Ground-glass opacity lung cancers—a review of the literature

Introduction

Background

The wide-spread increase in low-dose computed tomography (CT) screenings has led to an increase in the detection of ground-glass opacity (GGO) lung lesions (1,2). GGOs are non-specific radiological findings that may be transient, corresponding to benign conditions such as focal interstitial fibrosis, inflammation, or hemorrhage (3,4). Persistent GGOs can also represent invasive lung cancer, as well as preinvasive pathologies such as atypical adenomatous hyperplasia (AAH) and adenocarcinoma in-situ (AIS) (4). It has become apparent that invasive lung cancers presenting as GGO or part-solid GGO lesions are correlated with less-aggressive subtypes and have significantly better prognosis than those with pure-solid radiographic presentations (5). Due to this trend, clinicians have proposed that different management algorithms should be considered for GGO-associated lesions (4,6).

Knowledge gap

The importance of this topic has spawned new guidelines and reviews of literature in recent years (1,5-7). Evidence for improved prognosis and tissue-sparing treatments remains mainly retrospective, and therefore ongoing evaluation of current data trends with prolonged follow-up is essential to better define guidelines. The emerging evidence for non-operative management of GGO-associated cancers is limited and its role in treatment algorithms is not well understood. Though molecular mutations associated with GGO-tumors have been studied previously, the prognostic impact of specific mutations is not well understood.

Objective

In this narrative review of GGO associated lung cancer, we concentrate on the prognostic, clinical characteristics, and management strategies pertaining to lung malignancies presenting as GGOs, offering a comprehensive insight into this distinct radiological subtype. Our focus will be to build on previous reviews by addressing recent data published within the last 4 years. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-25/rc).

Methods

Search strategy

A search of the PubMed/Medline database for primary research involving GGO lung cancers from January 1^st, 2020 to April 25^th, 2024 was performed using the related medical subject heading (MeSH) terms for ground-glass opacities (GGO or ground-glass opacity or GGN or sub solid nodule) and lung cancer. Our search strategy is summarized in Table 1. The study was filtered to exclude reviews, case reports, case series, commentaries and meta-analyses. Secondary research such as commentaries, reviews and meta-analyses were removed as the goal was to review the latest advances in primary research. Descriptive studies such as case reports and case series were removed as our goal was to analyze the highest quality data with large patient populations. Publications were limited to articles published in the English language. A total of 792 articles were queued from this search.

Inclusion and exclusion criteria

Studies were included if they were primary research articles that related to primary lung cancers presenting as GGOs with a sufficient sample size to draw meaningful conclusions (set at cohort size of at least 20 patients). Articles were first assessed by title to exclude articles that clearly did not relate to primary lung cancers, were clearly not primary research (i.e., review articles or meta-analyses), or were case reports/case series. A total of 181 articles were eliminated at the title review stage, leaving 611 publications. Articles were then reviewed at the abstract level for inclusion criteria. An additional 305 articles were screened out at the abstract level for not being primary research, not relating to lung cancers, not relating to GGOs, or having cohort size of fewer than 20. A full-text review of the remaining 306 articles was then performed based on relevance to prognosis and treatment management. An additional 248 articles were eliminated for lack of relevance, leaving a total of 58 articles that were included.

Additional and supplemental articles

Additional articles were included in the study to supplement areas. To address the lack of articles regarding systemic therapies, additional searches in the PubMed/Medline for articles published between 2020 and 2024 were performed, using the related MeSH terms for ground glass opacities, lung cancer, and a variable third term that differed for each search. Using “Chemotherapy” resulted in 97 articles, of which 3 articles met our above inclusion criteria, “immunotherapy, resulted in 46 articles, 2 of which met inclusion criteria, “molecular-targeted therapy” resulted in 7 articles, 0 meeting inclusion criteria, “EGFR inhibitor” resulted in 29 articles, 2 meeting inclusion criteria, “VEGF” resulted in 5 articles, 0 meeting inclusion criteria, and “ALK inhibitor” resulted in 15 articles, 0 meeting inclusion criteria. One additional article relating to the effect on prognostic factors of GGO was added per suggestion of reviewers, resulting in a total of 66 articles. In addition, background references (11 reviews, 1 primary research paper from prior to 2020) were cited for the purpose of background information and context. A Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram summarizing the article identification and screening process is demonstrated in Figure 1.

