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Neoplasms

Colorectal cancer

Colorectal cancer (CRC) is a malignant neoplasm arising from the epithelium of the colon or rectum, most commonly adenocarcinoma. It is the third most common cancer worldwide and affects both sexes, with peak incidence in the sixth and seventh decades. The single most testable fact: screening with colonoscopy or fecal immunochemical testing (FIT) reduces mortality by detecting early-stage disease and removing precancerous polyps.

Practice questionsHigh-yield facts
ICD-10C18 (colon), C20 (rectosigmoid), C21 (rectum)
Typical patient60-year-old with hematochezia, weight loss, change in bowel habits
Key findingIron-deficiency anemia or positive fecal occult blood test
First-line treatmentSurgical resection with adjuvant chemotherapy for stage III
9 min readFor medical studentsUpdated 2026-10-14

Definition and epidemiology

Colorectal cancer is a malignant tumor originating from the mucosal lining of the large intestine. Approximately 95% are adenocarcinomas. The remainder include neuroendocrine tumors, lymphomas, and gastrointestinal stromal tumors.

CRC is the third most common cancer and the second leading cause of cancer death in both men and women in the United States. Globally, approximately 1.9 million new cases are diagnosed annually. Incidence rises sharply after age 50, with median age at diagnosis around 66 years. Incidence has been decreasing in older adults due to widespread screening but increasing in adults under 50 for unclear reasons.

Most cases are sporadic (70%), with 25% showing familial clustering and 5% arising from well-defined hereditary syndromes such as Lynch syndrome or familial adenomatous polyposis (FAP). Left-sided and rectal cancers are more common than right-sided tumors, though right-sided incidence is increasing.

High-yield for exams
  • Screening colonoscopy starting age 45–50 in average-risk individuals; every 10 years if normal
  • Lynch syndrome: autosomal dominant MMR gene defect, 70–80% lifetime CRC risk, right-sided tumors before age 50
  • FAP: APC mutation, hundreds of polyps, nearly 100% CRC risk by age 40; prophylactic colectomy indicated
  • Stage III colon cancer requires adjuvant FOLFOX or CAPOX chemotherapy for 3–6 months
  • Stage II-III rectal cancer receives neoadjuvant chemoradiation before total mesorecal excision
  • MSI-high or MMR-deficient metastatic CRC: treat with immunotherapy (pembrolizumab or nivolumab)
  • Anti-EGFR therapy (cetuximab, panitumumab) only if RAS wild-type; most effective in left-sided tumors
  • Iron-deficiency anemia in men or postmenopausal women requires colonoscopy to rule out CRC

Etiology and risk factors

The majority of CRC develops from adenomatous polyps through the adenoma-carcinoma sequence, which typically takes 10–15 years. Key risk factors include:

Genetic syndromes:

  • Lynch syndrome (HNPCC): autosomal dominant mismatch repair gene mutations; 70–80% lifetime CRC risk, often right-sided and before age 50
  • Familial adenomatous polyposis (FAP): APC gene mutation; hundreds to thousands of colonic polyps; nearly 100% CRC risk by age 40 without colectomy
  • MUTYH-associated polyposis: autosomal recessive; 10–100 polyps
  • Peutz-Jeghers syndrome, juvenile polyposis: hamartomatous polyps with increased CRC risk

Inflammatory bowel disease:

  • Ulcerative colitis and Crohn colitis increase risk proportional to disease extent and duration; risk rises after 8–10 years of disease

Dietary and lifestyle factors:

  • High red and processed meat intake
  • Low dietary fiber
  • Obesity, physical inactivity
  • Smoking and heavy alcohol use
  • Type 2 diabetes

Other factors:

  • Personal history of colorectal polyps or cancer
  • First-degree relative with CRC, especially if diagnosed before age 60
  • Prior pelvic radiation

Pathophysiology

Colorectal carcinogenesis follows several molecular pathways:

Chromosomal instability (CIN) pathway

The classic adenoma-carcinoma sequence accounts for 70–85% of sporadic CRC. Stepwise accumulation of mutations occurs: APC gene loss initiates polyp formation, followed by KRAS activation, loss of tumor suppressors (TP53, SMAD4), leading to invasive carcinoma. This pathway typically produces left-sided tumors.

