Superiority of ultrasound-guided over conventional transbronchial needle aspiration in biopsy of lymph nodes: Have we had sufficient evidence?

Conventional transbronchial needle aspiration (C-TBNA) has been utilized in sampling of mediastinal lymph nodes in lung cancer for more than three decades, with relatively high yields ≥80% in more bulky lymph nodes.[1] Compared with surgical staging, C-TBNA is usually performed under local anesthesia and conscious sedation in the bronchoscopy suite.[2] It is generally more convenient, less risky, and of economic advantage. In patients with multi-station or bulky N2 disease who are not suitable for surgery or other radical therapy, C-TBNA provides a minimally invasive and less expensive alternative to mediastinoscopy for diagnosis. Endobronchial ultrasound-guided TBNA (EBUS-TBNA), which was successfully introduced into daily clinical practice in the last decade, has led to a renewing in the sampling and staging of mediastinal lymph nodes.[34] Conventional TBNA and particularly EBUS-TBNA have become first-line tools for diagnosis and staging of lung cancer. In addition, their efficacy in benign mediastinal diseases to optimize the diagnostic yield has also attracted attentions, for example, they are helpful in making an accurate diagnosis of drug-resistant varieties of tuberculosis.[5] Recently, comparison on the clinical value of C-TBNA versus EBUS-TBNA in lung cancers (when they are both available) has been a contentious topic. In view of its ability to locate and sample lymph nodes with real-time guidance, EBUS-TBNA supposedly should allow better access to a wider range of lymph nodes stations, including more distal locations, smaller nodes and those in juxtaposition to vessels.[67] However, these putative benefits are based on an overall intuition. Sufficient evidence from randomized clinical trials (RCTs) with rigorous study design and reasonable outcome interpretation are in dire need for a clear clarification of these issues. There have been indeed several studies attempting to look at the advantage, or “superiority,” of whichever of these two procedures over the other in lung cancer and granulomatous disease. In these studies, the major advantages of EBUS-TBNA over C-TBNA were found to be improved safety, excellent diagnostic yield, and larger tissue sample obtained.[891011] So far, these authors acknowledged that their findings were largely derived from retrospective and/or observational analyses, rendering further validation warranted in prospective and interventional studies. Unfortunately, prospective and interventional studies in a satisfactory sense of comparing C-TBNA versus EBUS-TBNA are rare. A search in the literature published during the past 45 years via electronic databases PubMed, EMBASE and Cochrane Library, with search terms “endoscopic ultrasound,” “endobronchial ultrasound” or “transbronchial ultrasound,” “endosonography” and “transbronchial needle aspiration,” only hit five studies which seemingly focus on efficacy of C-TBNA and EBUS-TBNA.[12] Even so, the resultant studies were also limited by a bundle of factors. In a study, Jiang etal.[13] sought to compare the efficacy of C-TBNA and EBUS-TBNA for the diagnosis and staging of lung cancer, where no significant difference was noted between the two techniques in patients with mediastinal and hilar lymphadenopathy. However, the authors did not include adequate data for the analysis of the results. Such inadequacy in data inclusion was common and sometimes inevitable in the context of clinical practicing for currently available studies on this topic. It could be ethically problematic to conduct a large double-blind RCT that specifically answers with the competent robust power to the superiority of C-TBNA versus EBUS-TBNA in a patient population of lung cancers. Therefore, many studies offered retrospective and observational data obtained in consistency with the routine practicing of the investigators or in their institutions. Ideally, a comparison on these two diagnostic approaches should account for as possibly many factors which appear to influence the diagnostic yields, including the options of sedation and anesthesia, time of the aspiration, size and nature of lymph nodes, specimen preparation, prevalence of bulky lymphadenopathy, as well as rapid on-site evaluation by cytopathological examination. Blinding of pathologists who reviewed all the slides to the method used for sampling, subsequent surgical sampling and follow-up to confirm the “true-negative” and “false-negative” findings are also important to be addressed.[14] Moreover, among the very few studies, we could retrieve so far, the smaller sample size of study populations remains to be a significant drawback which hampers the level of evidence. Conclusions drawn might not be easily generalized until these factors are carefully examined with a proper strategy of the study. In a technical perspective, expertise of the operators can be greatly related to patient tolerability, outcomes, and efficacy with these two procedures.[15] As known, EBUS-TBNA can be challenging to learn. Current studies on the learning curve for EBUS-TBNA have shown it is longer than previous thought, and the recommended minimum number of procedures to achieve competency may be too low.[1617] Therefore, published data so far may be, at least partly, a reflection of learning curve in which bronchoscopists' decades of experience with conventional TBNA versus 2 to 3 years' experience with EBUS-TBNA was compared. It would be interesting to repeat certain studies with special considerations to the effects of learning curve, to provide more convincing evidence. In certain patients, C-TBNA was performed before EBUS-TBNA. This sequence may not exclude the probability of the cross contamination to EBUS-TBNA samples, but was, unfortunately, confusing in some studies.[18] Difficulty in obtaining data to compare the advantages of C-TBNA and EBUS-TBNA also arises in the real world as far as the manipulation is concern. For EBUS-TBNA, though Lee etal. suggested when at least one tissue core specimen is obtained by the first or second passes, two passes per lymph node station can be acceptable;[19] it seems reasonable to perform three TBNA passes per target site for optimal performance, and if only a single site is available, four or five passes per site should be carried out. Furthermore, when molecular testing is planned, a total of four passes should be obtained from the target site.[2021] Since conventional TBNA does not obtain the sample under direct visualization, the maximum diagnostic yield was usually obtained in five to seven needle passes.[22] However, in fact, rigorous completion of seven or more needle passes for C-TBNA to achieve the maximum diagnostic yield would not be feasible in all studies. Some investigators thus performed fewer punctures with C-TBNA than as recommended in other studies, which may decrease the overall sensitivity. Compared with surgical staging and mediastinoscopy, C-TBNA and EBUS-TBNA are considered safe procedures, yet one study indicated more complications with C-TBNA, although the difference was not statistically significant.[23] The aspects on complications remain to be adequately elucidated in larger studies. Finally, efforts to compare the efficacy between C-TBNA and EBUS-TBNA have been seldom extended to patients with benign pathologies where a biopsy of lymph nodes is also of diagnostic significance. Further analysis on these patient cohorts to find out whether there are differences between the two methods in the diagnostic yields (especially tuberculosis and sarcoidosis). The benefits of EBUS-TBNA versus C-TBNA may extend beyond the clinical purposes perse, to lowering the cost burden on the patients or the healthcare systems. Canadian Agency for Drugs and Technologies in Health found that the economic benefits that are associated with the improved yield resulting from the use of EBUS-guided procedures, and that the use of EBUS-TBNA instead of conventional TBNA could be a source of annual cost savings in the evaluation of thoracic lymphadenopathy.[24] However, EBUS-TBNA devices are expensive, and the costs for instrument maintenance are high because of their high damage rate, which may be obstacles to the widespread use of EBUS-TBNA,[25] especially in low-income countries. More data on the cost-effectiveness of C-TBNA versus EBUS-TBNA need to be explored in a global background with multinational collaborations. In summary, an absolute superiority of EBUS-over C-TBNA in biopsy of lymph nodes is yet to be further validated with sufficient evidence from future studies with multiple factors controlled, more patients included, and more collaboration between countries and regions.

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