Description

• Colon and rectal cancers (CRC) 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 2022 in the United States, there are 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer per the American Cancer Society (ACS).
• Colorectal cancer is expected to cause about 52,580 deaths during 2022.
• Incidence is relatively equal between men and women. Internationally, CRC is the third most common cancer in men and the second most common in women.

Prevalence
The lifetime risk for developing colon cancer in the United States is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) 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 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 have 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 Lynch syndrome, including hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, 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, C-MYC, C-SRC, HER-2/neu, BRCA1, BRCA2, TP53, and others.

Risk Factors

• Age
  • >90% of people diagnosed with sporadic colon cancer are >50 years of age.
  • Younger patients are more likely to have advanced disease at the time of diagnosis.
• Personal history of colorectal polyps
  • 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 7 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.
  • 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 and one second-degree relative
• Inherited syndromes
  • HNPCC
    • Often develops at young age (Average age at 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 CRC and other cancers including 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, and potentially microbiota.

General Prevention

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

• Screening methods:
  • Visualization-based tests:
    • Colonoscopy every 10 years
    • Flexible sigmoidoscopy every 5 years
    • Flexible sigmoidoscopy every 10 years + FIT yearly
  • Stool-based tests:
    • FIT annually
    • High-sensitivity fecal occult blood testing annually
    • FIT-DNA (sDNA) test every 1 to 3 years
  • Imaging-based tests:
    • CT colonography every 5 years
  • For patients who have a positive FIT, FOBT, or stool DNA test, a colonoscopy is recommended.
• Colonoscopy:
  • People with a history of polyps need frequent colonoscopy screening, with the interval depending on polyp number, size, and histology (1).
  • People who have a first-degree relative or two second-degree relatives with CRC or adenomatous polyps before age 60 years should begin colonoscopy at the age of 40 years or 10 years younger than the youngest age of relative at cancer diagnosis, whichever is earlier.
  • IBD patients should have surveillance colonoscopies every 1 to 2 years 8 to 10 years after diagnosis.
  • People with prior abdominal/pelvic radiation should be screened; however, recommendations vary typically starting between 30 and 40 years and occurring every 5 to 10 years thereafter.
  • 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 25 years.
    • Individuals with suspected FAP should have yearly flexible sigmoidoscopy beginning at age 10 to 12 years; if polyps are seen, a colonoscopy is recommended.
• Frequency of follow-up of polyps:
  • <1 year:
    • Following piecemeal (unable to remove with single loop) removal of a large polyp >15 mm
    • Serrated polyposis syndrome; meets one of the following criteria:
      • At least 5 serrated polyps proximal to sigmoid, with 2 or more 10 mm
      • Any serrated polyps proximal to sigmoid with family history of serrated polyposis syndrome
      • 20 serrated polyps of any size throughout the colon
  • 1 year:
    • Known FAP or at risk based on family history
  • 1 to 2 years:
    • IBD (Crohn disease or ulcerative colitis)
  • <3 years:
    • >10 adenomatous polyps
  • 3 years:
    • 3 to 10 tubular adenomas
    • Tubular adenoma 10 mm or larger
    • Sessile serrated polyp 10 mm or larger
    • Villous adenomatous polyp
    • High-grade dysplastic adenoma or serrated polyp on pathology
    • Sessile serrated polyp with dysplasia
    • Serrated adenoma
  • 5 years:
    • 1 sessile serrated polyp <10 mm without dysplasia;
    • History of colon cancer s/p surgery if initial 1-year follow-up is normal
    • One first-degree relative with CRC or advanced adenoma diagnosed before 60 years of age
    • Two first-degree relatives diagnosed at any age
  • 10 years:
    • Normal screening colonoscopy with no polyps
    • Hyperplastic polyps in rectum or sigmoid colon, <10 mm
    • <3 tubular adenomatous polyps on pathology, all <10 mm in size (can repeat in 5 years with risk factors)
    • One first-degree relative with CRC or advanced adenoma diagnosed at ≥60 years
    • Two second-degree relatives with CRC

Commonly Associated Conditions

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