Mediastinal lymph node cryobiopsy guided by endobronchial ultrasound: a comprehensive review of methods and outcomes

Introduction

The evaluation and diagnosis of mediastinal and hilar lymphadenopathy have evolved over the last several decades. Options for diagnosis offered are surgical methods, cervical or anterior mediastinoscopy (Chamberlain procedure), and less invasive methods, endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS). EBUS-guided transbronchial needle aspiration (EBUS-TBNA) is the preferred diagnostic modality for non-small cell lung cancer (NSCLC) and has been adopted as an initial diagnostic method per newer guidelines (1).

Depending on the underlying etiology, TBNA has varying results. For NSCLC, EBUS-TBNA has a sensitivity of 92.3% and a specificity of 100% (2). Molecular diagnostics, such as histological subtyping and genomic profiling in NSCLC, is possible in 86.5% of samples with EBUS-TBNA (3). In sarcoidosis, the diagnostic accuracy of EBUS-TBNA is 79% (4). The sensitivity of EBUS-TBNA in lymphoma is 66.2% (5).

Bronchoscopic cryobiopsy is a reasonably new development, gaining popularity in recent years. It uses compressed gas to cool surrounding tissue, known as the Joule-Thomson effect (6). The standard technique is to apply the probe adjacent to the target tissue, allow a temperature drop between –35 and –50 °C for several seconds to ensure adequate adhesion to surrounding tissues, and then remove the probe with attached tissue (7).

EBUS-guided transbronchial cryobiopsy (EBUS-TBC) for lymph node biopsy was first published in 2021. Compared to a yield by EBUS-TNBA of 53.2% for benign lesions and 25.0% for non-lung cancer tumors, the EBUS-TBC yield was 80.9% and 91.7%, respectively (8). The results suggest an advantage of cryobiopsy, especially in non-cancerous lymphadenopathy, and could potentially avoid the need for cervical mediastinoscopy. This paper serves to assess the literature regarding cryobiopsy, technique, as well as yield, outcome, and risk.

Methods

Literature search

A thorough literature search was conducted on PubMed, Cochrane, and Embase using the terms “EBUS cryobiopsy”, “transbronchial lymph node cryobiopsy”, and “lymph node cryobiopsy”.

The search was not limited to any region as long as an English translation was available. Articles from conferences were also included. There was no age filter applied for the patient population. Our cut-off date for this search was May 1, 2024.

Eligible studies included those in which bronchoscopic cryobiopsy probe was used to sample mediastinal or hilar lymph nodes and those that reported a diagnostic yield and safety outcomes.

Study selection

Two independent authors screened studies (A.J., S.K.) in regard to the title and abstract. Potential articles obtained from this initial review were then evaluated again by the full text by the same reviewers. Two authors individually assessed studies for bias utilizing the Quality Assessment Data Abstraction and Synthesis-2 (QUADAS-2). Studies were assessed in regard to patient selection, index test, reference standard, flow and timing. The reviewers then calculated the risk of bias and applicability concerns in each previously mentioned category as low, high, or unclear (Table 1).

Data extraction and analysis

Data extraction was performed utilizing pre-specified tables of baseline characteristics, the diagnostic yield of cryobiopsy, needle size, number of cryo-biopsies performed, cooling time, wall incision techniques, and complications.

Results

The literature search yielded 45 articles. After excluding ten duplicates, 35 articles were selected based on their titles and abstracts. After this evaluation, 16 studies were found to be possibly useful for our review. Subsequently, the full texts of these articles were reviewed. Five articles were then excluded, the reason listed are as follows: review papers (n=1), articles without relevant outcomes (n=2), and abstracts and case reports (n=2) (Figure 1). A total of 11 studies were included in the final review (Table 1) (8-18).

Figure 1 Flowchart of the search process for the review related to EBUS cryobiopsy of hilar and mediastinal lymph nodes. EBUS, endobronchial ultrasound.

