Solitary and multifocal ground glass opacities—a narrative review of current management and future directions in the face of increasing incidence of detection

Introduction

Background

Ground-glass opacities (GGOs), or subsolid nodules, are hazy areas of increased density seen on high-resolution computed tomography (CT) that are not associated with underlying vessels or bronchial walls, as defined by the Fleischner society (1). GGOs can be solitary or multiple and are classified into pure GGOs (pGGOs) or part-solid GGOs (psGGOs), the latter combining hazy and soft tissue component, like solid nodules (2). Recommendations for interval imaging depends on size, number, and morphology, but may vary with patient factors such as smoking history, demographic, pulmonary co-morbidities, age, sex, race, family history, and even nodule location. The primary recommendations are for solitary nodules, whether solid or GGO.

Rationale and knowledge gap

Significant discordance remains even among radiologist classification when categorizing a nodule as pGGO and psGGO (3). GGOs may arise due to infection, fibrosis, edema, hemorrhage, and cancer which may occur in up to 63% of cases (Table 1) (4,5). Although these all may present as pGGOs or psGGOs, assessing malignant potential solely on imaging is difficult since factors like patient exposures, risk factors, clinical history, lesion evolution, and even the psychological impact on the patient influences management. One psGGO in a low-risk patient may warrant observation, while a pGGO with a compelling history may prompt intervention. No clear criteria exist for when to intervene versus observe and which to observe in the setting of, making decisions subjective and practice dependent. Management becomes even more complex with multifocal GGOs (mGGOs), given limitations on how much lung tissue can be removed and whether alternative therapies or observation should be considered in this setting.

This diagnostic challenge is becoming increasingly common as the use of CT has increased by an average of 450% annually for chest imaging alone (6). This will only continue to increase as lung cancer screening (LCS) using low-dose CT (LDCT) for high-risk patients becomes more widespread.

Objective

We present the natural history of GGOs, current surveillance and management options and their outcomes, and future directions that may contribute to better characterizing GGOs, differentiating benign and malignant etiologies, and provide additional data points to assist in clinical decision making for patients. We review the current literature and developments regarding GGOs expanding upon prior reviews (7,8). Additionally, we review current literature addressing patients with mGGOs using existing data on solitary GGOs. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2025-1-70/rc).

Methods

We conducted a literature search for GGOs. We included articles that looked at monitoring/surveillance, diagnosis, and treatments for GGOs. Our search was based on English articles currently indexed on PubMed and was reviewed by all authors for completeness (Table 2).

Diagnosis

Imaging

GGOs are primarily diagnosed by CT of the chest with evaluation and follow-up criteria put forth by the Fleischner Society. It is recommended that all CT images be performed with thin sections of less than 1.5 millimeters (mm) and reconstructed with coronal and sagittal views to allow accurate volume measurement and characterization of smaller nodules, which is particularly important in the setting of GGOs to discern the solid components within a lesion. Figure 1 shows the difference between pGGO and psGGO (9).

Figure 1 Arrows pointing to a spectrum of GGOs on CT imaging. (A) Pure GGO; (B) part-solid GGO with a solid component <50%; (C) part-solid GGO with a solid component >50%. These figures are printed from Sun et al. (9), published under a Creative Commons Attribution 4.0 International License (CC BY 4.0, http://creativecommons.org/licenses/by/4.0/). CT, computed tomography; GGO, ground-glass opacity

The average diameter of lesions should be obtained by calculating the average of the long and short axes of the nodule. This is a better predictor of tumor volume as well as malignancy yield (10). Volumetric analysis can be used as an additional data point to track nodule changes. This can be performed manually, partially automated, or fully automated with the latter two being favored given the reproducibility in image interpretation with segmentation of the image into solid and non-solid components. However, there remains variability in software that may skew results. As such, the Fleischner Society recommends volumetric analysis be performed with identical programs and versions across all images to provide consistency (2,11,12). Incidence of malignancy based on CT findings is shown in Table 3 (13-15).

Tissue sampling

Diagnosis may be achieved with tissue sampling. This can be performed minimally invasively with image guidance, bronchoscopically, or surgically.

