Description

• Colon and rectal cancers (CRCs) are often grouped together but are two distinct clinical entities that differ in their prognosis, presentation, staging, and management.
• CRC is the third leading cause of cancer-related deaths in men and women in the United States.

Epidemiology

Incidence

• Estimated that in 2023 in the United States, there are 106,970 new cases of colon cancer and 46,050 new cases of rectal cancer per the American Cancer Society (ACS).
• The annual incidence of colorectal cancer was 33% higher in men than women from 2015 to 2019.
• Colorectal cancer is expected to cause about 52,550 deaths during 2022.
• Internationally, CRC is the third most common cancer and the second leading cause of cancer death.

Prevalence
The lifetime risk of developing colorectal cancer in the United States is about 1 in 23 (4.3%) for men and 1 in 26 (3.9%) for women.

Etiology and Pathophysiology

• Progression from the first abnormal cells to colon cancer occurs over 10 to 15 years.
• High-risk polyps: multiple polyps, villous or dysplastic polyps, and larger polyps; hyperplastic polyps are less likely to evolve into CRC.
• Both genetic and environmental factors are linked to CRC.

Genetics

• <10% of CRC cases are linked to an inherited gene. Patients with early-onset CRC have a higher percentage of genetic causes, suggesting family members to have an early screening.
  • Many of these are inherited in an autosomal dominant fashion:
    • APC, a tumor-suppressor gene, is altered in familial adenomatous polyposis (FAP).
    • Genes encoding DNA mismatch repair (MMR) enzymes are implicated in hereditary nonpolyposis colon cancer (HNPCC), formerly known as Lynch syndrome, including hMLH1, hMSH2, hMSH6, hPMS2, EPCAM, and others.
    • STK11, a tumor-suppressor gene, is altered in Peutz-Jeghers syndrome.
  • A smaller portion of patients with familial CRC may have a recessive gene.
    • MUTYH defects lead to issues with the base excision repair gene. This MUTYH-associated polyposis (MAP) may present as a variant form of FAP.
• Sporadic cases of CRC have been linked to oncogenes: KRAS, PIK3CA, APC, TP53, BRCA1, BRCA2, BRAF.

Risk Factors

• Age
  • The incidence of colon cancer starts to increase significantly between the age of 40 and 50 years old. ~87% of those with new CRC diagnosis will be ≥50 years old.
  • Younger patients are more likely to have advanced disease at the time of diagnosis.
• Personal history of colorectal polyps
  • The risk increases with multiple polyps, villous polyps, larger polyps (>1 cm), and presence of dysplasia.
• Personal history of cancer
  • 30% increase in risk of developing metachronous (new primary tumors unrelated to the patients’ previous cancers) colon cancer
  • 2–4% incidence of local recurrence with colon cancer, 3–5% incidence of synchronous colon cancer
  • History of radiation therapy to the abdomen/pelvis
• Personal history of inflammatory bowel disease (IBD)
  • The risk of CRC begins approximately 8 years after the onset. Prevalence of CRC in ulcerative colitis and Crohn disease is ~3%, with a cumulative risk of CRC of 2% at 10 years, 8% at 20 years, and 18% at 30 years.
  • Ulcerative colitis with pancolitis up to 10-fold risk of CRC, 8 to 10 years after initial diagnosis.
• Family history of CRC
  • Having a single first-degree relative with a history of CRC increases risk by ~1.7-fold.
  • The risk is more than double for those who have a history of CRC or polyps in:
    • Any first-degree relative <50 years of age
    • ≥2 first-degree relatives, regardless of age
    • One first-degree relative and one second-degree relative
• Inherited syndromes
  • HNPCC
    • Often develops at young age (The average age of diagnosis of CRC is 48 years.)
    • Often presents with right-sided lesions and cancer often recurs
    • Lifetime risk of CRC is 52–69%; also associated with endometrial and other cancers
    • Accounts for ~3% of all CRCs
  • FAP
    • Affected individuals develop hundreds to thousands of polyps in colon and rectum, typically presenting during childhood.
    • CRC usually present by age 40 years in untreated patients; however, most have prophylactic colectomies.
    • Accounts for <1% of CRCs
    • Variants include Gardner and Turcot syndromes as well as attenuated FAP (AFAP).
  • Peutz-Jeghers syndrome
    • Individuals may have hyperpigmented mucocutaneous lesions (mouth, hands, feet) and large polyps in GI tract discovered as an adolescent.
    • 81–93% risk for cancers including CRC, cancers of pancreas, breast, cervix, testes, and lung
  • BRCA1 and BRCA2 syndromes
    • Some data suggest that carriers of BRCA1 may have increased risk for early CRC; however, more evidence is needed to recommend early screening.
• Race and ethnicity
  • African Americans have the highest CRC incidence and mortality rates in the United States; likely due to social determinants of health
• Lifestyle factors
  • Smoking, obesity, sedentary activity, insulin resistance, high-fat and low-fiber diet, red and processed meat, excessive alcohol consumption, and potentially microbiota

