Ulcerative colitis (UC) patients are well known to carry a higher risk of developing colorectal dysplasia and cancer. These lesions develop from chronic inflamed mucosa and progress through dysplasia to adenocarcinoma, termed the ‘inflammation-dysplasia-carcinoma sequence’ (1,2). In clinical settings, early detection of the neoplasia is the key to improving the prognosis just as in most cancers. However, UC-associated neoplasias often develop in flat or mildly elevated lesions and are distributed multifocally within an area of intestinal inflammation, making it hard to detect them in early phase during colonoscopy (3–5).

The benefit of neoplasia surveillance colonoscopy in UC has been established. At present, the recommended surveillance strategy involves frequent random biopsies aimed at detecting dysplasia/cancer (6–9). However, this method is limited by sampling error, requires considerable time and cost, and has resulted in only a modest reduction in cancer incidence and mortality (10). Previously, the use of a targeting biopsy on conventional white light imaging (WLI), in which tissue specimens are obtained only when endoscopic findings indicate the possibility of neoplasia, thereby yielding a smaller number of samples, has been proposed (11,12). However, it is still controversial whether a targeted biopsy should replace a random biopsy.

Several advanced endoscopic imaging techniques, such as chromoendoscopy (CE) with dye-spraying (13–15), narrowband imaging (NBI) (16,17) and autofluorescence imaging (AFI) (18,19), which provide a more detailed visualization of the mucosa by enhancing morphology and vascularization, have been developed to improve upon the accuracy afforded by conventional WLI. In sporadic colorectal tumors, it has been clearly shown that these imaging techniques facilitate early detection allowing for the removal of the lesions, thus avoiding the need for surgery (13). Advanced endoscopic imaging may also provide better definition and delineation of early stage neoplastic lesions even in UC, increased yield of detection and a decrease in the number of biopsies taken. However, little is known about the role of these techniques in UC-associated neoplastic lesions (20–22).

This pilot study was conducted to analyze the endoscopic characteristics of neoplastic lesions associated with UC using advanced endoscopic imaging techniques. In particular, we validated the role of AFI quantification for the first time.

As shown in Table I, all 11 patients had extensive colitis with the median disease duration of 14 years. The background mucosal status of all patients was in the remission stage according to the Mayo endoscopic score (0 or 1 point).

Clinicopathological features of the neoplastic lesion are presented in Fig. 1. All of the 15 neoplastic lesions were macroscopically identified, including 8 HGD and 7 cancer. The lesion was mostly located in the distal colon (13/15, 86.7%) with the mean size of 8.6 mm. The shape was protruding in 46.7% (7/15), flat elevated in 40.0% (6/15) and flat in 13.3% (2/15). The color was red in 60.0% (9/15), same colored in 33.3% (5/15) and discolored in 6.7% (1/15).

We next analyzed the macroscopic features of the neoplastic lesions using advanced endoscopic imaging techniques. On CE, the lesion was classified into pit patterns type I to V with type I and II representing non-neoplastic pattern and type III, IV and V representing neoplastic pattern. Of 15 lesions examined in this study, 13 lesions (86.7%) showed neoplastic pit patterns in the order of type IV (branch- or gyrus-like crypts) > type III_L (large tubular or roundish crypts) > type V_I (irregular crypts) (Fig. 2). Two of the lesions could not be classified into pit patterns and the pattern was thus regarded as unclassified.

On NBI, the lesion was classified into type I to III capillary patterns with type I representing a non-neoplasm, type II representing adenoma and type III (subdivided into IIIa and IIIb) indicating cancer. Of the 11 lesions examined, one lesion (0.9%) was identified as type I (faintly visible microvessels surrounding the pits), 3 lesions (27.3%) as type II (elongated and increased thicker vessels surrounding the pits) and 7 lesions (63.6%) as type IIIa (increased thick vessels unevenly sized with branching and curtailed irregularity) (Fig. 3).

On AFI, in general the non-neoplastic lesions appear green and neoplastic lesions appear purple. In the present study, information was available for 8 lesions from a total of 15 lesions because 7 lesions were excluded due to insufficient bowel preparation which may disrupt autofluorescence. Of these, 5 lesions (62.5%) were colored green and 3 lesions (37.5%) colored purple (Fig. 4).

