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The Role of Endobronchial Ultrasound in Lung Cancer Diagnosis and Staging: A Comprehensive Review
Review
The Role of Endobronchial Ultrasound in Lung Cancer Diagnosis and Staging: A Comprehensive Review Ioannis Kokkonouzis,1,2 Alexios S. Strimpakos,1 Ioannis Lampaditis,2 Sotirios Tsimpoukis,1 Kostas N. Syrigos1 Abstract Endobronchial ultrasound (EBUS) technology is a relatively new bronchoscopic method of visualizing the tracheobronchial tree, the surrounding pulmonary parenchyma, and the mediastinal structures, with a particular role in lung cancer diagnosis, staging, and treatment. There are 2 types of probes used in EBUS: the peripheral or radial probe (RP) and the linear or convex probe (CP) EBUS, which have technical differences and distinct diagnostic abilities. Both are used for EBUS-guided biopsies and transbronchial needle aspirations (TBNA), which increases the diagnostic yield over conventional bronchoscopic techniques, thus providing advanced information on staging, diagnosis, and treatment. Complications of EBUS are rare, and they are usually related to the underlying biopsy procedure and the operator’s experience. EBUS examination duration is usually short, and it can be performed as an outpatient procedure. Interestingly, EBUS combinations with other current and evolving techniques, eg, electromagnetic navigation, are feasible and have a role in therapeutic interventions and molecular diagnostics. In conclusion, EBUS is a safe and accurate technique that is comparable with current criterion standard procedures, eg, mediastinoscopy. More training is required for the vast majority of respiratory physicians, and precise diagnostic algorithms are needed so that more patients benefit from this development. Clinical Lung Cancer, Vol. 13, No. 6, 408-15 © 2012 Elsevier Inc. All rights reserved. Keywords: Bronchoscopy, Diagnostic techniques, Endoscopy, Lung carcinoma, Mediastinal staging
Introduction Lung cancer remains a leading problem in modern oncology due to challenges in diagnosis and treatment, and, eventually, poor prognosis. In the United States, approximately 220,000 new cases are diagnosed per year and 160,000 deaths are estimated.1 Non–small-cell lung cancer (NSCLC) is the most-common histologic type of lung cancer, with a 5-year survival rate of all stages remaining dismal, at 15%, although higher rates of 5-year survival are feasible when diagnosed at very early stages (up to 73% in 1 Oncology Unit, 3rd Department of Medicine, Sotiria General Hospital, Athens School of Medicine 2 Department of Pulmonary Medicine, Hellenic Air Force and Veterans General Hospital, Athens, Greece
Submitted: Aug 20, 2011; Revised: Apr 27, 2012; Accepted: May 1, 2012; Epub: Jun 12, 2012 Address for correspondence: Konstantinos N. Syrigos, MD, Oncology Unit, Third Department of Medicine, Athens University School of Medicine, Building and Z, Sotiria General Hospital, Mesogion 152, 115 27 Athens, Greece E-mail contact: [email protected]
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stage Ia, 58% in Ib and 46% in IIa).1 Even though noninvasive techniques, such as computed tomography (CT) and positron emission tomography (PET) provide information for the assessment of a lung lesion, their accuracy is not sufficient to distinguish between a malignant and a benign lesion.2 When we refer to lung cancer, early diagnosis with the least-invasive method and acquisition of sufficient tissue sampling are extremely important.3 Endobronchial ultrasound (EBUS) is a minimally invasive technique that can be of use in lung cancer diagnosis and staging. The purpose of this review is to present technical aspects of the EBUS technology but, furthermore, to focus on its utility, especially in the diagnosis of possible malignant lung lesions not visible with fiber-optic bronchoscopy (FB) as well as in the staging of mediastinum lymph nodes. A computerized literature search of scientific articles published to June 2011 and cited in the PubMed database was performed. Search terms included “endoscopic ultrasound (EBUS)” and “lung cancer” and (“diagnosis” or “staging”). In the present article, we have included the main published studies that examined the role of this relatively new field of bronchoscopy.
1525-7304/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2012.05.001
Figure 1 Types of Endobronchial Ultrasound, Illustrating the Radial Probe Endobronchial Ultrasound With and Without Balloon Inflation (A), and the Linear or Convex Probe Endobronchial Ultrasound (B)
A
B
sound wave receiver. The probe can be positioned beside the tracheal or bronchial wall and, if needed, the balloon can be inflated with water for injection. It then rotates 360° to obtain detailed images of the bronchial structures. When the pathologic lesion has been located, the probe is removed and a biopsy instrument (forceps, needle, or brush) is inserted through the working channel of the bronchoscope to obtain tissue specimens. An ultraminiature probe of 20MHz is also available. It is placed into a guide sheath and finally inside the working channel of a flexible bronchoscope. RP-EBUS helps evaluate tumor invasion and depth, and the nature of suspicious peripheral lung lesions, but it also assesses central mediastinal lesions, particularly under the carina. More recently, it has recently been used as an imaging tool in treatment decisions.7-11 Nowadays, the evaluation of mediastinal lesions has been facilitated by the use of CP-EBUS probe. This type of probe incorporates a 7.5-MHz ultrasound transducer at the tip of a flexible bronchoscope, and it is mechanically similar to esophageal ultrasound–fine needle aspiration endoscopes (EUS-FNA) used in gastroenterology. It has an outer diameter of 6.9 mm and a 2-mm instrument channel, and the oblique views are of 30°, with a depth of 50 mm. Biopsy instruments are inserted through a separate working channel. If the probe remains in close contact with the bronchial surface, then the use of an inflated balloon is not necessary. Ultrasonographic, whitelight, and Doppler images are simultaneously obtained, which visualizes all major vessels of the chest. Real-time biopsies of the lymph nodes can be carried out with a 22-gauge needle inserted through the working channel.12 But, due to its bulky size, the oral route for insertion is opted, which sometimes necessitates intubation. At least 3 samples are needed for an adequate result. A rapid on-site evaluation by a cytologist provides quick and accurate answers.12,13 Hence, CP-EBUS can play a role in the diagnosis of a possibly malignant lung lesion and the simultaneous staging of mediastinal lymph nodes, especially when no distal metastases are present.5,7 The indications of EBUS in lung cancer are listed in Table 1.
