Surg Endosc (2015) 29:2121–2125 DOI 10.1007/s00464-014-3962-3
and Other Interventional Techniques
Endoscopic mucosal resection for staging and treatment of early esophageal carcinoma: a single institution experience Justin T. Huntington • Jon P. Walker Michael P. Meara • Jeffrey W. Hazey W. Scott Melvin • Kyle A. Perry
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Received: 7 April 2014 / Accepted: 25 October 2014 / Published online: 4 December 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Endoscopic mucosal resection (EMR) has emerged for evaluation and treatment of esophageal nodules. We report our initial experience with EMR for T staging and management of early esophageal cancer. Methods We reviewed patients undergoing EMR for esophageal adenocarcinoma between 2008 and 2013. The primary outcome measure was needed for esophagectomy. Secondary outcomes included complete eradication of adenocarcinoma, recurrence or persistence of cancer, nodal status for those undergoing esophagectomy, and complications of endoscopic treatment. Results During the study period, 24 patients underwent EMR demonstrating carcinoma, and a grossly margin negative endoscopic resection was achieved in all cases. Ten patients (42 %) had evidence of submucosal invasion and were referred for esophagectomy. Patients with margin negative EMR (n = 10, 42 %) or positive radial margins
Presented at the SAGES 2014 Annual Meeting, April 2–5, 2014, Salt Lake City, Utah. J. T. Huntington (&) M. P. Meara J. W. Hazey W. S. Melvin K. A. Perry Division of General and Gastrointestinal Surgery, The Ohio State University, Columbus, OH 43210, USA e-mail:
[email protected] K. A. Perry e-mail:
[email protected] J. P. Walker Division of Gastroenterology, The Ohio State University, Columbus, OH, USA K. A. Perry The Ohio State University Medical Center, 410 W. 10th Avenue, N729 Doan Hall, Columbus, OH 43210, USA
(n = 4, 16 %) underwent endoscopic surveillance and treatment with radiofrequency ablation or repeat EMR as needed. Thirteen patients (93 %) with intramucosal cancer (IMC) have been successfully managed with ongoing endoscopic surveillance and treatment with a median follow-up of 15.5 months. One patient underwent esophagectomy due to recurrent IMC in the setting of longsegment multifocal high-grade dysplasia. There were no esophageal perforations, one patient developed a self-limited gastrointestinal hemorrhage following EMR, and one had an esophageal stricture following endoscopic management. Conclusions IMC can be successfully managed endoscopically and thus esophagectomy is avoided in a significant proportion of patients. Endoscopic management may be utilized in the setting of complete resection or radial margin involvement without evidence of submucosal invasion. Close endoscopic follow-up is of paramount importance even in those with negative margins, because recurrent disease may occur following EMR in these patients. Keywords Esophageal cancer Endoscopic management Endoscopic mucosal resection Endoscopic resection Endoluminal therapy
The incidence of esophageal adenocarcinoma has increased over 500 % in the US over the past 3 decades, a rate greater than any other cancer diagnosis [1–3]. Currently, esophageal cancer affects over 16,000 Americans each year, the majority of which are adenocarcinomas, and over 14,000 deaths resulted from esophageal cancer in the United States in 2008 [4]. In some patients, chronic gastroesophageal reflux disease results in metaplastic transformation of the
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normal squamous cell epithelium to Barrett’s esophagus (BE) which may progress to high-grade dysplasia (HGD) and even esophageal adenocarcinoma [5, 6]. The overall 5-year survival rate for all patients with esophageal cancer is less than 20 %, making early detection and the need for early intervention imperative [5–8]. Treatment of early esophageal adenocarcinoma has traditionally required esophagectomy. While this approach has a relatively high cure rate for early cancers, it is associated with serious complications and carries the highest mortality rate among elective gastrointestinal surgical interventions [9]. Endoscopic mucosal resection (EMR) provides a minimally invasive technique that is useful for diagnosis and treatment of early esophageal cancers, particularly intramucosal cancer (IMC) [8–13]. In some countries, EMR has supplanted esophagectomy as the standard therapy for superficial esophageal cancers [9]. When used in conjunction with endoscopic ultrasound and PET scan for clinical staging, EMR offers the potential to obtain tissue for diagnosis and histologic evaluation of submucosal invasion, which is associated with substantially higher rates of lymph node metastasis and warrants esophagectomy [14, 15]. The objective of this study was to evaluate our early experience with EMR for the evaluation of esophageal nodules for the staging and treatment of early esophageal adenocarcinoma.
