**2. The role of colonoscopy in preventing colorectal cancer**

Colonoscopy plays a dual role in preventing colorectal cancer. First, endoscopic examination of the colon and rectum is the gold standard in the diagnosis of neoplastic and preneoplastic lesions in the large intestine. On the other hand, the development of therapeutic techniques such as polypectomy or more complex techniques like endoscopic mucosal resection or endoscopic submucosal dissection, allows the removal of some of these lesions. Indeed, endoscopic resection is curative in almost all preneoplastic lesions (benign lesions) and may be curative in early malignant lesions, which are those that only affect the mucosa and submucosa.

Colonoscopy is useful for the diagnosis of cancer and precancerous lesions. Unquestionably, despite radiological techniques are useful for diagnosis, the role of colonoscopy is essential firstly to confirm the radiological findings and also to obtain biopsy specimens for histological diagnosis. Colorectal cancer is frequently presented as proliferative lesions that produce some stenosis of the intestinal lumen, with ulcerated surface and even with hemorrhagic necrotic areas (Figure 2); sometimes they are polypoid lesions that can also have ulcerated areas (Figure 3), or just be circumscribed ulcerations (Figure 4).

Fig. 2. Malignant lesion covering the entire circumference that produces stenosis of the intestinal lumen, with ulcerated surface, hemorrhagic necrotic areas and bleeding easily at the touch of endoscope

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 199

Fig. 5. The picture shows two large pedunculated polyps. Adenomatous tissue is easily

Fig. 6. Sessile polyp, with wide-based attachment, in which it does not recognize any pedicle

differentiated from the pedicle, consisting of normal mucosa, non-neoplastic

Fig. 3. Sessile polyp, with wide-based attachment, embossed surface, with ulcerated areas and a friable mucosa. Biopsies from the lesion suggest adenocarcinoma arising in a villous adenoma

Fig. 4. Ulcer that affects 2 / 5 parts of the circumference of intestinal lumen, with raised and indurated edges. Biopsies suggested undifferentiated adenocarcinoma

Fig. 3. Sessile polyp, with wide-based attachment, embossed surface, with ulcerated areas and a friable mucosa. Biopsies from the lesion suggest adenocarcinoma arising in a villous adenoma

Fig. 4. Ulcer that affects 2 / 5 parts of the circumference of intestinal lumen, with raised and

indurated edges. Biopsies suggested undifferentiated adenocarcinoma

Fig. 5. The picture shows two large pedunculated polyps. Adenomatous tissue is easily differentiated from the pedicle, consisting of normal mucosa, non-neoplastic

Fig. 6. Sessile polyp, with wide-based attachment, in which it does not recognize any pedicle

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 201

Fig. 8. Laterally spreading tumor with granular surface, with sharply demarcated edges

Fig. 9. Endoscopic polypectomy by polypectomy snare of a pedunculated lesion of about 7 mm in diameter, located in proximal transverse colon. The pathological study revealed the

after performing vital staining with indigo carmine 2%

presence of a tubular adenoma with low grade dysplasia

The diagnosis of polyps is also quite distinctive, as outgrowths on the colonic mucosa with variable size and morphology. They can present as pedunculated lesions (Figure 5), sessile lesions (Figure 6), or as flat or very slightly raised lesions (Figure 7). Occasionally, lesions can be almost undetectable during a conventional colonoscopy, so some special techniques such as chromoendoscopy or modern techniques of Narrow Band Imaging and Computed Virtual Chromoendoscopy can be helpful to identify and study the lesions more accurately (Figure 8). After these lesions have been located and characterized, we should think in the possibility to perform the resection of the lesion by polypectomy (Figure 9) or endoscopic mucosal resection (Figure 10).

Although, in general, the role of colonoscopy in preventing CRC can be summarized in the above, there are some differences in the groups of patients that have been differentiated according to their risk of developing the disease. For this reason, then we will discuss in greater detail, the place of colonoscopy in the screening strategies proposed for each of these patients.

Fig. 7. Flat polyp, located in right colon close to the ileocecal valve. The lesion has a thickness of a few millimeters and a granular surface

### **2.1 Usefulness of colonoscopy in preventing CRC in average risk population**

This is the largest group of individuals who would be subsidiaries of CRC prevention programs, so the group would consume a greater amount of resources. In fact, most colorectal carcinomas are sporadic, appearing in patients who have neither family history of disease or conditions predisposing to disease.

The prevention strategy that arises in this population is, once assumed the failure of primary prevention, it takes place secondary prevention. That is, it is an early diagnosis of cancer or

The diagnosis of polyps is also quite distinctive, as outgrowths on the colonic mucosa with variable size and morphology. They can present as pedunculated lesions (Figure 5), sessile lesions (Figure 6), or as flat or very slightly raised lesions (Figure 7). Occasionally, lesions can be almost undetectable during a conventional colonoscopy, so some special techniques such as chromoendoscopy or modern techniques of Narrow Band Imaging and Computed Virtual Chromoendoscopy can be helpful to identify and study the lesions more accurately (Figure 8). After these lesions have been located and characterized, we should think in the possibility to perform the resection of the lesion by polypectomy (Figure 9) or endoscopic

Although, in general, the role of colonoscopy in preventing CRC can be summarized in the above, there are some differences in the groups of patients that have been differentiated according to their risk of developing the disease. For this reason, then we will discuss in greater detail, the place of colonoscopy in the screening strategies proposed for each of these

Fig. 7. Flat polyp, located in right colon close to the ileocecal valve. The lesion has a

**2.1 Usefulness of colonoscopy in preventing CRC in average risk population** 

This is the largest group of individuals who would be subsidiaries of CRC prevention programs, so the group would consume a greater amount of resources. In fact, most colorectal carcinomas are sporadic, appearing in patients who have neither family history of

The prevention strategy that arises in this population is, once assumed the failure of primary prevention, it takes place secondary prevention. That is, it is an early diagnosis of cancer or

thickness of a few millimeters and a granular surface

disease or conditions predisposing to disease.

mucosal resection (Figure 10).

patients.

