Endoscopic Ultrasound Fine-Needle Aspiration in the Staging of Non‑Small‑Cell Lung Cancer

Precise mediastinal staging of non-small-cell lung cancer is extremely important, as mediastinal lymph node metastases generally indicate unresectable disease. Reliance on computed tomography (CT) and positron-emission tomography (PET) alone to stage and determine resectability is limited by false-positive results. Whenever possible, pathologic confirmation of metastases is desirable. Mediastinoscopy and transbronchial fine-needle aspiration are widely established but imperfect modalities. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has emerged as a diagnostic and staging tool because of its safety, accuracy, and patient convenience. We reviewed 13 prospective studies evaluating the comparative performance of EUS for staging lung cancer. We conclude that EUS is a valuable staging modality. Further studies of the role of EUS compared to other modalities such as integrated PET/CT and endobronchial ultrasound (EBUS) are forthcoming.

Lung cancer is the leading overall cause of cancer death in the United States. Metastasis to the mediastinal lymph nodes occurs in nearly one-half of patients.[1] Accurate staging of patients with non-small-cell lung cancer (NSCLC) is critical for prognosis, selection of those with potentially resectable and curable disease, and determination of eligibility for clinical research studies. With the improvements in image resolution and the increasingly complex use of multimodal therapies, more patients with suspected lung cancer require precise staging. Pathologic confirmation of clinically suspicious mediastinal lymph nodes is required to select patients for surgery with curative intent.

Although an increasing variety of competitive and complementary staging techniques are available, there is no consensus on how best to stage patients with the greatest accuracy and least morbidity.[2] Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) has emerged over the past decade as a minimally invasive and effective technique to evaluate the posterior mediastinum. The ideal staging approach is non- or minimally invasive, accurate, safe, and cost-effective. Rapidly evolving techniques such as integrated ¹⁸F-fluorodeoxyglucose positron-emission tomography (PET)/computed tomography (CT), and endobronchial ultrasound (EBUS) need to be assessed in the context of well-established techniques such as transbronchial fine-needle aspiration (TBNA) and mediastinoscopy.

This review will focus on the comparative performance and future applications of EUS-FNA in staging patients with suspected or known NSCLC.

Background

Patients with ipsilateral or subcarinal mediastinal lymph node metastases (N2) or contralateral mediastinal lymph node involvement (N3, stage IIIB) are not appropriate for surgical resection.[3] Patients with regional metastases are best approached with multimodality therapy, while surgery alone is reserved for patients without nodal and/or distant metastases.[4] The vast majority of patients with suspected NSCLC undergo initial staging with CT of the chest, or increasingly, CT with integrated PET-CT. These examinations, however, are not recognized as definitive proof of N2-N3 disease.[5] Furthermore, while CT can in some circumstances identify unresectability (invasion of the great vessels), it lacks sufficient sensitivity to detect small mediastinal metastases.[6]

Toloza et al conducted a meta-analysis of 20 studies with a total of 3,438 patients and reported a sensitivity of 57% and specificity of 82% for CT in the detection of positive mediastinal lymph nodes.[7] While PET is widely thought to be more accurate than CT, false-positive results are common (up to 39%).[8] PET alone cannot generally differentiate left- from right-sided hilar activity. Toloza et al performed another meta-analysis of 18 studies with 1,045 patients and reported a pooled sensitivity of 84%, specificity of 89%, positive predictive value (PPV) of 79%, and negative predictive value (NPV) of 93% for PET scanning in staging mediastinal lymph nodes in NSCLC patients.[7]

TBNA is used to assess the posterior mediastinum. However, it is an invasive, blind technique associated with complications such as bleeding and pneumothorax.[9] Mediastinoscopy-long considered the gold-standard in this setting-is the most invasive technique. It is costly, requires general anesthesia, may necessitate hospital admission, and while safe, is associated with the greatest morbidity.[10,11]

EUS is an outpatient, real-time guided technique that has proven safe and effective in the evaluation of the posterior mediastinum. Additionally, EUS can detect celiac, left adrenal, and some hepatic metastases. EUS does not, in most cases, visualize the anterior mediastinum and, as a highly specialized technique, has been slow to be adopted as part of the routine work-up of patients with NSCLC.