EBUS Images
EBUS Equipment, Technology, and Indications Since the early 1990s, technologic advances in ultrasound has led to the introduction of EBUS in the field of interventional bronchoscopy.4 Two types of EBUS are available according to the probe used: the radial probe EBUS (RP-EBUS) and the linear or convex probe EBUS (CP-EBUS) (Figure 1).5 The 20-MHz RP-EBUS is positioned inside a water-inflatable balloon and is inserted through the working channel of the bronchoscope. This ultrasound frequency provides very high resolution (⬍1 mm) images and offers an excellent view of the various airway layers and peribronchial structures.6 The rotating piezoelectric crystal acts as a signal generator and ultra-
The typical ultrasonographic view of the normal lung is a “snowstorm-like” whitish image, which represents air-containing lung tissue. On the contrary, a solid lesion appears darker and more homogeneous and, in most cases, it is well defined by a bright line, which helps distinguish it from normal lung tissue.13 Kurimoto et al14 used a 20-MHz RP-EBUS mini-probe to describe 3 classes and 3 subclasses of lung lesions based on internal structure: type I has a homogeneous pattern (Ia, with vessels and bronchioles; Ib, no vessels or bronchioles), type II is characterized by hyperechoic dots and an arcs pattern (IIa, without vessels; IIb, with vessels), whereas type III has a heterogeneous pattern (IIIa, hyperechoic dots and short lines; IIIb, without hyperechoic dots and short lines). In the same study, 92% of type I lesions were benign and 99% of type II and III were malignant. Although analysis of the results of this study suggests that the ultrasonographic features are correlated with histologic features, more prospective evidence is needed.14 Fujiwara et al15 studied the utility of EBUS features in predicting metastatic lymph nodes and found that round shape, heterogeneous pattern, distinct margin, and the presence of a coagulation necrosis sign are independent predictive factors. The size of lymph nodes on
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EBUS: Lung Cancer Diagnosis and Staging Table 1 Indications of Endobronchial Ultrasound Bronchoscopy in Lung Cancer To assess the depth of endobronchial extent: diagnosis of early and locally advanced lung cancer To reach a diagnosis of a solitary pulmonary node and lung lesion To assess the location, size, structure, and infiltration of enlarged mediastinal and/or hilar lymph nodes and perform biopsy Tissue sampling for molecular diagnostics Airway assessment before therapeutic bronchoscopy intervention in inoperable lung cancer
EBUS has been shown to correlate with increased risk of malignancy.16
Mediastinal Staging: EBUS-Guided Transbronchial Needle Aspirations Compared With Other Techniques Lymph node staging is a key point in lung cancer management that affects patients’ treatment and outcome. Several noninvasive methods have been used, including CT, magnetic resonance imaging (MRI), PET, and PET-CT for lung cancer staging. Abnormal findings on PET or CT require further confirmation by cytologic or histologic examination of the abnormality. The current criterion standard method in mediastinal staging is mediastinoscopy, an invasive surgical procedure, which provides a definite tissue diagnosis at 100% specificity and almost 80% sensitivity. Mediastinoscopy is costly, it is performed in the operating room, and it requires general anesthesia. It may provide access to bilateral high and low paratracheal nodes (stations 2R, 2L, 4R, and 4L), pretracheal nodes (stations 1 and 3), and anterior subcarinal nodes (station 7). However, posterior subcarinal (station 7), inferior nodes (stations 8 and 9), anterior mediastinal nodes (station 6), and aortopulmonary nodes (station 5) cannot be accessed with this technique, although the latter could be reached via anterior mediastinotomy (also known as the Chamberlain procedure) or extended cervical mediastinoscopy. The rates of morbidity and mortality for mediastinoscopy are low (2% and 0.08%, respectively). Another invasive procedure is the video-assisted thoracoscopy or video-assisted thoracic surgery (VATS), a surgical technique mostly useful for the evaluation of the T parameter of staging. VATS is also performed with the patient under general anesthesia but provides access only to one side of the mediastinum, with the right side nodes being straight-forwardly accessible. The rate of complications for VATS is approximately 2%, with no mortality reported. There is a wide range of sensitivity (37%-100%) according to the published studies, which has not been adequately explained yet. Specificity is 100% but the false-negative rate almost reaches 15%.17-19 A less-invasive procedure is the CT fluoroscopy– guided biopsy, which has an overall sensitivity and specificity of 89% and 100%, respectively. It might be helpful in selected patients with extensive mediastinal involvement. However, it may be complicated by development of pneumothorax in approximately 10% of patients, which requires evacuation by insertion of a chest catheter.20 The addition of transbronchial needle aspirations (TBNA) lymph node sampling through video-bronchoscope expanded the role of interventional bronchoscopy in the invasive evaluation of mediastinal pathology and, more specifically, in the diagnosis of lung carcinoma. In 1983, dedicated equipment, eg, the Wang needles, was
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developed for lymph node sampling.21,22 Several studies have been performed to evaluate the role of TBNA in mediastinal staging. A meta-analysis conducted by Holty et al23 reported a sensitivity of 39% and a specificity of 99%. Detterbeck et al20 published, in 2007, the American College of Chest Physicians evidence-based clinical practice guidelines on “Invasive Mediastinal Staging of Lung Cancer” and reported an overall sensitivity for TBNA of 78%, ranging from 14% to 100% and a specificity of 100% (false-positive rate 0%), although few studies showed positive results when further invasive evaluation was performed. It should be noted that false-negative results reached approximately 28%, ranging from 0% to 66%.20 As a result, according to the American College of Chest Physicians guidelines, blind TBNA is less useful and is not indicated in patients with normal mediastinum, without extensive mediastinal lymph node enlargement. Rare complications have been reported, including pneumothorax, pneumomediastinum, and pericarditis but no death.20,23,24 However, only 10%-30% of pulmonologists regularly perform TBNA, mainly due to a lack of needle monitoring, difficulties in performing the procedure, and a false belief that it is not useful.25,26 The introduction of RP-EBUS and real-time CP-EBUS provided pulmonary physicians and thoracic surgeons with a new and safe modality, and with a higher diagnostic yield to access the superior (1, 2, 3, 4) subcarinal, (7) hilar, (10) interlobar (11), and lobar (12) node stations. An early CP-EBUS–TBNA study was performed by Yasufuku et al27 with 70 patients with hilar and/or mediastinal lymphadenopathy visible on CTs. Its sensitivity was 95.7% and the specificity was 100% in patients with confirmed or suspected lung cancer. Thus, thoracotomy was avoided in 6 patients, and other invasive procedures, such as mediastinoscopy and thoracoscopy, were avoided in 17 patients.27 A further prospective study, by the same team, with 108 patients with similar characteristics reported a sensitivity of 94.6%, specificity 100%, and negative prognostic value of 89.5%. According to the study, use of the CP-EBUS–TBNA spared 29 patients from mediastinoscopy, 8 from thoracotomy, and 9 from a CT-guided percutaneous biopsy. In the aforementioned studies, a positive cytology result was considered sufficient for a definite diagnosis and only when cytology was negative, further surgical intervention or continuous clinical follow-up was required.28 Another study, again by Yasufuku et al,29 compared the efficacy of CT, PET, and CP-EBUS–TBNA in predicting lymph node staging in 102 patients, who were candidates for curative thoracic surgery, with suspected or pathologically confirmed lung cancer. The sensitivity and specificity of CT, PET, and EBUS-TBNA were 76.9% and 87.5%, 80% and 91.5%, and 92.3% and 97.4%, respectively. Similar results were reported in a retrospective analysis of 106 patients with metastatic
Ioannis Kokkonouzis et al lung cancer and lymph nodes ⱖ5 mm, in which the sensitivity of EBUS-TBNA was 92% and its negative prognostic value was 95.3%.29 Lee et al13 conducted a prospective study with 91 patients with strongly suspected or histologic confirmed NSCLC, with lymph node diameter of 5-20 mm, and accessible by CP-EBUS–TBNA. They reported sensitivity of 93.8%, specificity of 100%, and negative prognostic value of 96.9%.13 A smaller study, by Rintoul et al,30 with 18 patients with suspected or known lung cancer and nodular enlargement or the presence of peribronchial or paratracheal masses on CT, reported less encouraging results. The sensitivity, specificity, and negative prognostic value were 85%, 100%, and 71.4%, respectively.30 The usefulness of EBUS in mediastinal staging and its comparable results to mediastinoscopy have been demonstrated in many other published studies.31-39 In the largest prospective study so far, Herth et al40 conducted real-time CP-EBUS–TBNA in 502 consecutive patients with suspected lung cancer in whom there was evidence of mediastinal and hilar lymph node enlargement. From a total number of 572 lymph nodes that were biopsied (with mean diameter of 1.6 cm), diagnosis was provided by 535 (94%). The sensitivity and specificity were 94% and 100%, respectively.40 Regarding the role of EBUS-TBNA in suspected NSCLC without CT lymph node enlargement and with negative mediastinal PET findings, 156 nodes were detected, of which 97 were sampled. Malignancy was detected in 9 cases and missed in 1 case. The sensitivity and specificity were 89% and 100%, respectively, whereas the negative predictive value was 98.9%.41 Overall, the diagnostic yield for CP-EBUS–TBNA seems to be continuously improving as has been shown by more recently published studies with sensitivity values that ranged from 95% to 100%, with specificity of 100%, and with accuracy that rated from 96% to 98.5%.42-45 This is probably attributed to the experience gained by clinicians performing this technique. Esophageal ultrasound (EUS) permits mediastinal lymph node sampling through the esophageal wall with little risk of bleeding. This technique allows easy access to the inferior pulmonary ligament, esophageal, subcarinal and aortopulmonary nodes (stations 9, 8, 7, and 5, respectively). However, anterior-lateral to the trachea nodes (stations 2R, 2L, 4R, and 4L) are barely accessible by EUS but can be visualized by EBUS. A combination of EUS and EBUS, a method known as medical mediastinoscopy, seems promising and able to provide an almost full assessment of the mediastinum. In a study performed in 138 patients, the efficiency of CP-EBUS–FNA for full mediastinal sampling was compared with blind TBNA and with the combination of EBUS-FNA–EUS-FNA. It was reported that the real-time EBUS-FNA was more sensitive than TBNA (69% vs. 36%) but less accurate than the combination of EUS-FNA–EBUS-FNA, which showed a higher sensitivity (93%) and negative predictive value (97%) than either technique alone.46 The combination of EUS and EBUS, by using only a single CPEBUS bronchoscope and conducting it as one single procedure, was also evaluated in 150 patients, with a likely diagnosis of NSCLC. Surgical confirmation and clinical observation followed. The sensitivity of EUS-FNA was 89% and of EBUS-FNA was 92% but, of the combination, rated 96% and a negative predictive value of 95%.47 No complications were observed.47 In a similar prospective trial, the
