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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.105 no.4 Madrid abr. 2013 



The role of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in non small cell lung cancer (NSCLC) patients: SEED-SEPD-AEG Joint Guideline

Papel de la punción guiada por ecoendoscopia en pacientes con carcinoma de pulmón de células no pequeñas (CPNM): guía clínica de consenso Sociedad Española de Endoscopia Digestiva (SEED) - Sociedad Española de Patología Digestiva (SEPD) - Asociación Española de Gastroenterología (AEG)



Enrique Vázquez-Sequeiros1, Fernando González-Panizo Tamargo2, Ángel Barturen3, Ángel Calderón4, José Miguel Esteban5, Gloria Fernández-Esparrach6, Antonio Gimeno-García7, Angels Ginés6, José Lariño8, Mercedes Pérez-Carreras9, Rafael Romero10, José Carlos Subtil11 and Juan Vila12

1Department of Gastroenterology. Hospital Ramón y Cajal. Madrid. Universidad de Alcalá, IRYCIS. Madrid, Spain
2Department of Gastroenterology. Hospital Universitario Quirón. Madrid. Spain
3Department of Gastroenterology. Hospital Cruces. Bilbao, Spain
4Department of Gastroenterology. Hospital Basurto. Bilbao, Spain
5Department of Gastroenterology. Hospital Clínico San Carlos. Madrid, Spain
6Unit of Endoscopy. Department of Gastroenterology. Hospital Clinic. CIBEREHD. IDIBAPS. Universidad de Barcelona. Barcelona, Spain
7Department of Gastroenterology. Hospital Universitario. Tenerife, Spain
8Department of Gastroenterology. Hospital Clínico. Santiago de Compostela, Spain
9Department of Gastroenterology. Hospital 12 de Octubre. Madrid, Spain
10Department of Gastroenterology. Hospital Virgen Macarena. Sevilla, Spain
11Department of Gastroenterology. Clínica Universitaria Navarra. Pamplona, Navarra. Spain
12Servicio de Gastroenterología. Hospital de Navarra. Pamplona, Navarra. Spain





Lung cancer is one of the most frequent neoplasms in our environment, and represents the first cause of cancer related death in western countries. Diagnostic and therapeutic approach to these patients may be complicated, with endoscopic ultrasound guided fine needle aspiration (EUS-FNA), classically performed by gastroenterologists, playing a very important role. As this disease is not closely related to the "digestive tract", gastroenterologists have been forced to update their knowledge on this field o adequately diagnose this significant group of patients. The recent advent of modern and promising techniques like endobronchial ultrasound guided fine needle aspiration (EBUS-FNA) have prompted new approaches for diagnosis and staging of this type of patients. In this clinical guideline, the "Sociedad Española de Endoscopia Digestiva" (SEED), "Sociedad Española de Patología Digestiva" (SEPD) and the "Asociación Española de Gastroenterología", have jointed efforts to update the existing knowledge on the field and provide their members with evidence based recommendations.

Key words: Endoscopic ultrasound. Fine needle aspiration. Lung cancer. Staging.


El cáncer de pulmón es una de las neoplasias más frecuentes en nuestro medio y la principal causa de muerte por cáncer en países occidentales. El manejo diagnóstico y terapéutico de estos pacientes es complejo, desempeñando en el mismo un papel muy relevante la punción guiada por ultrasonografía endoscópica (USE-PAAF), que clásicamente realizan los gastroenterólogos. Al tratarse de una enfermedad no relacionada con el "aparato digestivo", los gastroenterólogos han tenido que actualizar sus conocimientos en este campo, para diagnosticar de forma adecuada a este nutrido grupo de pacientes. La incorporación en estos últimos años de nuevas y prometedoras técnicas, como la punción aspirativa transbronquial guiada por ecobroncoscopia (USEB-PAAF), han modificado el acercamiento al diagnóstico y estadificación de estos pacientes. En la presente guía clínica, la Sociedad Española de Endoscopia Digestiva (SEED), la Sociedad Española de Patología Digestiva (SEPD) y la Asociación Española de Gastroenterología (AEG), han aunado esfuerzos para actualizar el grado de conocimiento existente sobre este tema y dar recomendaciones basadas en la evidencia a sus miembros.

