Pathology and Prognosis of Persistent Stable Pure Ground-Glass Opacity Nodules After Surgical Resection

GENERAL THORACIC Pathology and Prognosis of Persistent Stable Pure Ground-Glass Opacity Nodules After Surgical Resection Sukki Cho, MD, HeeChul Yang, MD, Kwhanmien Kim, MD, and Sanghoon Jheon, MD Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi; and Department of Thoracic and Cardiovascular Surgery, College of Medicine, Seoul National University, Seoul, Korea Background. This study aimed to show the pathologic results of pure ground glass opacities (pggos) that showed no change in patients who underwent surgical resection. Methods. The data used in this study were collected from the records of patients who underwent surgical resection for pggos between January 2004 and December 2009. All pggos were detected and followed up until operation with high-resolution computed tomography at our hospital and were followed up by computed tomography of the chest at least 2 years after operation. Surgical resection was performed for patients with pggos if no change was observed after a minimum of 1 month of follow-up and if any growth of the nodules or newly formed solid components occurred in pggos of any size. Results. Forty-six patients were enrolled into the study group. No changes in the pggos during serial follow-up occurred in 39 patients (84.8%), and 7 patients (15.2%) underwent surgical resection because of growth of the lesions or newly developed solid lesions during follow-up. Of 39 patients in the no-change group, pathologic types of the cancerous pggos in 23 patients included adenocarcinoma in situ in 21 patients, minimally invasive adenocarcinoma in 1 patient, and invasive adenocarcinoma in 1 patient. In the change group, 5 patients were diagnosed with cancer. Between the two groups, there was no difference in sex, time intervals, or tumor size. Neither group had lymph node metastasis or recurrence. Conclusions. This study showed the pathology of persistent stable pggo postoperatively, which confirmed the 59% chance of a cancer diagnosis including adenocarcinoma in situ, minimally invasive adenocarcinoma, or invasive adenocarcinoma. (Ann Thorac Surg 2013;96:1190 5) Ó 2013 by The Society of Thoracic Surgeons The number of cases of early detection of focal ground-glass opacity nodules (GGOs) has been increasing exponentially because of computed tomography (CT) screening programs and with advances in the quality of high-resolution computed tomography (HRCT). GGOs can be classified further as either pure GGOs (pggos) or mixed GGOs. Nodules of the former type are round, homogeneous, well-defined lesions harboring no areas of soft tissue density, whereas in the latter type, the area of parenchymal architecture is completely obscured within the nodule [1]. Among them, persistent GGOs are thought to have a strong malignant potential, and they also correspond to focal fibrosis, atypical adenomatous hyperplasia (AAH), and early-stage lung cancer [2, 3]. Most lung cancer featuring pggos is diagnosed as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or, rarely, as invasive adenocarcinoma. Therefore, lung cancer featuring pggos, compared with solid types of lung cancer, rarely shows lymph node metastasis and has an outstanding prognosis, wherein the 5-year recurrence-free survival approaches 100% [4]. Accepted for publication May 17, 2013. Address correspondence to Dr Cho, Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, 166, Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea; e-mail: skcho@snubh.org. As thoracic surgeons have gained more experience with pggos a question has arisen regarding whether pggos require immediate surgical intervention, which has led long-term follow-up as a favorable option in their treatment. Although the surgical indications for GGO lesions are not well established, generally, when the size of a pggo lesion grows or when a newly developed solid component is observed, the operation may be performed. However, in most cases, pggo lesions neither change in size nor develop a solid component for a long time, and little is known about the pathologic findings in persistent pggos without those changes or about the prognosis of those that are diagnosed as cancer. Existing studies dealing with the natural history of pggos have been limited in determining the nature of unchanging but persistent pggos because those studies have reported only follow-up results without histologic analysis [5]. Therefore, this study aimed to show the pathologic results of pggos with no changes in patients who underwent surgical resection. Patients and Methods Patients The data used in this study were collected from the records of patients who underwent surgical resection Ó 2013 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2013.05.062

