Fig. 23.8  Real-time visualization of needle passing into a lymph node during CP-EBUS-TBNA

cytological evaluation (ROSE) using Diff-Quik staining. The remaining portion of the sample is placed in a 50 mL conical tube flled with a cell growth medium for cell block preparation.

Indication, Application, and Evidence

Prior to bronchoscopic ultrasound, conventional TBNA was once used as a minimally invasive technique to obtain a tissue diagnosis for intrathoracic adenopathy. Due to the variable yield with conventional TBNA, the radial probe ultrasound was used as a potential replacement with improved diagnostic yield. A study by Herth et al. reported the diagnostic yield of conventional TBNA compared to RP-EBUS for lymph

nodes other than in the subcarinal area to be higher with the RP-EBUS (84%) than conventional TBNA (58%) [33]. The major issue with both techniques was the inability to perform needle aspiration under direct real-time visualization which ultimately led to the development of the CP-EBUS [6]. Since the development of the CP-EBUS, it has become the gold standard for mediastinal staging of non-small cell lung cancer and indicated for the use in sampling mediastinal and central lung parenchymal lesions.

CP-EBUS forNon-malignant Mediastinal or Hilar Adenopathy

The presence of mediastinal adenopathy and other abnormalities is common incidental imaging fnding. Malignancy remains high in the differential in this setting, but there are a variety of benign diseases that can present with intrathoracic adenopathy.

Sarcoidosis is a multisystemic in ammatory disease of unknown etiology that can result in intrathoracic adenopathy, commonly confused radiographically for malignancy. The use of CP-EBUS-TBNA has outperformed the yield of conventional TBNA for the diagnosis of sarcoidosis and demonstrated improved diagnostic yield when performed in combination with conventional bronchoscopic biopsies (TBBx or endobronchial biopsy). A large multicentered randomized control study was published in 2013 by von Bartheld et al. comparing transbronchial

and endobronchial biopsies to endosonographic fne needle aspiration (EUS or CP-EBUS) of lymph nodes to detect non-caseating granulomas in patients with clinical or radiographic suspicion of stage I or II sarcoidosis. The diagnostic yield in the endosonographic group was 74% compared to only 48% in the other group [34]. Tremblay et al. conducted a prospective randomized control study comparing conventional TBNA with a 19-gauge needle and a CP-EBUS with a 22-gauge needle in 50 patients with intrathoracic adenopathy and a clinical suspicion for sarcoidosis. They reported an 83% diagnostic yield for CP-EBUS-TBNA compared to 54% for the conventional TBNA group [35, 36]. A meta-­ analysis reviewing the effcacy of CP-EBUS-­ TBNA for the diagnosis of sarcoidosis in 533 patients with the disease from 15 studies reported the diagnostic yield ranged from 54% to 93% with a pooled diagnostic yield of 79% [36]. These fndings have led to the recommendation of performing CP-EBUS-TBNA in patients suspected of having sarcoidosis with intrathoracic adenopathy [37].

Intrathoracic adenopathy can also occur as a consequence of bacterial, fungal, and mycobacterial infections. A study by Madan et al. evaluated 102 patients from an endemic population for tuberculosis who underwent CP-EBUS- TBNA for diagnosis. They sampled 216 lymph nodes and the diagnostic yield, defned as positive acid-­fast bacilli stain or positive necrotizing granulomas with supportive clinical investigation, was 84.8% [38]. The use of CP-EBUS- TBNA to diagnose a wide variety of infectious diseases causing mediastinal masses and intrathoracic adenopathy have been reported and shown to be effective [39, 40].

CP-EBUS has also been used for the diagnosis of bronchogenic cyst, thyroid nodules, intrathoracic goiters, parathyroid adenomas, and many other nonmalignant intrathoracic abnormalities [41, 42]. While most bronchogenic cyst can be diagnosed by CT imaging alone, some can mimic the appearance of soft tissue making it a diffcult diagnosis and require biopsy. In these cases, CP-EBUS can be used to perform TBNA to obtain tissue and make the diagnosis [43, 44].

