“Polypectomy at colonoscopy has been shown to reduce the subsequent risk of colorectal cancer. With the advent of national screening programs, the number of colonoscopies performed has increased worldwide. In addition, the recent drive for quality improvement combined with advances in colonoscopic technology has resulted in increased numbers of polyps detected, resected, and sent for histopathology leading to spiraling costs associated with the procedure. Being able to diagnose small polyps in vivo (optical diagnosis) would allow for adenomas to be resected and discarded without the need to retrieve them or send them for formal histopathology.”
Key points
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There are major potential advantages for patients, clinicians, and health care providers if optical diagnosis rather than conventional histopathology is used to characterize small polyps at colonoscopy.
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Correct allocation of surveillance interval is the key outcome measure in assessing the accuracy and clinical acceptability of a Resect and Discard, Diagnose and Disregard strategy.
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Standards for achieving high-quality optical diagnosis have now been defined.
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High levels of accuracy in optical diagnosis of small polyps have been achieved at expert centers, but this has not been replicated in community practice.
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There is a need for improved training, assessment, and quality assurance of optical diagnosis for a resect-and-discard, diagnose-and-disregard strategy to become widely acceptable and a standard of care.
Introduction
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality in the Western world. In the United States alone, 135,260 people were diagnosed with and 51,783 died of CRC in 2011. Most sporadic CRCs develop from adenomas in a well-described adenoma-carcinoma genetic sequence Fig. 1 . It involves a progression from normal epithelium to low-grade dysplastic adenoma to larger, protruding adenoma with high-risk features (high-grade dysplasia or villous component) and finally to invasive cancer as a result of mutations in several genes, including APC, KRAS, and p-53. This pathway is thought to account for approximately two-thirds of all CRCs (see Fig. 1 ).
Colonoscopy offers immediate therapeutic capability and resection of adenomas to halt the adenoma-carcinoma sequence, reducing the risk of CRC development. The evidence that colonoscopy prevents incident CRC and reduces mortality is indirect but substantial. Cohort studies of colonoscopy and polypectomy have suggested that, against Surveillance Epidemiology and End Results data, the rate of CRC detected was about 80% lower after polypectomy than expected for the population. An Ontario population-based cohort study of 2,412,077 individuals 50 to 90 years of age followed over 14 years found that for every 1% increase in complete colonoscopy rate, the hazard of death from CRC decreased by 3%. Additional evidence for a protective effect of colonoscopy with polypectomy can be extrapolated from flexible sigmoidoscopy trials, with the most recent randomized controlled trial that enrolled 170,432 participants demonstrating that the incidence of CRC in people attending for screening was reduced by 33% (0.67; 95% confidence interval [CI] 0.60–0.76) and mortality by 43% (0.57; 95% CI 0.45–0.72). Therefore, population-based screening is widely recommended and implemented in Europe and the United States. In the United States alone, more than 14 million screening colonoscopies are performed each year.
Currently, most polyps seen at colonoscopy are removed by endoscopic resection and sent for histopathology. Bleeding and perforation are the most common complications of polypectomy, with risks of 0% to 4% and 0% to 0.23%, respectively, reported in the literature, although they are likely to be higher in routine and community clinical practice.
Introduction
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality in the Western world. In the United States alone, 135,260 people were diagnosed with and 51,783 died of CRC in 2011. Most sporadic CRCs develop from adenomas in a well-described adenoma-carcinoma genetic sequence Fig. 1 . It involves a progression from normal epithelium to low-grade dysplastic adenoma to larger, protruding adenoma with high-risk features (high-grade dysplasia or villous component) and finally to invasive cancer as a result of mutations in several genes, including APC, KRAS, and p-53. This pathway is thought to account for approximately two-thirds of all CRCs (see Fig. 1 ).
Colonoscopy offers immediate therapeutic capability and resection of adenomas to halt the adenoma-carcinoma sequence, reducing the risk of CRC development. The evidence that colonoscopy prevents incident CRC and reduces mortality is indirect but substantial. Cohort studies of colonoscopy and polypectomy have suggested that, against Surveillance Epidemiology and End Results data, the rate of CRC detected was about 80% lower after polypectomy than expected for the population. An Ontario population-based cohort study of 2,412,077 individuals 50 to 90 years of age followed over 14 years found that for every 1% increase in complete colonoscopy rate, the hazard of death from CRC decreased by 3%. Additional evidence for a protective effect of colonoscopy with polypectomy can be extrapolated from flexible sigmoidoscopy trials, with the most recent randomized controlled trial that enrolled 170,432 participants demonstrating that the incidence of CRC in people attending for screening was reduced by 33% (0.67; 95% confidence interval [CI] 0.60–0.76) and mortality by 43% (0.57; 95% CI 0.45–0.72). Therefore, population-based screening is widely recommended and implemented in Europe and the United States. In the United States alone, more than 14 million screening colonoscopies are performed each year.
