Colorectal cancer is the third most common cancer worldwide, having a mortality of approximately half of its incidence, which makes it the fourth most common cause of cancer death [1]. This disease is slightly more common in men than in women, by 7–5. Additionally, risk increases with age.

Etiology

Genetic proneness varies from strong defined inherited syndromes, such as familial adenomatous polyposis, to ill-defined familial clustering [1]. Genetic and molecular mechanisms underlying are different. Some recent research indicates two main chains of sequence: a mutational pathway, involving microsatellite instability which appears mainly in hereditary nonpolyposis colon cancer and in a low proportion of sporadic carcinomas. The starting lesion is the adenoma, which is frequently detected and treated by routine endoscopic techniques. Nonneoplastic polyps are not considered precancerous unless they occur in polyposis syndromes. Inflammatory bowel diseases, such as chronic ulcerative colitis, require control by endoscopic surveillance due to the risk for colorectal cancer. Full recovery after surgery is linked to early diagnosis and anatomic compromise, which makes precise staging by histopathology very important. Other varieties of tumors are seldom diagnosed in the colon and rectum. Unknown carcinogens ingested unwittingly with food and drinks can interact directly with the cells of the colon and rectum mucosa if they are not previously inactivated, absorbed, or metabolized in the stomach and small intestine. Increasing epidemiological evidence indicates that certain dietary patterns, alcohol consumption, overweight, and a sedentary lifestyle are consistent risk factors for colorectal cancer. Fatty red meat products, such as cold cuts, sausages, and bovine viscera would increase risk probably due to their high saturated fat content. High-fat diets, rich mainly in cholesterol and saturated lipids, may favor colon cancer because of their high caloric content. Alternatively, they may lead to increased levels of biliary acids in the colonic lumen or unbalanced ratio of conjugated linoleic acid – CLA (conjugated linoleic acid). Further, consumption of protein, iron, and heterocyclic amines produced by cooking and N-nitroso compounds has also been involved. Heterocyclic amines formed during cooking of red meat are powerful mutagens and carcinogens. The type of beef meat preferred by South American population for barbecuing or iron-pan cooking is usually fatty rich (30–33% of total lipids). Thus, undesirable quality of cuts increases when other risky cooking procedures are added, such as high cooking temperatures with close and prolonged contact to charcoal smoke. These combinations probably enhance the production of heterocyclic amines.

Develops

CRC (Colorectal cancer) develops from genetic alterations that affect primarily genes encoding either intestinal homeostatic regulators or DNA mismatch-repair factors, predominantly in intestinal stem cells that become CSCs [2]. But when at the beginning of the millennium it was found that inflammatory bowel disease (IBD) patients have a several fold increased susceptibility to cancer, colorectal cancers in IBD—both Crohn’s disease and ulcerative colitis—patients were considered typical examples of inflammation-related or colitis-associated cancer (CAC). Alterations in the percentages of fora composition of the gut or changes in the presence of specific bacterial species might modulate that environment through the catabolism of natural mutagens and carcinogens, or that requires or is regulated by specific enzymatic activity provided by the commensal fora, with pro- or anti-inflammatory effects. Although IBDs became the major risk factors for CRC, still the relative increased risk for colorectal cancer in these patients is not higher than threefold compared with healthy controls, and the tumors usually appear after many years of intestinal pathology, with a cumulative lifetime risk of 18%; that is, most CRCs develop without any obvious preexisting intestinal infammatory pathology. Interestingly, IBD patients also have an increased susceptibility to lymphomas/leukemias, hepatocarcinomas, and other tumors, suggesting that the intestinal infammation due to the pathological immune responsiveness to the commensal microbiota is responsible for both local and systemic tumor-promoting effects. The immunosuppressive agents used in IBD therapy might also explain this increased susceptibility; however, the types of tumors that increased in the IBD patients are different from those observed in patients that had used that therapy in transplants. Epidemiological, pathological and molecular genetic studies have provided convincing evidence that most colorectal cancers arise in adenomatous polyps and that their complete removal arrests the development of cancer at that site [3]. People with familial adenomatous polyposis (FAP) typically have hundreds or thousands of adenomas and have an almost 100% risk of developing cancer. In sporadic disease, the risk of developing metachronous adenomatous polyps or colorectal cancer increases with the number of adenomas detected initially. It is not uncommon to see a focus of malignancy within a large adenoma or to see remnant adenomatous tissue adjacent to a carcinoma, particularly in early cancers. It is a less frequent finding in advanced cancers suggesting that the malignant tissue overgrows the adenomatous element. The chance of finding a focus of malignancy within an adenoma grows with increasing size, and with more advanced histology and dysplasia. Molecular genetic studies have provided further evidence for the concept of the adenoma to carcinoma sequence by demonstrating that the adenoma accumulates genetic abnormalities as it becomes larger, more severely dysplastic and progresses to malignancy.

