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Endoscopic submucosal dissection for resection of submucosal tumors of the colon and rectum: Within reach, or the edge of tomorrow?

      Abbreviations:

      EFTR (endoscopic full-thickness resection), GCT (granular cell tumor), GIST (gastrointestinal stromal tumor), MP (muscularis propria), NET (neuroendocrine tumor), PEECS (post-ESD electrocoagulation syndrome), POEM (per-oral endoscopic myotomy), SET (subepithelial tumor), SMT (submucosal tumor)
      The terms submucosal tumor (SMT) and subepithelial tumor (SET) are often used synonymously. SET has been suggested to more distinctly describe tumors of the muscularis mucosa, submucosal layer, and muscularis propria, whereas SMT more specifically describes tumors arising from the submucosal layer. Although SETs are usually benign, a subset including gastrointestinal stromal tumors (GIST), neuroendocrine tumors (NET), and granular cell tumors (GCT) have malignant potential. Management options for smaller SETs with suspected malignant potential have typically included serial endoscopic and endosonographic surveillance or resection with EMR, whereas larger lesions are generally referred for surgical resection. Endoscopic submucosal dissection (ESD) has emerged in recent years as a minimally invasive alternative for resection of SETs.
      • Park H.W.
      • Byeon J.S.
      • Park Y.S.
      • et al.
      Endoscopic submucosal dissection for treatment of rectal carcinoid tumors.
      The technique of ESD was developed in Japan in 2003 with the primary goal of en bloc complete resection of early gastric cancer.
      • Yamamoto H.
      • Kawata H.
      • Sunada K.
      • et al.
      Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood.
      ESD has been used for en bloc resection of superficial esophageal, gastric, duodenal, and colorectal neoplasms. Resection of colonic and duodenal lesions is particularly challenging because of the increased vascularity and the particularly thin intestinal wall in these locations, creating a high risk of perforation. ESD tools and techniques have further advanced to allow extension through the intestinal wall and muscularis propria (MP) layer to achieve endoscopic full-thickness resection (EFTR). The technique of tunneling within the submucosal space has transformed the treatment options for achalasia by per-oral endoscopic myotomy (POEM). Submucosal tunneling has also been used to facilitate resection of SETs of the esophagus and stomach. Initiating a tunnel several centimeters away from the target lesion mitigates the potential adverse events of perforation at the resection site and allows for a controlled closure at the tunnel entry site.
      The current study by Qi et al,
      • Qi Z.-P.
      • Shi Q.
      • Liu J.-Z.
      • et al.
      Efficacy and safety of endoscopic submucosal dissection for submucosal tumors of colon and rectum.
      entitled “Efficacy and safety of endoscopic submucosal dissection for submucosal tumors of colon and rectum,” is the first report of a large cohort of patients with long-term follow-up. The study is a retrospective evaluation of 412 patients who underwent ESD resection of SETs in the colorectum at the Zhongshan Hospital of Fudan University. The data provide important information regarding predictors of complete resection and adverse events. The procedures were performed by 4 endoscopists, all experts in ESD. The authors achieved complete resection in 86.9% of cases. Adverse events occurred in 10% of patients, with serious adverse events occurring in 3.2% (2.2% bleeding and 1% perforation). A higher rate of adverse events was seen in SETs removed from the colon as opposed to the rectum (8.7% vs 1.6%) and those originating from the MP as opposed to the mucosa/submucosa (13.6% vs 2.6%). Large tumor size (≥2 cm) was associated with post-ESD electrocoagulation syndrome (PEECS) (31.3% vs 5.8%), which was conservatively managed. The rate of complete resection did not differ relative to tumor size.
      The authors nicely demonstrate that their outcomes improved with increasing experience, with procedures performed in the first year of the study being a risk factor for serious adverse events. This provides insight into the demanding technical challenges of ESD in the colon, given the authors’ expertise. NETs represented 71.4% of all tumors, and 232 NETs (56% of all cases) measured ≤10 mm, with a significant a majority occurring in the rectum. An argument can be made that these small rectal NETs could have been effectively removed by EMR. The duration of cases in this study was not provided, although data from other studies have shown EMR to be faster than ESD. The authors reference their own data showing higher rates of complete resection of SETs by the use of ESD compared with EMR. A meta-analysis corroborated a higher complete resection rate for rectal NET by the use of ESD compared with EMR.
      • Zhong D.D.
      • Shao L.M.
      • Cai J.T.
      Endoscopic mucosal resection vs endoscopic submucosal dissection for rectal carcinoid tumours: a systematic review and meta-analysis.
      A study comparing band ligation EMR with ESD for rectal carcinoids, however, showed similar rates of complete resection (83% vs 81%), with significantly faster resection in the EMR group (6.4 vs 15.1 minutes).
      • Choi C.W.
      • Kang D.H.
      • Kim H.W.
