A comprehensive review of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA): staging, techniques, and future directions

Introduction

Endobronchial ultrasound (EBUS) and its role in modern medicine?

EBUS has emerged as the first-line technology for evaluating mediastinal lymph nodes in the workup of malignancy (1,2). This minimally invasive technique reached a turning point following the development of the convex probe in the early 2000’s, allowing for real-time ultrasonographic guidance of intranodal sampling and providing both diagnostic, and in certain cases, staging capabilities simultaneously (3). The ASTER trial was one of the first to highlight EBUS with transbronchial needle aspiration (TBNA) comparable sensitivity to mediastinoscopy (85% vs. 79%), with the added value of fewer complications and unnecessary thoracotomies, making it the preferred method for mediastinal staging in lung cancer (4). Since its introduction, studies have shown a pooled sensitivity of 90% and specificity of 99% for nodal evaluation in lung cancer (5). The utility of EBUS is not limited to evaluation of malignancy but also extends to evaluation of benign conditions such as sarcoidosis as well (6).

In the context of lung cancer, many patients will require invasive mediastinal lymph node staging as part of their evaluation and management plan, to guide clinical staging and determine surgical candidacy. The National Comprehensive Cancer Network (NCCN) recommends EBUS as the first-line modality over other techniques, both noninvasive [computed tomography (CT) and positron emission tomography-computed tomography (PET-CT)] and more invasive [mediastinoscopy and video-assisted thoracoscopic surgery (VATS)]. Sensitivity and specificity for mediastinal staging with CT are 55% and 80%, respectively, and only marginally improved with PET-CT (80%, 90%). On the invasive side, the sensitivity, specificity, and negative predictive value of cervical mediastinoscopy are 78%, 100%, 91% and 99%, 100%, 96% for VATS, respectively. EBUS has a sensitivity and specificity of 89% and 100%, with a negative predictive value of 91% (Table 1) (7). Furthermore, combining EBUS with PET-CT in patients with N0–N1 non-small cell lung cancer (NSCLC) provides a significant synergistic effect, lowering the risk of missing nodal metastasis. Mediastinal lymph nodes that appear benign on CT, PET, and EBUS have less than a 6% chance of malignancy (8). As a result of its high sensitivity, specificity, and strong negative predictive value, EBUS is now the standard approach for patients needing invasive mediastinal staging.

Given EBUS-TBNA’s practicality, its clinical applications have expanded. Advanced techniques like endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) and elastography enable sampling of lesions inaccessible via the endobronchial route and assessment of tissue elasticity (9). Other relevant applications involve contributing to targeted therapies and immunotherapy through molecular profiling, sampling pleural and cardiac lesions, addressing loculated mediastinal effusions, performing intertumoral therapy, and even diagnosing thyroid lesions (10).

This review paper aims to explore the challenges that advanced diagnostic bronchoscopists may encounter as they perform EBUS, address its application in invasive mediastinal staging with the 9th TNM (Tumor, Node, Metastasis) edition, the limitations in evaluating central airways, the selection and utilization of various relevant tools, and the diagnosis of lymphomas and other benign conditions.

Mediastinal staging

How should invasive mediastinal staging be conducted for optimal lung cancer treatment?

Accurate staging of the mediastinum is imperative to correctly guide treatment. Unfortunately, noninvasive imaging modalities such as CT and PET scans lack the sensitivity and specificity to inform therapeutic choice. One study from Japan found that 30% of patients with only N1 disease identified on CT scan (lymph nodes larger than 1 cm) had pathologic N2–N3 disease (11). A 2012 meta-analysis evaluated the negative predictive value of PET-CT for tumors less than or equal to 3 cm and found it to be 94% compared to 89% for tumors greater than 3 (12). Additionally, a 2007 study noted that 2.9% of patients with peripheral clinical stage 1 tumors based on CT and PET-CT were found to have N2 disease, compared to 21.6% for central tumors (13). These findings led to the NCCN recommendations for invasive mediastinal staging when: (I) the tumor is in the central lung field, (II) larger than 3 cm, or (III) when abnormal lymph nodes are identified based on CT scan size or PET scan avidity (14). This recommendation has led to the use of EBUS as a minimally invasive technique to stage known or potential malignancies.

