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Lung Cancer Figure 1: Flowchart for a Mediastinal Study Contrast enhanced CT

adequate samples, namely samples with neoplastic cells or lymphoid cellularity.36

Others have proposed a score based on the number of lymphocytes on the slide; using EBUS-TBNA and accounting only for the samples with more than 40 lymphocytes per field (magnification x40), the authors produced only one false-negative.37

Therefore, we Positive mediastinal nodes PET Negative mediastinal nodes

can suppose that using semi-quantitative criteria for evaluating adequacy can improve TBNA performance on healthy lymph nodes, modifying the value of a negative result in mediastinal staging.


N2 >10%

post-test probability*

N1 N0 Surgical Techniques

Positive STOP

N2 Negative >10%

Mediastinoscopy, thoracoscopy, etc.

*Bayes’ theorem.

CT = computed tomography; EUSFNA = endoscopic ultrasound-guided fine-needle aspiration; PET = positron emission tomography; SUV = standardised uptake value; T = tumour; TBNA = transbronchial needle biopsy; USTBNA = ultrasound-directed transbronchial needle aspiration.


However, despite a small amount of reported false-negatives (5–8%), a recent meta-analysis showed that in patients with normal-sized lymph nodes the false-negative rate may reach 25%.15

This happens above all for central5,16,17 or large tumours1,18 Negative

post-test probability*

<10% Surgery <10%

Grading 3* T SUV >10* T size* Central T*

Surgical techniques are considered as a source of reference for the evaluation of suspicious lymph nodes following a negative or inadequate cytological result. Of the surgical techniques, mediastinoscopy is the gold standard in the pre-operative staging of lung cancer. Its sensitivity is high (75–90%) and complications are rare, although potentially severe.5,38–41

paratracheal stations (levels one, two and four) and the subcarinal station (level seven, anterior).5 among surgeons;42

In general, this technique is not popular

in addition, the increasing availability and accuracy of ultrasound-guided minimally invasive techniques have been challenging the reference role of mediastinoscopy in recent years.43

Video-assisted thoracic surgery (VATS) can reach several mediastinal levels, in particular nodal stations five and six, but its sensitivity varies widely among series. The aorto-pulmonary window station five can be approached by Chamberlain’s anterior mediastinotomy when other techniques are not available or have failed.5

or for

tumours with an elevated standardised uptake value (SUV).18,19 Nevertheless, owing to its high performance, PET is considered the reference test for all potentially operable patients.20

Needle Aspiration Techniques

The use of TBNA in lung cancer staging has recently been steadily increasing. The sensitivity and specificity of this technique are around 76 and 98%, respectively.21 coupled with TBNA,22

When rapid on-site examination (ROSE) is the performance of TBNA increases owing to the

shorter duration and lesser risks of the procedure according to some authors,23

or because of better accuracy according to others.24,25

When supported by other complementary techniques, such as EBUS, TBNA yield may improve, and its sensitivity may rise >90% when a convex probe is used, which allows direct observation of the needle piercing the lymph node.26–29

Staging Protocols for Mediastinum It is well known that in clinical stage N0, histology–cytology finds nodal metastases in up to 20–25% of cases.18,44,45


mediastinal involvement (even without CT or PET abnormalities in the mediastinum) is more common if pathological hilar (N1) lymph nodes are present.18,46

Many risk factors for unforeseen mediastinal metastasis have been described,8,18,47–58

including tumour size, adenocarcinoma cell type, elevated levels of carcinoenmryonic antigen (CEA), central or right upper lobe location, tumour-related symptoms, patient age <65 years, tumour SUV >9–10 and pleural involvement. When risk factors are lacking, some authors suggest avoiding systematic lymph node dissection during surgical resection.59,60

However, in clinical practice the worthwhile

application of ultrasound appears limited to lymph nodes at American Thoracic Society (ATS) stations one and two (in such cases endoscopists have no definite safe landmarks for the puncture), to small lymph nodes (≤5mm) and when ROSE is not performed.30,31

Similar to TBNA, EUS-FNA

provides high sensitivity and specificity; its major limitations are lymph nodes anterior to the trachea and to the main bronchi.32–34

As for other needle aspiration techniques, a positive result can be considered definitive for staging, while surgical confirmation is generally required in the event of a negative result.5,35

This assumption

does not consider any qualitative evaluation of a non-diagnostic sample; in fact, to date no reliable criteria for distinguishing whether a sample comes from a lymph node or not have been identified. Martinez-Olondris et al. in a series of 194 patients demonstrated that the sensitivity of TBNA was 88% when the study included only


The European Society of Thoracic Surgery (ESTS) recommends direct resort to surgery in cT1N0 tumours only for squamous cell carcinoma, and to mediastinoscopy for other cell types; in the other clinical stages, minimally invasive techniques (EBUS-TBNA, EUS-FNA) and, if negative, mediastinoscopy are suggested. When PET is available, surgery is advised in clinical stage 1, except in central tumours, adenopathies >1.6cm and tumours with a low SUV.1


observations that the probability of mediastinal metastasis rises in line with the tumour SUV value18,19 ACCP5

conflict with the ESTS position. The

guidelines agree on avoiding further examinations in peripheral stage 1 tumours, but do not differentiate among cell types, and suggest cytological sampling irrespective of PET result when CT shows enlarged nodes and surgical confirmation of every negative needle aspirate. This argument is sometimes used due to the moderate negative predictive value of mediastinoscopy, which is not vastly different from that of EBUS-TBNA.61

node involvement seem to benefit from surgery,62–69

As only patients with microscopic many surgeons


However, it can only reach the

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