diagnostic accuracy of the combination was 97.2%, although not statistically significant.48 No serious complications from CP-EBUS– TBNA have been reported apart from 2 recent cases of infectious diseases attributed directly to the procedure.49 All of these promising results suggest that the cooperation of respiratory and gastroenterology physicians could lead to a single minimally invasive procedure that may offer an almost complete mediastinal staging without serious complications. However, mediastinoscopy might be considered for suspicious mediastinal nodes when EBUS and EUS are negative, although, according to a prospective study by Ernst et al,50 real-time EBUS provided a higher overall diagnostic yield than mediastinoscopy, especially for paratracheal and subcarinal lymph nodes (91% vs. 78%; P ⫽ .007).50,51 In conclusion, current clinical guidelines on mediastinal staging recommend that, for patients with extensive mediastinal tumor infiltration but no distant metastasis, radiographic assessment of the mediastinum is usually sufficient without the need for invasive confirmation (grade 2C). However, it is emphasized that CT is unable to assess solitary malignant lymph node enlargement and, therefore, invasive confirmation is recommended, regardless of PET findings. In this group of patients, the N2/N3 stage can be establish by using blind TBNA, EBUS-TBNA, EUS-FNA, CT fluoroscopy– guided biopsy, or a combination of the above, depending on their availability and the personnel’s experience (grade 1B). A negative biopsy result requires further confirmation by mediastinoscopy even in PET–positive nodes. Although mediastinoscopy is recommended in patients with centrally located tumors or N1 lymph node enlargement, EBUS-TBNA or EUS-FNA may be a reliable alternative option (grade 1B). In patients with small (⬍20 mm) peripheral lesions (clinical stage I) and positive PET of the mediastinum, a further invasive approach is required, mainly mediastinoscopy, but EBUSTBNA and EUS-FNA are again reasonable alternatives (grade 1C). In case of a negative PET, no further invasive technique is needed to assess the mediastinal lymph nodes (grade 1C). Finally, in patients with suspected left upper lobe malignancy, it is recommended to assess the aortopulmonary window nodes (by use of Chamberlain procedure, thoracoscopy, extended cervical mediastinoscopy, EUSFNA, or EBUS-TBNA) if no other lymph node station is involved (grade 2C).20 Overall, EBUS-TBNA seems to be the most costeffective approach for mediastinal staging in NSCLC, when compared with conventional TBNA and surgical mediastinoscopy.52
Diagnosis of Peripheral Lung Lesions Evaluation of lung lesions or solitary pulmonary nodules (SPN) not visible in routine flexible FB pose a real challenge for chest physicians because prompt and precise diagnosis is of critical importance. It makes a huge difference to distinguish a benign from a malignant lesion and primary disease from metastatic disease. In this context, more than 90% of the bronchoscopists still perform FB with endobronchial biopsies, transbronchial lung biopsies (TBB), and transbronchial needle aspirations (TBNA), mostly blindly or under the guidance of static CT images, or under fluoroscopy. These techniques somehow lack in sensitivity, which varies greatly, depending on the location of the lesion inside the parenchyma and its size. For example, the sensitivity for peripheral lung nodules of 2 cm or less in
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EBUS: Lung Cancer Diagnosis and Staging diameter ranges from 11% to 42% and, when fluoroscopy devices are involved, from 14% to 71%.53,54 One should always take into account the risk of radiation exposure for both patients and examiners during some of these interventional procedures and, therefore, radiation protection measures must be available on-site. Another consideration is the possibility of a nonvisible lesion and the execution of a finally blind biopsy.55 Alternatively, carrying out a percutaneous needle biopsy or aspiration for cytology with a CT-guided procedure improves the diagnostic accuracy up to 76% to 97% but poses several risks. These include the risk of seeding malignant cells in the pleural cavity and the risk of pneumothorax. The latter is greater for lesions located deep into the lung parenchyma and for patients with poor pulmonary function.56,57 An increased risk of complications also exists in older patients or in patients with poor pulmonary function if they undergo a surgical biopsy procedure such as VATS or open lung surgery. In these scenarios, the radial EBUS technique seems a reasonable option. Several studies have been performed, and many others are ongoing regarding the effectiveness of EBUS bronchoscopy. EBUS-FNA cytology has demonstrated a greater sensitivity than TBNA cytology in the diagnosis of lung lesions (78.9% vs. 89.5%).58 Shirakawa et al59 conducted a study that compared TBB by using RP-EBUS and fluoroscopic guidance (50 patients) and TBB under solely fluoroscopic guidance (42 patients). The accuracy of RP-EBUS– guided FB in distinguishing between lung cancer and benign disease was 84% and reached 100% when the probe was inserted in the lesion. Compared with TBB under fluoroscopy only, the addition of EBUS showed improved accuracy and specificity (P ⫽ .02) but not improved sensitivity (P ⫽ .06).59 In the same context, Kikuchi et al60 examined the influence of RP-EBUS– guided TBB in the diagnosis of small peripheral lung lesions (⬍30 mm) when combined with fluoroscopy. The overall diagnostic yield was approximately 58%, and, even in lesions ⬍20 mm in diameter, the sensitivity remained above 50%.60 The best results, so far, have been reported by a study led by Kurimoto et al,61 which combined the use of RP-EBUS with fluoroscopy and reported a diagnostic yield of 92% in lesions ⬎30 mm, 73% in lesions ⬍20 mm, and 77% in lesions between 20 and 30 mm.61 When EBUS-guided biopsy was studied with 54 patients with SPNs not visualized by fluoroscopy, the lesion was localized in 89% of them, and a definite diagnosis was established in 70%.62 The same team reported that, even in small lesions of approximately 22 mm in diameter, the diagnostic yield of EBUS-guided biopsy reached 70%.12 Other studies, however, have reported that EBUSguided biopsy or brushing, without fluoroscopy, was diagnostic in only 29.7% of patients with lesions ⱕ20 mm, whereas it retained a diagnostic yield of 75.6% in lesions ⬎20 mm.63 An interesting, prospective, randomized study by Paone et al64 in 221 patients with peripheral lung lesions assessed the diagnostic yield of radial EBUS-TBB (97 patients) vs. TBB (124 patients). Complete results were available for 201 patients who completed the follow-up. In patients diagnosed with lung cancer, sensitivity and accuracy were better with EBUS-TBB (79% vs. 55% and 85% vs. 69%, respectively). The bigger the lesions, the better these results were, and they were always better for the EBUS-TBB.64 Several other studies have examined and confirmed the superiority of EBUS-TBNA in the di-
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agnosis of pulmonary lesions not visible to conventional bronchoscopy.32,65-72 Eberhardt et al73 studied 118 patients with a define histologic diagnosis and reported a diagnostic yield of 88% when EUS-FNA was combined with real-time EBUS imaging. A summary of all major published studies on EBUS-FB for the definition of peripheral lesions and SPNs is listed in Table 2. Despite the significant advantages of EBUS, there are some concerns, such as the wide range in its diagnostic ability (between 60% and 92% in lesions ⱖ30 mm and between 30% and 70% in lesions ⬍20 mm) and its difficulty to visualize lesions ⱕ15 mm. A higher diagnostic yield can be achieved when the probe is positioned within the lesion on the ultrasound image than adjacent to the target.2 Present guidelines recommend performing transthoracic needle aspiration in patients with a small peripheral, possibly malignant, lesion when a tissue diagnosis is required (grade 1B). However, radial probe EBUS performed by an expert might increase the diagnostic yield of FB (even for peripheral lesions ⱕ20 mm in size) and can be considered before transthoracic needle aspiration (grade 2B). Finally, a negative biopsy of a suspicious lesion may require a more-invasive method to establish the diagnosis.22 It is worth mentioning that there is continuous evolution and expansion of EBUS applications, such as the combination of EBUS with electromagnetic navigation bronchoscopy. This examination requires the patient be positioned on an electromagnetic board, with an electromagnetic field is then created around the patient’s chest, and is combined with an advanced CT imaging system able to reconstruct images. Numerous reference points on the body are provided, which creates a “roadmap.” A flexible catheter with a position sensor is placed into the working channel of the bronchoscope within the electromagnetic field, and it is oriented by computer software. When the target lesion is located, the sensor probe is removed, and biopsy instruments are advanced to the same position. Although this is new and rather expensive, it shows the potential of EBUS technique.