Palabras clave: Ultrasonografía endoscópica. Punción con aguja fina. Cáncer de pulmón. Estadificación.



Lung cancer is the most common cause of cancer related mortality (1). In Spain, it has been estimated that incidence of lung cancer is approximately 20,000 new cases per year, which represents the 12 % of all neoplasms (1). Mortality associated with this type of tumor in our country reaches 20 %, higher than breast, prostate and colon cancer combined (1). Only about a third of these patients are amenable for surgical resection at the time of diagnosis and the overall 5-year survival has been estimated in 15 % (1).

For an adequate selection of candidates for surgery and/or neoadjuvant therapy, it is mandatory to obtain a tissue diagnosis confirmation of histology type and a tumor stage assessment. On figure 1 it is represented the most updated TNM Classification elaborated by the American Joint Commission on Cancer for the Lung Cancer (AJCC) that has been recently adopted by the "Sociedad Española de Patología del Aparato Respiratorio" (SEPAR) (2). As a general rule, stage I and II non-small cell lung cancer (NSCLC) are treated by surgery alone, while radiotherapy maybe an option for cure in patients at this stage of disease that have a poor performance status or are unfit for surgery. Patients on stage III present an elevated risk of tumor recurrence if treated by surgery or radiotherapy alone. For this reason stage IIIA patients are initially treated with chemotherapy and surgery or radiotherapy being performed afterwards; and stage IIIB patients are usually treated with chemo and radiation therapy combined. Finally, those patients with a stage IV disease are typically offered palliative chemotherapy (3).

This therapeutic algorithm should give us an idea on how important is to obtain an adequate diagnosis and staging in this type of patients to better select the most adequate treatment for those affected by this deadly disease (Fig. 2).



What is the role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in patients with clinical suspicion for lung cancer?

When a patient presents with a suspected lung cancer, further testing is usually indicated to histologically confirm diagnosis (tumor type) and to determine extension of the disease (tumor stage). Patient history, physical exam and laboratory testing are the initial steps when evaluating patients with suspicion for lung cancer (4). Afterwards, imaging of the lesion should be obtained to further characterize the primary lesion and its relationship with surrounding structures, to identify mediastinal lymph nodes suspicious for malignancy, and to exclude metastasis in the other lung, chest wall or in the upper abdomen (4). Computerized tomography (CT), either alone or combined with positron emission tomography (PET), and magnetic resonance imaging (MRI) are some of the techniques most frequently employed for this purpose (4). CT diagnosis of malignancy is based on size, and recent publications suggest that malignant nodes are those ≥ than 15 mm (2). Unfortunately, this size criterion is associated with a 40 % false positive rate and a 20 % of false negative results (2). Although PET scan is not only based on size, but on lymph node metabolism, and subsequently has a higher sensitivity than CT, its false positive rate is as high as 25 % (4). Therefore, unfortunately, lung cancer diagnosis cannot be confirmed by non invasive tests, and to obtain a tissue diagnosis confirmation minimally invasive techniques (flexible bronchoscopy with forceps biopsy and/or blind transbronchial fine needle aspiration [TBNA], CT-guided percutaneous fine needle aspiration [FNA}, endoscopic ultrasound guided fine needle aspiration (EUS-FNA), endobronchial ultrasound [EBUS] TBNA) or surgical exam (mediastinoscopy, thoracoscopy...) will be required (4). Selection of one technique or another for tissue diagnosis remains controversial, but certainly depends on several factors:

1. Performance characteristics of each test (diagnostic accuracy and safety)

2. Tumor location (central vs. peripheral).

3. Expertise available at each institution.



EUS-FNA may be useful in those patients who present a mediastinal mass or lymphadenopathy of unknown origin (benign vs. malignant) or have a non-small cell lung cancer that requires either cytologic confirmation or preoperative staging for treatment decision (5). Furthermore, the sample obtained by EUS-FNA may be employed not only for tumor histology assessment, but also for ancillary techniques such as immunohistochemistry or polimerase chain reaction. In those cases in which cytology is not conclusive, immunohistochemycal analysis in search for specific markers like TTF-1, p63 or CK5/6 may be helpful and increase diagnostic accuracy (6). A systematic review recently published, showed determination of endothelial growth factor receptor may predict response to tyrosine kinase in NSCLC patients (6). Whether histology needles may be better suited than cytology ones for immunohistochemical analysis, or may even preclude the need for onsite cytopathology assessment during procedure is unknown at present time.

EUS has been classically performed by gastroenterologists through the esophagus, allowing one to visualize and biopsy lesions located in the posterior and mid mediastinum (upper and lower paratracheal [stations 2 and 4L], aortopulmonary window [station 5], subcarinal [station 7], paraesophageal area [station 8], and inferior pulmonary ligament [station 9]) but not in the anterior mediastinum due to airway interposition that precludes US waves transmission (5,6). Furthermore, when the echoendoscope is advanced into the gastric cavity, the upper part of the retroperitoneum (e.g. adrenal glands) is visualized and biopsies may be obtained if lesions are found at this level (5,6).

Recent guidelines (2) from Pulmonologists Societies like the Spanish one, strongly recommend that: a) to explore the mediastinum in search for all nodes suspicious on PET-CT; b) the exam should be started by looking for N3 nodes, and continue with N2 and N1 nodes; c) nodes ≥ 5 mm should be sampled; d) a minimum of 3 passes per node are recommended before considering it negative; and e) if sample is contaminated, necrotic, bloody or insufficient, it should be considered indeterminate, and negativity should be confirmed by surgical techniques (2).

EUS-FNA indications

Due to its elevated diagnostic accuracy and safety, transoesophageal EUS-FNA is generally accepted nowadays as the standard in diagnosis of most mediastinal nodes and masses. The three main indications for EUS-FNA in the mediastinum are: a) diagnosis of mediastinal lymph nodes (stations 4L , 5, 7, 8, and 9) of unknown origin; b) staging of non small cell lung cancer (NSCLC); and c) biopsy of centrally located lung tumors (located in the vicinity of the esophagus).

EUS-FNA in patients with prior non diagnostic blind TBNA

It is important to highlight that EUS-FNA allows one to confidently diagnose the origin of the mediastinal lesion, either benign or malignant (NSCLC or another), even in those cases with prior non diagnostic blind TBNA (5-7). In a prospective cohort study, including a total of 50 patients with suspected sarcoidosis, Annema et al. demonstrated by means of EUS-FNA the presence sarcoidosis in 82 % of patients (71 % had a prior non-diagnostic bronchoscopy) (8). EUS-FNA may also allow one to diagnose malignancy in mediastinal lymph nodes unrelated with lung cancer (metastasis from other type of tumor: esophageal, breast, renal cell cancer...), with a diagnostic accuracy as high as 96 %, according to prospective cohort studies (9). Although bronchoscopy is the initial diagnostic test in patients with clinical suspicion for lung cancer, at least 30 % of times TBNA fails to reach a diagnosis. A recent meta-analysis including 13 studies evaluating the diagnostic usefulness of bronchoscopy TBNA in NSCLC, showed a sensitivity ranging from 39 % to 78 % (95 % CI [17 %-84 %]), and a specificity of 99 % (95 % CI [96 %-100 %]) (10). Moreover, one third of patients with lung cancer have mediastinal lymph nodes that after TBNA fails still need a diagnosis and staging as it is important for prognosis and allows to plan specific therapy in such patients. There is enough evidence in the literature supporting EUS-FNA is effective for diagnosis of these patients after TBNA has failed (10,11). Data coming from prospective controlled studies have demonstrated that EUS-FNA is able to correctly diagnose malignancy in up to 96% of malignant cases (10,11).