Figure 1 PRISMA flow diagram summarizing the article identification and screening process. GGO, ground-glass opacity; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitors; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

Data extraction

Each article was assigned into one of four categories based on the focus of our review: prognostic factors, surgical management, non-surgical management, and molecular factors. Articles were then reviewed in their entirety. Study methodology, goals/purpose, population and sample size, key results, follow-up times, and study conclusions were extracted. Findings were organized and grouped with other relevant studies for synthesis.

Results

Prognostic implications

The prognostic implications associated with pure GGO and part-solid GGO non-small cell lung cancer (NSCLC) cannot be overstated. There is data indicating that radiological analysis of the solid component size of GGO lung cancers correlates with pathological tumor invasion (8). Clinically, numerous retrospective studies have indicated that GGO tumors, or those with GGO components, tend to exhibit less aggressive biological behavior and correlate with an improved prognosis compared to pure-solid tumors (7,9-16). Large retrospective studies have demonstrated statistically significant improvement in overall survival (OS) and recurrence-free survival (RFS) associated with part solid GGO lesions (17,18). Furthermore, the absence of a GGO component on imaging has been identified as a risk factor for worse outcomes, even for early-stage lung cancer, with significantly worse RFS and OS in surgically resected lung cancer (19-22). Park et al. evaluated patients following surgical resection and found recurrent disease to be more common in patients with pure solid (36.1%) vs. those with a GGO component (16.2%). The presence of GGO was also found to be a favorable prognostic factor regarding time to recurrence and OS [adjusted hazard ratio (HR), 0.6 (P<0.001) for both]. OS at 5 years was 92.3% with GGO adenocarcinoma vs. 77.8% pure solid lesions (19). Sun and colleagues retrospectively analyzed early-stage lung cancer and found 5-year RFS and OS varied significantly when comparing pure-GGO, part-solid GGO, and pure-solid groups (RFS: 100% vs. 95.4% vs. 76.6%, P<0.0001) (OS: 100% vs. 98.9% vs. 87.5%, P<0.0001) (20).

A recent study aimed at redefining the prognostic impact of GGO in early-stage lung cancer found the 5-year OS rate for the part-solid group was impressive, exceeding 90%, regardless of the size of the solid component. Conversely, the solid group had poorer outcomes, with both 5-year RFS and OS rates lower than those of the part-solid group (21).

A multivariate analysis aimed to identify the clinicopathologic factors associated with lung cancer recurrence following resection showed the absence of GGO components to have a hazard ratio of 3.351. Of note, this study showed a 10-year OS rate of 89.6% and 70.7% respectively for the patients with GGO components and those without GGO (22). Other studies have shown 100% lung cancer specific survival rate following resection of pure GGO lesions (23).

Refining radiologic evaluation to better estimate pathologic tumor invasion and identify surgical candidates for limited resection is imperative. Pre-operative pathologic diagnosis cannot always be obtained, especially in the case of minimally invasive adenocarcinoma (MIA) or AIS. The ability to delineate these lesions from invasive cancer is important as two recent studies reported a 100% 10-year postoperative RFS rate for patients with AIS or MIA (23,24). The prognosis following surgery can be estimated when radiological features strongly correlate with pathological tumor burden. Generally, there is a worse prognosis with higher solid component ratios found on imaging (8,25). Ye et al. specifically investigated radiologic differences between AIS or MIA and invasive disease. Of 620 patients who underwent surgery based on suspicious GGO lesions, radiological diagnostic accuracy for pathological tumor invasion was 83%. Tumor size and solid component size were the two most important factors to identify pathologic tumor invasion, with 6 mm solid component size identified as the cutoff value to distinguish pathologic invasive adenocarcinoma from MIA and AIS. Of the tumors identified in the study, 100% of the pure GGO tumors smaller than 1 cm were MIA or AIS and 90% of those with tumor size over 2 cm contained invasive cancer (8).

