Squamous Reepithelialization after Circumferential Endoscopic Mucosal Resection of Superficial Carcinoma Arising in Barrett’s Esophagus

• Introduction
• Case Report
• Discussion
• References

Recent reports on the results of endoscopic ablation of Barrett’s mucosa have been promising, particularly when total mucosal ablation is coupled with aggressive acid-suppression treatment using high-dose proton-pump inhibitor therapy. There is also a considerable literature on reepithelialization after ablative treatments in Barrett’s esophagus. This report describes a case of multifocal superficial adenocarcinoma arising in Barrett’s mucosa that was successfully treated with total circumferential endoscopic mucosal resection, with a subsequent follow-up of more than 2 years. This is the first report describing the process of squamous reepithelialization after endoscopic mucosal resection in Barrett’s esophagus.

Introduction

Photodynamic therapy, with administration of a hematoporphyrin derivative, is currently the most widely used method of mucosal ablation in patients with Barrett’s esophagus [1]. Ablation is used to eradicate all intestinal metaplastic epithelium; in an acid-suppressed environment, squamous reepithelialization then take place at the site of injury. There have been many reports in the literature on reepithelialization after ablative treatments in Barrett’s esophagus [2].

However, only limited experience has been reported on the use of local endoscopic therapy in the treatment of intraepithelial high-grade dysplasia or early carcinoma in Barrett’s esophagus. The use of endoscopic mucosal resection (EMR) to treat early esophageal squamous-cell carcinoma is well documented in the Japanese medical literature [3]. However, only a few small case series have been published on successful management of esophageal adenocarcinoma solely with endoscopic treatment [4], partly because carcinoma in Barrett’s esophagus is less prevalent in Japan in comparison with early squamous-cell carcinoma.

We have previously reported a case of multifocal superficial adenocarcinoma arising in Barrett’s mucosa that was successfully treated with total circumferential EMR [5]. The technical aspects of the procedure are described in the article. The present report describes our experience with a further 1-year follow-up of the same patient.

Case Report

A 67-year-old man with a history of frequent heartburn had been taking H₂-receptor antagonists, which had provided partial relief for several years. He underwent a screening esophagogastroduodenoscopy, which revealed Barrett’s esophagus. One of the four-quadrant biopsy specimens from the Barrett’s mucosa disclosed adenocarcinoma, and he was therefore referred to us for further treatment. He reported no nausea, vomiting, weight loss, chest pain, or other symptoms. He had no past medical and surgical history and no significant family history. His physical examination was essentially unremarkable.

A repeat endoscopic examination showed a 6-cm length of Barrett’s mucosa in the distal esophagus, from 36 cm from the incisors to the gastroesophageal junction at 42 cm. The surface of the Barrett’s mucosa was hyperemic, with areas of coarse nodularity. Four-quadrant biopsies and multiple biopsies were taken (Figure [1]). Well-differentiated adenocarcinoma was detected in specimens 1 - 3 and 7, and a diagnosis of multifocal carcinoma in long-segment Barrett’s esophagus was therefore made. Endoscopic ultrasonography of the esophagus showed that the lesion was limited to the lamina propria mucosae, and no lymph-node metastases were noted in the paraesophageal region. Work-up for metastases, including computed tomography of the chest, was negative. The patient declined surgery, and after receiving thorough information regarding the risks and benefits, he agreed to undergo endoscopic treatment.

A total circumferential resection of the Barrett’s epithelium was performed, including approximately 2 cm of the proximal gastric mucosa (Figure [2]). The total length of the circumferentially denuded segment was approximately 7 cm. The procedure was completed with no immediate complications. The pathology corresponded to category 4, subdivision 3 (suspicion of invasive carcinoma) in the recently published Vienna classification of epithelial neoplasias of the gastrointestinal tract [6].

