Key points

Introduction

Colorectal cancer (CRC) can be considered a heterogenous disease appearing in various clinical contexts, such as sporadically, in those with an inherited predisposition, or in chronic inflammatory processes of the colon such as inflammatory bowel disease (IBD).

There are multiple molecular pathways that can lead to CRC, reviewed in the article Colorectal Neoplasia Pathways: State-of-the-Art by Ijspeert and colleagues elsewhere in this issue. Adenomatous polyps undergo sporadic accumulation of genetic mutations in multiple molecular pathways, including the adenomatous polyposis coli tumor suppressor gene and DNA mismatch repair genes, which can lead to mutations in the KRAS oncogene and p53 suppressor gene. Sessile serrated adenomas/polyps develop into CRC via a separate molecular pathway involving BRAF mutations and DNA methylation. Recent data suggest that traditional serrated adenomas develop through a pathway driven by epithelial over expression of the bone morphogenic protein antagonist GREM1.

Hereditary or familial syndromes give rise to approximately 3% of cases of CRC. The most common is hereditary nonpolypsis CRC or the Lynch syndrome, where a germline mutation in DNA mismatch repair genes occurs leading to microsatellite instability. The less well-recognized serrated polyposis syndrome is characterized by multiple serrated polyps, defined as patients with more than 20 serrated polyps throughout the colon or 5 or more serrated polyps proximal to the sigmoid with 2 or more that are at least 10 mm in size. Other genetic syndromes are either less common or produce so many polyps that advanced endoscopic imaging is not needed, for example, in familial adenomatous polyposis.

IBD has long been recognized to be associated with CRC, related to the carcinogenic effect of chronic inflammation combined with a genetic predisposition. A meta-analysis has estimated the cumulative probability of developing CRC in any patient, 30 years after a diagnosis of ulcerative colitis, at 18% ; however, population-based studies suggest that for patients with IBD overall, the risk may in fact be minimally elevated. There are no large studies confirming that surveillance reduces the mortality of ulcerative colitis–associated CRC. However, the benefit of continued surveillance has been described and it remains recommended practice in all international guidelines, with increasing focus on risk stratification to target efforts on higher risk patients.

Recognition of lesions with malignant potential is crucial, because detection and early removal of polyps reduces CRC mortality compared with population risk estimates. No randomised studies for colonoscopy for CRC prevention are available; however, a meta-analysis looking at 4 randomised, controlled trials and 10 observational studies found that flexible sigmoidoscopy for population screening showed a reduction in CRC rates in the distal colon. Variation in adenoma detection correlates with the incidence of postcolonoscopy CRC and death from CRC. Current white light techniques for colonoscopic detection of polyps and neoplasia yield a high miss rate of up to 22% of all adenomas and 2% to 6% of advanced colorectal adenomas and cancers.

It is, therefore, imperative to maximize polyp detection rates and to avoid missing polyps to maximize cancer prevention and minimize the risk of postcolonoscopy CRCs. Missed polyps and subsequent cancers can arise through suboptimal mucosal visualization, failure of complete polyp resection, or failed polyp detection.

In this review, we assess the potential benefits of additional electronic imaging above and beyond standard white light to improve polyp detection at colonoscopy.

Introduction

Colorectal cancer (CRC) can be considered a heterogenous disease appearing in various clinical contexts, such as sporadically, in those with an inherited predisposition, or in chronic inflammatory processes of the colon such as inflammatory bowel disease (IBD).

There are multiple molecular pathways that can lead to CRC, reviewed in the article Colorectal Neoplasia Pathways: State-of-the-Art by Ijspeert and colleagues elsewhere in this issue. Adenomatous polyps undergo sporadic accumulation of genetic mutations in multiple molecular pathways, including the adenomatous polyposis coli tumor suppressor gene and DNA mismatch repair genes, which can lead to mutations in the KRAS oncogene and p53 suppressor gene. Sessile serrated adenomas/polyps develop into CRC via a separate molecular pathway involving BRAF mutations and DNA methylation. Recent data suggest that traditional serrated adenomas develop through a pathway driven by epithelial over expression of the bone morphogenic protein antagonist GREM1.

Hereditary or familial syndromes give rise to approximately 3% of cases of CRC. The most common is hereditary nonpolypsis CRC or the Lynch syndrome, where a germline mutation in DNA mismatch repair genes occurs leading to microsatellite instability. The less well-recognized serrated polyposis syndrome is characterized by multiple serrated polyps, defined as patients with more than 20 serrated polyps throughout the colon or 5 or more serrated polyps proximal to the sigmoid with 2 or more that are at least 10 mm in size. Other genetic syndromes are either less common or produce so many polyps that advanced endoscopic imaging is not needed, for example, in familial adenomatous polyposis.