There is supporting retrospective data that has indicated tumors with solid components measuring 2 cm or less often have a more favorable prognosis, while those with solid components larger than 2 cm show more aggressive disease behavior (11). Others have shown higher recurrence rates associated with increased solid component to GGO ratios (25).

Data obtained by Wang and colleagues demonstrated that the GGO component was a strong prognostic factor indicating a more favorable prognosis in patients with stage 1 NSCLC who underwent resection. The study showed a 5-year OS and RFS rate of over 98% for the pure-GGO group, 96.0% and 86.5% in the part-solid group, and 88.0% and 75.5% in the solid group, respectively (16).

There is an emerging consensus that pure GGO-associated lung adenocarcinomas should be distinguished from other lung adenocarcinomas due to the improved prognosis and that the presence of GGO on CT lends to an increased survival (26-28). Many authors have suggested the presence of GGO to be an important parameter for the next revision of the clinical T classification (6,17,29). This is due to evidence that early-stage lung cancers with GGO components may be distinct tumor types distinguishable from those without a GGO component, and there is a possibility that the presence of GGO may provide accurate prognostic prediction for patients with small to moderate areas of tumor invasion (under 4cm in size) (16,17,23,29-32).

Although, some authors have warned that lesions with only a small proportion of GGO components [that is, with a consolidation tumor ratio (CTR) >0.75], are not linked to favorable survival, and recommend similar treatment algorithms to pure solid lesion (33).

Data has also shown that mixed GGOs have significantly better outcomes in terms of lymph node metastasis compared to pure-solid lesions when compared by size. A retrospective review of 591 patients with lung nodules showed that tumor size was a significant predictor of nodal metastasis in the pure-solid lesions but not in the mixed GGO group (34). Ongoing clinical trials aim to refine lymph node dissection strategies, taking into account radiologic and pathologic characteristics to optimize patient outcomes (35).

Effects on surgical management

Surgical resection remains the cornerstone of treatment for GGO lung cancer as there is a consensus that pure GGO malignancies can often be cured by surgery (17,36). Lobectomy has historically been the standard treatment for lung cancers based on data from early clinical trials, however, an evolving body of evidence suggests that because of the favorable prognosis associated with GGO lesions, less aggressive surgical interventions may be curative.

Sublobar resections, including segmentectomy or wedge resection, have emerged as viable alternatives to lobectomy. Retrospective data has shown a 10-year RFS and OS of over 98% for peripheral GGO dominant lung cancers removed with sublobar resection (37). The favorable prognosis of GGO lung malignancies is dramatic enough that recent clinical trials comparing sublobar vs. lobar resections for lung adenocarcinomas have excluded GGO lesions altogether (38).

The importance of lung parenchyma sparing procedures cannot be overstated. In the JCOG0802/WJOG4607L (39) study comparing lobectomy vs. segmentectomy for small NSCLC with CTR >0.5, causes of death other than lung cancer occurred more frequently in the lobectomy group (9.3%) compared to segmentectomy (4.9%) with similar OS after segmentectomy (94.3% at 5-year for segmentectomy group compared to 91.1% for the lobectomy group).

