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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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.^[1] The term “Lynch syndrome” was proposed in 1984 and has replaced “hereditary nonpolyposis colorectal cancer” (HNPCC).^[2][3] 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.^[4] 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.^[5][6]

• The earliest confirmed diagnosis of colorectal cancer was made by Michael Zimmerman in an ancient Egyptian mummy from the Dakhleh Oasis, dated to approximately 200–400 CE. This shows that colorectal malignancy is not a purely modern disease.

• 1895–1913: Aldred Warthin, a pathologist at the University of Michigan, began studying “Family G” in 1895. His seamstress had predicted that she would die of cancer, as many of her relatives had. Warthin published the kindred in 1913, documenting hereditary clustering of colon, gastric, and endometrial cancers. This was the first documented hereditary cancer predisposition family.^[1][2]
• 1960s–1971: Henry Lynch described additional kindreds and introduced the term “cancer family syndrome.” With Anne Krush, he published an update of Family G in 1971.^[2][7]
• 1984: C. Richard Boland proposed replacing “cancer family syndrome” with the eponym Lynch syndrome (initially Lynch syndrome I and II). The I/II distinction is no longer used.^[2][3]
• “Hereditary nonpolyposis colorectal cancer” (HNPCC) was coined to distinguish the disorder from familial adenomatous polyposis. It is now considered a misnomer, because affected individuals develop a broad spectrum of extracolonic cancers and may have multiple adenomas.^[3]

Key milestones in the recognition of Lynch syndrome

Year	Milestone
1989	Formation of the International Collaborative Group on HNPCC (ICG-HNPCC), led by Hans Vasen, Jukka-Pekka Mecklin, Meera Khan, and Henry Lynch, to coordinate international family registries and research[1][3]
1990	Amsterdam Criteria I: • ≥3 relatives with histologically confirmed CRC, one a first-degree relative of the other two • ≥2 successive generations affected • ≥1 CRC diagnosed before age 50 • Familial adenomatous polyposis excluded[1][3]
1993–1994	Discovery of microsatellite instability and identification of the first germline MMR genes (MSH2, MLH1), beginning the molecular era of Lynch syndrome. PMS2 and MSH6 were subsequently implicated.[1][8][7]
1998–1999	Amsterdam Criteria II broadened qualifying cancers to include endometrial, small bowel, ureteral, and renal pelvis tumors, to improve sensitivity[3]
Early 2000s	ICG-HNPCC merged with the Leeds Castle Polyposis Group to form the International Society for Gastrointestinal Hereditary Tumours (InSiGHT)[3]
2015 onward	Mismatch repair deficiency (dMMR)/MSI-high status recognized as a tumor-agnostic predictor of response to immune checkpoint inhibitors, the first histology-independent cancer treatment paradigm[3]

• Lynch syndrome is now defined molecularly by a pathogenic germline MMR (or EPCAM) variant, rather than by family-history criteria.^[8][3]
• Universal tumor MMR/MSI testing of newly diagnosed CRC, regardless of family history, has replaced reliance on Amsterdam/Bethesda criteria alone for case-finding.^[9]

• 1990: Fearon and Vogelstein published the genetic model of colorectal tumorigenesis (the adenoma–carcinoma sequence). It established CRC as the paradigm for stepwise, multigene solid-tumor carcinogenesis.^[4]
  • In this model, normal epithelium progresses to adenoma and then to invasive carcinoma over roughly 10–15 years, through sequential APC inactivation, KRAS activation, and TP53 loss. This is the chromosomal instability (CIN) pathway, which accounts for 70–90% of CRCs.^[10][11][12]
• A distinct serrated neoplasia pathway was recognized later and accounts for 10–20% of CRCs.^[10][11][12]
  • It is characterized by BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 promoter hypermethylation causing sporadic microsatellite instability.
  • These tumors typically arise in the proximal colon of older patients, with female predominance.
  • Recognition of this pathway refined the understanding of proximal versus distal tumor biology.

Milestones in U.S. colorectal cancer screening policy

Year	Milestone
1980	First formal American Cancer Society CRC screening guideline[5]
1995	USPSTF endorsement of fecal occult blood testing and flexible sigmoidoscopy[13]
2001	Medicare coverage of screening colonoscopy[13]
Mid-2010s	Multitarget stool DNA testing incorporated into screening options[13]
2018	American Cancer Society lowered the average-risk screening start age from 50 to 45 years, citing rising early-onset CRC incidence[5][6]
2021	USPSTF lowered the average-risk screening start age from 50 to 45 years[6][14]

• Early post-implementation data show increased uptake among adults aged 45–49 years, with persistent gaps in provider recommendation rates.^[14]

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.

The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC.

The picture below depicts the molecular pathogenesis of sporadic colon cancer:^[1]

Sporadic colorectal cancer originates from the epithelial cells that line the colon or rectum; it may involve the following:^[2]

• APC gene

• Produces the APC protein, which prevents the accumulation of β-catenin protein (responsible for stem cell renewal)

• Mutation of the APC protein leads to the accumulation of β-catenin protein and causes inappropriately high levels of stem cell renewal.

• TP53 gene

• Produces the p53 protein, which monitors cell division and promotes apoptosis if there are cell defects
• Mutations result in loss of control over cell division or apoptosis

• TGF-β and DCC (Deleted in Colorectal Cancer)

• Usually responsible for apoptosis, but deactivated in colorectal cancer

• Oncogenes

• Stimulate cellular division
• Mutations lead to over-activation of cell proliferation

The picture below depicts the molecular pathogenesis of colitis-associated colon cancer:^[1]

At a microbiological level, the development of colitis-associated colorectal cancers (CRC) can be linked to defects within the cell cycle.^[3]

Although it is poorly understood, the following five factors may be responsible for its neoplastic changes:^[1]

• Genetic instability^[4]
  • Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it occurs with 85% frequency.
  • Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it occurs with 15% frequency.

• Epigenetic alteration
  • Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon, while colitis-associated CRC can develop from multifocal dysplasia.^[5][6]
  • This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations.
• Chronic inflammation^[7]
  • COX-2 is triggered by inflammatory stimuli such as IL-1, IFN-γ, and TNF-α.
  • COX-2 expression is elevated in approximately 85% of adenocarcinomas.
• Oxidative stress^[8]
  • Oxidative stress results from inflammatory reactions which include inflammatory cells, activated neutrophils, and macrophages.
  • Macrophages produce large amounts of reactive oxygen and nitrogen species.
  • These reactive oxygen and nitrogen species can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes.