In invasive mediastinal staging, the evaluation of lymph nodes follows a systematic approach with the order based on the anatomical location of the primary tumor. The sequence starts with the contralateral mediastinal lymph node stations, followed by the ipsilateral mediastinal stations, and finally the ipsilateral hilum. It is recommended to sample all lymph nodes measuring ≥10 mm in the short axis, in addition to any suspicious nodes identified on pre-procedure imaging (15,16). Some key sonographic criteria indicative of malignancy include irregular margins, heterogeneous echotexture within a node, absence of central echogenic hilum, and presence of hypoechoic necrotic areas (17).

Adopting such a systematic approach has proven superior to sampling suspicious stations discovered by PET and has shown to minimize the associated risk of missing occult nodal disease (18-20). Equally concerning, Berim et al. found that malignant cells remained on a needle tip even after three consecutive 10 cc flushes, supporting the use of a contralateral approach when sampling lymph nodes to limit cross contamination (21). This methodical approach minimizes the risk, and clinical ramifications of incorrect staging.

What is the importance of accurate lymph node staging in the treatment of non-small cell lung cancer (NSCLC)?

The treatment of NSCLC is reliant on accurately staging lymph nodes. Curative surgery is often the recommended option in patients with clinical N0 (cN0) and clinical N1 (cN1) disease based on their preferences, functional status, and pulmonary function tests (22). As highlighted in the prior section, current guidelines recommend invasive mediastinal staging for tumors larger than 3 cm, centrally located, and those with PET/CT avidity or enlargement on CT (14). However, it is important to note the limitations of noninvasive modalities. Dezube et al. analyzed 2,157 patients with clinical T1aN0M0 NSCLC who underwent lobectomy with nodal evaluation. The reported occult disease incidence was 6.7%, with 5.1% presenting as N1 and 1.6% as N2 disease (23).

For patients who are not surgical candidates, stereotactic body radiotherapy (SBRT) has become an option for treatment with promising long-term outcomes (24,25). Unlike surgical patients, these patients will not undergo lymph node dissection to detect occult nodal disease. Therefore, evaluating N1 nodes even in the absence of a surgical indication is something to consider for preplanning treatment. If N1 nodes are positive, the radiation oncologist can potentially target the region with a radiation beam. Collin-Castonguay et al. studied 276 patients with clinical TxN0–1M0 who underwent surgery with dissection; 29 were found to be N1 positive, and 13 of those 29 with N1 disease were in stations identifiable by EBUS. The number needed to treat (NNT) to modify the stage of a patient with radiographic N0 disease was 10 (26). Therefore, mediastinal staging should be considered for patients not eligible for surgery and those being evaluated for targeted radiation therapy (27). The importance of accurate staging highlights the critical role of EBUS in managing NSCLC and its likely significant contribution to tailoring treatment strategies.

What are the updates to mediastinal staging in the 9th edition of the International Association for the Study of Lung Cancer (IASLC) Lung Cancer TNM?

The 8th edition of the TNM staging system, published in 2016, updated both T and M staging but kept N unchanged. The 5-year survival rates for N0, N1, N2 and N3 disease are 60%, 37%, 23%, and 9%, respectively. With the new update the IASLC has identified and defined subgroups combining location of metastatic nodes, nN (single station versus multiple stations), and absence versus presence of skip metastasis. With these subgroups, differences in survival outcomes were not noted in skip N2 metastatic disease, but were noted in single versus multi-station N2 disease. This has now been succeeded by the 9th edition; one can see in Table 2 the differences comparatively from the eighth to the ninth edition.

