**1. Introduction**

type XII as a marker of myofibroblastic differentiation during colorectal cancer meta‐

[20] De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. International journal of cancer 2008;123(10): 2229-2238.

[21] Kimura R, Fujimori T, Ichikawa K, Ajioka Y, Ueno H, Ohkura Y, Kashida H, Togashi K, Yao T, Wada R, Watanabe T, Ochiai A, Sugai T, Sugihara K, Igarashi Y. Desmo‐ plastic reaction in biopsy specimens of early colorectal cancer: A Japanese prospec‐

[22] Schmid SA, Dietrich A, Schulte S, Gaumann A, Kunz-Schughart LA. Fibroblastic re‐ action and vascular maturation in human colon cancers. International journal of radi‐

[23] Hirose M, Fukui H, Igarashi Y, Fujimori Y, Katake Y, Sekikawa A, Ichikawa K, Tomi‐ ta S, Imura J, Ajioka Y, Ueno H, Hase K, Ohkura Y, Kashida H, Togashi K, Nishigami T, Matsui T, Yao T, Wada R, Matsuda K, Watanabe T, Ochiai A, Sugai T, Sugihara K, Fujimori T. Detection of desmoplastic reaction in biopsy specimens is useful for pre‐ dicting the depth of invasion of early colorectal cancer: a Japanese collaborative

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176 Colonoscopy and Colorectal Cancer Screening - Future Directions

ation biology 2009;85(11): 1013-1025.

In the United States colorectal cancer (CRC) is the third more commonly diagnosed cancer in both sexes and it is also the third leading cause of cancer death among men and women [1]. In Europe CRC is the second leading cause of cancer death in both sexes [2]. These figures mean a heavy economic burden for any health system. The national cost of a year of CRC care in the United States has been estimated to be between \$4.5 and \$9.6 billion [3]. In Spain €180.6 million of annual loses in work productivity because of CRC have been reported [4].

Adenomatous polyps are the precursors of CRC in most of the cases. Through a progressive accumulation of mutations and following some of the described carcinogenetic pathways [5], a benign adenomatous polyp develops into an advanced adenoma with high-grade dys‐ plasia (HGD) and then progresses to invasive cancer (Figure 1). Invasive cancers confined to the wall of the colon (TNM stages I and II) are curable by surgery while more advanced can‐ cers are treated by a combination of surgery and chemotherapy.

Detecting cancer at an early stage or, even better, diagnosing and resecting adenomas before a carcinoma has developed improves outcomes. This was first confirmed in the initial report of the National Polyp Study [6] which showed a reduction in the incidence of colorectal can‐ cer of around 76% in patients in which a polypectomy had been performed. Recently, the same group has described in the same cohort of patients a reduction in mortality of 53% in the long term [7]. This is the rationale for population-based screening programs, designed to detect advanced adenomas and CRC at an early and curable stage. For instance, recently the results of a nationwide screening colonoscopy program in Germany have been reported of a nationwide screening colonoscopy program in Germany, showing that 69.6% of diagnosed CRC were stages I and II [8]. Therefore, screening for CRC with removal of adenomas and surveillance colonoscopy of patients who have been treated for adenomas or CCR is recom‐

© 2013 Bustamante-Balén; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

mended by Professional Societies and authorities [9-11]. Surveillance intervals after resec‐ tion of one or more adenomas are planned based primarily in the number, size and presence of advanced histological features [12]. Polyps larger than 10 mm, with villous component (> 25%) or with high-grade dysplasia are considered advanced adenomas and have a greater tendency to malignancy [13]. Detection and resection of these advanced adenomas is the main objective of the surveillance programs [14,15]. Therefore, submitting all resected pol‐ yps to pathologic evaluation is the standard of care.

whose largest polyp was diminutive (≤ 5 mm), small (6-9 mm) and large (≥ 10 mm) was 0.9%, 4.9% and 73.5% respectively [27]. The most recent study on this topic, a retrospective review of data from three prospective clinical trials has shown that the prevalence of ad‐

In vivo Optical Diagnosis of Polyp Histology: Can We Omit Pathological Examination of Diminutive Polyps?

