How Long Should Small Lung Lesions of Ground-Glass Opacity be Followed?

Original Article How Long Should Small Lung Lesions of Ground-Glass Opacity be Followed? Yoshihisa Kobayashi, MD,* Takayuki Fukui, MD,* Simon Ito, MD,* Noriyasu Usami, MD,* Shunzo Hatooka, MD,* Yasushi Yatabe, MD,* and Tetsuya Mitsudomi* Introduction: Pulmonary ground-glass nodules are frequently encountered. The purpose of this study was to evaluate the natural history of them and to gain some insights on how to follow them up. Methods: We retrospectively studied patients with pulmonary nodules that met the following criteria: (1) tumor diameter of 3 cm or less, (2) ground-glass opacity proportion of 50% or more, and (3) observation without treatment for 6 months or more. Between 1999 and 2012, 108 pulmonary lesions in 61 patients fulfilled these criteria. We reevaluated their computed tomography images and analyzed changes in their size. Results: The tumors were 1 cm or lesser in size in 69 lesions, 1.1 cm to 2 cm in 34, and 2.1 cm to 3 cm in five. The proportion of solid lesions was 0% for 82 lesions, 1% to 25% for 19, and 26% to 50 % for seven. At the median observation period of 4.2 years, 29 lesions had become larger, whereas the remaining 79 had persisted without changing in size (±1 mm). The median size change in the nodules that grew was 7 mm (range, 2 32 mm). All 29 tumors began to grow within 3 years of their first observation: 1 year or lesser in 13 lesions, after 1.1 years to 2 years in 12, and after 2.1 years to 3 years in four. Conclusions: Some small lung lesions exhibiting ground-glass opacity persisted without changes in size, whereas others grew gradually. The tendency to grow was clear within the first 3 years in all cases. Therefore, we conclude that these lesions should be followed for at least 3 years. Key Words: Follow-up, Ground-glass opacity, Lung cancer, Small lung lesion. (J Thorac Oncol. 2013;8: 309-314) Pulmonary nodules with ground-glass opacity (GGO) have been frequently observed since the clinical introduction of high-resolution computed tomography (CT). GGO is defined *Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan; Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Thoracic Surgery, Ichinomiya-Nishi Hospital, Ichinomiya, Japan; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan; and Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Tetsuya Mitsudomi, Department of Thoracic Surgery, Kinki University Faculty of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, 589 8511, Japan. E-mail address: mitsudom@surg.med. kindai.ac.jp Copyright 2013 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/13/0803-0309 as hazy opacity that does not obscure underlying bronchial structures or pulmonary vessels with high-resolution CT. 1 Moreover, GGO can be observed in a wide variety of clinical features; for example, nodular GGO is observed in malignancies and in benign conditions such as focal interstitial fibrosis, inflammation, and hemorrhage. 2 In addition, some patients present with multiple lesions, and it is often difficult to surgically resect all these lesions. Lesions that contain little or no GGO are regarded as radiologically invasive tumors and are usually candidates for surgical resection. 3 5 However, some lesions that contain a greater proportion of GGO often grow very slowly or even persist for years, without changes in size, and the optimal management of these lesions remains unclear. In our institution surgical resection is generally not performed for lesions that are 2 cm or smaller in size and exhibit 100% GGO at the initial presentation. However, during follow-up, many of these lesions demonstrate malignancy, and surgery should be considered when they begin to grow. However, patients who have previously undergone pulmonary resection or have bilateral multiple pulmonary nodules tend to be observed more conservatively even if the lesions are larger than 2 cm or contain solid component. Therefore, we decided the inclusion criteria of this study as pulmonary nodules that are 3 cm or lesser and exhibit 50% or more GGO component. The purpose of this study was to evaluate the natural history of these lesions and clarify how long patients showing such lesions should be followed to monitor for lesion growth. MATERIALS AND METHODS Patient Cohort We retrospectively studied patients with pulmonary nodules who met the following criteria: (1) tumor diameter of 3 cm or less, (2) GGO proportion of 50% or more, and (3) observation without treatment for 6 months or longer. Between 1999 and 2012, we encountered 108 pulmonary lesions in 61 patients who fulfilled the abovementioned criteria in our institution. These lesions were first detected at various situations: screening in 38 lesions, preoperative CT examination for other pulmonary lesions in 27, routine follow-up CT after pulmonary resection in 14, CT examination for disease in other organs in 29. We also reviewed the clinical courses of the patients who underwent pulmonary resection. The Institutional Review Board approved this study and waived the need for individual patient consent. Journal of Thoracic Oncology Volume 8, Number 3, March 2013 309

