Colorectal cancer

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer in the United States. Risk factors include a positive family history, hereditary syndromes, diet, and a number of conditions, such as inflammatory bowel disease. Most colorectal cancers (95%) are adenocarcinomas. Clinical signs are often nonspecific and may include a change in bowel habits, lower GI bleeding, and weight loss. These features as well as iron deficiency anemia in men older than 50 years of age and postmenopausal women are red flags for CRC. Since the introduction of screening with direct visualization or stool-based testing, early-stage carcinomas have become easier to diagnose in asymptomatic patients. Complete colonoscopy with histopathologic analysis confirms the diagnosis. Staging of the cancer is necessary to evaluate the extent of disease and determine the appropriate management. Curative surgical resection of colorectal cancers and metastases is preferred when feasible. The type and extent of resection depend on the stage of the cancer. In addition, for cancer stages ≥ II, chemotherapy is required for colon cancer and chemotherapy and/or radiation therapy for rectal cancer. Surveillance following CRC treatment is essential to identify and manage recurrence and/or metastases. As the incidence of CRC is high, screening for CRC is recommended for all individuals, starting at 45–50 years of age (earlier in high-risk individuals).

• Incidence [1][2]
  • Excluding skin cancers, colorectal cancer is the fourth most common cancer in the US overall
  • Accounts for ∼ 8% of all new cancer cases in the US
  • Peak incidence: between 65 and 74 years of age
• Prevalence: ∼ 0.4%
• Mortality: third leading cause of cancer-related deaths in the US overall

Epidemiological data refers to the US, unless otherwise specified.

Colorectal carcinogenesis pathways (molecular pathology)

• Chromosomal instability pathway in colon cancer: The adenoma-carcinoma sequence is the progressive accumulation of mutations in oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., APC, TP53) that results in the slow transformation of adenomas into carcinomas.
  • APC gene mutation (loss of cellular adhesion and increased cellular proliferation) → KRAS gene mutation (unregulated cellular signaling and cellular proliferation) → TP53 and DCC gene mutation
  • Most cases of sporadic CRC develop via this pathway.
• Microsatellite instability pathway in colon cancer: due to methylation or mutations in mismatch repair genes (MMR genes, e.g., MLH1 or MSH2)
• Hypermethylation phenotype pathway in colon cancer
  • CpG island methylator phenotype (CIMP): global hypermethylation of CpG islands → silencing of MMR gene expression
  • Associated with BRAF mutations
  • Up to 20% of sporadic CRCs develop from serrated polyps that underwent malignant transformation via this pathway.
• COX-2 overexpression
  • Associated with colorectal cancer
  • Possible protective effect of long-term use of aspirin and other NSAIDs

Risk factors for colorectal cancer [3]

• Age: older age (> 40 years) [4]
• Hereditary syndromes
  • Family history: Approx. 25% of individuals with colorectal cancer (CRC) have a positive family history.
  • Familial adenomatous polyposis: 100% of individuals will have developed CRC by the age of 40 years, Gardner syndrome, Turcot syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome)
  • Hereditary nonpolyposis colorectal cancer (HNPCC): progression to CRC in 80% of cases
• Associated conditions
  • Colorectal adenomas and serrated polyps (see “Colonic polyps”)
  • Inflammatory bowel disease: chronic inflammation → hyperplasia → non-polypoid dysplasia → neoplasia [5]
    • Ulcerative colitis
    • Crohn disease
  • Endocarditis and bacteremia due to S. gallolyticus [6]
  • Diabetes mellitus type 2
• Lifestyle
  • Smoking
  • Alcohol consumption
• Diet
  • Obesity
  • Processed meat
  • High-fat and low-fiber
• Pathogens: Streptococcus bovis, Clostridium septicum
• Other: History of abdominal radiation during childhood

Protective factors [3]

• Long-term use of aspirin and other NSAIDs
• Physical activity
• Diet rich in fiber and vegetables and lower in meat

Colorectal cancer can be asymptomatic, particularly during the early stages.

Constitutional symptoms [7]

• Weight loss
• Fever
• Night sweats
• Fatigue
• Abdominal discomfort (symptoms similar to diverticulitis, especially in carcinoma of the rectosigmoid or descending colon)

Right-sided colon carcinomas [7][8]

• Definition: large bowel malignancies arising from the cecum, ascending colon, or transverse colon
• Clinical features
  • Occult bleeding or melena
  • Manifestations of iron deficiency anemia (due to chronic bleeding)
  • Diarrhea

Iron deficiency anemia in men > 50 years of age and postmenopausal women should raise suspicion for colorectal cancer.