Fig. 8. Laterally spreading tumor with granular surface, with sharply demarcated edges after performing vital staining with indigo carmine 2%

Fig. 9. Endoscopic polypectomy by polypectomy snare of a pedunculated lesion of about 7 mm in diameter, located in proximal transverse colon. The pathological study revealed the presence of a tubular adenoma with low grade dysplasia

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 203

Fig. 10. Picture showing endoscopic mucosal resection of a large flat polyp placed in rectum. The size of the polypectomy snare allows us to approximate the size of the lesion, which is about twice the size of it, so about 6 cms. The resection is performed gradually, in several

The number and characteristics of the resected polyps are, therefore, the key factors to establish the date of the next examination. The existence of multiple adenomas (more than three) or a polyp that has a size greater than 10 mm or, regardless of size, the polyp has a villous component or high grade dysplasia (advanced adenoma); leads to set the following colonoscopy within three to five years. If the number of adenomas removed is larger than 10, we recommend surveillance colonoscopy within less than 3 years. When these conditions are not are satisfied (less than three adenomas, without advanced adenoma characteristics), the next examination should be done within five to ten years. In case of a first surveillance examination without evidence of new adenomas, subsequent colonoscopies should be

In patients who have been treated for colorectal cancer, as well as in patients with adenomas, we should have a complete study of the colon before surgery or at least within 6 months. In case of obstructive tumors in which it is impossible to complete a study by colonoscopy, we can complete the examination of the colon with a CT-colonography. Most clinical practice guidelines recommend a review of the surgical anastomosis within one year after the intervention, to rule out a possible anastomotic recurrence and then, the recommendations are the same as those for patients undergoing endoscopic polypectomy: the first examination after three years and the following ones, if not metachronous lesions were detected, should be performed at intervals of 5 years. In case of detecting lesions

fragments (piecemeal resection). By this way large lesions can be removed

during follow-up, its features will condition the surveillance.

performed every 5 years.

precancerous lesions, in order to ensure a treatment with the best outlook for cure. In the case of diagnosis of polyps, colonoscopy and polypectomy allow the resection of the lesions and, thus, to prevent the occurrence of CRC.

In this group the screening strategies accepted and recommended by different international and Spanish scientific societies are:


No comparative studies are available that allow us to establish which is the most cost effective strategy. Taking into account that the most questionable option is represented by radiological tests, it seems that the discussion focuses on the choice of test FOBT or colonoscopy. If we accept the numbers described in several studies, stating that, in patients at average risk, adenomas should be detected in at least 25% of screening colonoscopies, there are doubts about the profitability of the radiological techniques. However, at present, we do not have enough scientific evidence to choose any strategy, although there is an American study which points in this direction. In Spain it is estimated that the cost per year of life saved using immunological fecal occult blood annually is around € 1,200, and it is € 2,300 for sigmoidoscopy every 5 years or colonoscopy every ten years. Both cases demonstrate the low cost of these screening programs when we compared them with other established screening systems for other malignancies such as cervical or breast cancer, whose cost is approximately 5-6 times higher.

The screening of colorrectal cancer in average risk population implies a significant increase in the number of colonoscopies that we must perform in our units. There are some concers about this situation. Perharps, there are no enough endoscopists in our health system to answer this raising demand of colonoscopies. The spanish health system should consider this limitations before the implementation of a screening program.

#### **2.2 Prevention of colorrectal cancer in patients with personal history of polypectomy or CRC**

Patients in which colonic polyps were removed or that have been treated for colon cancer should be included in specific monitoring systems. So this is tertiary prevention, and the aim is to detect metachronous lesions that appear in the months or years after the onset of the initial lesion. This disclosure is based on the possibility that the patient could have synchronic small lesions that could have not been detected in the initial colonoscopy. When performing a new examination in a reasonable period of time, these lesions would be detected in early stages yet. On the other hand, it is also known that these patients have an increased risk of presenting new lesions in the future. The only test accepted by all societies for these patients is colonoscopy.

The frequency of follow-up colonoscopies will be determined by the type of lesions presented by the patients. Naturally, any recommendation is based on the fundamental principle that colonoscopies performed meet all the standards of quality: good bowel preparation, full colon examination and mean colonoscopic withdrawal times of at least 6 minutes. In fact, all the factors mentioned above, especially the last one, are significantly correlated with the rate of polyps detected at screening colonoscopy.

precancerous lesions, in order to ensure a treatment with the best outlook for cure. In the case of diagnosis of polyps, colonoscopy and polypectomy allow the resection of the lesions

In this group the screening strategies accepted and recommended by different international


No comparative studies are available that allow us to establish which is the most cost effective strategy. Taking into account that the most questionable option is represented by radiological tests, it seems that the discussion focuses on the choice of test FOBT or colonoscopy. If we accept the numbers described in several studies, stating that, in patients at average risk, adenomas should be detected in at least 25% of screening colonoscopies, there are doubts about the profitability of the radiological techniques. However, at present, we do not have enough scientific evidence to choose any strategy, although there is an American study which points in this direction. In Spain it is estimated that the cost per year of life saved using immunological fecal occult blood annually is around € 1,200, and it is € 2,300 for sigmoidoscopy every 5 years or colonoscopy every ten years. Both cases demonstrate the low cost of these screening programs when we compared them with other established screening systems for other malignancies such as cervical or breast cancer, whose cost is