EBUS as a Therapeutic Tool: A Glance at the Near Future EBUS seems to be the most appropriate technique for the determination of depth and extent of tumor invasion in the airway wall. The combination of EBUS with CT or MRI may be useful for the surgical planning of patients with lung cancer but also for esophageal and thyroid cancers. Going a step forward, EBUS technology also can be integrated in therapeutic interventions. Nakajima et al74 reported treatment of a patient with central airway stenosis caused by a mediastinal cyst by EBUS-TBNA, without evidence of recurrence 1 year later. Miyazu et al75 showed that RP-EBUS also could be used in selected patients with centrally located early-stage squamous cell lung cancer before photodynamic therapy (PDT). When lesions were recognized as extracartilaginous by EBUS, other treatments than PDT were opted, such as surgical resection, chemotherapy, and radiotherapy. Patients treated with PDT after EBUS achieved long-term remissions with no recurrences after 32 months of follow-up.75 The significance of the imaging accuracy obtained by EBUS was demonstrated in a series of 1174 therapeutic bronchoscopies, in which the interventional strategy and the used equipment had to be adapted in 43% of the patients (altered stent size, tumor debridement guidance,
Ioannis Kokkonouzis et al Table 2 Results of Studies That Assess the Diagnostic Yield of EBUS in Peripheral Lung Lesion and Solitary Pulmonary Nodules Type of Procedure
No. Patients
Size of Lesion (mm)
Diagnostic Yield (%)
Shirakawa et al59 (2004)
RP-EBUS and fluoroscopy with or without curette– forceps biopsy/brushing
50
–
84
Kikuchi et al60 (2004)
RP-EBUS with guide sheath and fluoroscopy with or without curette–forceps biopsy/brushing
24
⬍30
58
15
20-30
66.7
9
⬍20
53.3
81
⬍20
73
43
20-30
77
26
⬎30
90
Study (Year)
Kurimoto et al
61
(2004)
Yoshikawa et al63 (2007)
Yamada et al
Paone et al
Herth et al
65
64
62
(2007)
(2005)
(2002)
RP-EBUS with guide sheath and fluoroscopy with or without curette–forceps biopsy/brushing
RP-EBUS with guide sheath without fluoroscopy with or without curette–forceps biopsy/brushing
123 (all)
RP- and CP-EBUS–transbronchial forceps biopsy with guide sheath
RP-EBUS–transbronchial forceps biopsy
48
⬎30
98.68
38
20-30
37.9
37
⬍20
29.7
158
21 (SD 6mm)
67
40
⬍15
40
118
⬎15
76
87 (all)
RP-EBUS–transbronchial forceps biopsy
Dooms et al Chao et al
72
67
(2007)
(2009)
Huang et al69 (2009)
Koh et al32 (2008) Fielding et al68 (2008) Nakajima et al70 (2008) Tournoy et al
71
(2009)
78.7 ⬎30
82.8
20-30
75
⬍20
71
50 (all) 21
Herth et al12 (2006)
62
80 ⬍30
80
29
⬎30
79
RP-EBUS with guide sheath without fluoroscopy– transbronchial forceps biopsy
54
22 (SD 7mm), fluoroscopically invisible
70
EBUS–transbronchial forceps biopsy
50
37 (SD 20mm)
84
RP-EBUS–transbronchial biopsy, BW
94
60.6
EBUS–transbronchial biopsy and bronchial washing plus TBNA
88
78.4
11
⬍20
55
103
⬎20
66
CP-EBUS–transbronchial forceps biopsy with guide sheath
29
35
62
EBUS–transbronchial forceps biopsy with guide sheath
140
29
66
CP-EBUS–TBNA
35
94.3
CP-EBUS–TBNA
60
77
RP- and CP-EBUS–transbronchial forceps biopsy
Abbreviations: BW ⫽ bronchial washing; CP-EBUS ⫽ convex probe endobronchial ultrasound; EBUS ⫽ endobronchial ultrasound; RP ⫽ radial probe; SD ⫽ standard deviation; TBNA ⫽ transbronchial needle aspiration.
etc). Consequently, complications such as bleeding were prevented or minimized.11 In the era of personalized medicine and novel therapies, sufficient and good-quality tissue samples need to be obtained during an interventional procedure. Some scientists have explored the ability of EBUS-TBNA to obtain satisfactory material for further molecular
testing and treatment guidance. Mohamed et al76 showed that mediastinal lymph node biopsy specimens obtained by EBUS-TBNA in 36 patients with N2-NSCLC were adequate enough to perform immunohistochemical expression study of 6 cell cycle–related proteins (pRb, cyclin D1, p16 [INK4A], p53, p21 [Waf1], Ki-67). Nakajima et al74 reported that EGFR mutation testing on tumor biopsy speci-
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EBUS: Lung Cancer Diagnosis and Staging mens acquired by EBUS-TBNA was feasible and led to treatment with targeted therapy when appropriate.74 Similar findings and conclusions have been reported by others regarding the EGFR, KRAS, and EML-4/ALK fusion genes on tissue taken by using EBUS-TBNA.77,78,79
Conclusions Although EBUS presents a relative new endoscopic development in the field of interventional respiratory medicine, it shows a potential to play many important roles in everyday practice. Thus, EBUSbased technology may be used in the diagnosis of a lung or mediastinal lesion, staging of lung cancer, and treatment of an endobronchial abnormality. Equally important are its low complication rate, the short examination time, and its manageable cost, especially when compared with surgical invasive procedures. For these reasons, along with its diagnostic accuracy and its safety profile, EBUS might become a very valuable tool in everyday practice, especially in those places and countries where mediastinoscopy is not available or practiced. However, we should acknowledge that most of the data come from experienced centers of the most-developed countries, where there is mounting expertise and adequate resources. In centers of low volume or minimal budget, it is difficult to obtain or maintain satisfactory skills on EBUS and to comply with the recommendations of the European Respiratory Society and the American Thoracic Society, which require initial training with 40 supervised procedures and, thereafter, 25 procedures annually to maintain competency.80 Also, formal guidelines and structured algorithms are needed to encourage physicians to incorporate EBUS in the everyday’s clinical practice to minimize diversities between centers and to serve all patients equally.
Disclosure The authors have stated that they have no conflicts of interest.