Microsatellite instability (MSI) pathway

Defects in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) lead to MSI. Seen in Lynch syndrome and 15% of sporadic CRC (usually from MLH1 promoter hypermethylation). MSI-high tumors are often right-sided, mucinous, and have better prognosis but respond poorly to fluorouracil monotherapy.

CpG island methylator phenotype (CIMP)

Epigenetic hypermethylation of promoter regions silences tumor suppressor genes. Associated with BRAF mutations and right-sided location.

Serrated pathway

Serrated polyps (sessile serrated lesions) can progress to cancer via BRAF mutation and CIMP, accounting for 15–30% of CRC. These lesions are often flat, right-sided, and easily missed on colonoscopy.

CRC spreads by direct extension through the bowel wall, lymphatic spread to regional nodes, hematogenous spread (liver and lung are most common metastatic sites), and transperitoneal seeding.

Clinical features

Clinical presentation varies by tumor location and stage. Many early-stage cancers are asymptomatic and detected by screening.

Right-sided (cecum, ascending colon) tumors:

  • Often asymptomatic until advanced
  • Iron-deficiency anemia from occult bleeding (common)
  • Fatigue, weakness
  • Dull, vague abdominal pain
  • Palpable mass in right lower quadrant
  • Weight loss

Left-sided (descending, sigmoid colon) tumors:

  • Change in bowel habits: constipation, diarrhea, or alternating pattern
  • Hematochezia (bright red blood per rectum)
  • Tenesmus
  • Pencil-thin stools (late sign of obstruction)
  • Crampy abdominal pain
  • Bowel obstruction (more common than right-sided)

Rectal tumors:

  • Hematochezia, often mixed with stool
  • Tenesmus and urgency
  • Sensation of incomplete evacuation
  • Rectal pain (if locally advanced)

Advanced disease:

  • Constitutional symptoms: weight loss, anorexia, fatigue
  • Bowel obstruction or perforation
  • Hepatomegaly (liver metastases)
  • Ascites (peritoneal carcinomatosis)
  • Jaundice (biliary obstruction from liver metastases)

Physical examination may reveal abdominal mass, hepatomegaly, rectal mass on digital rectal examination, or signs of anemia.

Diagnosis

Diagnosis requires endoscopic visualization with biopsy and staging workup.

Screening and detection

Average-risk individuals (starting age 45–50):

  • Colonoscopy every 10 years (preferred; allows polyp removal)
  • Annual fecal immunochemical test (FIT) or high-sensitivity guaiac-based fecal occult blood test (gFOBT)
  • Stool DNA test (e.g., Cologuard) every 1–3 years
  • CT colonography every 5 years
  • Flexible sigmoidoscopy every 5 years

High-risk individuals:

  • First-degree relative with CRC: begin screening 10 years before relative's diagnosis or age 40
  • Lynch syndrome: colonoscopy every 1–2 years starting age 20–25
  • FAP: annual flexible sigmoidoscopy starting age 10–12; consider prophylactic colectometry
  • IBD: surveillance colonoscopy 8 years after diagnosis

Diagnostic workup

Colonoscopy with biopsy: gold standard; visualizes entire colon, allows tissue sampling and polyp removal. Histology confirms adenocarcinoma.

Laboratory tests:

  • Complete blood count (anemia)
  • Carcinoembryonic antigen (CEA): not diagnostic but useful for monitoring recurrence after treatment
  • Liver function tests

Staging investigations:

  • CT chest, abdomen, and pelvis with contrast: assess for metastases (liver, lung, peritoneum)
  • MRI pelvis (for rectal cancer): superior soft-tissue resolution for local staging, mesorectal fascia involvement
  • PET-CT: not routine; may be used in selected cases (equivocal liver lesions, recurrence)

TNM staging (American Joint Committee on Cancer):