The patient had been receiving omeprazole 40 mg daily since 1 week before the operation. A postoperative stricture was noted 7 days after the operation, and periodic bougienage with a dilator was performed once or twice a week. One month later, good control of the stricture was obtained, and squamous reepithelialization was observed in the whole of the area of the EMR. Six weeks after the operation, complete squamous reepithelialization with no Barrett’s mucosa was confirmed by biopsy (Figure [3]), and a new squamocolumnar junction was clearly noted 36 cm from the incisors (Figure [4]). An endoscopic pinch biopsy from just under the junction confirmed normal gastric mucosa.

Six months after the operation, a 24-h pH study was conducted after omeprazole had been discontinued for 1 week, and no acid reflux was noted. There was no evidence of local recurrence or lymph-node metastases during follow-up of 2 years. The patient was still asymptomatic at the follow-up examinations.

Discussion

In 1970, Bremner et al. reported the role of acid reflux in the development of esophageal columnar epithelium in the canine esophageal reflux model. In the study, mucosa was stripped from the distal esophagus in 35 dogs, and the authors stated that good squamous reepithelialization was observed in the control group (without reflux). This was the first report describing squamous reepithelialization [7].

Photodynamic therapy (PDT) has been successfully used since the late 1980 s as an alternative to surgery in patients with esophageal carcinoma. Studies on squamous reepithelialization in the early 1990 s in patients with Barrett’s esophagus (without malignancy) showed that squamous mucosa can replace endoscopically ablated segments of Barrett’s epithelium when gastric acid secretion is suppressed by chronic administration of omeprazole [8].

In a case report by Ertan et al. [9], a patient with Barrett’s esophagus associated with high-grade dysplasia and intramucosal esophageal adenocarcinoma refused surgery. As an alternative, he received neodymium-yttrium aluminum garnet (Nd:YAG) laser treatment and was maintained on omeprazole. The patient achieved and maintained squamous reepithelialization for 2 years, when a recurrence of the carcinoma was again treated with Nd:YAG laser. Reepithelialization was achieved again and maintained during 12 additional months of follow-up. In 10 patients with dysplasia or early adenocarcinoma who were treated with Nd:YAG laser and omeprazole 20 - 80 mg/day, a report by Gossner et al. [10] stated that regrowth of the squamous mucosa was observed in all 10 patients and that no acid reflux was documented with pH monitoring. The results of published studies have shown that reepithelialization of ablated areas with squamous cells takes place, provided that gastric acid suppression has been achieved.

As mentioned earlier, there have been many reports describing squamous reepithelialization after ablative therapy for Barrett’s epithelium with dysplasia and superficial cancer. One limitation of ablation techniques is that removal of the Barrett’s epithelium is potentially incomplete. There have been reports of squamous overgrowth of partially ablated Barrett’s epithelium, as well as the development of adenocarcinoma underneath areas of squamous reepithelialization [11]. Another drawback of these techniques is an inability to control the depth of tissue injury [12]. In addition, all techniques using chemical or thermal measures to ablate the epithelial cells make it impossible to detect occult carcinoma in the ablated epithelium during endoscopic surveillance.

In Japan, the incidence of Barrett’s esophagus and Barrett’s esophageal carcinoma is lower than in Western countries. Several small case series have been published on successful management of adenocarcinoma of esophagus solely with EMR. Several EMR techniques are available, and we have used the EMR cap (EMR-C) method since 1993 [13]. EMR procedures in the abdominal esophagus can be technically difficult. However, with this method, circumferential EMR is completed relatively easily even at the esophagogastric junction. The advantages of EMR in comparison with ablative techniques are that the mucosal layer can be completely denuded and that histopathological examination of the specimens collected can be carried out [5].

