INTRODUCTION — The prognosis of esophageal cancer is strongly associated with its stage, and the choice of initial treatment is highly dependent on clinical stage at diagnosis. As a result, accurate clinical staging is critical for selecting appropriate treatment options. Endoscopic ultrasonography (EUS) has a central role in the initial staging of esophageal carcinoma and may also be useful for detecting disease recurrence.
This topic review will focus on the role of EUS in the care of patients with esophageal cancer. An overview of the diagnosis and staging of esophageal cancer is presented separately. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)
PREOPERATIVE STAGING — Initial evaluation of the patient diagnosed with esophageal cancer centers on the assessment of their operative risk and tumor stage. Preoperative tumor staging is warranted in patients who are potential surgical candidates because their disease extent will influence treatment planning (eg, it may reveal that a patient is a candidate for endoscopic resection). (See "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Management of superficial esophageal cancer".)
Neoadjuvant chemotherapy with or without radiotherapy is typically recommended, rather than upfront surgery, for those with locally advanced (ie, T3 and/or node-positive) tumors. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)
Staging usually begins with a contrast-enhanced computed tomography (CT) scan of the neck, chest, and abdomen to evaluate for the presence of metastatic disease. However, with increasing availability, integrated fluorodeoxyglucose positron emission tomography (FDG-PET)/CT fusion scanning may be more accurate for the detection of stage IV disease and can be used as an initial staging assessment. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Evaluation for distant metastases'.)
A more detailed evaluation of locoregional disease extent (T and N stage) should be obtained if distant metastases are not demonstrated on cross-sectional imaging. A number of studies have demonstrated that EUS is more accurate than transabdominal ultrasound, CT scan, magnetic resonance imaging (MRI), or PET scanning for locoregional staging of esophageal cancer [1-17], with an overall accuracy of EUS for T and N staging of 90 percent [18].
Overall, study results will be influenced by the number of early versus advanced T-stage patients as EUS is more accurate in the latter population. A strong correlation exists between tumor differentiation, T-stage and lymph node status [19]. A meta-analysis of diagnostic test characteristics made the following estimates for EUS, CT, and FDG-PET, concluding that the three approaches were complementary [16]:
●For EUS, the sensitivity and specificity for detecting celiac lymph node metastases (considered regional lymph nodes in the staging classification, regardless of primary tumor location) were 85 percent (95% CI 72-99 percent) and 96 percent (95% CI 92-100 percent), respectively. Sensitivity and specificity for other regional lymph node metastases were 80 percent (95% CI 75-84 percent) and 70 percent (95% CI 65-75 percent), respectively.
●For CT, sensitivity and specificity for regional lymph node metastases were 50 percent (95% CI 41-60 percent) and 83 percent (95% CI 77-89 percent), respectively. For abdominal lymph node metastases (ie, nonregional, nonceliac abdominal nodes), these values were 42 percent (95% CI 29-54 percent) and 93 percent (95% CI 86-100 percent), respectively. For distant metastases, these values were 52 percent (95% CI 33-71 percent) and 91 percent (95% CI 86-96 percent), respectively.
●For FDG-PET, sensitivity and specificity for regional lymph node metastases were 57 percent (95% CI 43-70 percent) and 85 percent (95% CI 76-95 percent), respectively. For distant metastases, these values were 71 percent (95% CI 62-79 percent) and 93 percent (95% CI 89-97 percent), respectively.
The tumor, node, metastasis staging system of the American Joint Committee on Cancer and the Union for International Cancer Control for esophageal cancer (adenocarcinoma and squamous cell carcinoma) is used universally (2017, eighth edition) (table 1A and table 1B) and has a slight difference in the definitions of T4a disease compared with the prior version [20,21].
In general, the EUS report should include the endoscopic findings of tumor location, features (eg, circumferential extent, skip areas, presence/absence of Barrett’s), and anatomic landmarks (gastroesophageal junction, diaphragmatic hiatus, squamocolumnar junction), length of tumor, luminal diameter, as well as a description incorporating the T-stage including maximal wall thickness, N-stage (as per guidelines using N0 - N3), and specific features of identified lymph nodes (location, shape/size/border/echogenicity) [22]. Incomplete or limited staging due to tumoral stenosis should be described when present.