Materials and methods Patients This retrospective cohort study included a review of all patients undergoing EMR for esophageal nodules at The Ohio State University Wexner Medical Center between November 2008 and July 2013. Inclusion criteria included pathologic confirmation of adenocarcinoma following EMR. Patient data are maintained in a prospectively collected database approved by our Institutional Review Board. Endoscopic evaluation and endoscopic mucosal resection (EMR) All patients underwent upper endoscopy for complete evaluation of the entire esophageal mucosa and biopsy of any abnormalities. The diagnostic and therapeutic endoscopies were performed by one of three experienced providers: two gastrointestinal surgeons and one gastroenterologist. EMR was performed using either a standard EMR cap (Olympus America, Center Valley, PA) technique or multiband ligator technique (Duette Multiband
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Mucosectomy System, Cook Medical, Bloomington, IN) based on the endoscopist’s preference. Nodules were removed en bloc or in piecemeal fashion depending on the size of the lesion. All specimens were oriented to allow assessment of radial and deep resection margins by an experienced gastrointestinal pathologist. Patients also underwent radiofrequency ablation (RFA) of the remaining Barrett’s as clinically indicated using a standard protocol [10]. Endoscopic surveillance versus surgery Patients with positive deep margins or negative deep margins with evidence of submucosal invasion were referred for esophagectomy. Those with negative resection margins or positive radial margins were managed endoscopically. Those with positive radial margins underwent a repeat endoscopy with biopsy of the previous EMR site and any visible lesions 4 weeks following the initial EMR. Following evidence of complete endoscopic resection, serial endoscopic surveillance was performed at 3-month intervals and, if negative for recurrent malignancy for 1 year, the surveillance interval was increased to 6 months. Outcome measures The primary outcome measure was needed for esophagectomy based on tumor stage or disease progression. Secondary outcomes included complete eradication of adenocarcinoma, margin status of the initial endoscopic resection, recurrence or persistence of cancer, lymph node status at time of esophagectomy, and complications of endoscopic treatment.
Results Eighty-four patients underwent EMR for evaluation of esophageal nodules between 2008 and 2013, and 24 had biopsy-proven adenocarcinoma and met criteria for inclusion in this study. Patients had a mean age of 65 ± 8.5 years and 21 (88 %) were male. Three patients (12.5 %) underwent EMR for known adenocarcinoma and the remaining (87.5 %) were performed for diagnosis of a nodule or lesion. Endoscopic ultrasound (EUS) was used to evaluate and stage the lesion prior to EMR in nine patients (37.5 %). Three patients (12.5 %) in this series developed malignant esophageal nodules during the surveillance period following previous radiofrequency ablation for dysplastic BE. A total of 36 EMR procedures were performed in 24 patients. A complete gross resection was achieved in all cases. Complications occurred in 2 (5.6 %) cases. One
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patient required hospital admission for self-limited gastrointestinal bleeding that did not require blood transfusion. A second patient developed an esophageal stricture following radiofrequency ablation that was successfully managed with endoscopic dilation. The results of the initial EMR and allocation of patients to endoscopic or surgical management pathways is depicted in Fig. 1. Pathologic assessment demonstrated IMC in 20 (83.3 %) cases, moderately differentiated adenocarcinoma in 3 (12.5 %), and poorly differentiated adenocarcinoma in 1 (4.2 %). Ten (41.7 %) patients had positive deep margins or evidence of submucosal invasion. These patients were recommended to undergo immediate esophagectomy, and eight underwent esophagectomy while two refused surgical treatment and were subsequently lost to follow-up. Of the remaining 14 patients, ten had an endoscopic resection with negative radial and deep margins, and four had positive radial margins with negative deep margins and no evidence of submucosal invasion. These patients were offered endoscopic management. The population of interest for this study included the 14 patients with endoscopically managed intramucosal cancers. Those with positive radial margins (n = 4) showed no evidence of persistent cancer upon repeat endoscopy and biopsy at 1 month following endoscopic resection. EMR was used in conjunction with RFA for remaining BE in most cases. Three patients developed IMC following previous ablation treatment, and nine underwent subsequent RFA of residual BE, with successful elimination of dysplasia in all but 1 case. Endoscopic surveillance following definitive endoscopic therapy was conducted as outlined in the methods section with a median follow-up interval of 15.5 (3–30) months. One patient underwent an esophagectomy following initial
endoscopic management after developing recurrent IMC while undergoing radiofrequency ablation in the setting of long-segment multifocal high-grade dysplasia. Overall, successful endoscopic management of IMC was achieved in 13 patients (92.9 %) patients, including all four patients with positive radial margins. Nine patients in this series underwent an esophagectomy during the study period. As mentioned previously, eight of the ten patients who were offered esophagectomy due to deep margin on EMR did proceed to surgery. An additional patient developed IMC identified during surveillance in the endoscopic management group and elected to have esophagectomy. The pathology for that patient revealed IMC without evidence of lymph node metastasis.
