Resected lung adenocarcinoma with lymph node metastasis: is ground glass opacity component a prognostic factor?

Introduction

Due to the wide application of computed tomography (CT) in both lung cancer screening and clinical practice, more and more ground-glass opacity (GGO)-featured lung adenocarcinoma have been discovered (1,2). Usually, GGO-featured lung adenocarcinomas are diagnosed through lung cancer screening programs or as incidental CT finding (3), and are mostly early-stage diseases without lymph node involvement (4). Lung adenocarcinomas presenting as pure GGO is reported to have no lymph node metastasis, while 2.2% part-solid lesions are reported to have lymph node metastasis (4). Since the number of patients is quite limited, few studies have focused on the clinicopathologic characteristics and prognostic features of resected GGO-featured lung adenocarcinoma with lymph node metastasis.

Many researches indicated that GGO-featured lung adenocarcinoma have better prognosis compared to those presenting as pure solid lesions. Our previous study indicated that the 5-year lung cancer-specific overall survival (OS) rate of pure GGO, part-solid and pure solid lung adenocarcinoma were 100%, 98.13% and 80.27%, respectively (4,5). Although categorized into the same TNM (tumor, node, metastasis) stage, lesions with GGO component still showed better survival outcomes compared with solid lesions in clinical IA and IB lung adenocarcinomas (6-8). Some studies confirmed that the presence of even a small GGO component (≤25% and <50%) in lung adenocarcinoma predicted a better survival (9,10). However, whether GGO component is still related with a better survival in patients with lymph node metastasis remains unclear. Thus, we aim to summarize the clinicopathologic characteristics of GGO-featured lung adenocarcinoma with lymph node metastasis, and explore the prognostic value of GGO component as well as other clinicopathologic parameters in node-positive lung adenocarcinoma. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-170/rc).

Methods

Patient cohort

We retrospectively reviewed the medical record of patients who underwent pulmonary resection at Fudan University Shanghai Cancer Center (FUSCC) during May 2008 and December 2015. The inclusion criteria were: (I) patients diagnosed with lung adenocarcinoma; (II) a pathological N1/N2 disease according to the 8th tumor, node, metastasis (TNM) classification; (III) complete surgical resection with systemic lymph node resection; (IV) no distant metastasis. Systematic lymph node dissection was defined as complete dissection of at least three mediastinal lymph node stations (always subcarinal), as is described in the European Society of Thoracic Surgeons (ESTS) guidelines for intraoperative lymph node staging in non-small cell lung cancer (NSCLC) (11). Exclusion criteria were: (I) history of other malignancies; (II) neoadjuvant therapy; (III) not R0 resection; (IV) incomplete medical record; (V) not having received high-resolution CT scan in our institution. For preoperative staging, positron emission tomography (PET)/CT or biopsy under endobronchial ultrasonography (EBUS)/mediastinoscopy was performed for patients with bulky lymph nodes on CT images. Only patients with cN0/N1 disease received upfront surgery; those with biopsy confirmed cN2 diseases would receive either definitive chemoradiation therapy or induction chemotherapy ± surgery/radiotherapy (RT) according to initial treatment reaction. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the institutional review board of FUSCC (No. 2008223-9). Individual patient consent was waived because of the retrospective nature of this study.

Data collection and follow-up

Clinicopathologic information was collected from patients’ medical records, including sex, age, smoking history, performance score, comorbidities (including chronic bronchitis, emphysema, asthma, bronchiectasis, tuberculosis, pneumonia, coronary artery disease, hypertension, and diabetes mellitus), forced expiratory volume in the first second (FEV1)% predicted, maximum ventilation volume (MVV)% predicted. For tumors, presence of GGO component on CT images, CT size, CT consolidation size, extent of resection, surgery approach [video-assisted thoracic surgery (VATS) or muscle-sparing thoracotomy], pathological size and subtype, pT and pN staging according to the 8th TNM classification for lung cancer, number of lymph node resected and tested for positive, and adjuvant chemotherapy and RT were also extracted from patient’s medical records.

Routine postoperative follow-up for N1/N2 patients was arranged as every 3±1 months during the first 3 years. Enhanced chest CT scan and abdominal ultrasonography were performed every 3±1 months, while brain magnetic resonance imaging and bone scanning were performed every 6 months. The follow-up period was extended to every 6±1 months after 3 years, and every 12±3 months after 6 years. Follow-up was performed via the outpatient record and semi-annual telephone calls.