CP-EBUS for Malignant Mediastinal or Hilar Adenopathy

The importance of CP-EBUS in the diagnosis and staging of lung cancer is well established in the literature and its application has been extended to other malignant diseases of the mediastinum such as lymphoma, thymoma, and metastatic diseases with positive results [45–51].

Lymphoma has been reported to present with intrathoracic adenopathy in up to 75% of patients with Hodgkin’s Lymphoma making it a disease of interest for the use of CP-EBUS-TBNA for some time [52]. Previously, it was thought that fne needle aspiration of intrathoracic lymph nodes could not provide a diagnosis of lymphoma due to reported discordance between cytologic and histologic samples. This ultimately led to more invasive techniques to obtain adequate tissue including mediastinoscopy, thoracoscopy, and even thoracotomy [53]. Although still a valid concern, since the implementation of CP-EBUS as a platform to perform TBNA of the lymph nodes, many studies have shown success in diagnosing and subtyping lymphoma bronchoscopically, suggesting that prior results may have been due to technical issues and cytopathologic expertise. Kennedy et al. in 2008 published a study evaluating 25 patients with intrathoracic adenopathy suggestive of lymphoma who underwent CP-EBUS-TBNA lymph node biopsy with a 22-gauge needle. All samples were sent to on-site cytology and 24 of the 25 samples had adequate lymphoid tissue present with 10 patients positive for lymphoma and 14 patients labeled as benign. Of those 14 patients, 1 patient had a false negative result and contributed to the sensitivity of 91%, a specifcity of 100%, and a negative predictive value of 93% for diagnosis of lymphoma, but the ability to subtype these patients from the tissue obtained was not reported [54]. Another study published in 2010 by Steinfort et al. retrospectively reviewed a prospectively collected database to determine the utility of CP-EBUS-­ TBNA in the diagnosis of lymphoma. They evaluated 98 patients with isolated intrathoracic adenopathy and excluded all patients with clinical radiographic features of sarcoidosis leaving a total of 55 patients for evaluation. Of the 55

patients, 42 patients received a defnitive diagnosis and 21 of those patients were diagnosed with lymphoma. Of the patients diagnosed with lymphoma 16 were by CP-EBUS-TBNA but 4 of those patients required surgical biopsy to subtype the lymphoma due to low volume samples. Although the sensitivity and specifcity for a defnitive diagnosis was 57% and 100%, respectively, 76% of the patients with lymphoma were able to avoid a surgical biopsy for diagnosis [53]. A subsequent larger study published in 2015 evaluated 181 patients with clinical symptoms of lymphoma or a history of lymphoma with intrathoracic adenopathy to determine the value of CP-EBUS-TBNA to exclude the presence of lymphoma. Overall, 41.5% of the patients were diagnosed with lymphoma and the sensitivity of CP-EBUS-TBNA to diagnose and subtype lymphoma, de novo lymphoma, relapsed lymphoma, and Hodgkin’s lymphoma was 77%, 67%, 81%, and 57%, respectively. Additionally, the likelihood ratio for a patient to have lymphoma when the cytology results showed granulomatous in ammation to be 0.00 and when there was adequate/inadequate lymphoid tissue present to be 0.31 [50]. The current literature therefore supports the use of CP-EBUS-TBNA as the initial procedure to evaluate patients with intrathoracic adenopathy suggestive of lymphoma and it may prevent the use of more invasive procedures to obtain a defnitive diagnosis [37].

CP-EBUS for the Staging of Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths among men and women in the world and non-­ small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer [55, 56]. The implementation of lung cancer screening programs has led to an increase in the number of people diagnosed with lung cancer. This has resulted in an increase in the number of patients diagnosed with early-stage lung cancer which could potentially be treated with curative therapy [57, 58]. The American College of Chest Physicians’ evidence-based clinical practice guideline for the staging of NSCLC recommends invasive mediastinal staging in the absence of

known distant metastasis when there is discrete enlargement of mediastinal or hilar lymph nodes, a central tumor, a tumor >3 cm in diameter, or when mediastinal or hilar lymph nodes demonstrate increased uptake on PET scan [59]. The use of CP-EBUS for lung cancer diagnosis and staging greatly impacts the prognosis and management of lung cancer. In 2016, a new edition for TNM classifcation and staging was published with many changes that better defned the differences between NSCLC based on prognosis and treatment outcomes (Tables 23.2 and 23.3) [60]. CP-EBUS is considered the modality of choice for staging non-small cell lung cancer due to its overall superiority in accurate staging and the ability to be minimally invasive compared to other imaging and procedural techniques [59].

