Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and is the second leading cause of cancer death worldwide, accounting for roughly 9% of cancer deaths.^[1][2] In the United States it is the third most common cancer and the second leading cause of cancer death. Incidence is higher in males and older adults, and highest among American Indian/Alaska Native and non-Hispanic Black populations.^[3][4]

CRC has no single cause. It develops over roughly 10–15 years through the stepwise accumulation of genetic and epigenetic changes that transform normal colonic epithelium into adenocarcinoma. Three overlapping molecular pathways account for nearly all cases:

• the chromosomal instability (CIN) pathway
• the mismatch repair–deficient/microsatellite instability (dMMR/MSI) pathway
• the serrated neoplasia pathway, linked to BRAF mutation and the CpG island methylator phenotype (CIMP)^[5]

Germline defects in these pathways cause the hereditary syndromes, chiefly Lynch syndrome and familial adenomatous polyposis (FAP).^[6] About 70% of cases are sporadic, 20–25% show familial clustering without an identified syndrome, and 5–10% arise from defined hereditary syndromes.^[7] Modifiable exposures account for most population-attributable risk: excess body fatness, alcohol, red and processed meat, smoking, sedentary behavior, and low fiber intake. These are also implicated in the rising incidence of early-onset colorectal cancer (diagnosis before age 50).^[8]

The USPSTF recommends screening average-risk adults aged 45–75 years, individualizing the decision at 76–85 years, without preferring any one recommended test. A family history of CRC or advanced adenoma, Lynch syndrome, and other high-risk conditions call for earlier, colonoscopy-based screening. Any positive noninvasive test requires follow-up colonoscopy.^[9][10]

Only about 3–5% of adenomas progress to cancer.^[11] Untreated invasive disease spreads to regional lymph nodes and then hematogenously, chiefly to the liver. About 15–40% of patients present as a surgical emergency, most often obstruction or perforation, which independently predicts worse survival.^[12] Stage at diagnosis is the dominant prognostic factor: five-year relative survival exceeds 90% for localized disease and is about 12–16% for distant disease.^[13] Staging uses the TNM system (with AJCC stage grouping), based on depth of local invasion, lymph node involvement, and distant metastasis.

Patients may report a change in bowel habits, hematochezia, or rectal pain, and metastatic disease can cause dyspnea, abdominal pain, fractures, or confusion. Common signs include pallor, emaciation, and lethargy. CRC must be differentiated from irritable bowel syndrome, inflammatory bowel disease, hemorrhoids, anal fissures, diverticular disease, infectious colitis, and gastrointestinal lymphoma. Workup includes a complete blood count, chemistry profile, serum CEA, and iron studies; CA 19-9 is not part of standard NCCN workup.^[14] CT is used for staging, and MRI, endorectal ultrasound, and PET are used in selected cases. Diagnosis is confirmed by colonoscopy with biopsy.

Surgical resection is the foundation of curative treatment. Colon cancer is treated with segmental colectomy and regional lymphadenectomy, and mid and low rectal cancer with total mesorectal excision (TME). A complete (R0) resection with an adequate lymph node harvest determines oncologic outcome, and minimally invasive surgery gives equivalent outcomes in experienced hands.^[15] Systemic therapy is biomarker-driven. Before treating advanced disease, tumors are tested for KRAS, NRAS, and BRAF V600E mutations, HER2 amplification, and MMR/MSI status, and pretreatment DPYD genotyping is now part of fluoropyrimidine safety.^[14][16] The FDA added a Boxed warning recommending DPYD testing before capecitabine or fluorouracil; these agents should be avoided in patients with complete DPD deficiency, although no specific test platform is endorsed and data are insufficient to guide dose adjustment for many variants.^[14][16] The liver is the most common site of metastasis and the lung the second most common. Patients with resectable or convertible oligometastatic disease are candidates for curative-intent resection or ablation, and complete resection of liver-limited disease is associated with 5-year overall survival of approximately 30–58%.^[17][18] After curative treatment, surveillance colonoscopy is used to detect recurrence and metachronous tumors.

The earliest confirmed case of colorectal cancer (CRC) was identified in an ancient Egyptian mummy. Aldred Warthin began studying a cancer-prone kindred (“Family G”) in 1895 and first described it in 1913; this is now recognized as the first Lynch syndrome family.^[19] The term “Lynch syndrome” was proposed in 1984 and has replaced “hereditary nonpolyposis colorectal cancer” (HNPCC).^[20][21] In 1993–1994, microsatellite instability was discovered and the first mismatch repair (MMR) genes were identified. Fearon and Vogelstein’s 1990 adenoma–carcinoma model established CRC as the paradigm of stepwise genetic carcinogenesis.^[22] Organized screening began with the American Cancer Society’s 1980 guideline. In 2018 (ACS) and 2021 (USPSTF), the average-risk screening start age was lowered from 50 to 45 years.^[23][24]

The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. Sporadic instability originates from the epithelial cells that line the colon or rectum. Colitis-associated CRC includes genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas.