Pathophysiology

The consensus now holds that in the vast majority of sporadic cases, CRC arises within a precursor lesion, the adenomatous polyp [4]. The adenoma–carcinoma sequence hypothesis is supported by indirect evidence from several sources. Both CRC and polyps have a similar anatomic distribution. The mean age of onset of polyps predates the mean age of onset of carcinoma by several years, and cancer rarely develops in the absence of polyps. Patients with one or more large adenomatous polyps (≥1 cm) are at increased risk of developing CRC, most of which develop at the site of the polyp, if left in place. In addition, patients with genetic predisposition to colonic polyp formation are at greatly increased risk of CRC. Finally, several studies have shown that polypectomy significantly reduces the incidence of CRC. Importantly for imagingbased screening, the risk of a polyp harboring a carcinoma is related directly to the size of the lesion: in polyps less than 1 cm in size, the risk is estimated to be <1%; in polyps measuring 1–2 cm, the risk increases to 10%; and in polyps larger than 2 cm, the risk is 25% or more.  Initiation of CRC is thought to require only two mutations in the adenomatous polyposis coli (APC) gene (a tumor suppressor gene). APC mutations are seen in about 60% of sporadic CRC. The germline APC gene is mutated in familial adenomatous polyposis (FAP) coli. Progression from premalignant polyp to invasive carcinoma is the result of further mutations in other genes, including K-ras, DCC, and p53.

Pathogenesis

Most colorectal cancers, regardless of etiology, arise from adenomatous polyps [5]. A polyp is a grossly visible protrusion from the mucosal surface and may be classified pathologically as a nonneoplastic hamartoma (juvenile polyp), a hyperplastic mucosal proliferation (hyperplastic polyp), or an adenomatous polyp. Only adenomas are clearly premalignant, and only a minority of such lesions ever develop into cancer. Population-screening studies and autopsy surveys have revealed that adenomatous polyps may be found in the colons of 30% of middle-aged or elderly people; however, 1% of polyps ever become malignant. Most polyps produce no symptoms and remain clinically undetected. Occult blood in the stool may be found in 5% of patients with such lesions. Clinically, the probability of an adenomatous polyp becoming a cancer depends on the gross appearance of the lesion, its histologic features, and its size. Adenomatous polyps may be pedunculated (stalked) or sessile (flat-based). Cancers develop more frequently in sessile polyps. Histologically, adenomatous polyps may be tubular, villous (i.e., papillary), or tubulovillous. Villous adenomas, most of which are sessile, become malignant more than three times as often as tubular adenomas. The likelihood that any polypoid lesion in the large bowel contains invasive cancer is related to the size of the polyp, being negligible (2%) in lesions 1.5 cm, intermediate (2 to 10%) in lesions 1.5 to 2.5 cm in size, and substantial (10%) in lesions 2.5 cm. Following the detection of an adenomatous polyp, the entire large bowel should be visualized endoscopically or radiographically, since synchronous lesions are present in about one-third of cases. Colonoscopy should then be repeated periodically, even in the absence of a previously documented malignancy, since such patients have a 30 to 50% probability of developing another adenoma and are at a higherthan-average risk for developing a colorectal carcinoma. Adenomatous polyps are thought to require 5 years of growth before becoming clinically significant; colonoscopy need not be carried out more frequently than every 3 years.

Risk Factors

Main risk factors for CRC, obesity, lack of exercise, fat-rich diets, and use of alcohol and tobacco, particularly those related with nutrition, are environmental agents that affect the commensal microbiota [2]. Very likely those agents are responsible for the geographical variation in the incidence of colorectal cancer since these wide geographical variations are lost in migrating populations which acquire the same risk as the host populations within one generation. This latter fact does not support the alternative hypothesis that the same genetic alterations that affect inflammatory and immune intestinal homeostasis also predispose an individual to carcinogenesis in other tissues. The risk increases with the duration and severity of disease, and is higher in patients with a family history of CRC, extensive colitis, and PSC (primary sclerosing cholangitis) [6]. Decreased risk in recent reports may be associated with improved medical treatment of colitis. Cancers in UC (ulcerative colitis) tend to be multicentre and broadly infiltrating. They are difficult to recognize endoscopically because they arise from small, flat areas of dysplasia located in a background of ulceration and inflammation. They do not follow the typical adenoma carcinoma sequence seen in sporadic CRC in the general population. Newer techniques, including narrow-band imaging and chromo endoscopy may improve detection.

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