Indications for sampling include pGGOs between 5–10 mm that enlarge or progress to psGGOs, pGGOs between >10–15 mm that are persistent, psGGO >8 mm and persistent, or psGGOs with a solid component >6 mm on repeat imaging (16).

Percutaneous biopsy

Transthoracic needle biopsy (TTNB) is completed using CT to localize the tumor and obtain adequate tissue samples in a transthoracic fashion. Biopsies are performed using fine needle aspiration (FNA) or core needle biopsy (CNB). The diagnostic yield of either is debated and may vary depending on the size and characteristics of the target lesion (17).

Several studies have shown reasonably high levels of sensitivity and specificity in using TTNB for diagnosis. Pooled analysis of both CNB and FNA demonstrated sensitivities between 70–100% and specificities from 90–100% (18). Separating out the two techniques, CNB showed sensitivities ranged from 86–100% and specificity 80–100% while in FNA, sensitivities and specificities were between 67–95.6% and up to 100%, respectively (17-31). However, these results are variable depending on nodule size, solid-component, and operator dependent.

There is concern regarding the adequacy of tissue sampling using TTNB. Both FNAs and CNBs use instruments of specific sizes that limit the area of tissue that is surveyed. This is of particular concern for pGGOs which have less tissue architecture to sample or target radiographically and may have fewer cells to sample compared to solid nodules (25). Comparatively, psGGOs have been found to have a higher diagnostic yield and accuracy. False negative risk remains as the sampled area of the lesion itself may not be representative of the whole lesion thereby missing malignant tissue (22,29). There is a correlation between the size of the target lesion and diagnostic yield with smaller lesions having less accuracy, sensitivity, and specificity compared to larger lesions causing some to advocate for surgical resection of the lesion (32).

TTNB has complications; the most common is a pneumothorax with an incidence of 18–54%, of which up to 14.2% require thoracostomy tube placement (31,33). The second most common is pulmonary hemorrhage occurring in up to 7% of cases (33,34). Less common complications include hemoptysis, hemothorax, air embolism, tumor seeding, and death (35,36). Risk factors for complications include smaller lesions, longer distance between the pleura and lesions, and lesions not contacting the pleura, amongst others (35).

Its minimally invasive nature for tissue sampling is a primary advantage. It is ideal for peripheral lesions. Disadvantages are limited tissue sampling in larger lesions resulting in potential sampling error and the risk of complications. TTNB is less suitable for more central lesions given the higher risk of complications and distance traversed by the biopsy needle.

Endobronchial biopsy (EBB)

Tissue may also be sampled via EBB, in which a needle is passed through a bronchoscope into the target lesion. This is typically guided by endobronchial ultrasound (EBUS) for localization, and both FNA and CNB may be performed, similar to TTNB guidance to localize the lesion and like TTNB, both FNAs and CNBs can be done (37). EBB may be performed manually using a traditional bronchoscope or using robotic-assisted bronchoscopy (RAB) (38). There are two Food and Drug Administration (FDA)-approved platforms for RAB: ION and Monarch. Monarch uses electromagnetic navigation with a pre-procedure CT scan to map a pathway to the target lesion. The electromagnetic robotic catheter is detected by the sensors placed on the patient mapping the system in 3D space. This is combined with the CT scan generating a navigational path to the lesion. ION uses internal shape-sensing. It also utilizes a pre-procedural CT scan but instead of electromagnetic signals, ION employ an internal fiber to provide position and shape feedback. EBUS has been using an adjunct to improve diagnostic yield. RAB carries lower risk for pneumothorax compared to TTNB. With RAB, multiple and even bilateral biopsies can be performed during a single procedure (39).

Like TTNB, EBB, especially when combined with EBUS, demonstrates a high diagnostic yield (75–80%) and sensitivity (up to 90%) (40,41). Success is influenced by factors such as proximity of the to the bronchus, larger lesion size, proper positioning of the ultrasound probe, and use of adjuncts like fluoroscopy and RAB. Limitations include peripheral lesions, small lesions, and inability to localize the lesions with EBUS (41-46). Complications of EBB are similar to TTNB and include broncho- or laryngospasm, pneumonia, infection, pneumothorax, and hemorrhage (47-50).

