Is it really necessary to perform mediastinal lymphadenectomy in surgery for ground glass opacity-featured lung adenocarcinoma?
Review Article: Surgery: Mediastinal Surgery

Is it really necessary to perform mediastinal lymphadenectomy in surgery for ground glass opacity-featured lung adenocarcinoma?

Chaoqiang Deng1,2,3#^, Yang Zhang1,2,3#, Haiquan Chen1,2,3

1Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China; 2Institute of Thoracic Oncology, Fudan University, Shanghai, China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: C Deng, Y Zhang; (IV) Collection and assembly of data: C Deng, Y Zhang; (V) Data analysis and interpretation: C Deng; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

^ORCID: 0000-0002-3910-9519.

Correspondence to: Haiquan Chen, MD, PhD. Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai 200032, China. Email: hqchen1@yahoo.com.

Abstract: An increasing number of lung ground-glass opacity (GGO) are detected along with the popularity of low-dose computed tomography (LDCT) screening. Despite the excellent prognosis of GGO-featured lung cancers, systematic lymphadenectomy is still recommended for all resectable lesions. Much effort has been made to determine the conditions surrounding a limited resection for subsolid nodules. However, the necessity to perform systematic lymphadenectomy in radiologic GGO-featured lung adenocarcinomas (LUADs) remains controversial. Pure GGOs were reported had a 100% 5-year survival rate with no lymphatic metastasis, and the lymphatic metastasis rate in part-solid nodules (PSNs), especially in GGO-predominant PSNs, was significantly lower than that in pure solid nodules. The impact of lymphadenectomy on the prognosis and the specific predictors for lymphatic metastasis in PSNs are also discussed. Systematic lymphadenectomy was not yet proved to confer a survival benefit in patients with GGO-featured lung cancers. Integration of pre-/intra-operative information such as tumor size, consolidation tumor ratio (CTR) and pathological information is warrant for solid-predominant PSNs. Pre-invasive lesions rarely occurred lymph node metastasis and intraoperative frozen section (FS) results might provide pathological information before lymphadenectomy strategy determination. Finally, although randomized controlled trials are difficult to conduct in LUAD manifesting as GGO, more prospective studies are required to justify the indication of systematic lymphadenectomy.

Keywords: Ground-glass opacity (GGO); systematic lymphadenectomy; lymphatic metastasis rate; necessity

Received: 06 August 2021; Accepted: 04 July 2022; Published: 30 September 2022.

doi: 10.21037/amj-21-40

Introduction

Lung cancer is the leading cause of cancer death worldwide (1). Low-dose computed tomography (LDCT) screening for lung cancer is being implemented in China and the United States and is under consideration in many other countries (2-4). Along with the popularity of LDCT screening, an increasing number of lung ground-glass opacity (GGO) lesions are detected. Pure-GGO and part-solid nodules (PSNs) present different degrees of malignancy from those of pure-solid tumors, since even a small proportion of GGO components is associated with a favorable prognosis (5).

Surgery is the main treatment for early-stage non-small cell lung cancer (NSCLC) (6) using a standard procedure of lobectomy or pneumonectomy with systematic lymph node dissection (SND) (7,8). Although major randomized trials have not demonstrated that SND confers a survival benefit (9-12), the current guidelines still recommend SND for all resectable NSCLC irrespective of the stage, location and GGO component of the tumor. Several studies have reported that unlike radiologic pure-solid tumor without any GGO component, the estimated rate of lymph node metastasis in part-solid lung adenocarcinoma (LUAD) is approximately less than 5% (13-15). Moreover, animal model experiments even demonstrated lymphadenectomy altered endogenous antitumor mechanisms and accelerates the growth of tumor (16). The necessity to perform systematic lymphadenectomy in radiologic GGO-featured LUADs still remains controversial. In this review, therefore, we discuss this issue from aspects concerning prognosis, lymph node metastasis rates, corresponding predictive factors and random clinical trials (RCTs) of SND in radiological GGO-featured lung cancers.