General Prevention

• Lifestyle factors and medications that may reduce the risk:
  • Regular physical activity, diet high in fiber, and fruits/vegetables
  • There is conflicting evidence on folic acid, calcium, vitamin D, magnesium, NSAIDs, fish oil, and statins.

• Screening methods:
  • Visualization-based tests:
    • Flexible sigmoidoscopy every 10 years with a high-sensitivity fecal immunochemical test (FIT) yearly
    • Flexible sigmoidoscopy every 5 years
    • Colonoscopy every 10 years
  • Stool-based tests:
    • FIT annually
    • High-sensitivity guaiac-based fecal occult blood test (gFOBT) annually
    • Stool DNA-FIT every 1 to 3 years (e.g., Cologuard)
  • Imaging-based tests:
    • CT colonography every 5 years
  • For patients who have a positive FIT, gFOBT, or stool DNA-FIT test, a colonoscopy is recommended.
• ACG guideline recommends a colonoscopy or a FIT as a primary CRC screening method, and other methods are reserved for those unwilling or unable to undergo a colonoscopy or a FIT (1).
• Colonoscopy:
  • People with a history of polyps need frequent colonoscopy screening, with the interval depending on polyp number, size, and histology.
  • People who have a first-degree relative or two second-degree relatives with CRC or advanced polyps before age 60 years should begin colonoscopy at the age of 40 years or 10 years younger than the youngest age of the affected relative at cancer diagnosis, whichever is earlier.
  • Patients with IBD should start surveillance colonoscopies every 1 to 2 years 8 to 10 years after diagnosis.
  • Genetic testing may be appropriate for individuals with a strong family history of CRC or polyps:
    • Family members of a person with HNPCC should start colonoscopy at the age of 20 to 25 years or 2 to 5 years prior to the youngest age of the affected relative at the time of cancer diagnosis, whichever occurs first. This screening should be repeated every 1 to 2 years.
    • Individuals with suspected FAP should have colonoscopy every 1 to 3 years, beginning at the age of 10 to 14 years.
• Frequency of follow-up of polyps:
  • <1 year:
    • Following piecemeal (unable to remove with single loop) removal of a large polyp ≥20 mm
  • 1 year:
    • Known FAP or at risk based on family history
    • >10 adenomatous polyps
  • 1 to 2 years:
    • IBD (Crohn disease or ulcerative colitis)
  • 3 years:
    • 5 to 10 tubular adenomas <10 mm
    • 5 to 10 sessile serrated polyps
    • Tubular adenoma ≥10 mm
    • Sessile serrated polyp ≥10 mm
    • Adenoma with villous or tubulovillous histology and/or high-grade dysplasia
    • Sessile serrated polyp with dysplasia
    • Traditional serrated adenoma
  • 3 to 5 years:
    • 3 to 4 sessile serrated polyp <10 mm without dysplasia
    • 3 to 4 adenomas <10 mm
    • Hyperplastic polyps ≥10 mm
    • History of colon cancer s/p surgery if initial 1 year follow-up is normal
  • 5 to 10 years:
    • 1 to 2 sessile serrated polyp <10 mm without dysplasia
  • 7 to 10 years:
    • 1 to 2 adenomas <10 mm
  • 10 years:
    • Normal screening colonoscopy with no polyps
    • ≤20 Hyperplastic polyps in rectum or sigmoid colon, <10 mm
    • ≤20 Hyperplastic polyps proximal to sigmoid colon, <10 mm

Commonly Associated Conditions

• HNPCC, Gardner, Crail (Turcot), FAP, Peutz-Jeghers, and juvenile polyposis syndromes
• IBDs including Crohn disease and particularly ulcerative colitis with pancolitis