IBD has long been recognized to be associated with CRC, related to the carcinogenic effect of chronic inflammation combined with a genetic predisposition. A meta-analysis has estimated the cumulative probability of developing CRC in any patient, 30 years after a diagnosis of ulcerative colitis, at 18% ; however, population-based studies suggest that for patients with IBD overall, the risk may in fact be minimally elevated. There are no large studies confirming that surveillance reduces the mortality of ulcerative colitis–associated CRC. However, the benefit of continued surveillance has been described and it remains recommended practice in all international guidelines, with increasing focus on risk stratification to target efforts on higher risk patients.

Recognition of lesions with malignant potential is crucial, because detection and early removal of polyps reduces CRC mortality compared with population risk estimates. No randomised studies for colonoscopy for CRC prevention are available; however, a meta-analysis looking at 4 randomised, controlled trials and 10 observational studies found that flexible sigmoidoscopy for population screening showed a reduction in CRC rates in the distal colon. Variation in adenoma detection correlates with the incidence of postcolonoscopy CRC and death from CRC. Current white light techniques for colonoscopic detection of polyps and neoplasia yield a high miss rate of up to 22% of all adenomas and 2% to 6% of advanced colorectal adenomas and cancers.

It is, therefore, imperative to maximize polyp detection rates and to avoid missing polyps to maximize cancer prevention and minimize the risk of postcolonoscopy CRCs. Missed polyps and subsequent cancers can arise through suboptimal mucosal visualization, failure of complete polyp resection, or failed polyp detection.

In this review, we assess the potential benefits of additional electronic imaging above and beyond standard white light to improve polyp detection at colonoscopy.

History of colonic polyp detection

The ability to reliably detect subcentimeter polyps is a relatively new phenomenon that has come with the advent of increasingly sophisticated endoscopic equipment. Before the 1950s, barium radiographic studies and rigid sigmoidoscopy were used for investigation of the colon. Flexible endoscopic visualization of the mucosa of the gastrointestinal tract was made possible by the development of a coherent optical fiber bundle by Hopkins and Kapany. This led to the development of the first flexible gastroscope “fiberscope” reported in 1958, which was developed commercially by 1960. Combined with the use of fluoroscopy, endoscope location could be confirmed and correlated with the endoscopic findings. The next major development in endoscopy came when Sivak and Fleischer published findings of a new endoscope where the optical fiber bundle was replaced with an image sensor or charge-coupled device at the tip of the endoscope. This allowed the conversion of the light into electrical charges and reconstruction on a television monitor. By the 1990s, videocolonoscopy had largely replaced fiberoptic colonoscopy and as technology advanced, high-resolution endoscopy (HRE), and most recently high-definition endoscopy with 1080 lines of pixels was introduced in 2005 (see Fig 1 A and 2 A). Nevertheless, polyp miss rates continued to be significant for both adenomas and polyps.

Colonoscopic chromoendoscopy was introduced in the 1970s and involves enhancement of the mucosa by segmentally applying stains, such as methylene blue or indigo carmine. This not only improves localization and characterization of lesions during endoscopy (see Fig. 2 B), but also allows targeted biopsies of enhanced mucosal abnormality improving dysplasia detection in long-standing IBD, as well as increasing detection of neoplastic lesions in average risk subjects. Despite evidence supporting the use of chromoendoscopy, it has not become a widely adopted practice. This low use may be owing to a number of factors, including increased time required, cost, inadequate training, and interobserver variability.

Narrowed Spectrum Endoscopy (Virtual Chromoendoscopy)

Virtual chromoendoscopy may provide an alternative to conventional chromoendoscopy, because it does not require dye spray catheters and the use of dye. Rather, it relies on built-in technologies within the endoscope and processor that uses the innate properties of light to generate a tissue enhanced pseudoimage.

Conventional white light endoscopy (WLE) generates endoscopic images by shining white light (400–700 nm) onto tissue and uses a charge-coupled device to capture reflected light. Specific components of the mucosa and submucosa can be enhanced by manipulating the light reflected and the generated endoscopic images. This maneuver allows for detailed endoscopic examination of the mucosa and any abnormalities, without the need for dye.

