Current advances in mediastinal staging for non-small cell lung cancer: a narrative review

Introduction

Accurate mediastinal nodal staging is a cornerstone in the diagnostic pathway for patients with non-small cell lung cancer (NSCLC), as it enables the implementation of a tailored therapeutic approach.

Although imaging studies represent the initial step in detecting potential nodal disease, (minimally) invasive mediastinal staging remains essential to confirm malignant involvement and to exclude false positives, such as benign lymph node conditions. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-843/rc).

Methods

We performed a literature search in PubMed, Medline, Embase, CENTRAL, and CINAHL databases to identify relevant publications for the assessed topic of mediastinal staging for NSCLC (Table 1). The searches for the main review were conducted as: (mediastinum OR mediastinal) AND (staging OR EBUS OR EUS OR VATS mediastinal biopsy OR “minimal invasive mediastinal staging”). Further searches were conducted without using Boolean operators. Only publications in English language were included. Due to the narrative design of the review, a certain subjectivity in choice of studies included is likely.

Diagnostic imaging

In suspected cases of NSCLC, the diagnostic process typically begins with a contrast-enhanced computed tomography (CT) scan of the chest. This modality provides crucial information about the primary tumor, the potential extent of metastases, and any comorbid conditions, enabling an initial comprehensive assessment of the disease.

CT is the most accurate imaging modality for detailed anatomical evaluation of the primary tumor, including its exact size, extent, and relationships to adjacent structures. It is mandatory to assign suspected metastatic lymph nodes to their anatomical stations by the 9th Edition of the tumor-node-metastasis (TNM) Classification for Lung Cancer (1).

Lymph node size is particularly important when evaluating the likelihood of mediastinal metastases. A short-axis diameter of ≥1 cm on axial imaging is generally considered suspicious for metastatic involvement. Morphological features—such as nodal shape, necrosis, capsular disruption, and contrast enhancement—also assist in identifying potential malignancy. However, CT alone demonstrates limited diagnostic performance, with a sensitivity of 55–61% and a specificity of 79–81% (2-4).

Positron emission tomography (PET), particularly when combined with CT (PET/CT), offers improved diagnostic accuracy for mediastinal lymph node assessment. This nuclear imaging technique utilizes the radiotracer 18F-fluorodeoxyglucose (FDG), which mimics glucose uptake and is phosphorylated by intracellular hexokinase into 18F-FDG-6-phosphate. This metabolite becomes trapped within cells, accumulating in proportion to glucose metabolism, and provides a functional metabolic assessment of tissues (5).

Although PET has limited spatial resolution (approximately 4–5 mm with modern scanners), this is typically mitigated by performing a simultaneous contrast-enhanced CT scan during the same session, a now-standard practice (6). This combined PET/CT approach enhances patient comfort, streamlines the diagnostic process, and increases diagnostic accuracy, with sensitivity ranging from 65% to 85% and specificity from 79% to 93% (2,4,7-10).

Nonetheless, the risk of false positives and undetected micrometastases remains. Benign conditions, such as granulomatous or inflammatory diseases, can also exhibit increased FDG uptake (11-14). Therefore, PET-positive mediastinal lymph nodes should always be confirmed cytologically or even histologically (15).

Other imaging modalities, such as chest X-ray or magnetic resonance imaging (MRI), play a limited role in mediastinal lymph node staging. Chest X-rays provide minimal information on mediastinal structures and are generally reserved for the initial assessment of patients with nonspecific symptoms.

While some studies, particularly those involving advanced MRI techniques, have reported higher sensitivities and specificities than CT for detecting hilar and mediastinal lymph node metastases (87–88% sensitivity and 88–95% specificity), PET/CT and CT remain the primary non-invasive tools for mediastinal staging (16-20).

According to current guidelines, MRI is not recommended as a first-line imaging modality for lymph node staging in lung cancer. Its use should be reserved for specific clinical scenarios, particularly when evaluating T-stage features such as chest wall or vertebral invasion (2,21).

Non-surgical mediastinal staging

Given the limitations of imaging modalities in definitively assessing mediastinal lymph node involvement, invasive non-surgical techniques such as endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) have become essential tools for accurate staging. EBUS enables real-time, ultrasound-guided transbronchial needle aspiration (TBNA) of mediastinal and hilar lymph nodes through the tracheobronchial tree. At the same time, EUS allows access to posterior and inferior mediastinal stations via the esophagus. The two above mentioned techniques are complementary and, when combined, can assess nearly all mediastinal lymph node stations including stations 2, 4, 7, 8, and 9, as well as hilar (stations 10 and 11), with a reported pooled sensitivity of 89–94% and specificity approaching 100% in very experienced centers (22-24).