Ann Thorac Surg CHO ET AL 2013;96:1190 5 GROUND-GLASS OPACITY NODULES AFTER SURGICAL RESECTION for pggos between January 2004 and December 2009. We excluded patients with tumors that were 100% solid or mixed GGOs, or with tumor sizes larger than 3 cm. In the enrolled patients, all pggos were detected and followed up until operation with HRCT at our hospital. After the operation, all patients who were diagnosed with any type of lung cancer were observed at 3-month intervals with computed tomography (CT) of the chest, and patients who did not have a chest CT after a followup period of at least 2 years were also excluded from this study. This study was approved by the institutional review board of Seoul National University Bundang Hospital, and patients informed consent was waived because of the retrospective nature of the study design. Calculation of GGO Component The proportion of GGOs in a nodule was measured in the same way as that reported elsewhere [6]. In brief, the images were photographed with a window level of 600 H and a window width of 2,000 H as the lung window. The GGO was defined as a hazy increase in lung attenuation that did not obscure the underlying bronchial or vascular structures. Solid attenuation was defined as an increase in lung attenuation obscuring the underlying structures. A quantitatively estimated GGO area was defined as 1, the ratio of solid attenuation to the maximum tumor dimension. GGO lesions were classified as pure GGO lesions only if they had a 100% GGO proportion, and the remaining GGO lesions were classified as mixed GGO lesions [6, 7]. Surgical Indications In our institution, surgical resection was applied in three cases during this study period: (1) patients with pggos 10 mm or larger in diameter if no change was observed after the minimum 1-month follow-up period; (2) growth of the nodules or of newly formed solid components in pggos was detected during the follow-up HRCT; and 3) extrathoracic malignancy was present or, in the surgeons judgment based on their experience with pggos during this study period, initial CT findings strongly suggested cancer, in which case surgical resection was performed without a period of observation. Pathology The seventh edition of the tumor, node, metastasis (TNM) staging system for lung cancer was adopted for proper postoperative staging. Cell types were sorted by the regulations set forth in the 2011 guidelines of the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society [8]. An AIS is considered a cytologically bland lesion devoid of any invasion but able to progress to eventual invasive adenocarcinoma with the addition of further mutation and oncogene gene copy numbers. MIA is referred to as a lepidic predominant and low-grade tumor measuring 3 cm or less in diameter with an area of invasion limited to a maximum of 5 mm [8]. 1191 Surgical Procedures During the study periods, there was a guideline for the extent of surgical resection. If the preoperative diagnosis was not confirmed, wedge resection by use of videoassisted thoracic surgery (VATS) (aided by CT-guided hook-wire localization in some cases) was done first, and the tissue was sent to the pathology laboratory for a frozen section. If the tissue was malignant, anatomic resection and mediastinal node dissection were usually performed, whereas limited resection including wide wedge resection or segmentectomy was pursued in selected cases. Prognosis Local/regional recurrence was defined as ipsilateral pulmonary metastasis, bronchial or parenchymal resection margin, or mediastinal node metastasis, and distant recurrence was defined as metastasis of the contralateral lung or distant organs. It was not considered a recurrence if changes in size or density were observed in the GGO lesions that had already existed at the initial chest CT or if the newly developed GGO lesions showed different pathologic-molecular features after resection. Statistical Analysis Student s t test was used