Visualizing Paneth Cell Metaplasia: A Novel Approach to UC Endoscopic Cancer Surveillance

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by diffuse inflammation extending from the rectum to the proximal colon. Chronic, persistent inflammation of the mucosa increases the risk of cancer development in UC patients. While remarkable advances in medical treatment have reduced the number of surgical cases due to refractory against medical treatments in recent years, the proportion of surgeries performed for cancer development has increased [1]. Endoscopic care, such as disease monitoring and endoscopic submucosal dissection, has become an increasingly important component of the comprehensive management of UC [2], particularly, surveillance for UC‐associated neoplasia (UCAN) remains a significant challenge in current endoscopic practice. Despite the widespread adoption of technologies such as high‐definition endoscopy, chromoendoscopy, and image‐enhanced endoscopy (IEE), the detection and precise diagnosis of early‐stage UCAN remains challenging [3]. The primary reason for this lies in the biological characteristics of UC‐associated carcinogenesis. Specifically, UCAN develops against a background of chronically inflamed and remodeled mucosa, often presenting as flat lesions with indistinct borders, making detection difficult, even for endoscopy experts [4].

In this issue of Digestive Endoscopy, Tomioka et al. [5] reported on the ultra‐low concentration crystal violet staining method, crystal violet staining for colitis‐associated neoplasia (CV‐SCAN), developed to endoscopically visualize Paneth cell metaplasia (PCM). This study represents an attempt to endoscopically capture the “precancerous mucosal field” beyond the detection of individual neoplastic lesions, which aligns well with the current understanding of UCAN pathogenesis. The value of this research lies not in prompting immediate clinical implementation but in expanding the concept of endoscopic surveillance.

UCAN arises through a dysplasia–carcinoma sequence with distinct molecular mechanisms from sporadic colorectal cancer through continuous inflammation. UCAN follows a molecularly distinct pathway, leading to poorly differentiated adenocarcinoma, and often arises within a multifocal precancerous mucosal background, making early detection critically important. In addition, early molecular alterations, such as p53 abnormalities, can occur even in endoscopically normal mucosa. Therefore, the diagnosis of early lesions in UCAN relies on the immunohistochemical evaluation of markers such as p53 and Ki‐67.

Paneth cells are occasionally found in the cecum and proximal colon. However, the presence of Paneth cells in the distal colon is common in UC, indicating a long history of inflammation [6]. PCM has been noted as an indicator of mucosal remodeling due to chronic inflammation, associated with disease duration and cancer risk [7]; however, its assessment has been limited to histopathology until now. A notable aspect of this study is its translation of the pathological concept of distal PCM into an endoscopically detectable finding.

Several CV‐SCAN‐positive areas are indistinguishable from the surrounding mucosa under white‐light endoscopy, suggesting that they may capture biological changes preceding morphological alterations. This is significant for the readers of this journal as an attempt to integrate molecular pathological findings into real‐time endoscopic diagnosis.

CV‐SCAN is also relatively simple to perform. It requires only spraying an ultra‐low concentration (0.006%) of crystal violet using a spray catheter, without the need for special pretreatment, mucus removal, or prolonged staining. The staining appeared immediately and exhibited clear boundaries, indicating its potential for application in routine clinical practice. Furthermore, the authors emphasize the importance of both the presence or absence of staining and the interpretation of staining patterns. The distinction between uniform staining (CV‐Paneth) corresponding to PCM and non‐uniform staining (CV‐neoplasia) corresponding to neoplastic lesions aligns with conventional concepts in chromoendoscopy diagnosis and can be considered a mature diagnostic perspective.

Another noteworthy aspect of this study is the incorporation of molecular biological analysis. CV‐SCAN‐positive areas, increased expression of Paneth cell‐specific genes and small intestine‐related genes, and decreased expression of colon‐specific genes such as SATB2 were demonstrated. These findings support the notion that this is not merely a nonspecific reaction but rather captures biologically meaningful mucosal changes indicative of small intestinal metaplasia. Furthermore, increased expression of IL17RC, which is implicated in UCAN pathogenesis, was also observed, supporting the possibility that CV‐SCAN‐positive mucosa represents a precancerous state. However, molecular analyses were performed on a limited number of specimens, and caution is warranted regarding generalizability.

