Prognostic role of subsolid ground-glass opacity, pure ground-glass opacity, and solid nodules of the lung: a retrospective observational study

Introduction

In Italy, reports of lung cancer deaths in 2017 totaled about 34,000, with 23,400 men and 10,000 women affected. For men, lung cancer is the most common cause of cancer-related deaths, while for women, it ranks second. An estimated 41,000 new cases of lung cancer (27,550 in men and 13,300 in women) were reported in Italy in 2020. In men, it is the second most common neoplasia (14%) and in women, it is the third most common (7%) (1). Histologically, lung cancer can be divided into non-small-cell and small-cell tumors (2). Small-cell tumors or microcytomas are strictly smoke-related. Non-small-cell lung cancers (NSCLCs) comprise squamous cell carcinomas, adenocarcinomas, carcinoids, and large-cell tumors (2). The neoplasia is often discovered incidentally through radiological imaging (chest X-ray; CXR) or computed tomography [high-resolution computed tomography (HRCT) or contrast-enhanced computed tomography (CE-CT)]. Once a lung nodule is determined, the most important test to establish the staging is CE-CT, which, according to the latest guidelines, should be extended to the encephalon and upper abdomen to exclude secondary cancers that would make the patient inoperable. Currently, the only practicable screening for lung cancer in Italy is a CXR. On the other hand, the National Lung Screening Trial (US) formally reported for the first time that low-dose CT, as opposed to a standard CXR, could reduce lung cancer mortality in high-risk populations by 20% (1).

A consistent proportion of lung nodules accidentally found are not completely solid, showing a component not solid, defined as mixed ground-glass nodule (mGGN), or totally not solid, called pure ground-glass nodule (pGGN) (3-5). These aspects must be strongly considered regarding the incidence of cancer in GGN, which has been reported as high as 63%. GGNs have extremely complex and primarily very varied etiology and imaging features, which can underlie a wide spectrum of observed pathologies. They can develop quickly or very slowly.

The Fleischner Society in 1996 proposed the concept of ground-glass opacity (GGO), referring to shadows with slightly increased density compared to the surrounding parenchyma detected on HRCT. However, GGO areas may represent not only cancerous formations but also the consequences of various disease processes, such as infections, local hemorrhages, and interstitial fibrosis (5,6).

The ground-glass shape of a nodule can be caused, at the histopathological level, by morphological changes such as thickening of the alveolar septum, edema of the terminal air sacs, reduced air content in the alveoli, increased number of cells, and proliferation of alveolar epithelial cells (2-6).

The scientific community now defines pulmonary GGO nodules based on their density as mGGN when the low-density component exceeds 50% of the total nodule mass (6-10). To better define this concept, a consolidation tumor ratio (CTR) has been calculated as the index that assesses the proportion of the ground-glass component of a nodule. Specifically, when the non-solid density exceeds 50% of the nodule, the CTR is <0.50, and the nodule can be defined as pGGN. When the CTR is between 0.50 and 0.75, the nodule is defined as partially solid or m GGN, and when the CTR is equal to 1, the nodule is solid (3).

The latest guidelines of the Fleischner Society of Radiology indicate that no routine follow-up (FU) is recommended for pure GGNs under 6 mm in diameter (i.e., 5 mm or smaller), and a 1-year FU is recommended only for high-risk cases (3). A 6–12-month FU is recommended for pGGO nodules with a diameter of 6 mm or more, and then every 2 years for a total of 5 years (3).

For solitary part-solid nodules with a diameter of 6 mm or more, with a solid component having a diameter below 6 mm, a 3–6-month FU is recommended and then annually for a minimum of 5 years. If the nodule is unchanged after 3 months, the patient may become surgical because a nodule with both components underlies a high degree of malignancy (3,8).

Few patients experience distant metastases from pGGN lung cancer, which is typified by a painless course of disease progression. With a 100% 5-year survival rate following surgery, the prognosis is good (4-6). For mGGN, this is untrue. An editorial about the prognosis of GGO based on the predominant or main lesion was published by Sihoe et al. in 2018 (11). There is growing evidence that the one main or predominant lesion with the worst prognosis should be the one to guide management in a patient with multiple GGOs due to their independent characteristics. According to a Japanese study, the primary lesion’s size and solidity matter (12). A solid-dominant main GGO lesion with a size greater than 25 mm is associated with a poorer 5-year OS prognosis compared to a GGO-dominant lesion with a size of less than 25 mm (12-21).