Electromagnetic navigational biopsy

Electromagnetic navigation bronchoscopy has been a new take on both biopsy and pre-operative tissue marking to guide minimally invasive resection, with accuracy reported as high as 94%, allowing for either EBB or percutaneous, transthoracic needle aspiration (TTNA) in those even too peripheral for navigational bronchoscopy (Zeng et al.) (51). Recent results from the Navigational Bronchoscopy or Transthoracic Needle Biopsy for Lung nodules randomized control trial of 234 patients identified navigational bronchoscopy to be non-inferior to TTNA (79% vs. 73.6%, P=0.003 for non-inferiority) (52).

Surgical biopsy

Surgical biopsy represents the most invasive yet often the most definitive means of tissue sampling. This can be approached via video-assisted thoracoscopic surgery (VATS), robotic-assisted thoracoscopic surgery (RATS), or open thoracotomy. When feasible, a non-anatomic wedge resection is the most common approach with or without frozen section analysis depending on the level of suspicion. Certain cases may require anatomic resection (segmentectomy/lobectomy) for biopsy or for removal if a wedge resection is not feasible, but the lesion is highly suspicious.

The diagnostic yield of surgical biopsy is high, as the entire lesion can be resected and assessed with surrounding tissue margins to minimize sampling error. Additionally, mediastinal, and hilar lymph node sampling can be performed during the same operation, particularly when cancer is suspected.

The utility of surgical biopsy for GGOs varies. Some centers turn to it after unsuccessful, non-diagnostic, or infeasible percutaneous or endobronchial approaches. Others reserve surgical intervention for lesions highly suspicious for malignancy, without preoperative tissue diagnosis (32). The decision to proceed with surgical biopsy depends on factors such as risk-benefit assessment, alternative interventions, clinical suspicion or lesion evolution, information required for treatment planning, and patient factors including surgical fitness or diagnostic anxiety.

Current management options

Observation

The guidelines for routine surveillance in the setting of known GGOs are variable when based on radiographic findings and can be subjective based on clinician interpretation and patient factors. The various guidelines are highlighted in Table 4 (16). For the Fleischner Society, pGGOs less than 6 mm do not have to be followed unless there are suspicious morphology or patient risk factors. Those that are 6 mm or larger should be imaged at a 6–12-month interval and then every 2 years until 5 years (2).

In contrast to this, psGGOs have slightly more nuanced recommendations. Those that are smaller than 6 mm follow the same recommendations as pGGOs in that the detection of solid components at this size is largely unreliable and difficult to correlate. Lesions larger than this have surveillance guidelines based on the size of the solid component—for a solid component less than 6 mm, interval imaging between 3–6 months followed by annually for a minimum of five years is recommended whereas solid components 6mm or larger are recommended for the same initial interval imaging with the caveat that growing solid components or solid components larger than 8 mm should be considered for additional imaging such as positron emission tomography (PET)/CT and/or tissue sampling given the higher likelihood of malignancy. Nodular GGOs without prior histologic confirmation have been found to have malignancy rates as high as 95.2% (53).

However, while there are relatively objective guidelines provided for observation and interval imaging, there remains patient factors and practice subjectivity that change clinical practices. The surveillance intervals given as ranges allow clinical judgment based on high-risk features on imaging, high-risk patients based on clinical history, or psychosocial factors such as patient anxiety to reach a diagnosis. Additionally, logistics and feasibility of interval imaging and follow-up may play a role in surveillance where those that have better access to care or institutions with lack of infrastructure or interventional services may favor surveillance or vice versa.

Intervention

Ablation

Minimally invasive methods of addressing GGOs have emerged as potential alternatives to surgical intervention and resection. One promising method is ablation of the suspicious lesion to preserve lung tissue while directing therapy solely to the lesion. There are multiple techniques to ablation including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation (CA), and laser ablation (LA) (54). All these ablative techniques are performed percutaneously with image guidance with good results. Ablation serves as a therapeutic intervention rather than a diagnostic modality.

