Surgical resection of nodular ground-glass opacities without percutaneous needle aspiration or biopsy

With the recent technological and diagnostic advances, and with the widespread use of computed tomography (CT), nodular ground-glass opacities (nGGOs) are being increasingly detected. This increased detection has challenged the diagnosis and management of nGGOs, which have been addressed extensively in the last ten years. However, most approaches are currently not closely grounded in solid evidence [1]. The most recent National Comprehensive Cancer Network (NCCN) guidelines, version 2.2014 for lung cancer screening recommend nonsurgical biopsy or surgical excision of part-solid nodules measuring more than 8 mm that are suspicious for lung cancer upon fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT [2]. For pure GGOs measuring more than 10 mm with stable features upon low-dose CT (LDCT) follow-up, the NCCN guidelines recommend follow-up with LDCT for 6–12 months, nonsurgical biopsy, or surgical excision. On the other hand, in patients with part-solid nodules measuring more than 8 mm, the American College of Chest Physicians (ACCP) guidelines suggest repeat chest CT at 3 months, followed by further evaluation with FDG-PET/CT, nonsurgical biopsy, and/or surgical resection [3]. Especially, in part-solid nodules measuring more than 15 mm, they recommend prompt further evaluation with FDG-PET/CT, nonsurgical biopsy, and/or surgical resection. However, there are currently no clear criteria for deciding nonsurgical biopsy or surgical resection.

Bronchoscopic examination including biopsy is rarely helpful in the diagnosis of nGGOs, as these are usually located peripherally. On the other hand, percutaneous needle aspiration or biopsy (PCNA or PCNB) is an established diagnostic technique that has a high diagnostic yield [4, 5]; however, PCNA or PCNB has a lower sensitivity in smaller nodules [6, 7], and its role in the diagnosis of nGGOs is controversial, with no consensus existing regarding the optimal size threshold or technique [8]. Although recent studies have reported that PCNB provided a high diagnostic accuracy of up to 95% for nGGOs [9, 10], those rates may not be reproducible when strict standards are applied to the biopsy specimens under the new classification of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS), which introduced the concept of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) [11]. Small biopsy may not be suitable for determining tissue invasiveness.

In addition to pneumothorax or hemoptysis, the risk of malignant cell spread through the tract upon PCNA or PCNB has been addressed [12‐15]. Furthermore, the relatively high radiation exposure to the operators is a concern, as percutaneous biopsy of nGGOs is associated with a longer procedure time, owing to the smaller sizes and less solid components of these tumors.

Thin-section CT findings correlate closely with the pathologic diagnosis of nGGOs [16], and the attenuation, marginal characteristics, size, and development of a solid component are potentially helpful to predict malignancy [1, 17, 18]. Therefore, surgical resection of nGGOs without preoperative tissue diagnosis could be a reasonable strategy. However, the necessity of preoperative histologic confirmation by PCNA or PCNB in nGGOs has not been well evaluated.

Seoul National University Bundang Hospital (SNUBH) has used its own protocol for the management of nGGOs (Figure 1) that is basically similar to the NCCN guideline [2]. Briefly, we suggest direct surgical resection of nGGOs highly suspicious for malignancy, rather than nonsurgical biopsy. In this study, we evaluated the rate of malignancy, complications related to surgery, and the cost benefits of resecting nGGOs without prior tissue diagnosis when those nGGOs were highly suspected for malignancy based on their size, radiologic characteristics, and clinical courses.

The aim of this retrospective study was to investigate the necessity of preoperative biopsy for GGO nodules which were suspicious for malignancy. We evaluated the rate of malignancy, complications related to surgery, and the cost benefits of surgical resection of nGGOs without preoperative tissue diagnosis when those nGGOs were highly suspicious for malignancy in terms of size, radiologic characteristics, and clinical courses. Lack of adequate control group, such as randomly assigned GGO nodules with preoperative biopsy was the main limitation of this study. However, our study yielded four main findings: (1) the rate of malignancy was high (95.2%) in nGGOs highly suspected for malignancy based on clinical and radiologic characteristics; (2) only tumor size was a significant independent predictor of malignancy in the multivariate analysis; (3) the rate of complications related to surgery was low (6.7%), with no mortality and minimal morbidity; and (4) direct surgical resection without tissue diagnosis significantly reduced the total costs, days of hospitalization, and waiting time to surgery.