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63. Yoshikawa M, Sukoh N, Yamazaki K, et al. Diagnostic value of endobronchial ultrasonography with a guide sheath for peripheral pulmonary lesions without X-ray fluoroscopy. Chest 2007; 131:1788-93. 64. Paone G, Nicastri E, Lucantoni G, et al. Endobronchial ultrasound-driven biopsy in the diagnosis of peripheral lung lesions. Chest 2005; 128:3551-7. 65. Yamada N, Yamazaki K, Kurimoto N, et al. Factors related to diagnostic yield of transbronchial biopsy using endobronchial ultrasonography with a guide sheath in small peripheral pulmonary lesions. Chest 2007; 132:603-8. 66. Asano F, Matsuno Y, Tsuzuku A, et al. Diagnosis of peripheral pulmonary lesions using a bronchoscope insertion guidance system combined with endobronchial ultrasonography with a guide sheath. Lung Cancer 2008; 60:366-73. 67. Dooms CA, Verbeken EK, Becker HD, et al. Endobronchial ultrasonography in bronchoscopic occult pulmonary lesions. J Thorac Oncol 2007; 2:121-4. 68. Fielding DI, Robinson PJ, Kurimoto N. Biopsy site selection for endobronchial ultrasound guide-sheath transbronchial biopsy of peripheral lung lesions. Intern Med J 2008; 38:77-84. 69. Huang CT, Ho CC, Tsai YJ, et al. Factors influencing visibility and diagnostic yield of transbronchial biopsy using endobronchial ultrasound in peripheral pulmonary lesions. Respirology 2009; 14:859-64. 70. Nakajima T, Yasufuku K, Fujiwara T, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis of intrapulmonary lesions. J Thorac Oncol 2008; 3:985-8. 71. Tournoy KG, Rintoul RC, van Meerbeeck JP, et al. EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy. Lung Cancer 2009; 63:45-9. 72. Chao TY, Chien MT, Lie CH, et al. Endobronchial ultrasonography-guided transbronchial needle aspiration increases the diagnostic yield of peripheral pulmonary lesions: a randomized trial. Chest 2009; 136:229-36. 73. Eberhardt R, Anantham D, Ernst A, et al. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med 2007; 176:36-41. 74. Nakajima T, Yasufuku K, Shibuya K, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for the treatment of central airway stenosis caused by a mediastinal cyst. Eur J Cardiothorac Surg 2007; 32:538-40. 75. Miyazu Y, Miyazawa T, Iwamoto Y, et al. The role of endoscopic techniques, laser-induced fluorescence bronchoscopy, and endobronchial ultrasonography in choice of appropriate therapy for bronchial cancer. J Bronchol 2001; 8:10-6. 76. Mohamed S, Yasufuku K, Nakajima T, et al. Analysis of cell cycle-related proteins in mediastinal lymph nodes of patients with N2-NSCLC obtained by EBUSTBNA: relevance to chemotherapy response. Thorax 2008; 63:642-7. 77. Garcia-Olivé I, Monsó E, Andreo F, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for identifying EGFR mutations. Eur Respir J 2010; 35:391-5. 78. Schuurbiers OC, Looijen-Salamon MG, Ligtenberg MJ, et al. A brief retrospective report on the feasibility of epidermal growth factor receptor and KRAS mutation analysis in transesophageal ultrasound- and endobronchial ultrasound-guided fine needle cytological aspirates. J Thorac Oncol 2010; 5:1664-7. 79. Sakairi Y, Nakajima T, Yasufuku K, et al. EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Clin Cancer Res 2010; 16:4938-45. 80. Bolliger CT, Mathur PN, Beamis JF, et al. ERS/ATS statement on interventional pulmonology. European Respiratory Society/American Thoracic Society. Eur Respir J 2002; 19:356-73.
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The Role of Endobronchial Ultrasound in Lung Cancer Diagnosis and Staging: A Comprehensive Review Ioannis Kokkonouzis,1,2 Alexios S. Strimpakos,1 Ioannis Lampaditis,2 Sotirios Tsimpoukis,1 Kostas N. Syrigos1 Abstract Endobronchial ultrasound (EBUS) technology is a relatively new bronchoscopic method of visualizing the tracheobronchial tree, the surrounding pulmonary parenchyma, and the mediastinal structures, with a particular role in lung cancer diagnosis, staging, and treatment. There are 2 types of probes used in EBUS: the peripheral or radial probe (RP) and the linear or convex probe (CP) EBUS, which have technical differences and distinct diagnostic abilities. Both are used for EBUS-guided biopsies and transbronchial needle aspirations (TBNA), which increases the diagnostic yield over conventional bronchoscopic techniques, thus providing advanced information on staging, diagnosis, and treatment. Complications of EBUS are rare, and they are usually related to the underlying biopsy procedure and the operator’s experience. EBUS examination duration is usually short, and it can be performed as an outpatient procedure. Interestingly, EBUS combinations with other current and evolving techniques, eg, electromagnetic navigation, are feasible and have a role in therapeutic interventions and molecular diagnostics. In conclusion, EBUS is a safe and accurate technique that is comparable with current criterion standard procedures, eg, mediastinoscopy. More training is required for the vast majority of respiratory physicians, and precise diagnostic algorithms are needed so that more patients benefit from this development. Clinical Lung Cancer, Vol. 13, No. 6, 408-15 © 2012 Elsevier Inc. All rights reserved. Keywords: Bronchoscopy, Diagnostic techniques, Endoscopy, Lung carcinoma, Mediastinal staging
Introduction Lung cancer remains a leading problem in modern oncology due to challenges in diagnosis and treatment, and, eventually, poor prognosis. In the United States, approximately 220,000 new cases are diagnosed per year and 160,000 deaths are estimated.1 Non–small-cell lung cancer (NSCLC) is the most-common histologic type of lung cancer, with a 5-year survival rate of all stages remaining dismal, at 15%, although higher rates of 5-year survival are feasible when diagnosed at very early stages (up to 73% in 1 Oncology Unit, 3rd Department of Medicine, Sotiria General Hospital, Athens School of Medicine 2 Department of Pulmonary Medicine, Hellenic Air Force and Veterans General Hospital, Athens, Greece
Submitted: Aug 20, 2011; Revised: Apr 27, 2012; Accepted: May 1, 2012; Epub: Jun 12, 2012 Address for correspondence: Konstantinos N. Syrigos, MD, Oncology Unit, Third Department of Medicine, Athens University School of Medicine, Building and Z, Sotiria General Hospital, Mesogion 152, 115 27 Athens, Greece E-mail contact: [email protected]
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stage Ia, 58% in Ib and 46% in IIa).1 Even though noninvasive techniques, such as computed tomography (CT) and positron emission tomography (PET) provide information for the assessment of a lung lesion, their accuracy is not sufficient to distinguish between a malignant and a benign lesion.2 When we refer to lung cancer, early diagnosis with the least-invasive method and acquisition of sufficient tissue sampling are extremely important.3 Endobronchial ultrasound (EBUS) is a minimally invasive technique that can be of use in lung cancer diagnosis and staging. The purpose of this review is to present technical aspects of the EBUS technology but, furthermore, to focus on its utility, especially in the diagnosis of possible malignant lung lesions not visible with fiber-optic bronchoscopy (FB) as well as in the staging of mediastinum lymph nodes. A computerized literature search of scientific articles published to June 2011 and cited in the PubMed database was performed. Search terms included “endoscopic ultrasound (EBUS)” and “lung cancer” and (“diagnosis” or “staging”). In the present article, we have included the main published studies that examined the role of this relatively new field of bronchoscopy.
1525-7304/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2012.05.001
Figure 1 Types of Endobronchial Ultrasound, Illustrating the Radial Probe Endobronchial Ultrasound With and Without Balloon Inflation (A), and the Linear or Convex Probe Endobronchial Ultrasound (B)
A
B
sound wave receiver. The probe can be positioned beside the tracheal or bronchial wall and, if needed, the balloon can be inflated with water for injection. It then rotates 360° to obtain detailed images of the bronchial structures. When the pathologic lesion has been located, the probe is removed and a biopsy instrument (forceps, needle, or brush) is inserted through the working channel of the bronchoscope to obtain tissue specimens. An ultraminiature probe of 20MHz is also available. It is placed into a guide sheath and finally inside the working channel of a flexible bronchoscope. RP-EBUS helps evaluate tumor invasion and depth, and the nature of suspicious peripheral lung lesions, but it also assesses central mediastinal lesions, particularly under the carina. More recently, it has recently been used as an imaging tool in treatment decisions.7-11 Nowadays, the evaluation of mediastinal lesions has been facilitated by the use of CP-EBUS probe. This type of probe incorporates a 7.5-MHz ultrasound transducer at the tip of a flexible bronchoscope, and it is mechanically similar to esophageal ultrasound–fine needle aspiration endoscopes (EUS-FNA) used in gastroenterology. It has an outer diameter of 6.9 mm and a 2-mm instrument channel, and the oblique views are of 30°, with a depth of 50 mm. Biopsy instruments are inserted through a separate working channel. If the probe remains in close contact with the bronchial surface, then the use of an inflated balloon is not necessary. Ultrasonographic, whitelight, and Doppler images are simultaneously obtained, which visualizes all major vessels of the chest. Real-time biopsies of the lymph nodes can be carried out with a 22-gauge needle inserted through the working channel.12 But, due to its bulky size, the oral route for insertion is opted, which sometimes necessitates intubation. At least 3 samples are needed for an adequate result. A rapid on-site evaluation by a cytologist provides quick and accurate answers.12,13 Hence, CP-EBUS can play a role in the diagnosis of a possibly malignant lung lesion and the simultaneous staging of mediastinal lymph nodes, especially when no distal metastases are present.5,7 The indications of EBUS in lung cancer are listed in Table 1.