• Intestinal microbiota^[9]
  • Dysbiosis, characterized by loss of protective commensal organisms and expansion of pro-inflammatory or genotoxic bacterial species, is a proposed mechanism contributing to colitis-associated carcinogenesis; conversely, probiotic lactobacilli have been studied as a potential protective strategy that may reduce inflammation and tumor development in animal models of colitis.^[9]

• Early-onset CRC may possess a higher level of microsatellite instability due to germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2).^[10]
• Studies have shown a higher number of somatic genomic alterations involving TP53 and CTNNB1 as well as a lower number of APC, KRAS and BRAF variants in individuals with early-onset CRC.^{[11] [12] [13]}

From a genetic standpoint, colorectal cancer can be divided into three categories:^[14][15]

• Sporadic (approximately 70–80% of cases)
  • No indication of a hereditary component
• Familial (approximately 10–20% of cases)
  • Resulting from multifactorial hereditary factors and/or environmental exposures to non-genetic risk factors
• Hereditary (approximately 5–10% of cases)

• Hereditary nonpolyposis colon cancer (HNPCC) also known as Lynch Syndrome results from mutations in hMLH1, hMSH2, hMSH6, and PMS2
• Familial adenomatous polyposis (FAP) results from mutations in the APC gene located on the long arm of chromosome 5 (5q21–q22)^[16]
• MUTYH-associated polyposis (MAP) results from biallelic mutation of the MutY, E. Coli, Homolog gene which functions to remove adenine residues mispaired with 8-hydroxyguanine in DNA

• On gross pathology, a polypoid or fungating exophytic (growing outwards) lesion is characteristic of right-sided colorectal tumors including the ascending colon and cecum.^[17]
• Left-sided tumours tend to be circumferential and annular producing an “apple-core” appearance on barium enema x-ray.^[17]

According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas:^[18]

• Carcinomas
  • Adenocarcinoma
  • Mucinous adenocarcinoma
  • Signet-ring cell carcinoma
  • Small cell carcinoma
  • Adenosquamous carcinoma
  • Squamous cell
  • Medullary carcinoma
  • Undifferentiated carcinoma
• Neuroendocrine neoplasms
• Hamartomas
• Mesenchymal tumors
• Lymphomas

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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.^[1] 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)^[2][3]

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).^[4][5]

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^[2][6]

The three pathways differ in the type of genomic instability and the precursor lesion.^[2][3][1] The proportions below overlap and add up to more than 100%. This is because serrated-pathway tumors can become either MSI-high (through MLH1 methylation) or microsatellite-stable.^[5]

Principal molecular pathways of colorectal carcinogenesis

Feature	Chromosomal instability (CIN)	Mismatch repair deficiency (dMMR/MSI)	Serrated neoplasia (CIMP)
Approximate share of CRC	~70–85%[3][7]	~15%[3][6]	~15–20%[2][8]
Precursor lesion	Conventional adenoma (adenoma–carcinoma sequence)	Adenoma; in MLH1 Lynch carriers possibly no visible polyp (“shortcut” route)	Sessile serrated lesion or traditional serrated adenoma
Initiating event	Biallelic APC inactivation (less often CTNNB1 activation)	Germline MMR variant plus second hit (Lynch), or somatic MLH1 promoter hypermethylation (sporadic)	BRAF V600E mutation
Key later events	KRAS/NRAS, PIK3CA, 18q loss (SMAD4/DCC), TP53	Frameshift mutations in coding microsatellite genes (TGFBR2, ACVR2A, BAX)	CIMP-driven silencing of tumor suppressor genes, including MLH1
Microsatellite status	Microsatellite-stable (MSS)	MSI-high	MSI-high (when MLH1 is methylated) or MSS
Typical location	Left colon and rectum	Variable	Right (proximal) colon

• This is the classic adenoma–carcinoma sequence and the most common route to CRC.^[3][7]
• Initiation: biallelic loss of the APC tumor suppressor (or, less often, an activating CTNNB1/β-catenin mutation) switches on WNT/β-catenin signaling without control. The first visible lesion is the aberrant crypt focus.^[3][7][2]
• Progression: changes then accumulate in order:
  adenoma: KRAS or NRAS and PIK3CA mutations, and loss of heterozygosity at 18q (SMAD4/DCC)
  invasive carcinoma: TP53 mutation marks the transition.^[3][9][10]
• CIN tumors are usually MSS, occur more often in the left colon and rectum, and fall mainly into consensus molecular subtypes CMS2–CMS4.^[3]

• Cause: loss of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). This happens in one of two ways:
  germline: a pathogenic variant (Lynch syndrome)
  sporadic (more common): somatic MLH1 promoter hypermethylation.^[3][7][6]
• Consequence: a hypermutated tumor. Frameshift mutations build up in genes that contain coding microsatellites, such as TGFBR2, ACVR2A and BAX, and speed up progression.^[4]
• The route differs by gene in Lynch syndrome:^[11]
  • MSH2-associated tumors usually carry somatic APC mutations (75% vs 11% in MLH1-associated tumors).
  • MLH1-associated tumors more often carry somatic CTNNB1 mutations (50% vs 7%).
• “Shortcut” carcinogenesis in MLH1 carriers: some of these cancers may arise directly from MMR-deficient crypts without a visible polyp stage. One proposed model is a “two-in-one hit”: a single event (mitotic recombination on chromosome 3p) both inactivates the remaining MLH1 allele and activates CTNNB1.^[12][6]

• Precursors: sessile serrated lesions and traditional serrated adenomas, not conventional adenomas.^[2][8]
• Initiating event: activating BRAF V600E mutation, which drives constant MAPK signaling. It is present in most sessile serrated lesions.^[2][10]
• Progression: the CpG island methylator phenotype (CIMP) silences tumor suppressor genes. Silencing of MLH1 produces sporadic MSI-high CRC.^[2][10]
• APC mutations are uncommon in this pathway (~8% in one review), which separates it from the CIN route.^[10]
• Serrated-pathway tumors are strongly associated with:
  • right-sided location^[8]
  • smoking, which is more strongly linked to serrated lesions than to conventional adenomas^[13]
  • a disproportionate share of post-colonoscopy (interval) cancers^[8]

A minority of colorectal cancers arise from a monogenic germline predisposition.^[5][4]