General principles of EUS imaging — Dedicated echoendoscopes operating at frequencies of 7.5 and 12 MHz are able to visualize the esophageal wall as a five-layered structure (image 1 and figure 1):
●First hyperechoic layer: superficial mucosa
●Second hypoechoic layer: deep mucosa
●Third hyperechoic layer: submucosa
●Fourth hypoechoic layer: muscularis propria
●Fifth hyperechoic layer: adventitia
The ability to visualize the five layers permits a detailed understanding of the degree of tumor infiltration into the wall layers, providing an assessment of the tumor stage (T stage) (table 2 and image 2A-D) [23]. However, one limitation of standard echoendoscopes is that they operate at relatively low frequency and, as a result, cannot visualize the muscularis mucosa [24,25]. EUS miniprobes that scan at higher frequencies (picture 1) provide more detailed visualization of the esophageal wall by displaying alternating hyperechoic (bright) and hypoechoic (dark) bands that correspond to the histologic layers [26,27]:
●The first layer (hyperechoic) and second layer (hypoechoic) correspond to the interface with the lumen and mucosal epithelium
●The third layer (hyperechoic) and fourth layer (hypoechoic) correspond to deep mucosa (lamina propria)
●The fifth layer (hyperechoic) and sixth layer (hypoechoic) correspond to the muscularis mucosa interface and muscularis mucosa
●The seventh layer (hyperechoic) is the submucosa
●The eighth layer (hypoechoic) is the inner layer of the muscularis propria
●The ninth layer (hyperechoic) corresponds to connective tissue and the interface between the muscle layers
●The tenth layer (hypoechoic) corresponds to the outer layer of the muscularis propria
●The eleventh layer (hyperechoic) is the serosa/adventitia
This may have particular importance when evaluating superficial lesions for which nonsurgical therapy (such as endoscopic mucosal resection) is being considered. (See 'EUS for T staging of superficial tumors' below.)
EUS for T staging of superficial tumors — Early esophageal cancers are those that are classified as Tis (high-grade dysplasia, which includes all noninvasive neoplastic epithelial that was formerly called carcinoma in situ) or T1 tumors, which are split into T1a and T1b subcategories depending on the depth of invasion (table 1A and table 1B). These are referred to as superficial esophageal cancers. The risk of nodal metastases is higher for T1b than T1a tumors, and within these subcategories, risk may be further stratified according to depth of invasion and the presence of lymphovascular invasion (LVI). (See "Management of superficial esophageal cancer", section on 'Pathologic subclassification and the risk of nodal metastases'.)
The role of EUS for T staging and subsequent management of superficial tumors has been controversial. If the EUS identifies only mucosal (T1a) disease, endoscopic mucosal resection is usually the next step to remove the tumor and precisely define the depth of invasion. The pathology result from the endoscopic mucosal resection (particularly the presence or absence of LVI) can then be used to guide the decision as to whether endoscopic therapy alone is sufficient or if surgery should be performed. On the other hand, if the EUS identifies esophageal cancer that invades beyond the muscularis mucosa (T1b), or if there is evidence of lymph node involvement, then the patient usually undergoes surgical resection. (See "Surgical management of resectable esophageal and esophagogastric junction cancers" and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Management of superficial esophageal cancer".)
Studies on the accuracy of EUS for staging superficial esophageal cancer are discussed separately. (See "Management of superficial esophageal cancer", section on 'Accuracy of EUS in the staging evaluation'.)
Although T1 lesions can be identified using echoendoscopes operating at 7.5 and 12 MHz, distinguishing subgroups of the T1 stage (muscularis mucosa and/or submucosal invasion) (figure 2) can be problematic with these instruments because the frequencies are too low to visualize the muscularis mucosa. Small caliber ultrasound probes (commonly referred to as miniprobes or EUS miniprobes) scan at higher frequencies (12 to 20 MHz) than conventional echoendoscopes, and this results in high-resolution imaging but with a limited penetration depth of approximately 20 mm. The technical aspects and use of EUS miniprobes for determining disease extent in patients with superficial esophageal cancer are discussed separately. (See "Endoscopic ultrasound (EUS): Use of miniprobes for evaluating gastrointestinal lesions".)
EUS for staging locally advanced tumors — The large caliber of dedicated radial echoendoscopes (12.7 mm in diameter) may preclude complete EUS staging in patients with locally advanced esophageal tumors, which may be associated with esophageal stenosis. This was illustrated in a series of 113 patients who underwent esophagectomy in whom the accuracy of EUS for T and N staging was much higher for traversable (81 and 86 percent, respectively) as compared with nontraversable tumors (28 and 72 percent, respectively) [28].
Several options are available to improve accuracy in these settings:
●Although dilation of the esophageal lumen to a diameter of 14 to 16 mm with either a Savary dilator or a controlled radial expansion (CRE) balloon has been described, we typically do not dilate malignant esophageal strictures because of the high risk of perforation (up to 24 percent) [28-31].
Our practice is to perform endoscopy with a standard gastroscope initially at the time of EUS. If the gastroscope cannot traverse the stenosis, we do not dilate the lesion, as we infrequently are able to pass the echoendoscope even with this intervention. For patients with circumferential stenosis permitting passage of a gastroscope but not the echoendoscope, we may very carefully dilate the lesion. We are particularly cautious when semi-circumferential involvement is present, since the normal (and hence thinner) esophageal wall may be at increased risk of tearing in this setting, particularly if the proximal esophagus is dilated.