The screening of colorrectal cancer in average risk population implies a significant increase in the number of colonoscopies that we must perform in our units. There are some concers about this situation. Perharps, there are no enough endoscopists in our health system to answer this raising demand of colonoscopies. The spanish health system should consider

**2.2 Prevention of colorrectal cancer in patients with personal history of polypectomy** 

Patients in which colonic polyps were removed or that have been treated for colon cancer should be included in specific monitoring systems. So this is tertiary prevention, and the aim is to detect metachronous lesions that appear in the months or years after the onset of the initial lesion. This disclosure is based on the possibility that the patient could have synchronic small lesions that could have not been detected in the initial colonoscopy. When performing a new examination in a reasonable period of time, these lesions would be detected in early stages yet. On the other hand, it is also known that these patients have an increased risk of presenting new lesions in the future. The only test accepted by all societies

The frequency of follow-up colonoscopies will be determined by the type of lesions presented by the patients. Naturally, any recommendation is based on the fundamental principle that colonoscopies performed meet all the standards of quality: good bowel preparation, full colon examination and mean colonoscopic withdrawal times of at least 6 minutes. In fact, all the factors mentioned above, especially the last one, are significantly

this limitations before the implementation of a screening program.

correlated with the rate of polyps detected at screening colonoscopy.

and, thus, to prevent the occurrence of CRC.


and Spanish scientific societies are:

approximately 5-6 times higher.

for these patients is colonoscopy.

**or CRC** 

years.

Fig. 10. Picture showing endoscopic mucosal resection of a large flat polyp placed in rectum. The size of the polypectomy snare allows us to approximate the size of the lesion, which is about twice the size of it, so about 6 cms. The resection is performed gradually, in several fragments (piecemeal resection). By this way large lesions can be removed

The number and characteristics of the resected polyps are, therefore, the key factors to establish the date of the next examination. The existence of multiple adenomas (more than three) or a polyp that has a size greater than 10 mm or, regardless of size, the polyp has a villous component or high grade dysplasia (advanced adenoma); leads to set the following colonoscopy within three to five years. If the number of adenomas removed is larger than 10, we recommend surveillance colonoscopy within less than 3 years. When these conditions are not are satisfied (less than three adenomas, without advanced adenoma characteristics), the next examination should be done within five to ten years. In case of a first surveillance examination without evidence of new adenomas, subsequent colonoscopies should be performed every 5 years.

In patients who have been treated for colorectal cancer, as well as in patients with adenomas, we should have a complete study of the colon before surgery or at least within 6 months. In case of obstructive tumors in which it is impossible to complete a study by colonoscopy, we can complete the examination of the colon with a CT-colonography. Most clinical practice guidelines recommend a review of the surgical anastomosis within one year after the intervention, to rule out a possible anastomotic recurrence and then, the recommendations are the same as those for patients undergoing endoscopic polypectomy: the first examination after three years and the following ones, if not metachronous lesions were detected, should be performed at intervals of 5 years. In case of detecting lesions during follow-up, its features will condition the surveillance.

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 205

There is some agreement on the way to approach after detecting dysplasia. Due to the high incidence of synchronous adenocarcinoma with high-grade dysplastic foci, it is usually recommended to perform a total proctocolectomy after detecting high-grade dysplasia. In case a low-grade dysplasia, the decision is more controversial. If multiple foci of dysplasia on flat mucosa are detected, it is recommended to perform a proctocolectomy. On the other hand, if isolated foci of dysplasia are detected the recommendation should be to perform a new colonoscopy within approximately 3-6 months. Subsequently, following colonoscopies

Elevated lesions or masses can appear in patients with ulcerative colitis, and in many cases they are similar to adenomas. The presence of dysplasia on these raised lesions causes a difficult differential diagnosis with sporadic adenomas that are defined by the presence of dysplasia and whose treatment could be endoscopic polypectomy. Generally, we consider dysplasia-associated lesion or mass (DALM) if the lesion is located on "colitic" mucosa (even in quiescent ulcerative colitis), while if it appears on normal mucosa, it is probably sporadic adenoma. Sporadic adenoma should be treated as in the general population and DALM could also be endoscopically removed after ruling out the presence of dysplastic lesions in the surrounding mucosa. If this is not technically possible or perilesional mucosal biopsies present dysplastic foci, we should perform a total colectomy. If we have performed endoscopic resection of the lesion, we should take biopsies of the mucosa around the lesion in 3-6 months, and also the following colonoscopies should be performed every six months. The work for pathologist is not always easy and he can find cases in which, mainly due to the persistence of inflammatory activity, the findings are not definitive to confirm or exclude dysplasia. In these cases, endoscopy should be repeated within 3-6 months after an

As presented, colonoscopy is essential in monitoring these patients, being the only tool that allows taking biopsies to detect dysplasia. However, there is a long way to walk until we find the ideal strategy to make examinations less time-consuming and more cost effective. Everything suggests that modern endoscopic techniques (magnification endoscopy and chromoendoscopy) can be the key, but there is little scientific evidence by now. Secondly, the steps to follow in case of dysplasia seem to be more established. Finally, colonoscopy may have a therapeutic role if we detect low-grade dysplastic foci on lesions and masses

**2.4 Colorectal cancer screening strategies in patients with family history of CRC**

The risk of colorectal cancer is higher in those people who belong to families where cases of CRC have been recorded, even after having ruled out the possibility of polyposis syndromes and hereditary colorectal cancer. However, the risk depends on several factors: the number of relatives affected, the degree of kinship and age at which the neoplasm is detected. In second-degree relatives, excepting they were multiple family members affected, it is not justified any special CRC screening, and the recommendations are the same as for mediumrisk population. In case of multiple second-degree relatives affected, the different scientific societies recommend the same screening strategy as for people at average risk, but starting the screening program at age 40 years. In case of several first-degree relatives or a single family member younger than 60 years at the time of diagnosis, the only recommendation accepted is to perform colonoscopy every five years. The age to start the screening will be at 40 years of age or at age 10 years younger than the youngest case diagnosed in the family. The presence of a single first-degree relative older than 60 years increases the risk of

appropriate control of mucosa inflammation under a specific treatment.

should be performed every 6 months.

similar to adenomas.