The 9th edition of the Lung Cancer TNM staging published in January 2025 updated the N staging section as well as the M section, the latter we will not cover in this review. The N2 category has been split into N2a and N2b based on single station or multi-station involvement of ipsilateral mediastinal and/or subcarinal lymph nodes, respectively. The size of the lymph node, bulky vs non-bulky were not included in the update, nor were skip metastases. Of note, a skip metastasis is defined by the presence of N2 metastasis without the involvement of N1 lymph nodes in the hilar and intrapulmonary areas (single station N0N2 disease or skip metastasis). Factors associated with increased risk include males, patients over 60 years old, and patients who smoke (28,29). Skip metastasis frequency increases for tumors less than 3 cm in diameter and in association with an epidermal growth factor receptor (EGFR) mutation (29,30), and with tumors located in the lateral one-third of the lung field (31). On secondary analysis, a group examined the skip N2 nodal disease; it was found that skip N2 lesions were not significantly associated with poorer survival outcomes and therefore not included in the update (32). Analysis of overall survival of the N1 and N2a compared to the N2a and N2b groups showed that the former was much less pronounced than the latter. This suggests that the number of lymph node metastases has a higher impact on prognosis (32).

The update highlights the heterogeneity of the prior N2 lymph node stage classification. N2 disease in the 8th edition did not exclude surgical candidacy akin to N3 disease. However bulky multizone positive N2 disease complicated surgical decision-making adding complexity to potential resection (33). With the update, the clarification to single vs multi-station will help aid treatment decisions.

A group of Swiss expert thoracic oncologists attempted to clarify if these factors influenced their decision-making process regarding this heterogeneous population of Stage 3 N2 disease. They found that for multi-station bulky disease, radiotherapy was recommended by 74–83% of experts, while 22% recommended surgery with a neoadjuvant approach for single-station bulky disease. In cases of non-bulky disease, 91% of experts recommended surgery. For multi-station, single-zone disease, 83% recommended surgery, and for multizone non-bulky disease, 65% recommended surgery (34). While patient-specific outcomes were not directly measured, the Swiss group found that there was a stronger preference for a surgical approach with a smaller lymph node burden.

Currently, the European Society for Medical Oncology (ESMO) recommends surgery for N2 disease without mentioning additional risk factors such as bulky disease or multi-station (35). In contrast, the NCCN recommends both radiotherapy and surgery as options. Pöttgen et al. performed a meta-analysis comparing radio-chemotherapy versus surgery in stage 3 NSCLC and found no significant difference in overall survival. However, the large heterogeneity of the group, bulky vs. non-bulky, single station vs. Multi-station, complicates and questions the validity of the study (36). The updates in the nodal staging system allow a streamlined approach to these patients and highlight the importance of adequate N2 sampling.

Should station 10 nodes be routinely examined in lung cancer staging?

In the evaluation of lung cancer, there might be cases where redundant diagnostic modalities are employed with no significant benefit. For instance, sampling lymph nodes via EBUS-TBNA can both diagnose and stage a patient, eliminating the need for additional primary evaluations. EBUS can assess not only mediastinal but also hilar, interlobar, and lobar lymph nodes, the latter of which are often unreachable through mediastinoscopy (37). Guidelines recommend systematic staging of each lymph node section: ipsilateral hilar, ipsilateral mediastinal and contralateral hilar/mediastinal. However, it can be time-consuming and arduous to assess each station, with some lymph nodes being difficult to identify. This raises the question of which lymph node stations should be routinely assessed, specifically station 10.

