 1), vascular (n = 0) and pleural invasion (n = 5) or lymph node metastasis (n = 0). On the other hand, the tumors in the solid-dominant group frequently exhibited pathological invasiveness, including lymphatic (n = 26), vascular (n = 16) and plural invasion (n = 52) and lymph node metastasis (n = 18). There were significant differences in all of the characteristics between the two groups (lymphatic; p = 0.0026, vascular; p = 0.0214, and pleural invasion; p = 0.0004, and lymph node metastases; p = 0.0086, respectively). In the GGO-dominant group, 24 patients were alive without recurrence, while the remaining died of another cancer. Recurrence occurred in 34 patients in the solid-dominant group, and 16 died of the disease. The 5-year survival rate was 96% in the GGO-dominant group, compared to 71% in the solid-dominant group (p = 0.0120). Conclusions: In the GGO-dominant group, the malignant potential was low and the patients had a favorable prognosis after surgery, similar to the patients with GGO-dominant tumors diagnosed as cT1a-bN0M0. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The introduction of low-dose helical computed tomography (CT) for use in lung cancer screening has enabled lung cancer lesions to be identified at earlier and more curable stages of than could previously be detected with conventional radiography [1,2]. Among the nodules detected during CT screening, many cases of adenocarcinoma have been found [1,3].

∗ Corresponding author at: Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel.: +81 52 744 2376; fax: +81 52 744 2383. E-mail address: [email protected] (S. Nakamura). 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.

Some adenocarcinomas exhibit areas of ground glass opacity (GGO) on high-resolution computed tomography (HRCT), reflecting a lepidic growth pattern of tumor cells microscopically [4]. Therefore, lung tumors that display areas of focal GGO on HRCT contain components of histological lepidic tumor growth [5]. Such tumors exhibiting a lepidic growth pattern are less invasive and defined as in situ lesions [6]. Indeed, patients with GGO-dominant lung adenocarcinoma have been reported to have a good prognosis [7–10]. We previously demonstrated that T descriptors eliminating the area of GGO on HRCT more clearly classify the prognosis of patients with non-small cell lung cancer [11]. Several other radiological studies also recommend that only the solid area diameter of the tumor on HRCT be a candidate T descriptor in the next revision of the TNM classification [12–14]. However, almost all

S. Nakamura et al. / Lung Cancer 89 (2015) 38–42

of these reports concerning lung cancers with GGO components on HRCT limited the materials to tumors measuring ≤3.0 cm in diameter. Furthermore, in the newly recommended histological subtyping of lung adenocarcinoma [6], it is mentioned that the cutoff value of less than 3.0 cm is in keeping with the concept of the maximum accepted size for the pathological diagnosis of noninvasive adenocarcinoma. However, in daily practice, physicians sometimes encounter patients with adenocarcinoma of the lung showing larger tumor shadows with GGO components on HRCT. Therefore, we focused on a subset of large adenocarcinomas measuring >3.0 cm on HRCT in our previous cohort and investigated the association between tumors with extensive GGO areas on HRCT and the pathological results.

2. Materials and methods This study was approved by the institutional review board of Nagoya University Hospital (2014-0094). Between January 2005 and December 2011, 855 patients with primary lung cancer underwent surgical resection with curative intent at our institution. Of these patients, 118 had clinical T2aN0M0 tumors found to be adenocarcinomas of the lung. Of these patients, 113 underwent HRCT and had available follow-up data; these patients constituted the study population. All patients underwent a physical examination, chest radiography and magnetic resonance imaging of the brain as well as CT of the chest and abdomen for tumor staging and an evaluation of resectability before surgery. After 2006, 84 patients underwent [18 F]-fluoro2-deoxy-d-glucose (FDG) positron emission tomography and CT (PET-CT) preoperatively. After 2005, 84 tumors were examined for epidermal growth factor receptor (EGFR) gene mutations after resection. The patients were scheduled for follow-up every one to three months for two years after surgery and every six months thereafter. In patients with a high risk of recurrence, CT of the chest


