Colorectal Cancer

Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Almost all cases of CRC are adenocarcinoma, and the majority of lesions come from the malignant transformation of an adenomatous polyp. Since most CRC cases are asymptomatic, screening colonoscopy or stool tests are generally recommended in patients ≥ 50 years of age. Along with screening, diagnosis is reached by colonoscopy, which allows visualization as well as tissue sampling. Treatment is primarily surgical, with chemotherapy reserved for advanced disease.

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Overview

Epidemiology

  • 3rd most common cancer (among both men and women)
  • 2nd most common cause of death due to cancer in the United States
  • In the United States, incidence and mortality rates have been declining.
  • The majority are adenocarcinomas.
  • Most colorectal cancers (CRCs) arise from polyps (adenomatous or serrated).

Risk factors

  • Age ≥ 45 (94% of new CRC cases)
  • Hereditary syndromes: 
    • Familial adenomatous polyposis (FAP)
    • Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome
    • Peutz-Jeghers syndrome (PJS)
    • MUTYH-associated polyposis (MAP): mutation in the base excision repair gene mutY homolog
    • Family history of CRC
  • Colon pathologies:
    • Inflammatory bowel disease (IBD)
    • Large adenomatous polyps or previous CRC
  • Other medical conditions:
    • Cystic fibrosis
    • Abdominopelvic radiation
    • Conditions with increased insulin or insulin-like growth factor (e.g., diabetes, acromegaly, obesity)
    • Streptococcus bovis bacteremia
    • Renal transplantation
  • Lifestyle and social factors:
    • Smoking and alcohol consumption (> 4 drinks/day)
    • Diet (increased fat, red and processed meat, low fiber)
    • Low socioeconomic status

Etiology

Colorectal polyps

  • Abnormal tissue outgrowths arising from the colonic mucosa and extending into the lumen
  • Most common lesions from which CRC arises
  • Morphology:
    • Sessile: polyp without a stalk, with growth adjacent to the mass
    • Pedunculated: polyp with a stalk
  • 30% of the population has polyps by the age of 50.

Types of polyps:

  • Inflammatory polyps (non-neoplastic)
  • Hamartomatous polyps (↑ CRC risk if associated with PJS)
  • Sessile serrated lesions:
    • Sessile serrated adenomas/polyps (SSA/Ps)
    • Traditional serrated adenomas (TSAs)
    • Hyperplastic polyps (histologically similar to SSA; non-neoplastic)
  • Adenomatous polyps:
    • Tubular (> 80%)
    • Villous adenomas (majority are sessile)
    • Tubulovillous 

High-risk polyps:

  • Polyps > 1 cm in size
  • Adenomas with villous features (CRC risk > 3 times that of tubular adenomas) or high-grade dysplasia
  • Serrated polyps/adenomas

Polyp of sigmoid colon revealed by colonoscopy: The polyp is pedunculated (with a short stalk).

Image: “Colon polyp” by Dr. F.C. Turner. License: CC BY 2.5

Cancer development

Most polyps are benign. Malignant transformation is affected by a series of mutations and environmental factors.

Mutations:

  • Germline mutation: 
    • Occurs before fertilization
    • Can be transmitted (from parent to offspring)
    • Found in the common inherited syndromes (e.g., FAP, Lynch syndrome), which account for < 10% of CRCs
  • Somatic mutation:
    • Spontaneous mutation in sperm/ovum or zygote
    • Parent does not have the mutation, but future offspring can inherit.
    • Found in sporadic CRCs (> 70%)

APC (adenomatous polyposis coli) gene:

  • Most CRCs begin with adenomatous polyposis coli (APC) gene inactivation (either by germline or somatic mutation).
  • CRCs take 10–15 years to develop but can advance in a shorter time under certain conditions.
  • APC protein, encoded by APC gene, promotes β-catenin degradation.
  • Without APC protein: 
    • β-catenin activates T cell factor (Tcf)–dependent transcription of specific target genes.
    • These genes include MYC and cyclin D1 (oncogenes), which promote proliferation.
  • APC mutations: the initiating event for adenoma formation, but multiple genetic hits are required for CRC progression

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Pathophysiology

APC

Adenomatous polyposis coli is an initial gene mutation.