Station 10 lymph nodes sit in the region on the left below the superior margin of the main pulmonary artery and superior to the takeoff of the left upper lobe. On the right side, its region is from the inferior border of the azygous to the inferior border of the right upper lobe orifice. Wi et al. reported a significantly lower negative predictive value of station 10 nodes (82.4%) when compared to that of stations 11/12 (93.8%), due to its anatomically challenging location (38). This highlights the need for careful revision when evaluating station 10 samples and recommends evaluation for accurate mediastinal staging. Furthermore, a positive station 10 has been associated with worse prognosis (39). Okada et al. (2005) reported the 5-year survival rates for patients with ipsilateral nodal involvement up to station 11, station 10, and station 7 to be 41.4%, 37.9%, and 37.7%, respectively (40). Moreover, Riquet et al. (2017) reported 5-year survival rates for patients with hilar N1 (station 10), interlobar (station 11), and peripheral N1 (stations 12 to 14) involvement at 39%, 51%, and 53%, respectively (41). This further reiterates the necessity, despite the technical challenges, of carefully assessing station 10 lymph nodes due to their prognostic value.

Can we, in certain circumstances, safely omit evaluation of N3 nodes in lung cancer staging?

Evaluation of N3 nodes is a standard part of lung cancer staging, but this process is time-intensive resulting in increased anesthesia exposure. Subsequently, it is worth understanding the circumstances in which it may be safe to skip an evaluation. A retrospective cohort study assessing 174 patients with either PET-confirmed N0 or N1 disease did not find a single case of N3 involvement, after complete mediastinal staging with EBUS. This suggests that the likelihood of occult N3 disease is low in patients with PET-CT confirmed N0 or N1 disease (42). However, another retrospective study aimed to analyze the proportion of patients with malignant hilar N3 nodes showing negative PET-CT scan, which turned out to be 0.68% (43). A notable observation is that malignant N3 lymph nodes may not always exhibit positivity on PET/CT, further complicating their detection (38,43).

In our experience, routine examination of N3 nodes may not always be necessary for patients with negative PET-CT N0 or N1 disease with lymph node size of less than 5 mm. Intuitively, lesions with PET/CT enlargement or positivity should be carefully assessed and the risks of additional procedure time weighed against the risk of a false negative evaluation.

Bronchoscope and needle options, utility of rapid on-site evaluation (ROSE)

How and when should linear EBUS be used to access lung lesions and masses?

The principles for accurate transbronchial biopsy of mediastinal and intrapulmonary lesions can be summarized as follows: (I) selecting the correct airway to reach the target, (II) approaching the target as closely as possible, (III) confirming the target’s location before sampling, and (IV) sampling the same location as confirmed prior. This technique is achieved with EBUS-TBNA. With real time ultrasonographic guidance, EBUS-TBNA is considered a crucial minimally invasive procedure for evaluating centrally located tumors close to the major airways (44,45). Centrally located tumors are defined as those located in the inner one third (American College of Chest Physicians guidelines) or the inner two thirds (European Society of Thoracic Surgery guidelines and NCCN) (45).

As for peripheral lung nodules, a study evaluated the database of the Interventional Pulmonology Unit of Azienda Ospedaliero-Universitaria delle Marche (Ancona, Italy) with the objective of identifying peripheral lung nodules assessed by EBUS-TBNA. They detected 30 patients with nodules located peripherally to the subsegmental bronchi of the lower lobes and adjacent to a small bronchus greater than 3 mm in diameter. The diagnostic yield was 86.6%. Moreover, EBUS-TBNA could assess lesions beyond the subsegmental bronchi due to its transducer’s tip shape that narrows down from its maximum diameter (6.9 mm) to its end (3.3 mm) (46). This gives it the ability to expand the airway lumen, allowing the thinner part of the transducer to access the desired lesion. However, a major limitation is its inability to access the substantial bronchi of the upper lobes.

EBUS can access periesophageal masses and lesions by inserting the bronchoscope into the esophagus; the modality is known as transesophageal bronchoscopic ultrasound-guided fine needle aspiration or EUS-B-FNA. Mondoni et al. reported a diagnostic accuracy of 95.3% in 107 patients and 95.2% in the 99 of them with a final diagnosis of malignancy; the mean lesion size of this sample was 42.2 mm (range, 32–59 mm), with none being ≤30 mm (47). In our practice, this can be done under moderate sedation or general anesthesia, we will give pre-op antibiotics to the patient prior to esophagoscopy with planned biopsy.