Discussion This study examined our early experience with EMR for the evaluation and treatment of early esophageal adenocarcinoma. We found that EMR is an effective tool to manage IMC and can avoid an esophagectomy with an early success rate of over 90 %. The initial use of EMR allowed us to accurately assign patients to a treatment pathway based on tumor depth: EMR and ablation for patients with IMC, or esophagectomy for patients with submucosal invasion and risk of lymph node metastases. One patient in this series who was offered immediate esophagectomy had evidence of nodal metastases at the time of esophagectomy, and none of the patients who were initially managed endoscopically had lymph node metastases at the time of surgery. The EMRs performed in this series showed ten patients with evidence of deep margin or clear submucosal
Negative margins (n=10) Patients undergoing EMR (n=24)
Esophagectomy with T1aN0 disease (n=1)
Managed endoscopically (n=14) Positive radial margins (n=4)
Immediate esophagectomy recommended (n=10)
Fig. 1 Twenty four patients underwent EMR demonstrating carcinoma by pathology in our trial. Ten patients had positive deep margins or evidence of submucosal invasion and were recommended to undergo esophagectomy. Fourteen had intramucosal cancer with negative deep margins and were managed endoscopically. This
Documented resolution with no esophagectomy (n=9)
Documented resolution with no esophagectomy (n=4)
included ten with negative margins seen on the EMR specimen and four with positive radial margins. One of these patients ultimately required esophagectomy due to recurrent intramucosal cancer in the setting of long-segment multifocal high-grade dysplasia
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invasion. Studies have shown that patients with evidence of submucosal invasion have a significantly increased risk of lymph node metastases (16–24 %) compared to patients with IMC (less than 1 %). Given this risk, all patients with T1b lesions were managed surgically, even in the setting of a margin negative endoscopic resection [7, 16]. Given the increasing capabilities of surgeons and gastroenterologists with techniques including EMR and endoscopic submucosal dissection, it is likely that the rate of complete endoscopic resection of these tumors is likely to increase; however, esophagectomy will remain the mainstay of therapy until new, more sensitive, and less invasive methods of assessing for lymph node involvement are developed. Four patients had EMR specimens with positive radial margins. Because the true status of these margins can be difficult to assess due to cautery artifact, these patients were managed endoscopically in our protocol. Each patient underwent subsequent endoscopy with biopsies of the EMR scar and adjacent tissue, and none of these patients were found to have residual cancer. While the early results are encouraging, follow-up of these patients will be of paramount importance. Other studies have reported similar success managing patients in this manner [8, 15, 16]. However, in a series of 27 patients, Mino-Kenudsen et al. found that 56 % of patients with positive radial margins and 86 % of patients with positive deep margins developed a recurrence with a median follow-up of 6 months [17]. Esophagectomy has proven efficacious for the management of early esophageal cancers, with high five-year survival rates in patients with stage 1 disease [7]. This efficacy comes at a heavy cost however, as this procedure carries a high morbidity rate and has been shown to significantly impact patient quality of life, particularly in the first postoperative year [18, 19]. Recently, studies of endoscopic management have challenged this paradigm. Endoscopic management for early esophageal (T1a) and gastric adenocarcinomas has proven effective with very low morbidity and mortality [15–17]. In this study, 90 % of patients were successfully managed endoscopically, with only two complications, both of which were self-limited and had a minimal impact on patient activities of daily living. In a similar series, Saligram et al. reported complete remission of cancer following EMR for T1a lesions in 96 % of patients and there were no deaths from esophageal carcinoma [12]. The protocol in this study utilized EMR in conjunction with radiofrequency ablation for eradication of Barrett’s esophagus following endoscopic tumor resection. Ablative therapy alone cannot eliminate nodular disease and routine biopsies do not provide an adequate assessment of margins to adequately stage these lesions. Therefore, combination therapy with EMR and ablation is recommended [5, 10,