●Ultrasound catheters introduced through the biopsy channel of the endoscope may traverse tight strictures due to their small caliber (3 mm in maximum diameter). Although this may improve the accuracy of T and N staging [32], limited depth of penetration can lead to incomplete assessment of locoregional spread. (See "Endoscopic ultrasound (EUS): Use of miniprobes for evaluating gastrointestinal lesions".)
Accuracy of EUS for determining unresectability — The definition of a T4 tumor has been refined in 2017 guidelines. In the staging classification, tumors staged as T4b are considered unresectable, while advanced tumors (T4a) at EUS typically results in chemoradiation (in the absence of distant metastases) followed by restaging and surgical resection if possible [33]. In the guidelines, T4a tumors include tumors involving the pleura, pericardium, diaphragm for both SCC and adenocarcinomas (table 1A-B), and for adenocarcinomas of the distal esophagus and esophagogastric junction (EGJ), they include tumors invading the azygos vein, diaphragm, or peritoneum [34].
Unresectability is also suggested by EUS in patients with tumors arising above the level of the carina, with extension through the esophageal wall into the mediastinum. It may be difficult or impossible to obtain a safe margin of resection between the tumor and the trachea and/or bifurcation in such patients [35].
EUS for preoperative lymph node staging — Endosonographic criteria that are suggestive of malignant involvement of visible lymph nodes include a width greater than 10 mm, round shape, smooth border, and echo-poor pattern (table 3 and image 3) [36,37]. Of these, an echo-poor pattern and width >10 mm appear to be the most specific for malignancy. When all four suspicious features are present in a visualized lymph node, there is an 80 to 100 percent chance of metastatic involvement [36,37]. However, only 25 percent of malignant nodes will have all of these features. These results demonstrate the limitations of EUS criteria for preoperative determination of lymph node staging, especially if the nodes are small.
The lymph node stage is further categorized according to the number of involved nodes (no involved nodes (N0), 1 or 2 (N1), 3 to 6 (N2), and 7 or more (N3)) involved lymph nodes, but not the location of the nodes. However, most EUS/CT/PET staging studies have not included this refinement when reporting N staging accuracy.
As noted above, EUS has an accuracy of more than 80 percent for detecting malignant nodes in the cervical paraesophageal, right recurrent laryngeal, left paratracheal, upper and lower paraesophageal, infra-aortic, infracarinal, lower posterior mediastinal, and perigastric regions. Greater numbers of malignant-appearing periesophageal lymph nodes detected by EUS predicted worse survival [38,39]. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)
The demonstration of clinically suspicious lymph nodes may support the selection of induction chemoradiotherapy over surgery alone, particularly in a patient with T2 disease [40]. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)
Endoscopic ultrasound-guided fine-needle aspiration biopsy — Endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) may improve the accuracy of N staging by providing cytologic confirmation of metastatic disease from accessible nodes, as long as the primary tumor is not in the pathway of the aspiration needle. EUS FNA cytology results may not be reliable if the needle has to traverse the primary tumor.
Although staging studies with EUS in esophageal carcinoma have utilized EUS FNA, subsequent data have suggested that accuracy of EUS-guided fine needle biopsy (FNB) and EUS FNA are similar for evaluating solid lesions and that EUS FNB may have advantages with respect to efficiency [41]. (See "Endoscopic ultrasound-guided fine needle aspiration in the gastrointestinal tract" and "Endoscopic ultrasound-guided fine needle biopsy in the gastrointestinal tract".)
Sensitivity, specificity, and accuracy of EUS FNA for locoregional lymph nodes are all over 85 percent when surgical resection specimen or cytology results are considered as the gold standard [42-44]. The accuracy of EUS FNA for esophageal cancer staging appears to be similar to that reported for other gastrointestinal malignancies (table 4) [45-48].
EUS FNA appears to improve the accuracy of nodal staging beyond that achieved by EUS alone. One study compared lymph node staging using EUS alone in a historical cohort of 33 patients versus 31 patients who underwent EUS FNA of non-peritumoral lymph nodes for preoperative lymph node staging [47]. Compared with EUS alone, EUS FNA was associated with significantly better sensitivity (93 versus 63 percent) and accuracy (93 versus 70 percent). A comparison of specificity was limited in this study, since only one patient underwent a biopsy for which benign pathology was reported. EUS FNA was less costly than CT FNA and surgery. The cost-saving was principally a result of a reduction in unnecessary surgery [49].
These results were supported by a prospective study that compared the performance characteristics of CT, EUS, and EUS FNA for preoperative lymph node staging of esophageal carcinoma in 125 patients [50]. EUS FNA was more sensitive than CT (83 versus 29 percent) and more accurate than CT (87 versus 51 percent) or EUS (87 versus 74 percent) for nodal staging (table 5). Direct surgical resection was contraindicated in 77 percent of patients due to detection of advanced locoregional/metastatic disease.