#### **2.3 CRC screening in patients with inflammatory bowel disease**

People suffering from inflammatory bowel disease, especially ulcerative colitis have an increased risk of colon cancer. The risk is only increased in patients with extensive disease, thus it is not indicated endoscopic surveillance in patients with ulcerative colitis that only affects the rectosigmoid region. However there are a number of factors that are associated with a significant rise in the incidence of colon cancer. Indeed, the risk increases significantly if there are family history of colon cancer, if primary sclerosing cholangitis is associated with ulcerative colitis and, undoubtedly, if it is a disease with difficult control with persistent inflammation and presence of inflammatory pseudopolyps. Patients with Crohn's disease with extensive colonic involvement may also have an increased risk of developing colon cancer, so surveillance should also be extended to this group of patients.

The risk increases significantly after 8-10 years of development, being that the moment in which it is recommended to start the monitoring programs. Naturally, and taking into consideration that what we are looking for is the presence of dysplasia, colonoscopy with biopsy of colorectal mucosa is the only valid screening strategy. However, the evidence supporting this colorectal cancer screening is poor. Several studies suggest that the inclusion of patients in screening programs improves the prognosis of the disease because many cases would be diagnosed in early stages. In contrast, other studies doubt about the utility of specific screening programs, since most malignancies would be diagnosed as interval cancers.

Although scientific evidence is little and poor, the majority of international clinical practice guidelines, and also guidelines available in Spain, recommend to start with screening from 8-10 years after development of the disease in extensive colitis, and from 15 years in colitis that just involve the left colon. As explained before, it is not justified to perform any kind of endoscopic screening in patients with only rectal involvement. Initially it would be recommended to perform colonoscopy every 2-3 years, and then to increase in frequency because the incidence of colon cancer increases with duration of disease. It has been suggested to perform colonoscopies every two years after 20 years since the diagnosis of the disease and annually after 30 years of development of ulcerative colitis. It is also included in most guidelines the recommendation to intensify surveillance in patients with sclerosing cholangitis due to its association with an increased risk of CRC, indicating to perform an annual colonoscopy at the time of diagnosis of primary sclerosing cholangitis.

The best way to prevent the appearance of colon cancer is an early detection of dysplasia. Therefore, we should carefully explore all of the colon mucosa, trying to detect any mucosal lesion (minimum mucosal elevation, polyp, mass ...) and if so, we should take biopsies. Additionally, biopsies from the entire colonic mucosa should be systematically taken and the most widely recommendation accepted is taking 4 biopsy specimens every 10 cm of intestine. As expected, the examinations are hardworking and, with the available evidence, we can not ensure its cost effectiveness. In order to make these examinations less timeconsuming and possibly more cost effective, several studies propose to take biopsies in a targeted way, using magnification endoscopy and chromoendoscopy. Thus, these techniques help us to choose the areas that we need to biopsy, and this could probably improve the detection of dysplasia and also they can help us in reducing the number of biopsies that should be taken. At the present time confocal endomicroscopy is under study. This technique allows subsurface histological diagnosis in situ, without taking biopsies, and it could probably be more helpful detecting dysplasia. However, these are very long examinations, and this technique requires an expensive technology and a specialized training by the endoscopist, so it becomes a technique restricted to highly specialized centers.

People suffering from inflammatory bowel disease, especially ulcerative colitis have an increased risk of colon cancer. The risk is only increased in patients with extensive disease, thus it is not indicated endoscopic surveillance in patients with ulcerative colitis that only affects the rectosigmoid region. However there are a number of factors that are associated with a significant rise in the incidence of colon cancer. Indeed, the risk increases significantly if there are family history of colon cancer, if primary sclerosing cholangitis is associated with ulcerative colitis and, undoubtedly, if it is a disease with difficult control with persistent inflammation and presence of inflammatory pseudopolyps. Patients with Crohn's disease with extensive colonic involvement may also have an increased risk of developing colon cancer, so surveillance should also be extended to this group of patients. The risk increases significantly after 8-10 years of development, being that the moment in which it is recommended to start the monitoring programs. Naturally, and taking into consideration that what we are looking for is the presence of dysplasia, colonoscopy with biopsy of colorectal mucosa is the only valid screening strategy. However, the evidence supporting this colorectal cancer screening is poor. Several studies suggest that the inclusion of patients in screening programs improves the prognosis of the disease because many cases would be diagnosed in early stages. In contrast, other studies doubt about the utility of specific screening programs, since most malignancies would be diagnosed as interval cancers. Although scientific evidence is little and poor, the majority of international clinical practice guidelines, and also guidelines available in Spain, recommend to start with screening from 8-10 years after development of the disease in extensive colitis, and from 15 years in colitis that just involve the left colon. As explained before, it is not justified to perform any kind of endoscopic screening in patients with only rectal involvement. Initially it would be recommended to perform colonoscopy every 2-3 years, and then to increase in frequency because the incidence of colon cancer increases with duration of disease. It has been suggested to perform colonoscopies every two years after 20 years since the diagnosis of the disease and annually after 30 years of development of ulcerative colitis. It is also included in most guidelines the recommendation to intensify surveillance in patients with sclerosing cholangitis due to its association with an increased risk of CRC, indicating to perform an

**2.3 CRC screening in patients with inflammatory bowel disease** 

annual colonoscopy at the time of diagnosis of primary sclerosing cholangitis.

endoscopist, so it becomes a technique restricted to highly specialized centers.