  • Most adenomas and CRCs begin with APC gene inactivation (either by germline or somatic mutation).
  • After the initiating event, CRCs take 10–15 years to develop (shorter time in certain conditions).
  • APC protein, encoded by APC gene, promotes β-catenin degradation.
  • Without APC protein: 
    • β-catenin (of the WnT pathway) activates Tcf–dependent transcription of specific target genes.
    • These genes include MYC and cyclin D1 (oncogenes), which promote proliferation.

Molecular mechanisms of tumorigenesis

Multiple genetic hits are required for CRC progression.

Accumulation of mutations and molecular events:

Accumulation of mutations and molecular events (e.g., genetic alteration, DNA methylation, overexpression) contributes to carcinogenesis.

  • Chromosomal instability (CIN):
    • Structural chromosomal aberrations (deletions or loss of heterozygosity)
    • Results in either promotion of oncogenes or reduction of tumor suppressor genes (TSGs)
    • Seen in genetic alterations of APC
    • Other genes: DCC, TP53/p53, and SMAD4 (tumor suppressor genes) or KRAS (a proto-oncogene)
    • 85% of CRCs develop through this mechanism.
  • Microsatellite instability (MSI):
    • Also called mutator phenotype/mismatch repair pathway
    • Microsatellites: repeated, abnormal, short sequences of nucleotide bases caused by mismatch repair deficiency
    • Cause: germline mutation of genes MLH1, MSH2, or PMS2 leading to dysfunctional DNA mismatch repair (MMR) enzymes
    • Microsatellite accumulation: found in MSI-high (MSI-H) tumors
    • Biologic hallmark of Lynch syndrome
    • Seen in up to 15% of sporadic CRCs
  • CpG island methylator phenotype (CIMP+) pathway:
    • DNA hypo- or hypermethylation can change gene expression.
    • High methylation of CpG islands (cytosine followed by a guanine base, linked by phosphodiester bond) occurs in TSG.
    • Methylation inactivates TSG, leading to tumor progression.
    •  Found in CIMP+ tumors

Cyclooxygenase (COX)-2 overexpression: 

  • COX-2: overexpressed in 43% of adenomas and 86% of carcinomas
  • COX-2 inhibition reduces the number of intestinal polyps.

Morphologic mechanisms of tumorigenesis

Adenoma-carcinoma sequence:

  • Sequence followed by most CRCs
  • Progression: early adenoma (tubular or tubulovillous) → advanced adenoma (villous) → adenocarcinoma
  • Adenomatous polyps: 
    • Develop with disrupted epithelial renewal
    • Replacement of surface cell lining becomes dysplastic as the adenomas increase in size.
  • APC mutation common
  • Associated molecular pathway(s): CIN

Adenoma-carcinoma sequence from normal colon to carcinoma: CRC formation begins with APC gene mutation (inherited or acquired) and methylation abnormalities. Other changes can include KRAS gene mutation. Late in the process, p53 deletion, loss of heterozygosity (LOH) at 18q21 (involving SMAD2 and SMAD4), with overexpression of COX-2 can contribute to further growth and progression to cancer. The accumulation of mutations, rather than the timing of occurrence, is most crucial in carcinogenesis.

Image by Lecturio.