Recently, May et al. [14] reported the short-term and long-term results of local endoscopic treatment in a large series of 115 patients with high-grade dysplasia and early adenocarcinoma in Barrett’s esophagus. Four patients were switched to esophagectomy and another patient died of myocardial infarction during the course of the endoscopic treatments. Endoscopic treatment was unsuccessful in only two of 110 patients. The overall complication rate was 9.5 %, and the calculated 3-year survival rate was 88 %. On the basis of these results, local endoscopic therapy appears to be an effective and safe alternative to esophagectomy in patients with high-grade dysplasia and early adenocarcinoma. All of the patients were receiving concomitant chronic acid-suppression treatment with PPIs, but the authors do not comment on reepithelialization after the procedure.

Biddlestone et al. [15] have proposed three possible mechanisms to explain the process of squamous regrowth: encroachment of adjacent squamous epithelium; extension of epithelium from the submucosal gland duct to form squamous islands; and squamous metaplasia within the Barrett’s mucosa itself. In the case reported here, the esophageal gland ducts and Barrett’s mucosa were thoroughly resected during EMR, and the squamous epithelium may therefore have proliferated from the adjacent squamous mucosa. There is a study whose findings provide support for this speculation: Inoue et al. [16] investigated the healing process after EMR in artificial esophageal ulcers in a canine model. Esophageal EMR was carried out in five dogs, which were then sacrificed immediately after the procedure, and 2, 6, 14 and 56 days later, respectively. Esophagectomy was carried out postmortem, and the healing process in the ulcer was inspected sequentially in microsections. On day 6 after the EMR, regenerative epithelium was found to be proliferating at the edge of the ulcer and extending into the ulcer bed. On day 14 after the EMR, the ulcer bed was completely covered with one or two layers of thin squamous epithelium.

It has been reported that an acid-free environment is critical for squamous regrowth after tissue injury [2]. In the present case, the patient had been receiving PPIs since 1 week before the operation, so that the gastric acid secretion would have been well suppressed at the time of the EMR procedure. Another point to note in this case is that it was possible to control a stricture after circumferential EMR using periodical bougienage. After successful control of the stenosis, the narrowed segment can be beneficial for maintaining an acid-free environment in the esophageal lumen. This was confirmed with 24-h pH-metry after 1 week of discontinuation of omeprazole, which showed that the total time with pH < 4 was 3.3 %. The patient is now free of heartburn and the other GERD symptoms that he had suffered for more than two decades.

Despite the success achieved in this patient, the use of EMR as an alternative to surgery cannot currently be recommended in all patients with early Barrett’s cancer. The same also applies to ablative therapy. Patients with intramucosal cancer who are good candidates for surgery and who agree to undergo esophageal resection should undergo surgery. It is currently uncertain which techniques are most successful for eradicating Barrett’s epithelium, dysplasia, or early adenocarcinoma and for preventing recurrences. A number of issues need to be considered, including expertise, cost, and the availability of the equipment needed for EMR. Ideally, a randomized trial comparing EMR, ablative therapy, and surgical therapy in patients with early adenocarcinoma in Barrett’s esophagus should be conducted to define the operating costs, the patients’ postprocedural quality of life, and the morbidity rates and survival.

References

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  CrossrefPubMedSearch in Google Scholar
• 15 Biddlestone L R, Barham C P, Wilkinson S P. et al . The histopathology of treated Barrett’s esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.  Am J Surg Pathol. 1998;  22 239-245
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H. Satodate, M. D.

Digestive Disease Center

Showa University Northern Yokohama Hospital · 35-1 Chigasaki-chuo, Tsuzuki-ku · Yokohama 224-8503 · Japan

