En bloc resection: does it really matter?

Gastrointestinal endoscopy has increasingly become a therapeutic procedure rather than a solely diagnostic one. In the field of early neoplasia of the digestive tract, therapeutic endoscopy started many years ago when polypectomies of pedunculated colonic adenomas became widely practiced. In current practice, precancerous lesions throughout the digestive tract, and even early invasive cancers, are removed endoscopically.

Traditionally, endoscopic resection of upper gastrointestinal neoplasia was performed using the endoscopic resection cap technique, which was introduced by Inoue in 1993 [1], and later using ligate-and-cut techniques such as the multiband mucosectomy [2]. Endoscopic resection with any cap-based technique, however, is restricted in terms of the maximum size of a single resection. With the current cap-based resection devices, lesions of 2 cm or less can be resected en bloc, whereas larger lesions require a piecemeal resection technique. With the Japanese at the frontline, an alternative resection technique that enables en bloc resection of lesions of any size has been developed – the endoscopic submucosal dissection (ESD) technique.

Endoscopic mucosal resection (EMR) is used as the primary resection tool in Western countries, whereas ESD is mostly practiced in Eastern countries. This situation is partly the result of differences in incidences of precancerous lesions: in Japan, the high incidence of gastric cancer and the institution of a nationwide screening program for early gastric cancer have contributed to the development of the ESD technique and its dissemination throughout the gastrointestinal community. In contrast, in the West, most early neoplastic lesions are found in the colon and in Barrett’s esophagus, organs in which ESD is particularly difficult. However, ESD is being increasingly practiced in the West, with acceptable outcomes in specialized centers [3] [4] [5].

ESD is generally considered to be a complex and potentially dangerous endoscopic modality, requiring a high level of endoscopic skill. Even in expert hands, ESD carries a non-negligible risk of perforation: large series on ESD in early gastric cancer report perforation rates of 1.2 % – 5.2 % [6], and in colonic ESD these rates are even higher [7] [8]. ESD requires dedicated training, and the learning curve is known to be long. Given the complexity of ESD, the long learning curve, and the relatively high risk of complications, why do we still embark on ESD and subject our patients to potential hazards such as perforation? What makes ESD a better treatment option for early gastrointestinal neoplasia than EMR?

Obviously, the answer lies in the more controlled way of lesion dissection compared with EMR, and – more importantly – the possibility of en bloc resection of larger lesions. En bloc resection is one of the well-adopted dogmas in oncology; many oncologists will support the notion that cancer should always be resected en bloc. The key question here, however, is whether the benefits of en bloc resection justify the associated risks of ESD, in the setting of endoscopic treatment of early neoplasia. There are certainly many studies reporting on the higher incidence of local recurrence after piecemeal EMR compared with ESD [9]. However, these series are all retrospective case series comparing EMR of lesions in an early time period with ESD performed in later years, and these series are highly subject to cohort bias. For instance, over time, the experience of the endoscopist in the delineation of lesions will increase, simply due to more exposure to early neoplastic lesions. In addition, over time, the optical resolution of the endoscopes has improved dramatically, which has also improved the endoscopist’s ability to delineate a lesion accurately. The only way to avoid this type of bias would be to perform a randomized controlled trial, prospectively comparing ESD with piecemeal EMR; no such studies exist. In addition, it is important to keep in mind that local recurrence is only a surrogate parameter, whereas the real interest for patients is the disease-free survival. And even if the local recurrence rates are higher after piecemeal EMR than after ESD – and I do believe they are – what is the clinical relevance of this advantage of ESD over EMR when local recurrence can potentially be cured by additional endoscopic resection anyway?

Let’s come back to the most important potential conceptual advantage of ESD over EMR: the ability to perform an en bloc resection for lesions of any size. What are the advantages of en bloc resection over piecemeal resection? First, en bloc resection enables a definite assessment of the lateral resection margins, especially in countries where piecemeal resection specimens are not reconstructed before sending the specimens to the histopathologist, as is usually the case in the West. In the current issue of Endoscopy, Sekiguchi et al. add one important argument to the importance of appropriate assessment of the lateral resection margin in early gastric cancer [10]. In case of a tumor-positive lateral resection margin, the length of the tumor-positive lateral resection margin was predictive for local tumor recurrence: a tumor-positive lateral resection margin of more than 5 mm was associated with a local recurrence rate of up to 40 %, compared with only 6 % for positive lateral margins of 5 mm or less. With these data in mind, one could argue for an early repeat resection in case of long tumor-positive lateral margins whereas a conservative approach would suffice in cases of shorter tumor-positive margins.

