Role and Challenges of Endoscopic Ultrasonography‐Guided Tissue Acquisition for Para‐Aortic Lymph Node Staging

Among all solid cancers, pancreatic cancer has one of the poorest prognoses, with a 5-year overall survival rate of 11% [1]. Node metastasis impacts both therapeutic options and prognosis, making the development of a reliable diagnostic modality for N-staging essential. Endoscopic ultrasonography-guided tissue acquisition (EUS-TA) has become extensively employed for diagnosing pancreatic cancer with a high diagnostic ability [2]. In clinical practice, EUS-TA is applied for evaluating both the primary lesion and its resectability, including vascular invasion and liver metastasis [2, 3]. However, data on the diagnostic ability of EUS-TA in lymph node metastasis diagnosis is scarce, and the role of EUS-TA against para-aortic lymph node (PALN), which is particularly significant with respect to cancer staging and prognosis, has not been well established [4, 5]. A previous study by Kurita et al. compared the diagnostic capability of EUS-TA and positron emission tomography with computed tomography (PET-CT) for PALN metastasis in patients with pancreatobiliary cancer and revealed the superiority of EUS-TA over PET-CT in terms of sensitivity and specificity [6]. However, no studies have directly compared the diagnostic performance of EUS-TA with that of CT, the gold standard imaging modality for pancreatobiliary cancer diagnosis and staging. Accurate diagnosis of PALN metastasis is crucial in evaluating resectability, as PALN involvement by pancreatobiliary cancer is classified as a metastatic disease, significantly impacting treatment options [4, 5]. Moreover, a previous meta-analysis revealed that metastatic PALN was correlated with poor prognosis [5]. Therefore, preoperative evaluation of PALN status is extremely valuable for clinical decision-making; however, anatomical issues have made tissue sampling a challenge for both endoscopists and radiologists, hindering accurate diagnosis. In this issue of Digestive Endoscopy, Hara et al. investigated the diagnostic performance of EUS-TA and CT for PALN staging in a cohort of 162 patients, the majority of whom had pancreatobiliary cancer and demonstrated that EUS-TA had higher sensitivity (85.1% vs. 28.4%) and accuracy (93.2% vs. 64.8%) in diagnosing PALN metastasis than CT [7]. Notably, the high diagnostic accuracy and safety of EUS-TA for small PALNs with a short axis of < 10 mm that are difficult to diagnose as malignant using CT has successfully provided novel insights into evaluating N-staging and resectability for patients with pancreatobiliary cancer. Based on the results of their study, we aimed to discuss which patients should undergo EUS-TA for PALNs, when, where, how, and for which lesions. First, which patients should undergo PALN staging using EUS-TA? In cases where distant metastasis is already evident on other imaging modalities, EUS-TA for PALN staging is unnecessary as the therapeutic decision-making is unaffected by PALN metastasis. In patients with pancreatic cancer, those suspected of localized pancreatic cancer on the basis of CT before EUS and whose staging would change depending on the PALN status would be good candidates for EUS-TA of PALN. Every precaution should be taken to mitigate false-positive results in PALN staging as they can result in unnecessary exclusion from potentially curative surgery, ultimately impacting patient prognosis. This study showed EUS-TA as having a very low false-positive rate and could therefore be a reliable diagnostic modality for evaluating resectability by PALN staging. Second, when is the appropriate timing for EUS-TA for PALN staging? In the study by Hara et al., PALNs were visualized and punctured during the same endoscopic session as the puncture of the primary lesion [7]. Considering the physical burden on patients, it is logical to combine both the diagnosis of the primary lesion and the evaluation of its resectability into a single endoscopic session; however, considering that puncture against PALNs using a new needle is preferred owing to risks of tissue contamination, using multiple puncture needles in a single EUS examination causes increased costs. Therefore, we should carefully evaluate other imaging modalities, including CT; select cases in which the presence of PALN metastasis is useful for therapeutic decision-making; and perform EUS-TA for PALN staging together with the diagnosis of the primary lesion. However, following confirmation of the primary lesion diagnosis, when PALN staging is required on the basis of reevaluation of resectability using other imaging modalities, including PET-CT, performing EUS-TA for PALNs on another EUS session would be acceptable. Third, from where should EUS-TA be approached for PALNs? As comprehensively described by Hara et al., lateroaortic and interaorticocaval PALNs can be visualized via the stomach and duodenum, respectively [7]. Therefore, depending on the PALN location, EUS-TA is performed via either the transgastric or transduodenal approach. In this study, each approach route was selected with approximately equal frequency [7]. Transgastric puncture is often more technically challenging than transduodenal puncture; therefore, the difficulty of the EUS-TA may vary depending on the location of the PALNs. Efforts should be taken to identify a safe and appropriate puncture route, considering factors including the intervening vessels and the scope stability. Accurate PALN visualization based on anatomical understanding is essential for puncture. Therefore, routine training in visualizing