Approach to patients with positive vertical margins after endoscopic resection of Barrett’s neoplasia

Endoscopic eradication therapy (EET) has revolutionized the management of Barrett’s esophagus (BE)-related neoplasia (patients with early esophageal adenocarcinoma [EAC], high grade dysplasia [HGD], and select cases with low grade dysplasia), reducing the morbidity and mortality related to esophagectomy and preventing EAC-related mortality [1] [2] [3]. The basic principles of EET include endoscopic resection (ER) using endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for any visible lesion (technique of ER ideally based on lesion characteristics), followed by ablation of the remaining BE epithelium to reduce the risk of metachronous neoplasia. The goal of EET should be complete eradication of intestinal metaplasia and complete eradication of neoplasia, followed by enrollment in endoscopic surveillance programs for early detection of BE-related neoplasia recurrence. ER plays a pivotal role in both the management of patients with BE-related neoplasia and the overall success of any EET program. ER specimens routinely undergo histopathological assessment for overall highest grade of neoplasia, depth of neoplastic invasion, tumor differentiation, lymphovascular invasion, and tumor/dysplasia involvement of lateral and vertical margins. It is expected that the number of patients with a tumor-positive vertical margin (R1v) will increase given the expanding indications of EET and increased overall uptake of this management strategy for this patient population. While current guidelines recommend consideration of adjunct surgery in patients with R1v, this recommendation is based on minimal data describing outcomes and risk of residual neoplasia after R1v. Should all patients with R1v undergo esophagectomy? What is the risk of residual neoplasia in patients with R1v on follow-up endoscopy or surgical specimens after esophagectomy?

“This blanket recommendation of esophagectomy for all patients with a positive margin may not be appropriate and will most likely result in “unnecessary esophagectomy” in a significant proportion of patients without high risk features associated with lymph node metastasis.”

In this issue of Endoscopy, van Tilburg et al. present their retrospective cohort study, which addressed the above knowledge gaps and evaluated outcomes in patients after ER for BE-related neoplasia with confirmed tumor-positive vertical margins (R1v), specifically addressing the proportion of patients with residual neoplasia (primary end point), defined as the presence of HGD or EAC detected during the first endoscopic follow-up [4]. Patients with R1v were identified from the nationwide Dutch Barrett Expert Center registry (n=110; EMR 73 and ESD 37). Resection specimens in patients with macroscopically successful ER (n = 101) were reassessed by experienced gastrointestinal pathologists in a blinded fashion, providing a consensus diagnosis of R1 (cancer cells unequivocally infiltrating the resection margin), R0 (absence of cancer cells in the margins), or not assessable (Rx).

There are several key takeaways from this study. First, expert pathology reassessment resulted in confirmation of R1v status in 75% of patients and 25% were downstaged to R0 (9%) and Rx (16%). Second, among patients with confirmed R1v, 50% had residual neoplasia during endoscopic follow-up or in the surgical resection specimen (HGD or EAC), and residual neoplasia was less common in ESD than in EMR specimens. Third, among patients with endoscopic reassessment, 48% of patients had a visible suspicious lesion within 1 cm of the ER scar (residual neoplasia confirmed in 88% of these patients), and biopsies from a normal appearing ER scar did not detect additional neoplasia. Fourth, among patients with R1v who received endoscopic follow-up (median follow-up 37 months), 16% of patients had local recurrence. The limitations of this study, as acknowledged by the investigators, include the observational nature of the study, limited sample size of cases within each category, lack of standardization in terms of follow-up and management plans, and generalizability of the results to nonexpert centers.