EBUS Images
EBUS Equipment, Technology, and Indications Since the early 1990s, technologic advances in ultrasound has led to the introduction of EBUS in the field of interventional bronchoscopy.4 Two types of EBUS are available according to the probe used: the radial probe EBUS (RP-EBUS) and the linear or convex probe EBUS (CP-EBUS) (Figure 1).5 The 20-MHz RP-EBUS is positioned inside a water-inflatable balloon and is inserted through the working channel of the bronchoscope. This ultrasound frequency provides very high resolution (⬍1 mm) images and offers an excellent view of the various airway layers and peribronchial structures.6 The rotating piezoelectric crystal acts as a signal generator and ultra-
The typical ultrasonographic view of the normal lung is a “snowstorm-like” whitish image, which represents air-containing lung tissue. On the contrary, a solid lesion appears darker and more homogeneous and, in most cases, it is well defined by a bright line, which helps distinguish it from normal lung tissue.13 Kurimoto et al14 used a 20-MHz RP-EBUS mini-probe to describe 3 classes and 3 subclasses of lung lesions based on internal structure: type I has a homogeneous pattern (Ia, with vessels and bronchioles; Ib, no vessels or bronchioles), type II is characterized by hyperechoic dots and an arcs pattern (IIa, without vessels; IIb, with vessels), whereas type III has a heterogeneous pattern (IIIa, hyperechoic dots and short lines; IIIb, without hyperechoic dots and short lines). In the same study, 92% of type I lesions were benign and 99% of type II and III were malignant. Although analysis of the results of this study suggests that the ultrasonographic features are correlated with histologic features, more prospective evidence is needed.14 Fujiwara et al15 studied the utility of EBUS features in predicting metastatic lymph nodes and found that round shape, heterogeneous pattern, distinct margin, and the presence of a coagulation necrosis sign are independent predictive factors. The size of lymph nodes on
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EBUS: Lung Cancer Diagnosis and Staging Table 1 Indications of Endobronchial Ultrasound Bronchoscopy in Lung Cancer To assess the depth of endobronchial extent: diagnosis of early and locally advanced lung cancer To reach a diagnosis of a solitary pulmonary node and lung lesion To assess the location, size, structure, and infiltration of enlarged mediastinal and/or hilar lymph nodes and perform biopsy Tissue sampling for molecular diagnostics Airway assessment before therapeutic bronchoscopy intervention in inoperable lung cancer
EBUS has been shown to correlate with increased risk of malignancy.16
Mediastinal Staging: EBUS-Guided Transbronchial Needle Aspirations Compared With Other Techniques Lymph node staging is a key point in lung cancer management that affects patients’ treatment and outcome. Several noninvasive methods have been used, including CT, magnetic resonance imaging (MRI), PET, and PET-CT for lung cancer staging. Abnormal findings on PET or CT require further confirmation by cytologic or histologic examination of the abnormality. The current criterion standard method in mediastinal staging is mediastinoscopy, an invasive surgical procedure, which provides a definite tissue diagnosis at 100% specificity and almost 80% sensitivity. Mediastinoscopy is costly, it is performed in the operating room, and it requires general anesthesia. It may provide access to bilateral high and low paratracheal nodes (stations 2R, 2L, 4R, and 4L), pretracheal nodes (stations 1 and 3), and anterior subcarinal nodes (station 7). However, posterior subcarinal (station 7), inferior nodes (stations 8 and 9), anterior mediastinal nodes (station 6), and aortopulmonary nodes (station 5) cannot be accessed with this technique, although the latter could be reached via anterior mediastinotomy (also known as the Chamberlain procedure) or extended cervical mediastinoscopy. The rates of morbidity and mortality for mediastinoscopy are low (2% and 0.08%, respectively). Another invasive procedure is the video-assisted thoracoscopy or video-assisted thoracic surgery (VATS), a surgical technique mostly useful for the evaluation of the T parameter of staging. VATS is also performed with the patient under general anesthesia but provides access only to one side of the mediastinum, with the right side nodes being straight-forwardly accessible. The rate of complications for VATS is approximately 2%, with no mortality reported. There is a wide range of sensitivity (37%-100%) according to the published studies, which has not been adequately explained yet. Specificity is 100% but the false-negative rate almost reaches 15%.17-19 A less-invasive procedure is the CT fluoroscopy– guided biopsy, which has an overall sensitivity and specificity of 89% and 100%, respectively. It might be helpful in selected patients with extensive mediastinal involvement. However, it may be complicated by development of pneumothorax in approximately 10% of patients, which requires evacuation by insertion of a chest catheter.20 The addition of transbronchial needle aspirations (TBNA) lymph node sampling through video-bronchoscope expanded the role of interventional bronchoscopy in the invasive evaluation of mediastinal pathology and, more specifically, in the diagnosis of lung carcinoma. In 1983, dedicated equipment, eg, the Wang needles, was
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developed for lymph node sampling.21,22 Several studies have been performed to evaluate the role of TBNA in mediastinal staging. A meta-analysis conducted by Holty et al23 reported a sensitivity of 39% and a specificity of 99%. Detterbeck et al20 published, in 2007, the American College of Chest Physicians evidence-based clinical practice guidelines on “Invasive Mediastinal Staging of Lung Cancer” and reported an overall sensitivity for TBNA of 78%, ranging from 14% to 100% and a specificity of 100% (false-positive rate 0%), although few studies showed positive results when further invasive evaluation was performed. It should be noted that false-negative results reached approximately 28%, ranging from 0% to 66%.20 As a result, according to the American College of Chest Physicians guidelines, blind TBNA is less useful and is not indicated in patients with normal mediastinum, without extensive mediastinal lymph node enlargement. Rare complications have been reported, including pneumothorax, pneumomediastinum, and pericarditis but no death.20,23,24 However, only 10%-30% of pulmonologists regularly perform TBNA, mainly due to a lack of needle monitoring, difficulties in performing the procedure, and a false belief that it is not useful.25,26 The introduction of RP-EBUS and real-time CP-EBUS provided pulmonary physicians and thoracic surgeons with a new and safe modality, and with a higher diagnostic yield to access the superior (1, 2, 3, 4) subcarinal, (7) hilar, (10) interlobar (11), and lobar (12) node stations. An early CP-EBUS–TBNA study was performed by Yasufuku et al27 with 70 patients with hilar and/or mediastinal lymphadenopathy visible on CTs. Its sensitivity was 95.7% and the specificity was 100% in patients with confirmed or suspected lung cancer. Thus, thoracotomy was avoided in 6 patients, and other invasive procedures, such as mediastinoscopy and thoracoscopy, were avoided in 17 patients.27 A further prospective study, by the same team, with 108 patients with similar characteristics reported a sensitivity of 94.6%, specificity 100%, and negative prognostic value of 89.5%. According to the study, use of the CP-EBUS–TBNA spared 29 patients from mediastinoscopy, 8 from thoracotomy, and 9 from a CT-guided percutaneous biopsy. In the aforementioned studies, a positive cytology result was considered sufficient for a definite diagnosis and only when cytology was negative, further surgical intervention or continuous clinical follow-up was required.28 Another study, again by Yasufuku et al,29 compared the efficacy of CT, PET, and CP-EBUS–TBNA in predicting lymph node staging in 102 patients, who were candidates for curative thoracic surgery, with suspected or pathologically confirmed lung cancer. The sensitivity and specificity of CT, PET, and EBUS-TBNA were 76.9% and 87.5%, 80% and 91.5%, and 92.3% and 97.4%, respectively. Similar results were reported in a retrospective analysis of 106 patients with metastatic
Ioannis Kokkonouzis et al lung cancer and lymph nodes ⱖ5 mm, in which the sensitivity of EBUS-TBNA was 92% and its negative prognostic value was 95.3%.29 Lee et al13 conducted a prospective study with 91 patients with strongly suspected or histologic confirmed NSCLC, with lymph node diameter of 5-20 mm, and accessible by CP-EBUS–TBNA. They reported sensitivity of 93.8%, specificity of 100%, and negative prognostic value of 96.9%.13 A smaller study, by Rintoul et al,30 with 18 patients with suspected or known lung cancer and nodular enlargement or the presence of peribronchial or paratracheal masses on CT, reported less encouraging results. The sensitivity, specificity, and negative prognostic value were 85%, 100%, and 71.4%, respectively.30 The usefulness of EBUS in mediastinal staging and its comparable results to mediastinoscopy have been demonstrated in many other published studies.31-39 In the largest prospective study so far, Herth et al40 conducted real-time CP-EBUS–TBNA in 502 consecutive patients with suspected lung cancer in whom there was evidence of mediastinal and hilar lymph node enlargement. From a total number of 572 lymph nodes that were biopsied (with mean diameter of 1.6 cm), diagnosis was provided by 535 (94%). The sensitivity and specificity were 94% and 100%, respectively.40 Regarding the role of EBUS-TBNA in suspected NSCLC without CT lymph node enlargement and with negative mediastinal PET findings, 156 nodes were detected, of which 97 were sampled. Malignancy was detected in 9 cases and missed in 1 case. The sensitivity and specificity were 89% and 100%, respectively, whereas the negative predictive value was 98.9%.41 Overall, the diagnostic yield for CP-EBUS–TBNA seems to be continuously improving as has been shown by more recently published studies with sensitivity values that ranged from 95% to 100%, with specificity of 100%, and with accuracy that rated from 96% to 98.5%.42-45 This is probably attributed to the experience gained by clinicians performing this technique. Esophageal ultrasound (EUS) permits mediastinal lymph node sampling through the esophageal wall with little risk of bleeding. This technique allows easy access to the inferior pulmonary ligament, esophageal, subcarinal and aortopulmonary nodes (stations 9, 8, 7, and 5, respectively). However, anterior-lateral to the trachea nodes (stations 2R, 2L, 4R, and 4L) are barely accessible by EUS but can be visualized by EBUS. A combination of EUS and EBUS, a method known as medical mediastinoscopy, seems promising and able to provide an almost full assessment of the mediastinum. In a study performed in 138 patients, the efficiency of CP-EBUS–FNA for full mediastinal sampling was compared with blind TBNA and with the combination of EBUS-FNA–EUS-FNA. It was reported that the real-time EBUS-FNA was more sensitive than TBNA (69% vs. 36%) but less accurate than the combination of EUS-FNA–EBUS-FNA, which showed a higher sensitivity (93%) and negative predictive value (97%) than either technique alone.46 The combination of EUS and EBUS, by using only a single CPEBUS bronchoscope and conducting it as one single procedure, was also evaluated in 150 patients, with a likely diagnosis of NSCLC. Surgical confirmation and clinical observation followed. The sensitivity of EUS-FNA was 89% and of EBUS-FNA was 92% but, of the combination, rated 96% and a negative predictive value of 95%.47 No complications were observed.47 In a similar prospective trial, the