Kobayashi et al. Journal of Thoracic Oncology Volume 8, Number 3, March 2013 Radiological Evaluation of the Lesions A chest CT was performed for each patient. For patients with multiple lesions at the first presentation, only those lesions meeting the abovementioned criteria were included. The maximum diameters of each lesion on the lung window were measured. We defined growth as an increase of 2 mm or more in size. We scored the GGO ratio by visually estimating the proportion of the GGO component in each tumor without measuring the diameter, as we previously reported. 6 GGO was defined as an area with a slight, homogenous increase in density, which did not obscure the underlying vascular markings. 7 We evaluated all the CT images during the follow-up period and analyzed changes in size over time. The interval between CT examinations was at the physician s discretion: every 3 to 12 months. The CT examinations were performed with a window level of 500 Hounsfield units (HU) to 700 HU and a window width of 1000 HU to 2000 HU as a lung window setting for 2- to 5-mm sections. Most CT scans were acquired with the uses of multidetector CT, except for nine lesions. During only the early period of follow-up, single-detector CT examinations were performed for the nine lesions. Pathological Diagnosis The pathological diagnosis was classified according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. 8 RESULTS Characteristics of the Patients and Their Pulmonary Lesions The characteristics of 108 pulmonary lesions that were observed in 61 patients at the first presentation are shown in table 1. Approximately two thirds of the patients were women and never smokers. At the time of initial observation, 19 patients (31 %) had undergone prior pulmonary resection and 20 patients (33 %) had bilateral multiple lesions. Among these 39 patients, eight patients fulfilled both of them. The histologic diagnoses of prior resected lesions included adenocarcinoma in 13 patients and preinvasive lesions including atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) in five patients. In the remaining one patient the pathological diagnosis of the lesion was not clear because 6-mm pure GGO had been unsuccessfully resected by video-assisted thoracic surgery. The median tumor size was 0.95 cm (range, 0.4 2.5 cm). Approximately three fourths of the lesions exhibited 0% solid components and were pure GGO lesions. Changes in Size of the 108 Pulmonary Lesions After the median observation period of 4.2 years, 29 of the 108 lesions (27%) had become larger, whereas the remaining 79 lesions (73%) had persisted without changing in size (±1 mm). The median size change in the nodules that grew was 7 mm (range, 2 32 mm). CT images of two representative TABLE 1. Characteristics of 61 Patients and Their 108 Lesions at the First Presentation Characteristics Number of Patients % Age (yr) Median (range) 61 (35 78) Sex Male 22 36 Female 39 64 Smoking history Never 40 66 Former/current 19 31 Unknown 2 3 Prior pulmonary resection Yes 19 31 No 42 69 Bilateral multiple lesions Yes 20 33 No 41 67 Number of lesions 1 40 66 2 10 16 3 4 6 4 4 6 5 1 2 7 1 2 8 1 2 Number of lesions Tumor diameter (cm) 1 69 64 1.1 2 34 31 2.1 3 5 5 Solid component (%) 0 82 76 1 25 19 18 26 50 7 6 pulmonary nodules with GGO are shown in Figure 1. The change in size of each lesion from the first presentation to the last CT examination is shown in Figure 2A. Even for lesions that were 1 cm or smaller, some became larger during this time period (Fig. 2B), and some pure GGO lesions also grew in size (Fig. 2C). During the same observation period, the proportion of the solid component increased in 17 of the 108 lesions (16%). Of these, 14 lesions grew in size, whereas the remaining three lesions persisted without changing in size. The solid component began to increase within 1 year for two of these lesions and during the seventh year of observation for one lesion. Growth Tendency among the 29 Pulmonary Lesions To analyze the growth tendency of the 29 pulmonary lesions during the observation period, all changes in size between CT examinations were analyzed; these changes are 310 Copyright 2013 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 8, Number 3, March 2013 Follow-up Period of Ground-Glass Opacity FIGURE 1. Computed tomography images of two representative pulmonary nodules with GGO. A, A part solid (1% 25 %) GGO lesion became larger and increased the solid component (26% 50 %) after 3.3 years. B, However, a pure GGO lesion had persisted without changing in size for 6.3 years. GCO, ground-glass opacity. shown in Figure 3. All 29 lesions began to grow within 3 years from the time of the first observation; of these, 13 lesions grew after within 1 year, 12 lesions grew after 1.1 years to 2 years, and four lesions grew after 2.1 years to 3 years. Pulmonary Resection Twenty-one of the studied patients, who had a total of 26 lesions, underwent pulmonary resection (Table 2). We basically performed pulmonary resection when the lesions began to grow in size or the solid component began to increase. However, there were no clear-cut criteria