Lobectomy is associated with a higher mortality rate, not only from other illnesses, but also from secondary cancers which may require the need for further lung resection. Eligibility for extent of resection should also be considered, as factors such as age, cardiopulmonary function, prior history of pneumonectomy, and presence of multiple nodules can limit a patient’s ability to tolerate extensive surgical resection. However, patients with poor cardiopulmonary function that are unable to tolerate lobectomy may be eligible for less extensive resections. Due to the significance of lung parenchyma preservation on long-term survival the radiological evaluation and accuracy to predict tumor invasiveness is essential (39).

Recent clinical trials have aimed to evaluate the efficacy and safety of segmentectomy in GGO associated tumors. Aokage et al. demonstrated the efficacy and safety of segmentectomy for GGO lesions with a diameter of 3 cm or less given adequate surgical margins (40). At 5 years the relapse free survival was 98% (40). Suzuki and colleagues conducted a study to evaluate the efficacy and safety of sublobar resection for treating small peripheral GGO predominant lung cancers. Their findings showed that sublobar resection, with adequate margins, resulted in a low risk of relapse for radiographically favorable, N0 disease measuring 2.0 cm or less (41). Additional authors have suggested wedge resection as an appropriate choice for ≤2 cm GGO-dominant NSCLC (15,42). There is evidence that wedge resection for pure-solid lesions should be cautioned (15,33).

There is some data that suggests the size of the solid component of a GGO as a superior predictor of histological features and prognosis than the overall lesion size. Lin et al. suggested a solid component size of ≤2 cm might be a more suitable criterion for selecting patients for sublobar resections, rather than focusing solely on the total lesion size (43).

The solid component of the tumor can also play a role in the decision to perform a lymphadenectomy, as retrospective data shows a higher lymph node metastasis rate associated with increased solid components. In a study involving 768 lung cancer patients with GGO components the rates of lymph node metastasis were 0% for the pure GGO group, 3.8% for the GGO predominant group, and 6.9% for the solid predominant group (44). Although lymph node involvement in GGO-related lung adenocarcinoma is uncommon, the decision to perform and the extent of lymphadenectomy remains a subject of debate (16,45). Emerging evidence suggests that systematic lymph node dissection may not always be necessary, particularly for lesions with favorable prognostic features. Xu and colleagues discovered that there were no occurrences of pathological mediastinal lymph nodes in cases of pure GGOs, while 3.8% were observed in semisolid GGOs. They suggest that mediastinal lymph node sampling (MLNS) is sufficient for semisolid GGOs with a CTR of 0.5 or less (12). However, for patients with GGO CTR greater than 0.5, mediastinal lymphadenectomy (MLD) or MLNS should still be considered. Woo et al. concluded that conducting extended N2 MLD for pulmonary lesions with a CTR ranging from 0.3 to 0.7 might result in unfavorable early postoperative outcomes, without offering significant long-term oncological advantages (46). A recent multicenter prospective trial on selective MLD identified various criteria based on tumor characteristics but the authors opted not to perform MLD on lesions with a CTR of less than 0.5 due to their positive clinical outcomes (47).

While GGO-associated lung cancer is generally considered indolent, surveillance after surgical resection is crucial. Post-operative monitoring should be tailored to individual patients, with consideration given to factors such as tumor size, location, histological subtype and preoperative growth (48). For patients with small, non-invasive GGO lesions, without preoperative growth and without solid components, surveillance protocols may be less intensive, reflecting the favorable prognosis associated with these lesions as data suggest that lymphovascular invasion is a predictor for recurrence after non-curative sublobar resection (49).

Effects on non-surgical management

Various non-surgical treatment options for GGO lung cancers have been tested, but evidence for alternatives to surgery remains limited. Alternative forms of locoregional therapies such as stereotactic ablative therapy (SABR) and microwave ablation (MWA). Systemic therapies, including chemotherapy, and immunotherapy have also been proposed as alternatives to surgery, particularly for patients that are poor surgical candidates.