Once it has been determined mediastinal and hilar lymph node assessment for staging NSCLC is required, understanding which lymph nodes will need a biopsy is key. Two groups assessed the ability of ultrasonographic lymph nodes features to predict nodal metastasis using CP-EBUS. Fujiwara et al. performed a retrospective analysis of 1061 lymph nodes from 461 patients who underwent CP-EBUS-TBNA staging for NSCLC at a single center. Images of all lymph nodes were evaluated by 3 expert reviewers who were blinded to the results of the CP-EBUS-TBNA. The ultrasonographic appearance was classifed into six characteristics which were compared to the fnal pathologic diagnosis for each lymph node. Of the six features, round shape, distinct margin, heterogeneous echogenicity, and presence of coagulation necrosis sign were found to be independently predictive of lymph node metastasis. The presence of any one of the four features increased the risk of lymph node metastasis and the absence of all 4 characteristics had a negative predictive value of 96% for malignancy within the node [32]. An additional study published in 2011 by Memoli et al. prospectively assessed 227 lymph nodes in 100 patients who had suspected or confrmed NSCLC and underwent CP-EBUS-TBNA at a single center. Five ultrasound characteristics were recorded which included size, shape, echogenicity, border defnition, and number of lymph nodes at each

station. Size greater than 10 mm and oval or round shape were the only two ultrasonographic features that increased the probability of lymph node malignancy. Of note, 10% of lymph nodes less than 10 mm in size were confrmed to have

malignancy which supports the widely used >5 mm cut off to perform a needle biopsy [61]. These fndings show that although ultrasonographic characteristics may be able to predict lymph node metastasis the low sensitivity and

negative predictive value do not support the ability to rule out malignancy without a biopsy.

Additional concerns to be considered include the ability to reach the lymph node and which modality will provide that access. Of the current modalities to perform biopsies of intrathoracic lymph nodes CP-EBUS provides the best accessibility (Fig. 23.9). CP-EBUS can provide access to the upper and lower paratracheal, hilar, and interlobar lymph nodes bilaterally. It also has the capability of reaching the paraesophageal lymph nodes if introduced through the esophagus, but generally cannot reach the sub or para-aortic lymph nodes. In comparison, mediastinoscopy is limited to the mediastinum and has diffculty effectively accessing more posteriorly located station 7 lymph node, while endoscopic ultrasound (EUS) is limited only to left paratracheal, paraesophageal, and pulmonary ligament lymph nodes. The concept of performing EBUS and EUS in one setting to obtain a complete mediastinal lymph node evaluation has been raised, but the clinical utility and resource constraints are debatable and will be discussed later.

The ability of CP-EBUS to guide real-time TBNA of mediastinal and hilar lymph nodes has led to its widespread use in staging NSCLC, replacing previous modalities. In 2005, Yasufuku et al. frst described the use of CP-EBUS for mediastinal staging in 105 patients who had confrmed or suspected NSCLC with suspicious

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Fig. 23.9  Nodal stations and the modalities able to access the indicated lymph nodes

mediastinal lymph nodes in the node (N) 2 or N3 station. They sampled 163 lymph nodes which resulted in 64 patients diagnosed with cancer. Of

the remaining patients with negative CP-EBUS-­ TBNA, 7 were followed clinically for 12 months which resulted in a benign course and 37 underwent thoracotomy for further sampling with 33 of the 37 patients showing no evidence of N2 or N3 metastasis. This study yielded a diagnostic accuracy of 96%, sensitivity of 94.6%, specifcity of 100%, negative predictive value of 89%, and positive predictive value of 100% [62]. Since this study, many other studies supporting this data and comparing other modalities for mediastinal staging to CP-EBUS have been published.