Hereditary syndromes covered in the source material

Syndrome	Germline gene(s)	Mechanism and colorectal phenotype
Lynch syndrome	MLH1, MSH2, MSH6, PMS2; EPCAM deletions (silence MSH2)	Most common hereditary CRC syndrome; autosomal dominant constitutional MMR deficiency.[6][4] 10-year CRC risk under surveillance is similar in MLH1 and MSH2 carriers (11.3% vs 11.4%) and lower in MSH6 carriers (4.7%). MSH2 carriers have a higher 10-year risk of advanced adenoma than MLH1 carriers (17.8% vs 7.7%).[11]
Familial adenomatous polyposis (FAP)	APC	Constitutive WNT activation; hundreds to thousands of colonic adenomas, with near-universal progression to CRC if untreated.[4][7]
Polymerase proofreading–associated polyposis	POLE, POLD1 (monoallelic)	Ultramutated tumor phenotype.[14]
Serrated polyposis syndrome	Rare germline RNF43 variants	Serrated-pathway polyposis; a germline cause is found in only a minority of patients.[14]

MSI-high status alone does not establish Lynch syndrome. Most sporadic MSI-high CRCs arise through the serrated pathway, via somatic MLH1 promoter methylation, and carry BRAF V600E.^[2][6] MSI-high tumors that are BRAF wild-type and lack MLH1 methylation suggest a germline MMR cause.^[2][6]

The inflammatory tumor microenvironment, made up of immune cells, stromal cells and the intestinal microbiome, shapes colorectal tumorigenesis.^[9][10] How much the microbiome and inflammation contribute to starting the CIN pathway versus the serrated pathway is not well established.^[10]

• The exact mechanism of adenoma-skipping (“shortcut”) carcinogenesis in MLH1-associated Lynch syndrome is not fully defined. It is relevant to why colonoscopic surveillance may protect MLH1 carriers less well.^[12][6]
• No single standardized marker panel defines CIMP across studies, which makes studies hard to compare.^[2]

Colorectal cancer must 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 must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, and endometritis.^{[1][2][3][4][5][6]}

Other conditions that can be mistaken for colorectal cancer include the following:

• Benign colon polyps
• Infectious colitis
• Arteriovenous malformation (AVM)
• Carcinoid/neuroendocrine tumors
• Small intestine carcinomas
• Gastrointestinal lymphoma
• Pregnancy
• Appendicitis
• Hernia
• Lactose intolerance
• Flatulence
• Ulcer
• Cholecystitis

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Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide.^[1] In the United States, overall CRC incidence and mortality continue to decline. That decline comes from adults 65 years and older. Incidence and mortality are rising in adults younger than 65 years, driven mainly by distal colon and rectal tumors.^[2] Early-onset CRC (diagnosis before age 50 years) is increasing in the US and in many high-income countries.^[3] Marked racial and ethnic disparities persist. American Indian/Alaska Native and Black populations carry the highest burden.^[4]

• GLOBOCAN 2022 estimated 1,926,425 new CRC cases and about 904,000 CRC deaths worldwide in 2022, or nearly 1 in 10 cancer cases and deaths. CRC ranks third in incidence and second in cancer mortality.^[1][5]
• Incidence varies about 10-fold by region:^[1]
  • Highest rates are in Europe, Australia/New Zealand, and Northern America. Denmark has the highest rate in men and Norway the highest in women.
  • Lowest rates are in most of Africa and South/Central Asia.
• Incidence is rising in transitioning economies (Eastern Europe, South-Eastern and South-Central Asia, South America). This is attributed to Westernized diets, obesity, and sedentary behavior.^[1]
• Age-standardized incidence and mortality are higher in males than in females in every world region.^[5][6]
• Projections put annual new cases at roughly 2.4–3.2 million by 2040–2050, driven mainly by population aging and growth.^[5][6]

• The American Cancer Society (ACS) estimates 158,850 new CRC diagnoses and 55,230 CRC deaths in the US in 2026.^[2]
• CRC is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US.^[2]
• In adults younger than 50 years, CRC is the leading cause of cancer death in men and the second leading cause in women.^[2][3]

Overall US CRC incidence fell about 0.9% per year from 2013 to 2022. Trends differ sharply by age.^[2]

US colorectal cancer incidence and mortality trends by age^[2]

Age group	Incidence trend (2013–2022)	Mortality trend
20–49 years	Increasing about 3% per year	Increasing about 1% per year since 2004
50–64 years	Increasing about 0.4% per year	Increasing about 1% per year since 2019
≥65 years	Decreasing about 2.5% per year	Decreasing about 2.3% per year

• Nearly 45% of new US CRC cases now occur in adults younger than 65 years, up from 27% in 1995.^[2][7]
• Birth-cohort effect: each generation born since about 1950 has had higher CRC risk at younger ages than the one before.^[2][4]

• Rising incidence in younger adults is concentrated in distal colon and rectal tumors.^[2]
• After decades of decline, rectal cancer incidence has risen about 1% per year since 2018. Rectal cancer now makes up about 32% of CRC diagnoses, up from 27% in the mid-2000s.^[2][4]

Age-adjusted CRC burden relative to White individuals in the US^[4][2]

Population	Incidence	Mortality
Black	About 11% higher	About 40% higher
American Indian/Alaska Native (combined)	About 48% higher	About 44% higher
Alaska Native	More than double	More than double

• Alaska Native individuals have the highest CRC incidence and mortality of any US population. American Indian individuals have the second-highest burden.^[2]
• From 1999 to 2024, age-adjusted CRC mortality declined in every sex and racial group. Males stayed higher than females throughout. Black individuals had the highest mortality and Asian/Pacific Islander individuals the lowest.^[8]
• Screening uptake:^[4]
  • Up-to-date screening rose from about 38% in 2000 to 72% in 2023.
  • Uptake remains lower among Hispanic (56%), Asian (58%), and American Indian/Alaska Native (59%) adults.
  • Uptake is especially low at ages 45–49 years (37%) and 50–54 years (55%).

Early-onset CRC (EOCRC) is CRC diagnosed before age 50 years.

