Pulmonary ground glass opacity tumor: a curable subtype of lung cancer when treated within the “surgical curative time window”

Introduction

With wide application of thoracic computed tomography (CT) in clinical practice these years, incidental pulmonary nodules, especially small-sized lung cancers have been fortunately detected. Radiologically, pulmonary nodules are categorized into solid and subsolid nodules, also called as ground glass opacities (GGOs). Because of the high accessibility of thoracic CT scan in Asia, which is quite different from the real practice in western countries, a high prevalence of GGOs has been increasingly detected (1-3). Though GGO is a nonspecific radiologic sign, persistent GGOs possibly indicate lung invasive or pre-invasive diseases (4). Published studies have shown that pulmonary GGO tumor exhibits special clinicopathologic characteristics with favorable prognosis, and is a special stage of its natural evolution of lung cancers (5,6). However, there are still several unconfirmed issues in management of pulmonary GGOs. Here, we provide the overview of recent advances in epidemiology, surveillance and treatment strategies of pulmonary GGO tumors.

Screening and surveillance

Special epidemiologic characteristics of GGO tumors: younger females or nonsmokers

Results of two largest controlled trials, the American National Lung Screening Trial (NLST) and European Nelson trial, have confirmed the efficacy and necessity of low-dose thoracic CT for lung cancer screening for smokers and ever-smokers older than 55 years old, which are traditionally regarded as the high-risk population of lung cancers (7,8). In east Asia, because of the high availability of low-dose CT scan, people younger than 55 years old or those who do not smoker can get CT scans if they want, a high prevalence of lung cancer is found in these people. Therefore, lung cancer screening programs have been applied in a wider range of the populations including people younger than 55 years old and those who do not smoke (3). In 2017, Chinese researchers conducted a community-based lung cancer screening study in Shanghai, and found that the detection rate of lung cancer was surprisingly higher in women or non-smokers than that in the smokers (mainly men). Of note, among these CT-detected lung cancers, 70.4% were radiologically GGOs, and 92.6% were pathologically adenocarcinomas (1). In 2020, results of regular health examinations among six Chinese hospital employees also indicated similar findings that the early-staged lung cancer was highly detected in female and nonsmoking employees. Moreover, among these screening detected tumors, 96% were radiologically GGOs, and 98.8% were adenocarcinomas (2). Thereafter, there were two studies from Asia which reproduced the same phenomena (3,9). Results of these Asian screening studies indicate that the lung cancer detection rate in non-smokers is equal to, or even higher than that in smokers or ever-smokers, and most screening detected lung cancers are radiologically GGOs (see Table 1). Considering that most non-smokers are women in east Asia, results of these studies show that females or non-smokers have been a high-incidence population of pulmonary GGO tumors. Therefore, the low-dose CT screening program should be considered for these people, and younger aged females or non-smokers have become a “high detection rate population” of lung cancer now. In 2023, a systemic review and meta-analysis confirmed the efficacy of low-dose CT screening for early-staged lung cancer in Asian females and non-smokers (12). Though the specific cause of the high prevalence of GGO tumors in these people remains unknown, it would be interesting to know whether the similar phenomenon could be found if low-dose CT screening had been widely applied in younger non-smoker populations in North America or Europe.

The “younger age” and “lower frequency of CT scan” screening strategy for females or nonsmokers

According to previous studies, the prevalence of lung cancer could not be ignored in people younger than 55 years old (3,12), or even in teenagers (13). In one study, there were 12 patients aging from 13 to 20 who were incidentally detected GGO tumors through CT scan. In Zhang’s study, the lung cancer detection rate in hospital employees younger than 40 years old was 1.0%, and 2.6% in those between 40 and 55 years, while 2.9% in those older than 55 years old (2). Accordingly, a wider range of younger people should be included in low-dose CT screening. However, there was one concern that a wider application of CT screening in younger and non-smoking people would result in over-diagnosis and unnecessary resections, because most screening detected lung cancers in females and non-smokers are GGOs, which grow indolently and patients have a very favorable prognosis (5,14-16). This concern was reasonable, and to address this, a longer screening interval should be encouraged. For smokers and ever-smokers older than 55 years old, the interval of 1 year was recommended in the Early Lung Cancer Action Project (ELCAP) (17) and NLST trials (7), and the interval of 1, 2, 2.5 years for four rounds was designed in Nelson trial (8). According to previous studies that the doubling times of pure GGOs was nearly 831 and 457 days of mixed GGOs, compared with 149 days for solid nodules (18), a longer screening interval of at least 2–3 years might be appropriate for people with suspicious GGOs after a baseline CT screening. Therefore, two strategies including “younger age” and “lower frequency of CT scan” should be advocated, when low-dose CT screening is conducted in the “high detection rate population” of lung cancer: females or nonsmokers.