Currently there are 3 different systems that enhance the mucosal appearance that are available commercially: (1) narrow band imaging (NBI) by Olympus (Tokyo, Japan), (2) Fuji intelligent color enhancement (FICE) by Fujinon (Tokyo, Japan), and (3) i-scan (Pentax, Tokyo, Japan).

NBI utilizes the principle that light wavelength determines depth of tissue penetration. Special filters are placed in front of the xenon lamp that narrows the spectrum to blue light of 400 to 430 nm and green light of 525 to 555 nm. The blue short wavelength (centered at 415 nm) not only has penetration limited to the mucosa, but has been shown to correspond with the peak absorption spectrum of hemoglobin ; thus, mucosal structures containing high hemoglobin content, such that vessels seem to be brown. The longer wavelength light (centered at 540 nm) penetrates deeper into the submucosa and corresponds with a secondary absorption peak of hemoglobin, highlighting submucosal vasculature as cyan ( Figs. 1 and 2 C).

A sporadic adenoma viewed using high-definition white light endoscopy (HD-WLE) and narrow band imaging (NBI). ( A ) A 7-mm adenoma seen with HD-WLE in the ascending colon (Lucera Elite, Olympus Keymed, UK). ( B ) The same adenoma seen with NBI. Note the lesion stands out browner owing to highlighting of increased microvessel density compared with the background mucosa; however, this has not translated into higher detection rates in meta-analysis.

A nonpolypoid colorectal neoplasm in quiescent ulcerative colitis. ( A ) An area of abnormal pit pattern with a “velvety” appearance was seen during high definition white light colonoscopy for surveillance of longstanding ulcerative colitis. ( B ) Use of chromoendoscopy ( dye spray ) with indigocarmine 0.2% revealed a flat (Paris 0-IIb) lesion with a circumscribed boarder with a diameter of approximately 30 mm. ( C ) Assessment with narrow band imaging (NBI; Olympus, Tokyo, Japan) is also shown to clarify the pit pattern, but the border is not as distinct as with chromoendoscopy. ( D ) Assessment with autofluorescence imaging (AFI; Olympus) also helps to differentiate the neoplastic tissue ( pink/purple ) from the surrounding normal mucosa ( green ). Biopsy confirmed low-grade dysplasia.

FICE uses an algorithm that takes an ordinary endoscope image and decomposes the light according to wavelengths. Selective wavelength images are then combined to reconstruct a real-time image. There are 10 channels with each channel corresponding with 3 specific virtual, electronic filters resulting in images with various tissue depth penetrations, and hence tissue enhancements.

I-scan uses 3 algorithms for image enhancement. (1) Surface enhancement allows minor changes in structure to be seen by enhancing the edge. This is achieved by analyzing the difference in luminance intensity of the pixels in this area with the edge components being enhanced. (2) Contrast enhancement identifies pixels of lower luminance intensity and subsequently enhancing the blue component of these pixels. This gives areas of low luminance such as depressed areas a bluish color. (3) Tone enhancement decomposes the ordinary color image into light wavelength components of red, green, and blue. These components are then adjusted along a tone curve and reconstructed to produce an image with increased contrast of color tone.

Autofluorescence imaging

Autofluorescence imaging (AFI) is another modality of mucosal enhancement manufactured by Olympus (Tokyo, Japan). Autofluorescence is the natural emission of light from biological molecules, endogenous fluorophores, when light of a suitable wavelength is absorbed. When cellular components and tissue state changes during pathologic processes, this alters the amount and distribution of endogenous fluorophores; hence, the autofluorescence generated. In neoplastic epithelial cells, there is increased fluorescence from mitochondrial cofactors nicotinamide adenine dinucleotide (plus hydrogen) and flavin adenine dinucleotide (FAD), but reduced fluorescence from collagen in the stroma. Thickening of the mucosa and increased blood flow in adenomatous lesions also attenuate excitation light and block the autofluorescence signal.

The autofluorescence endoscope generates blue light (390–470 nm) and green light (540–560 nm) via rotating color filters in front of the xenon light. After excitation by the shorter wavelength blue light, fluorophores emit autofluorescence of longer wavelengths (500–630 nm). A filter in front of the separate AFI charge-coupled device blocks the reflected blue excitation light, but enables the tissue autofluorescence as well as the reflected green light to filter through. These images are then integrated by the processor to generate a pseudocolor image where normal tissue and vessels appear green and dysplastic tissue as magenta (see Fig. 2 D).

Clinical application of electronic imaging at colonoscopy