The role of PCNA or PCNB in the diagnosis of nGGOs remains limited [8]. Hur et al. [24] reported the sensitivity of CT fluoroscopy-guided needle biopsy as 67% for diagnosing malignancy in 28 patients with nGGO lesions. In another study of 40 individuals with nGGOs, the diagnostic yield of percutaneous CT-guided core biopsy was 84% (16/19), whereas it was non-diagnostic in three patients (16%) [25]. Two of these underwent surgical resection and were diagnosed as lung adenocarcinoma. In our study, 26 patients underwent PCNA or PCNB and the diagnostic accuracy was found to be 65.4% (17/26) under the IASLC/ATS/ERS classification of lung adenocarcinoma. All nGGOs that were resected after PCNA or PCNB were in fact malignant. Four nGGOs diagnosed as benign lesions and another four nGGOs with non-diagnostic results on PCNA or PCNB underwent surgical resection based on strong clinical suspicion for lung cancer, and were demonstrated to be invasive adenocarcinomas.

Recently, several studies have shown that the diagnostic accuracy of PCNB was greater than 90% for nGGOs [9, 10]; however, these results may be dependent on the experience and skills of the operators, and may hence not be fully reproducible. In this context, the third edition of the ACCP guidelines on the diagnosis and management of lung cancer stated that nonsurgical biopsy should not be used to exclude malignancy considering its unsatisfactory sensitivity and limited negative predictive value [3].

VATS lobectomy for patients with early-stage lung cancer is a standard surgical treatment, and is associated with lower morbidity and improved survival rates compared with open thoracotomy [26]. Recently, several studies have suggested that thoracoscopic limited resection is a valid surgical technique for nGGOs selected by thin-section CT scans [27]. With the widespread use of VATS, it is possible to diagnose and treat nGGOs simultaneously.Recommendations for the management of nGGOs have been used by SNUBH (Figure 1). These recommendations state that, regardless of the presence of a solid component, surgical resection should be considered if there is an increase in size ≥2 mm or development of a solid component in a pure GGO. In pure GGOs ≥10 mm, we suggest repeat chest CT at 3 months. In GGOs without significant changes in the initial 3 months of follow-up, we recommend surgical excision for nGGOs ≥15 mm, whereas we recommend chest CT follow-up for one year or surgical excision for nGGOs measuring 10–15 mm in size. In part-solid GGOs ≥10 mm with clinical suspicion of malignancy, we recommend surgical resection even if these do not show significant changes at the initial one-month follow-up.

Heo et al. [23] evaluated 113 patients who underwent surgical resection in SNUBH from January 2008 to May 2009 without prior tissue diagnosis for highly suspicious pulmonary nodules, including solid and GGO lesions. In their retrospective study, 45/50 (90%) patients with nGGOs had malignancy; and they reported that presence of a solid component, bubble lucency, irregular margin, and larger size correlated with malignancy. Although many other studies have also reported that larger size, irregular border, partly solid attenuation, internal air bronchograms, and central bubbly lucency were associated with higher rates of malignancy [19, 28, 29], some studies have reported conflicting results. In a study of 53 pure nGGOs in 49 patients, no significant differences in the morphologic characteristics and size were observed between malignant and benign nodules [30], although it is possible that this study was underpowered to detect differences [3]. However, in our study including a larger number of nGGOs, the maximal diameter was the only predictive factor of malignancy, and there were no significant differences in the morphologic features on CT between malignant and benign lesions.

We speculate that the failure to detect morphologic factors to distinguish benign from malignant nGGOs was mainly influenced by selection bias. Not all patients with an nGGO lesion underwent surgical resection. Only patients who were highly suspected to have malignancy based on the tumor size, radiologic characteristics, and clinical courses underwent surgical resection, although 14 of the resected nGGOs did not meet the SNUBH protocol in this study. This may explain the higher malignancy rate (95.2%) and lower proportion of AAH (4/330, 1.2%) in the present study compared to previous studies, which have reported malignancy rates between 58.7-75.0% [19, 30] and proportions of AAH between 5.7%-20.9% [30, 31].

In conclusion, upon careful selection of nGGOs that are highly suspicious for malignancy, surgical resection of nGGOs without tissue diagnosis is recommended as it reduces costs and the length of hospital stays.