  • T: depth of invasion (Tis in situ, T1 submucosa, T2 muscularis propria, T3 subserosa, T4 perforation or adjacent organs)
  • N: regional lymph node involvement (N0 none, N1 1–3 nodes, N2 ≥4 nodes)
  • M: distant metastases (M0 absent, M1 present)

Stage grouping:

  • Stage I: T1-2, N0, M0
  • Stage II: T3-4, N0, M0
  • Stage III: any T, N1-2, M0
  • Stage IV: any T, any N, M1

Molecular testing (on tumor tissue):

  • MSI or mismatch repair (MMR) status: all CRC should be tested (guides Lynch screening and immunotherapy eligibility)
  • RAS (KRAS, NRAS) and BRAF mutations: required before anti-EGFR therapy in metastatic disease
  • HER2 amplification: may guide targeted therapy in metastatic disease

Differential diagnosis

The differential diagnosis depends on presenting symptoms:

For hematochezia or positive FOBT:

  • Hemorrhoids
  • Diverticular disease
  • Angiodysplasia
  • Inflammatory bowel disease (ulcerative colitis, Crohn disease)
  • Polyps (adenomatous, hyperplastic)
  • Anal fissure
  • Ischemic colitis

For altered bowel habits and abdominal pain:

  • Irritable bowel syndrome
  • Infectious colitis
  • Diverticulitis
  • Inflammatory bowel disease
  • Small bowel obstruction
  • Ovarian or other pelvic masses (in women)

For iron-deficiency anemia:

  • Gastric cancer or peptic ulcer disease
  • Celiac disease
  • Angiodysplasia
  • Menstrual blood loss (premenopausal women)

For obstructive symptoms:

  • Diverticular stricture
  • Crohn stricture
  • Volvulus
  • Adhesions

Colonoscopy with biopsy is essential to distinguish colorectal cancer from mimics.

Management

Treatment is multidisciplinary and depends on stage, location, and patient factors.

Surgical resection

Surgery is the primary curative treatment for non-metastatic CRC.

Colon cancer:

  • Segmental colectomy with removal of tumor, adequate margins (≥5 cm), and regional lymph nodes (minimum 12 nodes for adequate staging)
  • Right hemicolectomy for cecal and ascending lesions
  • Left hemicolectomy or sigmoid colectomy for descending and sigmoid lesions
  • Laparoscopic approach is standard when feasible (equivalent oncologic outcomes, faster recovery)

Rectal cancer:

  • Total mesorectal excision (TME): en bloc removal of rectum and surrounding mesorectal fat to minimize local recurrence
  • Low anterior resection (LAR) for upper/mid-rectum with colorectal or coloanal anastomosis
  • Abdominoperineal resection (APR) for low rectal tumors near anal sphincter (permanent colostomy)
  • Transanal excision for selected T1 tumors

Neoadjuvant therapy (rectal cancer)

Stage II-III rectal cancer (T3-4 or node-positive):

  • Short-course radiation (5 fractions) followed by surgery within 1 week, or
  • Long-course chemoradiation (fluoropyrimidine-based) for 5–6 weeks, surgery 6–12 weeks later
  • Reduces local recurrence and may allow sphincter-preserving surgery
  • Total neoadjuvant therapy (chemotherapy + chemoradiation before surgery) is increasingly used for high-risk tumors

Adjuvant chemotherapy (colon cancer)

Stage III (node-positive): adjuvant chemotherapy for 3–6 months reduces recurrence and improves survival

  • Regimens: FOLFOX (fluorouracil, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin)
  • Fluoropyrimidine monotherapy may be used in low-risk stage III or elderly/frail patients

Stage II (node-negative): adjuvant therapy benefit is smaller; consider in high-risk features (T4, perforation, obstruction, inadequate lymph node sampling, poorly differentiated histology, lymphovascular invasion). MSI-high tumors do not benefit from fluorouracil alone.

Rectal cancer: adjuvant chemotherapy after neoadjuvant chemoradiation and surgery is standard for node-positive disease.

Metastatic disease (Stage IV)

Goals are to prolong survival, control symptoms, and in selected cases achieve cure through resection of metastases.