Burden

• EOCRC accounts for about 14% of US CRC cases, with about 20,805 US diagnoses in 2022.^[3]
• Worldwide there were 184,709 new EOCRC cases in 2022. CRC is the most common early-onset gastrointestinal cancer.^[3]

US incidence trends

• US EOCRC incidence has risen about 2–3% per year.^[3]
• The steepest rise is in adults younger than 40 years, from 4.1 to 5.5 per 100,000 between 2013 and 2022.^[3]
• A 50-state analysis found the rate of increase sped up from 1.27% per year (2001–2012) to 3.00% per year (2012–2017).^[9]
  • The fastest rise was at ages 20–24 years and in non-Hispanic White individuals.

Age, stage, sex, and race/ethnicity

• About half of US CRC diagnoses before age 50 occur at ages 45–49 years. This group is already eligible for screening.^[2][7]
• About three-quarters of CRC in younger adults is diagnosed at an advanced stage.^[7]
• EOCRC is more common in males (male-to-female incidence rate ratio about 1.20).^[3]
• EOCRC incidence is rising in every US racial and ethnic group. Relative increases have been especially rapid among non-Hispanic Black and Hispanic individuals.^[3]
• Compared with later-onset disease, EOCRC patients are more often Black (15% vs 11%) or Hispanic (9% vs 5%).^[3]

Global trends

• EOCRC incidence is rising worldwide, especially in high-income countries, including:^[3][10]
  • Australia, New Zealand, South Korea, Canada, and the UK
  • Several European countries
• A few countries, including Italy, Austria, and Lithuania, have seen EOCRC rates fall.^[3]
• From 1990 to 2021, global age-standardized EOCRC death and disability rates declined even as incidence rose.^[11]

Areas of uncertainty

• The cause of rising EOCRC incidence is unknown.^[4] Proposed contributors are covered in risk factors.
• Detection or reporting artifact may contribute to the rise. However, distant-stage disease is also increasing, which points to a true rise in incidence.^[12][10]
• The steepest increases are in adults younger than 40 years, who fall below current screening thresholds. Whether screening younger adults would improve outcomes is unresolved.^[3][4]

• Rising incidence in younger adults led the ACS to lower the average-risk screening start age from 50 to 45 years in 2018. The ACS reaffirmed age 45 in 2026.^[2][4]
• General-population statistics do not capture hereditary risk. For hereditary syndromes, see Lynch syndrome and Familial adenomatous polyposis.

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).^[1][2] Lynch syndrome and classic FAP carry the highest individual lifetime risk: 15–52% and nearly 100%, respectively.^[1] 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).^[3][4][5] This chapter covers risk stratification only. Diagnostic criteria, genetic testing algorithms, and surveillance protocols for FAP and Lynch syndrome are covered in their own microchapters.

Risk factor	Type	Approximate magnitude	Strength of evidence
Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM)	Hereditary, nonmodifiable	Lifetime CRC risk 15–52%, varies by gene[1]	Established
Classic familial adenomatous polyposis (APC)	Hereditary, nonmodifiable	Near 100% by middle age if untreated[1]	Established
Long-standing ulcerative colitis or Crohn’s colitis	Medical	About 2–3-fold overall; cumulative risk about 1%, 3%, and 7% at 10, 20, and 30 years[6][7]	Established
IBD with concomitant primary sclerosing cholangitis	Medical	More than 3-fold higher odds of CRC/dysplasia than IBD without PSC[6]	Established
Family history of CRC in a first-degree relative	Nonmodifiable	Increased; risk rises with more affected relatives and with younger age at their diagnosis	Established
Personal history of advanced adenoma or CRC	Medical	Increased metachronous neoplasia risk	Established
Higher body fatness (BMI, waist circumference, waist-to-hip ratio)	Modifiable	Strong evidence of increased risk; EOCRC adjusted OR 1.93[3][5]	Strong (convincing/probable)
Alcohol; red and processed meat	Modifiable	Increased risk[3]	Strong (convincing/probable)
Greater adult-attained height	Nonmodifiable	Increased risk[3]	Strong (convincing/probable)
Cigarette smoking	Modifiable	Increased risk[3]	Established
Sugar-sweetened beverages	Modifiable	EOCRC RR 2.18 for ≥2 servings/day versus <1 serving/week[4]	Emerging
Diabetes mellitus or insulin resistance	Medical	Associated with increased risk; EOCRC data inconsistent[5]	Probable
Antibiotic exposure, microbiome alteration, early-life or in-utero exposures	Environmental	Not quantified	Hypothesized, not validated[8]

• Lynch syndrome (hereditary nonpolyposis colorectal cancer) is the most common hereditary CRC syndrome. It accounts for about 3% of all CRC and is enriched 2–3-fold among early-onset cases.^[8]
  • It is caused by autosomal dominant germline pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, or by EPCAM deletions. The result is microsatellite instability.^[1]
  • Median age at CRC diagnosis is 45–60 years, compared with about 67 years for sporadic CRC. Extracolonic cancer risk is also increased (endometrial, ovarian, gastric, urothelial).^[1][8]
• Familial adenomatous polyposis is caused by autosomal dominant germline APC mutations and affects about 1 in 10,000 people. Classic FAP confers near 100% CRC risk by middle age without colectomy. Attenuated FAP (AFAP) has fewer polyps and later onset.^[1][2]
• Other polyposis and predisposition syndromes collectively account for 1–2% of CRC.^[8][2] These include:
  • MUTYH-associated polyposis (biallelic, autosomal recessive)
  • Polymerase proofreading-associated polyposis (POLE/POLD1)
  • Serrated polyposis syndrome (RNF43)
  • Pathogenic variants in SMAD4, BRCA1/2, ATM, and PALB2
• Age at onset is the strongest clinical clue to hereditary disease. About 1 in 5 patients with EOCRC carries a pathogenic cancer-susceptibility variant.^[8]

• Family history: Risk rises with the number of affected first-degree relatives and with younger age at their diagnosis. Risk is highest with multiple affected relatives or a relative diagnosed before age 50–60, especially with advanced adenomas.
• Personal history of adenomas or CRC: Multiple adenomas, adenomas ≥1 cm, or villous/tubulovillous histology increase metachronous risk.
• Inflammatory bowel disease:
  • Long-standing ulcerative colitis and Crohn’s colitis increase CRC risk about 2–3-fold overall. Limited proctitis is excluded. The mechanisms are chronic inflammation and field cancerization.^[6][7]
  • Contemporary population-based cumulative risk is about 1%, 3%, and 7% at 10, 20, and 30 years of disease. Older estimates were 2%, 8%, and 18%. The decline is attributed to better medical therapy and surveillance colonoscopy.^[6][7]
  • Risk increases with greater anatomic extent, longer duration, family history of CRC, and concomitant primary sclerosing cholangitis (PSC). PSC more than triples CRC/dysplasia odds.^[6][7]
  • Pediatric-onset IBD raises the overall cancer rate about 2-fold in Crohn’s disease and about 2.5-fold in ulcerative colitis. This excess is driven mainly by gastrointestinal cancers.^[9]
• Other conditions associated with increased risk:
  • Abdominal or pelvic radiation, including in childhood cancer survivors
  • Acromegaly, which carries an increased prevalence of adenomatous polyps
  • Immunosuppression, including solid organ transplant recipients
  • Ureterosigmoidostomy, with neoplasia near the ureterocolic anastomosis

