Preoperative mediastinal staging: targeted versus systematic nodal sampling

Accurate mediastinal staging is a crucial step in patients with non-small cell lung cancer (NSCLC). Current guidelines for NSCLC mediastinal staging (1,2) recommend minimally invasive endosonography-based techniques [such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and/or endoscopic ultrasound fine-needle aspiration (EUS-FNA)] over surgical techniques for the invasive staging of the mediastinum. Moreover, the European Society of Thoracic Surgeons (ESTS) guidelines recommend performing systematic nodal sampling during endosonography. Although not specifically defined in the guidelines, systematic nodal sampling can be defined as a complete assessment (and detailed reporting) of nodal stations 4R, 4L and 7, sampling the largest node measuring >5 mm on ultrasonography as well as ¹⁸F-fludeoxyglucose (FDG)-avid lymph nodes (LNs) within each of these nodal stations (1). Therefore, a systematic staging by means of EBUS involves examining all accessible LN stations sequentially, starting with N3 nodal stations followed by N2 and then N1 stations (3).

Despite these recommendations, systematic EBUS-TBNA is inconsistently performed in routine clinical practice. In an international survey of mediastinal staging practices amongst 153 interventional bronchoscopists published by Guinde et al., only 69.2% of respondents reported performing a systematic examination (4). Moreover, a study by Miller et al., involving proctored simulated EBUS-TBNA staging, revealed that fewer than half of general pulmonologist performed an appropriate systematic staging (5). This lack of adherence to the ESTS guidelines is also evident in scientific articles. A meta-analysis by Leong et al., which included 9 studies focused on the diagnostic performance of EBUS-TBNA in patients with normal mediastinum on positron emission tomography/computed tomography (PET/CT), showed that 46.8% of patients had <2 LN sampled (6). In summary, although recommended, systematic nodal staging through EBUS-TBNA is not usually performed, and incomplete samplings are carried out in some institutions.

Non-systematic nodal samplings can be performed-based on PET/CT features, anatomical location, ultrasonographic features (B-mode) and/or nodal size. Regarding nodal size, as previously mentioned, the ESTS recommends sampling the largest LN measuring >5 mm in stations 4R, 4L and 7 as a minimum requirement. Caupena et al. (7) analysed the nodal size in a study including patients with a normal mediastinum on PET/CT and mediastinal nodal metastases in surgical specimens, and the largest LN within each station was malignant only in 39 (58.2%) of cases. Following this approach, strategy consisting in sampling only the largest LN of each nodal station by means of EBUS-TBNA would have a sensitivity of 67% for detecting mediastinal metastases. So, the authors concluded sampling only the largest LN is not reliable, moreover in patients with normal mediastinum on PET/CT. Anatomical-based sampling has also been proposed by Soumage et al. (8) in a study of patients with normal mediastinum on PET/CT and invasive mediastinal staging indication (cN1, T ≥3 cm and/or central tumor location) who underwent resection surgery directly (with LN dissection). Of the 541 patients included, 59 presented N2 metastases, 41 (69%) of which were located within lobe-specific lymphatic drainage stations reachable by EBUS-TBNA (4R, 2R, 4L, 2L and 7) and 18 metastases out of the reach of EBUS-TBNA (stations 5,6,8 and 9). Based on their results, the authors affirmed that this strategy is as sensitive as systematic staging; however, the patients did not undergo a real preoperative EBUS; only virtual, N3 stations were not assessed. Therefore, their results should be interpreted with caution. Finally, staging based on PET/CT features, which involves exclusively sampling the FDG-avid nodes, is commonly known as targeted sampling (TS) or hit-and-run strategy.

In contrast to the previously described methods, systematic staging has been extensively studied. In patients with early-stage NSCLC on PET/CT, the prevalence of N2 occult disease diagnosed by systematic staging ranges from 12% to 35% (9-11). This highlights the significance of systematic staging, as it can reduce postoperative upstaging by identifying radiologically occult mediastinal disease (6).

Additionally, several studies have investigated the diagnostic accuracy between systematic staging and targeted PET/CT-based staging in various clinical contexts. In patients with a pathological mediastinum on PET/CT, systematic staging has been shown to provide relevant clinical information compared to targeted PET/CT in many cases (12-14).

Relevant clinical information, which is defined by the authors as the percentage of patients whose EBUS-TBNA findings result in an upstaging from N2a disease to N2b or from N2 disease to N3 disease compared with the PET/CT results (and, consequently, the findings of a targeted EBUS-TBNA sampling), occurs in up to 10–13% of cases (13).