Left-sided colon carcinomas [7][8]

• Definition: large bowel malignancies arising from the splenic flexure, descending colon, sigmoid colon, or the rectosigmoid junction
• Clinical features
  • Changes in bowel habits (size, consistency, frequency)
  • Blood-streaked stools
  • Colicky abdominal pain (due to obstruction)

Bowel obstruction occurs earlier in left-sided colon carcinomas because the distal colon has a smaller lumen than the proximal colon and contains solid fecal matter.

Rectal carcinomas [7][8]

• Definition: large bowel malignancies located ≤ 15 cm from the anal verge [9]
• Clinical features
  • Hematochezia
  • ↓ Stool caliber (pencil-shaped stool)
  • Rectal pain
  • Tenesmus
  • Flatulence
  • Fecal incontinence

Cancers located ≤ 15 cm proximal to the anal verge are considered rectal carcinomas; cancers above this point are considered colon cancers.

Consider colorectal cancer in every patient with rectal bleeding, even if there is a history of hemorrhoids or diverticular disease.

Metastatic disease [10]

CRC can metastasize through hematogenous, lymphatic, transperitoneal, and contiguous routes. Symptomatic metastases may be the first manifestation of CRC.

• Liver metastases (most common site of metastasis: ; 40–50%)
  • Ascites, abdominal distention
  • Hepatomegaly, RUQ pain
  • Jaundice [11]
  • Anorexia, early satiety
• Lung metastases
  • Dyspnea
  • Cough
  • Hemoptysis
  • Pleural effusion
• Peritoneal metastases
  • Ascites, abdominal distension, diffuse abdominal pain
  • Bowel obstruction
• Evidence of distant lymphatic spread: Virchow node (rare) [12]

Typically, cancers of the colon and upper rectum initially metastasize to the liver via the portal vein, and cancers of the lower rectum initially metastasize to the lung via the inferior vena cava.

Red flags for colorectal cancer [13][14][15]

The sensitivity and specificity of symptoms of colorectal cancer are limited. The following features have the strongest association with CRC, especially in patients with risk factors for colorectal cancer, and should always prompt further investigation.

• Melena, hematochezia
• Altered bowel habits
• Unexplained weight loss
• Unexplained iron deficiency anemia, especially in men older than 50 years of age and postmenopausal women

All patients with suspected CRC should undergo a complete colonoscopy with biopsy of suspicious lesions. Once the diagnosis is confirmed, additional tests to stage the cancer are required to guide management.

Initial workup [9][16]

Digital rectal examination

• Indication: all patients with lower gastrointestinal bleeding (LGIB) or other red flags for CRC
• Findings
  • Distal rectal cancers may be palpable.
  • Evidence of blood on DRE may indicate CRC.
• Important considerations
  • DRE is a part of the routine clinical evaluation in patients with lower gastrointestinal symptoms.
  • Endoscopic evaluation is essential if there is any suspicion for CRC, such as:
    • Inconclusive DRE in a patient with LGIB
    • Any risk factor for CRC
    • Any red flag for CRC
  • Assess sphincter tone during DRE to plan optimal surgical resection for rectal cancer.

Flexible sigmoidoscopy with or without anoscopy [13]

• Indication: Consider in patients with scanty intermittent hematochezia and all of the following features.
  • Age < 40 years
  • No other red flags for CRC
  • No risk factor for CRC
• Important consideration: Patients who do not fulfill any of these criteria require a complete colonoscopy.
• Findings and next steps
  • Inconclusive sigmoidoscopy or lesion that raises concern for malignancy : Perform a complete colonoscopy.
  • Benign pathology confirmed: Manage accordingly (see, e.g., “Hemorrhoids” and “Anal fissures”).