Recurrence-free survival (RFS) was calculated from the date of surgery to the date of any local or distant recurrence. Non-cancer-related deaths or deaths related to other malignancies were censored at date of death. OS was calculated from the date of surgery to the date of death from any cause. Diagnosis of recurrence was confirmed by biopsy if possible, and imaging (i.e., PET/CT scan or brain magnetic resonance imaging) was performed to support the clinical diagnosis and the decision to initiate subsequent treatment.

Statistical analysis

Baseline characteristics were reported as median [interquartile range (IQR)] for continuous variables and frequency (percentage) for categorical variables. Age, FEV1% predicted, MVV% predicted, CT size, CT consolidation size, pathological size, number of lymph node resected and tested for positive were recorded as continuous variables. Comparisons between groups were performed using Mann-Whitney U test and Fisher’s Exact test for continuous variables and categorical variables, respectively.

There were far fewer patients with part-solid nodules than with solid ones (34 vs. 635), and there were obvious imbalances in baseline characteristics. Thus, propensity score matching (PSM) was applied to determine the prognostic value of GGO. PSM is based on a logistic regression model, and the following variables were adjusted: sex, age, smoking history, comorbidity status, extent of resection, surgery approach, pT stage, pN stage, pathological subtype, CT consolidation size, and adjuvant chemotherapy and RT. The PSM process was performed using the nearest method, 1:4 matching of each group. Baseline standardized mean differences were calculated before and after matching. Survival curves were plotted using the Kaplan-Meier method and compared between solid and part-solid groups with the log-rank test.

Multivariable Cox proportional hazard model was also performed to identify independent prognostic factors for node-positive lung adenocarcinoma, and results were presented as hazards ratio and 95% confidence interval. For the Cox regression model, sex, age, smoking history, performance score, comorbidity, presence/absence of GGO component on CT images, CT consolidation size, pN stage, pathological subtype, extent of resection and adjuvant therapy (chemotherapy and/or RT) were chosen for analysis. CT consolidation size was chosen to represent lesion size based on the 8th edition of TNM classification, since pathological invasion size was not individually reported during the research time. Variables with P value <0.05 in multivariable analysis were included in the final regression model.

Statistical analyses and survival curves were conducted by R (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria). Survival rates were calculated using IBM SPSS Statistics 25 (SPSS, Chicago, IL, USA). Statistical significance was defined as a two-tailed P<0.05.

Results

A total of 669 patients with pathological N1/N2 lung adenocarcinoma were reviewed, including 635 solid (94.9%) and 34 part-solid (5.1%) lesions. The baseline characteristics of patients before and after PSM are summarized in Table 1. Of the 635 solid lesions, the median nodule size on CT was 31 mm (range, 10–89 mm); of the 34 part-solid lesions, the median nodule size on CT was also 31 mm (range, 15–68 mm), while median solid size was 24 mm (range, 12–62 mm), and median consolidation/tumor ratio (CTR) was 0.8 (range, 0.64–0.95). Obvious differences were noted between solid and part-solid groups, including that part-solid group has less male (23.5% vs. 51.8%), smoking (17.6% vs. 36.7%) and N2 patients (52.9% vs. 70.4%), and the consolidation size on CT tends to be smaller (24 vs. 31 mm). More acinar predominant adenocarcinoma (APA)-subtype were noticed in the part-solid group (76.5% vs. 50.2%), and the proportion of VATS surgery was higher (35.3% vs. 14.8%). For pT stages, no T1a or T3/T4 nodules was seen in the part-solid group, thus, stage IIIB was excluded in this group. No lepidic predominant adenocarcinoma (LPA) subtype was seen in both solid and part-solid groups. After 1:4 PSM, 136 patients and 34 patients were matched from solid and part-solid groups, respectively. In the final analysis model, the above-mentioned differences in baseline characteristics were all well-balanced (Table 1). To note, solid component size on CT was chosen as matching variable in order to include lesions with similar sizes in the survival analysis, so the total CT size of part-solid group were larger (31 vs. 25 mm, P=0.01) after PSM.

Survival outcomes stratified by TNM stages are displayed in Figure 1. For stage IIB, IIIA and IIIB diseases, the 5-year RFS rate after upfront surgery were 41.6%, 28.1% and 20.0%, and the OS rate were 67.3%, 48.1% and 23.8%, respectively. Comparing the survival outcomes between solid and part-solid groups before PSM, there were no significant difference in both RFS (P=0.51) and OS (P=0.10; Figure 2A,2B). For solid and part-solid groups, the 5-year RFS rate were 28.1% and 35.5%, respectively, and the 5-year OS rates were 49.4% and 54.7%, respectively. A slight but not significant advantage of part-solid group was noticed in OS, but not in RFS. After 1:4 PSM, the solid and part-solid group showed comparable prognosis in both RFS (P=0.71) and OS (P=0.82; Figure 2C,2D), and the slight advantage of part-solid group in OS was not seen. In the matched cohort, the 5-year RFS rate for solid and part-solid groups were 35.5% and 36.5%, and the 5-year OS rates were 55.6% and 67.1%, respectively.

