Endosonography-guided fine-needle aspiration for re-evaluation of lymph node status after neoadjuvant therapy in patients with esophageal cancer: is there any role for it?

Preoperative staging of esophageal carcinoma usually relies on the sequential assessment of the tumor TNM stage by computed tomography (CT) scan and/or positron emission tomography (PET)-CT, followed by endoscopic ultrasound (EUS) [1]. Identification of patients with locally advanced cancer (T3 and, more importantly, N1 disease) is crucial to indicate preoperative neoadjuvant therapy and increase the chances of cure [1]. EUS appears to be superior to other techniques for locoregional (TN) staging of these patients [1]. However, although highly accurate (80 % – 85 %), lymph node (LN) status assessment relies on subjective EUS criteria such as echogenicity, and roundness or sharpness of the LN border, which has somehow limited the credibility and reproducibility of EUS nodal stage assessment [1]. EUS-guided fine-needle aspiration (EUS-FNA) of LNs for cytologic confirmation of nodal status has been shown to be the best technique in patients with esophageal cancer [1].

Although oncology societies support the routine use of EUS-FNA in this setting in clinical practice, economic issues and, more importantly, the prolonged examination time required to perform EUS-FNA, have limited its incorporation into routine clinical practice. Some attempts have been made to improve the positive predictive value of EUS LN criteria by adding LN location, number of nodes identified or presence of an advanced tumor stage to the standard criteria [2]. Application of these modified EUS criteria for LN assessment could theoretically avoid EUS-FNA of LNs in 42 % of cases, as patients with ≤ 1 positive modified criteria or ≥ 6 positive modified criteria would have 100 % negative and positive predictive values, respectively [2].

“These results suggest that EUS lymph node (LN) criteria should not be applied for re-staging of LNs in patients with esophageal cancer and, more importantly, if a treatment decision after neoadjuvant therapy is to be taken based on LN status, EUS-FNA should be performed definitively, even in cases of nonmalignant-appearing LNs.”

It is important to state upfront that standard and modified EUS criteria for LN assessment have been designed and validated only for patients who have not undergone neoadjuvant therapy [1] [2]. Moreover, we do not really know how LN aspect may be modified after chemoradiotherapy, and how inflammation or edema may alter LN morphology, borders or echogenicity. It may be possible that we cannot rely on those criteria if LNs have to be re-evaluated after neoadjuvant therapy in order to decide on the next treatment, if applicable: 1) surgery vs. surveillance without surgery; 2) continue or discontinue chemoradiotherapy; 3) initiate salvage or novel therapies such as immune therapy.

In this issue of Endoscopy, results from the prospective study by van der Bogt et al. [3] suggest that EUS criteria for LN malignancy are not accurate enough to differentiate benign from malignant LNs in patients with esophageal cancer after neoadjuvant chemoradiotherapy. The study, conducted in 101 patients, showed that EUS was only able to detect 50 % of patients with malignant LNs 10 – 12 weeks after neoadjuvant chemoradiotherapy, with a specificity of 78 % [3]. However, when EUS-FNA of LNs was performed, sensitivity and specificity improved up to 75 % and 100 %, respectively. These results suggest that EUS LN criteria should not be applied for re-staging of LNs in patients with esophageal cancer and, more importantly, if a treatment decision after neoadjuvant therapy is to be taken based on LN status, EUS-FNA should be performed definitively, even in cases of nonmalignant-appearing LNs.

Although one may argue that, at the present time, re-evaluation of tumor extension after neoadjuvant therapy is probably not very useful in this setting (treatment is rarely modified after that), and available techniques such as CT, PET-CT or EUS are not really accurate to differentiate between inflammation and tumor, it seems reasonable to not give too much attention to this area [4]. However, there is no doubt that treatment of esophageal cancer requires further improvement to increase the likelihood of cure, which is currently quite low. Different measures have already been taken in this direction, such as the new edition (8th) of the TNM classification, which takes into consideration different subclassifications that may have important implications in therapeutic strategy and were not considered in previous editions: 1) clinical staging (cTNM): tumor extension prior to therapy; 2) pathologic staging (pTNM): determined after surgical resection; and 3) neoadjuvant pathologic staging (ypTNM): tumor stage after neoadjuvant therapy followed by surgery [5]. The new TNM classification of esophageal cancer includes differential aspects such as tumor histology type, location, and grade. Refinements to the TNM assessment made in the 8th edition make the classification more accurate and adaptable to current practice, and may influence therapeutic strategy [5]. A more precise and selective assessment of tumor extension in different clinical scenarios may help to identify, for example, elderly patients who could avoid surgery after adequate response to neoadjuvant therapy. There is an increasing number of patients with esophageal cancer who, either because of advanced age or high surgical risk, are not willing to undergo surgery after neoadjuvant therapy. It has been shown that up to 29 % of these patients have no residual disease on ypTNM (complete response) and it seems reasonable that survival may not be increased by undergoing surgery after completing adjuvant therapy [6]. To prove this concept, ongoing studies aim to determine whether active surveillance leads to noninferior survival, improved quality of life, and reduction in costs, compared with standard esophagectomy [7]. Definitive answers on this field are expected in the next few years. We believe that in these cases, a more accurate re-staging technique, such as EUS-FNA of LNs, will be of increasing interest in the future. Whether or not a positive or negative PET-CT result after neoadjuvant chemoradiotherapy may help in the selection of LNs that need to be sampled or even in the avoidance of EUS-FNA remains unclear, but studies in that direction are definitely needed.

Promising therapies, such as those specifically directed against human epidermal growth factor receptor-2 (e. g. trastuzumab or pertuzumab) or immune checkpoint inhibitors against programmed cell death receptor-1 (e. g. pembrolizumab and nivolumab) or programmed death ligand-1 (e. g. durvalumab) are currently being evaluated, with excellent results [8]. This more aggressive approach may revolutionize our diagnostic and therapeutic approach in esophageal cancer. The role of EUS and, more importantly, EUS-FNA is likely to increase in the future and we need to be prepared for that. The study by van der Bogt et al. is a step in that direction [3].

Publication History

Article published online:
25 February 2020

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