Persistent GGNs are those that do not go away after 3.4–5.6 months of FU (22,23). These GGNs have the potential to be malignant and may turn that way after a protracted developmental period. As a result, following the discovery of a pGGN, a specific amount of FU should be applied. In agreement with recent literature, we believe that FU is justified only for pGGO lesions in low-risk patients; otherwise, resection may be the safest path for the patient (22-24).

In the current Italian Association of Medical Oncology guidelines for lung cancer (25), the density criterion is not addressed. GGNs are assimilated with solid nodules, leaving doctors and surgeons with free will regarding the approach to monitoring or removing these nodules. However, overtreatment and overdiagnosis with consequent excessively long FU often occur (11).

This study aimed to present our experience regarding the treatment and management of GGNs by analyzing a population of patients with early-stage NSCLC (IA-IB-IIA) who underwent lobectomy and ilo-mediastinal lymphadenectomy at our center from 2010 to 2021 to confirm that a significant difference exists, in terms of prognosis and survival, between patients with pGGNs and those with mGGNs and solid nodules. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1825/rc).

Methods

Patients’ characteristics

This was a monocentric, retrospective, observational cohort study enrolling 133 patients undergoing major lung resection for pGGOs, mGGOs, or solid nodules from 2010 to 2020.

Patients were recruited according to the following criteria. (I) The inclusion criteria were: age 18–85 years; a diagnosis of NSCLC with histology as squamous cell or adenocarcinoma at stage IA-IB-IIA according to the 8th edition TNM (tumor-node-metastasis); single nodule; all patients underwent lobectomy via video-assisted thoracic surgery (VATS), robotic-assisted thoracic surgery, or thoracotomy, with a postoperative FU of at least 12 months. (II) The exclusion criteria were synchronous neoplasms and patients undergoing lung resections other than lobectomy (e.g., segmentectomies, atypical resections, bilobed). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the local Ethics Board Committee of Romagna (CEROM) (ID 2970, date of approval: 11.11.2022), Italy; patients’ consent has been taken according with the local Ethics Board Committee regulations.

Radiological evaluation

All patients underwent radiological checks by total-body CT with contrast enhancement before surgery. In particular, HRCT images were used to assess the GGO nodules. Every chest CT scan was performed at maximum inspiration, and any GGO nodules were detected after the fact. The largest axial diameter of the nodule on the lung window setting was used to determine the tumor’s diameter, and an area of increased opacification that completely covered up underlying bronchial structures and vascular markings was used to define consolidation. Two thoracic surgeons and an imaging specialist anonymously reviewed each nodule on the preoperative CT scans.

The GGNs were then classified into three groups based on the CTR as per Fleischner Society guidelines: solid nodules (CTR =1.0) and partially solid tumors divided into pGGN-predominant (0.5≤ CTR <0.75), and solid-predominant (0.75≤ CTR <1.0) groups. The impact of the tumor size was assessed based on the CTR using the Cox model.

All patients with solid nodules or mGGO underwent positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (¹⁸F-FDG PET/CT).

Flexible fiberoptic bronchoscopic examination and diagnosis

We used endobronchial ultrasonography with a guide sheath (EBUS-GS) to perform a bronchoscopic biopsy in an attempt to diagnose GGO-predominant-type lesions. Lesions of the GGO-predominant type have a lower diagnostic rate than lesions of the solid type. This could be explained by the lesions not being visible with X-ray fluoroscopy. It is difficult to determine the bronchial routes to GGO lesions in a constrained amount of time during an examination. We define only possible GGO with this procedure. Alternatively, a CT-guided biopsy was performed in selected cases.

Histological evaluation

Two pathology specialists inspected and documented every clinical specimen. The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) (26) was used to evaluate each nodule’s size, location, differentiation, lymph node status, pleural invasion, and lymphatic invasion.

Surgery

After the patient was positioned laterally, a double-lumen tracheal intubation was carried out.

A VATS approach was performed in all the patients enrolled. In case of technical difficulties, the surgical approach was converted into an open posterolateral thoracotomy. Using a preoperative CT-guided hook wire or finger exploration, the precise location of the nodule was determined. Cutting staplers at least 2 cm from the nodule edges allowed the lesions to be wedged. Based on the intraoperative histopathological findings, the surgeon decided on a surgical intervention, such as a lobectomy, after carefully evaluating the patient’s lung function.

FU

Every case was monitored beginning on the day of surgery. A physical examination and CXR were administered two weeks following the procedure. They also received chest HRCT every 3–6 months for the first 2 years, then, in case of non-modification of the radiological findings, every 1 year for 5 years. Every case was routinely monitored to evaluate quality of life, survival, long-term complications, and perioperative complications.