Resectable metastases (liver, lung):

  • Surgical resection of primary tumor and metastases (synchronous or staged) with perioperative chemotherapy may achieve long-term survival or cure in 20–40%

Unresectable metastases:

  • Systemic chemotherapy: FOLFOX, FOLFIRI (fluorouracil, leucovorin, irinotecan), or CAPOX
  • Biologic agents:
  • Anti-VEGF therapy: bevacizumab (all patients)
  • Anti-EGFR therapy: cetuximab or panitumumab (only if RAS wild-type, left-sided tumors preferred)
  • Immunotherapy: pembrolizumab or nivolumab for MSI-high or mismatch repair-deficient tumors (high response rates)
  • Targeted therapy: trastuzumab plus pertuzumab for HER2-amplified tumors (after progression on standard therapy)

Palliative care:

  • Stenting or diverting colostomy for obstruction
  • Radiation for symptomatic metastases (bone, brain)
  • Early integration of palliative care improves quality of life

Surveillance after curative treatment

  • History, physical examination, and CEA every 3–6 months for 2 years, then every 6 months to 5 years
  • CT chest, abdomen, pelvis annually for 3–5 years (high-risk patients)
  • Colonoscopy at 1 year, then every 3–5 years if normal

Complications and prognosis

Complications

Related to the tumor:

  • Bowel obstruction (especially left-sided tumors)
  • Perforation with peritonitis or abscess
  • Gastrointestinal bleeding (acute or chronic)
  • Fistula formation (colovesical, colovaginal)
  • Anemia and malnutrition

Related to treatment:

  • Surgical: anastomotic leak, wound infection, ileus, adhesions, stoma complications
  • Chemotherapy: neuropathy (oxaliplatin), diarrhea, neutropenia, hand-foot syndrome (capecitabine)
  • Radiation: proctitis, bladder dysfunction, sexual dysfunction, small bowel injury
  • Anti-EGFR therapy: acneiform rash, hypomagnesemia

Prognosis

Prognosis depends primarily on stage at diagnosis.

Five-year survival by stage (approximate):

  • Stage I: 90–95%
  • Stage II: 80–85%
  • Stage III: 65–75%
  • Stage IV: 10–15%

Favorable prognostic factors include early stage, well-differentiated histology, absence of lymphovascular or perineural invasion, adequate lymph node sampling, MSI-high status, and left-sided tumor location.

Recurrence occurs in 30–50% of stage II-III patients despite curative-intent treatment. Most recurrences develop within 2–3 years. Liver and lung are the most common sites.

Early detection through screening significantly improves outcomes by identifying cancers at earlier, more curable stages and preventing cancer through polypectomy.

Mnemonic

ALARM symptoms for colorectal cancer: Anemia, Loss of weight, Anorexia, Recent change in bowel habits, Melena/hematochezia

Practice questions

1. A 62-year-old man with no significant medical history presents for routine health maintenance. He has no gastrointestinal symptoms and denies weight loss or rectal bleeding. His father was diagnosed with colon cancer at age 58. Physical examination is unremarkable. Which of the following is the most appropriate screening test?

Answer: B. This patient has a first-degree relative with colorectal cancer diagnosed before age 60, placing him at increased risk. Screening should begin at age 40 or 10 years before the relative's diagnosis (age 48 in this case), whichever is earlier. Colonoscopy every 5 years is recommended for high-risk individuals, making colonoscopy now the most appropriate choice. Average-risk screening methods such as annual FOBT are insufficient for higher-risk patients.

2. A 58-year-old woman undergoes colonoscopy for iron-deficiency anemia. A 4-cm fungating mass is found in the cecum. Biopsy confirms moderately differentiated adenocarcinoma. CT chest, abdomen, and pelvis shows no metastases. She undergoes right hemicolectomy; pathology reveals invasion into the subserosa (T3) and 3 of 18 lymph nodes are positive for metastatic disease. Which of the following is the most appropriate next step?

