**2.3 Serrated pathway**

The serrated pathway was first described by Longacre and Fenoglio-Preiser in 1990 and differs from the classical adenoma-carcinoma sequence one because in this way there is the participation of other genetic alterations other than chromosomal instability and KRAS mutations like BRAF mutations and gene promoter hypermethylation. But in the serrated pathway, microsatellite instability can also be detected.

The serrated polyps are characterized by glandular serration in which the colonic epithelial crypts show luminal "saw-toothed" pattern. The nomenclature is not well established but the World Health Organization in 2010 classified them into three main groups: hyperplastic polyps, sessile serrated adenomas/polyps and traditional serrated adenomas [46].

Genetically, carcinoma arising from serrated polyps are MSI-H and shows epithelial serrations, clear, eosinophilic and abundant cytoplasm, vesicular nuclei, absence of necrosis, mucin production and presence of cell balls and rods. The finding of serrated lesion in the peripheral of an invasive carcinoma also leads to the diagnostic of this pathway.

Serrated adenocarcinoma is found in about 10% of sporadic colorectal cancers and is originated in the serrated polyp-carcinoma pathway. In this way, hyperplastic polyps now are recognized as neoplastic lesions because they may predispose

### **Figure 4.**

*Model of DNA repair proteins and molecular pathways for CCR with microsatellite instability. Modified from Kohzoh and Yamamoto [44].*

**33**

goal in these cases.

in clinical practice [47].

**3. Conclusion**

accomplished.

*A Genetic Perspective on Colorectal Cancer Progression DOI: http://dx.doi.org/10.5772/intechopen.85894*

to cancer in a sequence in which they progress to serrated adenomas and then to colorectal cancer in at about 7 years. It is not clear why only a few groups of hyperplastic polyps, mainly the ones located in the right colon, will progress to carcinoma and the answer is probably dependent on the genetic findings not elucidated until now. A great number of studies have shown that the right colon is not the same organ as the left colon and the right-sided cancer tends to be more aggressive and this difference is caused by the difference of genetic standard between the sides. The clinical management of hyperplastic polyps and serrated polyps is essential for avoiding the carcinoma transformation. The most important procedure for prophylaxis is the complete removal of these polyps in colonoscopy and the subsequent surveillance but it is not well established how to follow up. Just for comparison, in the classical adenomatous polyps, the size, number and histological variants (if tubular, villous or tubulovillous) are taken in account to determine the interval of surveillance and this knowledge is more than a decade old. For serrated polyps, as the understanding of this pattern of via is recent, the follow up is not clear hence studies have not shown yet which features are important to determine the risk of progression of these lesions. Moreover, the majority of serrated polyps will not progress to carcinoma and studies answering why are not yet available. A few studies have demonstrated that sessile serrated lesions larger than 10 mm are at high risk for carcinoma progress. But despite the lack of information and in order to prevent cancer arising via serrated pathway, the complete removal of serrated polyps is the

If there are significant differences regarding the genetic markers and pathological findings in serrated pathway, it is expected to have differences in the presentation of the disease and response to therapy. And some evidences have showed these: carcinomas arising from serrated pathway tends to have lesser 5-year survival but again the causes of this comportment are not available, and the answer may be

For now, it is clear that serrated pathway is a well-established pattern that explains the behavior of some hyperplastic and serrated polyps that could not have been explained in the classical adenoma-carcinoma sequence using CIN and MSI models. Even with lacks in knowledge for profound understanding, the pathological and molecular characterization of these polyps are constantly progressing and studies in the next few years will probably show the best way to manage these cases

There have been significant advances about tumor molecular biology, will allow us to apply this knowledge in more specific diagnostic techniques, a proper diagnosis, with the possibility of detecting earlier pre-malignant lesions and diagnoses. This applied research knowledge would allow the development of more efficient

The application of molecular biology knowledge in the diagnosis and treatment

of colorectal cancer generates a great impact on the accuracy of diagnosis and optimization of cancer therapy in order to individualize the treatment, thereby trying to reduce the uncertainty about the effectiveness of the treatment that will be

found as the genetic alterations becomes evident [47].

therapies for cancer, moreover, it can act in prevention.

