Laterally spreading tumor through the magnifying glass: we only see what we know

The practice of high-quality colonoscopy has changed the natural history of colorectal cancer (CRC), with CRC and its precursors being diagnosed at earlier stages at which curative endoscopic resection is the preferred therapy. Both CRC incidence and mortality continue to decline. Assuming such favorable time trends, why, then, has the post-colonoscopy CRC rate remained unchanged [1] [2]? One reason is that approximately one in five post-colonoscopy CRCs still results from incomplete polyp resection [3]. A subgroup of precursor lesions of CRC includes colorectal laterally spreading tumors (LSTs), which are associated with a high risk of malignancy. Performing endotherapy on these lesions is technically challenging, leading to incomplete resection and local recurrence. LSTs have only recently been recognized in Western countries [4] [5], and many questions on their endoscopic characteristics, histological diagnosis, and optimal treatment remain unanswered [6].

The study by Yamada et al. [7] from the National Cancer Center Hospital, Tokyo, Japan, in this issue of Endoscopy adds to the understanding of LSTs and offers some important clinical lessons. Detailed colonoscopic examination of LSTs predicts the depth of submucosal invasion and should be the first step towards their therapy. The authors describe endoscopic predictors of deep submucosal invasion in a cohort of 822 colorectal LSTs, resected en bloc, by endoscopic submucosal dissection (ESD) or surgery. Because piecemeal endoscopic mucosal resection (EMR) hinders accurate histopathological diagnosis, LSTs that were resected piecemeal were not included. Results showed that 19 % (95 %CI 16 – 23) of the granular type LSTs and 39 % (95 %CI 34 – 44) of the nongranular type LSTs were found to contain submucosal invasion, which was deep in 79 % and 54 % of cases, respectively. Independent predictors for deep submucosal invasion were the presence of a nodule larger than 10 mm, a circumscribed deep depression, and an invasive pit pattern. Because both granular type LSTs with a large nodule or depression and nongranular type LSTs are associated with a substantial risk of submucosal and multifocal invasion, the authors suggest that en bloc endoscopic resection should be the preferred therapy.

For a long time, EMR techniques and surgery were considered the first-line therapy options for treatment of large (> 10 mm) nonpolypoid colorectal neoplasms, also known as LSTs [8]. EMR is the therapy of choice for the resection of colorectal adenomas with intramucosal or superficial submucosal invasion (< 1000 μm from the lowest muscularis mucosae to the deepest area of invasion), because they are associated with a very low risk of lymph node metastasis. EMR is, however, limited by the size of the lesion. To avoid complications, LSTs larger than 20 mm are preferably resected in pieces. However, piecemeal resection is associated with a higher rate of incomplete resection and local recurrence than en bloc resection: 20 % vs. 3 %, respectively [9]. ESD has therefore emerged as a minimally invasive endoscopic technique for the resection of large LSTs en bloc [10]. ESD provides larger specimens, higher complete resection rates, and allows for more precise histopathological analysis than (piecemeal) EMR.

An important message of this study is that beyond technical skills, successful resection of LSTs warrants additional cognitive skills and strategic diligence. The rate of R0 resection (i. e. en bloc resection resulting in tumor-free horizontal and vertical cut margins) was similar in the ESD and surgery groups (96 % vs. 99 %), underlining outstanding technical performance. The authors used a standard endoscopy protocol to examine the LSTs in detail. After lesion identification with white-light colonoscopy, chromoendoscopy was applied using indigo carmine dye spraying to enhance visualization of the lesion margins. Relative size and endoscopic aspect (i. e. granular vs. nongranular type) were assessed. Then, magnifying chromoendoscopy was applied to screen for areas with invasive pit patterns. For example, when chromoendoscopy using indigo carmine identified a type VI (irregular) or VN (nonstructural) pit pattern, a crystal violet solution (0.05 %) that stains cell nuclei was additionally applied to enhance the visualization of the epithelial pit pattern [7]. If a noninvasive pit pattern was diagnosed, then LST was assumed to be an adenoma, or intramucosal cancer (Tis) or superficial submucosal invasive carcinoma (T1a cancer, i. e. submucosal invasion depth < 1000 μm) with a very low risk of lymph node metastasis, and ESD was performed. When deep submucosal invasive cancer (T1b cancer, i. e. submucosal invasion depth > 1000 μm) was suspected, surgery was recommended. Biopsies were only taken to confirm an invasive cancer before referral to surgery.