Risk factors for lung cancer in non-smokers

There are several factors including environmental exposures and genetic susceptibility associated with an increased risk of developing lung cancer in non-smokers, though the definite causes are still unclear now. First, environmental exposures such as secondhand smoke, chemical substances including asbestos, chromium, arsenic and radon have been linked to lung cancer (19). A meta-analysis showed that females who did not smoke got a 27% increase in risk of lung cancer when married to the smokers (20). Also, asbestos and radon exposures have been noted to attribute to increased lung cancer prevalence (19). Second, genetic predisposition such as the familial risk of lung cancer, genetic germline mutations has also been regarded as an important risk for non-smokers. Previous studies indicated that germline mutations such as EGFR V843I & T790M and YAP R331W were correlated with a significantly higher incidence of the familial lung cancers (21-23). In addition, one retrospective analysis showed that pathogenic germline variants such as BRCA1/2, PALB2, and CDKN2A were found in 88% patients of lung cancer (24). Notably, these risk factors might not attribute to the prevalence of lung cancer independently, so one risk model which incorporate all of these factors could help to identify the definite people with high risk, and then increase the efficiency of screening. One modified model PLCOall2014, which was based on the well-known PLCOm2012, has included all these risk predictors such as familial history, air pollution, secondhand smoke, and lung carcinogen exposures could discriminate non-smokers with high risk for screening (25). Recently, another Optimized early Warning model for Lung cancer risk (OWL) based on the UK Biobank, PLCO, and NLST populations showed a high clinical utility for helping screening individuals with high risks of lung cancer (26). These incorporated risk model could identify peoples with high risk of lung cancer as candidates of CT screening in non-smokers.

Mapping of radiologic and pathologic features

Radiologically, GGO is a nonspecific sign, which pathologically can be benign lesions such as inflammation or focal interstitial fibrosis. Nevertheless, persistent GGOs possibly indicate pre-invasive or invasive malignancies (4). Clinically, the surveillance and treatment strategy for GGO tumors is basically depended on radiologic features on high-resolution computed tomography (HRCT), so the radiologic and pathologic correlations of GGO tumors have been well studied. Results of most studies which evaluated the radiologic features to predict pathologic invasiveness for GGO tumors showed that a larger tumor size, a larger solid component size or a larger consolidation to tumor ratio (CTR) was associated with the pathologic invasive pattern (14,27,28). In 2002, Suzuki and his colleagues applied the tumor size and C/T ratio to predict pathologic noninvasive and invasive lung cancer, and they defined GGOs with tumor size ≤2 cm and C/T ratio ≤0.25 as pathologic noninvasive lung cancers (29). However, this definition shows its limitation according to the results of recent studies Japanese Clinical Oncology Group (JCOG) 0804 (30) and JCOG1211 (31). According to the World Health Organization (WHO) definition of lung adenocarcinoma, adenocarcinoma in situ (AIS) is a localized small (≤3 cm) adenocarcinoma with lepidic growth and lacking stromal, vascular, alveolar space or pleural invasion. Minimal invasive adenocarcinoma (MIA) is a small, solitary adenocarcinoma (≤3 cm) with a predominantly lepidic pattern and ≤5 mm invasion, while an adenocarcinoma with the invasion >5 mm is defined as invasive adenocarcinoma (IAD) (32). Previous studies showed that patients with AIS, MIA and lepidic predominant adenocarcinomas would have a nearly 100% postoperatively recurrence-free survival (RFS) (33-35). One prospective multi-center clinical study (ECTOP1008) evaluated the diagnostic yield of HRCT in identifying pathologic AIS/MIAs or IAD for patients with GGO tumors. Results of this study indicated that HRCT had a good performance in differentiating between AIS/MIAs and IADs. Tumors with the size ≤10 mm were associated with AIS/MIAs, while those with the size >20 mm were associated with IADs, and a solid component size of 6 mm could be clinically used to distinguish between AIS/MIAs and IADs (4).