• The WCRF/AICR Third Expert Report graded the following as strong evidence (convincing or probable) of increased risk:^[3]
  • Higher body fatness
  • Greater adult-attained height
  • Alcohol
  • Red and processed meat
• The same report graded the following as protective:^[3]
  • Physical activity
  • Whole grains and dietary fiber
  • Dairy products and calcium supplements
• Cigarette smoking is an independent risk factor.^[3]
• Sugar-sweetened beverages are an emerging risk factor, including for early-onset disease.^[3][4]
• Migration studies support a causal role for environment over genetic background. CRC risk among immigrants from non-Western countries rises toward host-country rates with longer residence, and dietary Westernization can raise risk within one generation.^[3]
• Diabetes mellitus and insulin resistance are associated with increased risk. The plausible mechanism is hyperinsulinemia acting as a growth factor for colonic mucosa.
• Clustering of behaviors: Combinations of unhealthy behaviors carry about 2.3–2.9-fold higher CRC risk than the lowest-risk profile. Examples are smoking plus heavy alcohol use plus inactivity, or obesity plus poor diet. Higher physical activity appears to partially offset other adverse exposures.^[10]

EOCRC is a distinct epidemiologic entity with rising global incidence. Most cases are sporadic, but about 15–20% carry an identifiable hereditary syndrome, chiefly Lynch syndrome. This proportion is higher than in later-onset disease.^[8][5] Risk factors largely mirror later-onset CRC, with distinct signals from large cohorts:

• Obesity: adjusted OR 1.93 (95% CI 1.15–3.25) in the Nurses’ Health Study II.^[5]
• Western dietary pattern (processed/red meat, butter, high-fat dairy, refined grains): OR 1.67 (95% CI 1.18–2.37) for early-onset high-risk adenomas in the highest versus lowest quintile.^[4]
• Sugar-sweetened beverages: RR 2.18 (95% CI 1.10–4.35) for ≥2 servings/day versus <1 serving/week.^[4]
• Sedentary behavior: prolonged television viewing is associated with increased EOCRC risk, especially rectal cancer.^[5]
• Alcohol and tobacco: established risk factors for EOCRC and advanced colorectal neoplasia.^[3][4][5]
• Vitamin D: total intake ≥450 IU/day is associated with lower risk (HR 0.49, 95% CI 0.26–0.83). This is observational data.^[4]
• Antibiotic exposure, gut microbiome alteration, and early-life or in-utero exposures are hypothesized contributors. They are not validated for clinical risk stratification.^[8]

• Obesity and diabetes in EOCRC: Large prospective cohorts show about 2-fold risk. Some case-control studies using BMI measured near diagnosis find no association, likely reflecting reverse causation.^[5]
• IBD-associated risk by ethnicity or region: Unresolved, and confounded by unequal access to surveillance and therapy.^[7]
• Isolated lifestyle risk factors: Major guidelines do not define a separate risk-adapted screening start age for patients with obesity or heavy alcohol use who lack a family history or hereditary syndrome.

• The younger the age at CRC diagnosis, the higher the pretest probability of a hereditary syndrome. Consider germline testing in patients diagnosed before age 50, even without a strong family history.^[8][4]
• A negative family history does not exclude Lynch syndrome or FAP. De novo mutations and incomplete family histories can mask both.
• Do not counsel IBD patients with outdated figures (e.g., 18–30% by 30 years of pancolitis). These overstate risk relative to surveillance-era data.^[7]
• Do not overlook concomitant PSC when stratifying IBD patients for surveillance intensity.^[6]
• Limited ulcerative proctitis does not carry the elevated CRC risk of more extensive colitis.^[6]
• Rectal bleeding, iron deficiency anemia, or a change in bowel habits in adults under 50 warrants a low threshold for colonoscopy.^[8][5]

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.^[1] 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.^[1] A family history of CRC or advanced adenoma, Lynch syndrome, and other high-risk conditions call for earlier, colonoscopy-based screening.^[2] Any positive noninvasive screening test requires follow-up colonoscopy.^[1] Post-polypectomy surveillance and the management of hereditary polyposis syndromes are covered in their own chapters.

Average risk means no prior CRC, adenomatous polyps, or inflammatory bowel disease, and no personal or family history of a genetic syndrome that confers high lifetime CRC risk (e.g., Lynch syndrome, familial adenomatous polyposis).^[1]

USPSTF 2021 recommendations for average-risk adults

Age (years)	Recommendation	Grade	Certainty of net benefit
50–75	Screen all adults	A	High certainty, substantial net benefit
45–49	Screen	B	Moderate certainty, moderate net benefit
76–85	Selectively offer, based on overall health, prior screening history, and patient preference; benefit is greatest in adults never previously screened	C	Small net benefit
>85	Screening not recommended	—	—

The 2021 statement replaced the 2016 USPSTF recommendation, which started screening at age 50.^[3] Two findings drove the lower starting age. First, microsimulation modeling estimated 22–27 additional life-years gained per 1,000 persons when screening starts at 45 instead of 50, with few added procedural complications. Second, the incidence of early-onset CRC has risen.^[1][4] CRC is now the leading cause of cancer death in men younger than 50 years and the second leading cause in women younger than 50 years.^[5]

U.S. guideline positions for average-risk adults

Organization	Starting age	Key features
USPSTF (2021)	45 (Grade B); 50–75 (Grade A)	No preferred test; choose through shared decision-making[1]
American Cancer Society (2018)	45 (qualified recommendation)	Was the first U.S. body to lower the starting age to 45[6]
ACG (2021) / USMSTF (2022)	45 (weak/conditional); 50 (strong)	Tiered approach. Tier 1 tests are colonoscopy every 10 years or annual FIT[7][2]
NCCN	45	Any recommended test[2]
American College of Physicians (2023)	50; consider not screening at 45–49	Discuss uncertain benefit at 45–49. Stop screening after age 75 or when life expectancy is 10 years or less. Advises against stool DNA, CT colonography, capsule endoscopy, urine, and serum tests. Suggested options include FIT every 2 years[8]