to compare the distribution of continuous data, and Fisher s exact tests were used to compare the frequencies of categoric measures between the groups. Disease-free survival was defined as the time from operation to the first diagnosis of local or distant disease recurrence or until the last follow-up visit. Overall survival was defined as the time from operation to death or the last follow-up visit. Disease-free and overall survival curves were estimated with the Kaplan-Meier method, and significance was assessed with the log-rank test. Results Patients During the study period, 149 patients were operated on for focal GGO lesions (Table 1). Eighty-six patients with mixed GGO lesions, 7 patients with tumors larger than 3 cm, and 3 patients who had a follow-up period of less than 2 years for CT were excluded. Seven patients who underwent surgical resection immediately after diagnosis with pggos were also excluded from this study. As a result, 46 patients were enrolled in this study group: 39 patients (84.8%) experienced no change of their pggo nodules during serial follow-up, which met the major indication for operation, and 7 patients (15.2%) underwent surgical resection because of growth of the lesions or new development of solid lesions during follow-up. There were 29 male patients (63.0%), and the mean age was 57.9 years (range, 31 to 80 years). In 27 patients (58.7%), GGO lesions were incidentally found on the CT scan during their regular health check-ups. No-Change Group in All pggos Among the 39 patients of the no-change group, 24 were male (61.5%), and the mean age was 55.9 years GENERAL THORACIC

GENERAL THORACIC 1192 CHO ET AL Ann Thorac Surg GROUND-GLASS OPACITY NODULES AFTER SURGICAL RESECTION 2013;96:1190 5 Table 1. Characteristics of pggos (n ¼ 46) Characteristic Frequency Sex, n (%) Male 29 (63.0) Female 17 (36.5) Age, mean (range), years 57.9 (31-80) Location, n (%) RUL/LUL 16 (34.8) / 11 (23.9) RML 1 (2.2) RLL/LLL 11 (23.9) / 7 (15.2) CT screening, n (%) No 19 (41.3) Yes 27 (58.7) Time intervals, n (%), days <90 5 (10.9) 90 180 16 (34.8) 180 360 11 (23.9) >360 14 (30.4) Surgical indications, n (%) No change 39 (84.8) Size or solid (þ) 7 (15.2) Surgical extent, n (%) Wedge 16 (34.8) Segmentectomy 7 (15.2) Lobectomy 23 (50.0) Pathology, n (%) Benign 18 (39.1) Cancer 28 (60.9) CT ¼ computed tomography; LLL ¼ left lower lobe; LUL ¼ left upper lobe; pggos ¼ pure ground glass opacities; RLL ¼ right lower lobe; RML ¼ right middle lobe; RUL ¼ right upper lobe. (range, 31 to 80 years) (Table 2). In terms of smoking history, 22 (56.4%) were never smokers, 11 (28.2%) were current smokers, and 6 (15.4%) were former smokers. The average time period from detection to operation was 306.8 days, and the time periods from detection to operation were shorter than 3 months in 4 patients (10.3%), 3 to 6 months in 16 patients (41.0%), 6 to 12 months in 11 patients (28.2%), and longer than 12 months in 8 patients (20.5%). The median size of the tumors was 9.0 mm (range, 6 to 18 mm), and the tumor sizes were smaller than 10 mm in 25 patients (64.1%) and 10 to 20 mm in 14 patients (35.9%). Twenty-three patients (59.0%) were diagnosed with cancer after undergoing surgical resection, and 16 patients (41.0%) were diagnosed with benign tumors. There was no difference in sex, size, time period, and smoking history between the two groups. However, the mean age at operation in the benign group was lower than that in the cancerous group (49.8 vs 60.3 years, p ¼ 0.015). The types of operations performed in this group included lobectomy, segmentectomy, and wedge resection, and they were performed on 20 patients (51.3%), 5 patients (12.8%), and 14 patients (35.9%), respectively. Lobectomy, segmentectomy, and wedge resection were performed on 14 (60.9%), 4 (17.4%), and 6 patients (21.7%) with cancerous lesions, and 6 (37.5%), 1 (6.3%), and 9 patients (56.2%) with benign lesions, respectively. Pathologic types of cancerous pggos in 23 patients included AIS in 21 patients (91.4%), MIA in 1 patient (4.3%), and invasive adenocarcinoma in only 1 patient (4.3%). The tumor size in the patient with MIA was 16 mm on the preoperative CT scan. Even though there was no change in size for 116 days, surgical resection was performed at the patient s request, and the size of the invasive component was reported to be 5 mm. The tumor size in the patient with invasive