Complete colonoscopy

Colonoscopy is the gold standard test for CRC as it allows for direct visualization and biopsy of polyps and suspicious lesions. [17]

• Indication: : all patients with suspected CRC
• Typical findings [18]
  • Ulceroproliferative friable mass
  • A biopsy is required to confirm the diagnosis (see “Pathology” section for details).
• Important considerations: Consider the following to identify synchronous tumors if colonoscopy cannot be completed (e.g., patients with occlusive CRC). [9][16]
  • Pretreatment CT colonography or capsule endoscopy [16][19]
  • Intra- or postoperative colonoscopy
  • In patients with rectal cancer, reattempt complete colonoscopy after neoadjuvant chemotherapy if there is evidence of tumor regression. [9]

A complete colonoscopy is imperative in all patients with suspected/confirmed CRC as multiple adenocarcinomas (synchronous tumors) are present in up to 5% of cases. [20]

Double-contrast barium enema (uncommonly performed)

• Indication: an alternative to CT colonography in patients who decline/cannot undergo a complete colonoscopy at presentation
• Findings
  • Endoluminal filling defect typically with irregular margins
  • Apple core lesion (napkin ring sign): sharply defined circumferential narrowing of the bowel caused by a stenosing CRC [16][21][22]
• Important considerations
  • Double-contrast barium enema is not routinely recommended because of its low diagnostic yield and the widespread availability of CT colonography. . [16][23]
  • Findings that raise suspicion for CRC on barium enema require biopsy and histopathological confirmation.

Preoperative staging

• All colorectal cancers: Assess for local and distant spread (T stage, N stage, and M stage). [16][24]
  • CT abdomen, pelvis, and chest (with IV and oral contrast)
  • Consider CTA or MRI of the liver if hepatic metastases are suspected. [25] [24]
  • Evaluate for specific sites of metastasis based on clinical suspicion (e.g., diagnostic laparoscopy and peritoneal cytology for suspected peritoneal metastasis). [26][27]
  • Typical findings of distant metastasis
    • Hepatic metastases: multiple hypodense lesions during the portal venous phase of CTA ; may show peripheral washout [25]
    • Pulmonary metastases: multiple, peripheral nodules of varying sizes [28][29]
    • See also “Differential diagnosis of pulmonary nodules” and “Metastatic liver disease.”
• Additional staging workup in rectal cancer [9]
  • Pelvic MRI with and without IV contrast: to determine T stage and N stage
  • Rectal endoscopic ultrasound: Consider in early tumor stages or if MRI is contraindicated.
  • Rigid proctosigmoidoscopy: to assess the distance of the tumor from the anus

Laboratory studies [16]

• Carcinoembryonic antigen (CEA): Obtain baseline levels in all patients before initiating treatment. ; [16]
  • Monitor CEA levels during treatment and follow-up to assess response to treatment and evaluate recurrence.
  • Should not be used for screening [30]
• CBC: may show microcytic anemia (iron deficiency anemia)
• Liver chemistries and coagulation: may be abnormal in patients with multiple hepatic metastases
• Counseling and genetic testing: for patients < 50 years of age with CRC or those with a family history of CRC at a young age (see “Revised Bethesda guidelines” for details)

CEA is a prognostic marker and should not be used to screen for colorectal cancer.

Once the diagnosis is confirmed, CRC should be staged to determine management. The American Joint Committee for Cancer (AJCC) TNM classification is currently the standard staging system used in clinical practice. The Dukes classification is a simplified approach to staging that is of academic interest but is not used to guide management.

Differential diagnoses based on clinical presentation

• Differential diagnoses of lower GI bleeding
• Differential diagnoses of diarrhea
• Differential diagnoses of constipation
• Differential diagnoses of large bowel obstruction
• Differential diagnoses of metastatic liver disease

Small bowel neoplasms

• Epidemiology
  • Less than 5% of all gastrointestinal cancers
  • Mainly benign lesions (> 95%)
  • Malignant small bowel cancers (1–3%)
    • 40% small bowel adenocarcinoma
    • 30% neuroendocrine tumors
    • 20% lymphoma
    • 10% gastrointestinal stromal tumors (GIST), leiomyosarcoma, liposarcoma, metastatic disease
• Diagnostics
  • Endoscopy
  • Ultrasound
  • Hydro-MRI
  • Capsule endoscopy
• Treatment
  • Resection of the small bowel
  • R1 resection requires adjuvant chemotherapy
• Complications
  • Bleeding
  • Ileus
  • Metastatic spread
  • Carcinoid syndrome in the case of neuroendocrine cancers of the small bowel
• Prognosis (if malignant): 5-year survival rate is ∼ 68% [33]

The differential diagnoses listed here are not exhaustive.

General principles [9][16]

• A multidisciplinary approach is recommended.
• Treatment depends primarily on the location of the tumor and the TNM stage.
  • Curative treatment is primarily surgical and may involve neoadjuvant or adjuvant chemotherapy and/or radiation therapy.
  • Palliative treatment may involve chemotherapy, radiation therapy, and, in some cases, surgery.
  • See “Treatment of colon cancer” and “Treatment of rectal cancer” for details.