USPSTF-endorsed screening strategies

Modality	Interval	Key points
Colonoscopy	Every 10 years	Reference standard; allows polypectomy and biopsy in the same session
Flexible sigmoidoscopy	Every 5 years	Examines the distal colon only; randomized trials show a mortality benefit
Flexible sigmoidoscopy + FIT	Sigmoidoscopy every 10 years plus annual FIT	Combination strategy
CT colonography	Every 5 years	Polyps detected require colonoscopy for removal
High-sensitivity guaiac fecal occult blood test (gFOBT)	Annual	Low-sensitivity guaiac tests are obsolete and should not be used
Fecal immunochemical test (FIT)	Annual	No dietary restriction required
Multitarget stool DNA–FIT (mt-sDNA)	Every 1–3 years	Combines FIT with DNA mutation and methylation markers

All noninvasive tests (gFOBT, FIT, mt-sDNA, blood-based assays) need a follow-up diagnostic colonoscopy when the result is positive. Patients who complete any recommended strategy do better than patients who are not screened at all.^[1][9]

Test accuracy against colonoscopy (2021 USPSTF evidence synthesis)

Test	CRC sensitivity	CRC specificity	Advanced adenoma sensitivity	Advanced adenoma specificity
High-sensitivity gFOBT	0.50–0.75	0.96–0.98	0.06–0.17	0.96–0.99
FIT (OC-Sensor, pooled)	0.74 (0.64–0.83)	0.94 (0.93–0.96)	0.23 (0.20–0.25)	0.96 (0.95–0.97)
FIT (OC-Light, pooled)	0.81 (0.70–0.91)	0.93 (0.91–0.96)	0.28 (0.19–0.37)	0.94 (0.91–0.97)
First-generation mt-sDNA–FIT (Cologuard)	0.93 (0.87–1.0)	0.84–0.85	0.43–0.47	0.89
Colonoscopy	Sensitivity for adenomas ≥10 mm: 0.89–0.95
CT colonography	Sensitivity 0.86–1.0; specificity not consistently reported

Source: Lin et al. and USPSTF 2021.^[9][1] FIT performance depends on the brand and the positivity threshold.

Next-generation mt-sDNA. In the BLUE-C study (about 20,000 asymptomatic adults who underwent colonoscopy), the next-generation mt-sDNA test had a CRC sensitivity of 93.9%, compared with 67.3% for FIT. Its sensitivity for advanced precancerous lesions was 43.4%, compared with 23.3% for FIT (P<0.001 for both comparisons). Detection of sessile serrated lesions was also much higher (45.8% vs. 5.2%). The trade-off was lower specificity for advanced neoplasia (90.6%; P<0.001 vs. FIT), which means more false-positive results that lead to colonoscopy.^[10]

Blood-based cell-free DNA tests. The FDA has approved two blood tests for average-risk adults aged 45 years and older: Shield and SimpleScreen CRC.^[11][12] These tests meet minimum thresholds for detecting CRC. Their sensitivity for advanced precancerous lesions is much lower than that of stool-based tests, so they contribute little to cancer prevention through polyp removal.^[13] In the PREEMPT CRC validation study, CRC sensitivity was 79.2%, and sensitivity for advanced precancerous lesions did not meet its prespecified acceptance criterion.^[14]

Guideline support for blood tests is limited:

• USPSTF 2021 did not include serum tests, and ACP advises against them.^[1][8]
• Neither USPSTF nor ACG currently recommends Shield.^[11]
• The optimal screening interval for blood tests has not been established.^[11]

Blood tests are best reserved for patients who decline every other recommended modality.^[15][13]

For patients at increased risk, colonoscopy is the preferred screening strategy.^[2]

Screening in increased-risk groups

Risk group	Starting age	Test and interval
One first-degree relative (FDR) with CRC or advanced adenoma diagnosed before age 60, or ≥2 FDRs diagnosed at any age	40, or 10 years before the youngest affected relative’s age at diagnosis, whichever is earlier	Colonoscopy every 5 years[2][16]
One FDR with CRC or advanced adenoma diagnosed at age ≥60	40	Any recommended test at average-risk intervals[2]
Lynch syndrome (confirmed MMR gene carrier)	20–25, or 2–5 years before the youngest family diagnosis if that was before age 25; later gene-specific starts have been proposed (see below)	Colonoscopy every 1–2 years[17]
Familial adenomatous polyposis	See the dedicated chapter
Personal history of adenomatous polyps or curative-intent CRC resection; inflammatory bowel disease of significant duration; prior abdominal or pelvic radiation; cystic fibrosis	Colonoscopy-based surveillance per disease-specific protocols, more intensive than average-risk screening[18]

Lynch syndrome. CRC risk and age at onset differ by mismatch repair gene:^[19]

• MLH1 and MSH2 carriers: lifetime CRC risk 58–82%, mean age at diagnosis 44–61 years.
• MSH6 and PMS2 carriers: lifetime risk 10–22%, mean age at diagnosis 55–66 years.

On this basis, some schemes start surveillance later, at about age 30 for MSH6 and about age 35 for PMS2.^[19]

Refer patients with suspected Lynch syndrome for genetic counseling and testing. Suggestive features include early-onset CRC, multiple affected relatives, and synchronous or metachronous tumors.^[17] All patients with early-onset gastrointestinal cancer should have germline genetic testing.^[16]

Benefits:

• Screening reduces CRC incidence through polypectomy and reduces CRC mortality through earlier detection.^[1]
• Modeling shows that starting at age 45 adds life-years with few additional procedural complications.^[1]

Harms:

• Most procedural harm comes from colonoscopy, whether done for primary screening or to follow up a positive noninvasive test.
• Tests with lower specificity, such as mt-sDNA compared with FIT, produce more false-positive results and more follow-up colonoscopies.^[10]