Currently, most polyps seen at colonoscopy are removed by endoscopic resection and sent for histopathology. Bleeding and perforation are the most common complications of polypectomy, with risks of 0% to 4% and 0% to 0.23%, respectively, reported in the literature, although they are likely to be higher in routine and community clinical practice.
Significance of small colorectal polyps
Increased awareness of the importance of colonoscopic quality in addition to advanced technology available to operators has led to increased polyp detection rates, at least in the published literature. More than 90% of polyps detected at colonoscopy are small (6–9 mm) or diminutive (≤5 mm), with the latter making up the majority. In a study of 13,992 asymptomatic patients who had a screening colonoscopy, 6360 (45%) patients had polyps and 83% of those had a largest polyp that was 9 mm or less in size. Furthermore, only 2549 out of 4942 (52%) were neoplastic with the rest composed of hyperplastic and inflammatory polyps and lymphoid aggregates. Similar findings were reported in a retrospective study of 10,034 patients who underwent colonoscopy over a 5-year period. Polyps that were 5 mm or less represented 81.6% of all polyps removed, and of those 47.9% were tubular adenomas. In a cumulative analysis of 18,549 patients who had a screening colonoscopy, 51% of diminutive polyps were adenomas (range 49%–61%). However, this proportion might be even lower in the rectum and sigmoid colon where there is high prevalence of small hyperplastic polyps, reducing the reported prevalence of adenomas to less than 20%.
Risk of cancer or advanced features (high-grade dysplasia or villous component >25%) in small and, particularly, in diminutive polyps is low ( Table 1 ).
| Study | Total Number of Diminutive Adenomas (Size Range) | Total Diminutive Advanced Histology (%) a | Total Number of Small Adenomas (Size Range) | Total Small Advanced Histology | Total Small Carcinoma |
|---|---|---|---|---|---|
| Shinya & Wolff, 1979 | — | — | 1661 (5–9 mm) | 249 (15.0%) b | 8 (0.5%) |
| National Polyp Study, 1990 | 1270 (<6 mm) | 25 (2.0%) b | 1230 (6–10 mm) | 155 (12.6%) b | — |
| Gschwantler, 2002 | 3016 (<5 mm) | 104 (3.4%) c 561 (18.6%) b | 2789 (5–10 mm) | 350 (12.5%) c 1080 (38.7%) b | 26 (0.9%) |
| Butterly et al, 2006 | 1305 (<6 mm) | 34 (2.6%) b | 487 (6–9 mm) 921 (5–10 mm) | 38 (7.8%) b 85 (9.2%) b | 2 (0.4%) 8 (0.9%) |
| Sprung, 2006 (abstract) | — | — | 6694 (5–10 mm) | — | 2 (0.03%) |
| Kim, 2007 | 759 (≤5 mm) | 3 (0.4%) | 291 (6–9 mm) | 11 (3.8%) b | 0 (0%) |
| Lieberman et al, 2008 d | 3744 (≤5 mm) | 62 (1.7%) | 1198 (6–9 mm) | 79 (6.6%) | 2 (0.2%) |
| Rex, 2009 | 4211 (≤5 mm) | 79 (0.87%) | 689 (6–9 mm) | 68 (5.3%) | 4 (0.04%) |
| Bretagne, 2010 | 520 (<5 mm) | 2.8% | |||
| Repici, 2011 | 627 (<5 mm) | 8.7% | 388 (6–9 mm) | 6.1% | — |
| Kolligs, 2013 | 198,954 (<5 mm) | 3.7% | 106,270 (5–9 mm) | 13.0% | — |
a Butterly and colleagues and Lieberman and colleagues reported one invasive carcinoma at this size category; Gschwantler and colleagues reported zero.
b High-grade dysplasia, villous and tubulovillous morphology (>25% villous elements), not invasive carcinoma.