Optimal criteria for identifying malignant lymph nodes based upon EUS criteria and for helping to select patients for whom EUS FNA is required continue to evolve. Initial experience suggests that a selective approach based on modified EUS criteria was cost-saving compared with an approach of routine FNA [51]. Furthermore, the modified EUS criteria (four standard criteria plus EUS-identified celiac lymph nodes, >5 lymph nodes, or EUS T3/4 tumor) were more accurate than standard criteria (hypoechoic, smooth border, round, or width >5 mm) at identifying malignant lymph nodes.
Interobserver variation and EUS learning curve — The accuracy of EUS is operator-dependent [52]. Interobserver reliability (different observers staging the same patients) is influenced by experience and tumor stage [18,53-56]. Technical factors, including balloon overinflation causing a blurring of the distinction between the esophageal wall layers, tangential imaging, and inadequate use of higher scanning frequencies (12 MHz), may be responsible for staging errors among inexperienced endosonographers [54,56,57].
Among expert endosonographers (>75 esophageal cancer examinations) [58], overstaging of esophageal carcinomas is more frequent than understaging, occurring in 8 to 14 percent of patients [59]. This is particularly evident in T2 lesions and may be attributed to peritumoral inflammation leading to an overestimation of mural penetration [59]. In contrast, understaging occurs in 3 to 15 percent of cases and is frequently associated with T3 tumors with microscopic infiltration of the adventitia that is beyond the resolution capabilities of the available echoendoscopes [8,56].
RESTAGING AFTER NEOADJUVANT THERAPY — One of the most controversial areas in oncology has been the optimal treatment of potentially resectable esophageal cancer, in particular, the benefit of multimodality therapy (ie, preoperative chemoradiotherapy or perioperative chemotherapy alone over resection alone). However, clinical practice is evolving toward initial (neoadjuvant) therapy rather than resection for tumors that are T3 and/or node-positive at presentation. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)
For patients who undergo preoperative chemoradiotherapy or chemotherapy alone, it is frequently desirable to evaluate the response to treatment prior to recommending tumor resection [60,61]. Unfortunately, the accuracy of endoscopic ultrasound (EUS) is limited in this setting. As an example, in a meta-analysis involving 16 studies with 724 patients, the pooled sensitivity and specificity of EUS in staging esophageal cancer after neoadjuvant chemotherapy varied with tumor stage (table 2) [60]. The sensitivity was relatively high in T3 disease (81 percent), while specificity was high in other T stages (T1, T2, and T4). Results did not appreciably change over time despite introduction of more sophisticated technology. A possible explanation for the discrepancy between endoscopic and subsequent pathologic staging is that EUS may not be able to differentiate between post-treatment inflammation/fibrosis and residual tumor.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Esophageal cancer".)
SUMMARY AND RECOMMENDATIONS
●Background – The prognosis of esophageal cancer is strongly associated with its stage, and the choice of initial treatment is highly dependent on clinical stage at diagnosis. As a result, accurate clinical staging is critical for selecting appropriate treatment options. (See 'Introduction' above.)
●Preoperative staging – Endoscopic ultrasonography (EUS) is the most accurate method for locoregional staging of esophageal cancer. EUS should be performed to assess T and N stage in patients being considered for surgery once distant metastases have been excluded by computed tomography and/or integrated fluorodeoxyglucose positron emission tomography (FDG/PET)/CT scan. The addition of EUS-guided fine-needle aspiration has further improved lymph node staging accuracy and should be performed routinely when confirmation of metastatic lymphadenopathy will alter the approach to treatment. In addition, studies have suggested that EUS-guided fine needle biopsy is an accurate alternative for tissue sampling in this setting. (See 'Preoperative staging' above and "Endoscopic ultrasound-guided fine needle aspiration in the gastrointestinal tract" and "Endoscopic ultrasound-guided fine needle biopsy in the gastrointestinal tract".)
●Other clinical applications – Limitations caused by locally advanced, stenotic tumors that preclude echoendoscope passage and, therefore, complete staging, are being overcome by smaller caliber instruments. (See "Endoscopic ultrasound (EUS): Use of miniprobes for evaluating gastrointestinal lesions".)
Reports comparing EUS with PET support the superior performance of EUS in locoregional staging. However, EUS has a limited role in restaging patients post chemotherapy and/or radiation therapy. (See 'Restaging after neoadjuvant therapy' above.)
The clinical manifestations, diagnosis, and staging of esophageal cancer are presented in more detail separately. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer".)
ACKNOWLEDGMENT — The author and UpToDate thank Dr. Enrique Vazquez-Sequeiros, who contributed to earlier versions of this topic review.
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