Thermal ablation techniques encompass RFA, MWA, and LA. RFA has been utilized in both pGGO and psGGO lesions and in biopsy-proven malignancy lesions with up to 96.4% overall survival (OS) and 100% cancer-specific survival (CSS) in the proven malignancy subgroup (55,56). Tumor recurrence was identified at a substantial 30.3%, with 60% of these patients’ demonstrating recurrence at distal sites. This group underwent repeat ablations or additional surgery to address their recurrent malignancy with effectiveness given the 100% CSS rates. Similarly, MWA has demonstrated promising efficacy for patients with GGOs that contained biopsy-proven adenocarcinoma whether pGGO or psGGO. 3-year progression-free survival (PFS), cerebrospinal fluid (CSF), and OS in one cohort was found to be 98%, 100%, and 96%, respectively (57). Local recurrence occurred in just one patient, and this was successfully managed with repeat MWA with no further recurrence at 2- and 3-year milestones.

Freezing techniques are primarily through CA. In one cohort, 14 patients with GGOs were treated with primary cryoablative techniques. At 2-year follow-up, all GGOs were successfully ablated with no recurrence after the initial therapy and did not require any additional intervention (58). These findings have been corroborated in larger reviews that extend analysis to show no lymph node recurrence or distant disease (59). However, in the event of prior therapy such as surgery, when patients may not represent further surgical candidates due to need to maintain pulmonary function, CA remains a viable alternative to manage recurrent or new GGOs (60-62).

Beyond the minimally invasive nature of ablative techniques, a second benefit is the possibility of repeated interventions in the setting of recurrence or progression. Ablation can be performed in patients who have had previous surgery or prior ablations with the significant benefit of organ preservation in those that cannot tolerate further lung resection or have baseline pulmonary function that would not tolerate tissue loss. However, a significant downside is the inability to sample lymph nodes which may impact the staging of cancer. The utility of lymph nodes in pGGO or ground-glass dominant psGGOs is debated with evidence in the literature that incidence of nodal metastasis is exceedingly low (55). None the less, pathological staging is limited without tissue sampling. Additionally, as with the percutaneous diagnostic methods, these image-guided ablative techniques carry similar risks of pneumothoraces, hemoptysis, and infection (56-58). Ablation therapy also has higher local recurrence rates compared to surgery, lack of pathologic confirmation, high incomplete ablation up to 29%, and limited long-term evidence.

Stereotactic body radiotherapy (SBRT)

An alternative therapy for patients who are medically inoperable, multifocal disease not amenable to surgical resection, or prefer non-operative management is SBRT. SBRT, like ablation, also serves as a therapeutic rather than a diagnostic modality. This has been shown to be highly effective in treating proven lung malignancies with PFS rates ranging between 67–80% around the 2-year mark (54,63-67). OS rates were as high as 90% for earlier stage cancers at 3 years with 100% for GGOs compared to 59% for those that had solid tumors treated with SBRT (65). Even amongst patients who were operative candidates, rates of local control, PFS, and OS have also been found to be comparable between surgery and SBRT (68).

Complications of SBRT occur infrequently and are characterized by the Radiation Therapy Oncology Group toxicity criteria. All patients in the studies above ranged between Grade 1 and 3, with the reported complications comprising chest wall pain, skin toxicity, and radiation pneumonitis. All were managed expectantly and did not limit therapy. However, some relative contraindications to SBRT include prior radiation therapy and co-morbidities such as interstitial lung disease (69). Thus, while SBRT remains a viable alternative for disease control and potential curative therapy for patients not amenable to surgical intervention, further study is required to define the optimal patient populations for SBRT and use in high-risk patients.

Resection

Surgical resection is recommended for diagnostic and therapeutic purposes at different intervals depending on the specific guideline that is being used. The Fleischner Society, Japanese Society for CT Screening, American College of Chest Physicians, National Comprehensive Cancer Network, American Association for Thoracic Surgery, and British Thoracic Society all have slightly nuanced recommendations for when to intervene, but are all variations of overall size, size of the solid component as criteria, and evolution over time (16,70). Generally, the preferred approach would be minimally invasive via VATS or RATS, but more extensive resections may require thoracotomies.

