Colorectal Cancer Disease Background

Introduction 

Colorectal cancer (CRC) is a carcinoma that arises from the epithelial lining of the colon or the rectum.  Rectal cancer is defined as cancerous lesions located ≤15 cm from the anal margin (with rigid proctoscopy).

Epidemiology 

The incidence of colorectal cancer is higher in males. The risk of colorectal cancer increases with age, with most cases affecting people >50 years of age. Globally, CRC is the third most common cancer worldwide, accounting for 10% of all cancer cases. It is the third most commonly diagnosed cancer in males and the second in females. In 2022 alone, there were as many as 1,142,286 new cases. The highest recorded incidence rates are in Australia and New Zealand, Europe, and North America. While the lowest incidence rates are found in Africa and South-Central Asia. However, it can be noted that in the past several years, CRC incidence rates have rapidly increased in several areas that are historically low risk, such as Spain, and several countries in Asia and Eastern Europe.  

Colorectal cancer is the second leading cause of cancer-related deaths worldwide with 538,167 deaths in 2022 alone. It is noted that rates of both incidence and mortality are substantially higher in males than in females.  

In Asia, colorectal cancer is the third most common cancer, accounting for 966,399 new cases in 2022. It is the fourth most common cause of cancer-related death in Asia with 462,252 deaths in 2022 alone. Among the Asian countries, Japan has the highest age-standardized incidence rate (ASR), having an ASR of 45.5 per 100,000 in men and 28.5 per 100,00 in women, even higher than those reported in some Western countries. Japan also has the highest age-standardized mortality rate among Asian countries. In the Philippines, it is the third most commonly diagnosed cancer with 20,736 new cases in 2022. While it is the fourth most common cause of cancer-related death with 10,692 deaths in 2022 in the Philippines.  

Epidemiology-PH

Pathophysiology 

Colorectal cancer is a multifactorial disease, with both environmental and genetic factors at play. The evolution to adenocarcinoma follows a relatively predictable course because of accumulated genetic and epigenetic alterations. The vast majority of colorectal cancer arises from a polyp with an aberrant crypt that eventually becomes an adenoma. Most of these polyps are benign or noncancerous. However, some may progress into cancer over time depending on the type or histology. Different types of polyps include adenomatous polyps of adenomas, hyperplastic and inflammatory polyps, and sessile serrated polyps (SSP) and traditional serrated adenomas (TSA). Most colorectal cancers arise from adenomatous polyp. Based on histology, adenomatous polyps are further divided into tubular, villous, and tubulovillous polyps. Among these different types of polyps, the villous and tubulovillous adenomatous polyps, and SSPs have the greatest potential to turn into cancer. At a molecular level, there seems to be 3 pathways leading to colorectal tumorigenesis. The first is the chromosomal instability pathway that occurs in familial adenomatous polyposis (FAP). The second involves genetic mutations in deoxyribonucleic acid (DNA) mismatch repair pathway seen in Lynch syndrome. Lastly, there is the pathway that is due to the hypermethylation of CpG rich islands in specific gene promoter regions commonly observed in serrated polyps.

Risk Factors 

Chances are increased markedly after the age of 50. Colorectal cancer incidence and mortality rates are highest among African-Americans.  

If there is a personal history of colorectal cancer, the chances of developing new cancers in other parts of the colon or rectum are still possible even after the removal of previous colorectal cancer, and the risk is increased in those who had their first colorectal cancer at a young age. A personal history of colorectal polyps such as adenomatous polyps, especially multiple, large ones (>2 cm has a reported 40% chance of malignant transformation), also increases the risk of developing colorectal cancer.  

Malignant transformation is higher for villous and tubulovillous adenomas. Approximately 95% of patients with FAP will develop adenomas by age 35 and if left untreated, have a 100% chance of developing colorectal cancer.  

Hereditary nonpolyposis colorectal cancer or HNPCC (Lynch syndrome) is transmitted as an autosomal dominant trait. The Amsterdam II criteria are utilized to identify high-risk families suspected of having HNPCC and are as follows:

• Colorectal cancer affecting ≥2 generations
• ≥3 relatives with a histologically diagnosed HNPCC-associated cancer (eg colorectal cancer, small bowel, endometrial, renal pelvis, or ureteral cancer)
• ≥1 colorectal cancers diagnosed at <50 years of age

In suspected Lynch syndrome without a known familial mutation, the first step in genetic diagnosis is identifying microsatellite instability (MSI) in tumor cells.

A personal history of inflammatory bowel disease (IBD) (ulcerative colitis, Crohn’s disease) increases the risk for colorectal cancer; therefore, colorectal screening should be done more frequently. The risk of colorectal cancer in a patient with ulcerative colitis depends on the extent of the colitis, duration of active disease and symptoms, and development of mucosal dysplasia. The risk of colorectal cancer in Crohn’s disease is also increased but to a lesser extent. In patients with ulcerative colitis, the overall incidence of colorectal cancer is 3.7%, with a 2% probability by 10 years, and 8% by 20 years. In patients with Crohn’s colitis, the risk for colorectal cancer is similar while it appears that there is no significant risk associated with proctitis.  

There is also an increased risk for colorectal cancer in patients with a family history of colorectal cancer. The risk is highest in those with >1 affected first-degree relative (parent, siblings) or in those whose first-degree relative had colorectal cancer at a young age.  

Type 2 DM also increases the risk of colorectal cancer and tends to have a less favorable prognosis. Both overweight and obese people are at increased risk of colorectal cancer. The pattern of fat distribution relates to the colorectal cancer risk (abdominal obesity being a stronger risk factor than truncal obesity or body mass index [BMI]). Obesity approximately increases by 2x the risk of adenomas (particularly, ≥1 cm, tubulovillous adenomas).  

Consumption of red and processed meats, fat and cholesterol-rich diets have been linked to an increased risk of colorectal cancer. Heavy alcohol consumption also increases the risk of colorectal cancer and is probably due to low levels of folic acid among heavy drinkers. Studies of recent years have found an association between smoking and colorectal cancer, with relative risks between 1.5 to 3. A sedentary lifestyle also increases the risk of colorectal cancer.

Risk Stratification            

Average risk includes individuals ≥45 years with no history of colorectal cancer, adenoma or sessile serrated polyps (SSP), inflammatory bowel disease, and negative family history. Increased risk includes individuals with a personal history of colorectal cancer, adenomatous or sessile serrated polyps, and inflammatory bowel disease, as well as those with a positive family history of colorectal cancer or advanced adenomatous polyps. High risk includes individuals with a personal or family history of polyposis syndromes and also includes those with a family history of HNPCC (Lynch syndrome).