Lu et al. retrospectively reviewed outcomes of 91 persistent ground-opacity lung lesions in 51 patients with history of lung adenocarcinomas that underwent at least two cycles of platinum-based (cisplatin or carboplatin) chemotherapy. At their mean follow-up period of 24.1 months, 94.5% of nodules remained stable in size, while the remaining 5 (5.5%) of nodules grew in size (50). Similarly, Zhang et al. investigated the use of chemotherapy for 44 patients with 55 GGO-lung cancers prior to surgical resection. They concluded that there was no radiologic or histologic response to chemotherapy and that chemotherapy should not be used to treat GGO-associated lung cancers (51). Both of these studies were limited by short follow-up times, particularly for indolent lesions such as GGO-associated lung cancers, with a mean follow-up of 24.1 months for Lu et al. and median of 10 months for Zhang et al. (50,51). Zhai et al. investigated adjuvant chemotherapy for stage IB-IIA GGO-associated lung adenocarcinomas, and found nomograms integrating pathological tumor size, CTR ≥0.75 and greater than 10 lymph nodes resected to have strong predictive ability for OS and DFS, suggesting that this is a useful tool for selecting patients that would most benefit from adjuvant chemotherapy (52).

Though few studies on immunotherapy were identified, two recent articles retrospectively analyzed Sintilimab, a PD-1 inhibitor, for GGO-associated lung cancers presenting as synchronous multiple primary lung cancers (sMPLC). In their 21 patient Phase Ib study, Xu et al. demonstrated an appropriate safety profile with only one patient developing a Grade 3 or higher adverse event. They noted moderate rates of pathologic response but relatively low rates of major pathologic response (tumors with less than or equal to 10% viable tumor cells on resection) (53). In their single arm phase II study with 36 patients, Cheng et al. found an adequate safety profile for no patients experiencing a Grade 3 or higher adverse event, with an objective response rate of 5.6% (2/36 patients) (54). Large studies, randomized studies with long follow-up times for GGO-associated cancers treated with immunotherapy have not been performed.

Two articles investigating targeted molecular therapies were identified, both studying EGFR tyrosine kinase inhibitors (TKIs). Kang et al. studied EGFR-TKI (Gefitinib and Erlotinib) on 51 pure ground-glass and 26 part-solid concurrent nodules in patients with stage IV NSCLC, finding a 50.8% rate of grade 2 or higher adverse events, most commonly skin rashes (26.7%), GI symptoms (8.9%) and mucositis (4.4%). 19.5% of nodules decreased in size after EGFR TKI therapy, and 4 (5.2%) of nodules completely disappeared (55). Cheng et al. also studied EGFR TKIs in their study of 143 patients with synchronous multiple primary lung cancer who had residual GGOs after operative management. In their study, 66 patients received postoperative EGFR TKI therapy, and 77 patients were only observed. They found a statistically significant difference in number of patients with reduction in size of residual GGOs, with 19.7% of patients treated with EGFR-TKI compared to 9.1% for the observation group (56). There has been little evidence from randomized control trials supporting radiation therapy in operable cases of non-small-cell lung carcinomas (57). Regardless, a handful of recent retrospective studies have attempted to explore the efficacy of stereotactic ablative radiotherapy (SABR) in GGO lung cancers. Onishi et al. studied 84 patients with stage IA GGO adenocarcinomas treated with SABR and found at 3 years a 0% local recurrence rate, a 2.6% distant recurrence rate, and 98.2% and 94.6% cause-specific and OS rates, respectively (58). Similarly, in their study of 99 patients treated with SABR with median follow-up of 33 months, Jang et al. found 100% local control without local recurrences, though 3% of patients had regional recurrences outside of the radiation field and 3% more had distant metastases (59). In their much larger (n=756) but still retrospective propensity-matching analysis comparing surgery and SABR in GGO stage I NSCLC, Tomita et al. found no statistically significant differences in OS or disease-free survival at their median follow-up periods of 66 months for the surgical group and 69 months for the SABR group (60). Though these studies suggest that SABR may eventually be demonstrated as a viable alternative to surgery, they are limited by their retrospective natures and short follow-up times, particularly given the indolent nature of GGO associated lung malignancies.