and abdomen was performed every six to 12 months according to the physician’s recommendation. When recurrence was suspected, additional imaging surveys were performed. HRCT images were obtained using 4- or 16-row multislice CT scanners (Aquilion; Toshiba Medical Systems, Tokyo, Japan) without contrast medium. An image sliced transversely at the center of the nodule was selected to measure the tumor diameter. For image reconstruction, we used a 0.5- to 2.0-mm slice thickness and a lung algorithm (FC50, FC82, FC83). The image size was 512 × 512 pixels. Image data stored in the Digital Imaging and Communications in Medicine format were transferred from the CT scanner to a personal computer for the image analysis. The images were displayed at lung window settings of a level of −600 HU and a width of 1500 HU. Two authors (N.S., F.T.) manually measured the maximum diameter of the pulmonary nodules on a computer screen and distinguished areas of GGO from solid regions, removing air space, air bronchograms and large vessels. In order to evaluate FDG accumulation, the tumor shadows were first examined visually by two experienced radiologists. For the semiquantitative assessments, regions of interest (ROIs) were overlaid on FDG-avid mediastinal tumors, and the SUVmax [the maximum ROI activity (MBq/g)/injected dose (MBq/body weight (g)] of each tumor was measured. GGO was defined as the presence of hazy increased opacity of the lungs with preservation of the bronchial and vascular margins. The solid area of the tumor was defined as the area observed after eliminating all regions of GGO in the entire nodule. The tumors were divided into two groups according to the CT findings. We defined the GGO-dominant group as including tumors showing a consolidation/total tumor size (C/T) ratio of ≤0.5 and the solid-dominant group as including tumors with a ratio of >0.5 (Fig. 1). Discrepancies in evaluating the diameter of the area of consolidation and the size of the whole tumor were resolved by averaging. All tumors were divided into three ranges based on the diameter measured only the consolidation area (eliminating the GGO area) on HRCT, and the correlation between those diameter and CT features of the tumor were evaluated.

Fig. 1. Examples of GGO-dominant and solid-dominant tumors on high-resolution computed tomography. (A) Maximum tumor size: 4.2 cm and solid tumor size: 2.0 cm. The patient was classified into the GGO-dominant group. (B) Maximum and solid tumor sizes: 3.5 cm and 2.8 cm, respectively. The patient was classified into the solid-dominant group.


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Continuous and categorical variables of patient demographics and postoperative and pathological characteristics between the GGO-dominant and solid-dominant groups were compared using Student’s t-test and Fisher’s exact test, respectively. Overall survival (OS) was defined as the time from surgery to death from any cause or the date of the last visit for patients without events. The definition of recurrence for disease-free survival (DFS) included the time from surgery to the detection of relapse and metastasis, death from any cause or the date of the last visit for patients without events. OS and DFS curves were estimated according to the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to estimate the hazard ratios, 95% confidence intervals (CIs) and effects of the clinical variables on the survival rates. A two-sided p value of 3.0 cm on HRCT in daily practice, and many surgeons have experienced patients with such resected tumors display an excellent prognosis. In the present study, tumors measuring >3.0 cm in the GGO-dominant group after surgery exhibited low-grade malignancy and the patients had an extremely favorable prognosis, similar to the patients with GGOdominant tumors diagnosed as clinical T1a-bN0M0. In conclusion, GGO-dominant clinical T2aN0M0 lung adenocarcinoma constitutes a uniform group of tumors that exhibit low-grade malignancy and are associated with an extremely favorable prognosis after resection, similar to GGO-dominant clinical T1a-bN0M0 lung adenocarcinomas. We believe that the cutoff value of 3.0 cm does not correspond to malignant behavior when dividing the lesions into subgroups among cases of GGO-dominant clinical T1a-T2aN0M0 lung adenocarcinoma. Further investigations with larger numbers of patients are needed to assess the malignant behavior of large-sized GGO-dominant tumors, including radiological and histological examinations, in order to accurately determine patient survival. Conflict of interest The authors have no conflicts of interest or funding to disclose. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at 011 References [1] Sone S, Takashima S, Li F, Yang Z, Honda T, Maruyama Y, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242–5. [2] Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early lung cancer action project: overall design and findings from baseline screening. Lancet 1999;354:99–105. [3] Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201:798–802. [4] Kuriyama K, Seto M, Kasugai T, Higashiyama M, Kido S, Sawai Y, et al. Ground-grass opacity on thin-section CT: value in differentiating subtypes of adenocarcinoma of the lung. Am J Roentgenol 1999;173:465–9.

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Does ground glass opacity-dominant feature have a prognostic significance even in clinical T2aN0M0 lung adenocarcinoma?

Recent studies have demonstrated that ground glass opacity (GGO)-dominant tumors correspond to pathologically low-grade adenocarcinomas and that patie...
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