Due to their minimally invasive nature, high accuracy, and low complication rates, procedures like EBUS-TBNA (often performed under conscious sedation) are recommended as first-line invasive staging tools in several guidelines. The European Society of Thoracic Surgeons (ESTS), the American College of Chest Physicians (ACCP), and the National Comprehensive Cancer Network (NCCN) all recommend EBUS and/or EUS as the preferred initial methods for invasive mediastinal staging in patients with suspected or proven NSCLC and abnormal mediastinal findings on CT or PET/CT (4,15,25). These guidelines also suggest that even in the presence of normal imaging, invasive staging should be considered in cases with centrally located tumors, enlarged or FDG-avid hilar nodes, or when the results will influence management decisions. If EBUS/EUS results are negative but representative and clinical suspicion remains high, surgical confirmation via mediastinoscopy or video-assisted mediastinal lymphadenectomy (VAMLA) is typically recommended to avoid understaging (Appendix 1).

EBUS and EUS have several practical advantages: they can be performed on an outpatient basis under light sedation, are associated with a low complication rate, and allow for real-time targeting of small lymph nodes or those close to vascular structures. These advantages are very important due to the positive impact on health-care resources and increased care costs (26).

However, a few limitations are related to both techniques. Operator expertise significantly influences diagnostic accuracy, and false negatives may occur, especially in the presence of micrometastases or when lymph nodes are difficult to access or visualize.

Although the literature provides clear evidence supporting the use of EBUS-TBNA for primary mediastinal staging of NSCLC, there is a lack of studies focused on restaging after induction therapy.

Achieving a pathological N0 status at the time of surgical resection represents a major prognostic determinant of improved survival in this subgroup of patients, underscoring the critical role of accurate and meticulous mediastinal restaging (27).

At present, FDG-PET/CT does not offer sufficient diagnostic accuracy to be used as a stand-alone modality for mediastinal restaging, as clinically relevant false-negative and false-positive results remain frequent (28,29).

The diagnostic performance of EBUS-TBNA is known to decline following induction therapy, largely due to treatment-related fibrosis and reduced lymph node cellularity.

To date, two meta-analyses have addressed this issue, reporting a pooled sensitivity of approximately 65% and pooled specificities of 98% and 99%, respectively. Notably, both analyses demonstrated substantial heterogeneity in sensitivity, with reported values ranging from 40% to 82% (30,31).

Ariza-Prota et al. have suggested that EBUS-guided transbronchial mediastinal cryobiopsy may provide improved diagnostic sensitivity, together with optimal sample adequacy for molecular and immunohistochemical analyses and a low proportion of non-diagnostic specimens (32).

Nevertheless, further large data are required before mediastinal cryobiopsy can be established as a standard approach for mediastinal restaging

Robotic staging

Since 2019, robotic-assisted bronchoscopy (RAB) platforms have become available for clinical use, primarily to facilitate precise navigation and tissue acquisition from peripheral pulmonary lesions. These systems, often used in conjunction with fixed or integrated (mobile) cone-beam computed tomography (CBCT), offer superior scope stability, fine-motor control, and navigational precision compared to conventional flexible bronchoscopes (33).

While EBUS/EUS-TBNA remains the gold standard for sampling stations 2, 4, 7, 8, 10, 11, and 12, it does not permit access to the aortopulmonary zone, specifically subaortic (station 5) and paraaortic (station 6) lymph nodes. These nodes traditionally require either EUS-FNA, which has a low diagnostic yield (66%), or invasive surgical procedures such as VATS or anterior mediastinotomy (Chamberlain procedure) (34).

Due to their design features, including enhanced steerability and needle stability, RAB systems enable both transbronchial and transparenchymal approaches to previously inaccessible mediastinal regions. When supplemented by intraprocedural CBCT, RAB provides a high level of spatial precision, allowing for safe needle advancement beyond the airway wall into the aortopulmonary region, thereby expanding the diagnostic landscape for nodal staging (35).

Initial clinical evidence from four case series involving seven patients supports the technical feasibility and safety of RAB-mediated aortopulmonary lymph node TBNA (36-39). In these cases, transpleural access to stations 5 and 6 was achieved without clinically significant complications. The pooled diagnostic yield was 88%, which is within the range of yields reported for VATS and anterior mediastinotomy (83–100%), but with the added advantage of minimal invasiveness (38).