In terms of the volume of lung sampled, several factors can be considered to determine the extent of resection. The first option would be a non-anatomic, wedge resection of the lesion of interest and surrounding lung parenchyma. This is useful for diagnostic purposes when the etiology of the GGO is unclear as the nodule can be sent for an intra-operative frozen section to determine further therapy. If malignancy is confirmed, the need for further resection and whether a segmentectomy or lobectomy is required is a subject of investigation in terms of optimal outcome. Variables that may factor into this decision are the degree to which a patient can tolerate resection based on pulmonary function testing, size of the lesion, final pathology, and existing margins on the resected specimen among many others (32,71). However, there are technical limitations that may render wedge resections unfeasible. Anatomically, those that are deeper in the lung parenchyma or centered near the hilum would not be wedgeable. According to Casiraghi et al., sublobar resections for either pGGOs or psGGOs were associated with higher recurrence risk (72). In addition, if the lesion cannot be localized either by manual palpation or with adjuncts such as indocyanine green (ICG) injection into the lesion or fiducial placement, a larger resection may be required to ensure lesion resection (73,74). C-arm cone beam CT (CBCT) is an alternative localization method that uses real time fluoroscopy to guide needle placement and improve microcoil placement. It utilizes a “push and pull” technique to place the distal end of the microcoil adjacent to the nodule and the proximal end extrapleurally. This has been useful in localization of small, peripheral, non-subpleural GGOs to facilitate non-anatomic wedge resection (75).

For those lesions that are not approachable via wedge resection, segmentectomy would be the next approach. Surgical planning can be performed using pre-operative imaging to identify the segment of interest and the relevant vasculature and airway. Localization of the lesion in this setting can be helpful as well, and segment margins can be determined using intravascular ICG to assess perfusion. Lobectomy may be favored in lesions that are sufficiently large, close to the hilum, or crossing segment margins. Historically, lobectomy may also be performed for intraoperatively confirmed malignancy, but some data suggests sub-lobar resections may be adequate from an oncologic perspective, particularly in IA non-small cell lung cancer (NSCLC) according to two recent randomized trials, the JCOG0802/WJOG4607L and CALGB/Alliance 140503 trials (76,77).

The downside to resection is that it is a major surgery that carries morbidity and mortality. It may result in the diagnosis of benign or otherwise indolent disease. It also creates adhesions which can make subsequent resections difficult, and lastly it can only be done so many times until pulmonary function prohibits it.

Table 5 goes over the various types of modalities used to treat pulmonary nodules (62,77-89).

Future directions

Despite being a well-established phenomenon, GGOs continue to be a diagnostic and therapeutic dilemma without uniform, objective, consensus guidelines between the relevant medical and surgical societies. Limitations notably arise from the subjective nature of radiographic interpretation, the broad differential of GGOs, the diverse nature of GGOs as an adenocarcinoma spectrum lesion, and patient and clinician factors that impact clinical care. Variations on care may exist even within a single institution depending on the above factors, much less on a global scale where pathological differences in GGOs may exist. However, given the ubiquity with which GGOs will be present as imaging practices change, the need for more nuanced, clinical data may be required to formulate an objective criterion to determine the appropriate management for these spectrum lesions. Options that may be developed and integrated include artificial intelligence (AI) analysis and molecular, genetic, or pathologic markers for diagnosis and treatment targets.

AI

AI is an emerging field within medicine with applications ranging from wearable health tracking technology to automated care delivery to machine learning algorithms to make diagnosis. This emerging arena is being leveraged to create efficient workflows and offers a certain degree of objectivity in data interpretation. It is in relation to this last point that AI offers intriguing opportunities towards the management of GGOs.

As discussed earlier in this review, there are several recommendations from different groups and societies focused on GGOs, with most, if not all, groups basing management strategies based on size, degree of solid component of the GGO, and trends over time of those two parameters. All these parameters are potentially biased by reader variability, resulting in an inevitable degree of subjectivity in interpreting radiographic results which may subsequently influence management strategies (90). Therefore, utilizing AI to analyze and measure suspicious lesions may represent an opportunity to provide more concrete data to contribute to a more objective management algorithm.