Surgery for colorectal cancer [9][16]

Curative surgery

• Surgery of primary tumor
  • Indicated in any resectable primary tumor with no metastasis or resectable distant metastases
  • Conventional or laparoscopic approach is possible [16]
  • Complete resection with clear margins (R0 resection) is associated with the best prognosis.
  • See “Surgery for colon cancer” and “Surgery for rectal cancer” for details.
• Regional lymph node dissection: performed routinely alongside resection of the primary tumor
  • Resection of mesenteric lymph nodes along the path of lymphatic drainage
  • Histological analysis of 12 removed lymph nodes to accurately define the lymph node status is required for accurate staging. [32]
• Resection of metastases
  • Indicated in patients with resectable metastases (e.g., liver and/or lung metastasis)
  • May significantly improve the survival of patients with limited metastatic disease.

Palliative surgery

Consider in patients with nonresectable distant metastases to prevent or treat complications of colorectal cancer.

• Intestinal bypass (e.g., ileocolonic anastomosis, colostomy) or enteral stenting for obstructing/occlusive CRC
• Tumor resection to manage immediately life-threatening complications, such as complete bowel obstruction, persistent GI bleeding, or perforation. [16]

Systemic therapy [9][16][34]

Systemic therapy is indicated in most patients with colon or rectal cancer. See “Treatment of colon cancer by stage” and “Treatment of rectal cancer by stage” for details. [34][35]

• Chemotherapy regimens
  • FOLFOX: folinic acid (leucovorin) PLUS 5-fluorouracil (5-FU) PLUS oxaliplatin
  • FOLFIRI: folinic acid (leucovorin) PLUS 5-fluorouracil (5-FU) PLUS irinotecan
  • CAPOX: capecitabine PLUS oxaliplatin
• Biologics
  • Anti-VEGF antibodies (e.g., bevacizumab)
  • EGFR antibodies (e.g., cetuximab)

Radiation therapy

• Rectal cancer: standard treatment modality in most stages of rectal cancer [9]
• Colon cancer
  • Not a standard modality because of adverse effects on the small intestine leading to enteritis and strictures
  • May be used in palliative care to treat bone and brain metastases [36][37]

Principles of colon cancer treatment [16]

The treatment of colon cancer is mainly surgical, supplemented with chemotherapy. Radiation therapy is not a standard therapeutic modality for colon cancers.

Surgery for colon cancer [16][38][39]

• Colectomy with lymph node dissection is indicated in all resectable tumors.
• The extent of the resection depends on the location of the tumor as well as the blood supply and lymphatic drainage of the affected region.
• En bloc resection of infiltrated adjacent tissue is recommended to obtain an R0 resection.
• In patients with peritoneal metastases, consider cytoreductive surgery in combination with intraperitoneal chemotherapy (HIPEC or hyperthermic intraperitoneal chemotherapy). [16]
• Bowel continuity should be restored via anastomosis when feasible; a stoma (temporary/permanent) may be needed. [40]

Principles of rectal cancer treatment [9][34]

Surgery for rectal cancer [9]

• The extent of the resection depends on the location of the tumor and the TNM stage.
• The sphincter tone and the distance of the tumor from the anal verge (e.g., via rigid proctosigmoidoscopy) should be assessed preoperatively to plan appropriate surgical resection.
• Consider gynecology and/or urology consult if imaging shows a regional spread past the rectum.

A complete TME is necessary to adequately assess the nodal status and prevent recurrence.

Gross pathology

• Right-sided colon carcinomas: mostly exophytic mass
• Left-sided colon carcinomas: mostly infiltrating mass

Histopathology

• Most common: adenocarcinoma (95%)
• Less common
  • Mucinous adenocarcinoma
  • Signet ring cell carcinoma
  • Small cell carcinoma
  • Adenosquamous carcinoma (rare)
  • Squamous cell carcinoma of the colon (rare)

95% of all colorectal cancers are adenocarcinomas.