The authors built upon previous Japanese experience correlating macroscopic appearance of LSTs with the depth of submucosal invasion [8] [11] [12]. Pit patterns were classified into 8 types: I, II, IIIL, IIIS, IV, VI (noninvasive), VI (invasive), and VN, as described previously [8] [12] [13]. Specifically, magnifying chromoendoscopy using crystal violet staining was applied to distinguish between type VI (invasive) and type VI (noninvasive) pit pattern. Type VI (noninvasive) pit pattern was defined as a poorly demarcated area with irregular crypts. By contrast, type VI (invasive) pit pattern was defined as a well-demarcated area with irregular and distorted crypts.

The paper presents one of the largest and most comprehensive LST cohorts reported by world leaders in advanced endoscopic resection techniques. The real-life practice lags behind. [Fig. 1] proposes a pathway for implementation of LST endotherapy in colonoscopy practice. Therapeutic endoscopists should specifically pay attention to case selection in order to distinguish LSTs that can be endoscopically resected from those requiring surgery, and LSTs for which en bloc (instead of piecemeal) resection is the optimal therapy. In most cases, an additional endoscopic examination should be performed to decide on the optimal treatment plan. Furthermore, access to referral centers with a large volume of therapeutic procedures (i. e. one referral center per one million adults) should be guaranteed. Endoscopic resection should be provided in a timely fashion [6]. Learning the chromoendoscopy technique, from equipment to materials and a standard protocol requires a systematic approach [14]. While recognition of a large nodule or a depressed area is not complicated, prediction of the depth of submucosal invasion with high confidence is challenging. Magnifying colonoscopes and additional training are required. Some very basic principles should be recalled: image-enhanced endoscopy entails not only image enhancement but also contrast enhancement in order to highlight mucosal detail. That being said, besides high-definition colonoscopes, selective chromoendoscopy is mandatory using a contrast agent or digital techniques to predict submucosal invasion [15]. Although such macroscopic assessment will never be perfect, detailed characterization of the lesion size, endoscopic subtype, and epithelial pit pattern refines the diagnosis and facilitates optimal therapy. In the current study, the endoscopists predicted deep submucosal invasion with high accuracy (approximately 90 %).

Fig. 1 Proposed pathway for the implementation of endotherapy for laterally spreading tumors in colonoscopy practice. EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.

Unarguably, the learning of advanced endoscopic resection techniques is a process: proficiency in EMR techniques must be achieved before ESD training can start. Then, additional technical skills can be developed, using video training, simulators, animal models, and training with experts. Detailed photodocumentation is a measure of quality performance.

Next, high-quality assessment of histopathology should be provided. In the study by Yamada, pathologists were trained to assess the depth of submucosal invasion. Unlike routine practice, resected specimens were sectioned at intervals of 2 – 3 mm instead of 5 mm in order to optimize the diagnostic yield. Case revision and dialog between endoscopist and pathologist will refine the diagnosis and improve outcomes. Clearly, training and credentialing in advanced endoscopic resection techniques should include additional pathology training. A standard protocol is required for macroscopic handling of the resection specimen and histological work-up. 

Ultimately, key performance indicators should be monitored. There are no standard quality metrics for ESD performance, but proposed candidates should be both process and outcome oriented (i. e. complication rate, proportion of patients with incomplete resection, and proportion of those in whom surgery could not be avoided). Reimbursement incentives for the additional time and difficulty of the procedure would encourage adoption of ESD in clinical practice. Furthermore, multicenter studies should address the long-term outcomes after endoscopic resection of LSTs (i. e. post-colonoscopy CRC rate, cost-effectiveness of endoscopic resection vs. surgery, and quality of life).

The cornerstone of best colonoscopy practice is nothing more than cultivating knowledge, eagerness, and persistence to acquire new skills, and to maintain and improve them. The study by Yamada et al. reframes our thinking about endoscopic and histological diagnosis of LSTs in the colon and rectum as a showcase towards their evidence-based treatment.

• References

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