The safety profile of EBUS-TBNA is well established with a low overall complication rate. A meta-analysis documented a complication rate of 0.15%, including a 0.08% incidence of pneumothorax requiring drainage (48). Infectious complications such as mediastinitis and pneumonia are rare but have been documented; a multicenter study involving 7,345 EBUS-TBNA procedures identified infectious complications in 0.19% of cases (49).

Is thin convex probe EBUS (CP-EBUS) the future of real-time ultrasound-guided lung biopsy?

The current limitation of the EBUS scope lies in the size and ability to reach peripheral targets. With the incorporation of real time imaging technology such as the radial probe endobronchial ultrasound (RP-EBUS) or cone-beam CT, bronchoscopists may be able to localize intrapulmonary lesions accurately, but wouldn’t be able to maintain tool’s position during sampling. This could be due to poor instrument stability, patient movement (coughing or breathing), or inability to pass the scope through the airway lumen. Addressing such challenges while attaining the ideal sampling standards could be possible with the introduction of the thin convex probe endobronchial ultrasound bronchoscope (TCP-EBUS).

As highlighted previously, various studies have documented the high sensitivity of conventional EBUS. A published meta-analysis has shown that EBUS-TBNA using a conventional CP-EBUS bronchoscope yielded a sensitivity of 91%. However, one notable limitation is its restricted ability to reach bronchi beyond the central lung fields and within the upper lobes. TCP-EBUS, on the other hand, has been shown to reliably and safely access the inner two-thirds of the lung fields for biopsy of intrapulmonary lesions under real-time ultrasound guidance (50). A remarkable advantage of this feature is the ability to biopsy both mediastinal lymph nodes and intrapulmonary lesions in a single examination.

The TCP-EBUS (BF-Y0046, Olympus Medical Systems Corp.) has a thinner tip (5.9 mm) and larger bending angle (170 degrees upward) to evaluate accessibility, operability, and TBNA capability of the TCP-EBUS. TCP-EBUS had a greater reach (14.7 mm in the endoscopic visibility range, 16.0 mm in the maximum reach) than the current CP-EBUS in a study by Wada et al. On porcine models. TCP-EBUS was able to visualize at least one to three distal bifurcations farther than CP-EBUS. This can be credited to TCP-EBUS having a smaller probe size, a shortened rigid part on the tip, a larger upward angulation range, and a decreased angle of the direction of the endoscopic view (51). These features combined allow better access to the peripheral airway with a sustained endoscopic view (Table 3).

The benefits of TCP-EBUS also extend beyond lung malignancy to also involve benign lung diseases such as pulmonary sarcoidosis. CP-EBUS has proven effective for diagnosing stages I and II pulmonary sarcoidosis with a diagnostic yield ranging from 83.3% to 94.4%, which is higher compared to transbronchial lung biopsy (52). It is suggested that TCP-EBUS, given its greater reach to distal N1 nodes, may even further enhance the diagnostic yield in this patient population.

How effective is rose in ensuring adequate tissue sampling for ancillary tests?

ROSE is a diagnostic tool used during EBUS-TBNA that seeks to ensure adequate tissue sampling, optimize the procedure, and inform subsequent steps. Some studies have shown ROSE to significantly enhance diagnostic outcomes, reduce needle passes trials, resulting in fewer complications. Although low, ROSE was found to have potential for false positive results in malignant and granulomatous conditions (53-55). A possible explanation may be due to the reactive bronchial epithelial cells mimicking neoplastic cells (56). This poses a notable challenge especially for less experienced cytopathologists and can lead to incorrect staging decisions, such as not sampling lower-level lymph nodes due to false-positive results at higher levels.