Figure 1 Kaplan-Meier curves of 669 patients included in this study, grouped by TNM stages. Recurrence-free survival (A) and overall survival (B) of pathological stage IIB (180 patients), IIIA (433 patients) and IIIB (56 patients) both showed significant differences. Shaded area: 95% confidence interval. TNM, tumor, node, metastasis.

Figure 2 Kaplan-Meier curves of 669 patients included in this study, grouped by with/without GGO component on CT images. Recurrence-free survival (A) and overall survival (B) difference between solid group (635 patients) and part-solid group (34 patients) before 1:4 PSM. Recurrence-free survival (C) and overall survival difference (D) between solid group (136 patients) and part-solid group (34 patients) after 1:4 PSM. None of the curves showed significant differences. Shaded area: 95% confidence interval. GGO, ground glass opacity; CT, computed tomography; PSM, propensity score matching.

Cox proportional hazard model identified CT consolidation size, pN2 stage and lobectomy resection extent as independent prognostic factors for RFS (Table 2). For OS, age, smoking history, CT consolidation size, pN2 stage, lobectomy resection extent and adjuvant therapy were identified as independent prognostic factors. These independent prognostic factors were chosen to form a final model, where pN stage showed a strongest prognostic value [RFS: P<0.001, hazard ratio (HR) =1.47, 95% confidence interval (CI): 1.19–1.83; OS: P<0.001, HR =1.84, 95% CI: 1.43–2.37]. Multivariable Cox regression model confirmed that GGO component was not an independent prognostic factor for either RFS (P=0.75; HR =0.93; 95% CI: 0.59–1.46) or OS (P=0.53; HR =1.19; 95% CI: 0.69–2.05).

Discussion

Although it is well-known that GGO component predicts better prognosis in early-stage lung adenocarcinoma (6-8), the prognostic value of GGO component in patients with lymph node metastasis remains unclear. It is crucial to note T stage as a pivotal prognostic factor in pN1/2 lung cancer (12). Moreover, GGO components play a significant role in T staging, thereby emphasizing the necessity to explore their prognostic relevance in pN1/2 patients. In this study, we gathered a group of patients (n=34) whose resected tumors manifested as part-solid lesions on CT images, and were pathologically confirmed to be N1/N2 diseases. Kaplan-Meier curves showed similar OS and RFS rates of stage IIB, IIIA and IIIB patients compared with previous study (13) (Figure 1). Comparisons between solid and part-solid group showed that patients with part-solid lesions had higher chance to be female, elderly-aged and nonsmokers, and had earlier-stage diseases. PSM based survival analysis and Cox proportional hazard model were performed to show that the presence of GGO component did not affect the prognosis of patients with node-positive lung adenocarcinoma as they do in early-stage tumors. Multivariable Cox regression model revealed that pN stage was the strongest independent prognostic factor of both RFS and OS in resected node-positive lung adenocarcinoma. Although the prognostic impact of CT consolidation size was also significant, the hazard ratio was not as high as pN stage. Resection extent of lobectomy also showed prognostic impacts toward RFS, while age, smoking history and adjuvant therapy only affected OS in this cohort. These factors were not the major concern of this study, and were more thoroughly discussed in other studies. The results of this study added evidence to the GGO related literature, and might help us understand the role of GGO component in lung cancer more thoroughly.