Percutaneous MWA is a recent thermal ablative technique first tested in lung cancers in the early 2000s (61), which has been studied extensively for surgically inoperable lung cancers, though no randomised controlled trials (RCTs) comparing MWA to surgery or SABR have been performed. Two retrospective studies since 2020 have studied the use of MWA in GGO NSCLCs. In their small feasibility study of 33 patients treated with MWA, Huang et al. noted a 100% technical efficacy rate, no procedure related deaths, and no deaths or local recurrence at median follow-up period of 18.1 months (62). In 2023, Yang et al. published their study of 87 patients with GGO cancers treated with percutaneous MWA, noting locoregional progression free survival rates of 96.6% and 96.6% at 3 and 5 years respectively and OS rate of 94.3% and 84.9% at 3 and 5 years respectively (63). Like SABR, additional, randomized studies are needed to assess the use of MWA as a primary treatment modality in operable cases of GGO lung cancers.

Prognostic molecular factors

In their 2020 review, Zhang et al. noted that one important gap in our knowledge was the genomic differences in fast and slow growing GGO lung cancers (7). Since then, several studies have attempted to explain the genomic make-up of GGOs and the prognostic impact of different mutations. While the most commonly identified genetic mutations in lung adenocarcinomas in general are EGFR, BRAF, KRAS, EML4-ALK and ROS1 mutations, gene detection panels for these mutations in GGOs found only EGFR (61.2% of sample) and KRAS (3.3% of sample) in sizable numbers, with EML4-ALK, ROS1, and BRAF mutations all occurring in 0.5% or fewer of the sample (64). Whole genome and broad panel sequencing have shown the most common driving mutations in GGOs to be EGFR, TP53, RBM10, and KRAS mutations (65,66). Li et al. also found that when categorized into pure GGO, heterogenous GGO and part-solid GGO, pure GGO had the lowest rates of EGFR, TP53 and RBM10 mutations while part-solid GGO had the most, suggesting that GGO progress from pure to heterogenous to part-solid GGOs as they acquire genetic architectural complexity (65).

EGFR driver mutations have consistently been found to be the most common mutations in GGOs. A 2021 meta-analysis of 22 studies noted that EGFR mutations were identified in 51.5% of GGO NCSLCs but found no significant association with EGFR mutation status and tumor progression (67). Other recent studies have found no association between EGFR mutations and either OS or RFS (68-70), though Suda et al. did note that the EGFR L858R mutations had statistically significant better survival when compared to the EGFR Exon 19 deletions (70). In their study of 325 patients with subsolid lung nodules, Xie et al. found worse RFS in patients with EGFR mutations, though importantly OS was not determined because the median survival time was not met at their median follow-up of almost 5 years (71). In their study of 325 patients with subsolid lung nodules, Xie et al. found worse RFS in patients with EGFR mutations, though importantly OS was not determined because the median survival time was not met at their median follow-up of almost 5 years (71). Interestingly, though certain EGFR mutations have long been associated with better prognosis in lung cancers in general (72), it is not clear that EGFR mutation status has prognostic potential for GGO lung cancers.

RBM10 mutations were found to be associated with a lepidic growth pattern on histology for GGO, which is classically associated with low levels of invasiveness (66). However, studies specifically assessing the prognostic importance of RBM10 in GGO have not been performed.