Answer: B. This patient has stage III colon cancer (T3N1M0) with lymph node involvement. Adjuvant chemotherapy with FOLFOX or CAPOX for 3–6 months is standard of care and significantly reduces recurrence risk and improves survival. Observation alone is inadequate for node-positive disease. Radiation is not routinely used for colon cancer (only rectal cancer). Neoadjuvant therapy is given before surgery, not after resection.

3. A 45-year-old man is diagnosed with metastatic colorectal cancer with multiple liver lesions. Biopsy shows adenocarcinoma, and molecular testing reveals microsatellite instability-high (MSI-H) status with loss of MLH1 and PMS2 expression. KRAS mutation is present. Which of the following is the most appropriate first-line systemic therapy?

Answer: C. MSI-high or mismatch repair-deficient metastatic colorectal cancer has high response rates to immune checkpoint inhibitors. Pembrolizumab or nivolumab is preferred first-line therapy for these patients, with superior outcomes compared to chemotherapy. Cetuximab is ineffective in KRAS-mutant tumors. While FOLFOX plus bevacizumab is standard chemotherapy, immunotherapy is now the preferred option for MSI-high disease. Trastuzumab targets HER2-amplified tumors, which is not mentioned here.

Frequently asked questions

What causes colorectal cancer?

Most colorectal cancers develop from adenomatous polyps through accumulated genetic mutations over 10–15 years (adenoma-carcinoma sequence). Major risk factors include age over 50, family history of CRC, hereditary syndromes (Lynch syndrome, FAP), inflammatory bowel disease (ulcerative colitis, Crohn disease), diet high in red and processed meat, obesity, smoking, and heavy alcohol use. About 5% of cases arise from inherited genetic syndromes.

What are the first symptoms of colorectal cancer?

Early colorectal cancer is often asymptomatic, which is why screening is crucial. When symptoms appear, they vary by location: right-sided tumors typically cause iron-deficiency anemia with fatigue and weakness from occult bleeding, while left-sided tumors cause change in bowel habits (constipation, diarrhea), hematochezia (blood in stool), and crampy abdominal pain. Rectal cancers present with bleeding, tenesmus (urge to defecate), and sensation of incomplete evacuation. Weight loss and anorexia suggest advanced disease.

How is colorectal cancer diagnosed?

Diagnosis requires colonoscopy with biopsy to visualize the tumor and confirm adenocarcinoma on histology. Colonoscopy is also the preferred screening method for average-risk adults starting at age 45–50. Alternative screening tests include annual fecal immunochemical test (FIT), stool DNA test, or CT colonography, but positive results require colonoscopy for confirmation. Staging workup includes CT chest/abdomen/pelvis to assess for metastases, MRI pelvis for rectal cancer, and tumor molecular testing (MSI status, RAS/BRAF mutations).

Is colorectal cancer curable?

Yes, colorectal cancer is curable when detected early. Five-year survival exceeds 90% for stage I disease treated with surgical resection. Stage II and III cancers require surgery plus chemotherapy (stage III) or radiation (rectal cancer), with cure rates of 65–85%. Even some stage IV patients with resectable liver or lung metastases can achieve long-term survival or cure with surgery and chemotherapy. Overall, earlier detection through screening dramatically improves curability, which is why screening programs are so important.

Colon cancer vs rectal cancer — what is the difference?

Colon cancer arises in the large intestine from cecum to sigmoid, while rectal cancer occurs in the last 15 cm of bowel before the anus. Treatment differs significantly: colon cancer is treated with segmental colectomy and adjuvant chemotherapy for node-positive disease, while rectal cancer often requires neoadjuvant chemoradiation before total mesorectal excision to reduce local recurrence risk. Rectal cancer surgery may require permanent colostomy for low tumors. Staging for rectal cancer includes pelvic MRI for local assessment, while colon cancer typically needs only CT imaging.

Key drugs

FluorouracilCapecitabineOxaliplatinIrinotecanBevacizumabCetuximabPanitumumabPembrolizumab
Lynch syndromeFamilial adenomatous polyposisUlcerative colitisCrohn diseaseColorectal polypsDiverticular diseaseHemorrhoidsIron deficiency anemia

Sources and further reading

StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C18

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.