CV‐SCAN technology holds the potential to significantly transform surveillance strategies for UC patients. CV‐SCAN positive areas reflected cumulative inflammatory alterations and were significantly associated with the history of UCAN, even during remission periods where conventional white‐light endoscopy showed no abnormalities.

This finding implies that changes in mucosal tissue structure due to chronic long‐standing inflammation can be visualized. Ultra‐high definition endoscopy is highly effective for assessing structural atypia in targeted areas [7]. However, its major limitation is the inability to efficiently identify lesions. While the utility of targeted biopsies has been demonstrated [8], CV‐SCAN may further improve their accuracy. CV‐SCAN may identify molecularly distinct lesions that are difficult to recognize using conventional white‐light endoscopy. Notably, the CV‐N pattern demonstrated high sensitivity (95.2%) and specificity (80.0%) for detecting low‐grade dysplasia (LGD), including lesions that are inconspicuous under white‐light endoscopy.

Consequently, CV‐SCAN may enable carcinogenic risk stratification based on endoscopic findings and the optimization of surveillance intervals according to this stratification, which has been difficult with previous methods. Furthermore, it is expected to improve the accuracy of assessing the presence of multiple lesions when determining indications for endoscopic treatment, which has advanced in recent years, and to promote the optimization of surveillance for endoscopic resection [9].

Nevertheless, important questions remain. The study is limited by its single‐center design, left‐sided application, and small number of UCAN cases. Although the incidence of UCAN is low in the right‐sided colon, the usefulness of this method for detecting right‐sided precancerous lesions, including serrated dysplasia, remains unclear because PCM can be observed even in normal right‐sided colon. Safety in the clinical application of CV‐SCAN is a critical consideration. Crystal violet has been widely used in chromoendoscopy, but animal studies have reported carcinogenicity with high‐dose, long‐term oral administration [10]. This protocol adopted strict measures to ensure safety. The crystal violet solution used was highly diluted at 0.006%, the application volume was limited to a small amount of approximately 40 mL, and it was confined to the left colon. Under these conditions, no adverse events were observed; however, concerns remain regarding cumulative exposure from repeated procedures. As a recommended practical strategy, CV‐SCAN should be performed initially in each patient. If negative, extending the interval before repeat procedures would minimize cumulative exposure while maintaining the diagnostic benefits. In accordance with current recommendations, CV‐SCAN should be used only in selected high‐risk patients, administered at the lowest effective dose, and performed under appropriate ethical supervision. Furthermore, the development of safer contrast agents is one of the important future issues.

On the other hand, remarkable progress has been made in IEE and in the evaluation of UC mucosal lesions using AI. With current technology, PCM cannot be detected based solely on endoscopic image findings. However, if it becomes possible to detect mucosal areas with PCM and diagnose subtle epithelial structural changes and vascular abnormalities through the combination of IEE and AI, we can anticipate moving away from staining techniques. If precancerous lesions can be detected without a staining solution, it will not only reduce the burden of surveillance endoscopy but also eliminate the need to consider the carcinogenic risk of the staining agents.

CV‐SCAN is an innovative technique that visualizes precancerous changes in UC patients and identifies molecularly distinct lesions difficult to detect with conventional endoscopic techniques. By enhancing risk stratification and implementing targeted surveillance, both clinical utility and safety can be achieved through patient selection and adherence to appropriate dose limitations.

Author Contributions

H.S.: conceptualization, article collection, data interpretation, and writing the original draft.

Funding

The author has nothing to report.

Ethics Statement

The author has nothing to report.

Conflicts of Interest

Hirotake Sakuraba is an associate editor of Digestive Endoscopy.

Linked Articles

This article is linked with Tomioka et al. To see this article, visit http://doi.org/10.1111/den.70096.