A newer modality of molecular analysis is single-cell RNA sequencing (scRNA-seq), which can measure gene expression levels of individual cells in a heterogeneous cell population as well as their interactions with the immune system (73). From scRNA-seq studies of GGO, it was revealed that GGO associated cancers have a high degree of CD8+ T cells, while solid nodule cancers had an immune-suppressive environment with exhausted T cells (74,75). It was also found that when compared with benign GGO lesions, early GGO associated adenocarcinomas had decreased number of natural killer (NK) cells, which correlated with IL-6 activity (76,77). ScRNA-seq has also identified genes such as SPINK1, SPP1, MUC21, CEACAM6, and CEACAM5 as differentially expressed genes with greater expression in tumor cells (76,78). CEACAM5 is particularly interesting both in that it has potential to be used as a serum biomarker and because several clinical trials are currently testing the use of monoclonal antibodies to CEACAM5 as lung cancer treatments (78).

The molecular environment of GGO associated lung cancers has been studied extensively in the past few years, but more research is needed to better understand the prognostic impact of different mutations, as well as the use of different gene expression profiles in the screening and treatment of lung cancers.

Strengths and limitations

Strengths

This study comprehensively reviewed the recent data on GGO-lung lesions and highlighted new data to address the current knowledge gaps. A large number of articles were identified for this review.

Limitations

The majority of the data continues to be retrospective in nature, which limits the strength of evidence. Although there is consensus among many clinicians that GGO-associated lung cancers have better prognoses and can be safely treated with less aggressive surgical or potentially non-surgical management, there is a need for targeted randomized control trials to strengthen claims. This review focused only on primary literature, and so insights from case studies, case series, commentaries, and other secondary analyzes were not captured in the review. The review also focused exclusively on publications in PubMed indexed journals, a relatively comprehensive database of quality medical literature, but any articles not accessible from the PubMed Database were not included in this review.

Conclusions

The management of GGO-related lung adenocarcinoma continues to evolve, guided by ongoing research efforts aimed at refining diagnostic and therapeutic approaches to improve patient outcomes. Given the risks of overtreatment of indolent lesions, at our own institution, we are inclined to offer surgical intervention of patients with GGO if they develop a solid component, or if the pure GGO component is demonstrating growth on serial imaging. There is consensus that small pure GGO and part-solid GGO with low CTR can be safely managed with sublobar resection in the correct clinical scenario. Several authors have suggested that the AJCC Staging Manual should be updated to better reflect the indolent nature of GGO-associated lung cancers. The current (8th) edition of the clinical T classification system assigns stages according to solid tumor size, wherein the tumor size is determined only by the greatest dimension of the solid component. Several studies have indicated that this staging system is overly simplified, as the prognosis for GGO-associated lesions is better than that of pure-solid lesions even within the same T stage and should be an explicit component of the clinical T staging system (17,21,29). Others have noted that CTR should also be included as a component of the staging system, as evidence shows that nodules with CTR >0.75 have similar prognoses to pure solid nodules, and those with CTR <0.25 have similar prognoses to pure GGOs (33). The presence of GGO and the measurement of the invasive component was first introduced in the 8^th edition of the IASLC TNM classification system. The current evidence suggests that the presence of GGO provides favorable prognostic information, and therefore future editions of the staging schema may incorporate GGO as a favorable T classification metric while international databases continue to collect this information for future analysis and validation. Surgical management remains the mainstay of treatment for most cases of GGO-associated lung cancer. Limited evidence suggests that non-surgical locoregional therapy options for GGO cancers such as through SABR or MWA may eventually be accepted as viable alternatives to surgery, but current RCT evidence is lacking. Systemic therapies such as chemotherapy, immunotherapy, and molecular targeted therapies (i.e., EGFR-TKIs) have been performed both as adjuncts with and alternatives to resection but current studies are generally limited by their retrospective nature, small sample sizes, and short follow-up. A wealth of research into the molecular and genetic environment of GGO lung cancers has been published in the last few years, but our understanding of the prognostic importance of key mutations associated with GGO cancer remains incomplete. Newer molecular studies including scRNA-seq may continue to advance our understanding of the molecular environment of GGO-associated lung cancers and the prognostic impact of specific mutations.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-25/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-25/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-25/coif). N.K.V. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from September 2023 to December 2025. The other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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