This is notable, as robotic and endoscopic approaches are associated with a favorable safety profile: minor complications occur in <1% of cases, in stark contrast to surgical techniques, which are associated with complication rates of up to 9%, including bleeding, infection, and postoperative pain (15). Notably, published RAB cases have not reported any significant vascular injury, despite the requirement for transpleural or extrapulmonary access (36-39). Nonetheless, the absence of real-time ultrasound guidance in current RAB systems necessitates careful procedural planning, utilizing CT-derived navigation maps and real-time CBCT or fluoroscopy, to ensure accurate targeting and minimize complications.

While the current body of evidence remains limited, these early findings suggest that RAB may safely extend the diagnostic reach of bronchoscopic staging to lymph node stations that are otherwise inaccessible without surgery. Its integration into multimodality staging workflows (particularly in centers equipped with CBCT) could offer a minimally invasive alternative with high diagnostic yield and a significantly reduced risk profile.

Although still in its early stages of clinical adoption, published evidence supports the use of RAB for mediastinal lymph node staging in NSCLC, particularly for the aortopulmonary window (station 5) and paraaortic (station 6) areas, which are beyond the reach of standard EBUS. Reported diagnostic yields ranged from 80% to 90%, and the absence of major complications underscores the potential of this technology to complement conventional staging approaches. RAB offers a novel, endobronchial route for assessing challenging mediastinal nodes that previously necessitated invasive surgery, thereby contributing to more accurate staging with a lower procedural burden. Despite the aforementioned advantages, the economic implications of this technology must be carefully considered, particularly in the setting of rising healthcare costs. Available evidence suggests that the costs related to platform acquisition and dedicated instrumentation may represent a substantial financial burden for healthcare institutions (40). Accordingly, well-designed prospective studies and multicenter trials are needed to better define its clinical role, refine appropriate indications, and standardize procedural techniques. In addition, formal evaluations of cost-effectiveness and return on investment across different healthcare systems are warranted.

Surgical mediastinal staging

Surgical mediastinal staging remains a key component in the diagnostic and staging pathway for patients with NSCLC, particularly when imaging or minimally invasive modalities yield inconclusive or discordant results. Although endosonographic techniques have advanced significantly, surgical approaches, including cervical mediastinoscopy, VAMLA, transcervical extended mediastinal lymphadenectomy (TEMLA), and video-assisted thoracoscopic surgery (VATS), continue to play an essential role in achieving accurate nodal assessment. These procedures provide the advantages of direct visualization, systematic lymph node sampling or dissection, and high diagnostic sensitivity.

Cervical mediastinoscopy

Cervical mediastinoscopy, first described by Carlens in 1959, was the cornerstone of invasive mediastinal staging for NSCLC for several decades (41). Performed under general anesthesia through a small suprasternal incision, it allows access to the right and left upper and lower paratracheal (stations 2R, 2L, 4R, 4L) and subcarinal (station 7) lymph nodes via a mediastinoscope advanced alongside the trachea. Current guidelines from the ACCP recommend systematic sampling from these five nodal stations during the procedure (4).

In terms of diagnostic performance, conventional mediastinoscopy demonstrates a median sensitivity of 78% and a negative predictive value of 91%, according to a pooled analysis of 26 studies involving 9,267 patients (4). However, its limitations include an inability to access certain nodal stations, which accounts for nearly half of the false-negative results.

Video-assisted mediastinoscopy (VAM) has increasingly supplanted the conventional approach in many centers due to its technical and educational advantages. The use of a video-mediastinoscope offers superior visualization and enables bimanual dissection, allowing not only nodal sampling but also systematic lymph node removal. This is particularly valuable at station 7, where complete excision can expose the esophagus, thereby providing explicit anatomical confirmation. A pooled analysis of 995 cases reported a higher sensitivity with VAM (89%) compared to conventional mediastinoscopy, while maintaining a similar negative predictive value (92%) (4). Beyond diagnostic performance, VAM improves surgical training and educational dissemination. The ability to project and record the operative field facilitates structured learning and intraoperative teaching without compromising procedural safety or efficiency (42). The ESTS now recommends VAM over conventional mediastinoscopy for mediastinal staging (15).