One of the inflection points in management changes according to the Fleischner Society is the solid component of psGGOs where lesions with solid components >6 mm are recommended for tissue sampling or for pGGOs that have developed a solid component. However, this can be challenging to maintain continuity in assessment as the optimal image requires thin cuts and to be in the correct tissue window (e.g., lung vs. soft tissue), both of which can influence measurements and visibility of solid versus non-solid components. With AI automation, this subjectivity could be eliminated with pre-protocolized CTs for GGOs and computer automated measurement and interpretation of size, shape, and specific ratio of solid and ground-glass make up of individual nodules compared to normal lung tissue. Algorithms based on this information have been developed to distinguish GGO imaging morphology that can be associated with specific diseases such as coronavirus disease 2019 (COVID-19) (91). Applications of techniques such as these using high-throughput, deep learning methods may be able to identify distinguishing features for other benign pathologies or malignancy, eventually with the sophistication to distinguish between pre-cancerous, early cancer, and late cancer morphologies (92). In addition, AI-determined GGOs compared to nodules with solid components may provide important prognostic value in addition to diagnosis where pGGOs have been shown to have improved survival (93).

The applications for AI extend beyond diagnostics, and it has applications for pathologic specimens as well. Machine learning algorithms have been applied for analyzing digital pathology slides for factors such as tumor heterogeneity and microvascular proliferation and correlating them with genomic and molecular biomarkers to determine outcomes such as prognosis and survival (94). This technology could prove highly valuable in terms of GGO biopsy specimen, where AI architectural analysis combined with molecular testing may yield valuable long-term information as to whether nodules will progress to malignancy, the overall impact on patient outcomes, and may provide guidance regarding the necessity of a surgical resection. Again, the utilization of AI in this arena provides a modicum of objective data via “AI-biomarkers” for otherwise subjective interpretation and prediction of future events (95).

Diagnostic and therapeutic molecular biomarkers

With the advent and advancement of targeted therapies over the past decade, there has been increasing interest in molecular biomarkers associated with malignancies. By identifying highly conserved or overexpressed markers on tumors, focused therapies have revolutionized oncologic care with excellent results in clinical trials and have now become frontline options. These genetic markers have also served as valuable diagnostic tools in identifying malignancies and distinguishing subtypes in addition to providing prognostic value when combined with radiographic findings.

Regarding lung cancers, several mutations have been identified that are highly associated with disease progression such as epidermal growth factor receptor (EGFR), K-ras, p53, TP53, MUC16, and ATR (96-98). When correlating with radiographic findings of GGOs, EGFR mutations were identified in 74% of all GGO type mutations suggesting some role in pathogenicity of cancer development. However, more interesting was the lack of p53 expression where higher levels of expression appeared to correlate with the development of solid components within a nodule, which has been shown to be demonstrative of more invasive cancer (99). Thus, measurement of p53 levels may serve as a valuable indicator for disease progression where any expression would suggest development of malignancy. Shao et al. applied machine learning to identify the AHNAK gene was significantly downregulated in tumor tissues promoting proliferation, invasion, and metastasis. This was found in early-stage lung adenocarcinoma presenting as GGOs, suggesting a potential biomarker (100).

Other valuable molecular targets that have emerged are checkpoint inhibitors targeting the endogenous programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis that is hijacked by tumors to evade the natural immune system (101). Expression of these protein ligands by tumors or lack thereof by the tumor or immune cells can provide valuable and specific diagnostic and therapeutic options available for the patients. While previous studies have focused on late-stage lung malignancies or inoperable tumors, recent advancements have shown efficacy of checkpoint inhibitors such as sintilimab in managing GGOs both as primary and adjuvant therapies (102-104). These studies have found utility in patients with multiple GGOs suspicious for metachronous disease and may offer an alternative to surgical resection for each lesion. However, results remain mixed with some studies only showing a response rate of 8.1% (105).