Traditionally, GGO on HRCT tends to correspond to the microscopically lepidic pattern, while the solid component of part-solid tumors is regarded as the invasive part including acinar, papillary, micropapillary and solid patterns on pathology. The lepidic pattern is defined as non-invasive part, which promises a very favorable prognosis for patients (36). Therefore, only the solid or invasive part is used as a descriptor of T-categories for radiologically GGO tumors or pathologically non-mucinous IADs in the 8th edition of the tumor-node-metastasis (TNM) in staging of pulmonary adenocarcinoma (36). Notably, the correlation that ground glass versus solid opacities tends to correspond respectively to lepidic versus invasive patterns seen pathologically is not always absolute (37). Clinically, there might be invasive pattern in GGO, and the solid area could be a benign or a fibrous scar harboring a stromal invasive component. One study (ECTOP1011) used the pathologic whole-mount section technique to evaluate the pathologic features of GGO and solid component on HRCT for GGO tumors. With application of the whole-mount section, the full pathologic view of the tumor was maintained, and precise matching of the same radiologic and pathologic sections was achieved. Results of this study indicated that there could be acinar, papillary and even micropapillary subtypes in GGOs, while there was fibrosis in solid opacities, besides invasive subtypes (38). Findings of this study might challenge the traditional concept of radiologic and pathologic correlations of GGO tumors, and provide valuable information for further understanding the radiologic and pathologic features of these tumors.

Resection within the “curative time window”: how to avoid over-treatment

According to studies of natural history of GGOs (18,39-42), persistent existence and slow progress are two significant characteristics of GGO tumors. Pulmonary GGO tumors have been regarded as a special clinical subtype of non-small cell lung cancers (NSCLCs) (5), and also been regarded as a special period during the dynamic evolution of lung adenocarcinoma (6). Because of its indolent nature and favorable prognosis of patients, selection of a conservative follow-up or an aggressive surgical resection is still a big controversy for GGO tumors. Also, the optimal surgical timing for the indolent tumors remains unclear. Generally, resection is considered when GGOs grow in size or develop a solid component during the follow-up period (43). According to the Fleischner Society guideline in 2017, surgical resection is recommended when the solid component is ≥5 mm for persistent part-solid nodules (44). In addition, the Japanese Society also recommended resection for lesions with GGO ≥15 mm, or the solid component size ≥8 mm, because they found a high prevalence of pathologic IAD of these lesions (43,45,46).

Notably, the natural evolution of GGO tumors has been clearly understood these years. Radiologically, a pure GGO grows gradually in size, or to a part-solid nodule, and eventually to a pure solid nodule (see Figure 1), while pathologically, AIS comes from the precancerous atypical adenomatous hyperplasia (AAH), and then grows to MIA, and ultimately IAD (6). Tumors at different stages during the radiologic or pathologic progressive trajectory of GGOs have different surgical outcomes. Considering the 100% 10-year RFS of pathologic AIS/MIAs and radiologic pure GGO nodules less than 3 cm (33-35), patient at this stage could be definitely cured. To the contrary, nearly 10–20% radiologic part-solid tumors or pathologic IAD exhibit postoperative recurrence, and these tumors are not curable (5,47). In 2023, Fu et al. proposed a definition of surgical curative time window including AIS and MIA stages in pathology as well as pure GGOs in radiology with tumor size <3 cm. They advocated that resection should be suggested within the curative time window to avoid over treatment, meanwhile to achieve a 100% survival rate (6). For patients with pathologic AIS and MIAs or radiologic pure GGOs, wedge resection is always preferable, because it is less invasive than segmentectomy or lobectomy. However, when the nodule grows to pathologic IAD or radiologic part-solid nodules, wedge resection might not be enough, while segmentectomy or lobectomy would be indicated, which was relatively more invasive. Notably, the scheduled resection should not adversely affect the individual’s living quality, career development and life trajectory.