Serrated polyp pathway:

  • Serrated polyps: also have malignant potential 
  • Seen in 10%–20% of cases
  • Progression: sessile serrated polyp/adenoma → adenocarcinoma
  • BRAF oncogene activation with KRAS mutations noted
  • Associated molecular pathway/s: 
    • CIMP (major mechanism that drives the serrated pathway toward CRC)
    • MSI

Schematic diagram of the classical (adenoma-carcinoma) and serrated pathways.
Upper half: serrated pathway of colorectal carcinogenesis, occurring in 10%–20% of CRCs. The pathway is associated with the following genetic features: BRAF/KRAS mutations, MSI (microsatellite instability), and CIMP (CpG island methylator phenotype). Serrated lesions can be hyperplastic polyps (HPPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The latter 2 are associated with dysplasia and progression to carcinoma.
Lower half: adenoma-carcinoma or classical pathway, occurring in most CRCs. Among the genetic features include mutations in APC/KRAS/p53 genes and chromosomal instability (CIN). Through this sequence, adenoma becomes adenocarcinoma.

Image: “Schematic diagram of the classical (adenoma-carcinoma) and serrated pathways” by Centre for Tumor Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. License: CC BY 4.0

Clinical Presentation

General clinical findings

  • Often asymptomatic, with CRC detected on screening colonoscopy
  • Symptomatic:
    • Systemic features: weakness, anemia, weight loss
    • Iron deficiency anemia in an elderly patient indicates colon cancer until proven otherwise.
    • Dependent on location

Right-sided carcinomas

  • Obstructive symptoms are not common:
    • Stool in the area (ileocecal valve to ascending colon) is still liquid.
    • Lumen is larger (than left side).
  • Lesions can grow, ulcerate, and lead to occult blood loss:
    • Iron deficiency anemia: fatigue, angina, palpitations
    • Melena 

Left-sided carcinomas

  • From the transverse to the descending colon, stool becomes formed.
  • Thus, cancerous lesions can impede passage of stool, causing:
    • Abdominal cramping or colicky pain
    • Changes in bowel habits (constipation alternating with loose stools)
    • Blood-streaked stools or hematochezia
    • Decreased stool caliber due to obstruction

Rectal cancers

  • Palpable ulcerating mass on rectal exam
  • Tenesmus 
  • Rectal bleeding
  • Obstruction

Metastasis

  • CRCs metastasize by direct extension or via hematogenous and lymphatic route. 
  • Sites of metastasis: 
    • Liver (1st site for intestinal tumors): abdominal distention, jaundice, ascites, hepatomegaly
    • Lungs (1st site for distal rectal tumors): cough, dyspnea (may be from pleural effusion), hemoptysis

Diagnosis

Colonoscopy

  • Diagnostic test of choice
  • Visualization of lesion(s) and tissue sampling (biopsy or lesion removal) can be performed.
  • Screening colonoscopy:
    • Asymptomatic patients
    • For the population with average risk: performed at age 50 years and above
    • Screening at a younger age depends on conditions and risks.
  • Diagnostic colonoscopy:
    • Performed in symptomatic patients
    • Indicated for those with abnormal imaging studies
  • Findings:
    • Polyps 
    • Carcinoma:
      • Bulky exophytic masses
      • Annular constricting lesions

Colon cancer found on colonoscopy and confirmed via biopsy

Image: “Primary tumor” by Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, Japan. License: CC BY 2.0

Computed tomography (CT) colonography

  • Virtual colonoscopy 
  • Requires mechanical preparation
  • Can be used in incomplete colonoscopy (e.g., obstruction, tortuous colon) or as an initial diagnostic test
  • Colonoscopy remains the gold standard.
  • Limitations:
    • Patients should be able to pass flatus.
    • Cannot perform biopsy or lesion removal

PILLCam 2

  • Colon capsule endoscopy: Patient swallows a capsule-sized endoscope.
  • Considered in patients with incomplete colonoscopy
  • Patients should have no obstruction.