• Ages 45–49: USPSTF (Grade B) and ACS recommend screening, and ACG/USMSTF issue a weak or conditional recommendation. ACP suggests clinicians consider not screening this group because the modeled net benefit is less certain.^[1][7][8]
• Older adults: ACP advises stopping screening after age 75. USPSTF and ACG favor an individualized decision at ages 76–85.^[8][1]
• Comparative effectiveness: No randomized trial compares mortality outcomes of colonoscopy with FIT or mt-sDNA. Conclusions about comparative effectiveness rely mainly on modeling and on accuracy studies done at a single time point.^[9]
• Blood-based tests: The optimal interval and the long-term effect on CRC mortality are unknown.^[13][11]
• Lynch syndrome: Gene-specific surveillance, including later starting ages for MSH6 and PMS2 carriers, has not been adopted uniformly across guidelines.^[19][17]

• A positive FIT, gFOBT, mt-sDNA, or blood-based test is not a diagnosis. Every positive result needs a diagnostic colonoscopy.^[1]
• Use only high-sensitivity gFOBT or FIT. Low-sensitivity guaiac tests are obsolete.^[1]
• Ask about family history of advanced adenoma as well as CRC, and record it at every screening encounter.^[2]
• Do not apply average-risk intervals to a patient with an FDR diagnosed before age 60. These patients need colonoscopy starting at 40, or 10 years before the relative’s age at diagnosis.^[2]
• Do not substitute a blood test for FIT or mt-sDNA in a patient who is willing to do stool-based testing, because blood tests detect far fewer advanced adenomas.^[13][15]
• MMR gene status, not family history alone, determines Lynch syndrome CRC risk and the appropriate surveillance age.^[19]

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.^[1][2] Only about 3–5% of adenomas ever progress to cancer.^[3] Untreated invasive disease spreads to regional lymph nodes and then hematogenously, chiefly to the liver.^[4]

About 15–40% of patients present as a surgical emergency, most often from obstruction or perforation, and emergency presentation independently predicts worse survival.^[5][6]

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.^[7] Tumor sidedness, histology, preoperative carcinoembryonic antigen (CEA), and molecular status (MMR/MSI, KRAS, BRAF) refine prognosis further.^[8]

Pathway	Approximate share of CRC	Key molecular events	Clinical behavior
Chromosomal instability (CIN; adenoma–carcinoma sequence)	~70%	Inactivating APC mutation with Wnt/β-catenin activation, followed by KRAS activation and TP53 loss[2]	Normal mucosa → adenoma → carcinoma over an estimated 10–15 years[2][1]
Serrated neoplasia pathway	~10–20%; up to ~30% may arise from clinically significant serrated polyps	BRAF mutation and CpG island methylator phenotype (CIMP); may yield microsatellite-stable or MSI-high cancer[9]	Sessile serrated lesions transition to cancer at <1% per year[9]
Mismatch repair–deficient (dMMR/MSI-high)	~15%	Sporadic (MLH1 promoter hypermethylation) or germline (Lynch syndrome)[1]	Accelerated progression; cancer can develop within a few years[2]

• People with synchronous adenoma and clinically significant serrated polyps may have both pathways active. They have a higher risk of advanced neoplasia at follow-up colonoscopy than people with adenomas alone.^[10]
• Inherited syndromes (familial adenomatous polyposis, Lynch syndrome) are covered in their own microchapters.

• CISNET modeling estimates 1–2 decades from normal mucosa to CRC.^[9]
• Most adenomas never become malignant within a normal lifespan. Only about 3–5% progress to cancer.^[3][11]
• Size and advanced histology are the main drivers of progression. Once an adenoma reaches ≥10 mm, cumulative CRC risk is about 1% at 1 year, 2.5% at 5 years, and 8% at 10 years.^[9]
• Tumor-associated chromosomal instability has been proposed as an independent predictor of adenoma-to-carcinoma progression. It is investigational and not validated for routine use.^[12]

• Untreated CRC invades through the bowel wall, spreads to regional lymph nodes, and disseminates hematogenously.
• The liver is the dominant metastatic site because of portal venous drainage. Lung, peritoneum, and bone follow.^[4]
• Dissemination can occur early, while the primary tumor is still small. Metastatic disease is the principal determinant of survival.^[4]
• Metastases may be synchronous (present at diagnosis) or metachronous (arising after primary treatment). Most recurrences after resection appear within the first 5 years.^[4]

Symptoms usually appear only once the tumor is advanced. Symptomatic patients have worse outcomes than patients whose cancer is found by screening.^[13]

• Right-sided (cecal/ascending) tumors tend to bleed occultly. They often present with iron deficiency anemia and related fatigue, dyspnea, or palpitations.^[13]
• Distal tumors more often cause overt rectal bleeding.^[13]
• Rectosigmoid tumors, where the lumen is narrower, more often cause altered bowel habits and obstructive symptoms. These include crampy pain, distension, constipation, and paradoxical overflow diarrhea.^[13]
• Unintentional weight loss is reported in up to half of symptomatic patients. Advanced disease can cause cancer cachexia.^[13]
• Several analyses have not found that diagnostic delay in symptomatic patients correlates strongly with stage or survival.^[13][14]

About 15–40% of CRC presents as a surgical emergency, most often obstruction or perforation.^[5] About 20% of patients with rectal cancer present with emergency symptoms.^[15]

Emergency presentation independently predicts worse survival. Five-year net survival is about 46% after emergency presentation versus about 65% after elective presentation.^[6] Emergency presentation is associated with lymphovascular invasion, perineural invasion, poor differentiation, and advanced stage.^[15]

Complication	Frequency	Prognostic significance
Obstruction	~8–20%; more common with left-sided tumors[5]	NCCN high-risk feature in colon cancer[5]
Perforation	~3–10%[5]	Occurs at the tumor or as a proximal “blowout” from closed-loop obstruction. Upstages disease and raises peritoneal carcinomatosis risk. Worse recurrence-free survival than obstruction (adjusted HR for recurrence ~3.7 in one series).[5] Mortality reaches ~65% for rectal tumor–related perforation.[16]
Gastrointestinal bleeding	Chronic occult bleeding is common	Chronic anemia usually does not change surgical timing.[17]

Contemporary best-practice reviews still individualize emergency management because head-to-head data are limited.^[18]

• Fistula formation (e.g., colovesical, colovaginal) and local invasion of adjacent organs.
• Recurrence can be local, regional, or distant (mainly liver and lung). Most recurrences occur within 5 years.^[4]
• Treatment-related morbidity includes anastomotic leak, stoma-related problems (permanent stoma is more common in rectal cancer), chemotherapy toxicity, and radiation effects. Bevacizumab specifically increases bowel perforation risk.^[17] Detailed toxicity profiles are covered in the treatment microchapters.