To quantify AFI intensity, the G/R ratio was determined for each lesion after adjustments for the surrounding mucosal values. Of note, the G/R ratio was significantly lower in the neoplastic area than the adjacent non-neoplastic area involved in UC (p=0.00014) and the non-neoplastic area uninvolved in UC (p=0.00651) (Fig. 5). The G/R ratio was not associated with the size or histological type of the lesion. Fig. 6 exemplifies the endoscopic and histological images of colorectal cancer in one patient with long-standing extensive colitis.

Currently, several advanced endoscopic imaging techniques have been attempted to improve the limitation of conventional endoscopy (13–19). In this pilot study, we analyzed the endoscopic characteristics of neoplastic lesions associated with UC using these advanced techniques, including CE, NBI and AFI.

A better understanding of cancer risk factors may allow endoscopic resources to be more focused on patients at higher risk. It is well established that the risk for colorectal cancer increases with the duration (more than 7 years) and anatomic extent of UC (1). In line with this established observation, our study showed that neoplastic lesion tended to develop in patients with a long history of extensive colitis. Another risk, a history of primary sclerosing cholangitis, was not observed in this study probably due to the small number of the patients in this study.

The neoplastic lesions in our study were predominantly located in the distal colon (86.7%), appeared protruded (46.7%) or flat elevated (40.0%), and were colored red (60.0%). These findings are consistent with previous reports describing how dysplasia and early cancer were characterized by low protruding or flat mucosa, often associated with redness (29–33).

CE is used to better define the superficial mucosa. CE with dye agents enhances the mucosal detail and permits a more precise characterization. Kudo et al classified the pit patterns into types I to V (24,25). As reported by Sada et al (29), some neoplastic lesions associated with UC have a neoplastic type III_S to III_L or type IV-type pit patterns. In contrast, Hata et al (30,31) reported that type III or IV pit patterns were not observed in some dysplastic lesions. Our study showed that 13 of the 15 dysplasia/cancer lesions (86.7%) were representative of the neoplastic pit pattern, suggesting that CE is helpful to detect and discriminate neoplastic lesions in UC although coexisting inflammatory changes may modify the mucosal detail.

NBI is an endoscopy system, which enables a clear visualization of the microvasculature of colorectal lesions (26,27). Previous investigations have shown that NBI is effective in distinguishing neoplastic colorectal lesions in sporadic settings (16,17). Our present study showed that 7 of the 11 dysplasia/cancer lesions (63.6%) were representative of the neoplastic capillary pattern. Together with the results from recent randomized trials demonstrating that NBI was a reasonable alternative to CE (34–37), NBI is one of the available modalities to distinguish neoplastic lesion associated with UC.

AFI is a novel technique that is based on the fact that tissues exhibit fluorescence when exposed to ultraviolet (<400 nm) or shorter waveband visible light (mostly blue) (19). Recent investigations have demonstrated the usefulness of AFI in discriminating colorectal neoplasia in sporadic setting (18). However, the available data on AFI for UC surveillance is sparse.

On AFI, neoplastic tissue is visible as a purple lesion on a green background fluorescence of normal colonic tissue (18,19). Our study showed that a purple lesion was observed only in 37.5% of the neoplastic lesions, indicating that the qualitative analysis of the AFI color, green or purple, is not so helpful for detecting neoplasia associated with UC. One possible explanation is that the AFI color is altered according to the grade of inflammation (38,39). This is probably due to several factors that modify the AFI color both in inflammation and neoplasia, such as tissue architecture, light absorption and scattering properties, the biochemical content, or metabolic status of the tissue (40,41).

Inomata et al demonstrated that quantitative analysis of the AFI color using the G/R ratio was effective in distinguishing sporadic neoplastic lesions (28). The most important observation in the present study is that we found for the first time that the G/R ratio is helpful in discriminating dysplasia/cancer in UC as well. The G/R ratio was not associated with the lesion size or histological type, supporting the idea that this index is available even for smaller lesions. Quantitative AFI, rather than qualitative, has therefore the potential for detection of early neoplastic changes in UC. The field of AFI is still young and multiple questions remain unanswered. However, our results in AFF quantification are very promising but as we gain more experience, these will be better defined, hence the need for further investigations.

There are several limitations to our study. First, this was a single-center analysis involving only a limited number of patients with a retrospective design. Second, because of a retrospective design, the diagnosis in the study subjects had been established. Although advanced endoscopic imaging such as CE, NBI and AFI look very promising, large-scale, prospective study will be needed to assess their place in the surveillance of UC patients.

In conclusion, this pilot study suggested that endoscopic analysis based on advanced imaging, in particular AFI quantitation, is helpful to detect early stage neoplastic lesions in long standing UC.