Prognosis and resection strategy

It is well known that GGO presence is associated with excellent survival in LUAD (17-21). Hattori et al. (20) demonstrated the 5-year overall survival (OS) among clinical stage IA LUAD was 91.2% for GGO and 68.9% for solid nodules. Similarly, Miyoshi et al. (18) reported that the survival rate of the patients having a GGO nodule was significantly higher than that without GGO components. Fu et al. (22) further separated GGO lesions and reported the 5-year recurrence-free survival (RFS) for patients with pure GGO, part-solid, and solid nodules among invasive stage I NSCLC was 100%, 87.6%, and 73.2%, respectively. Under such circumstance, whether to perform lobectomy for GGO-featured NSCLC remains controversial. Appropriate determination of the extent of lung excision and lymph node dissection (LND) is important, and there has been much effort to determine the conditions surrounding a limited resection for a subsolid adenocarcinoma. Studies have demonstrated that limited resection for GGOs smaller than 20 mm have similar results to those obtained with standard lobectomy (23,24) while lobectomy is indicated for GGOs with over 25% of the solid component. National Comprehensive Cancer Network (NCCN) guidelines (25) recommend that limited resection is appropriate for peripheral GGO lesions with size ≤2 cm and ≥50% ground-glass appearance, which mainly based on several recent RCTs. The Japan Clinical Oncology Group (JCOG 0201) (26) defined GGO with size ≤3 cm and consolidation tumor ratio (CTR) ≤0.5 as “radiological noninvasive”, and the 5-year OS of this “noninvasive” group was 96.7%. Another JCOG0804 (27) investigated the application of sublobar resection in peripheral GGO lesions with size ≤2 cm and CTR ≤0.25 and reported the 5-year RFS was 99.7%. However, there is still no consensus on the most appropriate surgical treatment for GGO with CTR >0.5 and two RCTs (JCOG 0802 in Japan and CALGB 140503 in the United States) are undergoing.

The lymph node metastasis rate in GGO

Similar to the discussion of resection, the introduction of a subsolid LUAD fueled a debate about the necessity of SND. SND has been considered as an important factor in radical surgical resection for lung cancer patients. However, it is not always necessary. Proponents emphasize that it is more accurate with the respect to staging, than the limited LND. Gajra et al. (28) reported that SND increased chance of survival of the patient by removing the occult N2 disease. Darling et al. (10) conducted a RCT comparing complete mediastinal LND with lymph node sampling and the former identified occult N2 disease in 4% of patients, although it did not improve survival compared with lymph node sampling. Conversely, opponents of SND have asserted that it could potentially result in more adverse events, such as bleeding, chylothorax, or longer hospitalization.

Nevertheless, we have to know the exact rate of nodal involvement in subsolid LUAD before determining the proper LND strategy. Yoshida et al. (29) first reported that in patients with lung carcinoma smaller than 1 cm, only 1% of part-solid LUAD had node metastasis. Ye et al. (30) demonstrated that pN1 was observed at 2% and pN2 at 1% in patients with clinical stage 1A, part-solid lung cancer. It is noteworthy that the entire cohorts in these two studies performed SND testing, which made the conclusions more meaningful. Our group (13) also reported that among clinical stage IA LUAD, no patients with pure GGOs had lymphatic metastasis, and the lymphatic metastasis rate in PSNs (7/312, 2.2%) was significantly lower than that in pure solid nodules (41/152, 27.0%). A summary of studies regarding lymph node metastasis rate of patients with lung cancer presenting as GGO was shown in Table 1. In addition to lymph node metastasis, the impact of lymphadenectomy on the prognosis of patients with GGO-featured lung cancers was also analyzed in several studies. Moon et al. (31) retrospectively reviewed 358 patients with clinical stage IA NSCLC and found that in GGO-predominant patients, the 5-year RFS rate among no mediastinal lymph node evaluation (NoMLE) group, mediastinal lymph node sampling (MLS) group, and mediastinal lymph node dissection (MLND) group showed no difference. Hattori et al. (32) reviewed 462 patients with radiological part-solid LUAD and found the extent of lymphadenectomy was not associated with survival outcomes after propensity score matching. Based on the above findings, SND may be unnecessary for pure GGO-featured lung cancer as well as some with PSNs.

Table 1

Summary of studies regarding lymph node metastasis of patients with lung cancer presenting as ground-glass opacity

First author, year No. of patients Staging Lymph node metastasis rate
Pure GGOs PSNs
Ye, 2014 651 (pGGOs: 55, PSNs: 292, solid nodules: 304) Clinical stage IA 0% 2% of pN1and 1% of pN2
Hattori, 2017 497 (PSNs with 0.5≤ CTR <1: 177, solid nodules: 320) Clinical stage IA NA 2% of pN1and 2% of pN2
Hattori, 2018 634 (PSNs: 356, solid nodules: 278) Clinical stage IA NA 2.8%
Ye, 2019 988 (pGGOs: 501, PSNs: 329, solid nodules: 158) Clinical stage IA 0% 2.2%
Tsutani, 2014 239 [pGGO and PSNs (0< CTR <0.5)] Clinical stage IA 0.8%
Hattori, 2017 1,029 (nodules containing GGO: 503, solid nodules: 526) Clinical stage I 1% of pN1and 1% of pN2
Zhang, 2019 2,749 (pGGOs and PSNs: 581, solid: 2,168) Pathological stage I–III There was no lymph node metastasis in PSNs with CTR ≤0.5

GGO, ground-glass opacity; PSN, part-solid nodule; pGGO, pure ground-glass opacity; CTR, consolidation tumor ratio.