**AA ≥10 mm**

76 (1.5%)

737 (5.3%)

6 (0.5%)

**Table 1.** Absolute prevalence of advanced adenomas according to the largest polyp size. AA: advanced adenoma;

Moreover, it remains unclear the practical role of advanced histological features in assessing the individual risk of CRC and in planning the management of patients with colonic polyps. First, there is a substantial interobserver variability in the diagnosis of the villous compo‐ nent and even HGD, with kappa index ranging from 0.35 to 0.48 and 0.38 to 0.69 respective‐ ly [28,29]. This problem may be even greater in polyps less than 10 mm [30]. Second, it is not clear that villous component or HGD are independent predictors of the subsequent develop‐ ment of advanced adenomas during follow-up. In the case of villous component the pub‐ lished studies do not separately identify patients whose most advanced polyp is a tubulovillous or villous adenoma < 10 mm in size, therefore the risk of this subgroup of polyps cannot be accurately assessed [31]. High grade dysplasia has not been shown to be an inde‐ pendent risk factor for metachronous advanced neoplasm in the NCI Pooling Project after

Taking all these data as a whole it appears clear that the standard practice of submitting all diminutive polyps found in colonoscopy to pathological assessment may have little clinical impact on the management of patients, and may result in substantial costs. Waiting for the pathological report may induce a delay in informing the patient and in recommending the next colonoscopy surveillance interval. In this context, some authors are recommending a "resect and discard" strategy to be applied to diminutive polyps found anywhere in the col‐ orectum. Following this strategy the histology of a diminutive polyp would be assessed by an appropriate endoscopic method, the assessment would be recorded by means of a high-

**HGD ≤ 5 mm**

2 (0.04%)

1 (0.007%)

1 (0.08%)

(0.26%)

NA - - -

**HGD 6-9 mm**

1 (0.02%)

9 (0.06%) **HGD ≥10 mm**

http://dx.doi.org/10.5772/53205

179

0

45 (0.3%)

(0.08%)

19 (0.82%) 227 (9.9%)

0 1

vanced histological features in diminutive polyps is 0.5%.

105 (2.1%) 67

**AA 6-9 mm**

12 (0.2%)

(1.3%)

62 (0.4%)

3 (0.26%)


**AA ≤ 5 mm**

32 (0.6%)

45 (0.3%)

3 (0.26%)

HGD: high-grade dysplasia; NA: non-applicable

adjustments for size and histology [32].

**Study (n patients)**

Unal [22] (n = 5087)

Tsai [21] (n = 5087)

Bretagne [25] (n = 2294)

Lieberman [26] (n = 13992)

Gupta [23] (n = 1150)

**Figure 1.** Development of CRC from normal tissue to adenocarcinoma

However, most of the adenomas diagnosed in colonoscopies are 5 mm or less (diminutive polyps). In symptomatic patients the proportion of adenomas larger than 10 mm is between 5 and 15% [16-18]. A report from our group using chromoendoscopy to improve the adeno‐ ma detection rate showed that 73% of adenomas were < 5 mm [19]. This is also the situation in screening colonoscopy, with reported proportions of adenomas < 5 mm of around 80% [20]. A significant proportion of diminutive polyps, between 23% and 40%, are not even ade‐ nomas [21-24]. Overall, the prevalence of advanced histology in diminutive polyps seems low, although there is some heterogeneity in the literature due to different inclusion criteria (screening versus symptomatic patients; patients only with polyps less than a specific size, etc.), differences in the performed analysis (per-patient, per-polyp) and probably also due to the variability in the pathologic interpretation of dysplasia and proportion of villous compo‐ nent (table 1).

A recent systematic review with stringent inclusion criteria (average-risk asymptomatic population, clear definition of advanced adenoma, definition of the method adopted to as‐ sess polyp size, reported prevalence of advanced adenomas according to polyp size, and at least 500 subjects included) showed that the prevalence of advanced lesions among patients whose largest polyp was diminutive (≤ 5 mm), small (6-9 mm) and large (≥ 10 mm) was 0.9%, 4.9% and 73.5% respectively [27]. The most recent study on this topic, a retrospective review of data from three prospective clinical trials has shown that the prevalence of ad‐ vanced histological features in diminutive polyps is 0.5%.

mended by Professional Societies and authorities [9-11]. Surveillance intervals after resec‐ tion of one or more adenomas are planned based primarily in the number, size and presence of advanced histological features [12]. Polyps larger than 10 mm, with villous component (> 25%) or with high-grade dysplasia are considered advanced adenomas and have a greater tendency to malignancy [13]. Detection and resection of these advanced adenomas is the main objective of the surveillance programs [14,15]. Therefore, submitting all resected pol‐

However, most of the adenomas diagnosed in colonoscopies are 5 mm or less (diminutive polyps). In symptomatic patients the proportion of adenomas larger than 10 mm is between 5 and 15% [16-18]. A report from our group using chromoendoscopy to improve the adeno‐ ma detection rate showed that 73% of adenomas were < 5 mm [19]. This is also the situation in screening colonoscopy, with reported proportions of adenomas < 5 mm of around 80% [20]. A significant proportion of diminutive polyps, between 23% and 40%, are not even ade‐ nomas [21-24]. Overall, the prevalence of advanced histology in diminutive polyps seems low, although there is some heterogeneity in the literature due to different inclusion criteria (screening versus symptomatic patients; patients only with polyps less than a specific size, etc.), differences in the performed analysis (per-patient, per-polyp) and probably also due to the variability in the pathologic interpretation of dysplasia and proportion of villous compo‐

A recent systematic review with stringent inclusion criteria (average-risk asymptomatic population, clear definition of advanced adenoma, definition of the method adopted to as‐ sess polyp size, reported prevalence of advanced adenomas according to polyp size, and at least 500 subjects included) showed that the prevalence of advanced lesions among patients

yps to pathologic evaluation is the standard of care.