Both conventional mediastinoscopy and VAM demonstrate excellent safety profiles when performed by experienced surgeons. A review of seven retrospective cohorts and one prospective audit reported low morbidity (0–5.3%) and near-zero mortality (0–0.05%) for conventional mediastinoscopy. Similarly, VAM showed favorable outcomes, with a morbidity range of 0.83–2.9% and no procedure-related deaths (43). A more recent single-center series of 1,970 mediastinoscopies (including 243 VAM procedures) reported an overall complication rate of 1.3%, with major bleeding in only 0.25% of cases and no perioperative mortality. The median operative time was 18 minutes, and over 96% of procedures were performed on an outpatient basis (44). However, caution is warranted in specific clinical scenarios, such as re-operative procedures or prior mediastinal irradiation, where fibrosis may increase procedural complexity and risk.

The ESTS recommends confirmatory VAM following negative endosonographic staging when mediastinal nodal involvement remains a clinical concern (e.g., in patients with PET-positive nodes or centrally located tumors) (15). However, confirmatory mediastinoscopy may be omitted in patients with a low or intermediate risk of N2/N3 disease (e.g., normal PET-CT), provided that systematic EBUS/EUS has sampled at least three mediastinal stations (including 4L, 4R, and 7) with adequate needle passes and without suspicious findings. This recommendation is based on meta-analyses indicating a negative likelihood ratio of 0.12–0.15 for such staging, suggesting that up to 12–15% of patients with negative endosonography may still harbor occult mediastinal metastases (45-47). Similarly, the NCCN advises confirmatory mediastinoscopy for patients with abnormal PET-CT findings (25), while the ACCP endorses confirmatory mediastinoscopy without specifying precise criteria (4).

As endosonographic techniques have improved, the routine need for confirmatory mediastinoscopy after a negative EBUS has been called into question. Recent data indicate that when systematic EBUS (with or without EUS) is negative, the likelihood of undetected mediastinal metastasis is relatively low. A meta-analysis of 29 studies reported a sensitivity of 66.9% [95% confidence interval (CI): 55.8–77.1%] for confirmatory VAM and 96.7% (95% CI: 95.1–98%) when combined with EBUS-TBNA. The corresponding negative predictive value improved from 79.2% for EBUS-TBNA alone to 91.8% for the combined approach. Importantly, the number needed to treat to gain additional diagnostic information from confirmatory mediastinoscopy after a negative EBUS-TBNA was 23.8 (95% CI: 19.3–31.2), meaning that approximately 23 of every 24 patients would derive no added benefit (48). These findings have prompted some institutions to adopt a more selective approach to confirmatory mediastinal staging.

Further support for this selective strategy comes from a recent randomized, noninferiority trial evaluating whether confirmatory mediastinoscopy can be safely omitted in patients with resectable NSCLC and negative findings on systematic endosonographic staging. In this study, 360 patients were randomized to either immediate tumor resection or confirmatory mediastinoscopy followed by resection. The primary endpoint—rate of unforeseen N2 disease—was 8.8% in the immediate resection group versus 7.7% in the mediastinoscopy-first group, meeting the predefined noninferiority criteria in the intention-to-treat analysis (P=0.0144) (49). These findings support the safe omission of confirmatory mediastinoscopy in well-staged patients, enabling a more individualized and efficient diagnostic pathway without compromising oncologic safety.

VAMLA and TEMLA

To increase the diagnostic yield of cervical mediastinal staging, two more advanced surgical techniques—VAMLA and TEMLA—were introduced approximately two decades ago (50,51). Both aim to improve staging accuracy through systematic and complete removal of mediastinal lymph nodes along with surrounding adipose tissue.

VAMLA builds upon standard VAM by enabling en bloc dissection of nodal stations accessible via the cervical approach. This allows for a more comprehensive and structured lymphadenectomy compared to conventional sampling. In contrast, TEMLA is a more extensive procedure, performed through a 5–6 cm cervical collar incision with sternal elevation using a retraction hook. Dissection is carried out under direct vision and with video assistance, granting access to a broader range of lymph node stations, including 1, 2R, 2L, 3a, 4R, 4L, 5, 6, 7, and 8.

The enhanced nodal access of TEMLA comes at the cost of increased invasiveness. In a retrospective study of 276 patients with prior negative EBUS/EUS, TEMLA demonstrated significantly higher sensitivity (96.2% vs. 87.8%; P<0.01) and negative predictive value (99.6% vs. 82.5%; P<0.01) compared to endosonography (52). In that cohort, however, morbidity was relatively high at 7.2%, including a 2.5% incidence of recurrent laryngeal nerve palsy, while mortality remained low at 0.4%.