Stage is the strongest predictor of survival.

Stage	5-year relative survival, United States (SEER)[7]	5-year net survival, population-based colon cancer cohort[6]
All stages combined	~64% (rectum ~67%; colon ~63%)	—
Stage I / localized	>90% (colon and rectum)	~96% (stage I)
Stage II	—	~87%
Stage III / regional	~70% (regional)	~61%
Stage IV / distant	~12% (colon); ~16% (rectum)	<10%

• The higher overall survival for rectal cancer partly reflects a larger share of localized rectal disease at diagnosis.^[7]
• Across seven high-income countries (ICBP SURVMARK-2), 5-year net survival was about 59–71% for colon cancer and 62–71% for rectal cancer. The widest international variation was in regional and distant disease.^[19]
• Survival trends in Japan (CONCORD-3) are consistent with these patterns.^[20]
• Stage III paradox: in granular AJCC substage data, some stage IIIA cancers have better survival than stage IIB/IIC cancers. This reflects the benefit of adjuvant therapy in node-positive disease and understaging of high-risk node-negative tumors. Substage-specific survival figures should be interpreted with this in mind.

• Tumor sidedness: left-sided colon cancer has better 5-year net survival than right-sided (~66% vs ~59%). The difference is most evident in metastatic disease.^[6]
• Histology: poor differentiation, mucinous histology, and signet-ring histology carry a worse prognosis.^[8]
• Lymph node yield: examining ≥12 nodes is recommended for accurate staging. Inadequate yield risks understaging node-negative disease. The number of negative nodes is prognostic in stage IIIB/IIIC.^[8]
• Tumor deposits, lymphovascular invasion, and perineural invasion are independent adverse factors.^[8]
• Obstruction and perforation are NCCN high-risk features in colon cancer.^[5][8]

• Preoperative CEA gives prognostic information independent of stage. It should be measured before resection to establish a baseline for surveillance. An elevated preoperative value predicts a worse outcome.^[21]
• In colorectal liver metastases, high CEA before and after hepatectomy independently predicts poorer overall and recurrence-free survival.^[22][23]
• CEA may be a less reliable prognostic marker in younger patients. Circulating tumor DNA (ctDNA) is an emerging, complementary biomarker but is not yet standard for prognostication.^[24]

Universal mismatch repair (MMR)/microsatellite instability (MSI) testing is recommended for all newly diagnosed CRC.^[8]

Marker	Prognostic implication	Clinical note
dMMR/MSI-high	Favorable prognosis after adjustment for stage[8]	Stage II MSI-high colon cancer has a good prognosis and does not benefit from adjuvant fluorouracil monotherapy.[8]
KRAS mutation	In resected stage II/III disease, independently predicts worse overall survival (HR ~1.25–1.27). The effect is largely confined to microsatellite-stable (MSS) tumors.[25][26]	Any KRAS/NRAS mutation predicts lack of benefit from anti-EGFR antibodies (cetuximab, panitumumab). See the treatment microchapters.[8]
BRAF V600E	In resected stage II/III disease, independently predicts worse overall survival (HR ~1.43–1.49), mainly in MSS tumors.[25][26]	In MSI-high tumors, KRAS/BRAF mutations do not carry the same adverse effect. MSI-high tumors with these mutations have had better outcomes than MSS wild-type tumors.[27]

• Median survival for CRC with liver metastasis is about 12 months in population-based data. It falls sharply as additional metastatic sites are involved.^[28]
• Adverse factors in hepatic metastatic disease include:^[29][23]
  • Synchronous presentation
  • Short disease-free interval
  • Multiple and large lesions
  • High CEA
  • Extrahepatic (lung, bone) metastases

Early-onset CRC (EOCRC), diagnosed before age 50, is rising and is increasingly viewed as a biologically distinct entity.^[30]

• Presentation: predominantly distal colon and rectum (>70% left-sided), more often at an advanced stage, with more poorly differentiated, mucinous, or signet-ring histology.^[14][31]
• Symptoms: symptoms precede 70–95% of diagnoses. Rectal bleeding, abdominal pain, and changed bowel habits are often attributed to benign disease.^[14][31]
• Somatic profile: more MSI-high and TP53/CTNNB1 alterations, and fewer APC, KRAS, and BRAF mutations, than late-onset disease.^[32]
• Prognosis: stage-matched survival is broadly comparable to late-onset disease, so outcomes are driven mainly by stage rather than age.^[32] Some cohorts report similar or shorter survival overall, largely reflecting later stage at diagnosis.^[30]
• Risk factors and germline evaluation in EOCRC are covered in the risk factors and genetics microchapters.

• Which individual adenomas will progress cannot yet be predicted. Chromosomal instability and proteomic or molecular signatures are promising but not validated for routine use.^[3][12]
• Whether EOCRC carries an independently worse prognosis, or warrants distinct treatment paradigms, remains unresolved.^[30][32]
• Optimal emergency management of obstructing CRC (stent vs diverting stoma vs upfront resection) lacks definitive head-to-head data. Recommendations rest on moderate- to low-quality evidence and local expertise.^[17][18]
• The prognostic value of CEA in young patients is uncertain. ctDNA is not yet standard for prognostication.^[24]
• The stage III substage paradox reflects the limits of anatomic staging without molecular refinement.

• The roughly decade-long adenoma-to-carcinoma window is the biologic basis for screening and polypectomy-based prevention.^[2]
• Iron deficiency anemia in an adult, especially from occult bleeding, should prompt evaluation for right-sided colon cancer.^[13]
• Order MMR/MSI testing on every new CRC. Missing it forfeits Lynch syndrome detection, immunotherapy eligibility, and stage II treatment refinement.^[8]
• Interpret KRAS/BRAF prognosis in the context of MSI status. Their adverse effect is largely confined to MSS tumors.^[27]
• Measure CEA before resection.^[21]
• Avoid colonic stenting when anti-angiogenic therapy is planned or when perforation is present or suspected. Avoid stenting distal rectal tumors.^[17][16]
• Do not proceed directly to emergent resection of locally advanced rectal cancer when diversion would preserve neoadjuvant therapy.^[16]
• In a patient under 50 with rectal bleeding or changed bowel habits, do not reflexively attribute symptoms to hemorrhoids or irritable bowel syndrome. Arrange colonoscopy.^[14]