Second, en bloc resection might facilitate the proper judgment of other relevant histopathological parameters, such as depth of tumor invasion and vertical resection margins. However, the relevance of lateral and deeper resection margins and other histopathological parameters, and the more controlled way of dissection that is possible with ESD compared with EMR, might be different for different tumor types or different organs. In addition to early gastric cancer, EMR and ESD are performed for early esophageal squamous cell cancer (ESSC), for Barrett’s-related neoplasia, and for colorectal neoplasia. These lesions all have their own characteristics and their own tumor biology.

In early ESSC, spread of tumor cells to adjacent lymph nodes occurs in a much earlier phase than in Barrett’s cancer, early gastric cancer, or colorectal cancer. Infiltration into the muscularis mucosae is already associated with a significant increase in lymph node metastasis, and submucosal invasion, even minimal submucosal invasion, is considered an indication for surgical resection or chemoradiation. Therefore, in early ESSC, en bloc resection might be of particular value for the most optimal assessment of depth of invasion. In addition, the squamous esophagus harbors epithelial glandular structures that are located in the submucosa. Anecdotal reports mention the possibility of epithelial dysplasia reaching into these ducts. Dysplasia of epithelium of these mucosal glands should be considered as mucosal dysplasia but can easily be mistaken for submucosal tumor infiltration in cases of a piecemeal resection that has cut through the neck of such a gland.

The clinical behavior of early Barrett’s neoplasia differs considerably from that of early ESSC. In ESSC, invasion into the muscularis mucosae is already associated with the occurrence of lymph node metastasis, whereas in Barrett’s-related early neoplasia infiltration into the muscularis mucosae, and even limited submucosal invasion, carry a low risk of tumor-positive lymph nodes [11]. In addition, Barrett’s cancer often arises in a field of dysplastic Barrett’s epithelium, and therefore the lateral margins are much less important than in ESSC or early gastric cancer. Indeed, even with ESD, an R0 resection is relatively uncommon [12]. Therefore, excision of early Barrett’s cancer is generally considered an indication for ablation of all Barrett’s epithelium, thereby dealing with lateral resection margins positive for dysplasia. Large series of endoscopic treatment with (piecemeal) EMR, with or without additional ablation of the remaining Barrett’s epithelium, show a very high disease-free survival [13] [14], with an almost negligible perforation risk in expert hands [15]. Therefore, in Barrett’s-related neoplasia, the additional value of en bloc resection by means of ESD will possibly not counterbalance the downside of ESD in terms of perforation risk.

In colorectal sessile lesions, another lesion-related factor comes into play. Within laterally spreading tumors (LSTs), considerable differences in “biological behavior” exist between granular-type (LST-G) and nongranular-type (LST-NG) lesions. In LST-G, the incidence of malignancy per se and the incidence of submucosal invasion is much lower than for LST-NG lesions [16], with the so-called uniform LST-G having the lowest risk [17]. Most colorectal flat lesions, at least in the West, have a granular endoscopic type. In LST-G, the advantage of en bloc resection with the associated superior histopathological evaluation is therefore probably much less relevant. In addition, series have shown that although the early local recurrence rate of piecemeal EMR of rectal lesions is as high as 6 % – 20 %, repeat endoscopic resection of residual adenomatous tissue after 3 – 6 months is usually possible [18] [19].

What could be learned from all this? The general lesson here should be that the choice of EMR or ESD should be weighed carefully, and the decision for a specific resection technique should be influenced by the involved organ, tumor type, and the expertise of the endoscopist. In early ESSC and early gastric cancer, ESD would be the preferred technique in most cases, whereas in Barrett’s-related neoplasia EMR will suffice in the vast majority of patients, with low complication rates and excellent patient outcomes. Only in patients with (deeply) submucosally invading esophageal adenocarcinoma who are unfit for surgery might ESD be preferred, given the ability to control the plane of dissection in order to achieve optimal local tumor control by avoiding irradical vertical resection margins. In colorectal lesions, ESD should probably be reserved for LST-NG lesions, or depressed lesions with a high suspicion of invasive cancer. Given these restrictions in indication, only a limited number of endoscopists who are proficient in ESD will be required in the West, and centers of expertise should be established, to which general endoscopists may refer patients. It will be the responsibility of endoscopists running these referral centers to refine ESD technology, making it easier, safer, and faster, and to further unravel the true value of en bloc resection for all different types of early neoplasia of the digestive tract.