Figure 1 The gradual growth patterns of persistent GGOs. (A) One pure GGO nodule grew in size within a follow-up period of 4 years (red arrows). (B) One pure GGO nodule grew the solid component with a follow-up period of 2.5 years (red arrows). (C) One pure GGO nodule with a rapid growth during a follow-up of 3 years (red arrows). GGO, ground glass opacity.

Sublobar resection

Though lobectomy is still regarded as the standard surgical extent for NSCLCs, sublobar resection including segmentectomy and wedge resection has been preferred for small-sized and early-staged tumors, especially for GGO tumors (48). In 2020, JCOG 0804 confirmed the efficacy of sublobar resection (mainly wedge resection) for GGO tumors with CTR ≤0.25 & T ≤2 cm that the 5-year RFS was 99.7% (30), and researchers updated the 10-year RFS (98.6%) and 10-year overall survival (98.5%) at the 103rd annual meeting of American Association of Thoracic Surgery in 2023. In the same year, JCOG 1211 confirmed the efficacy of segmentectomy for GGO predominant tumors with 0.25< CTR ≤0.5 & T ≤2 cm and CTR ≤0.25 & 2< T ≤3 cm that the 5-year RFS was 98% (31). However, most of these GGO predominant tumors in the two studies were pathologically AIS and MIAs, and patients with AIS and MIAs exhibited nearly 100% overall survivals. Therefore, the following question was whether sublobar resection was appropriate for pathologic IAD? In 2024, Zhang et al. conducted a retrospective study to evaluate whether wedge resection could be applied for GGO predominant IAD. Their results confirmed the efficacy of wedge resection for these tumors with T ≤2 cm with the 5-year RFS of 97.8% (49). Moreover, the prospective randomized controlled trial JCOG0802 showed a non-inferior overall survival of segmentectomy compared with that of lobectomy for radiologically solid predominant tumors with 0.5< CTR ≤1 & T ≤2 cm, and researchers advocated that segmentectomy should be the standard surgery for these small-sized tumors (50). However, the most controversial issue in JCOG0802 was that the local recurrence rate in segmentectomy group was 1-fold higher than that in lobectomy group, so some researchers are still skeptical for the conclusion in JCOG0802. Notably, most studies are from Asia including Japan and China. There was one prospective randomized controlled study CALGB140503 in United States which compared the efficacy of sublobar resection and lobectomy for clinical T1aN0 diseases with tumor size ≤2 cm and without intraoperative N1/N2. Results of this study indicated sublobar resection could provide a comparable 5-year disease-free survival (64.1% vs. 63.6%), 5-year RFS (71.2% vs. 70.2%) and 5-year overall survival (78.9% vs. 80.3%) than lobectomy did (51). However, in CALGB140503, the percentage of GGOs was unknown. Therefore, according to results of these studies, for GGO predominant tumors, sublobar resection including wedge resection and segmentectomy could be a superior choice compared with lobectomy, with advantages of reserving more lung parenchyma as well as providing comparable survivals. However, for solid predominant tumors, segmentectomy should be carefully selected considering the higher local recurrence rate in segmentectomy group in JCOG0802, and lobectomy might be still the safest option.