Imaging modalities such as chest computed tomography (CT) and positron emission tomography have shown to be helpful but suboptimal for determining a defnitive nodal stage in NSCLC. A pooled analysis of the use of CT scans and PET scans for staging of the mediastinal and hilar lymph nodes yielded a sensitivity of 55% for CT scans and 77% for PET scans [59]. In 2006, Yasufuku et al. prospectively compared the performance of CP-EBUS-TBNA to CT scan and PET scan for mediastinal staging in 102 patients with confrmed or suspected lung cancer who were thought to be candidates for surgical resection. The entire group underwent CT and PET scan followed by CP-EBUS-TBNA prior to surgery. The patients who underwent CP-EBUS-­ TBNA and confrmed to have stage I, II, IIIA with only a single positive N2 station were considered operable and underwent thoracotomy with lymph node dissection. Of the 26 patients confrmed to have mediastinal metastasis, CP-EBUS-TBNA correctly staged 24 patients resulting in a sensitivity of 92%, specifcity of 100%, negative predictive value of 97%, and overall diagnostic accuracy of 98%. This was considerably better than CT scan (sensitivity 77%, specifcity 55%, negative predictive value 88%, diagnostic accuracy 61%) and PET scan (sensitivity 80%, specifcity 70%, negative predictive value 92%, diagnostic accuracy 73%) [63]. A similar study in 2008 published by Herth et al. evaluated 100 patients with suspected NSCLC that had CT scans negative for enlarged intrathoracic adenopathy and PET scans negative for any intrathoracic lymph node uptake. All the patients underwent CP-EBUS-TBNA with biop-

sies of any lymph node ≥5 mm and subsequently underwent either a mediastinoscopy or thoracotomy with lymph node dissection which was used as the standard of reference for comparison. 8 patients with no intrathoracic adenopathy on CT and PET scan were found to have positive results for lung cancer on CP-EBUS-TBNA and only 1 patient negative for lung cancer with CP-EBUS-EB was found to have a lymph node metastasis at the time of surgery. The overall results in this study reported a sensitivity of 89%, specifcity 100%, and negative predictive value of 99% for CP-EBUS-TBNA [64]. A third study compared the use of CP-EBUS-TBNA to integrated PET/CT for the diagnosis of intrathoracic lymph node metastasis in 129 patients with suspected or confrmed operable NSCLC. A total of 117 patients underwent analysis and 27 patients were found to have lymph nodes positive for lung cancer on CP-EBUS-TBNA. Of the 90 patients that were found to have negative lymph nodes on CP-EBUS-TBNA 3 patients had malignancy found at surgery. The sensitivity (90%), specifcity (100%), negative predictive value 97%), and diagnostic accuracy (97%) of CP-EBUS-TBNA compared to integrated PET/CT (70%, 60%, 85%, 62%, respectively) was again superior [65].

Mediastinoscopy was traditionally considered the gold standard modality for invasive staging of the mediastinal lymph nodes. Despite this long-­ standing title, mediastinoscopy has limited access to the paratracheal and subcarinal lymph nodes and no ability to sample the hilar lymph nodes. These sampling limitations resulted in reported sensitivities ranging from 40 to 92%, making CP-EBUS a more optimal tool for completely sampling lymph nodes for lung cancer staging. Supporting evidence by Ernst et al. reported 66 patients who were surgical candidates with lesions suspicious for NSCLC and intrathoracic adenopathy limited to the paratracheal and subcarinal lymph nodes. All patients underwent mediastinoscopy and a CP-EBUS-TBNA within a week of the mediastinoscopy with a defnitive diagnosis found in 49 or the 66 (76%) patients. Patients with limited IIIA disease or better were offered surgical resection which resulted in 61 patients undergoing surgery. In the per-patient