The best way to prevent the appearance of colon cancer is an early detection of dysplasia. Therefore, we should carefully explore all of the colon mucosa, trying to detect any mucosal lesion (minimum mucosal elevation, polyp, mass ...) and if so, we should take biopsies. Additionally, biopsies from the entire colonic mucosa should be systematically taken and the most widely recommendation accepted is taking 4 biopsy specimens every 10 cm of intestine. As expected, the examinations are hardworking and, with the available evidence, we can not ensure its cost effectiveness. In order to make these examinations less timeconsuming and possibly more cost effective, several studies propose to take biopsies in a targeted way, using magnification endoscopy and chromoendoscopy. Thus, these techniques help us to choose the areas that we need to biopsy, and this could probably improve the detection of dysplasia and also they can help us in reducing the number of biopsies that should be taken. At the present time confocal endomicroscopy is under study. This technique allows subsurface histological diagnosis in situ, without taking biopsies, and it could probably be more helpful detecting dysplasia. However, these are very long examinations, and this technique requires an expensive technology and a specialized training by the There is some agreement on the way to approach after detecting dysplasia. Due to the high incidence of synchronous adenocarcinoma with high-grade dysplastic foci, it is usually recommended to perform a total proctocolectomy after detecting high-grade dysplasia. In case a low-grade dysplasia, the decision is more controversial. If multiple foci of dysplasia on flat mucosa are detected, it is recommended to perform a proctocolectomy. On the other hand, if isolated foci of dysplasia are detected the recommendation should be to perform a new colonoscopy within approximately 3-6 months. Subsequently, following colonoscopies should be performed every 6 months.

Elevated lesions or masses can appear in patients with ulcerative colitis, and in many cases they are similar to adenomas. The presence of dysplasia on these raised lesions causes a difficult differential diagnosis with sporadic adenomas that are defined by the presence of dysplasia and whose treatment could be endoscopic polypectomy. Generally, we consider dysplasia-associated lesion or mass (DALM) if the lesion is located on "colitic" mucosa (even in quiescent ulcerative colitis), while if it appears on normal mucosa, it is probably sporadic adenoma. Sporadic adenoma should be treated as in the general population and DALM could also be endoscopically removed after ruling out the presence of dysplastic lesions in the surrounding mucosa. If this is not technically possible or perilesional mucosal biopsies present dysplastic foci, we should perform a total colectomy. If we have performed endoscopic resection of the lesion, we should take biopsies of the mucosa around the lesion in 3-6 months, and also the following colonoscopies should be performed every six months.

The work for pathologist is not always easy and he can find cases in which, mainly due to the persistence of inflammatory activity, the findings are not definitive to confirm or exclude dysplasia. In these cases, endoscopy should be repeated within 3-6 months after an appropriate control of mucosa inflammation under a specific treatment.

As presented, colonoscopy is essential in monitoring these patients, being the only tool that allows taking biopsies to detect dysplasia. However, there is a long way to walk until we find the ideal strategy to make examinations less time-consuming and more cost effective. Everything suggests that modern endoscopic techniques (magnification endoscopy and chromoendoscopy) can be the key, but there is little scientific evidence by now. Secondly, the steps to follow in case of dysplasia seem to be more established. Finally, colonoscopy may have a therapeutic role if we detect low-grade dysplastic foci on lesions and masses similar to adenomas.

#### **2.4 Colorectal cancer screening strategies in patients with family history of CRC**

The risk of colorectal cancer is higher in those people who belong to families where cases of CRC have been recorded, even after having ruled out the possibility of polyposis syndromes and hereditary colorectal cancer. However, the risk depends on several factors: the number of relatives affected, the degree of kinship and age at which the neoplasm is detected. In second-degree relatives, excepting they were multiple family members affected, it is not justified any special CRC screening, and the recommendations are the same as for mediumrisk population. In case of multiple second-degree relatives affected, the different scientific societies recommend the same screening strategy as for people at average risk, but starting the screening program at age 40 years. In case of several first-degree relatives or a single family member younger than 60 years at the time of diagnosis, the only recommendation accepted is to perform colonoscopy every five years. The age to start the screening will be at 40 years of age or at age 10 years younger than the youngest case diagnosed in the family. The presence of a single first-degree relative older than 60 years increases the risk of

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 207

Fig. 11. Flat lesion in the right colon in a patient with quiescent ulcerative colitis, studied by

The interval between examinations in these cases is determined by finding the adenomadysplasia-carcinoma progression significantly shortened or even that it does not exist. It has been shown that performing examinations every 3 years had managed to reduce the incidence and the CRC mortality in more than 60%. However, widespread recommendations propose to perform colonoscopies every 1 or 2 years. Patients operated on for CRC in the context of Lynch syndrome have a high possibility of metachronous lesions, so post-resection surveillance recommendation is the same as the screening strategy for relatives at risk. The age at onset of endoscopic surveillance is usually established around 20-25 years of age or 10 years younger than the youngest case in the family, choosing the option that happens before. In conclusion, in people from families with Lynch syndrome it is justified to perform surveillance programs. The only acceptable alternative is to conduct endoscopic surveillance and, based on current evidence, conventional endoscopy may not be sufficient. The use of chromoendoscopy and magnification endoscopy may be useful, so monitoring of these patients should be performed in specialized endoscopy units with endoscopists trained in

The classic form of familial adenomatous polyposis (FAP) is characterized by the development of hundreds of polyps in the colon, usually after puberty. Its pattern of inheritance is autosomal dominant and in the absence of surgical treatment, 100% of patients would develop cancer. An attenuated form of familial adenomatous polyposis has been identified. Individuals with attenuated FAP develop 20-100 adenomatous polyps and the average age of diagnosis is ten years later than in the classic form. There is the possibility of

developing polyps at other gastrointestinal levels or tumors in other locations.