Studies evaluating ROSE have indicated that it neither improves diagnostic yield nor reduces procedure time during TBNA, but it is associated with fewer needle passes and fewer indications for additional interventions (57). Additionally, and despite these advantages, ROSE does not have any impact on the overall procedural time of EBUS-TBNA (54). Some of the diagnostic challenges facing ROSE include low baseline cellularity of the aspirates, contamination, difficulty identifying lesions with bland cytologic features, the unspecific overlapping cytomorphological features, and pathologist-related factors (53). The limitations of ROSE must be taken into consideration in the context of such a crucial step in lung cancer staging and management plan.

As for guidelines on handling EBUS-TBNA specimens, both direct smears and cell blocks are acceptable, but cell block is the preferred substrate when immunohistochemistry and next-generation sequencing are anticipated (58). For PD-L1 testing, current evidence supports PD-L1 immunohistochemistry on cytology preparations provided local validation (particularly for non-formalin-fixed material) (59,60). Regarding molecular profiling, a meta-analysis of 21 studies found that EBUS-TBNA provides adequate material for next generation sequencing in ~86% of cases (61).

How can needle size optimize tissue sampling in EBUS-TBNA?

Numerous studies have investigated the impact of needle sizes on the diagnostic yield of EBUS-TBNA. There have been no studies showing the superiority of one needle size over another for malignant diagnosis. A prospective trial involving 90 patients compared biopsies sampled using 19-G and 22-G needles, and found no significant differences in diagnostic yield, sensitivity for malignancy, presence of tissue cores, or cell count (62). Another prospective trial that included 50 patients compared biopsies using 21-G and 25-G needles and found no significant difference in specimen adequacy or diagnostic yield [74% for the 21-G needle and 80% for the 25-G needle (P=0.607)] (63). A third prospective study comparing 19-G and 21-G needles in 60 patients found no significant difference in diagnostic yield (89.4% vs. 88.7%, P=0.71) (64). With the advent, however, of direct cancer therapy, a meta-analysis noted that, in addition to the comparable diagnostic yields of the different needle sizes, the 19-G needle was noted to provide fewer passes to achieve ROSE adequacy call and higher sample cellularity for molecular and immunohistochemical testing (65).

The type of needle is also a consideration when approaching a patient with a broad differential diagnosis, including sarcoid and lymphoma. Specifically, providers often need architecture to clinch the diagnosis. Core needle biopsies are one option with EBUS TBNA, and can be obtained with large bore (often defined as 19-G) or specialty needles. One such specialty core needle, ProCore (Cook Medical) is designed specifically to obtain a core tissue biopsy. This needle comes in size 25- and 22-G, and has a side cutting window or a core trap to obtain tissue along with aspirate cells. A randomized study was performed of 100 patients comparing ProCore versus a standard needle. While there was a trend to improved diagnostic yield in subjects with sarcoidosis, it was not clinically significant (66). A second specialty needle to mention is a crown cut or “Franseen Tip”, this needle has three symmetrical beveled edges with the theory of incising and preserving tissue more evenly as it cuts. In one study of 24 patients, there was equivalent diagnostic accuracy; however, the crown cut needle was superior to the conventional needle in detecting granulomas and histiocytes. The downside of the crown cut needle described in this study was penetration of the bronchial wall in some cases (67). Utilization of specialty needles can tailor your approach to different diagnostic challenges; however, none have been shown to significantly improve diagnostic yield for conditions such as sarcoidosis or lymphoma. To combat the challenging diagnosis, we will discuss further techniques in a future section.

Beyond the needle size and type, the number of aspirations and agitations is also crucial. A study by Lee et al. performed EBUS-TBNA in 163 mediastinal nodes in 102 NSCLC patients. They recommended three aspirations per lymph node station to achieve maximal diagnostic values with sensitivity and specificity of 95.3% and 100% (68). By prospectively exploring three vs. ten agitations in 86 NSCLC patients, Fielding et al. further demonstrated that three agitations are not inferior to ten agitations for smear cellularity (P=0.44), DNA yield (P=0.84), or DNA integrity (P=0.20). On the contrary, there was significantly less contamination by erythrocytes from three agitations (P=0.008) (69). The application of the suction technique was assessed in a study and compared to the slow-pull capillary technique; it was found that the latter was significantly associated with the acquisition of tissue cores, enhancing diagnostic accuracy (85.71% vs. 66.67%, P=0.039). There was, however, no significant differences in blood contamination (70).