analysis there was no statistically signifcant difference in diagnostic yield when comparing CP-EBUS-TBNA to mediastinoscopy (89% vs. 79%; p = 0.1). But in the per-lymph node analysis, there was a statistically signifcant difference for CP-EBUS-TBNA diagnostic yield compared to mediastinoscopy (91% vs. 78%; p = 0.007), which was due entirely to the difference in yield at station 7 with CP-EBUS [66]. Annema et al. also randomized 241 patients with potentially resectable NSCLC to compare mediastinoscopy with endosonographic staging which consisted of EUS-FNA and CP-EBUS-TBNA. All patients with no evidence of nodal metastasis on CP-EBUS-TBNA also underwent mediastinoscopy. Endosonographic staging with mediastinoscopy showed a greater sensitivity compared to mediastinoscopy alone (94% vs. 79%; p = 0.02) and a 11% (7% vs. 18%) absolute reduction in thoracotomies [67]. An additional study published by Yasufuku et al. illustrated that CP-EBUS-TBNA is equivalent to mediastinoscopy for staging NSCLC and is associated with fewer complications. They evaluated 153 patients with NSCLC who required mediastinal staging. All patients underwent CP-EBUS-TBNA immediately followed by cervical mediastinoscopy and any patient who was found without evidence of N2/N3 disease during staging underwent surgical lung and lymph node resection. The results were similar between CP-EBUS-TBNA and mediastinoscopy sensitivities (81% vs. 79%), negative predictive values (91% vs. 90%), and diagnostic accuracy (93% vs. 93%) [68].

Several years prior to the development of CP-EBUS the endoscopic ultrasound (EUS) was commonly used by gastroenterologists. Like CP-EBUS, EUS has a camera for visualization while inside the gastrointestinal tract and an ultrasound transducer for real-time sonographic visualization during fne needle aspiration. EUS-­ FNA has also been used to diagnose mediastinal masses and assist in mediastinal staging of lung cancer but has limited application due to its inability to sample lymph nodes to the right or anterior to the trachea and any hilar lymph nodes. CP-EBUS-TBNA has the advantage of sampling the paratracheal and hilar lymph node stations

but has its own limitation in accessing lymph nodes at the aortopulmonary window, lower esophagus, and inferior pulmonary ligament [31, 62] (Fig. 23.9). The combination of the two modalities to sample the mediastinum for lung cancer staging are complementary and can easily access all intrathoracic lymph nodes except the nodes in the aortopulmonary window and upper prevascular stations. Several published studies have assessed the combination of the two modalities for lung cancer staging with promising results [69, 70]. In 2010, Herth et al. assessed 150 patients suspected to have NSCLC and no evidence of extrathoracic metastasis which resulted in 139 patients who were confrmed to have NSCLC that were included in the analysis. The patients underwent CP-EBUS-TBNA and EUS-­ FNA by a single operator using only a CP-EBUS scope resulting in 619 lymph node biopsies. Additionally, all patients underwent either thoracotomy, thoracoscopy, or 6–12 months follow-up to confrm the endosonographic results. They found the prevalence of mediastinal lymph node metastasis was 52% (71/139 patients) with 65/71 (91%) of the positive lymph nodes detected by CP-EBUS-TBNA, 63/71 (89%) by EUS-FNA, and 68/71 (96%) with combined modalities. The sensitivity (96%) of the combined approach was superior to either CP-EBUS-TBNA (92%) or EUS-FNA (82%) alone [71]. Hwango et al. also assessed the effcacy of combined CP-EBUS-­ TBNA and EUS-FNA to stage NSCLC. They enrolled 150 patients with suspected or confrmed NSCLC and performed both CP-EBUS-TBNA and EUS-FNA which resulted in 38 patients with mediastinal lymph node metastasis diagnosed by CP-EBUS and an additional 3 patients by EUS. Of the 109 patients not found to have metastatic lymph nodes, 7 patients were excluded from the analysis and 4 patients were found to have metastatic disease during surgical dissection. The sensitivity, negative predictive value, and diagnostic accuracy for CP-EBUS-TBNA were 84.4%, 93.3%, and 95.1%, respectively, which was improved with EUS-FNA in the combined analysis to 91.1%, 96.1%, and 97.2%, but not to a statistical signifcance. One outcome that showed statistical signifcance was the higher