adenocarcinoma was 15 mm, and surgical resection was performed after a 552-day follow-up period. This patient had a history of surgical resection for lung cancer 2 years before the observation period. By contrast, the benign disease group consisted of 13 patients with AAH and 3 patients with other conditions (each with fibrosis, hemorrhage, and metaplasia). Among the 39 patients with persistent pggos, multiple lesions were found only in those who were later diagnosed with cancer (n ¼ 7). All the multiple lesions were detected concurrently with the resected lesion. However, because they were located in different regions from the resected lesion, and all were smaller than 10 mm, it was decided to observe those lesions. Comparison Between No-Change Group and Change Group in Cancerous pggos Among the 7 patients of the change group, 5 patients (71.4%) were diagnosed with cancer (Table 3). Among those 5 cancerous patients, 3 were diagnosed with invasive adenocarcinoma and 2 with MIA. In comparison with the no-change group, there was no difference in sex, time intervals, or tumor size, but in the change group, the patients were a little older. Neither group had lymph node metastasis or recurrence. In terms of cell types, the number of cases of invasive adenocarcinoma in the change group was statistically significantly higher than that in the no-change group, although the number of the cases was small (p ¼ 0.022). Comment Most studies of pggos have been limited to discovering its natural history based on the information gained from long-term follow-up in the absence of surgical procedures. Because patients in those studies did not undergo operation, tissue confirmation was not made, which means that pggos that did not show any change in size could not be pathologically identified, and annual HRCT could not give any information other than the size of the nodules which did not show any change. Kodama and colleagues [9] conducted a study of 19 patients with pggo nodules, performed surgical resection on 10 patients of 11 with changes in size of the nodules, and diagnosed 5 of them with lung cancer. Because 4 of those 5 patients with lung cancer had undergone surgical procedures for lung cancer, they concluded that a history of lung cancer should significantly raise the index of suspicion. Chang and colleagues [5] also reported that more than 90% of patients with pggos did not experience any

Ann Thorac Surg CHO ET AL 2013;96:1190 5 GROUND-GLASS OPACITY NODULES AFTER SURGICAL RESECTION Table 2. Difference Between Cancer and Benign Lesions in No-Change pggos (n ¼ 39) Characteristic Cancer (n ¼ 23) Benign (n ¼ 16) p Value Sex, male, n (%) 16 (69.6) 8 (50.0) 0.217 Age, mean, years 60.3 11.9 49.8 13.8 0.015 Smoking history, n (%) 0.538 Never 12 (52.2) 10 (62.4) Current 8 (34.8) 3 (18.8) Former 3 (13.0) 3 (18.8) Time intervals, n (%), days 0.070 <90 2 (8.7) 2 (12.5) 90 180 8 (34.8) 8 (50.0) 180 360 5 (21.7) 6 (37.5) >360 8 (34.8) 0 (0.0) Surgical extent, n (%) 0.080 Wedge 5 (21.7) 9 (56.3) Segmentectomy 4 (17.4) 1 ( 6.3) Lobectomy 14 (60.9) 6 (37.4) Size on CT, median, mm 10.0 8.0 0.193 Size on pathology, median, mm 11.0 8.0 0.072 1193 GENERAL THORACIC CT ¼ computed tomography; pggos ¼ pure ground glass opacities. tumor growth during the long-term follow-up period, and even in growing pggos, an indolent clinical course was noted. However, in that study as well, simple follow-up without pathologic confirmation was the only available option for most of the patients who showed no change in size, and as those authors explained, none of the patients in that study underwent tissue confirmation, meaning that they could not calculate the prevalence of primary lung cancer in this patient cohort. Surgical indications for pggos are described differently in various studies. Chang and colleagues [5] stated that if pggos displayed an internal solid portion or were greater than 10 mm in diameter, operation was considered if patient consent was provided. However, if the pggo was less than 10 mm in diameter and did not possess a solid portion, thinsection CT scans were obtained within a short follow-up period of 3 months, again at 6 months, and annually thereafter. To date, common surgical indications for pggos have included increasing size of the tumor or new development of the solid component. In our institution, our policy was that surgical resection could be performed