Statistical analysis

Overall survival (OS) was calculated from the date of surgery until death or the last FU. The OS was estimated using Kaplan-Meier curves, with log-rank tests for univariate analysis and Cox regression for multivariate analysis. Values of P<0.05 were considered statistically significant.

Results

We analyzed 133 patients, of whom 74 women (mean age 73 years, range 18–85 years) and 59 men (mean age 71 years, range 18–85 years) underwent surgery for stage I and IIA NSCLC (8th edition TNM). The patients’ characteristics are shown in Table 1.

Among all the patients, 79 (59%) had no declared previous cancer history, and 51 (39%) showed previous neoplasms; 3 (3%) patients had no data. Of these patients, 31 (23%) were former smokers, and 68 (52%) were active cigarette smokers.

We considered three groups of patients according to the nodule density based on the radiological findings, as described in the methods. In particular, of all the patients who underwent lobectomy, 66 (49%) showed a solid nodule, with a mixed nodule for 29% [37] and pGGO for 23% [30]. The data showed that nodules were followed for 3 months on average before re-evaluation with a CT scan and subsequent surgery.

All 133 patients underwent preoperative study and staging. The most common pathological stage was IA with 89 (67%) cases, followed 35 (26%) by IB and 9 (7%) by IIA.

In the preoperative study, 83 (62%) patients showed an uptake in the PET scan, and 50 (38%) were ¹⁸F-FDG PET/CT-negative. pGGO nodules had a greater tendency to PET negativity vs. mixed and solid nodules, as already indicated in the literature (12,27).

A study with FOB was performed in only 74 out of 133 patients (56%) due to the distance from the bronchi or the absence of bronchial involvement.

Finally, EBUS was performed in only 24 patients: 15 solid and 9 mixed. These were mainly patients with solid nodules, and only a few mixed, because the echo methodology cannot distinguish pGGO nodules from the surrounding lung parenchyma.

After the FU and preoperative study, all 133 patients underwent pulmonary lobectomy and ilo-mediastinal lymphadenectomy, with 81 VATS and 52 open approaches, all at our center. They were then followed for varying FU times, averaging 5 years.

Figure 1 shows the mortality curve for patients with solid nodules in relation to postoperative FU time. A 25% mortality was observed only around year 6 of FU. This is consistent with the current literature, which indicates 5-year survival for more than 75% of patients (28).

Figure 1 The curve shows the mortality rate for the GGO patients (group 1 and group 2) in relation to the months of post-surgery follow-up. GGO, ground-glass opacity.

As shown in Figure 2, of 133 patients analyzed, the OS was 81% [95% confidence interval (CI): 72–88%] 5 years after surgery, much better than for solid nodules. The mean survival time was 98 months. Specifically in relation to the density of nodules, Figure 3 shows the OS for each group of patients. In particular, in the pGGN group, two deaths occurred, including one within 5 years, for a survival rate of 97%, far exceeding the national survival averages for lung cancer (28). Additionally, the 5-year survival rate was 96%. In the group of partially solid nodules with a GGO component below 50%, nine deaths occurred, of which eight were within 5 years, for a survival rate of 80.5% (Figure 3).

Figure 2 The curve shows the OS of all patients recruited for the study. OS, overall survival.

Figure 3 The curves show the OS of the patients split into the three groups based on the density of the nodules. OS, overall survival.

In the solid nodule group, 16 deaths occurred overall from disease recurrence, with 14 within 5 years and a survival rate of 79%, consistent with ISS statistics for lung cancer (Figure 3).

The log-rank test to assess the OS based on density was significant (Pr > chi² =0.0440). The multivariate analysis through the Cox model confirmed density as a risk factor, with hazard ratio (HR) =8.37 (95% CI: 1.03–68.12) for group 2 vs. 1 and HR =8.66 (95% CI: 1.06–70.90) for group 3 vs. group 1. Extending the FU to over 6 months after diagnosis was not indicated as a significant risk factor (P=0.57), whereas the patient’s age was very important (HR =1.07, 95% CI: 1.001–1.13).

To summarize, in terms of OS, whereas pGGN differed significantly from solids, mGGN did not. This is very important to consider, suggesting more attention when a nodule is not totally pure. Although common guidelines are not yet established for GGNs, we strongly suggest considering surgery as the best treatment in cases of mGGN.