Another relevant factor is the material of the needle. This was highlighted in a study that retrospectively compared cobalt chromium and stainless steel 22-G needles. The results showed that cobalt chromium needles had a higher rate of diagnostic histological specimens (71.0% vs. 58.7%, P=0.039) and fewer samples with cartilage contamination (7.6% vs. 16.5%, P=0.034). Procedure times were also shorter with cobalt chromium needles (22 vs. 26 min, P=0.007) (71).

Advanced techniques for the approach to nonmalignant, lymphoma lymph nodes

How does the EBUS-TBNA technique change when considering alternative diagnoses such as lymphoma or sarcoid?

When approaching a patient with bulky symmetric bilateral hilar and paratracheal lymphadenopathy, one must consider sarcoidosis on the differential. Alternatively, when approaching a patient with bulky asymmetric and often contiguous lymph nodes, lymphoma should be considered. In both these conditions and in NSCLC, the PET scan is avid and under EBUS there are not significant ultrasonographic findings that will clinch the diagnosis. Unfortunately, the diagnostic yield of EBUS-TBNA for sarcoidosis is lower than that for carcinoma. In one study of 258 patients with sarcoid on the differential, the diagnostic yield was 66% (72). A similar study of 304 patients with concern for sarcoidosis found that the diagnostic yield with EBUS-TBNA was 80% (73).

The diagnostic challenge extends to lymphoproliferative disease as well when using EBUS-TBNA. The sensitivity for EBUS-TBNA for lymphoma has been reported to be between 57–67% for de novo or recurrent disease (74). For conditions such as sarcoidosis, lymphoma and other mediastinal lymphadenopathies, it is believed the lack of architecture obtained from an array of needle samples leads to poor diagnostic yield and no difference in sensitivity. For a pathologist, it is important to be able to view the morphology of the lymph node, as it can be a challenge to diagnose Hodgkins Lymphoma without identifying Reed-Sternberg cells. Further fibrosis or underlying granulomatous components affect the diagnosis. Therefore, when these conditions are included in your differential, one’s approach to biopsy must prioritize obtaining architecture. A retrospective study compared the sensitivity and diagnostic yield of samples obtained using 19-G needles, 21-G, or 22-G needles in 137 patients, and found no significant difference for the diagnosis of sarcoidosis or lymphoma. Further as discussed prior, switching to a core or cutting TBNA needle does not significantly improve yield. This diagnostic challenge has led to the use of intranodal forceps and cryobiopsy to obtain larger histological specimens.

Does combining EBUS-TBNA with intranodal forceps or cryobiopsy improve diagnostic outcomes in alternative diagnosis such as sarcoidosis or lymphoma?

In order to address these limitations, newer biopsy techniques to facilitate larger sampling have been explored including intranodal forceps and intranodal cryobiopsy. EBUS-guided intranodal forceps biopsy (EBUS-IFB) provides a complementary tool for efficient tissue sampling (75). It involves passing small mini forceps into targeted lymph nodes following EBUS-TBNA needle puncture. The specimen therefore can be processed as a histological specimen rather than cytology.