CVC, Set 4

these techniques.

**2.5.2 Familial adenomatous polyposis** 

developing the disease but in a lesser way, so the recommendations are the same as if there were second-degree relatives affected.

In summary, if there is a family history of colorectal cancer, the risk is increased respecting to the average risk population. If there is a low risk family history, as well as medium-risk population, the acceptable screening tests include fecal occult blood testing, colonoscopy and radiological tests. By contrast, if there is a high risk family history the only accepted screening test is colonoscopy because there are higher possibilities of detecting cancer or polyps.

#### **2.5 Hereditary CRC syndromes: non-polyposis colorectal cancer and familial adenomatous polyposis**

#### **2.5.1 Hereditary non-polyposis colorrectal cancer or Lynch syndrome**

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant disease which represents less than 2% of total CRC. It is mostly due to mutations in DNA repair genes and, clinically, it is characterized by the development of neoplasia in young people (under 50 years) with high preference for right colon, with great tendency to develop synchronous and metachronous neoplasms as well as in other organs (urinary tract, biliary tract, endometrium, pancreas, stomach, small intestine and ovary). It is more uncommon to find development of osteomas, skin or brain tumors. Pathologically it is characterized by a strong tendency to present a mucinous histology.

The diagnosis is based on the Amsterdam criteria: at least three relatives affected, one of whom is a first degree relative of the other, at least two successive generations involved and at least one case diagnosed of cancer before age 50. Then, these criteria were found to be too strict and were expanded to include the associated non-colorectal cancers (Amsterdam II). In any case, these criteria have poor sensitivity for the diagnosis of the disease, although its specificity is very high. Therefore, the Bethesda criteria were established, suspecting the disease by demonstrating on the resected tumor the presence microsatellite instabilty (expression of mutations in repair genes). It is mandatory to perform a genetic analysis whether if diagnosis is based on the Amsterdam criteria or on the analysis of microsatellite instability. If the mutation responsible for the disease is detected in a patient, the family members should be studied, and only those who file such mutations will be subsidiary to perform the screening program.

The aim of endoscopic surveillance of people belonging to families with Lynch syndrome is the early detection of cancer or polyps and their removal when it is possible. In many cases, precancerous lesions are flat lesions, and may not be detected by non-endoscopic techniques, so the only acceptable diagnostic technique for monitoring is the colonoscopy. Even these lesions are difficult to detect with conventional endoscopy, which may explain the high frequency of interval cancers. For this reason it was suggested to use more sophisticated endoscopic techniques (Narrow Band Imaging and chromoendoscopy) to facilitate the detection of these lesions. In our experience, chromoendoscopy seems to be easier to perform and to interpret. To do it, it is essential a correct colon cleansing and staining of the colonic mucosa with a solution of Indigo Carmine 0.2%. This will significantly improve the detection of flat lesions, almost imperceptible by conventional colonoscopy. The use of magnification endoscopy can further improve diagnostic accuracy. Computed virtual chromoendoscopy (CVC or FICE, Fujinon) (Figure 11) can be an alternative to conventional chromoendoscopy (Figure 12), avoiding the use of colorants and making even shorter examinations, but of course, it depends on the availability of this technology. The use of NBI (Figure 13) may be helpful for the characterization of lesions, but this technique may be more complicated than chromoendoscopy.

developing the disease but in a lesser way, so the recommendations are the same as if there

In summary, if there is a family history of colorectal cancer, the risk is increased respecting to the average risk population. If there is a low risk family history, as well as medium-risk population, the acceptable screening tests include fecal occult blood testing, colonoscopy and radiological tests. By contrast, if there is a high risk family history the only accepted screening

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant disease which represents less than 2% of total CRC. It is mostly due to mutations in DNA repair genes and, clinically, it is characterized by the development of neoplasia in young people (under 50 years) with high preference for right colon, with great tendency to develop synchronous and metachronous neoplasms as well as in other organs (urinary tract, biliary tract, endometrium, pancreas, stomach, small intestine and ovary). It is more uncommon to find development of osteomas, skin or brain tumors. Pathologically it is

The diagnosis is based on the Amsterdam criteria: at least three relatives affected, one of whom is a first degree relative of the other, at least two successive generations involved and at least one case diagnosed of cancer before age 50. Then, these criteria were found to be too strict and were expanded to include the associated non-colorectal cancers (Amsterdam II). In any case, these criteria have poor sensitivity for the diagnosis of the disease, although its specificity is very high. Therefore, the Bethesda criteria were established, suspecting the disease by demonstrating on the resected tumor the presence microsatellite instabilty (expression of mutations in repair genes). It is mandatory to perform a genetic analysis whether if diagnosis is based on the Amsterdam criteria or on the analysis of microsatellite instability. If the mutation responsible for the disease is detected in a patient, the family members should be studied, and only those who file such mutations will be subsidiary to