Fax: + 81-45-949-7927 ·

Email: hitoshi-satodate@nifty.com

References

• 1 Gossner L, May A, Sroka R. et al . A new long-range through-the-scope balloon applicator for photodynamic therapy in the esophagus and cardia.  Endoscopy. 1999;  31 370-376
  Thieme ConnectPubMedSearch in Google Scholar
• 2 Overholt B F. Acid suppression and reepithelialization after ablation of Barrett’s esophagus.  Dig Dis. 2000-2001;  18 232-239
  CrossrefPubMedSearch in Google Scholar
• 3 Takeshita K, Tani M, Inoue H. et al . Endoscopic treatment of early oesophageal carcinoma or gastric cancer.  Gut. 1997;  40 123-127
  PubMedSearch in Google Scholar
• 4 Barr H, Shepherd N A, Dix A. et al . Eradication of high-grade dysplasia in columnar-lined (Barrett’s) oesophagus by photodynamic therapy with endogenously generated protoporphyrin 9.  Lancet. 1996;  348 584-585
  CrossrefPubMedSearch in Google Scholar
• 5 Satodate H, Inoue H, Yoshida T. et al . Circumferential endoscopic mucosal resection of carcinoma arising in Barrett’s esophagus: report of a case.  Gastrointest Endosc. 2003;  58 288-292
  CrossrefPubMedSearch in Google Scholar
• 6 Schlemper R, Dawsey S, Itabashi M. et al . Differences in diagnostic criteria for esophageal squamous carcinomas between Japanese and Western pathologists.  Cancer. 2000;  88 996-1006
  CrossrefPubMedSearch in Google Scholar
• 7 Bremner C G, Lynch V P, Ellis F H. Barrett’s esophagus: congenital or acquired? An experimental study of esophageal mucosal regeneration in the dog.  Surgery. 1970;  68 209-216
  PubMedSearch in Google Scholar
• 8 Sampliner R E, Hixon L J, Fennerty M B. et al . Regression of Barrett’s esophagus by laser ablation in an antacid environment.  Dig Dis Sci. 1993;  38 365-368
  CrossrefPubMedSearch in Google Scholar
• 9 Ertan A, Zimmerman M, Younes M. Esophageal adenocarcinoma associated with Barrett’s esophagus: long-term management with laser ablation.  Am J Gastroenterol. 1995;  90 2201-2203
  PubMedSearch in Google Scholar
• 10 Gossner L, May A, Stolte M. et al . KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett’s esophagus.  Gastrointest Endosc. 1999;  49 8-12
  CrossrefPubMedSearch in Google Scholar
• 11 Sampliner R E, Fass R. Partial regression of Barrett’s esophagus: an inadequate endpoint.  Am J Gastroenterol. 1993;  88 2092-2094
  PubMedSearch in Google Scholar
• 12 Bremner R M, Mason R J, Bremner C G. Ultrasonic epithelial ablation of the lower esophagus without stricture formation: a new technique for Barrett’s ablation.  Surg Endosc. 1998;  12 342-347
  CrossrefPubMedSearch in Google Scholar
• 13 Inoue H, Takeshita K, Hori H. et al . Endoscopic mucosal resection with a cap-fitted panendoscope for esophagus, stomach, and colon mucosal lesions.  Gastrointest Endosc. 1993;  39 58-62
  CrossrefPubMedSearch in Google Scholar
• 14 May A, Gossner L, Pech O. et al . Local endoscopic therapy for intraepithelial high-grade neoplasia and early adenocarcinoma in Barrett’s esophagus: acute-phase and long-term results of new treatment approach.  Eur J Gastroenterol Hepatol. 2002;  14 1085-1091
  CrossrefPubMedSearch in Google Scholar
• 15 Biddlestone L R, Barham C P, Wilkinson S P. et al . The histopathology of treated Barrett’s esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.  Am J Surg Pathol. 1998;  22 239-245
  CrossrefPubMedSearch in Google Scholar
• 16 Inoue H, Maruyama M, Takeshita K. et al . Healing process of the artificial ulcer induced by endoscopic esophageal mucosal resection [in Japanese with English abstract].  Gastroenterol Endosc. 1991;  33 711-714
  PubMedSearch in Google Scholar

H. Satodate, M. D.

Digestive Disease Center

Showa University Northern Yokohama Hospital · 35-1 Chigasaki-chuo, Tsuzuki-ku · Yokohama 224-8503 · Japan

Fax: + 81-45-949-7927 ·

Email: hitoshi-satodate@nifty.com