178 Colonoscopy and Colorectal Cancer Screening - Future Directions

**Figure 1.** Development of CRC from normal tissue to adenocarcinoma

nent (table 1).


**Table 1.** Absolute prevalence of advanced adenomas according to the largest polyp size. AA: advanced adenoma; HGD: high-grade dysplasia; NA: non-applicable

Moreover, it remains unclear the practical role of advanced histological features in assessing the individual risk of CRC and in planning the management of patients with colonic polyps. First, there is a substantial interobserver variability in the diagnosis of the villous compo‐ nent and even HGD, with kappa index ranging from 0.35 to 0.48 and 0.38 to 0.69 respective‐ ly [28,29]. This problem may be even greater in polyps less than 10 mm [30]. Second, it is not clear that villous component or HGD are independent predictors of the subsequent develop‐ ment of advanced adenomas during follow-up. In the case of villous component the pub‐ lished studies do not separately identify patients whose most advanced polyp is a tubulovillous or villous adenoma < 10 mm in size, therefore the risk of this subgroup of polyps cannot be accurately assessed [31]. High grade dysplasia has not been shown to be an inde‐ pendent risk factor for metachronous advanced neoplasm in the NCI Pooling Project after adjustments for size and histology [32].

Taking all these data as a whole it appears clear that the standard practice of submitting all diminutive polyps found in colonoscopy to pathological assessment may have little clinical impact on the management of patients, and may result in substantial costs. Waiting for the pathological report may induce a delay in informing the patient and in recommending the next colonoscopy surveillance interval. In this context, some authors are recommending a "resect and discard" strategy to be applied to diminutive polyps found anywhere in the col‐ orectum. Following this strategy the histology of a diminutive polyp would be assessed by an appropriate endoscopic method, the assessment would be recorded by means of a highresolution photograph and the polyp then would be resected and discarded. The endoscopic assessment of histology would be used to make an immediate recommendation regarding the next colonoscopy surveillance interval. Finally, when multiple diminutive rectosigmoid hyperplastic polyps are suspected endoscopically, histology can be established by real-time endoscopic assessment and documented by photography without the need of resection and pathological evaluation [33].

group of lesions ≤ 5 mm was analyzed. Conventional colonoscopy, chromoendoscopy and magnification chromoendoscopy were compared in the study by Fu et al. [42], and the latter

In vivo Optical Diagnosis of Polyp Histology: Can We Omit Pathological Examination of Diminutive Polyps?

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181

Magnification chromoendoscopy has also been evaluated in the prediction of malignant his‐ tology and invasive depth of cancer with variable results. Overall, it seems that its sensitivi‐ ty and accuracy are lower. For instance, Bianco et al. [43] showed that endoscopic differentiation between invasive and noninvasive neoplasm had a PPV of 79% and a NPV of 95%. Hurlstone et al. reported an accuracy of 78% and a specificity of 50% [44]. Some au‐ thors use a modification of the Kudo classification with different subtypes of the type V pat‐

In conclusion, high-magnification chromoendoscopy allows the prediction of histology even in small and diminutive lesions, but is better differentiating nonneoplastic from neoplastic lesions than differentiating invasive from noninvasive neoplasms. Moreover, it must be kept in mind that overall accuracy is not 100%, despite the fact that a technology with a NPV of 95% for adenomatous histology fulfils the PIVI criteria for leaving suspected rectosigmoid

Angiogenesis is a main step in the progression of neoplasms; therefore the diagnosis based on vascular morphological changes seems ideal for early detection and diagnosis of co‐ lon neoplasms. NBI enhances the visibility of the capillary network on the surface layer of

Normal mucosa displays a regular hexagonal or honeycomb-like pattern of capillary vessels around the crypt of the gland. This capillary meshwork, named meshed capillary (MC), is invisible or faintly visible (Figure 2a). In the neoplastic lesion, vessels grow thicker, with increasing diameter size, disruption and rise of vessel density as the lesion progresses. There‐ fore, recognizing the lesion becomes easier because it appears as a brownish area (Figure 2b).

was found to have the highest accuracy (95.6%).

tern that may be quite cumbersome to use [45].

hyperplastic polyps ≤ 5 mm in size in place [33].

*2.2.1. Predicting histology by means of vascular features*

**Figure 2.** NBI image of normal mucosa (a) and a diminutive adenoma (b)

**2.2. Narrow-band imaging**

the mucosa.