The aim of endoscopic surveillance of people belonging to families with Lynch syndrome is the early detection of cancer or polyps and their removal when it is possible. In many cases, precancerous lesions are flat lesions, and may not be detected by non-endoscopic techniques, so the only acceptable diagnostic technique for monitoring is the colonoscopy. Even these lesions are difficult to detect with conventional endoscopy, which may explain the high frequency of interval cancers. For this reason it was suggested to use more sophisticated endoscopic techniques (Narrow Band Imaging and chromoendoscopy) to facilitate the detection of these lesions. In our experience, chromoendoscopy seems to be easier to perform and to interpret. To do it, it is essential a correct colon cleansing and staining of the colonic mucosa with a solution of Indigo Carmine 0.2%. This will significantly improve the detection of flat lesions, almost imperceptible by conventional colonoscopy. The use of magnification endoscopy can further improve diagnostic accuracy. Computed virtual chromoendoscopy (CVC or FICE, Fujinon) (Figure 11) can be an alternative to conventional chromoendoscopy (Figure 12), avoiding the use of colorants and making even shorter examinations, but of course, it depends on the availability of this technology. The use of NBI (Figure 13) may be helpful for the characterization of lesions, but

test is colonoscopy because there are higher possibilities of detecting cancer or polyps.

**2.5 Hereditary CRC syndromes: non-polyposis colorectal cancer and familial** 

**2.5.1 Hereditary non-polyposis colorrectal cancer or Lynch syndrome** 

characterized by a strong tendency to present a mucinous histology.

this technique may be more complicated than chromoendoscopy.

were second-degree relatives affected.

**adenomatous polyposis** 

perform the screening program.

Fig. 11. Flat lesion in the right colon in a patient with quiescent ulcerative colitis, studied by CVC, Set 4

The interval between examinations in these cases is determined by finding the adenomadysplasia-carcinoma progression significantly shortened or even that it does not exist. It has been shown that performing examinations every 3 years had managed to reduce the incidence and the CRC mortality in more than 60%. However, widespread recommendations propose to perform colonoscopies every 1 or 2 years. Patients operated on for CRC in the context of Lynch syndrome have a high possibility of metachronous lesions, so post-resection surveillance recommendation is the same as the screening strategy for relatives at risk. The age at onset of endoscopic surveillance is usually established around 20-25 years of age or 10 years younger than the youngest case in the family, choosing the option that happens before.

In conclusion, in people from families with Lynch syndrome it is justified to perform surveillance programs. The only acceptable alternative is to conduct endoscopic surveillance and, based on current evidence, conventional endoscopy may not be sufficient. The use of chromoendoscopy and magnification endoscopy may be useful, so monitoring of these patients should be performed in specialized endoscopy units with endoscopists trained in these techniques.

#### **2.5.2 Familial adenomatous polyposis**

The classic form of familial adenomatous polyposis (FAP) is characterized by the development of hundreds of polyps in the colon, usually after puberty. Its pattern of inheritance is autosomal dominant and in the absence of surgical treatment, 100% of patients would develop cancer. An attenuated form of familial adenomatous polyposis has been identified. Individuals with attenuated FAP develop 20-100 adenomatous polyps and the average age of diagnosis is ten years later than in the classic form. There is the possibility of developing polyps at other gastrointestinal levels or tumors in other locations.

The Role of Colonoscopy in the Prevention of Colon and Rectal Cancer 209

preserved the rectum (for example in attenuated FAP it is a good option, if there are few

Fig. 13. Flat lesion, about 10 mm, located in the hepatic flexure of colon, visualized with NBI. This is a IIa lesion according to the Paris classification. Endoscopic resection and histological

Due to these patients may have adenomas in other locations of the upper gastrointestinal tract, other endoscopic procedures should be performed. It is recommended to perform a gastroscopy every 4-5 years starting from age 25. If no adenomas are detected, another possibility is to take random biopsies on the duodenal folds. Additionally, it is recommended using side vision duodenoscope for further examination of the papillary area to detect ampulomas. Treatment of duodenal adenomas is controversial. Endoscopic resection of them seems to be not very effective, especially if they are many, and it is a technique that is not exempt of complications. The severity of the lesions is established by Spiegelman classification, which takes into account the number of adenomas, size, histological type and presence of dysplasia. In patients with duodenal adenomas Spiegelman stage I-II disease, endoscopic surveillance could be performed every 2-3 years, but in patients with more complex cases, monitoring should be stricter, like performing endoscopy every 6-12 months, but probably surgical treatment should be the best option in these cases. On the other hand,

endoscopic removal of the most significant adenomas could delay surgical decision.

There are some other forms of polyposis, like MYH-associated polyposis (MAP) which appears to be similar to other hereditary conditions as attenuated familial adenomatous polyposis, so screening strategies in people with MAP should be similar to screening in

study of it showed a villous adenoma with high grade dysplasia

people with attenuated FAP.

polyps in rectum), endoscopic examination should be performed every 6-12 months.

Fig. 12. Flat lesion, almost imperceptible to conventional endoscopy, which clearly demarcates with 0.2% indigo carmine. This is a patient who performed a colonoscopy as colorectal cancer screening method because he belonged to a family that fulfilled the Amsterdam criteria for diagnosing HNPCC. This is a lesion that, according to the Paris classification of superficial gastrointestinal neoplasia, can be a category IIc (excavated or depressed). According to its size (about 25 mm) endoscopic resection can not be considered. Indeed, the study of the surgical specimen showed the presence of adenocarcinoma with infiltration of the muscularis propria (pT2)

The diagnosis is based on detection of polyps by endoscopy and histologic confirmation of the presence of adenomas. Then, genetic testing should be performed to identy APC gene mutations. However, mutations are not identified up to 30% of cases. Most diagnoses occur in relatives of patients affected, who are included on endoscopic surveillance programs. The recommended strategy in most guidelines is performing sigmoidoscopy every 1-2 years from 13-15 years of age and up to 40. From this age, they are recommended every 5 years until 60 years. In attenuated FAP, screening begins at age 10 years older than in classical FAP, and as polyps are more likely to appear on the right colon, colonoscopy should be complete. Also, chromoendoscopy may improve the detection rate of polyps on these patients.

