Transplantation of Mucosa From Stomach to Esophagus to Prevent Stricture After Circumferential Endoscopic Submucosal Dissection of Early Squamous Cell

Endoscopic submucosal dissection (ESD) in the esophagus is an expert technique for “en bloc” resection of even widespread mucosal cancers of ≥1.5 cm. ESD can provide a quasi-surgical specimen for adequate histopathologic evaluation and significantly reduces the risk of local recurrence compared with conventional widespread endoscopic mucosal resection (“piecemeal” EMR).1Ono S. Fujishiro M. Niimi K. et al.Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms.Gastrointest Endosc. 2009; 70: 860-866Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 2Hochberger J. Kruse E. Wedi E. et al.Training in endoscopic mucosal resection and endoscopic submucosal dissection.in: Cohen J. Successful gastrointestinal endoscopy. Wiley-Blackwell, Oxford, UK2011: 204-237Crossref Scopus (12) Google Scholar However, secondary stricture formation is the major drawback for resections ≥60% of the esophageal circumference. Multiple dilation sessions may be required, limiting quality of life. Experimental approaches include transplantation of buccal, dermal, or submucosal intestinal cell grafts as well as systemic and local steroid applications.3Lopes M.F. Cabrita A. Ilharco J. et al.Grafts of porcine intestinal submucosa for repair of cervical and abdominal esophageal defects in the rat.J Invest Surg. 2006; 19: 105-111Crossref PubMed Scopus (43) Google Scholar, 4Yamaguchi N. Isomoto H. Nakayama T. et al.Usefulness of oral prednisolone in the treatment of esophageal stricture after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.Gastrointest Endosc. 2011; 73: 1115-1121Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 5Ohki T. Yamato M. Ota M. et al.Prevention of esophageal stricture after endoscopic submucosal dissection using tissue-engineered cell sheets.Gastroenterology. 2012; 143: 582-588.e2Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar However, clinical experience is very limited so far. Since March 2011, we have been performing animal experiments concerning tubular esophageal resection and retransplantation of esophageal and gastric mucosal patches in pigs under an approved protocol with first preliminary but encouraging results when the following clinical case presented. A 72-year-old man was referred with biopsy-proven high-grade intraepithelial neoplasia, suspicion of an early squamous cell cancer in the cervical esophagus. Prior history included a T2N0 rectal cancer curatively treated with abdominoperineal resection and terminal sigma anus praeter several years ago. High resolution magnifying and chromoendoscopy (EG 590 ZW; Fujifilm, Tokyo, Japan) found a circumferential mucosal tumor spreading within the upper esophageal sphincter area (Paris Type IIab; 17.5-25 cm). A 1 × 10-mm tumor tongue reached cranially to the distal hypopharynx (Figure 1). Staging was UT1a, N0 on endoscopic ultrasonography; computed tomography of the neck, chest, and abdomen was negative. Options were discussed with our interdisciplinary tumor board: Total surgical esophagectomy with cervical saliva fistula/gastric feeding tube; thermoablation with doubtful result owing to a tumor thickness of ≥3 mm; primary chemoradiation; and widespread ESD with an increased risk of stricture formation. Board and patient favored an attempt of ESD en bloc resection. Because the need for repeat postinterventional dilation sessions was most probable, the patient agreed to an experimental approach of ESD plus gastroesophageal mucosal transplant as “compassionate use.” On April 13, 2011, the endoscopic procedure was performed under general anesthesia. After digital chromoendoscopy proximal and distal markings of the resection area were made using a 1.5-mm FlushKnife (Fujifilm) followed by submucosal injection of 6% hydroxyethylic starch (Voluven; 1.5 mL of 0.8% indigo carmine/500 mL; epinephrine, 1:250,000). A circumferential tubular en bloc submucosal dissection was successfully performed from the hypopharynx through the upper esophageal sphincter into the cervical esophagus (17–27 cm aborally). The tubular specimen was retrieved and macroscopically ≥5 mm tumor-free craniocaudal margins confirmed (Figure 1Ai–vi). A second, widespread ESD measuring 9 cm in length and 4-6 cm in width followed encompassing the entire anterior wall of the gastric antrum (Figure 1Bi). The gastric specimen was retrieved and cut into 3 pieces because isolated mucosa tend to retract to about 30% of its initial size owing to a contraction of the “muscularis mucosae” (Figure 1Bii, iii). Antral mucosa was chosen owing to a thick muscular layer of the antrum and a low quantity of acid-secreting parietal cells. The 3 mucosal patches were first attached to the “muscularis propria” by hemoclips and then fixed by means of an uncovered metal mesh stent (Ultraflex; Boston Scientific, Natik, MA) to allow the absorption of fluid and nutritional components from the luminal side (Figure 1Biv, v, vi). Because of the risk of laryngeal compression and potential severe pain after stent placement, the esophageal sphincter area was spared for a span of 1.5-2.0 cm. The stent was removed on post-procedure day 20. Stripes of vital gastric mucosa could be seen on EGD before discharge on day 24. Histopathologic evaluation of the esophageal tumor specimen revealed a pT1a, G2, V-, L-, R0 early squamous cell cancer invading the “lamina propria” of the mucosa to a depth of 150 μm (m2), but not the submucosa with histologically tumor-free cranial, caudal, and basal margins. Therefore, the risk of lymph node metastasis was judged <2%. Within 5 months after the intervention, the area of mucosal transplant had grown nearly circumferentially in the cervical esophagus (Figure 2A, C). Biopsies confirmed gastric antral mucosa, HP negative (Figure 2B). However, the patient had initial problems with repeat stricture formation of a 1-cm segment in the upper sphincter region that, owing to technical issues, had not been treated with the autologous tissue transplant (see above) and served quasi as “natural” control in our patient. Meanwhile, the patient has been followed for >32 months without further complaints. Worldwide, esophageal cancer is the 8th most common cancer, with squamous cell cancer being the most common subtype. In the Western world, the rate of adenocarcinoma of the esophagus (Barrett’s cancer) has increased 10-fold within the last 20 years.6Brown L.M. Devesa S.S. Chow W.H. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age.J Natl Cancer Inst. 2008; 100: 1184-1187Crossref PubMed Scopus (559) Google Scholar Surgical treatment is still highly invasive and in current multicenter studies may even reach a mortality of 6.7%–13.1%, an early morbidity of 15%–32%, and a late morbidity of 47%.7Chang A.C. Ji H. Birkmeyer N.J. et al.Outcomes after transhiatal and transthoracic esophagectomy for cancer.Ann Thorac Surg. 2008; 85: 424-429Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Endoscopic treatment modalities have proved valuable for severe dysplasia and early cancers limited to the mucosa and have been able to replace operative resection, especially for patients at elevated operative risk. An international consensus statement recently recommended focal EMR of suspicious areas of proven high-grade intraepithelial neoplasia or mucosal cancers followed by radiofrequency ablation (Halo system; Covidian-BarrX, Sunnyvale, CA) of the remaining Barrett’s segment.8Bennett C. Vakil N. Bergman J. et al.Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process.Gastroenterology. 2012; 143: 336-346Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar However, treatment with thermoablation does not allow a histopathologic specimen to be analyzed and recent reports have highlighted the risk of the development of subsquamous neoplasia after radiofrequency ablation in neoplastic Barrett’s segments.9Titi M. Overhiser A. Ulusarac O. et al.Development of subsquamous high-grade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett's esophagus.Gastroenterology. 2012; 143: 564-566.e1Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Among endoscopic resection modalities, only ESD is able to provide a quasi-surgical en bloc specimen of even widespread or multifocal lesions plus surrounding precancerous mucosa. However, a major limiting factor for widespread ESD in the esophagus is a high potential for secondary stricture formation. This first described case of a gastroesophageal endoscopic mucosal transplant with 32 month follow-up after widespread ESD for an early squamous cell cancer of the cervical esophagus adds another potential treatment option and a new perspective for systematic comparative studies in this field. Video Clip 1 shows the initial findings in this case with circumferential spread of the lesion in the cervical esophagus through the sphincter area into the hypopharynx. Marking of the upper and lower resection field is followed by submucosal injection of hydroxyethylic starch (Voluven 6%, indigocarmine, and epinephrine; see above) with subsequent circumferential caudal and cervical incision. In the following, a tubular caudocranial resection is performed using the 1.5-mm Flushknife (Fujifilm). The esophageal specimen is set free and drops down toward the stomach to be retrieved (not shown). In the following, a second ESD in the gastric antrum is performed, the specimen cut into 3 slices which are attached to the muscular layer of the denuded area in the cervical esophagus by means of clips and a noncovered metal stent. The sphincter area had to be spared. Video Clip 2 shows the result in the cervical esophagus 18 month later. The gastric mucosal transplant has spread out circumferentially in the cervical esophagus but the fingerprints of the metal stent can still be seen distally. Gastroesophageal mucosal transplantation for stricture prevention after widespread EMR or submucosal dissection for early cancers or high grade dysplasia seems feasible with an excellent long-term result in this unique case described and opens a new perspective in this field. Presented as video case at the DGVS annual meeting, September 19–22, 2012, Hamburg, Germany, and at the 17th Annual Video Forum at Digestive Disease Week, Orlando, Florida, May 18–21, 2013. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJlYzVhNzI3YWI3NWExYzI0ZDVkYzQ1YzVkYmJhNmM4OCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjgwNDY1ODU4fQ.Vg1oTzPvRgFhClW-U_LnbANs8hDCjyuT5b578loq3gcMnBtpCCQTihMm-GHgaZyxGQuLENmwtdwudbLt5BeyZ8RS16koQ8T52Wf6hcb2rSw0NyFGHOkaOO4cQcjtjYl50HTClPMAIQtBZkuNvxi4lA8MGjLnDpex7QnilAwNkRgnqmN46Tp09QktBJytYvPMAmj20biN9HUlr643AqxDYaP1DnU57jhCDD7le8kRUXyr5YmPa-w0Telt2Q9OFi-gsc9M1skCc48REBXf9yERMJ2Bs7a8AuwAWZL9cLXnWno-IRH3OEzQDmchCNrs0sstggYAFPkI7kdKC2gdDxrvcQ Download .mp4 (22 MB) Help with .mp4 files Video 1eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIzZmI1MjBkNjVjZmVlZDBjODc0MTBhMGU3OTUyMTUyZiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjgwNDY1ODU4fQ.m7KnlOcTzUb9wv30mhJTx5h9LDn0g05whT7HQIrgQBTbxCjHHNEU1f0dSZpzdOAuQfW3kYDmd62O86bdrDYmJcmd7L1El1sKa1JZN9J4KZIDE14355OfZ8KleQChakA1n-mrNUX1fQL7ECXTNl6dt48UPqeQsk1UBjlHeY_fNYwMzhehM3XTm_hPve6_rp_M_kXei0v0z69Q9sTbAPfNElPsdjEHX25JCdtuCejbTE6m4O3FM78MlSPjsZIvAGRPmDjKkFqPZBnLN9Im69ImRHrHsDZRMB8hfVgOyfn7yG7FzjNICjAxu3s37XN6O9FK8HyJfxyQsyi3m_60wCfIkA Download .mp4 (7.89 MB) Help with .mp4 files Video 2