Colorectal cancer has no single cause. It develops through a stepwise build-up of genetic and epigenetic changes that turn normal colonic epithelium into adenocarcinoma, usually over 10–15 years.^[25] Three overlapping molecular pathways account for nearly all cases:

• the chromosomal instability (CIN) pathway
• the mismatch repair–deficient/microsatellite instability (dMMR/MSI) pathway
• the serrated neoplasia pathway, which is linked to BRAF mutation and the CpG island methylator phenotype (CIMP)^[5][26]

Germline defects in these same pathways cause the hereditary colorectal cancer syndromes. The best known are Lynch syndrome (germline mismatch repair genes) and familial adenomatous polyposis (germline APC).^[6][27]

The pathway a tumor follows has clinical consequences. It determines:

• tumor location and precursor lesion type
• microsatellite status
• whether an MSI-high tumor is sporadic or Lynch-associated^[5][28]

Colorectal cancer may be differentiated from other diseases that cause unexplained weight loss, unexplained loss of appetite, nausea, vomiting, diarrhea, anemia, jaundice, and fatigue, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hemorrhoids, anal fissures, and diverticular disease. There are less common conditions that may be confused as colorectal cancer such as infectious colitis and gastrointestinal lymphoma.

Colorectal cancer is the third most commonly diagnosed cancer in the world, and accounts for 8% of all cancer-related deaths annually. In the United States, the prevalence of colorectal cancer is 376.3 per 100,000 persons, and the incidence is 42.9 per 100,000 persons. The incidence of colorectal cancer is higher in males, the elderly, and in the African American race.

Colorectal cancer (CRC) risk reflects hereditary, personal/medical, and modifiable lifestyle factors. About 70% of cases are sporadic. Roughly 20–25% show familial clustering without an identified syndrome. Approximately 5–10% arise from defined hereditary syndromes, chiefly Lynch syndrome and familial adenomatous polyposis (FAP).^[7][29] Lynch syndrome and classic FAP carry the highest individual lifetime risk: 15–52% and nearly 100%, respectively.^[7] Modifiable exposures account for most population-attributable risk. These include excess body fatness, alcohol, red and processed meat, smoking, sedentary behavior, and low fiber or whole-grain intake. They are also increasingly implicated in the rising incidence of early-onset colorectal cancer (EOCRC, diagnosis before age 50).^[8][30][31]

Colorectal cancer (CRC) screening of asymptomatic adults lowers CRC incidence by finding and removing precancerous adenomatous and serrated lesions, and lowers CRC mortality by detecting cancer at an earlier stage.^[9] The U.S. Preventive Services Task Force (USPSTF) recommends screening average-risk adults aged 45–75 years and individualizing the decision at ages 76–85 years. It does not prefer any one recommended test.^[9] A family history of CRC or advanced adenoma, Lynch syndrome, and other high-risk conditions call for earlier, colonoscopy-based screening.^[10] Any positive noninvasive screening test requires follow-up colonoscopy.^[9] Post-polypectomy surveillance and the management of hereditary polyposis syndromes are covered in their own chapters.

Most colorectal cancer (CRC) develops slowly, over roughly 10–15 years, from a resectable precursor lesion through the chromosomal instability (adenoma–carcinoma), serrated, or mismatch repair–deficient pathways. This long window is the biologic basis for screening and polypectomy.^[25][5] Only about 3–5% of adenomas ever progress to cancer.^[11] Untreated invasive disease spreads to regional lymph nodes and then hematogenously, chiefly to the liver.^[32]

About 15–40% of patients present as a surgical emergency, most often from obstruction or perforation, and emergency presentation independently predicts worse survival.^[12][33]

Stage at diagnosis is the dominant prognostic factor. Five-year relative survival exceeds 90% for localized disease and is about 12–16% for distant disease.^[13] Tumor sidedness, histology, preoperative carcinoembryonic antigen (CEA), and molecular status (MMR/MSI, KRAS, BRAF) refine prognosis further.^[14]

Colorectal cancer staging is an estimate of the amount of penetration of the cancer. It is performed for diagnostic and research purposes and to determine the optimal method of treatment. Staging is based on the TNM classification system which depends on the extent of local invasion, the degree of lymph node involvement, and whether there is distant metastasis. Staging uses the AJCC/UICC TNM system (8th edition) with AJCC prognostic stage grouping. The older Dukes and Astler–Coller systems are historical and have been superseded.^[15][34]

The history of a patient with colorectal cancer may include a family history of polyps/colorectal cancer or a history of inflammatory bowel disease. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain. Metastatic symptoms include dyspnea, abdominal pain, fractures, and confusion.

