Colorectal Cancer for the ABIM

Colorectal Cancer for the American Board of Internal Medicine Exam

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States.
Men and women are equally affected, with a peak incidence between 50 and 70 years of age.
Over 90% of cases occur after age 50, leading to the recommendation of routine screening starting at this 45.

Age: Incidence increases significantly after age 50.
Dietary factors: High intake of red and processed meats, low fiber diets, and high alcohol consumption are associated with increased risk.
Smoking and obesity are modifiable risk factors.
Family history of colorectal cancer or adenomatous polyps significantly increases risk, particularly with first-degree relatives diagnosed before age 60.
Genetic predisposition:
Familial adenomatous polyposis (FAP): Caused by mutations in the APC gene, leading to hundreds to thousands of adenomatous polyps and nearly 100% lifetime risk of CRC if untreated.
Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer, HNPCC): An autosomal dominant disorder caused by mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Associated with a lifetime risk of 70-80%.
Inflammatory bowel disease: Patients with long-standing ulcerative colitis or Crohn’s disease involving the colon have an elevated risk due to chronic inflammation and dysplasia.
Personal history of adenomatous polyps or CRC increases the risk of recurrence.

CRC develops from adenomatous polyps via the adenoma-carcinoma sequence over 10 to 15 years. Mutations accumulate in oncogenes and tumor suppressor genes such as APC, KRAS, and TP53.
Microsatellite instability (MSI) is another pathway involved in CRC, particularly in Lynch syndrome. MSI results from defective DNA mismatch repair.
Tumors are classified as either sporadic or hereditary based on genetic factors, with the majority being sporadic.

Screening is essential for early detection, reducing mortality by identifying premalignant polyps or early-stage cancer.
Colonoscopy is the gold standard, recommended starting at age 45 for average-risk individuals and at a younger age for those with risk factors.
Other options include:
Fecal immunochemical test (FIT) or high-sensitivity guaiac fecal occult blood test (gFOBT): Detects occult blood in the stool, recommended annually.
Flexible sigmoidoscopy: Can visualize the distal colon, recommended every 5 years.
CT colonography: A noninvasive imaging option performed every 5 years.
Multitarget stool DNA test: Combines stool DNA testing with a FIT, performed every 3 years.
Patients with a family history of CRC or polyps should begin screening 10 years before the age at which their relative was diagnosed or at age 40, whichever is earlier.

Early-stage CRC is often asymptomatic, which is why screening is critical.
Right-sided (proximal) CRC: More likely to present with iron deficiency anemia, fatigue, and weight loss due to occult bleeding.
Left-sided (distal) CRC: Often presents with changes in bowel habits (e.g., constipation, diarrhea, or alternating bowel patterns), hematochezia, and tenesmus.
Rectal cancer: May cause rectal bleeding, pain, and a sense of incomplete evacuation.
Systemic symptoms: Weight loss, anorexia, and fatigue can occur in advanced disease.
Metastasis: The most common site of metastasis is the liver, followed by the lungs and peritoneum.

Colonoscopy with biopsy confirms the diagnosis of CRC.
Pathology typically reveals adenocarcinoma, which accounts for over 95% of CRC cases.
CT scans of the chest, abdomen, and pelvis are used for staging and to assess metastatic disease.
Carcinoembryonic antigen (CEA) is a tumor marker used to monitor treatment response and detect recurrence, although it is not useful for initial diagnosis.
Staging follows the TNM system:
T: Depth of tumor invasion.
N: Regional lymph node involvement.
M: Distant metastasis.

Stage 0: Carcinoma in situ, confined to the mucosa.
Stage I: Tumor invades the submucosa or muscularis propria, without lymph node involvement.
Stage II: Tumor invades through the muscularis propria, no lymph nodes involved.
Stage III: Lymph node involvement, but no distant metastasis.
Stage IV: Distant metastasis (e.g., liver, lungs).

Surgical resection is the definitive treatment for localized CRC. The extent of surgery depends on the tumor's location:
Right or left hemicolectomy: For right- or left-sided colon cancers.
Sigmoidectomy: For tumors in the sigmoid colon.
Low anterior resection (LAR): For rectal cancer with sufficient distal margin.
Abdominoperineal resection (APR): For distal rectal cancers involving the sphincters.
Adjuvant chemotherapy is indicated for:
Stage III disease.
Stage II disease with high-risk features (e.g., poor differentiation, lymphovascular invasion).
Common regimens include 5-fluorouracil (5-FU) or capecitabine combined with oxaliplatin (FOLFOX).
Neoadjuvant chemoradiation is often used for rectal cancer to shrink tumors and improve resectability.
Metastatic CRC is treated with systemic chemotherapy:
FOLFOX or FOLFIRI (irinotecan-based regimen) with or without targeted agents such as bevacizumab (anti-VEGF) or cetuximab (anti-EGFR).
Resection of isolated liver or lung metastases may improve survival in selected patients.
Immunotherapy is indicated for CRC with microsatellite instability (MSI-high), particularly in the metastatic setting, using agents like pembrolizumab or nivolumab.

The prognosis is highly dependent on the stage at diagnosis:
Stage I: 5-year survival >90%.
Stage II: 5-year survival 70-85%.
Stage III: 5-year survival 50-70%, depending on lymph node involvement.
Stage IV: 5-year survival <10%, though selected patients with limited metastases may have improved outcomes with aggressive treatment.
Surveillance after treatment includes periodic colonoscopy and CEA monitoring.

Dietary modifications: High-fiber diets, increased intake of fruits and vegetables, and reduced consumption of red and processed meats are recommended.
Aspirin: Low-dose aspirin has been shown to reduce CRC risk in certain high-risk individuals.
Polyp removal during routine colonoscopy can prevent the progression to cancer.
Genetic counseling and regular screening are essential for those with hereditary syndromes like FAP or Lynch syndrome.

Key Points

Colorectal cancer is a common and lethal malignancy, but early detection through screening greatly reduces mortality.
Risk factors include age, diet, family history, and genetic syndromes like Lynch syndrome and FAP.
Colonoscopy is the gold standard for screening and diagnosis, with biopsy confirming the disease.
Surgery is the cornerstone of treatment for localized disease, with chemotherapy and radiation used in advanced or high-risk cases.
Metastatic CRC is managed with systemic chemotherapy, targeted therapies, and sometimes immunotherapy for MSI-high tumors.
Regular screening and lifestyle modifications (diet, aspirin use) are key preventive measures.