because prior pulmonary resection and the presence of bilateral lung lesions should be considered. Among the resected 26 lesions, 12 lesions grew in size and the median size change in them was 7.5 mm. In addition, relatively large lesions or part solid lesions were considered for resection even if no changes were observed. The remaining 14 lesions showed no changes but the median tumor size was 1.25 cm and six of them contained solid component. Among 21 patients, 17 patients underwent open lung surgery and the remaining four underwent video-assisted thoracic surgery. Limited surgical resections, including segmentectomy and wedge resections, were performed in 16 patients (76%). Limited resection was chosen for the following reasons: prior resection or bilateral lung lesions in nine, showing 100% GGO in six, and location which ensure the margin of resection by segmentectomy in one. The histologic diagnoses mainly included preinvasive lesions and minimally invasive adenocarcinoma. Lymph nodes dissection was performed in 13 of 21 patients and all were diagnosed as stage IA. Epidermal growth factor receptor (EGFR) mutation analyses were performed in 21 lesions, and 19 lesions (90%) harbored EGFR mutation. Kirsten rat sarcoma (KRAS) mutation analyses were performed in 16 lesions, and all these lesions were wild type. After a FIGURE 2. The changes in size of the 108 evaluated lesions, (A) from the time of the first presentation to the last computed tomography examination. B, Some of the 69 lesions that were 1 cm or less in size became larger, (C), some of the 82 pure GGO lesions also grew in size during the observation period. GCO, ground-glass opacity. median follow-up period of 20.1 months, all the patients who underwent pulmonary resection were alive without recurrence. DISCUSSION In this study, some of the small lung lesions exhibiting GGO on CT persisted without changing in size, whereas Copyright 2013 by the International Association for the Study of Lung Cancer 311

Kobayashi et al. Journal of Thoracic Oncology Volume 8, Number 3, March 2013 The tumor size (mm) 0 1 2 3 4 Years from the first presentation (year) Onset of growth: 1 year 1.1-2 year 2.1-3 year CT examination operation FIGURE 3. The changes in size of all 29 lesions that grew. The changes in size between CT examinations were measured to analyze each lesion s tendency to grow. The first changes in size are shown with highly colored lines and subsequent changes are shown with light-colored lines. All 29 lesions began to grow within the first 3 years of observation. CT, computed tomography. others gradually grew in size over time. Moreover, the tendency to grow was clear within the first 3 years in all cases. This study is the first report to analyze the time at which lesions with GGO begin to grow, and our results indicate that patients with such lesions should be followed for at least 3 years to accurately evaluate lesion growth. In cases of lung cancer, many reports have described correlations between radiological findings of GGO and pathological features. AAH and AIS are typically manifested as pure GGO, whereas more advanced adenocarcinomas may include a larger solid component within the GGO region. 4,5 In addition, some reports have described the tumor doubling time (TDT) of lung tumors that exhibit mainly GGO. Hasegawa et al. 9 reported that the mean TDT of 19 pure GGOs was 813 days, and Aoki et al. 10 reported that the mean TDT of six AIS, five of them exhibiting 50% or more GGO component, was 880 days. We computationally simulated the size changes of small lung lesions based on these data and found that a 5-mm lesion would grow to 6.7 mm to 6.8 mm in size within 3 years, whereas a 10-mm lesion would grow to 13.3 mm to 13.6 mm size within the same period. These calculated changes in size seem to be detectable by CT analysis, and these data concur with our experimental data that all evaluated lesions began to grow within the first 3 years of observation. We sought to evaluate the pathological differences between lung lesions with GGO that persisted without changing in size and those that gradually grew. In general, lung adenocarcinomas are thought to follow a linear multistep progression, whereby AAH progresses to AIS and is followed by invasive adenocarcinoma. However, Yatabe et al. 11 suggested a novel scenario for the progression of lung adenocarcinoma, which does not support this linear progression schema, whereby KRAS-mutated AAH rarely progresses to more advanced tumors. Their scenario is based on the distribution of KRAS mutations. KRAS mutations were shown to decrease with progression and were detectable in 33% of cases of AAH, 12% of cases of AIS, 8% of minimally invasive adenocarcinomas, and 0% of well-differentiated adenocarcinomas. 12 However, the overall frequency of KRAS mutations in lung adenocarcinoma was limited to 13%. 