Several studies have demonstrated the interobserver variability among pathologists in the diagnosis of BE-related neoplasia [5]. In addition to the interobserver variability for the diagnosis of neoplasia, this study also highlights the variability among pathologists in the assessment of ER margins, providing credence to our current guideline recommendations that suggest expert pathology review in patients with BE-related neoplasia being considered for or undergoing EET [1] [3]. The pathologists identified several issues during assessment of ER specimens that precluded optimal histologic assessment, including tangential cutting, suboptimal embedding, curled lateral margins, and cauterization and pinning artifacts. Endoscopists and pathologists managing patients with BE-related neoplasia need to standardize protocols on the optimal handling of ER specimens (pin specimens on cork, avoid overstretching, pins should not perforate areas of neoplasia) at an institutional/center level, and this should ideally be addressed in future guidelines. Standardized definitions for margin assessment in ER specimens are required. These data also suggest that endoscopic reassessment should be considered after 8–12 weeks in order to detect residual neoplasia and to determine an appropriate management strategy in patients without signs of or risk factors for lymph node metastasis (deep submucosal invasion sm2/3, poorly differentiated grade of EAC, or lymphovascular invasion). All of the above can be best achieved when patients with BE-related neoplasia receive centralized care and are managed at expert centers – centers with high case volumes, endoscopists with training in endoscopic imaging and resection, expert pathologists (those with a special interest in BE-related neoplasia, high volume of cases, and recognized as an expert in the field by peers), and access to a multidisciplinary team that includes surgeons and medical and radiation oncologists [1] [3].

Standardization of assessment of ER specimens has the potential to reduce the interobserver variability among pathologists. There is growing interest in the use of deep learning algorithms to improve histopathologic diagnostic capabilities of BE-related neoplasia [6]. Whether these artificial intelligence platforms can be used to improve diagnostic accuracy among pathologists in ER specimens needs to be explored in future studies. The results of the Tilburg et al. study challenge the conventional wisdom that all patients with R1v should be considered for surgery [7]. This blanket recommendation of esophagectomy for all patients with a positive margin may not be appropriate and will most likely result in “unnecessary esophagectomy” in a significant proportion of patients without high risk features associated with lymph node metastasis. Ongoing and future prospective studies need to externally validate the results of this study and define the appropriate surveillance strategy (high quality endoscopic surveillance, endoscopic ultrasound, and computed tomography/positron emission tomography scan) and frequency in patients with R1v without residual neoplasia during endoscopic reassessment. The ultimate priority in this population of patients is to provide a personalized approach for BE-related neoplasia in patients with R1v resections after ER, prioritizing an “organ-preserving” approach in patients at low risk for progression.

Publikationsverlauf

Artikel online veröffentlicht:
07. Mai 2024

• References

• 1 Rubenstein JH ST, Wani S. et al. American Gastroenterological Association Clinical Practice Guideline: Endoscopic eradication therapy of Barrett’s esophagus and related neoplasia. Gastroenterology. Forthcoming. 2024
• 2 Wani S, Qumseya B. Standards of Practice Committee. et al. Endoscopic eradication therapy for patients with Barrett’s esophagus-associated dysplasia and intramucosal cancer. Gastrointest Endosc 2018; 87: 907-931.e9
• 3 Shaheen NJ, Falk GW, Iyer PG. et al. Diagnosis and management of Barrett’s esophagus: an updated ACG guideline. Am J Gastroenterol 2022; 117: 559-587 DOI: 10.14309/ajg.0000000000001680. (PMID: 35354777)
• 4 van Tilburg L, Verheij EPD, van de Ven SEM. et al. Vertical tumor-positive resection margins and the risk of residual neoplasia after endoscopic resection of Barrett’s neoplasia: a nationwide cohort with pathology reassessment. Endoscopy 2024; DOI: 10.1055/a-2272-9794.
• 5 Wani S, Mathur SC, Curvers WL. et al. Greater interobserver agreement by endoscopic mucosal resection than biopsy samples in Barrett’s dysplasia. Clin Gastroenterol Hepatol 2010; 8: 783-788
• 6 Faghani S, Codipilly DC, David V. et al. Development of a deep learning model for the histologic diagnosis of dysplasia in Barrett’s esophagus. Gastrointest Endosc 2022; 96: 918-925.e3
• 7 Pimentel-Nunes P, Libanio D, Bastiaansen BAJ. et al. Endoscopic submucosal dissection for superficial gastrointestinal lesions: European Society of Gastrointestinal Endoscopy (ESGE) Guideline – Update 2022. Endoscopy 2022; 54: 591-622 DOI: 10.1055/a-1811-7025. (PMID: 35523224)