EUS diagnosis of T4 NSCLC patients

At present time, mediastinal tumor invasion is often assessed during surgery because CT scan has a very limited performance as well as PET-CT because of its limited anatomic resolution. Some reports have suggested EUS-FNA permits determine if the lung tumor invades mediastinal organs (e.g. left atrium), stage T4 that should contraindicate surgery, with a sensitivity and specificity of 87 % and 98 %, respectively (12). In a cohort of 424 patients with suspected lung cancer, EUS had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 39 %, 100 %, 100 %, 92 %, and 92 % in assessing T4 tumors (12).

EUS-FNA in NSCLC patients with enlarged mediastinal lymph nodes on CT scan, or PET positive lymph nodes

Patients with these features (enlarged or metabolically active nodes), will typically undergo sampling, as the sensitivity and specificity of imaging alone in the detection of lymph node metastasis is insufficient. Sensitivity, specificity and diagnostic accuracy of EUS-FNA in this clinical scenario has been estimated in a large number of prospective studies as high as 83-97 %, 84-100 %, and 94-97 %, respectively (5-7,9-20). In summary, there is enough evidence supporting the fact that EUS-FNA plays a major role in the diagnosis and lymph node staging of lung cancer patients at present time, after CT or PET have identified nodal disease in the posterior mediastinum.

EUS-FNA in NSCLC patients with no enlarged mediastinal lymph nodes on CT scan

Although it does appear to be clear that EUS-FNA is indicated in the mediastinal staging of patients with suspected lung cancer, particularly in patients with enlarged (short axis > 10 mm) lymph nodes or PET-positive lymph nodes, there is not a clear answer on what is the role of EUS-FNA on patients with node negative NSCLC on CT. Although, there are less data regarding this issue, some studies suggest that 20 % of NSCLC patients with a negative CT scan do have malignant nodes at surgery (18,21-23). Prospective cohort studies conducted in 76 unselected patients have been able to prove that EUS-FNA is able to efficiently detect those metastasis (25 % in that cohort of patients with a negative CT) (23). Another prospective, controlled comparison study assessed the role of EUS and EUS-FNA in patients with CT node negative NSCLC (18). Eighty consecutive patients were evaluated, all of them underwent EUS and EUS-FNA exam. Diagnostic accuracy of EUS/EUS-FNA was 91 %, while CT was only 71 %. The negative predictive value of EUS-FNA was 92 %. Two of the patients evaluated presented a N3 NSCLA (even with a negative CT scan) (18). Similar results have been published in other prospective controlled comparisons between CT and EUS-FNA including 47 patients with NSCLC (22). Recent guidelines recommend to complete tumor staging in the following cases: a) after a negative PET-CT, except in the case of centrally located NSCLC as they usually contact with the mediastinum; and b) in tumors with low metabolism (2).

EUS-FNA of distant lymph nodes in NSCLC patients

EUS-FNA may also detect and biopsy lymph nodes in distant areas like the celiac region (classified as M1 disease by the TNM Classification). Results from a prospective controlled study conducted in over 113 lung cancer patients proved that 11 % of patients had celiac nodes, and all of them were positive at EUS-FNA (vs. 50 % for CT guided biopsy) (24). Preliminary reports, have also suggested that molecular analysis (CEA, CK19, KS1/4, lunx, muc 1, PDEF) may be conducted on samples obtained by means of EUS-FNA, and these analysis may help us identify unknown micrometastasis or even determine patient outcome (25).