if the lesion was larger than 1 cm, but if the lesion was smaller than 1 cm, the patient was put under observation first, and if the lesion grew in size or formed a solid component, then surgical resection was performed. However, as surgeons built up more experience with Table 3. Difference Between Change and No-Change Groups in Cancerous pggos Characteristic Change Group (n ¼ 5) No-Change Group (n ¼ 23) p Value Sex, male, n (%) 3 (60.0) 16 (69.6) 0.678 Age, n (%), years 0.004 <65 0 (0.0) 13 (56.5) 65 70 1 (20.0) 6 (26.1) 70 75 4 (80.0) 2 (8.7) >75 0 (0.0) 2 (8.7) Time intervals, n (%), days 0.153 <90 1 (20.0) 2 (8.7) 90 180 0 (0.0) 8 (34.8) 180 360 0 (0.0) 5 (21.7) >360 4 (80.0) 8 (34.8) Cell types, n (%) 0.022 AIS 2 (40.0) 21 (91.4) MIA 1 (20.0) 1 (4.3) ADC 2 (40.0) 1 (4.3) Size on CT, median, mm 10.0 10.0 1.000 Size on pathology, median, mm 11.0 11.0 1.000 ADC ¼ adenocarcinoma; AIS ¼ adenocarcinoma in situ; CT ¼ computed tomography; MIA ¼ minimally invasive adenocarcinoma; pggos ¼ pure ground glass opacities.

GENERAL THORACIC 1194 CHO ET AL Ann Thorac Surg GROUND-GLASS OPACITY NODULES AFTER SURGICAL RESECTION 2013;96:1190 5 pggos, upon a surgeons preference, surgical resection was performed for lesions larger than 5 mm in some cases, or lesions larger than 1 cm were sometimes put under close observation for a certain period of time [10].If no size change was observed after a certain period of time, especially in case of peripheral lesions, the operation was performed by VATS, which enables a simple, less invasive procedure. In the study by Ohta and colleagues [1], pggos underwent VATS wedge resection after CT-guided marking if the tumors had not diminished after several months of follow-up. They suggested that although an increase in size or density absolutely required surgical removal, a decrease in size did not exclude such a requirement. However, no existing evidence shows that operation is not required for pggos that show no change. Hence, studying the outcomes in patients who have undergone surgical resection for pggos without change in size or density during follow-up could generate a guideline on whether or not this group of patients needs surgical treatment. In our study, 59% of the patients without any change were diagnosed with cancer, and 41% were diagnosed with benign tumors. It is noteworthy that among 16 patients with benign tumors, 13 patients were diagnosed with AAH. Given that AAH is thought to be a precursor or even an early-stage lesion of bronchioloalveolar carcinoma or adenocarcinoma [11, 12], more than 90% of patients could have been associated with lung cancer. Among the 23 patients diagnosed with lung cancer, 21 patients (91.4%) had either very-early-stage lung cancer or indolent AIS, which was previously defined as bronchioloalveolar carcinoma of Noguchi type A or B [13]. Therefore, it may be fair to diagnose patients in the no-change group with cancer and to perform surgical resection in those patients. However, to provide firm evidence to support the idea that surgical resection should be performed in patients in a no-change group, the prognosis of the no-change group after the procedure, such as lymph node metastasis or the recurrence rate, should first be determined. Not solely because they are diagnosed with cancer, but also because recurrence rates and lymph node metastasis are different between the two groups, surgical resection could be an acceptable approach to detection and treatment in the early stage. However, this study did not show any differences in lymph node metastasis or recurrence rate between the two groups, although a longer follow-up period should be required because a 5-year period is not a sufficient follow-up time for lung cancer featuring GGO [14]. Among the 5 patients who experienced a change in size or density, the rate of invasive adenocarcinoma was as high as 40% (2/5), but the sizes of the total lesion and invasive component were 20 and 12 mm, and 11 mm and 7 mm in each patient, respectively. This means that even though the lesions were invasive adenocarcinoma, because they were very small early-stage cancer, it cannot be said that the operations were performed late. Whether or not this slight growth can change the patients prognosis is unknown; however, this type of disadvantage is much smaller for subsolid than for solid nodules [15]. Therefore, the operation can be