Reported technique

The procedure for performing lymph node cryobiopsy varies among bronchoscopists. Nine studies reported procedures performed under moderate sedation, and two reported using general anesthesia for the performed procedures. Only one study utilized a rigid tracheoscope for intubation for the procedure (11). After a surveillance bronchoscopy and lymph node identified by EBUS, almost all studies performed a TBNA to create a puncture site for the cryoprobes to enter the mediastinal space (Figure 2). Needle gauge size varied; most studies used 22G, but 19G and 21G were also used. Cheng et al. also used forceps with TBNA to create an incisional track (9). Two studies used a high-frequency needle knife to make a small incision adjacent to the target before probe placement. The knife was then removed and replaced with a probe (8,10).

Figure 2 Execution of EBUS-guided lymph node cryobiopsy. (A) Bronchial view of mediastinal space puncture-site access after TBNA. (B) Cryoprobe entering the puncture site under direct visualization. (C) Direct visualization via EBUS of cryoprobe entering lymph node. (D) Frozen tissue surrounding the cryoprobe tip after the probe is removed en-bloc. These images are published with the patient’s consent. EBUS, endobronchial ultrasound; TBNA, transbronchial needle aspiration.

Erbe offers three sizes of single-use, flexible cryoprobes—1.1, 1.7, and 2.4 mm (19,20). All studies were performed with a cryoprobe size of 1.1 mm, except for one by Gershman et al., who also used the 1.7-mm probe (13). The probe was advanced through the working channel into the lesion under direct visualization and further guided by real-time ultrasound imaging. Optimal location was left to the discretion of the proceduralists, who generally avoided areas with abundant blood flow or massive necrosis. After placing the cryoprobe, it was activated to cool down with nitrous oxide. Six studies froze tissue for 3 to 4 seconds (12-17), two studies for 5 to 6 seconds (11,18), and the remaining studies froze tissue for 7 seconds (8-10).

In all studies, the operator removed the bronchoscope and cryoprobe with attached frozen biopsy en-bloc from the airway. Since the sample from cryobiopsy is significantly larger than the working channel of the bronchoscope, it cannot be extracted through the channel. Samples were retrieved in saline and immediately placed in formalin. Rapid on-site evaluation (ROSE) was not routinely used. Compared to TBNA, cryobiopsy delivered larger biopsy sizes (0.46–0.47 vs. 0.18–0.20 mm) (16). Cheng et al. obtained cryobiopsy samples of 8.1 mm² compared to forceps biopsy sizes of 2.1 mm² (9).

The overall procedural time varied among studies, but performing cryobiopsy took additional time. Velasco-Albendea et al. and Ariza-Prota et al. reported 10 minutes to obtain a cryobiopsy in addition to the time taken to perform EBUS (16,21). Fan et al. reported a difference in total time between EBUS-TBNA alone or with the addition of EBUS-TBC as 17.0 vs. 22.3 minutes (10). Zhang and colleagues reported the difference between performing EBUS-TBNA and EBUS-TBC as 2 minutes (8). Oikonomidou found it took 20–30 minutes to perform EBUS-TBNA but 30–40 minutes to perform EBUS-TBC (22). However, lymph node cryobiopsy took less time than lymph node forceps biopsy (1.7 vs. 3.3 minutes) (9).

Indications & contraindications

Any lymph node traditionally accessed through the bronchial tree is amenable to cryobiopsy (i.e., stations 2, 4, 7, 10 & 11). All patients needed to meet the criteria for bronchoscopy and EBUS. Mediastinal cysts or abscesses are usually excluded. The standard size of lymph nodes biopsied was ≥1 cm. Fan et al. did not specify size limitation, but the average diameter of lymph nodes biopsied via cryobiopsy was 2.0 cm (10).

In some studies, the surrounding vascularity was measured via the Doppler-mode blood flow via ultrasound and categorized per Nakajima et al.’s grading system: grade 0: no blood flow or minimal flow; grade I: a few vessels directed toward the center of the lesion; grade II: punctiform or rod-shaped flow signals or vessels found as a long strip of a curve; and grade III: rich flow with at least five vessels with different diameters and a twist or helical-flow signal (23). For lesions that were grade III, indicating significant blood supply, another node or site was selected to limit complications (10).