EUS-FNA

EUS has been used in the diagnosis and staging of gastrointestinal malignancies for more than 20 years. Using a transesophageal approach, EUS can evaluate the posterior mediastinum (subcarina), the aortopulmomary window, left paratracheal area, and select distant sites such as the celiac and left adrenal axis. Initially, EUS was performed without biopsy as an imaging test to evaluate mediastinal lymph node metastases. Several sonographic features of malignant lymph nodes have been proposed-features such as size > 1 cm, rounded, hypoechoic, and sharply defined. These sonographic criteria however do not reliably distinguish malignant nodes from benign reactive lymph nodes. The sensitivity and specificity of EUS without FNA for diagnosing mediastinal lymph node metastases ranges from 54% to 75%, and 71% to 98%, respectively.[12,13] The introduction of FNA for tissue confirmation has markedly improved accuracy to 94%-95%.[14-16]

EUS-FNA can be performed in an outpatient setting. The technique, procedure time, and complication rate is similar to that of standard esophagogastroduodenoscopy (EGD). FNA is performed under direct visualization using a flexible linear-array echoendoscope (Figures 1 and 2). The surrounding blood vessels can be visualized by Doppler sonography. Patients can be typically discharged after 30 minutes of postprocedural observation. Reports of bleeding, infection, and pneumothorax are extremely rare. An attendant cytotechnician or cytopathologist increases the yield and accuracy of EUS-FNA.

Methods

Using PubMed searches and a manual review of journals, 13 studies[14-26] were chosen based on the following criteria: (1) prospective nature; (2) published in a peer-reviewed journal; (3) mediastinal nodal biopsy confirmed by histology at the time of resection, or long-term clinical follow-up; (4) source data available for calculation of sensitivity, specificity, NPV, and PPV.

Table 1 lists the studies that met these criteria, in chronologic order. These studies were performed on heterogenous populations, with proven or suspected NSCLC, often on the basis of an abnormal chest CT or PET. The total number of patients included in this analysis was 940. The sensitivity range was 29% to 96%, and was generally over 80%. The low sensitivity in one study may be explained by the selection of patients with a normal mediastinum by CT.[25] The specificity and PPV approached 100% in most other studies. The NPV ranged from 50% to 97%, and in most reports was higher than 80%. In one report EUS-FNA detected two false-positive mediastinal lymph nodes.[26] In that study patients underwent surgical pathologic confirmation even if the EUS-FNA revealed mediastinal metastases. In retrospect, one lesion was thought to be a sharply defined aspect of the primary tumor masquerading as a node.

While no report specifically examined the rate of untoward events, complications were extremely rare. Of the 13 studies (involving 767 patients), 11 reported no complications from EUS-FNA. All reported complications were minor, including self-limited stridor during the procedure (n = 1), sore throat (n = 6) , nausea and vomiting (n = 1), and cough (n = 1).[24] No mediastinitis, esophageal perforation, or significant bleeding occurred, and prophylactic antibiotics were not generally administered.

EUS-FNA vs CT

CT and EUS are widely considered complementary approaches. CT is most useful for imaging the primary tumor and for distant metastases, whereas EUS provides a focused examination of the mediastinum and selected adjacent sites. Direct comparisons of EUS and CT in detecting mediastinal adenopathy have been performed (Table 2). Three studies evaluated the utility of EUS-FNA in patients with enlarged mediastinal lesions by CT.[15,21,22] Sensitivity of EUS-FNA in these three studies ranged from 91% to 96%. Two studies included patients with no identified mediastinal lymph node involvement by CT.[20,25] EUS provided added benefit in this population as well by sparing patients unnecessary additional surgical procedures. Importantly, EUS-FNA can detect advanced disease in approximately one in four patients whose CT implies early-stage disease.