performed when nodules grow in size or solid components are newly formed, which supports current surgical indications for pggos. One issue this study further explored was whether or not older patients with pggos should undergo operation. With longer life expectancy and increasing interest in health, more regular health checkups have been implemented in elderly people. In this study as well, 5 of 10 patients who were older than 70, had pggos detected on the low-dose CT scan from a regular health checkup, and 4 of those patients were diagnosed with cancer. Accurate evaluation of recurrence and survival in those 4 patients should be obtained from additional follow-up. However, the authors personally suggest that surgical indication could be limited to the change group in elderly patients and also suggest that the operation be performed when the solid component has newly formed rather than when the size has increased. Evidence for this was reported in some studies in which the maximum dimension of only the solid component was found to be a more suitable prognostic factor than the maximum tumor dimension [16]. In other words, simple growth on images proving pathologic growth of the GGO portion will not have an influence on prognosis, but CT images showing a newly formed solid component, which is pathologically invasive, will have a great influence on prognosis. There were some limitations of this study. Because the study was retrospective, the surgeons preference may have been affected too much by the surgical indications, and owing to the relatively short follow-up, differences in recurrence or cancer-related death could not be identified. In conclusion, this study showed the pathology of persistent stable pggo postoperatively, which confirmed the 59% chance of the cancer diagnosis including AIS, MIA, or invasive adenocarcinoma. References 1. Ohta Y, Shimizu Y, Kobayashi T, et al. Pathologic and biological assessment of lung tumors showing ground-glass opacity. Ann Thorac Surg 2006;81:1194 7. 2. Godoy MCB, Naidich DP. Subsolid pulmonary nodules and the spectrum of peripheral adenocarcinomas of the lung: recommended interim guidelines for assessment and management. Radiology 2009;253:606 22. 3. Lee HY, Lee KS. Ground-glass opacity nodules: histopathology, imaging evaluation, and clinical implications. J Thorac Imaging 2011;26:106 8. 4. Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience. J Thorac Cardiovasc Surg 2005;129:991 6. 5. Chang B, Hwang JH, Choi YH, et al. Natural history of pure ground-glass opacity lung nodules detected by low-dose computed tomography. Chest 2013;143:172 8. 6. Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. Early peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan. Ann Thorac Surg 2002;74:1635 9. 7. Austin JH, Muller NL, Friedman PJ, et al. Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 1996;200:327 31. 8. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244 85.

Ann Thorac Surg CHO ET AL 2013;96:1190 5 GROUND-GLASS OPACITY NODULES AFTER SURGICAL RESECTION 9. Kodama K, Higashiyama M, Yokouchi H, et al. Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years. Ann Thorac Surg 2002;73: 386 92. 10. Oh JY, Kwon SY, Yoon HI, et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer 2007;55:67 73. 11. Kitamura H, Kameda Y, Ito T, Hayashi H. Atypical adenomatous hyperplasia of the lung: implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 1999;111:610 22. 12. Pueblitz S, Hieger LR. Expression of p53 and CEA in atypical adenomatous hyperplasia of the lung. Am J Surg Pathol 1997;21:867 8. 1195 13. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung: histologic characteristics and prognosis. Cancer 1995;75:2844 52. 14. Nakao M, Yoshida J, Goto K, et al. Long-term outcomes of 50 cases of limited-resection trial for pulmonary groundglass opacity nodules. J Thorac Oncol 2012;7:1563 6. 15. Matsuguma H, Mori K, Nakahara R, et al. Characteristics of subsolid pulmonary nodules which show growth during follow-up with computed tomography. Chest 2013;143:436 43. 