Complications

The most common complication was bleeding. Bleeding was classified per a previously published scale by Ernst et al. and Yarmus et al. as follows: grade 0: no suctioning required; grade 1: bleeding requiring suctioning and wedging for 2 minutes or less; grade 2: bleeding requiring wedging for at least 3 minutes; grade 3: bleeding requiring instillation of epinephrine or iced saline; and grade 4: bleeding requiring hemodynamic support including transfusion of blood products, selective mainstem intubation, bronchial blocker placement, hospital admission, or other surgical intervention (24,25). Most studies reported minor bleeding (grade 0–1). Pneumothorax or pneumomediastinum was another reported complication noted on post-procedural radiography. These occurred at a rate of <2% and resolved without further intervention. Salcedo Lobera et al. reported that out of the 50 patients involved in their study, two patients experienced hypoxemia requiring an increase in oxygen supplementation, and 1 developed a vocal cord hematoma; however, all patients were discharged home on the same day as the procedure (17). None of the above complications were statistically significant compared to the control group, suggesting that cryobiopsy offers no significant additional procedural risk.

Yield

Overall yield

Several recent studies have compared the efficacy of EBUS-TBC vs. EBUS-TBNA (Table 1).

The overall mean and median yield of EBUS-TBC reported in the studies was 91.9% and 92.4% compared to 76.6% and 78.2% or EBUS-TBNA alone with a corresponding range of 60–100% and 54–87.5% respectively (Table 2). One study looked at the yield of cryobiopsy when the ROSE of the EBUS-TBNA was indeterminate or nondiagnostic. Cryobiopsy achieved diagnosis in 33 of 46 cases compared to 19 of 46 patients with EBUS-TBNA alone (18).

Benign etiologies

For benign etiologies of lymphadenopathy, including sarcoidosis and tuberculosis, cryobiopsy reportedly had a higher yield in several studies (8-10,14,16). The overall median reported yield for benign lymphadenopathy diagnosis with EBUS-TBC was 94% compared to 60% with EBUS-TBNA alone with a range of 78.7–100% and 53.2–100% respectively (Table 3).

Malignant etiologies

The overall yield for detection of malignant lesions overall was reportedly 94.36% with EBUS-TBC and 86.85% with EBUS-TBNA. The diagnostic yield for common lung tumors was 95.21% with EBUS-TBC and 92.67% with EBUS-TBNA (8-12,14-17). EBUS-TBC outperformed EBUS-TBNA significantly in detection of uncommon tumors in the lung with reported yield of 90.14% with EBUS-TBC and 57.75% with EBUS-TBNA (8-12).

Lymphoma

Cheng et al. reported successful lymphoma diagnosis in 13 out of 15 cases using EBUS-TBC compared to 11 with forceps biopsy (9). Fan et al. included ten patients with lymphoma with EBUS-TBC, providing the diagnosis in 8 patients compared to 5 with EBUS-TBNA (10). Zhang reported an 88% (7/8) yield for lymphoma vs. 13% for TBNA alone (8). Ariza-Prota et al. reported 4 cases of lymphoma in their cohort, and all of them were diagnosed with EBUS-TBC (16). In the study by Maturu et al., EBUS-TBC was able to identify two additional cases of lymphoma after negative ROSE with EBUS-TBNA (18).

Sarcoidosis

Cheng et al. reported a yield of 92% for sarcoidosis with EBUS-TBC (11/12) compared to 75% with EBUS-TBNA alone (9). Zhang et al. reported a 100% yield (15/15) for sarcoidosis with EBUS-TBC compared to 66% with TBNA (8). Fan et al. included 16 patients in their cohort diagnosed with sarcoidosis with an EBUS-TBC yield of 100% compared to 75% for TBNA (10). Poletti et al. reported 13 patients diagnosed with sarcoidosis with EBUS-TBC compared to 11 with EBUS-TBNA (11). Gershman et al. and Gonuguntla et al. reported 11 and 1 case of sarcoidosis testing positive both with EBUS-TBC and EBUS-TBNA (13,14). Maturu et al. reported 2 cases of sarcoidosis detected with EBUS-TBC that were not detected with TBNA (18). Only one study by Salcedo Lobera et al. reported a higher detection rate with EBUS-TBNA (4 cases) than EBUS-TBC (2,17).