Discussion

Because no official guidelines exist for the approach to GGO nodules, every center tends to treat them uniquely, according to their experience (29,30). The GGO nodule, especially if pure, could hide a benign pathology, and the diagnosis can be challenging even if the radiology and pneumology innovations are invaluable. However, the necessity to standardize levels of care is urgent, using the correct approach even for mixed GGO as well as in terms of long-term FU (31).

Some critiques exist regarding the approach used, especially when faced with a new-onset pulmonary nodule measuring >6 mm and with GGN aspects (32). Several studies suggest long radiological FUs for GGO nodules without making distinctions based on the proportion of density and without differentiating between pure and mixed (22,23). However, some studies have highlighted the high importance of performing a more complete study with total-body PET-FDG (26), and others have proposed a more aggressive approach with early surgical treatment (27-29), which seems to be closest to our concept.

The objective of our study was to demonstrate, using data collected from over 10 years’ experience treating GGO nodules, that they may be controlled with long-term FU when pure and small (below 7 mm). However, we showed that, when GGNs contain a solid component, their trend in mortality and recurrence overlaps completely with solid nodules (Figure 3). Therefore, we believe that, even in mGGN, the most correct approach is early surgery, which seems also to be the safest option (29).

Our data showed that preoperative FUs for mGGNs that are performed too late (over 3 months) from when they have been noted by chest CT may lead to adverse events in patients’ prognoses, as illustrated in the results section.

In our study, minor resections, such as wedges and anatomical segmentectomies, were deliberately eliminated from the database to standardize the approach, the FU period, and the surgical treatment, to focus our attention on the density of the nodules as the only variant.

We strongly believe that the nodule density should be the variable considered first over the nodule location, size, and metabolic activity. Additionally, for pGGNs and mGGNs at stage I, for the dimension and density of the nodule, total-body PET-FDG is inconclusive. For this reason, mixed GGN may indicate a more aggressive approach by surgery.

Many studies agree with this thought process and have assigned key importance to nodule density (30-32). We believe that with the same histology and size, the nodule density is an element that can strongly influence prognosis, as supported by several studies (15-18).

In accordance with the previous literature, we analyzed the OS of patients who were resected with pulmonary lobectomy and subsequently underwent FU in our center (30-32). The outcome showed a trend for patients with both solid and mixed nodules that was almost identical, although patients with pGGOs differed greatly (Figure 3). Thus, albeit with some limitations linked to our retrospective cohort study and the limited population of 133 patients, for nodules of this size, the surgical method (e.g., lobectomy) has been almost completely replaced by anatomic segmentectomies. We are conscious that this represents a limitation of our study, and further research will need to compare the surgical approach in terms of anatomic segmentectomies vs. lobectomies concerning the possible impact of mGGNs on prognosis, in terms of recurrence and survival.

Beyond the surgical approach, the density, like the other variables of a nodule, is arguably an important prognostic factor, and its CTR should always be calculated.

We believe that when a GGN appears, a 3-month FU is always justified since it could conceal a benign or malignant pathology. However, if the nodule detected at the check-up CT scan has changed in dimension or even shown changes in density but not size, a surgical strategy is preferable and must be considered.

Limitations

The study is retrospective and observational. We are conscious that the small sample has led to considerable uncertainty in the estimates of relative risks, as evidenced by the wide confidence intervals, which, however, do not include the null value for the factor under study (density). In multivariate analysis, the limited sample size and the limited availability of data prevented the adjustment of the density effect for any other confounding factors, however the results obtained seem suggestive and preparatory to the design of further multicenter studies with “greater power”.

Conclusions

The patients we examined appeared to form a population homogeneous with the general population in terms of age, sex, and many other descriptive variables. Our three subgroups formed according to nodule density were alike and shared histology and tumor staging as well as the numbers of individuals in the subgroups.

The statistical analysis of OS showed that patients with pGGO nodules had a 5-year postoperative survival rate that differed greatly from the other two groups. Patients with solid and subsolid nodules instead had an almost identical survival rate, as shown in Figure 3. This seems to indicate that the GGO component is a positive prognostic index in NSCLC, but only for those nodules with a GGO component exceeding 50% with 0.5< CTR <0.75. When the solid component dominates, the tumor adopts a pattern comparable to a purely solid tumor.

To summarize, FU can be applied for nodules with pGGO characteristics, although an early radical surgery is preferable for nodules that, while having a GGO component, show a solid portion exceeding 50%, even if they are small.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1825/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1825/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1825/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1825/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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the local Ethics Board Committee of Romagna (CEROM) (ID 2970, date of approval: 11.11.2022), Italy; patients’ consent has been taken according with the local Ethics Board Committee regulations.

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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