## *A Genetic Perspective on Colorectal Cancer Progression DOI: http://dx.doi.org/10.5772/intechopen.85894*

*Multidisciplinary Approach for Colorectal Cancer*

sporadic or hereditary nature (HNPCC) [45].

cancer [44].

**2.3 Serrated pathway**

serrated adenomas [46].

diagnostic of this pathway.

detected.

**Figure 4** shows the model of DNA repair proteins in patients with colorectal

Studies performed in CCR demonstrated a positivity index for greater microsatellite instability in young patients or located in proximal segments of the colon. A study restricted to rectum tumors, the incidence of repair errors was only in 2% of cases, confirming the relationship between microsatellite instability and tumors located in the right or transverse colon [45]. The CCR associated with repair errors tend to present the same location and biological behavior independent of their

The serrated pathway was first described by Longacre and Fenoglio-Preiser in 1990 and differs from the classical adenoma-carcinoma sequence one because in this way there is the participation of other genetic alterations other than chromosomal instability and KRAS mutations like BRAF mutations and gene promoter hypermethylation. But in the serrated pathway, microsatellite instability can also be

The serrated polyps are characterized by glandular serration in which the colonic epithelial crypts show luminal "saw-toothed" pattern. The nomenclature is not well established but the World Health Organization in 2010 classified them into three main groups: hyperplastic polyps, sessile serrated adenomas/polyps and traditional

Genetically, carcinoma arising from serrated polyps are MSI-H and shows epithelial serrations, clear, eosinophilic and abundant cytoplasm, vesicular nuclei, absence of necrosis, mucin production and presence of cell balls and rods. The finding of serrated lesion in the peripheral of an invasive carcinoma also leads to the

Serrated adenocarcinoma is found in about 10% of sporadic colorectal cancers and is originated in the serrated polyp-carcinoma pathway. In this way, hyperplastic polyps now are recognized as neoplastic lesions because they may predispose

*Model of DNA repair proteins and molecular pathways for CCR with microsatellite instability. Modified from* 

**32**

**Figure 4.**

*Kohzoh and Yamamoto [44].*

to cancer in a sequence in which they progress to serrated adenomas and then to colorectal cancer in at about 7 years. It is not clear why only a few groups of hyperplastic polyps, mainly the ones located in the right colon, will progress to carcinoma and the answer is probably dependent on the genetic findings not elucidated until now. A great number of studies have shown that the right colon is not the same organ as the left colon and the right-sided cancer tends to be more aggressive and this difference is caused by the difference of genetic standard between the sides.

The clinical management of hyperplastic polyps and serrated polyps is essential for avoiding the carcinoma transformation. The most important procedure for prophylaxis is the complete removal of these polyps in colonoscopy and the subsequent surveillance but it is not well established how to follow up. Just for comparison, in the classical adenomatous polyps, the size, number and histological variants (if tubular, villous or tubulovillous) are taken in account to determine the interval of surveillance and this knowledge is more than a decade old. For serrated polyps, as the understanding of this pattern of via is recent, the follow up is not clear hence studies have not shown yet which features are important to determine the risk of progression of these lesions. Moreover, the majority of serrated polyps will not progress to carcinoma and studies answering why are not yet available. A few studies have demonstrated that sessile serrated lesions larger than 10 mm are at high risk for carcinoma progress. But despite the lack of information and in order to prevent cancer arising via serrated pathway, the complete removal of serrated polyps is the goal in these cases.

If there are significant differences regarding the genetic markers and pathological findings in serrated pathway, it is expected to have differences in the presentation of the disease and response to therapy. And some evidences have showed these: carcinomas arising from serrated pathway tends to have lesser 5-year survival but again the causes of this comportment are not available, and the answer may be found as the genetic alterations becomes evident [47].

For now, it is clear that serrated pathway is a well-established pattern that explains the behavior of some hyperplastic and serrated polyps that could not have been explained in the classical adenoma-carcinoma sequence using CIN and MSI models. Even with lacks in knowledge for profound understanding, the pathological and molecular characterization of these polyps are constantly progressing and studies in the next few years will probably show the best way to manage these cases in clinical practice [47].