The necessity of SND in PSNs

To further determine the necessity of SND, as well as develop a standardized guideline for LND in part-solid lung cancer, a model based on pre-/intra-operative information, such as tumor size, CTR and intraoperative frozen section (FS) pathology, is warrant. Okada et al. (33) revealed that adenocarcinoma with high SUVmax and low GGO ratio is more closely associated with LN metastasis. However, measuring SUVmax value greatly affected by measurement methods, which may provide no advantage in predicting LN metastasis. As aforementioned, Hattori et al. (32) also showed that none of part-solid LUAD with CTR ≤0.5 had a LN metastasis. Similarly, Zhang et al. (34) revealed there was no LN metastasis in 151 patients with invasive part-solid LUAD with CTR ≤0.5. Among them, the tumor size of six patients even exceeded 3cm. Our previous studies have indicated that tumor histology such as atypical adenomatous hyperplasia (AAH)/adenocarcinoma in situ (AIS)/minimally invasive adenocarcinoma (MIA) might be able to guide lymphadenectomy (35,36), since pre-invasive lesions rarely occurred LN metastasis and FS might provide pathological information before lymphadenectomy strategy determination. For cases diagnosed as AAH/AIS/MIA by FS intra-operatively, SND might not be necessary. Nevertheless, whether FS could be an efficient method to diagnose invasive degree of lung cancers and to guide final lymphadenectomy strategy mostly depends on the discrimination accuracy. Liu et al. (37) showed the accuracy of FS to distinguish AAH/AIS/MIA from invasive adenocarcinoma was 96%. Moreover, patients undergoing limited resection of invasive LUAD misdiagnosed as AAH/AIS/MIA by FS analysis showed excellent prognoses (38). Sublobar resection without lymphadenectomy was consequently conducted for patients with AAH/AIS/MIA and the 5-year RFS turned out to be 100% (37). In this regard, there is the possibility of setting up the prediction model for the pathologic LN status and effectively guide lymphadenectomy strategy for PSNs.

RCTs for GGO

Nevertheless, considering the excellent survival of GGO-featured lung cancer, RCTs regarding LND strategies require excessive sample size and follow-up time. It may be very difficult or even impossible to conduct such RCTs. There is an ongoing prospective observational clinical trial validating the selective LND strategy based on radiologic and pathologic features in Fudan University Shanghai Cancer Center (FUSCC) (NCT03216551) (39). All enrolled patients are still performed systematic mediastinal LND, and the accuracy of mediastinal lymph node metastasis determination by selective mediastinal LND strategy is then analyzed. Specifically, CTR ≤0.5 is one of the conditions for predicting no mediastinal lymph node metastasis, which indicated the systematic lymphadenectomy might be unnecessary. Another prospective observational study using paraffin pathological whole sections to determine the correlation between ground glass components and pathological subtypes is also ongoing in FUSCC, which may provide extra pathological information for lymph node status prediction preoperatively.

Conclusions

Whether systematic lymphadenectomy should be used in GGO-featured lung cancers depends on numerous clinical-pathological variables. SND may be unnecessary for GGO-predominant lesions and especially for pure GGO nodules. However, the necessity of systematic lymphadenectomy in solid-predominant nodules and corresponding predictors for lymph node status remains controversial. Given the difficulty to conduct such RCTs in LUAD manifesting as GGO, RCTs may not be necessary to determine the optimal lymphadenectomy strategy. Nevertheless, the necessity to perform systematic lymphadenectomy, no matter in GGO- or solid-predominant lung cancers, requires more prospective studies to justify the indication.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sara Ricciardi) for the series “Thoracic Malignancy, Controversies in N Parameter” published in AME Medical Journal. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-21-40/coif). The series “Thoracic Malignancy, Controversies in N Parameter” was commissioned by the editorial office without any funding or sponsorship. The authors have no other 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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doi: 10.21037/amj-21-40
Cite this article as: Deng C, Zhang Y, Chen H. Is it really necessary to perform mediastinal lymphadenectomy in surgery for ground glass opacity-featured lung adenocarcinoma? AME Med J 2022;7:24.

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