Waiting or acting: timing and strategy for multiple ground-glass opacities

With advancements in lung cancer screening and the increasing use of computed tomography (CT) imaging in routine clinical practice, the incidental findings of multiple ground-glass opacities (GGOs) have become more frequent (1,2). These lesions are often associated with early-stage lung cancer, but definitive guidelines for their management have not been established. Clinicians have long faced challenges in determining the optimal approach for managing multiple GGOs, a topic of ongoing debate in the field.

The Fleischner Society released management guidelines for GGOs in 2013 and updated them in 2017, which include recommendations for follow-up in cases of persistent pulmonary nodules (3,4). However, these guidelines primarily focus on follow-up imaging and omit detailed analyses of clinical and oncologic outcomes.

Clinicians managing multiple pulmonary nodules, particularly GGOs in patients with prior lung resections or when complete resection is infeasible, often face challenging decisions. Scenarios such as the inability to resect all nodules or the need for extensive pulmonary resection pose significant dilemmas. Several studies have indicated that ground-glass dominant nodules do not negatively impact survival. Conversely, the size and solid components of dominant nodules are consistently associated with worse prognoses (5-8). Recent studies, including those from the Japan Clinical Oncology Group (JCOG) , have highlighted the favorable prognosis of GGOs, suggesting that sub-lobar resection may suffice and raising further questions about the necessity of aggressive early intervention (9,10). However, determining the optimal timing for surgical intervention remains a key challenge. While size and solid component development are established risk factors, clinical experience suggests that additional factors, such as nodule growth rate, patient comorbidities, and functional lung reserve, should also be considered. In particular, GGOs that transition from pure to part-solid morphology or demonstrate rapid volumetric doubling times may warrant early surgical intervention, whereas stable pure GGOs could be monitored more conservatively.

One of the initial studies initiated by the Thoracic Surgical Oncology Group (TSOG), established by the American Association for Thoracic Surgery, focused on evaluating the feasibility and safety of active surveillance in patients with multiple GGOs (11). Conducted across 23 institutions, the study enrolled 337 patients with at least two GGOs smaller than 3 cm, predominantly of ground-glass appearance. Patients underwent CT scans at 6- to 12-month intervals for prospective follow-up, with the study aiming for a total follow-up period of 5 years. Patient characteristics were analyzed as part of this ongoing research. The mean age of the patients was 70 years, and the majority (79%) had a history of smoking. Half of the patients (51%) had a previous history of lung cancer. A total of 1,467 nodules were observed during the follow-up. Over a median follow-up period of 16.1 months, no lung cancer-related deaths were reported. While the current median follow-up period of 16.1 months in this study provides preliminary insights, it remains insufficient to fully characterize the long-term oncologic behavior of GGOs, considering their typically slow progression. Previous studies have suggested that significant changes in pure GGOs, particularly the emergence of solid components, often occur beyond three years of follow-up (12,13). Therefore, the planned 5-year follow-up in this study is essential for determining the true natural history of multiple GGOs and identifying the optimal timing for intervention.

A key strength of this study is its detailed tracking of each GGO in individual patients. Unlike previous research that generally focused on patients as a whole, this study evaluates the clinical significance and natural history of each GGO separately. This approach allows for a deeper understanding of how specific nodule characteristics influence their progression or stability over time, which could lead to more tailored and precise management strategies.

Another notable strength lies in the prospective design of the study and its well-balanced composition of the study population. Most previous studies have been retrospective observational studies, whereas the prospective design of this study can provide stronger evidence for the outcomes. While most prior studies were largely included patients already diagnosed and treated for lung cancer, this study incorporates both patients with a prior lung cancer diagnosis (51%) and those without one (49%). This distinction is particularly important because it provides an opportunity to compare these two groups, potentially clarifying whether multiple lung nodules should be interpreted as second primary cancers or metastatic lesions. This differentiation has been a longstanding challenge in the field, and the study’s design offers valuable insights into this issue.

Additionally, this study’s population differs from those included in ongoing Asia-based prospective studies (14), notably regarding racial composition and smoking prevalence. These differences enable comparisons across diverse populations, which could reveal important variations in the natural history and progression of GGOs. Such comparisons will help determine whether findings from studies in predominantly Asian populations are applicable to other patient groups, thereby enhancing the generalizability of the results. By addressing these aspects, the study provides valuable contributions to understanding the management of multiple GGOs, offering data that could shape future clinical guidelines.

While the study’s strength lies in its design as a multicenter prospective study, disparities in patient recruitment among the 23 participating institutions were observed, with a few institutions recruiting very few or no patients.

This publication serves as an interim report, presenting the characteristics of the enrolled patient cohort. However, the findings align with previous prospective studies, which have also shown that the presence or progression of sub-solid nodules does not significantly affect survival. Nonetheless, this study provides additional value by offering an analysis of individual GGOs rather than treating patients as a homogenous group. By distinguishing between patients with and without prior lung cancer and meticulously tracking each individual nodule, this study contributes nuanced insights into how GGOs behave over time, which has been a limitation in prior studies. These aspects will be critical in refining surveillance strategies and guiding future clinical guidelines.

The TSOG 102 study represents the prospective study focusing on patients with multiple GGOs, making it a valuable resource for understanding the management of these patients. Its design and detailed tracking of individual nodules provide critical insights into the clinical course and progression of GGOs. The study holds the potential to establish evidence-based strategies for the management of multiple GGOs, and its long-term results are highly anticipated.

Acknowledgments

None.

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.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-6/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-6/coif). The authors have no conflicts of interest to declare.

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