EUS-FNA for re-staging NSCLC patients

Another special situation that may be found in clinical practice is the persistence of lymphadenopathy after treatment of malignancy. As this feature is not a definitive sign of tumor presence or recurrence, pathological sampling and diagnosis is essential for determining the appropriate treatment. In this regard, results from a recent publication comparing results of re-staging 28 NSCLC patients after chemo-radiation therapy by CT/PET and EUS-FNA, showed that EUS-FNA had a 92.3 % diagnostic accuracy and a 91.6 % negative predictive value (26). Concordance between EUS-FNA findings and metabolic response during FDG-PET of lymph node metastases occurred in approximately 50 % of patients (26). These results support that restaging with EUS-FNA after induction chemoradiotherapy reliably predicts the absence of nodal metastasis. However, other recent publication of a study on 58 patients showed less optimistic results, with a sensitivity and negative predictive value of 44 % and 58 %, respectively (27).

EUS-FNA of mediastinal lymph nodes safety

A large number of studies, summarized in recently published guidelines, have demonstrated that EUS-FNA of mediastinal lesions is safe, especially for solid lesions (28). The complication rate of EUS-FNA was estimated in 0.5% for solid mediastinal masses or nodes and 14 % for mediastinal cysts (28). Infection, hemorrhage or perforation are some of the complications that have been reported associated with this technique (28). Only 3 cases of tumor seed related to EUS-FNA have been reported, none of them happened in NSCLC patients (28)


EUS should be clearly distinguished from endobronchial ultrasound (EBUS), which is performed through the airway during bronchoscopy and, contrarily to EUS, permits an excellent visualization of the anterior mediastinum. EBUS is a more recent acquisition for tissue diagnosis that still is consolidating in clinical practice, and allows one to access and biopsy those areas that are blind to the classical transesophageal EUS. While EUS-FNA is generally performed by gastroenterologists, the EBUS-TBNA technique is typically conducted by pulmonologists. EBUS-TBNA permits one to obtain biopsies from mediastinal lymph nodes located in the paratracheal, subcarinal or hilar area in an effective and safe manner (29-32) (Fig. 1).

Indications for EBUS-TBNA

At present time, there are three main indications for EBUS-TBNA: a) staging of NSCLC patients; b) tissue diagnosis of mediastinal masses and lymph nodes and endobronchial lesions; and c) guidance of endobronchial therapy (29-35).

EBUS-TBNA compared with blind TBNA

Prospective cohort studies conducted in 200 consecutive patients comparing EBUS-TBNA and blind TBNA have shown EBUS-TBNA to be more accurate at diagnosing these patients (84 vs. 58%) (33). Similar results have been reported in meta-analysis including 11 observational studies with 1,299 patients (34).

EBUS-TBNA compared with EUS-FNA

Although results reported in the literature for EUS-FNA and EBUS-TBNA are excellent, it has to be acknowledged that each technique presents certain technical limitations that preclude one to sample all mediastinal regions (33-35). Both techniques sample different areas of the mediastinum, and it seems reasonable to use a combination of both techniques to obtain a complete mediastinal lymph node study when staging patients with NSCLC. In a prospective, blinded, comparative and controlled study including 138 patients with suspected lung cancer, the sensitivity of combined EUS-FNA + EBUS-TBNA (93 %), was significantly superior to that achieved by EUS-FNA alone, EBUS-TBNA alone, blind TBNA, blind TBNA + EBUS-TBNA, blind TBNA + EUS-FNA (69 %, 69 %, 36 %, 76 % and 79 %, respectively) (35).

Based on literature results, it seems a reasonable approach to start with EUS-FNA when imaging techniques like CT suggest lymph nodes and/or masses are located in the lower or posterior mediastinum, while EBUS-TBNA should be preferred when target lesions are in the upper or anterior mediastinum (33-35). If EUS-FNA and/or EBUS-TBNA are not available in a specific Institution, surgical techniques like mediastinoscopy should be employed for diagnosis (33-35). EBUS (using the radial miniprobe) may also be employed for tumor T staging in NSCLC or to diagnose extension in endobronchial lesions. When a peripheral pulmonary nodule is identified, EBUS-TBNA may be useful for imaging and biopsy (diagnostic accuracy greater than 70 %) (36).