Lymph node involvement is relatively rare among GGO-featured tumors, raising difficulty for detailed study targeting these patients. Suzuki et al. reported that lymphatic invasion was rarely found in nodules with GGO component >50%, while the rates were 5% and 24% in nodules with GGO component <50% and pure solid nodules (14). Our previous study also revealed that CTR ≤50% and 50%< CTR <100% with nodule size ≤10 mm were a reliable predictor of node-negative status in lung adenocarcinoma (15). In this current study, all patients with part-solid nodules on CT image had CTR >50% and CT size over 10 mm, and was in minority of the whole patient cohort (34 of 669, 5.1%), which is consistent with former studies. The low lymph node involvement rate is considered to result from the indolent, or less aggressive growth pattern of GGO-featured lung cancer (16). Moreover, the majority of GGO-featured pulmonary nodules were detected from lung cancer screening programs or incidental CT scans, and are more often preinvasive or early-stage adenocarcinoma, thus are naturally related with earlier stages and better prognosis (17,18). Notably, other factors such as driver-mutations also serve as important prognostic factors. In our previous study, we revealed that epidermal growth factor receptor (EGFR) mutation was a strong poor prognostic factor in patients with radiologic solid, histologic acinar pattern-predominant adenocarcinoma/papillary pattern-predominant adenocarcinoma/invasive mucinous adenocarcinoma, and pathologic stage II and III lung adenocarcinomas (19). Plus, KRAS-mutated patients had greater cumulative recurrence rate and worse OS than KRAS wild-type patients. The OS of patients harboring KRAS-G12C/V mutations was shorter than that of other KRAS-mutated patients (20). Also, as immunotherapy targeting programmed death-1 (PD-1) and its ligand PD-L1 is an established treatment modality for NSCLC, it is important to know whether PD-L1 expression is a prognostic marker for these patients (21,22). Data from the second-line phase 3 trials of nivolumab and atezolizumab in NSCLC showed increasingly greater efficacy compared with chemotherapy in patients whose tumors expressed PD-L1 on tumor cells (TCs) and/or immune cells (ICs) (22,23). However, PD-L1 expression is neither prognostic nor predictive for survival benefit with adjuvant platinum-based chemotherapy (24). Nevertheless, lymph node involvement exists in a certain portion of patients with GGO-featured nodules, and requires independent research. The results of this study indicated a comparative prognosis of node-positive lung adenocarcinoma with solid and part-solid CT appearance. Therefore, node-positive patients might need to be excluded in future studies concerning prognostic impacts of GGO component.

As for the reason why GGO does not remain a prognostic factor in patients with lymph node metastasis, two possibilities are discussed below. Firstly, when lymph node metastasis occurs, tumor becomes regional instead of local disease, which indicates that the tumor has already reached a point of upgraded invasiveness, so that the original growth pattern has much less impact on its biological behavior. Hattori et al. found that the presence of a GGO component still has a notable impact on a favorable prognosis in clinical stage IA radiologic invasive NSCLC (0.5≤ CTR ≤1.0), with a 5-year OS significantly different between pure-solid and part-solid tumors (82.7% vs. 95.3%, P<0.001) (9). Aokage et al. also reported a significant survival difference between adenocarcinoma with and without GGO component in clinical IA1 and IA2 patients (both P<0.01), whereas the trend did not reach the level of significance in clinical IB patients (P=0.14) (25). However, Nakamura et al. discovered that in clinical T2aN0M0 stage IB lung adenocarcinoma, GGO-dominant group had significantly better OS compared with solid-dominant group (P=0.01, indicating the prognostic value of GGO component in clinical stage IB patients) (6). The discrepancies among existing studies might have indicated that the impact of GGO component on each stage of the disease is not fully understood. This trend did not seem to continue when the tumor came with lymph node metastasis in this study. Secondly, the GGO component on CT images does not necessarily correspond to a lepidic growth pattern within the tumor which indicates an indolent disease. Instead, GGO component is related to numerous pathological entities, including acinar or papillary adenocarcinoma subtypes (26), inflammation infiltration around the tumor, or even tumor spread through air spaces (STAS) (27,28), which can be related to either better or worse prognosis, as well as having different reaction to available treatment. Combining these two points, it is understandable why GGO component does not indicate better prognosis in node-positive lung adenocarcinoma.

There are several limitations of this study. The patient number with GGO component on CT image and lymph node metastasis of 34 is relatively small, and can be the underlying reason of a negative result. Yet, since the incidence of N1/N2 disease in GGO-featured tumors is rare, this study is an important complement to the existing studies of GGO-featured lung cancer. Secondly, since this study focused on the prognostic value of GGO component in patients with advanced-stage lung adenocarcinoma, and lacks further investigation into the pathological nature of such GGO component, we cannot answer questions such as how could GGO component affect tumor’s reaction to treatment before and after surgery. Further investigations are needed for the clarification of these questions.

Conclusions

In conclusion, GGO component is not a significant prognostic factor in patients with N1/N2 M0 lung adenocarcinoma. Indication of upfront surgery for GGO nodules suspected for lymph node-positive lung cancer should be the same with solid nodules. When studying the prognostic impacts of GGO component, patients with lymph node metastasis should be excluded.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of People’s Republic of China (No. 81930073), the Shanghai Technology Innovation Action Project (No. 20JC1417200), the Cooperation Project of Conquering Major Diseases in Xuhui District (No. XHLHGG202101), the National Key R&D Program of China (No. 2022YFA1103900), and Shanghai Anticancer Association EYAS PROJECT (No. SACA-CY21B07).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-170/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-170/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-170/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-170/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). This study was approved by the institutional review board of Fudan University Shanghai Cancer Center (No. 2008223-9). Individual patient consent was waived because of the retrospective nature of this study.

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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