diagnostic accuracy of the combination was 97.2%, although not statistically significant.48 No serious complications from CP-EBUS– TBNA have been reported apart from 2 recent cases of infectious diseases attributed directly to the procedure.49 All of these promising results suggest that the cooperation of respiratory and gastroenterology physicians could lead to a single minimally invasive procedure that may offer an almost complete mediastinal staging without serious complications. However, mediastinoscopy might be considered for suspicious mediastinal nodes when EBUS and EUS are negative, although, according to a prospective study by Ernst et al,50 real-time EBUS provided a higher overall diagnostic yield than mediastinoscopy, especially for paratracheal and subcarinal lymph nodes (91% vs. 78%; P ⫽ .007).50,51 In conclusion, current clinical guidelines on mediastinal staging recommend that, for patients with extensive mediastinal tumor infiltration but no distant metastasis, radiographic assessment of the mediastinum is usually sufficient without the need for invasive confirmation (grade 2C). However, it is emphasized that CT is unable to assess solitary malignant lymph node enlargement and, therefore, invasive confirmation is recommended, regardless of PET findings. In this group of patients, the N2/N3 stage can be establish by using blind TBNA, EBUS-TBNA, EUS-FNA, CT fluoroscopy– guided biopsy, or a combination of the above, depending on their availability and the personnel’s experience (grade 1B). A negative biopsy result requires further confirmation by mediastinoscopy even in PET–positive nodes. Although mediastinoscopy is recommended in patients with centrally located tumors or N1 lymph node enlargement, EBUS-TBNA or EUS-FNA may be a reliable alternative option (grade 1B). In patients with small (⬍20 mm) peripheral lesions (clinical stage I) and positive PET of the mediastinum, a further invasive approach is required, mainly mediastinoscopy, but EBUSTBNA and EUS-FNA are again reasonable alternatives (grade 1C). In case of a negative PET, no further invasive technique is needed to assess the mediastinal lymph nodes (grade 1C). Finally, in patients with suspected left upper lobe malignancy, it is recommended to assess the aortopulmonary window nodes (by use of Chamberlain procedure, thoracoscopy, extended cervical mediastinoscopy, EUSFNA, or EBUS-TBNA) if no other lymph node station is involved (grade 2C).20 Overall, EBUS-TBNA seems to be the most costeffective approach for mediastinal staging in NSCLC, when compared with conventional TBNA and surgical mediastinoscopy.52
Diagnosis of Peripheral Lung Lesions Evaluation of lung lesions or solitary pulmonary nodules (SPN) not visible in routine flexible FB pose a real challenge for chest physicians because prompt and precise diagnosis is of critical importance. It makes a huge difference to distinguish a benign from a malignant lesion and primary disease from metastatic disease. In this context, more than 90% of the bronchoscopists still perform FB with endobronchial biopsies, transbronchial lung biopsies (TBB), and transbronchial needle aspirations (TBNA), mostly blindly or under the guidance of static CT images, or under fluoroscopy. These techniques somehow lack in sensitivity, which varies greatly, depending on the location of the lesion inside the parenchyma and its size. For example, the sensitivity for peripheral lung nodules of 2 cm or less in
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EBUS: Lung Cancer Diagnosis and Staging diameter ranges from 11% to 42% and, when fluoroscopy devices are involved, from 14% to 71%.53,54 One should always take into account the risk of radiation exposure for both patients and examiners during some of these interventional procedures and, therefore, radiation protection measures must be available on-site. Another consideration is the possibility of a nonvisible lesion and the execution of a finally blind biopsy.55 Alternatively, carrying out a percutaneous needle biopsy or aspiration for cytology with a CT-guided procedure improves the diagnostic accuracy up to 76% to 97% but poses several risks. These include the risk of seeding malignant cells in the pleural cavity and the risk of pneumothorax. The latter is greater for lesions located deep into the lung parenchyma and for patients with poor pulmonary function.56,57 An increased risk of complications also exists in older patients or in patients with poor pulmonary function if they undergo a surgical biopsy procedure such as VATS or open lung surgery. In these scenarios, the radial EBUS technique seems a reasonable option. Several studies have been performed, and many others are ongoing regarding the effectiveness of EBUS bronchoscopy. EBUS-FNA cytology has demonstrated a greater sensitivity than TBNA cytology in the diagnosis of lung lesions (78.9% vs. 89.5%).58 Shirakawa et al59 conducted a study that compared TBB by using RP-EBUS and fluoroscopic guidance (50 patients) and TBB under solely fluoroscopic guidance (42 patients). The accuracy of RP-EBUS– guided FB in distinguishing between lung cancer and benign disease was 84% and reached 100% when the probe was inserted in the lesion. Compared with TBB under fluoroscopy only, the addition of EBUS showed improved accuracy and specificity (P ⫽ .02) but not improved sensitivity (P ⫽ .06).59 In the same context, Kikuchi et al60 examined the influence of RP-EBUS– guided TBB in the diagnosis of small peripheral lung lesions (⬍30 mm) when combined with fluoroscopy. The overall diagnostic yield was approximately 58%, and, even in lesions ⬍20 mm in diameter, the sensitivity remained above 50%.60 The best results, so far, have been reported by a study led by Kurimoto et al,61 which combined the use of RP-EBUS with fluoroscopy and reported a diagnostic yield of 92% in lesions ⬎30 mm, 73% in lesions ⬍20 mm, and 77% in lesions between 20 and 30 mm.61 When EBUS-guided biopsy was studied with 54 patients with SPNs not visualized by fluoroscopy, the lesion was localized in 89% of them, and a definite diagnosis was established in 70%.62 The same team reported that, even in small lesions of approximately 22 mm in diameter, the diagnostic yield of EBUS-guided biopsy reached 70%.12 Other studies, however, have reported that EBUSguided biopsy or brushing, without fluoroscopy, was diagnostic in only 29.7% of patients with lesions ⱕ20 mm, whereas it retained a diagnostic yield of 75.6% in lesions ⬎20 mm.63 An interesting, prospective, randomized study by Paone et al64 in 221 patients with peripheral lung lesions assessed the diagnostic yield of radial EBUS-TBB (97 patients) vs. TBB (124 patients). Complete results were available for 201 patients who completed the follow-up. In patients diagnosed with lung cancer, sensitivity and accuracy were better with EBUS-TBB (79% vs. 55% and 85% vs. 69%, respectively). The bigger the lesions, the better these results were, and they were always better for the EBUS-TBB.64 Several other studies have examined and confirmed the superiority of EBUS-TBNA in the di-
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agnosis of pulmonary lesions not visible to conventional bronchoscopy.32,65-72 Eberhardt et al73 studied 118 patients with a define histologic diagnosis and reported a diagnostic yield of 88% when EUS-FNA was combined with real-time EBUS imaging. A summary of all major published studies on EBUS-FB for the definition of peripheral lesions and SPNs is listed in Table 2. Despite the significant advantages of EBUS, there are some concerns, such as the wide range in its diagnostic ability (between 60% and 92% in lesions ⱖ30 mm and between 30% and 70% in lesions ⬍20 mm) and its difficulty to visualize lesions ⱕ15 mm. A higher diagnostic yield can be achieved when the probe is positioned within the lesion on the ultrasound image than adjacent to the target.2 Present guidelines recommend performing transthoracic needle aspiration in patients with a small peripheral, possibly malignant, lesion when a tissue diagnosis is required (grade 1B). However, radial probe EBUS performed by an expert might increase the diagnostic yield of FB (even for peripheral lesions ⱕ20 mm in size) and can be considered before transthoracic needle aspiration (grade 2B). Finally, a negative biopsy of a suspicious lesion may require a more-invasive method to establish the diagnosis.22 It is worth mentioning that there is continuous evolution and expansion of EBUS applications, such as the combination of EBUS with electromagnetic navigation bronchoscopy. This examination requires the patient be positioned on an electromagnetic board, with an electromagnetic field is then created around the patient’s chest, and is combined with an advanced CT imaging system able to reconstruct images. Numerous reference points on the body are provided, which creates a “roadmap.” A flexible catheter with a position sensor is placed into the working channel of the bronchoscope within the electromagnetic field, and it is oriented by computer software. When the target lesion is located, the sensor probe is removed, and biopsy instruments are advanced to the same position. Although this is new and rather expensive, it shows the potential of EBUS technique.
