Colorectal Cancer for USMLE Step 3

Colorectal Cancer for the USMLE Step 3 Exam

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths in the United States.
Most cases occur in individuals over age 50, but there is a rising incidence in younger populations.
Risk is increased in individuals with a family history or hereditary conditions, such as Lynch syndrome or familial adenomatous polyposis (FAP).

Age: Incidence increases significantly after 50 years.
Diet: High consumption of red and processed meats, low fiber intake, and excessive alcohol.
Genetic syndromes:
Lynch syndrome (HNPCC): Due to mutations in DNA mismatch repair genes (MLH1, MSH2), it confers a 70-80% lifetime risk.
Familial adenomatous polyposis (FAP): Caused by APC mutations, leading to hundreds of adenomatous polyps and almost 100% lifetime CRC risk.
Inflammatory bowel disease: Chronic ulcerative colitis and Crohn’s disease significantly elevate CRC risk.
Obesity, smoking, and physical inactivity also contribute to risk.

CRC arises through the adenoma-carcinoma sequence, a multistep accumulation of genetic mutations:
APC gene mutations initiate adenoma formation.
KRAS mutations promote adenoma growth.
TP53 mutations lead to progression to carcinoma.
An alternative pathway, microsatellite instability (MSI), is caused by defects in mismatch repair genes, particularly in Lynch syndrome.

Right-sided CRC: Presents with vague symptoms like fatigue, weight loss, and iron deficiency anemia due to occult bleeding. Right-sided tumors often grow larger before causing obstruction.
Left-sided CRC: More likely to present with hematochezia, changes in bowel habits (e.g., constipation, diarrhea, narrowing of stool), and obstruction.
Rectal cancer: Often presents with tenesmus, rectal bleeding, and a sensation of incomplete evacuation.
Advanced disease may involve liver metastases (hepatomegaly, jaundice) or lung metastases (dyspnea, cough).

Colonoscopy is the gold standard for CRC screening and prevention, allowing for both visualization and polyp removal.
Other screening modalities include:
Fecal immunochemical test (FIT): Detects occult blood in the stool, recommended annually.
Flexible sigmoidoscopy: Screens the distal colon every 5 years.
CT colonography: Noninvasive imaging recommended every 5 years.
Screening is typically initiated at age 45 for average-risk individuals and earlier for those with family history or genetic syndromes.

Colonoscopy with biopsy confirms the diagnosis, revealing adenocarcinoma in the vast majority of cases.
Staging involves CT scans of the chest, abdomen, and pelvis to evaluate for metastasis.
Carcinoembryonic antigen (CEA) is a tumor marker used for monitoring treatment response and recurrence.

The TNM staging system is used:
T: Tumor depth and local invasion.
N: Lymph node involvement.
M: Distant metastasis, with common sites including liver and lungs.
Stage I: Tumor confined to the bowel wall.
Stage II: Tumor extends through the bowel wall but without nodal involvement.
Stage III: Lymph node involvement.
Stage IV: Distant metastasis.

Surgical resection with negative margins is the primary treatment for localized CRC. Procedures include hemicolectomy or sigmoidectomy, depending on tumor location.
Adjuvant chemotherapy is indicated for stage III disease and high-risk stage II disease, typically using FOLFOX (5-fluorouracil and oxaliplatin).
For metastatic CRC, systemic chemotherapy (FOLFOX or FOLFIRI) combined with targeted agents (e.g., bevacizumab, cetuximab) is used.
Palliative treatments may be employed in advanced cases to improve quality of life.

Lifestyle changes: A diet high in fiber, regular physical activity, and reduced intake of red/processed meats reduce CRC risk.
Aspirin use may reduce the risk of CRC in high-risk individuals, particularly those with Lynch syndrome.
Screening and polyp removal are the most effective preventive measures.

Key Points

Colorectal cancer develops through the adenoma-carcinoma sequence, with mutations in APC, KRAS, and TP53 driving progression.
Microsatellite instability is a hallmark of Lynch syndrome, caused by defective mismatch repair genes.
Colonoscopy is the gold standard for screening, with routine screening starting at age 45 for average-risk individuals.
Right-sided CRC presents with anemia and vague symptoms, while left-sided CRC presents with hematochezia and bowel habit changes.
Surgical resection is the primary treatment, with chemotherapy used in advanced stages and metastatic disease.
Prevention includes regular screening, polyp removal, and lifestyle modifications (high-fiber diet, physical activity).