From the AGA Journals

Review explores the boundaries of endoscopic resection for esophageal adenocarcinoma

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Patient selection remains key

Barrett’s esophagus (BE) is the only known precursor lesion to esophageal adenocarcinoma, a cancer with rising incidence and stage-dependent survival. Early detection of BE-related neoplasia provides the opportunity to intervene through endoscopic eradication therapy and avoid the morbidity associated with esophagectomy. Verheji and colleagues, a group from a robust BE expert center in the Netherlands, provide a comprehensive and detailed overview of the role of endoscopic therapy for superficial esophageal adenocarcinoma (EAC), which is gaining popularity. In this review, they nicely highlight the benefits of this approach as a minimally invasive, organ-preserving, safe, and effective treatment option.

Jennifer M. Kolb, MD, MS, is assistant professor of medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA. She also is affiliated with VA Greater Los Angeles Health Care System. Dr. Jennifer M. Kolb

Dr. Jennifer M. Kolb

The importance of appropriate patient selection for endoscopic therapy can’t be overstated. After initial staging endoscopic mucosal resection, EACs should be characterized as low risk versus high risk (tumor invasion into the submucosa, poor differentiation, presence of lymphovascular invasion, or tumor-positive deep resection margin). This distinction is critical since these histologic features are currently the best-known predictors of the risk of lymph node metastases and therefore guide therapy to endoscopy versus surgery. Low-risk superficial cancers have very low rates of lymph node metastases and therefore are best managed with endoscopic therapy. The most common technique is multiband mucosectomy, where flat, superficial cancers (Paris type O-IIa) are removed piecemeal through a repeated sequence of band and snare cautery with high rates of success, rare risk of perforation or bleeding, and reasonably low (< 10%) rates of stricture. Endoscopic submucosal dissection can be considered for larger or bulkier lesions with suspected submucosal invasion where en bloc resection is optimal. At present, high-risk superficial EAC should still be referred to surgery. Some patients may not be candidates for esophagectomy or may be unwilling to undergo a large, morbid operation, however. The authors are involved in the prospective PREFER trial evaluating a protocol of strict endoscopic follow-up (endoscopy with endoscopic ultrasound every 3 months for 2 years, followed by every 6 months in years 3-4, then annually) after endoscopic resection of high-risk superficial EAC in patients without baseline metastases as an alternative to surgery. Whether or not this strategy of watchful waiting may be a reasonable alternative will likely take a few more years to answer. Nonetheless, we have already seen a dramatic shift toward endoscopic therapy for superficial EAC that has been fueled by innovation, new technologies, and improved techniques.

Jennifer M. Kolb, MD, MS, is assistant professor of medicine, Vatche and Tamar Manoukian Division of Digestive Diseases University of California, Los Angeles. She also is affiliated with VA Greater Los Angeles Health Care System. She has no relevant conflicts of interest.



A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Eva P. D. Verheij a PhD candidate at Amsterdam UMC, Netherlands Courtesy Eva P. D. Verheij

Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

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