An alternative option for the management of small-sized lung nodules with ground-glass opacity on thin-section computed tomography: a watch-and-wait approach

With the development of thin-section computed tomography (CT), lung nodules with ground-glass opacity (GGO) have been incidentally detected on check-up CT scans (1). Most GGOs show as small lesions on thin-section CT and are simply categorized as having partly solid components (part-solid GGO) or no solid components (pure GGO). These small-sized GGO nodules have been observed at appropriate intervals or have required intervention with sublobar resections because most small-sized GGO nodules are diagnosed as lepidic-predominant lung cancer, which has a favorable prognosis (2-4). GGO itself can potentially significantly influence a favorable prognosis in lung cancer. Lung cancer with pure GGO has an extremely favorable prognosis (5,6). The prognosis of patients with partly solid GGO is better than that of patients with pure solid lesions without GGO (7). Therefore, when discussing the strategy for deciding between observation and intervention, the ratio of the solid component to the total tumor with GGO [consolidation-to-tumor ratio (CTR)] and the total size of the GGO are important.

The CTR is calculated as the ratio of the maximum size of the solid component to the maximum size of the GGO, and each size is an important factor in determining the strategy for GGO nodules (8). European guidelines recommend follow-up until the size of the solid component has increased to 6 mm (9). In Japan, the follow-up guidelines for small lung nodules have been revised based on recent clinical data on the radiologic-pathologic correlation of the solid portion on thin-section CT (10,11). Previously, intervention was indicated when the total tumor size of GGO was ≥1.5 cm or the solid size was ≥5 mm. The solid size was revised from 5 to 8 mm, based on published papers (10,11).

Previously, the traditional standard procedure for lung cancer was a lobectomy combined with lymphadenectomy (12). However, sublobar resections have become acceptable for lung cancers ≤2 cm in size based on prospective clinical trials (JCOG0802/WJOG4607L and CALGB140503) (13,14). These trials indicated sublobar resection in patients with lung cancer, with or without a GGO component. Therefore, sublobar resection is more appropriate for patients with a GGO component than for those with only a solid component. Wedge resection is the simplest sublobar resection procedure, and segmentectomy and subsegmentectomy are indicated depending on the tumor location. If the tumor is located in the deep parenchyma of the visceral pleura, segmentectomy or subsegmentectomy is indicated to secure sufficient surgical margins (15). In performing sublobar resections, securing a sufficient surgical margin is essential to prevent local recurrence, and this has been discussed for subsolid lung adenocarcinomas (16,17). Although segmentectomy is preferable to wedge resection to ensure a sufficient surgical margin in cases where the tumor is in the deep parenchyma, it remains unclear which procedure is better for treating GGO-dominant lung cancer. However, since wedge resection is simple and easy with few operative complications, it is recommended as a curative surgery for small-sized GGO-predominant lung cancers if a sufficient surgical margin can be secured.

Furthermore, minimally invasive surgeries, such as thoracoscopic or robotic approaches, are undisputedly preferable for performing sublobar resections for small-sized lung cancers, since recovery is expedited.

Approximately 10 years ago, many surgical interventions were performed for small-sized GGO nodules, and the long-term outcomes of these intensive interventions have recently been reported. Li et al. revealed that the prognoses of pathologically diagnosed adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma with pure GGO were favorable (6,18). Niimi et al. reported favorable prognoses in patients with radiologically less invasive lung cancer in a prospective clinical trial (19). Yoshino et al. reported favorable long-term outcomes in patients with peripheral GGO-dominated lung cancer (20). Recently, we also demonstrated 10-year disease-specific and overall survival of 100% and 96.2%, respectively, in a prospective study on sublobar resections of tumors ≤2 cm in size and with ≥80% GGO ratio using preoperative thin-section CT combined with positron emission tomography (21). Thus, small GGO-dominant lung cancers have extremely favorable prognostic characteristics.

Single, small-sized lung cancers with GGO components can have favorable outcomes following sublobar resections. In a clinical trial, Huang et al. showed that patients with GGO lesions are characterized by multiple lesions (22). Multiple GGO lesions are occasionally observed in patients with GGO lesions on thin-section CT. The surgical strategy for multiple GGOs would be slightly different from that for single GGO lesions, because intervention or observation must be selected and the appropriate procedure must be planned step-by-step for each individual GGO nodule. Usually, GGOs ≥15 mm in size or GGO lesions with ≥6 or 8 mm of solid components are indicated for intervention, according to the guidelines described above (9-11). The first operation for multiple GGOs requires a modified procedure from that used to perform sublobar resection for a single GGO, and thoracic surgeons should recognize the need to plan multistage surgeries. In these multistage surgeries, thoracic surgeons must be aware of the difficulties in dividing the pulmonary vasculature and bronchus in subsequent surgeries, due to severe adhesions caused by the first surgery. Therefore, a modified procedure is required during the initial surgery to avoid difficulties in dissecting the pulmonary vessels and bronchi during the subsequent surgeries. If an anatomical segmentectomy is required during the first surgery, extensive dissection around the hilum constructions and excessive coverage of the parenchyma with a polyglycolic acid sheet to prevent postoperative air leakage should be avoided. If a polyglycolic acid sheet is used to control air leakage, it should be used within a minimal area. In contrast, wedge resection may be preferable to segmentectomy because wedge resection does not require hilum dissection and adhesions are limited.

Based on the favorable long-term outcomes of recent clinical trials on small-sized lung cancers with GGO components, this observation could naturally be derived as an alternative option for managing small-sized GGO nodules. Similar to other low-grade malignant diseases, GGO-dominant lung cancer is indolent. The GGOs are slow-growing, and the growth rate is significantly different depending on the CTR. In particular, pure GGO takes an extremely long time to reach 2 mm in size (23). Lee et al. reported that 13.0% of the GGO lesions grew during 136 months of follow-up, although the initial tumor size was <6 mm (24). A prospective study (the TSOG102 study) considered the indolent natural history of GGO nodules. The Japan Clinical Oncology Group is conducting the multicenter study JCOG1906 (EVERGREEN study) to prospectively evaluate watchful waiting in early-stage lung cancer with GGO (25). Although the primary endpoint of the TSOG102 study is 5-year lung cancer-specific survival for patients with more than two GGO lesions, that of the JCOG1906 study is 10-year overall survival for patients with three GGO lesions. It would be meaningful to assess the appropriate follow-up methods for multiple GGO lesions in various settings. Favorable outcomes of watch-and-wait, including outcomes of these studies, are expected. However, rare cases of lung nodules with GGO components changing from noninvasive to invasive cancer during the observation period should not be ignored. Lee et al. demonstrated three significant risk factors for GGO growth: bubble lucency, development of a new solid component, and history of cancer other than lung cancer in the retrospective study. Furthermore, in GGO nodules with evidence of growth, the median time to detection of a new solid component was 18.1 months after being stable for the first 5 years of follow-up. GGO growth was detected at a median time of 23.6 months after the discovery of a new solid component (24). The prospective TSOG102 study should provide valuable data that show the appropriate CT follow-up term and some significant risk factors of GGO growth. This will allow more precise balancing of observation and intervention for small-sized GGO nodules, enabling better management of patients with GGO in the future.

The watch-and-wait approach may be an alternative option for small-sized GGO-predominant lung cancers, and favorable outcomes are expected in the TSOG102 study.

Acknowledgments

I would like to thank Editage (www.editage.jp) for English language editing.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-8/coif). H.K. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from March 2024 to February 2026. The author has no other conflicts of interest to declare.

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