Colon Cancer

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Basics

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 second leading cause of cancer deaths and the third most common cancer in men and women in the United States.
  • Screening for colon cancer reduces the incidence of and mortality from colon cancer.

Epidemiology

Incidence
  • Estimated that in 2019 in the United States there are 101,420 new cases of colon cancer and 44,180 new cases of rectal cancer per the American Cancer Society
  • Colorectal cancer is expected to cause about 51,020 deaths during 2019 (1).
  • Incidence is relatively equal between men and women. Some databases suggest a trend toward increased incidence in the under-50 population.

Prevalence
  • The lifetime risk for developing colon cancer in the United States is about 1 in 22 (4.49% for men and 1 in 24 (4.15%) for women
  • Incidence and death rates have been declining due to improved screening, prevention, and treatment.

Etiology and Pathophysiology

  • Progression from the first abnormal cells to the appearance of colon cancer usually occurs over 10 to 15 years, a disease characteristic that contributes to the effectiveness of screening and prevention.
  • High-risk polyp findings include multiple polyps, villous or dysplastic polyps, and larger polyps. Hyperplastic polyps are less likely to evolve into CRC.
  • Multiple genetic and environmental factors have been linked to the development of 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 that genetic counseling and perhaps a colorectal-cancer specific multigene panel could be recommended for patients with early-onset CRC.
    • 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.
  • 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)
    • 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.
    • Determined by severity, duration, and extent of inflammation
    • Ulcerative colitis with pancolitis confers up to a 10-fold risk of CRC, occurring around 8–10 years after initial diagnosis of pancolitis.
  • Family history of CRC
    • Having a single first-degree relative with a history of CRC increases risk ~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
      • 1 first-degree and 1 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
      • Accounts for <1% of CRCs
      • Variants include Gardner and Turcot syndromes as well as AFAP (attenuated FAP).
    • 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 increased risk for other cancers
    • BRCA1 and BRCA2 syndromes
      • Some data suggests 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. It is unclear whether this is inherited or due to lower rates of access to screening.
    • Colonoscopy is underutilized, particularly in minorities.
    • Several gene mutations have been identified among Ashkenazi Jews, but there is not substantial evidence to adjust screening.
  • Lifestyle factors
    • Smoking, obesity, sedentary activity, insulin resistance, high-fat and low-fiber diet

General Prevention

  • Several options exist for colon cancer screening. Stool-based testing such as guaiac fecal occult blood test (gFOBT) and fecal immunochemical test (FIT) or FIT-DNA tests are less invasive, but endoscopic testing (flexible sigmoidoscopy or colonoscopy) offers ability to provide intervention if polyp discovered.
  • Lifestyle factors that may reduce risk:
    • No study has evidence strong enough to modify risk stratification/screening based on protective factors.
    • Regular physical activity, diet high in fiber and fruits/vegetables
    • There is conflicting evidence on folic acid, calcium, vitamin D, magnesium, NSAIDs, fish oil, statins

    ALERT
    The U.S. Preventive Services Task Force (USPSTF) strongly recommends screening for colorectal cancer beginning at 50 years (American Cancer Society and some others recommend initiating screening at 45 years) and continuing until 75 years. USPSTF gives this an “A” grade, meaning screening’s benefits far outweigh its harms. For persons ages 76–85 years old, screening should be based on overall health status and life expectancy and should involve shared decision making between the patient and health care provider.

  • Screening methods:
    • Visualization-based tests:
      • Colonoscopy every 10 years
      • Flexible sigmoidoscopy every 5 years
      • Flexible Sig. every 10 years + FIT yearly
    • Stool-based tests:
      • FIT annually
      • Fecal occult blood testing annually
      • FIT-DNA (sDNA) test every 1–3 years
    • For patients who have a positive FIT, gFOBT, or stool DNA test, colonoscopy is recommended.
  • Screening in high-risk groups:
    • The American College of Gastroenterology recommends screening African American patients starting at age 45 years.
    • 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 adenomatous polyps before age 60 years should begin colonoscopy at age 40 or 10 years younger than the youngest age of relative at cancer diagnosis, whichever is earlier.
    • People with IBD should have regular surveillance colonoscopy with biopsies to detect dysplasia; guidelines generally indicate starting surveillance by 8 to 10 years of onset of symptoms followed by surveillance every 1 to 2 years.
    • People with prior abdominal/pelvic radiation should be screened; however, recommendations vary, typically starting between 30–40 years and occurring every 5–10 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. Annual screening by visualization is recommended. Those who test positive for the gene linked to FAP may consider colectomy.
  • Frequency of screening for routine follow-up:
    • <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
    • 1–2 years:
      • Inflammatory Bowel Disease (Crohn’s or Ulcerative Colitis)
    • <3 years:
      • >10 adenomatous polyps
    • 3 years:
      • 3–10 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 or older
      • Two second-degree relatives with CRC

-- To view the remaining sections of this topic, please or --

Basics

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 second leading cause of cancer deaths and the third most common cancer in men and women in the United States.
  • Screening for colon cancer reduces the incidence of and mortality from colon cancer.