16. Maeyashiki T, Suzuki K, Hattori A, Matsunaga T, Takamochi K, Oh S. The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg 2013;43:915 8. GENERAL THORACIC INVITED COMMENTARY The introduction of multidetector computed tomography (CT) scanners that acquire high-resolution, thin-section images has vastly advanced our ability to detect lung nodules. This new technology has unveiled for us a world of pulmonary nodules not previously appreciated. These include nodules that either are familiarly solid but increasingly smaller or others that are so subtle in texture that they escaped detection by prior generations of CT scanners. These latter nodules, commonly referred to as pure ground glass nodules (pggns), are hazy attenuations of the lung parenchyma that do not obscure the underlying lung architecture. Although these nodules are frequently (but not always) associated with lung cancer, they present the clinician and radiologist with a difficult dilemma because their precise natural history and pathologic characteristics are not well defined. In this issue of The Annals, Cho and colleagues [1] confront this challenge head on and report the pathologic findings in 53 patients with pggns who underwent surgical resection. The core of their message lies in the 39 patients whose pggns remained stable after 1 month of followup. In this group, lung cancer was found in 23 patients (91% adenocarcinoma in situ). The authors conclude that It could be rational to perform surgery on the no change group since 92.3% of those patients who underwent surgery were diagnosed with lesions related to cancer. For the sake of scientific discourse, this commentary will take the position that the truth about managing pggns is yet to be revealed. For starters, the study is limited by the absence of that commonly overlooked variable: the missing denominator. A recent study from the author s institution reported on 143 pggns, of which more than 80% remained stable in size and texture after a follow-up period of 4 years [2]. Therefore, it seems likely that the current study may reflect the results in a highly selected group of patients referred for surgical consideration. Interestingly, investigators of the prospective randomized Multicenteric Italian Lung Detection trial (MILD) recently reported on 48 pggns detected in the low-dose CT arms of the trial [3]. Of those lesions, 39% either resolved or decreased in size after a mean follow-up time of 50 months. These results from a prospective controlled trial clearly show that the malignant propensity of these unique abnormalities is not preordained. Assuming that some of the remaining nonresolving pggns are in fact adenocarcinoma in situ, one must wonder about the biologic behavior of these tumors and whether they should be considered within the scope of overdiagnosed cancers. If these are truly indolent lesions, then surgical resection would be considered as overtreatment for a pseudodisease. This is a seminal issue as we consider the wider implementation of CT screening for lung cancer, wherein the potential for harm and unnecessary treatment are not trivial. This is especially pertinent because the intraoperative localization of these lesions is problematic and might lead to lobar resection for what eventually proves to be benign disease. Finally, and as is often said, context is everything. The detection of pggns in otherwise healthy individuals in a screening program may have different implications than the detection of pggns by surveillance of patients with a history of lung cancer, in whom the probability of a second primary lung cancer seems higher. Until the results of prospective controlled trials are available for guidance, surgical intervention for pggns should be carefully considered and applied only if the nodule shows evidence of growth or the emergence of a solid component. Therefore, this commentary counsels: primum non nocere. Nasser K. Altorki, MD Division of Thoracic Surgery Department of Cardiothoracic Surgery Suite M-404 Weill Cornell Medical College 525 E 68th St New York, NY 10065 e-mail: nkaltork@med.cornell.edu References 1. Cho S, Yang HC, Kim K, Jheon S. Pathology and prognosis of persistent stable pure ground-glass opacity nodules after surgical resection. Ann Thorac Surg 2013;96:1190 5. 2. Lee SW, Leem CS, Kim TJ, et al. The long-term course of ground-glass opacities detected on thin-section computed tomography. Respir Med 2013;107:904 10. 3. Silva M, Sverzellati N, Manna C, et al. Long-term surveillance of ground-glass nodules: evidence from the MILD trial. J Thorac Oncol 2012;7:1541 6. Ó 2013 by The Society of Thoracic Surgeons 0003-4975/$36.00 Published by Elsevier Inc http://dx.doi.org/10.1016/j.athoracsur.2013.06.017