On the other hand, EUS-FNA has been shown to be very sensitive, accurate and safe for diagnosis of centrally located lung masses (diagnostic accuracy 97 %, and no complications in a prospective cohort including 32 patients) (37). EBUS-TBNA, as well as EUS-FNA, may be useful for diagnosis of sarcoidosis, as they may detect granulomas in the biopsy (38-40).

Diagnostic accuracy of these US guided techniques is superior to blind TBNA, EUS-FNA and EBUS-TBNA might qualify as the technique of choice to diagnose sarcoidosis.

EBUS-TBNA of mediastinal lesions safety

Safety of EBUS-TBNA is well documented in a systematic review of 18 observational studies including 1,782 patients (41). In that review, only minor complications (cough, agitation, blood at puncture site) were identified in < 1 % of patients (41).

Surgical techniques for mediastinal lymph node sampling

Although it is not the aim of this guideline, it is important to be familiar with surgical techniques competing with EUS-FNA, and to understand advantages and limitations of each of them.

Cervical mediastinoscopy

Cervical mediastinoscopy is a surgical technique, not a minimally invasive test, that allows one to sample lymph nodes located in the upper paratracheal area (stations 2R and 2L), lower right and left paratracheal (station 4R and 4L), anterior part of the subcarinal area (station 7) and occasionally hilar nodes (stations 10R and 10L). Prospective cohort studies have shown mediastinoscopy has an elevated diagnostic yield (higher than 90 %, with < 5 % complication rate) (42,43). A recent publication of a prospective, randomized, multicenter trial including 241 NSCLC patients, directly compared the diagnostic staging accuracy of: a) "mediastinoscopy" vs. b) "EUS-FNA followed by EBUS-TBNA and, in those negative cases, followed by mediastinoscopy" (43). Sensitivity of mediastinoscopy alone was significantly lower than the combined strategy (79 %, 95 % CI [66 % -88 %] vs. 94 %, 95 %CI [85 % -98 %] respectively; p = 0,02). Overall, the sensitivity of medastinoscopy was lower than EUS-FNA/EBUS-TBNA (80 %, 95 % CI [68 % -89 %] vs. 94 %, 95 % CI [85 % -98 %] respectively; p = 0.04). Furthermore, it should be mentioned that the combined strategy decreased two times the need for thoracotomies.

Mediastinotomy and thoracoscopy

Other surgical techniques such as anterior mediastinotomy (samples station 4L, subaortic/station 5, paraaortic/station 6, and subcaribal area/station 7) or thoracoscopy (samples azigos/station 4R, station 5, 6, paraesophageal/station 8 and pulmonary ligament/station 9) are only used when other less invasive tests (e.g. EUS-FNA, EBUS-TBNA...) are unable to reach a diagnosis. Thoracoscopy has been proven in prospective cohort studies to be more reliable than radiologic tests for detection of pleural or mediastinum involvement (44-46). Prospective cohort studies have shown thoracoscopy significantly improves staging accuracy in patients with suspected stage IIIB NSCLC (46).

However, at present time, most lung cancer patients will be diagnosed by means of non invasive tests (like EUS-FNA or EBUS-TBNA) in an outpatient basis, reducing the costs and risks of this type of techniques. For this reason, mediastinoscopy, mediastinotomy and thoracoscopy are generally reserved only for those cases in which minimally invasive tests have failed (42,43).

Pleural effusion in NSCLC patients

When staging a patient with a lung cancer, it is not infrequent that a pleural effusion is found in the preoperative work up. In patients with a clinical suspicion for NSCLC is mandatory to puncture this pleural effusion to exclude a malignant origin. It has been estimated that approximately 65 % of them will be malignant, and may require even more than one thoracentesis or a thoracoscopy and biopsy to establish a definitive diagnosis (47-51). EUS provides excellent visualization of both pleuras, and EUS-FNA may be performed in a safely and accurate manner from the esophagus as shown in prospective studies (47-51).