Larson et al randomly assigned 104 patients to one group in whom EUS-FNA was only performed if CT demonstrated enlarged lymph nodes (> 1 cm) as compared to a group in whom all patients underwent EUS-FNA regardless of the result of CT.[27] The frequency of unnecessary thoracotomies was significantly lower in the EUS-FNA group, compared to the group in whom EUS-FNA was done only if the nodes were enlarged (9% vs 25%; P = .03). A total of 39 patients had not undergone EUS-FNA, according to the criteria of conventional work-up, however 9 (23%) were diagnosed with mediastinal metastases. The study suggests EUS-FNA is useful regardless of CT findings.

EUS-FNA vs PET

The role of EUS-FNA after PET remains controversial. It is generally recommended that suspicious adenopathy on PET undergoes pathologic confirmation. One small study compared EUS-FNA with PET and CT for the detection of mediastinal lymph node involvement.[17] A total of 33 patients with suspected lung cancer underwent CT, PET, and EUS-FNA. Each examiner was blinded to the results of the other tests. The sensitivity and specificity of EUS-FNA were superior to CT, PET, and the combination of CT and PET (Table 2). Another study including 79 patients compared EUS-FNA to PET and CT prospectively. [28] Although precise calculation of sensitivity and specificity was not possible because of incomplete pathologic confirmation, EUS-FNA was equally sensitive to, and more specific than PET.

Two studies evaluated the utility of EUS-FNA in patients with PET avidity in the mediastinum and/or upper retroperitoneum.[18,19] Annema et al showed a high sensitivity (93%) and perfect specificity of EUS-FNA in this setting.[18] Approximately 72% of the study patients had separate PET hot spots suspicious for N2/N3 disease, 22% had a centrally located primary tumor with indeterminate mediastinal metastasis, and 6% had presumed N1 disease. EUS confirmed N2/N3 disease in 69% of patients who were PET-positive; one-third of these lesions were outside the reach of mediastinoscopy. About 28% of the PET-positive patients were found to have no mediastinal lymph node metastases on EUS-FNA, and 70% were deemed free of mediastinal metastases at surgery. This result emphasizes the importance of pathologic confirmation of PET-avid findings. Integrated PET-CT was reported to be more accurate than CT alone, PET alone, and visual correlation of PET and CT.[29] EUS-FNA has not yet been compared to integrated PET-CT.

No prospective study has been conducted to evaluate the use of EUS-FNA in patients with a negative PET scan. A patient with normal mediastinal lymph nodes on PET but malignant mediastinal metastases found by EUS-FNA was presented in a case report.[30] This case suggests the utility of EUS-FNA even in patients with no mediastinal lymph node metastases on PET. Considering the high cost of PET ($2,200 Medicare fee) and the fact that the procedure is still not available in many countries, EUS should be applied early in the work-up of patients with NSCLC.

EUS-FNA vs Mediastinoscopy

EUS-FNA and mediastinoscopy are competitive techniques with some overlapping abilities. Two prospective studies directly compared EUS-FNA to mediastinoscopy.[23, 26] In one study, 107 patients with proven NSCLC underwent both EUS-FNA and mediastinoscopy for preoperative staging.[26] All of the 80 patients without mediastinal lymph node involvement at mediastinoscopy proceeded to thoracotomy with tumor resection (regardless of the result of EUS-FNA). EUS-FNA was performed on a voluntary basis for study purposes only. Surgical pathologic staging was compared with preoperative findings.

In another study from Denmark, 60 patients with verified (n = 50) or suspected (n = 10) potentially operable NSCLC underwent both EUS-FNA and mediastinoscopy.[23] Patients with negative mediastinal lymph node involvement at both EUS-FNA and mediastinoscopy subsequently had thoracotomy (88%) or clinical follow-up (12%). Both studies demonstrated a superior sensitivity of EUS-FNA to that of mediastinoscopy (Table 2). The first study showed that the combination of EUS-FNA and mediastinoscopy increased the sensitivity to 86% compared to EUS-FNA alone (61%) or mediastinoscopy alone (53%). In the latter study, mediastinoscopy did not provide additional benefit to EUS-FNA.