In a systematic review of 20,562 average-risk patients undergoing screening colonoscopy, advanced adenomas were detected in 1155 out 20,562 subjects (pooled prevalence of 5.6%, 95% CI 5.3–5.9). In addition, the study showed that 0.9% of patients with diminutive-only lesions had an advanced adenoma and 0.04% had cancer. This finding led the investigators to conclude that, assuming a 5.6% prevalence of advanced adenomas and 3.3% per year progression of advanced adenoma to cancer, the 5-year CRC risk associated with diminutive advanced adenomas would be 0.04% (compared with prescreening 5-year CRC risk of 0.92% for the general population). Recently there has been interest in serrated adenomas/polyps. These lesions are thought to be the precursors for the alternative serrated pathway to CRC development and are now considered premalignant similar to adenomas. Although surface appearances are often similar to simple hyperplastic polyps, the prevalence of serrated polyps/adenomas in diminutive polyps seems to be very low, 0.3% to 0.5%.
As diminutive polyps are of such limited significance, some colonoscopic imaging tests, such as computed tomography colonography, do not report them. Two prospective Scandinavian studies followed up 194 diminutive polyps after 2 and 3 years. They showed that no diminutive polyp increased to a size of greater than 5 mm and no cases of high-grade dysplasia or cancer were detected.
As approximately 50% of small polyps are non-neoplastic, many polypectomies are performed unnecessarily, increasing the risks of the procedure. Even small polyps, with little risk of harboring cancer, are currently resected and sent for histopathology as the number of adenomas is one of the best determinants of long-term risk of advanced neoplasia and allows an informed decision regarding future surveillance intervals. Unlike the American and European guidelines on polyp surveillance, the British Society of Gastroenterology’s guidelines use the size and number of adenomas as the main determinants of surveillance intervals and do not take into account the advanced histologic features (high-grade dysplasia or villous architecture), which have a low prevalence in diminutive polyps and have been questioned as predictors of subsequent advanced neoplasia. Similarly, European guidelines for quality assurance in CRC screening and diagnosis recommend that local practice determines whether or not to use advanced features to determine surveillance intervals.
An ability to correctly diagnose a diminutive polyp during colonoscopy (optical diagnosis) would allow for rectosigmoid hyperplastic polyps to be diagnosed and left in situ (diagnose and disregard) and for diminutive adenomas to be resected and discarded (resect and discard) without a need to retrieve the polyp for formal histopathology, especially as 7% to 19% of small polyps may not be successfully retrieved or are unsuitable for histologic analysis because of diathermy artifact. In addition, small polyps may be misclassified at standard histopathology because of incorrect orientation and limited sectioning of the specimen (14% in a recent series ).
A frequently cited drawback of optical diagnosis is the lack of ability to distinguish between different grades of dysplasia (high vs low) and the presence of villous features. As mentioned earlier, both of these have been shown to be inconsistent in terms of ability to predict the risk of future neoplasia. Correlation between size and histology of adenomas mean that these two factors act as confounders. Furthermore there is a wide interobserver variability between histopathologists when reporting on the degree of villous architecture. A systematic review and meta-analysis on baseline risk factors for advanced adenomas found that there was no difference between villous versus tubular histology. Although a few individual studies have suggested that high-grade dysplasia confers a higher risk of development of advanced adenomas, this has not been confirmed by a large pooled study that used individual data from 6 other studies. Therefore, optical diagnosis, which would be possible on all polyps seen, represents a paradigm change as it would enable surveillance intervals to be determined immediately after colonoscopy. This concept is attractive for physicians, patients, and health care providers as the management pathway is potentially streamlined and costs reduced.
Kessler and colleagues performed modeling of real-time endoscopy histology followed by resection and discarding of less than 6 mm polyps versus resection and submission for histology on 4474 consecutive colonoscopies in which 10,400 polyps were removed, 9042 of them less than 6 mm (diminutive). They found that at $75 per specimen, at least $151,000 could be saved for each 1000 patients with at least one diminutive polyp and less than 1 in 1100 patients with diminutive polyps removed would have an undetected cancer in any removed polyp. If an assumption is made that 40% of 1.6 million annual colonoscopies performed in the United States detect at least one diminutive polyp, the potential savings from not sending these polyps for histopathologic assessment is greater than $95 million. Using a resect-and-discard policy for diminutive polyps would result in annual savings of $33 million when applied to colonoscopy screening of the US population (corresponding to overall savings of $330 million, assuming a cumulative period of 10 years to screen just less than a quarter of the US population). Additional costs are incurred by bringing patients back for a follow-up appointment simply to determine the surveillance interval.