Generally, the most common signs of colorectal cancer are emaciation, lethargy, and pallor. Other signs include low-grade fever, discomfort on palpation, ascites, rectal bleeding, rectal mass, and jaundice.

The laboratory findings associated with colorectal carcinoma are the following: CBC, FOBT, serum CEA and CA 19-9 concentration, serum iron concentrations, serum vitamin B12 and folate concentrations, and liver function tests.

CT of the chest, abdomen, and pelvis with contrast is the recommended modality for detecting pulmonary and other distant metastases. Chest radiography has low sensitivity (lung-metastasis yield ~6–8%) and is not the standard staging test.^[15]

CT scan is used to determine the extent of involvement of colon cancer, most commonly in the abdomen and lungs.

MRI is used to characterize indeterminate liver lesions (with diffusion-weighted imaging) and for local staging of rectal cancer; it is not used for routine assessment of lung or brain disease in CRC.^[15][14]

Abdominal ultrasound can be used to look for tumors in the liver, gallbladder, pancreas, or elsewhere in the abdomen, but it is insufficient in identifying colorectal cancer. The two special types of ultrasound exams that can be performed to evaluate colon and rectal cancers are endorectal ultrasound and intraoperative ultrasound.

Other imaging tests that can be used for colorectal cancer are endoscopy, PET scan, barium study, and angiography.

A biopsy and genetic testing can be performed when a suspected lesion is found on colonoscopy.

Systemic therapy for colorectal cancer (CRC) includes:

• Adjuvant chemotherapy for resected colon cancer
• Neoadjuvant and perioperative therapy for rectal cancer
• Systemic therapy for metastatic disease (mCRC)

Surgical resection is the foundation of curative treatment, and radiation is used for rectal but not colon cancer; both are covered in their own microchapters. Drug selection is now biomarker-driven. Before systemic therapy for advanced disease, NCCN requires testing for:^[14]

• KRAS, NRAS, and BRAF V600E mutations
• HER2 (ERBB2) amplification/overexpression
• Mismatch-repair/microsatellite instability (MMR/MSI) status

Multigene panel testing is preferred because it also detects rare actionable alterations (POLE/POLD1, RET, and NTRK fusions).^[14] Primary tumor sidedness determines the value of anti-EGFR therapy.^[17] Pretreatment DPYD genotyping is now part of fluoropyrimidine safety.^[16]

Surgical resection is the main curative-intent treatment for colon cancer and rectal cancer. Chemotherapy and radiotherapy are sequenced around it according to stage, tumor site, mismatch repair status, and tumor biology.^[15][14]

Colon cancer is treated with segmental colectomy and regional lymphadenectomy matched to the tumor’s lymphovascular drainage. Mid and low rectal cancer is treated with total mesorectal excision (TME).^[15][35]

Two principles govern modern practice:

• A complete (R0) resection along embryologic planes, with an adequate lymph node harvest, determines oncologic outcome.^[15][14]
• In experienced hands, minimally invasive surgery gives oncologic outcomes equivalent to open surgery, with faster recovery.^[36]

Surgery also has defined roles in three other settings:

• Resectable liver and lung metastases.
• Emergency presentations: obstruction, perforation, and bleeding.
• Selected locally advanced disease after neoadjuvant therapy.

Anastomotic leak is the most consequential complication of colorectal resection. Extended resection for hereditary syndromes (familial adenomatous polyposis, Lynch syndrome) is covered in the dedicated chapters.

The liver is the most common site of colorectal cancer metastasis, and the lung is the second most common. Treatment of metastatic colorectal cancer (mCRC) is now driven by tumor biology. Mismatch repair (MMR)/microsatellite instability (MSI) status, extended RAS status, BRAF V600E, HER2 (ERBB2), and primary tumor sidedness determine first-line systemic therapy.^[14][17] Multidisciplinary review separates two groups. Patients with resectable or potentially convertible liver- or lung-limited oligometastatic disease are candidates for curative-intent resection and/or ablation. Patients with unresectable disease receive molecularly selected systemic therapy. Complete (R0) resection of liver-limited disease is associated with 5-year overall survival (OS) of approximately 30–58%.^[18][37]

Most colorectal cancers could be preventable through screening, maintaining an improved and healthy lifestyle.

Secondary prevention of colorectal cancer, as opposed to primary prevention, indicates that a person has already had the disease and there are steps being taken to prevent cancer recurrence, usually as metachronous tumors. This involves surveillance colonoscopy 1 year after resection (or 3–6 months after surgery if no complete preoperative colonoscopy was performed), then at 3 years, then every 5 years if no advanced neoplasia is found, alongside history/physical, CEA, and CT surveillance for stage II–IV disease. Intervals are shortened if advanced adenomas are detected.^[38][14]

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