The author of the first study concluded that EUS-FNA and medi-astinoscopy are complementary, consistent with the technical aspects of each procedure. EUS-FNA allows wider access to the posterior mediastinum, including the subcarinal node stations, the inferior mediastinum, and the aortopulmonary window. Anterior lymph nodes, including those in the right paratracheal/pretracheal lymph nodes are generally not reachable because of interposed tracheal air. On the other hand, mediastinoscopy allows access to the pre/paratracheal and anterior subcarinal mediastinum, but posterior mediastinal lymph nodes are generally out of reach.

The authors of the second study concluded EUS-FNA was superior to mediastinoscopy. However, the unexpectedly low sensitivity of mediastinoscopy in this study makes its interpretation difficult. The sensitivity of mediastinoscopy in the first study (53%) was also lower than reported in the meta-analysis.[31] In the latter study, all EUS-FNA was performed by one experienced endoscopist, whereas mediastinoscopy was done by four different surgeons. The difference in the number of operators between the two procedures is important since EUS-FNA is considered the most operator-dependent procedure of the various invasive staging modalities.

EUS-FNA vs EBUS

Endobronchial ultrasound (EBUS) is the newest diagnostic tool for mediastinal staging and is being evaluated in large prospective comparisons with EUS. Two prospective studies combined EUS-FNA with endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA).[32,33] The difference in sensitivity between the two procedures was not statistically significant, and the combined approach had higher sensitivity and accuracy than either modality alone (Table 3). The patients were selected based on abnormal CT or PET findings in both studies. Additional larger trials are necessary to evaluate the utility of the combined approach in unselected lung cancer populations. It is thought that combined EUS-FNA/EBUS-TBNA will be shown to provide total "medical mediastinoscopy" and obviate the need for surgical exploration.

Discussion

The role of EUS in the work-up of lung cancer continues to evolve. Although beyond the scope of this review, several studies have reviewed the performance of EUS as an initial diagnostic procedure for a primary mass, and the results are promising.[16,34-36] Studies have also demonstrated both the high sensitivity and high specificity of EUS-FNA for staging T4 tumors (direct invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina; or malignant pleural effusion), both retrospectively[37] and prospectively.[26] However, the role of EUS for T-staging carries special caveats, and EUS in this context should not be routinely applied.

A few studies have examined the role of EUS-FNA to evaluate mediastinal response to neoadjuvant chemotherapy.[38,39] More experience in this area is forthcoming. Cost-efficacy was evaluated prospectively[19] and in decision-analysis modeling.[40,41] These studies demonstrated a cost benefit with EUS-FNA compared to mediastinoscopy and concluded that EUS-FNA could reduce the cost of staging by 16% to 40%. The cost of mediastinoscopy in these studies was very conservative, calculated based on the assumption that patients would stay in a hospital for 3 days.[19]

As EUS continues to establish itself in the community, attention has been given to the training and credentialing of this specialized technique. We believe that performing EUS at a high level requires the completion of a dedicated 4th-year fellowship after the traditional 3-year training in general gastroenterology. Among the various indications for EUS, mediastinal exams are among the most readily learned. In one study, the learning curve for EUS-FNA was assessed using two residents,[19] who performed 29 and 25 procedures, respectively, and failed to achieve the ability of experienced operators.

In practice, among those who perform EUS in the community, the accuracy of EUS-FNA might be lower than that reported in this review. The American Society for Gastrointestinal Endoscopy recommends a minimum of 150 cases of supervised EUS, 50 of which should include FNA.[42]. Since lung cancer is not in the clinical domain of most gastroenterologists, other specialists are now vying for access to EUS. "Mini-courses" in mediastinal EUS are now increasingly available to both pulmonologists and thoracic surgeons.

Conclusions

EUS-FNA has established itself as a powerful tool for staging patients with NSCLC. The precise role of EUS in the era of integrated PET-CT scanning awaits further study, while the evidence base in both tertiary and community centers is mounting. EUS-FNA is a safe, highly accurate, and minimally invasive technique that can spare patients from additional diagnostic testing and, more importantly, unnecessary major surgery. It is expected that combined EUS-EBUS will eventually obviate much of the need for surgical staging. As EUS continues to gain widespread incorporation in lung cancer staging protocols, other specialists are likely to acquire the necessary skills to perform transesophageal sonography.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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