Further imaging studies

  • Air contrast barium enema may show apple core lesion.
  • CT scan:
    • For preoperative staging
    • Detects associated complications (e.g., obstruction, perforation, fistula)
    • Detects metastasis
  • Pelvic magnetic resonance imaging (MRI) or transrectal endoscopic ultrasonography (US):
    • For rectal cancers 
    • For assessment of cancer depth through the rectal wall and perirectal lymph nodes

Laboratory tests

  • Carcinoembryonic antigen (CEA):
    • Tumor marker for CRC; obtained with proven CRC
    • Not used for screening or diagnostic test
    • Prognostic value: preoperative CEA > 5 ng/mL has worse prognosis.
    • Non-normalization of values after surgery: indicative of persistent disease
  • Complete blood count (CBC): may show anemia
  • Metabolic panel:
    • May show additional metabolic abnormalities
    • Elevated alkaline phosphatase: most common liver abnormality associated with liver metastasis

Staging

After establishing the diagnosis of CRC, staging the disease is needed for appropriate management.

TNM (tumor, node, metastasis) staging system: 

  • Determines disease extent
  • Findings based on: 
    • Preoperative examination (e.g., ascites, lymph nodes)
    • Imaging results: 
      • CT scan (chest/abdomen/pelvis)
      • MRI (identifies more metastatic hepatic lesions)
      • Transrectal endoscopic US (for rectal cancer)
    • Endoscopy (with biopsy) and lymph node biopsy
StageTumor (T)Regional lymph nodes (N)Distant metastasis (M)
Stage 0
  • Tis: carcinoma in situ (intramucosal carcinoma)
  • N0: no regional lymph nodes involved
  • M0: no distant metastasis
Stage I
  • T1: invasion into the submucosa through muscularis mucosa
  • T2: invasion into the muscularis propria
  • N0: no regional lymph nodes involved
  • M0: no distant metastasis
Stage II
  • T3: invasion through the muscularis propria and into the pericolorectal tissues
  • T4a: invasion through the visceral peritoneum
  • T4b: invades or adheres to adjacent organs or structures
  • N0: no regional lymph nodes involved
  • M0: no distant metastasis
Stage III
  • Any T
  • N1: metastasis in 1–3 regional lymph nodes or any number of tumor deposits present and all identifiable lymph nodes are negative
    N2: metastasis in 4 or more regional LNs
  • M0: no distant metastasis
Stage IV
  • Any T
  • Any N
  • M1a: metastasis to 1 site or organ; no peritoneal metastasis
  • M1b: metastasis to 2 or more sites; no peritoneal metastasis
  • M1c: metastasis to peritoneal surface (alone or with other site metastasis)

Prevention

  • Adults (50–59 years of age):
    • United States Preventive Services Taskforce: daily low-dose aspirin for primary prevention of CRC
    • Individuals should have:
      • No bleeding risk 
      • At least 10 years of life expectancy
      • ≥ 10% of 10-year CVD risk
  • Individuals with average risk:
    • Initiated at 50 years of age (45 years of age for African Americans)
    • Options for screening:
      • Annual high-sensitivity guaiac-based fecal occult blood test (HSgFOBT)
      • Annual fecal immunochemical test (FIT)
      • sDNA-FIT test every 3 years
      • Flexible sigmoidoscopy every 5 years (limited to distal part of the colon)
      • Colonoscopy every 10 years
      • CT colonography every 5 years
    • A positive screening stool-based test, CT colonography, or sigmoidoscopy warrants a colonoscopy. 
    • Screening generally not recommended after age 75
  • Individuals with a family history of CRC/advanced adenoma/advanced serrated lesion:
    • Colonoscopy at age 40 or 10 years earlier than the age of diagnosis of the 1st-degree relative (whichever comes first)
    • Repeat every 5 years