• References

• 1 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
• 2 Soehendra N, Seewald S, Groth S et al. Use of modified multiband ligator facilitates circumferential EMR in Barrett’s esophagus. Gastrointest Endosc 2006; 63: 847-852
• 3 Schumacher B, Charton JP, Nordmann T et al. Endoscopic submucosal dissection of early gastric neoplasia with a water jet-assisted knife: a Western, single-center experience. Gastrointest Endosc 2012; 75: 1166-1174
• 4 Repici A, Hassan C, Pagano N et al. High efficacy of endoscopic submucosal dissection for rectal laterally spreading tumors larger than 3 cm. Gastrointest Endosc 2013; 77: 96-101
• 5 Pimentel-Nunes P, Mourão F, Veloso N et al. Long-term follow-up after endoscopic resection for gastric superficial neoplastic lesions in Portugal. Endoscopy 2014; In press
• 6 Oda I, Suzuki H, Nonaka S et al. Complications of gastric endoscopic submucosal dissection. Dig Endosc 2013; 25 (Suppl. 01) 71-78
• 7 Saito Y, Kawano H, Takeuchi Y et al. Current status of colorectal endoscopic submucosal dissection in Japan and other Asian countries: progressing towards technical standardization. Dig Endosc 2012; 24 (Suppl. 01) 67-72
• 8 Lee EJ, Lee JB, Lee SH et al. Endoscopic submucosal dissection for colorectal tumors – 1,000 colorectal ESD cases: one specialized institute’s experiences. Surg Endosc 2013; 27: 31-39
• 9 Cao Y, Liao C, Tan A et al. Meta-analysis of endoscopic submucosal dissection versus endoscopic mucosal resection for tumors of the gastrointestinal tract. Endoscopy 2009; 41: 751-757
• 10 Sekiguchi M, Suzuki H, Oda I et al. Risk of recurrent gastric cancer after endoscopic resection with a positive lateral margin. Endoscopy 2014; 46: 273-278
• 11 Alvarez-Herrero L, Pouw RE, Van Vilsteren FGI et al. Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens. Endoscopy 2010; 42: 1030-1036
• 12 Neuhaus H, Terheggen G, Rutz EM et al. Endoscopic submucosal dissection plus radiofrequency ablation of neoplastic Barrett’s esophagus. Endoscopy 2012; 44: 1105-1113
• 13 Phoa KN, Pouw RE, van Vilsteren FG et al. Remission of Barrett’s esophagus with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology 2013; 145: 96-104
• 14 Pech O, May A, Manner H et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology 2014; 146: 652-660.e1
• 15 Alvarez-Herrero L, Pouw RE, van Vilsteren FG et al. Safety and efficacy of multiband mucosectomy in 1060 resections in Barrett’s esophagus. Endoscopy 2011; 43: 177-183
• 16 Uraoka T, Saito Y, Matsuda T et al. Endoscopic indications for endoscopic mucosal resection of laterally spreading tumours in the colorectum. Gut 2006; 55: 1592-1597
• 17 Imai K, Hotta K, Yamaguchi Y et al. Should laterally spreading tumors granular type be resected en bloc in endoscopic resections?. Surg Endosc 2014; [Epub ahead of print] DOI: 10.1007/s00464-014-3449-2.
• 18 Barendse RM, van den Broek FJ, Dekker E et al. Systematic review of endoscopic mucosal resection versus transanal endoscopic microsurgery for large rectal adenomas. Endoscopy 2011; 43: 941-949
• 19 Terasaki M, Tanaka S, Oka S et al. Clinical outcomes of endoscopic submucosal dissection and endoscopic mucosal resection for laterally spreading tumors larger than 20 mm. J Gastroenterol Hepatol 2012; 27: 734-740