13 With regard to the clinical aspects of these cases, Takigawa et al. 14 reported that the prognosis of patients with stage IA adenocarcinoma was not significantly different from that of the same stage patients with additional AAH. Chapman et al. 15 also reported similar results in patients with stage IA adenocarcinoma. These data suggest that not all AAHs influence overall survival. On the basis of previous genetic and clinical reports and our radiological data, we hypothesize that lung GGO lesions demonstrating growth progress to advanced adenocarcinoma, whereas others without growth persist as AAH, which does not influence survival. Moreover, these lesions should be distinguished after performing at least 3 years of CT observation, and only the former type should be surgically resected. Our hypothesis seems to be useful to reduce unnecessary resections for lesions detected in the CT screening. Pulmonary nodules with GGO will be detected increasingly because of the positive result of the National Lung Screening Trial in the United States. 16 Moreover, Nederlands Leuvens Longkanker Screeningsonderzoek (NELSON), Dutch-Belgian randomized lung cancer screening trial, is ongoing in Europe. 17 However, the surgical intervention strategy for lesions with GGO has not been established. The American Association for Thoracic Surgery has proposed the following recommendations: (1) both pure and partially solid GGOs 10 mm or smaller should be followed by CT evaluation until the patient reaches 79 years of age, unless changes are observed; and (2) lesions with GGO greater than 10 mm should be either followed by CT evaluation or considered for biopsy or surgical resection, even if no changes are observed. 18 In addition, Asamura 19 suggested the following strategy: (1) lesions that are 15 mm or less and exhibit 100% GGO should be observed by CT evaluation, whereas surgical intervention should be considered if overt growth or a newly developing solid component is observed; (2) lesions that are larger than 15 mm and exhibit 100% GGO should observed by CT evaluation, whereas surgical intervention should be considered even if no changes are observed; and (3) partially solid GGOs should be resected at the time of the first presentation. However, these strategies do not specify how long lesions without noticeable changes should be monitored for growth changes. 312 Copyright 2013 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 8, Number 3, March 2013 Follow-up Period of Ground-Glass Opacity TABLE 2. Characteristics of the 21 Patients (with a Total of 26 Lesions) Who Underwent Pulmonary Resection Characteristics Number of Patients % Surgical procedure Lobectomy 5 24 Segmentectomy 10 47 Wedge resection 6 29 Number of lesions Histologic type AAH 1 4 AAH/AIS 1 4 AIS 10 38 AIS/MIA (nonmucinous) 1 4 MIA (nonmucinous) 8 31 Lepidic predominant 3 11 Acinar predominant 1 4 Papillary predominant 1 4 EGFR mutation L858R 12 46 19del 4 15 G719A 1 4 L861Q 1 4 20ins 1 4 Wild type 2 8 Unknown 5 19 KRAS mutation Wild type 16 62 Unknown 10 38 AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; EGFR, epidermal growth factor receptor; KRAS, Kirsten rat sarcoma; MIA, minimally invasive adenocarcinoma. In clinical practice, limited surgical resection is sometimes considered for pulmonary lesions with GGO. In our study, 16 of 21 patients (76%) underwent limited resection because most of these patients had additional lesions in other lobes. As each of these patients survived without recurrence, limited resection might be reasonable for select patients. There are two ongoing clinical studies in Japan to assess the efficacy of limited surgical resection for small lung cancer lesions, including a phase III trial comparing lobectomy and segmentectomy for small radiologically invasive lung cancer 20 and a phase II trial of wedge resection for small radiologically noninvasive lung cancer. 21 In addition, there have been several reports on the relationship between morphology and EGFR mutations in adenocarcinoma, and these have demonstrated AIS harboring EGFR mutations in 67% to 68% of the cases. 22,23 Among the 21 lesions with EGFR mutation analyses, 19 lesions (90%) harbored EGFR mutation in our study, and both GGO and EGFR mutations were associated with adenocarcinoma histology, female sex, and nonsmoking status. Moreover, the pulmonary lesions resected in our study initially exhibited large GGO components and grew gradually. Although our patient cohort was highly selective, these findings suggest that EGFR tyrosine kinase inhibitors may represent a therapeutic option for patients with multiple lesions in numerous lobes, who fulfill the abovementioned criteria. There are several limitations in our study. First, measurement errors should be considered. There are several reports on measurement errors. Johnsson et al. 24 reported that the 95% limits of agreement concerning the mean of the observers measurement were ± 2.1 mm. Oda et al. 25 suggested that the threshold for identifying an increase in the measured volume of a GGO nodule is a 30% increase, based on their data of intraobserver and interobserver measurement errors. Especially in our study, a part of lesions were examined with single-detector CT during the early period of follow-up. Second, the results were based on the lesions of highly selected patients because our study was retrospectively designed. 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