Peritoneal carcinomatosis [43][44]

• Definition: a terminal feature of abdominal cancers (most commonly of the ovary, appendix, or colon) characterized by seeding of the tumor to the peritoneum
• Epidemiology: : depends on underlying malignancy; peritoneal carcinomatosis develops in ∼ 10% of individuals with colorectal cancer [45]
• Etiology: primary tumor metastasizes to the peritoneal surface
• Clinical features
  • Ascites
  • Fistulas
  • Fatigue
  • Abdominal pain, nausea, cachexia
• Diagnostics: CT is preferred; typically shows metastatic studding (tumor nodules studding the surface of the peritoneum) and omental caking
• Treatment
  • Operable disease: involves cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC), systemic chemotherapy, targeted therapy, and/or immune checkpoint inhibitors
  • Inoperable disease: experimental pressurized intraperitoneal aerosolized chemotherapy or repeated intraperitoneal chemotherapy infusion
• Complications: bowel, biliary, and/or ureteral obstruction
• Prognosis: : poor; 5-year survival rates after cytoreductive surgery and HIPEC are approx. 40%

We list the most important complications. The selection is not exhaustive.

All patients with CRC should be followed up closely after curative treatment to ensure early identification and management of recurrence. These recommendations are consistent with the American Society of Colon and Rectal Surgeons' 2015 guidelines. [46][47][48]

• Patient history, physical examination, CEA level
  • Every 3–6 months for 2 years
  • Every 6 months for an additional 3 years
• CT chest/abdomen/pelvis: annually for 5 years
• Colonoscopy
  • 1 year after preoperative colonoscopy
  • Every 3–5 years in the further follow-up, depending on findings
• Proctoscopy/sigmoidoscopy
  • Recommended additional follow-up modality after the treatment of rectal cancer
  • Every 6–12 months for 3–5 years
  • May be supplemented with endorectal ultrasound
• Recommended duration of close follow-up: 5 years following the completion of curative treatment

90% of recurrences occur within the first five years following treatment. [48]

• Five-year survival rate [2]
  • Localized disease: 90%
  • Regional spread: 72%
  • Distant metastases: 14%
  • All stages combined: 65%

Screening modalities and screening intervals depend on individual risk factors and differ for individuals at average risk and those at high risk of CRC.

Individuals at average risk (general population) [49][50][51]

• Criteria for average risk of CRC include:
  • No history of CRC, IBD, or adenomatous polyps
  • No family history of hereditary colon cancer syndromes (e.g., HNPCC, familial adenomatous polyposis)
• Recommended screening age
  • All individuals ≥ 45 years of age [49][51]
  • The decision to continue screening in patients aged 75–85 years should be made on a case-by-case basis. [49]
• Screening modalities: Consider individual risk factors and patient preference when choosing a screening method.
  • Direct visualization
    • Gold standard: Complete colonoscopy every 10 years if no polyps or carcinomas are detected
    • Alternatives
      • CT colonography or capsule endoscopy every 5 years [50]
      • Flexible sigmoidoscopy every 5–10 years
  • Stool-based testing
    • Annual fecal immunochemical testing (FIT)
      • Uses antibodies to detect occult GI bleeding
      • Has a higher sensitivity for CRC than FOBT
      • All positive stool-based test results need to be confirmed using colonoscopy.
    • Annual fecal occult blood test (FOBT)
      • Used to detect the presence of blood in feces that is not visibly apparent.
      • Used as a screening tool for colorectal carcinoma, but upper gastrointestinal bleeding (e.g., from a peptic ulcer) can also yield positive results
      • A positive result merits additional follow-up (e.g., upper endoscopy, colonoscopy)
      • Has poor sensitivity for detecting polyps
    • Multitargeted stool DNA test every 3 years
      • A stool-based assay that detects certain mutations typical for early colorectal carcinoma, such as mutations of the KRAS gene.
      • Used as a screening tool for colorectal carcinoma
      • Positive tests are followed up with colonoscopy

Individuals at high risk [21][50]

• Control modifiable risk factors for CRC. [52][53][54]
  • Increase physical activity.
  • Optimize nutrition.
  • Decrease or stop alcohol consumption and smoking.
  • Optimize treatment of conditions that increase the risk of CRC (e.g., IBD, HTN, diabetes, hyperlipidemia). [52]
• Long-term aspirin therapy may reduce the incidence of CRC. [50][55]
  • Low-dose aspirin may be considered based on shared decision making if all of the following parameters are met:
    • Age 50–69 years with life expectancy > 10 years
    • No comorbidity or use of other pharmacotherapy that increases the risk for bleeding
    • Risk of cardiovascular disease ≥ 10% for the next 10 years (see “ASCVD risk assessment” and “10-year ASCVD risk categories” for details)
    • High likelihood of adherence to aspirin therapy for at least 10 years
  • Important considerations
    • Aspirin therapy does not replace screening for CRC or alter screening intervals.
    • It is unclear if aspirin therapy provides additional benefits over CRC screening or if its benefits outweigh the risks.

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