Adrenal gland metastasis in NSCLC patients

Another important point when evaluating a patient with NSCLC is the evaluation of the adrenal glands (27-29). It has been estimated that at least 4 % of NSCLC patients will present a nodule in the adrenal gland at the time of diagnosis (52,53). CT scan and MRI have shown in prospective cohort studies a sensitivity, and specificity to detect adrenal nodules that ranges from 98 %-100 % and 92 %-95 %, respectively (54-56). PET scan is also very accurate for detection of adrenal gland metastasis in NSCLC patients (92-93 %) (57). At present time, EUS-FNA is the technique of choice for tissue diagnosis confirmation of adrenal gland metastasis (58,59). This is due to its elevated diagnostic accuracy and less than 1 % rate of complications as shown in prospective cohort studies evaluating consecutive unselected patients (58). In that study, EUS-FNA of the adrenal gland modified the TNM staging of the patient in 70 % of cases, and the treatment in 48% of them (gained surgery 25 %, avoided surgery 5 %, surgically verified benign disease 5 %, no cancer and no further work up 5%, and no cancer, control computed tomography, and then no further workup 8 %) (58). A malignant left adrenal gland lesion was found in 28 % and was significantly associated with shorter survival, making authors conclude that EUS-FNA of an enlarged adrenal gland in patients with known or suspected NSCLC had a significant impact on TNM staging, treatment, and survival. Recent guidelines recommend to sample enlarged adrenal glands (left or right), only on those cases in which cytology result may have an impact on patient management (2,28).

Impact of EUS-FNA on NSCLC patient management and cost

A number of studies have been reported investigating the impact of EUS-FNA on patient management and cost (60,61). A total of 213 consecutive patients with mediastinal nodes were evaluated in a retrospective study, and a positive EUS-FNA result was obtained in 84 % of patients, resulting in a modification of patient therapy in all of them (84 %), with no impact in the remaining patients (16 %) (61). Authors estimated that by performing EUS-FNA in that cohort of patients, a reduction in cost of €100.593 was obtained, with a mean cost reduction of €472 (SD = €607) per patient. Similar results were demonstrated in a cost minimization analysis comparing EUS-FNA vs. EUS-FNA combined with EBUS-TBNA vs. bronchoscopy and mediastinoscopy (61). This study evidenced that the combination EUS-FNA/EBUS-TBNA was the most economical approach for patients with suspected NSCLC. Sensitivity analysis also demonstrated that if probability of malignant lymph nodes is less than 32.9 % (like in patients with a CT-scan with no nodes larger than 10 mm), EUS-FNA would be the most economic technique. However, if pre-test probability of having malignant lymph nodes in superior to that percentage (like in those cases with enlarged nodes on CT-scan), the combination EUS-FNA/EBUS-TBNA is the most economic strategy for diagnosis (61). Prior studies were also able to prove that in patients with mediastinal lymphadenopathy EUS-FNA is the most economic test to obtain a tissue diagnosis confirmation when prevalence of malignant nodes exceeds 24 % or EUS-FNA sensitivity is above 76 % (62). If prevalence of malignancy is below 24 % or EUS-FNA sensitivity does not reach 76 %, mediastinoscopy is the most economic approach (62). In a recent prospective, multicenter study conducted on 241 patients with resectable NSCLC, authors demonstrated that the rate of futile thoracotomies was reduced from 18 % to 7 % if EUS-FNA was performed (63).