Epidemiology

Incidence
  • Estimated that in 2019 in the United States there are 101,420 new cases of colon cancer and 44,180 new cases of rectal cancer per the American Cancer Society
  • Colorectal cancer is expected to cause about 51,020 deaths during 2019 (1).
  • Incidence is relatively equal between men and women. Some databases suggest a trend toward increased incidence in the under-50 population.

Prevalence
  • The lifetime risk for developing colon cancer in the United States is about 1 in 22 (4.49% for men and 1 in 24 (4.15%) for women
  • Incidence and death rates have been declining due to improved screening, prevention, and treatment.

Etiology and Pathophysiology

  • Progression from the first abnormal cells to the appearance of colon cancer usually occurs over 10 to 15 years, a disease characteristic that contributes to the effectiveness of screening and prevention.
  • High-risk polyp findings include multiple polyps, villous or dysplastic polyps, and larger polyps. Hyperplastic polyps are less likely to evolve into CRC.
  • Multiple genetic and environmental factors have been linked to the development of 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 that genetic counseling and perhaps a colorectal-cancer specific multigene panel could be recommended for patients with early-onset CRC.
    • 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.
  • 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)
    • 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.
    • Determined by severity, duration, and extent of inflammation
    • Ulcerative colitis with pancolitis confers up to a 10-fold risk of CRC, occurring around 8–10 years after initial diagnosis of pancolitis.
  • Family history of CRC
    • Having a single first-degree relative with a history of CRC increases risk ~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
      • 1 first-degree and 1 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
      • Accounts for <1% of CRCs
      • Variants include Gardner and Turcot syndromes as well as AFAP (attenuated FAP).
    • 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 increased risk for other cancers
    • BRCA1 and BRCA2 syndromes
      • Some data suggests 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. It is unclear whether this is inherited or due to lower rates of access to screening.
    • Colonoscopy is underutilized, particularly in minorities.
    • Several gene mutations have been identified among Ashkenazi Jews, but there is not substantial evidence to adjust screening.
  • Lifestyle factors
    • Smoking, obesity, sedentary activity, insulin resistance, high-fat and low-fiber diet

General Prevention

  • Several options exist for colon cancer screening. Stool-based testing such as guaiac fecal occult blood test (gFOBT) and fecal immunochemical test (FIT) or FIT-DNA tests are less invasive, but endoscopic testing (flexible sigmoidoscopy or colonoscopy) offers ability to provide intervention if polyp discovered.
  • Lifestyle factors that may reduce risk:
    • No study has evidence strong enough to modify risk stratification/screening based on protective factors.
    • Regular physical activity, diet high in fiber and fruits/vegetables
    • There is conflicting evidence on folic acid, calcium, vitamin D, magnesium, NSAIDs, fish oil, statins

    ALERT
    The U.S. Preventive Services Task Force (USPSTF) strongly recommends screening for colorectal cancer beginning at 50 years (American Cancer Society and some others recommend initiating screening at 45 years) and continuing until 75 years. USPSTF gives this an “A” grade, meaning screening’s benefits far outweigh its harms. For persons ages 76–85 years old, screening should be based on overall health status and life expectancy and should involve shared decision making between the patient and health care provider.

  • Screening methods:
    • Visualization-based tests:
      • Colonoscopy every 10 years
      • Flexible sigmoidoscopy every 5 years
      • Flexible Sig. every 10 years + FIT yearly
    • Stool-based tests:
      • FIT annually
      • Fecal occult blood testing annually
      • FIT-DNA (sDNA) test every 1–3 years
    • For patients who have a positive FIT, gFOBT, or stool DNA test, colonoscopy is recommended.
  • Screening in high-risk groups:
    • The American College of Gastroenterology recommends screening African American patients starting at age 45 years.
    • 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 adenomatous polyps before age 60 years should begin colonoscopy at age 40 or 10 years younger than the youngest age of relative at cancer diagnosis, whichever is earlier.
    • People with IBD should have regular surveillance colonoscopy with biopsies to detect dysplasia; guidelines generally indicate starting surveillance by 8 to 10 years of onset of symptoms followed by surveillance every 1 to 2 years.
    • People with prior abdominal/pelvic radiation should be screened; however, recommendations vary, typically starting between 30–40 years and occurring every 5–10 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. Annual screening by visualization is recommended. Those who test positive for the gene linked to FAP may consider colectomy.
  • Frequency of screening for routine follow-up:
    • <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
    • 1–2 years:
      • Inflammatory Bowel Disease (Crohn’s or Ulcerative Colitis)
    • <3 years:
      • >10 adenomatous polyps
    • 3 years:
      • 3–10 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 or older
      • Two second-degree relatives with CRC

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