the aorta from both gastric and duodenal routes and evaluating the surrounding lymph nodes is essential. It should also be noted that there are limitations to the visualization of PALNs on EUS, especially those located to the right side of the aorta. Fourth, how should EUS-TA be performed for PALNs? In the study by Hara et al., 22-gauge fine-needle aspiration (FNA) needles were employed in most cases [7]. A recent meta-analysis has found the superiority of fine-needle biopsy (FNB) needles over FNA needles in terms of diagnostic accuracy for lymph node diagnosis [8]. In the study by Hara et al., the average size of PALNs to be punctured was 11.3 and 6.7 mm in the long and short axes, respectively [7], suggesting that puncture using an FNB needle can be technically challenging. In fact, the study included six cases (3.7%) wherein technical success was achieved by switching from the FNB needle to the FNA needle [7]. Considering the excellent results of the study, the FNA needle may be preferable, especially for puncturing PALNs measuring < 10 mm. Recently, there has been a growing clinical demand to submit tissue samples obtained using EUS-TA for a comprehensive genomic profile. Therefore, selecting the FNB needle for diagnosing the primary lesion and the FNA needle for PALN staging is logical. Lastly, what size of PALNs is a good indication for EUS-TA? One of the strengths of the study by Hara et al. is that it compared the diagnostic performance of EUS-TA with that of CT according to the PALN size [7]. Based on the definition of malignant PALNs as those with a short axis of ≥ 10 mm, the diagnostic accuracy of CT for PALNs with a short axis of 5–10 mm was low at 51.5%. This finding indicates that differentiating malignant from benign PALNs with a 5–10-mm diameter using CT is unreliable. Conversely, the diagnostic accuracy of EUS-TA for PALNs measuring 5–10 mm was satisfactory at 92.9% [5]. Considering that the diagnostic accuracy of CT was as high as that of EUS-TA for PALNs with a short axis of < 5 or ≥ 10 mm, PALNs with a 5–10-mm short diameter in particular are favorable indications for EUS-TA should be recognized. However, since it is realistically impossible to puncture all PALNs visualized on EUS, the target PALNs should be selected taking into account not only their size but also other morphological characteristics and other imaging modalities such as PET-CT. The exciting insights provided by Hara et al. from real-world clinical practice shed light on the role of EUS-TA in PALN staging; however, challenges remain to be addressed. First, we occasionally encounter cases of unsuccessful EUS-TA due to PALN inaccessibility or insufficient sampling. In such cases, alternative image enhancement technologies that can improve diagnostic capability are desirable. Miyata et al. reported the usefulness of contrast-enhanced harmonic EUS (CH-EUS) in N-staging as an alternative imaging modality [9]. The study demonstrated that CH-EUS had a significantly higher diagnostic performance for lymph node diagnosis than standard fundamental B-mode EUS by defining heterogeneous enhancement patterns in CH-EUS as malignant. Furthermore, the study revealed that N-staging using CH-EUS and EUS-TA had comparable diagnostic accuracy, and CH-EUS achieved correct N-staging in cases wherein EUS-TA was unsuccessful [9]. Regarding technical improvements to the puncture technique, a recent randomized controlled trial reported that EUS-TA using the fanning technique had comparable diagnostic accuracy in diagnosing pancreatic cancer with EUS-TA under CH-EUS guidance [10]. Considering the lack of additional costs, EUS-TA using the fanning technique may be a good alternative. Thus, there remains potential for further improving the diagnostic ability of PALN staging by combining EUS-TA with image enhancement technology or by refining the puncture technique. Another challenge is detecting micrometastasis in the lymph nodes. In lymph node metastasis, cancer cells may infiltrate only a small portion of the lymph node, making accurate N-staging challenging. In the study by Hara et al., in three cases wherein EUS-TA led to false-negative results based on the resected specimen postoperatively, the tumor population in the lymph nodes was < 25% in all cases [7]. Current imaging modalities are restricted in their ability to accurately diagnose the small patchy distribution of tumors in the lymph nodes, and further advances in imaging technology are required. Furthermore, in cases of minute PALN metastasis, which can only be diagnosed by EUS-TA, there is no established evidence as to whether palliative chemotherapy should be performed without resecting the primary lesion. Given the current progress in neoadjuvant or adjuvant chemotherapy, this issue will require careful and thorough discussion in the future. In conclusion, Hara et al. provided novel insights into the clinical significance of EUS-TA in staging PALNs. This study underscores the role of EUS-TA in PALN staging and offers a glimpse into the remaining challenges. To confirm the suitability and generalizability of their exciting results on EUS-TA for PALN staging, further multicenter prospective studies with a larger cohort are warranted. Drafting of the manuscript: Kosuke Minaga. Critical revision of the manuscript: Masatoshi Kudo. Both authors have read and agreed to the submitted version of the manuscript. The authors would like to thank Enago (www.enago.jp) for the English language review. Author Kosuke Minaga is an Associate Editor of Digestive Endoscopy. The other author declares no conflict of interest for this article.