EBUS as a Therapeutic Tool: A Glance at the Near Future EBUS seems to be the most appropriate technique for the determination of depth and extent of tumor invasion in the airway wall. The combination of EBUS with CT or MRI may be useful for the surgical planning of patients with lung cancer but also for esophageal and thyroid cancers. Going a step forward, EBUS technology also can be integrated in therapeutic interventions. Nakajima et al74 reported treatment of a patient with central airway stenosis caused by a mediastinal cyst by EBUS-TBNA, without evidence of recurrence 1 year later. Miyazu et al75 showed that RP-EBUS also could be used in selected patients with centrally located early-stage squamous cell lung cancer before photodynamic therapy (PDT). When lesions were recognized as extracartilaginous by EBUS, other treatments than PDT were opted, such as surgical resection, chemotherapy, and radiotherapy. Patients treated with PDT after EBUS achieved long-term remissions with no recurrences after 32 months of follow-up.75 The significance of the imaging accuracy obtained by EBUS was demonstrated in a series of 1174 therapeutic bronchoscopies, in which the interventional strategy and the used equipment had to be adapted in 43% of the patients (altered stent size, tumor debridement guidance,
Ioannis Kokkonouzis et al Table 2 Results of Studies That Assess the Diagnostic Yield of EBUS in Peripheral Lung Lesion and Solitary Pulmonary Nodules Type of Procedure
No. Patients
Size of Lesion (mm)
Diagnostic Yield (%)
Shirakawa et al59 (2004)
RP-EBUS and fluoroscopy with or without curette– forceps biopsy/brushing
50
–
84
Kikuchi et al60 (2004)
RP-EBUS with guide sheath and fluoroscopy with or without curette–forceps biopsy/brushing
24
⬍30
58
15
20-30
66.7
9
⬍20
53.3
81
⬍20
73
43
20-30
77
26
⬎30
90
Study (Year)
Kurimoto et al
61
(2004)
Yoshikawa et al63 (2007)
Yamada et al
Paone et al
Herth et al
65
64
62
(2007)
(2005)
(2002)
RP-EBUS with guide sheath and fluoroscopy with or without curette–forceps biopsy/brushing
RP-EBUS with guide sheath without fluoroscopy with or without curette–forceps biopsy/brushing
123 (all)
RP- and CP-EBUS–transbronchial forceps biopsy with guide sheath
RP-EBUS–transbronchial forceps biopsy
48
⬎30
98.68
38
20-30
37.9
37
⬍20
29.7
158
21 (SD 6mm)
67
40
⬍15
40
118
⬎15
76
87 (all)
RP-EBUS–transbronchial forceps biopsy
Dooms et al Chao et al
72
67
(2007)
(2009)
Huang et al69 (2009)
Koh et al32 (2008) Fielding et al68 (2008) Nakajima et al70 (2008) Tournoy et al
71
(2009)
78.7 ⬎30
82.8
20-30
75
⬍20
71
50 (all) 21
Herth et al12 (2006)
62
80 ⬍30
80
29
⬎30
79
RP-EBUS with guide sheath without fluoroscopy– transbronchial forceps biopsy
54
22 (SD 7mm), fluoroscopically invisible
70
EBUS–transbronchial forceps biopsy
50
37 (SD 20mm)
84
RP-EBUS–transbronchial biopsy, BW
94
60.6
EBUS–transbronchial biopsy and bronchial washing plus TBNA
88
78.4
11
⬍20
55
103
⬎20
66
CP-EBUS–transbronchial forceps biopsy with guide sheath
29
35
62
EBUS–transbronchial forceps biopsy with guide sheath
140
29
66
CP-EBUS–TBNA
35
94.3
CP-EBUS–TBNA
60
77
RP- and CP-EBUS–transbronchial forceps biopsy
Abbreviations: BW ⫽ bronchial washing; CP-EBUS ⫽ convex probe endobronchial ultrasound; EBUS ⫽ endobronchial ultrasound; RP ⫽ radial probe; SD ⫽ standard deviation; TBNA ⫽ transbronchial needle aspiration.
etc). Consequently, complications such as bleeding were prevented or minimized.11 In the era of personalized medicine and novel therapies, sufficient and good-quality tissue samples need to be obtained during an interventional procedure. Some scientists have explored the ability of EBUS-TBNA to obtain satisfactory material for further molecular
testing and treatment guidance. Mohamed et al76 showed that mediastinal lymph node biopsy specimens obtained by EBUS-TBNA in 36 patients with N2-NSCLC were adequate enough to perform immunohistochemical expression study of 6 cell cycle–related proteins (pRb, cyclin D1, p16 [INK4A], p53, p21 [Waf1], Ki-67). Nakajima et al74 reported that EGFR mutation testing on tumor biopsy speci-
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EBUS: Lung Cancer Diagnosis and Staging mens acquired by EBUS-TBNA was feasible and led to treatment with targeted therapy when appropriate.74 Similar findings and conclusions have been reported by others regarding the EGFR, KRAS, and EML-4/ALK fusion genes on tissue taken by using EBUS-TBNA.77,78,79
Conclusions Although EBUS presents a relative new endoscopic development in the field of interventional respiratory medicine, it shows a potential to play many important roles in everyday practice. Thus, EBUSbased technology may be used in the diagnosis of a lung or mediastinal lesion, staging of lung cancer, and treatment of an endobronchial abnormality. Equally important are its low complication rate, the short examination time, and its manageable cost, especially when compared with surgical invasive procedures. For these reasons, along with its diagnostic accuracy and its safety profile, EBUS might become a very valuable tool in everyday practice, especially in those places and countries where mediastinoscopy is not available or practiced. However, we should acknowledge that most of the data come from experienced centers of the most-developed countries, where there is mounting expertise and adequate resources. In centers of low volume or minimal budget, it is difficult to obtain or maintain satisfactory skills on EBUS and to comply with the recommendations of the European Respiratory Society and the American Thoracic Society, which require initial training with 40 supervised procedures and, thereafter, 25 procedures annually to maintain competency.80 Also, formal guidelines and structured algorithms are needed to encourage physicians to incorporate EBUS in the everyday’s clinical practice to minimize diversities between centers and to serve all patients equally.
Disclosure The authors have stated that they have no conflicts of interest.
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