When individuals are diagnosed, prophylactic colectomy should be considered. The standard surgery is proctocolectomy with ileo-anal reservoir. In patients with reservoir, endoscopic examinations should be performed every 3 years. In patients who have

Fig. 12. Flat lesion, almost imperceptible to conventional endoscopy, which clearly demarcates with 0.2% indigo carmine. This is a patient who performed a colonoscopy as colorectal cancer screening method because he belonged to a family that fulfilled the Amsterdam criteria for diagnosing HNPCC. This is a lesion that, according to the Paris classification of superficial gastrointestinal neoplasia, can be a category IIc (excavated or depressed). According to its size (about 25 mm) endoscopic resection can not be considered. Indeed, the study of the surgical specimen showed the presence of adenocarcinoma with infiltration of

The diagnosis is based on detection of polyps by endoscopy and histologic confirmation of the presence of adenomas. Then, genetic testing should be performed to identy APC gene mutations. However, mutations are not identified up to 30% of cases. Most diagnoses occur in relatives of patients affected, who are included on endoscopic surveillance programs. The recommended strategy in most guidelines is performing sigmoidoscopy every 1-2 years from 13-15 years of age and up to 40. From this age, they are recommended every 5 years until 60 years. In attenuated FAP, screening begins at age 10 years older than in classical FAP, and as polyps are more likely to appear on the right colon, colonoscopy should be complete. Also, chromoendoscopy may improve the detection rate of polyps on these

When individuals are diagnosed, prophylactic colectomy should be considered. The standard surgery is proctocolectomy with ileo-anal reservoir. In patients with reservoir, endoscopic examinations should be performed every 3 years. In patients who have

the muscularis propria (pT2)

patients.

preserved the rectum (for example in attenuated FAP it is a good option, if there are few polyps in rectum), endoscopic examination should be performed every 6-12 months.

Fig. 13. Flat lesion, about 10 mm, located in the hepatic flexure of colon, visualized with NBI. This is a IIa lesion according to the Paris classification. Endoscopic resection and histological study of it showed a villous adenoma with high grade dysplasia

Due to these patients may have adenomas in other locations of the upper gastrointestinal tract, other endoscopic procedures should be performed. It is recommended to perform a gastroscopy every 4-5 years starting from age 25. If no adenomas are detected, another possibility is to take random biopsies on the duodenal folds. Additionally, it is recommended using side vision duodenoscope for further examination of the papillary area to detect ampulomas. Treatment of duodenal adenomas is controversial. Endoscopic resection of them seems to be not very effective, especially if they are many, and it is a technique that is not exempt of complications. The severity of the lesions is established by Spiegelman classification, which takes into account the number of adenomas, size, histological type and presence of dysplasia. In patients with duodenal adenomas Spiegelman stage I-II disease, endoscopic surveillance could be performed every 2-3 years, but in patients with more complex cases, monitoring should be stricter, like performing endoscopy every 6-12 months, but probably surgical treatment should be the best option in these cases. On the other hand, endoscopic removal of the most significant adenomas could delay surgical decision.

There are some other forms of polyposis, like MYH-associated polyposis (MAP) which appears to be similar to other hereditary conditions as attenuated familial adenomatous polyposis, so screening strategies in people with MAP should be similar to screening in people with attenuated FAP.

**15** 

*Japan* 

*Cardiovascular Diseases* 

**Recent Advances in Diagnostic** 

**Endoscopy for Colorectal Neoplasm** 

Yoji Takeuchi, Noboru Hanaoka and Masao Hanafusa

*Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and* 

Colorectal cancer is one of the most common causes of cancer-related death in the western world (Jemal et al., 2009). Most non-hereditary colorectal cancers arise from benign adenomas (Morison et al., 1974). It has been reported that removal of adenomatous polyps reduces the risk of subsequent colorectal cancer by as much as 80% (Winawer et al., 1993). Therefore, detection and removal of colorectal adenomas, as well as of cancer in the early stages, is utmost importance in improving the prognosis of patients with colorectal cancer. Although colonoscopy is one of the most reliable methods for diagnosis of colorectal neoplasms, conventional colonoscopy could be improved by addressing some of its

In this article, the new and promising technologies that comprise image-enhanced endoscopy (IEE) are reviewed, and a new colonoscopic strategy that incorporates some of

It is generally known that conventional colonoscopy fails to detect some colorectal neoplasms (Rex, et al., 1997) and that such failure may lead to interval cancers between successive colonoscopies. To date, many attempts have been made to improve screening and surveillance colonoscopy. Mounting a transparent hood (TH) on the tip of the colonoscope helps in the detection of colorectal neoplasms by pressing and flattening the colonic folds, thus improving the endoscopic view (Hewett & Rex, 2010). On the other hand IEE, including the total colonic dye-spray method, narrow-band imaging (NBI), flexible spectral imaging color enhancement (FICE) and autofluorescence imaging (AFI) offers the possibility of increasing the detection rate of colorectal neoplasms by increasing the visibility of

Although the reasons for overlooking colorectal neoplasms are unknown, there are two major possibilities (Fig. 1). One is that the overlooked lesions are small and hidden behind colonic folds. Endoscopists should check possible blind spots by using 'mechanical' devices which allow them to look behind colonic folds. The other possible reason is that the overlooked lesions are flat and similar in color to the surrounding mucosa, which makes

**2. Detection of colorectal neoplasms using colonoscopy** 

**1. Introduction** 

shortcomings.

these techniques is proposed.

colorectal neoplasms.