Herth et al. reported on the efficacy and safety of sampling subcarinal lesions using EBUS-TBNA and EBUS-IFB. In their study, 75 patients underwent EBUS-TBNA with 19- and 22-G needles. IFB was subsequently performed through the defect made by the 19-G needles. They found a specific diagnosis was made in 36% of patients using the 22-G needle, 49% with the 19-G needle, and 88% with the IFB. Interestingly, the pronounced increase in diagnostic yield with IFB was particularly evident in patients with sarcoidosis (88% vs. 36%, P=0.001) and lymphoma (81% vs. 35%, P=0.038) (76). To further demonstrate the added value of EBUS-IFB, a study evaluated its role when EBUS-TBNA ROSE failed to provide a diagnosis. In patients with a non-diagnostic EBUS-ROSE, EBUS-transbronchial forceps biopsy (TBFB) led to positive diagnostic results in an additional 8/30 patients (27%) (77). A meta-analysis of six observational studies that included 443 patients reported a pooled overall diagnostic yield of 67% for EBUS-TBNA alone and 92% for EBUS-TBNA combined with EBUS-IFB with complications that included pneumomediastinum (1%), bleeding (0.8%), and respiratory failure (0.6%) (78).

Transbronchial cryobiopsy has emerged as a complementary technique for increasing sampling yield, characterized by a more preserved cellular architecture and fewer crush artifacts (79). When forceps were compared with cryobiopsy, a randomized controlled trial found that supplementing EBUS-TBNA with either technique increased diagnostic yield with no significant difference between both combinations (85.7% for forceps vs. 91.6% for cryobiopsy, P=0.106). However, the samples obtained by cryobiopsy qualified more for molecular testing than those from forceps biopsies (100.0% vs. 89.5%, P=0.036) (80). A prospective trial evaluated the efficacy of EBUS-TBNA followed or preceded by EBUS-guided transbronchial lung cryobiopsy (EBUS-TBLCB) in a 1:1 distribution in a cohort of 196 patients with mediastinal lesions (≥1 cm). Compared to TBNA, the overall diagnostic yield of cryobiopsy was significantly higher (91.8% vs. 79.9%, P=0.001) (81). This study was followed by a randomized open lab trial comparing combined EBUS-TBNA and cryobiopsy vs EBUS-TBNA alone as the control. They found the addition of cryobiopsy to standard sampling significantly increased the diagnostic yield for mediastinal lesions (82). Further the combined approach resulted in an improved suitability of tissue samples for molecular and immunological analysis of NSCLC. Additionally, cryobiopsy shared the same adverse event risk and profile to intranodal forceps biopsy.

When approaching a diagnosis of lymphoma or sarcoidosis, often these lymph nodes can be challenging to sample for an array of reasons such as calcification, prior treatment or the nature of the location. One study by Pathak et al. performed in this subset of 25 patients (concerned for lymphoproliferative disorder or sarcoid) with use of electrocautery if needed. In the study initial TBNA with a 22-G was utilized; in 10 patients, a subsequent electrocautery incision was required with a power setting of 20 W, to allow entry of the forceps the lymph node. In this study 1.5 mm or 1.8 mm forceps were used as opposed to miniforceps (1.0 mm). In conclusion, the diagnostic yield improved to 86% from 73% when the techniques of TBNA and intranodal forceps biopsy (INFB) were combined (72). There was one patient who developed pneumomediastinum after the procedure that did not require intervention; no other patients in this study had any clinically significant complications.

For patients with concern of nonmalignant diagnosis or lymphoma, one must consider the utilization of intranodal forceps or cryobiopsy. These advanced techniques have favorable safety profiles and obtain architectural tissue that will improve one’s diagnostic yield.

Conclusions

EBUS-TBNA has become a cornerstone in mediastinal staging, evaluating central lesions, and addressing non-malignant conditions. It is a safe, time efficient procedure that can be performed under moderate sedation or general anesthesia. This technique is accessible to many providers including but not limited to interventional pulmonologists, advanced diagnostic bronchoscopists, and thoracic surgeons.

As treatments for lung cancer advance, the tools we choose and how we used them are crucial for optimizing outcomes. The ongoing development and expanding applications of EBUS will continue to improve patient outcomes and advance the standards of care in thoracic medicine.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1202/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1202/coif). The authors have no conflicts of interest to declare.

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