What is the optimal modality for optical diagnosis?
White Light Colonoscopy
Conventional white light colonoscopy has been used to attempt to characterize colonic polyps, both in still images and in vivo. However, white light colonoscopy has a limited accuracy (59%–84%) in differentiating neoplastic from non-neoplastic polyps ( Table 2 ).
| No. | Mean Size (mm) (Range) | Sens (%) | Spec (%) | Acc (%) | |
|---|---|---|---|---|---|
| Machida et al, 2004 | 43 | 7.5 (2–25) | 85.3 | 44.4 | 79.1 |
| Apel et al, 2006 | 273 | 2.95 | 93.0 | 60.0 | 81.0 |
| De Palma et al, 2006 | 240 | 3.0–4.0 | 91.4 | 68.3 | 76.3 |
| Fu et al, 2004 | 206 | 3.0–4.0 | 88.8 | 67.4 | 84.0 |
| Su et al, 2006 | 110 | — | 82.9 | 80.0 | 81.8 |
| Tischendorf et al, 2007 | 100 | 10.6 (2–50) | 63.4 | 51.9 | 59.0 |
| Chiu et al, 2007 | 180 | 5.33 (2–20) | 62.1–65.2 | 85.4–74.4 | 67.2–68.3 |
| Ignjatovic et al, 2011 | 80 | 4.5 | 69.0 | 60.0 | 64.0 |
| Longcroft-Wheaton et al, 2011 | 232 | 4.7 (2–9) | 75.0 | 64.0 | 71.0 |
Chromoendoscopy
Chromoendoscopy has been in used in Japan to characterize small polyps during colonoscopy. By highlighting the shape of the colonic crypts, a pit pattern can be seen. Kudo pit-pattern is the most widely used classification system. Kudo pit patterns I and II indicate non-neoplastic lesion, IIs, IIL and IV neoplastic lesion and V neoplastic lesion with submucosal invasion. This pattern is highly accurate with experts achieving accuracy of more than 90% for polyp characterization when using magnifying colonoscopes and chromoendoscopy. However, there is an appreciable learning curve of 200 to 300 histologically confirmed lesions to achieve that degree of accuracy. The extra training, equipment, and time required for magnifying chromoendoscopy have not made it popular in the West, where it is rarely used outside academic centers ( Table 3 ).
| No. of Lesions | Mean Size (mm) | Sens (%) | Spec (%) | Acc (%) | |
|---|---|---|---|---|---|
| Kato, 2006 | 3438 | >5 | 42.0 | 98.0 | 75.0 |
| Togashi, 2006 | 923 | 1–11 | 73.0 | 92.0 | 88.0 |
| Konishi, 2003 | 405 | 1–10 | 93.0 | 85.0 | 92.0 |
| De Palma et al, 2006 | 240 | 3–4 | 97.5 | 94.3 | 95.4 |
| Tischendorf et al, 2007 | 100 | 10.6 (2–50) | 91.7 | 90.0 | 91.0 |
| Chiu et al, 2007 | 180 | 5.33 (2–20) | 91.3–97.2 | 74.4–90.5 | 91.1–92.2 |
Narrow Spectra Technologies
In recent years, several image-enhancing push-button technologies have been developed, such as Narrow Band Imaging (NBI, Olympus, Tokyo, Japan), i-SCAN (Pentax, Mississauga, ON), and Fujinon Intelligent Color Enhancement (FICE, Fujinon Inc, Wayne, NJ). These technologies have been integrated into the colonoscope and can achieve the benefits of chromoendoscopy in a quicker, cheaper, and more user-friendly way.
Most studies have assessed NBI, a blue light optical imaging modality that enhances mucosal detail and, in particular, vascular structures, allowing assessment of vascular pattern intensity and the typical-appearing meshed brown capillary network of adenomas ( Fig. 2 ). As neoplastic tissue is characterized by increased angiogenesis, adenomas appear darker when viewed with NBI. Recently a consensus of experts developed and validated a classification system for the characterization of small colonic polyps: the NBI International Colorectal Endoscopic (NICE) classification. This classification uses color, vessels, and surface pattern to differentiate between hyperplastic and adenomatous polyps and is applicable for nonmagnified NBI imaging ( Table 4 ).