COVID-19

GGOs can be from infectious causes including COVID-19. The most frequent imaging finding on chest radiograph or CT is bilateral GGOs. Presence of GGOs in COVID-19 patients has prognostic implications, including an association with mortality in older adults. A study by Roig-Marín and Roig-Rico found patients >70 years that had GGOs on imaging at the time of their admission to the hospital for COVID-19, had a significantly higher risk of mortality compared to those who did not. Bilateral GGOs were most associated with mortality and a significantly higher risk for heart failure, respiratory failure, acute kidney injury, and ICU admission (106,107).

Patients with GGOs who survived their hospitalization should be followed with repeat CT to determine the resolution or the development of fibrotic/reticular changes. These chronic changes can reduce lung function tests and potentially cause degeneration to malignancy.

GGOs from COVID-19 had higher levels of IFN-γ, IL-4, and IL-2. IL-2 was determined to be an independent biomarker predictor of GGOs, based on multivariate analysis. IL-2 contributes to the cytokine storm in the inflammatory state during COVID-19. The elevated levels of IL-2 will therefore lead to increased inflammation and, in turn, increased mortality (108).

Global resource variability

We acknowledge that many of these proposed resources may not be readily available globally and even in the low-to-income setting. Therefore, a major part of the future direction is to improve accessibility and cost-effectiveness and develop a treatment algorithm tailored to their specific situation.

Real-world implications

Multidisciplinary pulmonary nodule programs, which include GGO management, suggest favorable cost-effectiveness and clinical outcomes. This would help facilitate interdepartmental coordination, streamline the diagnostics process, reduce unnecessary investigations, and improve outcomes. According to Roberts et al., The Massachusetts General Hospital Pulmonary Nodule and Lung Cancer Screening Clinic showed that a multidisciplinary method had 95% of patients following clinic recommendations which could potentially reduce healthcare costs (109,110). To implement AI and molecular biomarkers to the multidisciplinary approach, it would require training of the personnel involved but would help in the standardization of management of GGOs.

Classification system

Current classification guidelines

Existing classification systems for GGOs focus primarily on pathological features of the nodule (111). The Noguchi classification system divided lesions into six categories based on tumor growth patterns (Types A–F) with groups identifying GGO presence in Types A–C (112,113). Correspondingly, these appeared to have increasing solid component with Type A representing pGGO, Type B having mixed-density psGGO, and Type C representing psGGO with concerning central density (114).

The Noguchi classification was subsequently replaced by a new pathological classification system developed by a consortium represented by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new system provided a more multidisciplinary approach and incorporated pathologic, clinical, molecular, radiologic, and surgical elements to the classification system (112). The group incorporated key features in distinguishing different degrees of invasiveness, important biologic markers and utility for different clinical scenarios, radiographic features of different types of malignancy, and surgical recommendations for different subtypes of lung cancer. However, the system remains pathologically based with recommendations focused on nodules with proven tissue diagnosis. There remains a challenge of differentiating benign and malignant etiologies and subsequently, observation or intervention with GGOs identified on imaging.

To that end, developing a classification system based on well-established data such as the prior pathological systems and machine-learned, objective data may prove to be a valuable resource to guide management. Similar systems exist for pathologies elsewhere such as intraductal papillary mucinous neoplasms (IPMNs) in the pancreas or polyps in the colon where imaging characteristics, location, associated serum or fluid cytology markers, size, change over time, and pathological findings categorize lesions as “worrisome” or “high-risk” and influence screening intervals or recommended interventions (113,115).