In the recent multicentre clinical trial published by Steinfort et al. (15), among 155 patients with locally advanced NSCLC on PET/CT who underwent invasive staging by means of systematic EBUS-TBNA, in 18 (12%) patients systematic EBUS-TBNA found a greater disease extent compared with PET/CT staging alone and when compared with a hypothetical TS. For all these patients, systematic EBUS-TBNA resulted in significant changes to treatment. So, compared with PET/CT-based TS, systematic sampling (SS) enhances the sensitivity of EBUS-TBNA for the diagnosis of mediastinal nodal metastases and determines the extent of the mediastinal disease more accurately.

Although several ultrasonographic (B-mode) criteria have been proposed as predictors of malignancy (16), studies comparing ultrasonographic B-mode-based TSs with SSs are rare. In a recent article, Sullivan et al. (17), compared ultrasonographic-based TS versus SS in patients with cN0–N1 NSCLC, using an ultrasonographic score [Canada Lymph Node Score (CLNS)] (18). The CLNS includes four ultrasonographic characteristics: short-axis diameter ≥10 cm, absence of central hilar structure, presence of defined nodal margins (>50%) and central necrosis (18). In the validation study including 57 patients with cN0 disease on PET/TC, LNs were evaluated for ultrasonographic features at the time of EBUS-TBNA and defined as “triple-normal” if they were classified as normal on CT scanning, PET scanning (non FDG avidity) and a CLNS <2. The authors found that triple-normal LNs were malignant in only 5.6% of cases. However, as we said previously, not all negative results were confirmed by surgery, and all the included patients had normal mediastinum on imaging techniques with a low prevalence of mediastinal involvement (19).

In the recent noninferiority trial by Sullivan et al. (17), patients were crossed from TS to SS. During TS, triple-normal LNs were not sampled. Afterwards, patients were crossed over to SS and all LNs were sampled. During TS, one malignant LN was diagnosed, and during SS, 8 LNs not previously sampled during TS were found to be malignant. Afterwards, 2 more malignant LNs were detected during surgery. The authors reported an incidence of missed nodal metastases (MNM) in the systematic arm of 0.78% (2 out of 256 LNs) and 2.34% (6/256) for the targeted arm. With a difference in MNM of 1.56%, the authors conclude that TS based on the CLNS is not inferior to SS in patients with NSCLC and cN0/N1 disease on PET/CT (the authors had previously set a noninferiority threshold of 6%). However, in our opinion the study has several flaws. It is unclear if all patients underwent resection surgery for histological confirmation of MNM. Some of them would have a presurgical diagnosis of N2 disease and thereby were not eligible for surgery. Moreover, the calculation of MNM incidence is also unclear. If SS diagnosed 8 malignant nodes and there were 2 MNM in surgical specimens, the total number of malignant nodes missed by TS should be 10 (3.9%) instead of 6 (2.34%). Therefore, the difference of MNM rate between TS and SS would be of 3.22% instead of 2.34%. Although still below the noninferiority margin of 6%, as Korevaar and Annema mentioned (20), it is to be considered that this noninferiority margin is larger than the overall incidence of nodal metastases of the population [11 out of 256 (4.29%)] and thereby impossible to exceed. Finally, although the CLNS was designed for the evaluation of LNs, analysing MNM on a “per LN basis” rather than a “per patient basis” is problematic. Studies focused on mediastinal staging typically use patients as the unit of analysis. The sensitivity of SS was not reported, and should be considerably higher than TS since four patients with MNM were missed in the TS, considering the total population was 91 patients.

The potential advantages of TS include reducing the procedural time and complications. Regarding the procedural time it is always preferred to perform SSs with general anaesthesia to avoid decreasing patient tolerance during the evaluation of suspected LNs. Regarding complications, a prospective study demonstrated that the number of punctures (higher in SSs) was related to the incidence of infectious complications, although this relation was not statistically significant, and the procedural time did not show it either (21).

The recently published proposals for the revision of the N categories in the forthcoming ninth edition of the tumor, node and metastasis classification for lung cancer (22), recommend adding new subdescriptors to N2 category: N2a for single-station involvement, and N2b for multiple-station involvement (N2b). Significant survival differences between these groups increase the value of exploring even negative stations in PET/CT. Invasive mediastinal staging procedures should not only detect where the nodal metastases are but also which nodal stations are free of disease. Therefore, in this new era, systematic samples are more advisable over TSs. Otherwise, a procedure that only detects mediastinal nodal metastases but does not describe the mediastinal stations completely may end up being only a diagnostic instead of a staging procedure. Thereby leading to subsequent requirement for more procedures. Hence, systematic staging, even in early-stage lung cancer, is preferred over targeted.

Acknowledgments

Funding: None.

Footnote

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