      • et al.
      Comparison of endoscopic resection therapies for rectal carcinoid tumor: endoscopic submucosal dissection versus endoscopic mucosal resection using band ligation.
      The biologic complexity of NET is highlighted by the 7 patients who were found to have distant metastases, representing 2.4% of all NET cases. Assessment for distant metastases was performed with cross-sectional imaging, with CT or magnetic resonance imaging performed every 6 to 12 months in tumors with malignant potential.
      An argument can be made for the resection of all SETs with malignant potential, namely, GIST, NET, and GCT, which encompassed the majority of lesions in this study (74.3%). The remaining lesions, however, were predominantly lipomas (16.5%), which represented the majority of resected lesions over 2 cm. Lipomas are typically diagnosed by their endoscopic and EUS characteristics and generally do not require resection unless they cause symptoms. A conundrum that this study demonstrates is that smaller lesions (<1 cm) with malignant potential could have likely been removed quickly and safely with EMR, whereas ESD resection of larger lesions (>2 cm) should considerably be approached with caution because of the higher risk of adverse events. This suggests a “sweet spot” for the endoscopic resection of lesions with malignant potential measuring between 1 and 2 cm. However, this would have limited the number of cases to 64 over the course of 6.5 years between 4 endoscopists at a high-volume center. The authors demonstrated that the rate of complete resection improved over time with increasing experience. Thus, limiting the volume of cases with stricter indications may also diminish the quality of resection.
      It is notable that the 22 tumors involving the MP (74% <1 cm, 21% 1-2 cm, and 4% >2 cm) were removed by the ESD enucleation technique, namely, peeling away the capsule of the lesion from the MP by use of an insulating tip knife. An overall perforation rate of 1% was reported. The frequency with which maneuvers were required to close immediate or suspected perforations was not reported. For colonic lesions arising from the MP, it may be expected that perforation closure or EFTR with subsequent closure would frequently be required to achieve complete resection. No increase in overall adverse events or decrease in complete resection was seen in cases of MP tumors, although there was a higher rate of PEECS.
      The study by Qi et al,
      • Qi Z.-P.
      • Shi Q.
      • Liu J.-Z.
      • et al.
      Efficacy and safety of endoscopic submucosal dissection for submucosal tumors of colon and rectum.
      as noted by the authors, is limited by its retrospective methodology, which may underestimate certain adverse events, such as delayed bleeding. The study was performed at a single center by expert endoscopists, which limits the general applicability of their findings. A comparison with other resection modalities such as EMR and surgery was not performed. Despite these limitations, the authors are to be commended for providing valuable information in a large group of patients with long-term outcomes data, with median follow-up of 43 months.
      Emerging techniques and closure devices, such as EFTR with subsequent closure or submucosal tunneling endoscopic resection, may provide another means of achieving complete resection of lesions of the MP. A full-thickness endoscopic resection device has been recently developed (Ovesco Endoscopy, Tubingen, Germany) that allows for nonexposed resection of colorectal SETs, whereby duplication of the intestinal wall is achieved before resection. A 14-mm over-the-scope clip and a preloaded snare are integrated into a cap 23 mm in diameter. In a study of 181 colorectal lesions, an overall R0 resection rate of 76.9% was achieved, with an R0 resection rate of 87% in subepithelial tumors. The challenge of endoscopic resection in the colon is highlighted by the R0 resection rate of 58% for lesions >2 cm and an overall perforation rate of 3.3%.

      Schmidt A, Beyna T, Schumacher B, et al. Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications. Gut. Epub 2017 Aug 10.

      Future studies comparing EFTR, ESD, and EMR for the resection of colorectal SETs by endoscopists with various degrees of ESD experience would be of interest.
      The study by Qi et al
      • Qi Z.-P.
      • Shi Q.
      • Liu J.-Z.
      • et al.
      Efficacy and safety of endoscopic submucosal dissection for submucosal tumors of colon and rectum.
      identifies ESD as a feasible method for the resection of colorectal SETs and provides important data identifying the most suitable lesions and experience required. Endoscopist experience and volume will continue to be an important factor, because significant ESD experience is needed for the performance of high-quality ESD of SETs in the colorectum. The authors determine that lesions larger than 2 cm, those in the colon rather than the rectum, and those originating from the MP layer are associated with increased adverse events and should be approached with caution. Emerging techniques and device technology for EFTR may expand the options for endoscopic resection of SET, particularly those originating from the MP layer.

      Disclosure

      All authors disclosed no financial relationships relevant to this publication.

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