Who should be trained to perform biopsies in NSCLC patients

Finally, there is an opened discussion about the person who should perform the biopsy in lung cancer patients. The answer for such a question is not straight forward. There is no doubt that NSCLC and other mediastinal lesions will require an expert in pulmonology for best diagnosis and treatment, and gastroenterologists are not adequately prepared to be in charge of these patients. Pulmonologists have classically relied on blind-TBNA for diagnosing these patients, but results have been clearly unsatisfactory, due to the blindness of the technique and inaccessibility to certain stations. With the advent of EBUS-TBNA following a transbronchial route, the blindness limitation has been solved and pulmonologist performance has dramatically increased (33-35). Gastroenterologists have been performing transesophageal EUS-FNA for about two decades, and have proven that EUS-FNA reaches most stations located in the posterior and mid mediastinum and infradiaphragmatic area with excellent results (5-9). As this technique is widely available at present time in Gastroenterology Units, and there is growing evidence that a combined approach (EUS-FNA/EBUS-TBNA) obtains the best results in terms of sensitivity, accuracy, impact on therapy and cost, we would advocate to make a reasonable use of both techniques (33-35). If lymph nodes are located in the anterior/superior mediastinum, we would recommend to directly select EBUS-TBNA, and if located in other areas, select EUS-FNA. Although a personal opinion, it seems reasonable that pulmonologists and not gastroenterologists perform the transbronchial approach (EBUS-TBNA), and gastroenterologists, more familiarized with the transesophageal route perform EUS-FNA. As EUS-FNA and EBUS-TBNA may have a significant impact on patient management, it is our believe that there is a crucial need to spread the technique from specialized centers with experience in both of them.


Summary and recommendations

1. Transesophageal EUS-FNA permits visualize and biopsy lesions located in the posterior and mid mediastinum in a safe and effective manner, even in those cases with prior non diagnostic blind TBNA. Evidence level 2++, Recommendation grade B.

2. EUS-FNA has been proven to be highly sensitive, specific and accurate for diagnosis of patients with enlarged mediastinal lymph nodes on CT scan (> 10 mm), or PET positive (metabolically active nodes). Evidence level 2++, Recommendation grade B.

3. The use of EUS-FNA should be recommended in NSCLC patients with a negative CT scan, as EUS-FNA is able to detect unknown metastasis in up to 25 % of them. Evidence level 2++, Recommendation grade B.

4. EUS-FNA has been proven to be useful to assess patient response to neoadjuvant therapy (negative predictive value 70-90 %). Evidence level 2++, Recommendation grade B.

5. The combination of EUS-FNA and EBUS-TBNA is the most accurate method for minimally invasive diagnosis and staging of lung cancer patients. It is recommended to start sampling those lesions that may provide the most advanced tumor stage. Evidence level 1+, Recommendation grade A.

6. EUS-FNA of centrally located lung masses is safe and accurate and should be more frequently indicated (diagnostic accuracy: 97 %). Evidence level 2-, Recommendation grade C.

7. Surgical techniques (mediastinoscopy, mediastinotomy or thoracoscopy) should be reserved only for those cases in which less invasive tests (e.g. EUS-FNA, EBUS-TBNA...) are unable to reach a diagnosis. Evidence level 4, Recommendation grade D.

8. EUS provides excellent visualization of both pleuras, and EUS-FNA of pleural effusions may be performed in a safely and accurate manner from the esophagus. Evidence level 3, Recommendation grade D.

9. In patients with NSCLC, EUS-FNA is the technique of choice for tissue diagnosis confirmation of adrenal gland metastasis. In this clinical setting, EUS-FNA will have a significant impact on TNM staging, treatment, and patient survival. Evidence level 2+, Recommendation grade C.

10. Cost analysis studies have evidenced that the combination EUS-FNA/EBUS-TBNA is the most economical approach for patients with suspected NSCLC if pre-test probability of having malignant lymph nodes is less than 32.9 % (e.g. patients with a CT-scan with no nodes larger than 10 mm). If a prevalence > 32-9 % of malignant lymph nodes is expected, EUS-FNA would be the most economic technique. Evidence level 1+, Recommendation grade A.

11. If lymph nodes are located in the posterior mediastinum, EUS-FNA should be employed as the first diagnostic test for tissue diagnosis confirmation. For other locations, EBUS-TBNA should be recommended. Evidence level 1+, Recommendation grade A.



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Enrique Vázquez-Sequeiros
Department of Gastroenterology
Hospital Universitario Ramón y Cajal
Ctra. de Colmenar Viejo, km 9,100
28034 Madrid, Spain

Received: 11-03-2013
Accepted: 27-03-2013

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