VAMLA, while less extensive than TEMLA, also achieves superior nodal yield compared to standard mediastinoscopy. In experienced centers, it has demonstrated 100% sensitivity and negative predictive value (53-55). Nevertheless, the use of both VAMLA and TEMLA remains limited in routine practice due to technical complexity, resource demands, and longer operative times. Consequently, these techniques are generally reserved for specialized centers, specific high-risk scenarios requiring maximal staging accuracy, or inclusion in surgical trials.

Re-mediastinoscopy (reMS)

Mediastinoscopy may have a role after induction therapy, even in patients who previously underwent staging mediastinoscopy, a procedure referred to as reMS. Although reMS is conceptually similar to standard mediastinoscopy, it is technically more challenging due to peritracheal adhesions, which may result in reduced diagnostic accuracy compared with the initial procedure. The primary objective of reMS is to obtain new biopsies from lymph nodes that were positive at the initial mediastinoscopy or to sample additional nodal stations in order to exclude subclinical disease progression. Despite not being routinely performed, published series on reMS report a low complication rate, with overall morbidity ranging from 0% to 4% (56-58).

VATS

VATS allows access to all ipsilateral mediastinal lymph nodes, including the subaortic (station 5) and para-aortic (station 6) nodes, which are inaccessible by standard mediastinoscopy or endosonography. This surgical approach enables the acquisition of large tissue samples; however, VATS is more invasive than cervical mediastinoscopy, requires double-lumen endotracheal intubation, and may be limited by pleural adhesions. Access to the left lower paratracheal (station 4L) nodes can also be technically challenging, and contralateral mediastinal nodes are generally not accessible.

In a pooled analysis of four studies involving 246 patients, VATS demonstrated a median sensitivity of 99% and a negative predictive value of 96% for mediastinal staging (4). An additional series of 669 patients reported a mean complication rate of 2% (range, 0–9%) and no procedure-related mortality, supporting the safety and reliability of this procedure in experienced hands (4).

Beyond nodal staging, VATS is also valuable for clarifying the T stage, particularly when imaging raises suspicion for T4 lesions that may contraindicate resection (59-61). In selected cases, it may also reveal occult pleural studding or malignant effusion not detected on imaging, further informing decisions regarding resectability (62-65).

Emerging surgical trends

Recent advances in surgical technology have facilitated the development of less invasive approaches to mediastinal staging in NSCLC. Uniportal VATS has been applied in this context due to its favorable postoperative profile, including shorter chest tube duration, reduced hospital stays, and less postoperative pain (66). A further evolution is the subxiphoid uniportal VATS approach, which is gaining attraction for the resection of NSCLC (67-69). Although technically demanding, this approach enables complete mediastinal lymphadenectomy in the hands of experienced surgeons (70). Its central access allows for visualization of anterior mediastinal nodes and bilateral pleural cavities through a single incision, thereby avoiding potential intercostal nerve injury. While not currently used as a dedicated mediastinal staging procedure, it may facilitate comprehensive nodal dissection in selected surgical candidates.

Robotic-assisted thoracic surgery (RATS) is another evolving approach that may influence mediastinal staging. Compared to VATS, robotic systems can facilitate a more meticulous lymph node dissection during NSCLC resection due to enhanced visualization and wristed instrumentation (71). These technical advantages could support the adaptation of robotic platforms for dedicated mediastinal staging. However, such an approach has not been established and would require thorough evaluation of its clinical utility and cost-effectiveness, especially in comparison to existing, less resource-intensive techniques.

Conclusions

Minimally invasive techniques, owing to their high diagnostic yield and low complication rates, represent essential tools in the mediastinal lymph node staging algorithm. Surgical approaches remain a viable option in select, well-defined clinical scenarios. RAB holds promise as a potentially transformative innovation in the near future.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Erik R. de Loos, Aimée J. P. M. Franssen and Peter B. Licht) for the series “Current Advances and Innovations in Surgical Lung Cancer Treatment” published in Translational Lung Cancer Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-843/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-843/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-843/coif). The series “Current Advances and Innovations in Surgical Lung Cancer Treatment” was commissioned by the editorial office without any funding or sponsorship. F.M. received financial support from Intuitive to attend meetings and conferences without any specific conflict of interest related to the submission of this manuscript. T.G. reports receiving grants, royalties, consulting fees, honoraria, and support for attending meetings from Intuitive, which are not related to the submitted work. 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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