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12]. When used together, EMR and RFA have shown similar success in terms of disease eradication to RFA alone; however there are limitations to the studies in terms of heterogeneity and short follow-up intervals [13, 20–23]. These studies did suggest an increased risk of stricture formation when RFA follows an aggressive EMR. In this series, one patient developed a symptomatic esophageal stricture following RFA that was responsive to endoscopic dilation. An important concern regarding endoscopic management of esophageal cancer is the potential to develop recurrent or harbor unrecognized persistent disease following initial endoscopic treatment. As described above, initial efficacy rates reported in this series and others have been very high, but recurrences have been described, and long-term follow-up studies are lacking. Further, EMR only addresses depth of invasion in terms of initial staging, but does not address nodal or distant disease. Do to this limitation, staging may be improved if endoscopic ultrasound is utilized in conjunction with EMR to evaluate depth of invasion and peritumoral lymph node status in patients with larger nodules. The failure of endoscopic management in this series resulted from the development of a recurrent nodule that contained IMC in the setting of long-segment BE with multifocal HGD. Although a second margin negative EMR without evidence of submucosal invasion was achieved, the decision was made to proceed with esophagectomy due to the aggressive nature of his disease. Also, three patients in this series presented for their initial EMR for evaluation of an esophageal nodule that developed following radiofrequency ablation of dysplastic BE. In each of these cases, submucosal invasion was identified at the time of EMR, and each patient underwent an esophagectomy without evidence of lymph node metastases. Although not common, other studies have reported similar results, with a subset of patients developing cancers that require surgical resection following initially successful endoscopic management [13]. These results underscore the importance of careful and frequent endoscopic management of these patients. Patients’ willingness to comply with this follow-up regimen is an important factor in selecting patients for this approach, and should be considered when deciding between endoscopic and surgical management. This study is limited by its small sample size, and limited follow-up. We recommend anyone with positive radial margins to undergo repeat endoscopy at 1 month and to have biopsy of the scar to look for residual carcinoma as the radial margin may be difficult to evaluate by pathology due to cautery effect. After negative margins initially or negative biopsy following positive radial margins, patient should undergo endoscopy every 3 months for a year and this may be increased to every 6 months if negative at
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1 year. Although it was a 5-year trial, our median followup was 15.5 months because two patients died from unrelated causes and more patients underwent definitive endoscopic management in the last 2 years of the study. To date, long-term studies of patients undergoing EMR for early esophageal cancer are lacking, and follow-up for these patients is of critical importance. Larger prospective trials with long-term follow-up are required to establish the efficacy of endoscopic management for early esophageal carcinoma. In summary, EMR is an effective, low morbidity procedure for evaluating depth of invasion and treating early esophageal adenocarcinoma. In conjunction with mucosal ablation, this treatment approach spares patients with IMC the morbidity and mortality associated with esophagectomy. Although larger studies are needed to make definitive recommendations, Endoscopic management of IMC appears to be a safe, effective alternative to esophagectomy. Acknowledgments The authors would like to thank Rebecca Dettorre, MA, CCRC, Research Coordinator for the Center for Minimally Invasive Surgery, for her assistance with this project. Disclosures Drs. Huntington, Walker, Meara, Hazey, Melvin, and Perry report no biomedical financial interests or potential conflicts of interest relevant to the subject matter of this manuscript.
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