Molecular testing

Three studies compared the ability to run molecular testing on the available specimens. Zhang et al. reported that 93% of cryo samples were adequate for molecular testing compared to 73% for TBNA (8). Fan et al. reported 97% of samples with cryo as adequate for molecular and programmed death-ligand (PD-L) testing compared to 79% with TBNA (10). Ariza-Prota et al. and Genova et al. reported all samples as adequate for molecular testing (12,16).

Discussion

Cryobiopsy of pulmonary tissue is an established technique to obtain a pathological diagnosis in interstitial lung disease. It has also been validated in tumor debulking, foreign body extraction, and endobronchial tissue diagnosis. Cryobiopsy for mediastinal and hilar lymphadenopathy has gained popularity over the past few years. The need for targeted treatments, including immunotherapy and chemotherapy in the case of NSCLC, requires a significant amount of tissue to obtain molecular and genetic profiles of the tumors. Similarly, in the case of benign lung diseases, a greater sample size might be needed to delineate the underlying architecture of the lymph node, making EBUS-TBC an attractive option for diagnosis.

Multiple methods of introducing the cryoprobe have been described, and practice varies across providers, but generally, the results have been excellent, and complication rates remain low. Initial studies (8-10) used the high-frequency knife to create a hole in the airway wall to access the lymph node. This technique may require expertise. However, most recent studies have reported using the hole already created by the TBNA to introduce the cryoprobe, which might have an easier learning curve for experienced EBUS operators.

Cryobiopsy outperformed TBNA in most studies for diagnosis of sarcoidosis and pneumoconiosis. One study (17) reported significantly higher cases of proliferative histiocytosis diagnosed with the use of cryobiopsy. It also performed remarkably well in diagnosing benign etiologies of lymphadenopathy compared to TBNA alone, making it an attractive option when such a diagnosis is clinically suspected.

Cryobiopsy also outperformed EBUS-TBNA for detection of malignant lesions, regardless of if they were common or uncommon lung tumors. Cryobiopsy also obtained sufficient tissue for molecular testing as overall sample adequacy was reportedly around 95%. Similarly, the detection and tumor characterization rates for lymphoma were significantly higher in the cryobiopsy group, with an overall yield of over 90%. This marks a remarkable improvement on TBNA, which in literature has a reported sensitivity of around 77% (26). This increase in yield might be explained by the need for histologic analysis rather than cytologic analysis needed for the characterization of lymphomas, which might not be possible with samples from TBNA.

Since the end-date of our literature review, Romero et al. and Chandragiri et al. have since published a comprehensive review of EBUS-TBC (27,28). However, these studies included case reports, which we did not include, and overall fewer randomized controlled trials. These studies, when read along ours, provide a broader literature review.

Limitations

One major limitation is the inconsistent lymph node size criteria used across studies. Most studies included in this review utilized a size threshold of greater than 1 cm for biopsies, which contrasts with the widely accepted clinical guidelines recommending biopsy for nodes larger than 0.5 cm in EBUS (29). This divergence introduces selection bias and limits the generalizability of the findings, especially for smaller lymph nodes that are frequently biopsied during standard EBUS procedures. The complication rate could be higher when aiming at doing a cryobiopsy of a smaller lymph node.

The adequacy of next-generation sequencing in EBUS-TBNA may be underestimated in this review. Our article compared studies that did molecular testing in the same lymph node between EBUS-TBNA and EBUS-TBC. The largest one of them by Zhang et al. reported a difference of 93% vs. 73% for the ability to run molecular testing on EBUS-TBC vs. EBUS-TBNA respectively (8). The other two trials were of smaller number and included 5 or less patients. There was also no standardized definition for adequacy of molecular testing. This is in contrast to systematic reviews which report higher rates of adequacy (94.5% for EGFR and 94.9% for ALK mutations) by EBUS-TBNA (30).

Lastly, the financial implications of EBUS-TBC are not well reported. There were no mentions of cost analysis in the listed studies.

Conclusions

Overall, cryobiopsy is a safe procedure with excellent results that can be used as an adjunct to already practiced techniques. The benefit of preventing repeat procedures with better yield from the addition of EBUS-TBC might compensate for the additional procedural time required. There is a need for standardization of the procedure techniques and training structure. Large multi-center studies are needed to integrate cryobiopsy into algorithms for mediastinal node sampling.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-39/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-39/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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