Factors that could be incorporated into a GGO classification system can include many of the same characteristics. Important variables to consider, but are not limited to, pGGO vs. psGGO, size, change in size over time, percentage of solid component, location of solid component (central vs. peripheral), characteristics (spiculated vs. smooth border), nodule location (specific lobe, central vs. peripheral), gene mutations, molecular markers, and pathologic features if available. These can also be sub-categorized based on patient risk factors such as smoking, radiation exposure, and personal or family history of cancer or syndromes to develop a full, risk-profile phenotype for patients who are more likely to have malignancy or benign disease. This type of classification system may provide more objective data for when to observe or intervene on GGOs like IPMNs or a framework for developing alternative screening intervals like colonic polyps.

mGGOs

Of special note and arguably more clinically challenging of an entity are mGGOs. These multi-centric lesions may be all pGGOs, psGGOs, or mixes of both, unilobar or multilobar, and unilateral or bilateral. Recommendations from groups such as the Fleischner Society primarily focus on solitary nodules with cursory recommendations on mGGOs, where the suspected primary diagnosis is infectious (2). mGGOs exhibit biologic heterogeneity with the majority representing independent primary tumors rather than intrapulmonary metastases. They do exhibit convergent evolution on common oncogenic pathways. Approximately 70–75% of mGGOs have discordant EGFR mutations indicating a unique clonal origin. However, they do develop functional convergence on common oncogenic pathways such as the RTK/RAS pathway. As stated previously, EGFR is the most common gene mutation in GGOs. Synchronous GGOs in the setting of an EGFR mutant adenocarcinoma also harbor EGFR mutations, which is not seen in EGFR wild-type adenocarcinoma. This supports the fact that although GGOs are independent clonally, they may have similar field effect. Multi-ground glass nodule (GGN), should be staged as multiple primaries. Heterogeneity requires multidisciplinary evaluation and various molecular tests on multiple lesions to guide treatment (116-119). The likelihood of malignancy must be considered, particularly with persistence longer than 3–6 months, if any of the lesions are 6mm or larger, or if there are multiple GGOs 6 mm or larger. Management is always based on the most suspicious nodule in this situation. However, in the setting of malignancy, this presents a therapeutic challenge from a surgical perspective. While surgical resection is curative for early-stage cancer, organ and lung function preservation is a special consideration for patients with mGGOs. Even a healthy patient would have a limit to the number of resections that would be tolerated, much less patients who are at risk of cancer such as smokers or patients with pulmonary co-morbidities that have depressed lung function. This is critical as patients with mGGOs should expect progression of remaining lesions following resection of any suspicious lesions, thereby likely requiring further surgery.

As such, alternative diagnostic and therapeutic modalities are necessary in the setting of mGGOs. Molecular testing of mGGO may help in diagnosis and direct treatment. Objective diagnostic criteria using AI and classification systems can provide a framework for when to observe or intervene and on which lesions amongst the many to intervene. Wu et al. conducted a prospective, multicenter trial evaluating active surveillance of three or more mGGOs in which they found 33% of their patient population had progression of GGOs while only 3% had progression in less than 5 years (120). Novel therapeutic modalities such as ablation, SBRT, or targeted molecular therapies provide organ-preserving methods for treating malignancies with promising outcomes that may obviate the need for surgical resection. With the rising rates of both solitary GGO and mGGO detection in the modern era with LCS and in the post-COVID world, research and guidelines for appropriate management will need to develop, and practice patterns must evolve.

Limitations

Our study has several limitations. First, as a narrative review we did not perform any analytic overview. Our review is also subject to inclusion bias by the authors despite our standardized search protocol. Next, we only included English language articles. While the authors included systematic reviews and randomized trials when applicable, many of the articles referenced were descriptive review articles in nature or single center experiences and should be viewed in light of that.

Conclusions

In summary, the evaluation and management of GGOs remains complex given their variable etiologies, ranging from benign inflammatory conditions such as COVID-19 to invasive malignancy. All GGOs should undergo surveillance imaging; however, the optimal interval still is up for discussion. GGOs should be biopsied if persistent on interval imaging by either robotic bronchoscopy or transthoracic. There are many different treatment options, but only surgical resection allows for the removal of the specimen and assessment of lymph nodes. However, surgical resection in the setting of mGGOs can be challenging as it can adversely affect lung function and create adhesions. mGGOs may represent synchronous cancers, so therefore they pose an extreme challenge in evaluation and management. Molecular tests and biomarkers can help with the assessment of GGOs; however, there remain challenges in accessibility to these tests. A multidisciplinary team is needed to help standardize the evaluation and management of GGOs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2025-1-70/rc

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