Selective or no lymphadenectomy

According to previous studies, the prevalence of lymph node metastasis (LNM) was obviously lower in GGO tumors compared with that in pure solid tumors. In 2013, Tsutani et al. reported the prevalence of LNM was 5% in part-solid tumors (52). In 2019, Ye et al. reported that no LNM was observed in pure GGO tumors, while the prevalence of LNM was 2.2% in part-solid tumors. In GGO predominant tumors, the prevalence was 1.2%, while 3.5% in solid-predominant tumors (5). In 2021, Aokage et al. reported the prevalence of LNM in solid predominant tumors in JCOG0201 was 2.6% (11/420) (53). In 2024, Maniwa et al. showed that the prevalence of LNM was 1.5% in part-solid tumors, and that of N2 disease was 0.5% in JCOG0802 (54). In 2025, Mimae et al. showed the prevalence of LNM was only 0.1% in GGO predominant tumors, so they suggested omitting lymph node dissection for GGO predominant tumors (55) (see Table 2). Therefore, the prevalence of LNM in pure GGO or GGO predominant tumors was very low, so systemic mediastinal lymph nodes dissection should be omitted for these tumors. Results of one recent randomized controlled trial (ECTOP1009) confirmed that systemic mediastinal lymph node dissection could not provide survival benefits, while lead to a higher prevalence of perioperative complications for patients with GGO predominant tumors (60). However, for solid predominant tumors, selective lymph node dissection might be still suggested, considering a low but non-negligible risk of LNM. In 2016, Hishida et al. proposed a lobe-specific lymph node dissection strategy that inferior mediastinal (subcarinal) nodes were not dissected for upper lobe tumors, and superior mediastinal nodes were not dissected for lower lobe tumors for selected patients with early-staged NSCLCs (61). In 2023, Zhang et al. recommended a more detailed selective lymph node dissection including six strategies based on the segment location, radiologic and intra-operative pathologic features of nodules for early staged tumors. The six strategies of selective lymph node dissection may be clinically practical, which can be adopted in daily clinical practice (62). Of note, these selective lymph node dissection strategies greatly depend on the pathologic evaluation of the hilar lymph node status (N1) during the surgical operation. Therefore, a delicate hilar lymphadenectomy and accurate intraoperative pathology are very important for the efficacy of the proposed selective lymph node dissections.

Follow-up strategy for persistent GGOs: how to avoid over-diagnosis

The most important issue on management of GGOs is how to avoid over-diagnosis. According to the I-ELCAP, NLST and Nelson trials, a regular follow-up strategy should be advocated for CT-detected GGOs to avoid over-diagnosis. During the follow-up period, transient GGOs resolve, while malignant GGOs persistently exist. Notably, the indolent growth pattern of GGOs and low mortality of patients can warrant a longer follow-up interval compared with solid nodules. According to the Fleischner society guideline, for GGOs less than 6 mm, no follow-up was needed (44). However, according to one Japanese study in 2015, nearly 10% GGOs less than 5 mm would grow and 1% would develop into MIA or IAD (41). Moreover, previous studies indicated the median volume doubling time of pure GGOs was 700–900 days (14,38), so a follow-up interval of at least 3 years for persistent GGOs less than 6 mm might be reasonable. For pure GGOs between 6–15 mm, a follow-up interval of 2 years might be appropriate. For pure GGOs ≥15 mm, studies indicated most were IAD, so surgery was recommended. For part-solid nodules, the median volume doubling time was about 450–700 days (18), a follow-up interval of 1–2 years could be recommended for part-solid nodules with a solid component less than 6 mm. For part-solid nodules with a solid component ≥6 mm, studies indicated a high possibility of IAD (27,63,64), thereafter surgical resection should be recommended. Importantly, resection should be avoided if the individual’s life expectancy is shorter than the natural course of GGOs. Moreover, a longer follow-up period (>5 years) might be necessary because one study indicated that 13% of GGOs grew more than 2 mm after the 5 years of stability, and 16% developed a solid component (65) (see Figure 2).

Figure 2 The follow-up and resection strategies for persistent CT-detected GGOs. *, follow-up period should be more than 5 years; when GGOs grow or develop solid components or solid components grow during the follow-up period, resection could be considered. CT, computed tomography; GGO, ground glass opacity.

Conclusions

Pulmonary GGO tumors show distinct clinicopathologic characteristics, which can be regarded as a special subtype of NSCLCs. Younger females or nonsmokers are the new “high-detection rate” population of GGO tumors. Considering the special epidemiologic features, a low frequency of screening interval could be encouraged for this population. Because of the indolent instinct and favorable prognosis of these tumors, less invasive surgery including preserving more normal pulmonary parenchyma and lymph nodes should be advocated when resection is considered for certain candidates. The gradual growth pattern of GGO tumors makes radical treatment within the surgical curative time window possible for patients with GGO tumors. Furthermore, efforts should be made on revealing definite causes of the indolent tumors and identifying the specific tumors with rapid growth pattern in the future.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1373/prf

Funding: This work was supported in part by the National Natural Science Foundation of People’s Republic of China (Nos. 82430099 and 81930073) and the National Key R&D Program of China (No. 2022YFA1103900).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1373/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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