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Management

General principles

  • Resection of primary cancer:
    • Treatment of choice for almost all patients with resectable lesions
    • Can be laparoscopic or open surgery
  • Regional lymph node dissection (at least 12 lymph nodes) is performed with resection (aids in determining additional adjuvant therapy).
  • Chemotherapy:
    • Adjuvant chemotherapy: given depending on stage of colon carcinoma
    • Neoadjuvant chemotherapy and/or radiotherapy: given for patients with rectal carcinoma (T3 or higher, node-positive cancers) 
    • Chemotherapy regimens:
      • FOLFOX (5-fluorouracil/5-FU + folinic acid/leucovorin + oxaliplatin) regimen
      • FOLFIRI (5-fluorouracil + folinic acid + irinotecan)
      • CAPOX/XELOX: oral capecitabine (Xeloda) used with oxaliplatin

The stage of CRC and molecular biology (in the case of targeted therapy) dictate the roles of surgical and pharmacologic treatments.

Carcinoma in a polyp

  • Endoscopic removal or polypectomy
  • When invasive cancer is suspected, tattooing is done (for localization if an invasive lesion is found or if additional therapy/surgery is needed).
  • Factors indicating high risk for residual cancer or nodal metastasis (consider radical surgery):
    • Poorly differentiated histology
    • Cancer at stalk margin
    • Lymphovascular invasion
    • T2 lesion
    • Invasive carcinoma in a sessile polyp

Colon cancer stage I–III

  • Wide resection of the lesion with regional lymphadenectomy is performed.
  • Surgical options:
    • Right hemicolectomy: lesion(s) in the cecum and right colon (can be extended to include transverse colon)
    • Left hemicolectomy: lesion(s) in the splenic flexure and left colon (can be extended to include transverse colon)
    • Sigmoid colectomy: sigmoid colon 
    • Total abdominal colectomy:
      • Synchronous colon cancers
      • FAP
      • HNPCC
  • Multivisceral resection with negative margins of the involved structure is recommended in patients who have an invasion of the contiguous organs or adhesions with adjacent structures.
  • Chemotherapy options:
    • Stage I: no adjuvant therapy
    • Stage II: controversial; those at high risk of recurrence may benefit from adjuvant therapy
    • Stage III (node-positive disease): 
      • Significant benefit from adjuvant therapy
      • MSI-H tumors: do not benefit from 5-FU based chemotherapy

Metastatic disease or stage IV

  • The majority do not have a resectable (curable) disease.
  • Chemotherapy: standard treatment and can slow tumor progression
  • Isolated liver/lung lesions: Metastatic lesions confined to the liver or lung can be resected.
  • The addition of biologic agents/targeted therapy improves survival in suitable patients.
  • Unresectable metastatic disease: 
    • Address the associated complication(s) (obstruction, perforation).
    • Local ablative techniques (cryosurgery, radiofrequency coagulation, embolization, hepatic intra-arterial chemotherapy) or radiation

Rectal cancer

  • Preoperative (neoadjuvant) chemotherapy and/or radiotherapy: 
    • In T3 or greater tumors
    • Recommended in all node-positive tumors
  • Operative approach post-chemotherapy depends on:
    • Level of the tumor above the anal verge
    • Size and depth of penetration
    • Patient’s overall clinical status
  • For minimally invasive, small (less than 3 cm), well-differentiated T1 rectal tumors: transanal excision
  • Most stage II–III:
    • Low anterior resection (LAR): 
      • Sphincter-preserving surgery
      • Moderately or well-differentiated tumors within 2 cm of the anal sphincter 
      • Poorly differentiated tumors within 5 cm of the anal sphincter
    • Abdominoperineal resection (APR)
      • Total rectal excision with a permanent colostomy
      • Moderately or well-differentiated tumors < 2 cm from the anal sphincter
      • Poorly differentiated tumors < 5 cm from the anal sphincter
  • Unresectable rectal cancer: palliative treatment with a diverting colostomy

Role of targeted therapy

  • Gene profiling of tumor tissue: performed to find specific molecular abnormalities and determine treatment options 
  • Used with chemotherapy or on its own when cancer has progressed on chemotherapy
    • Anti-VEGF (vascular epidermal growth factor):
      • Bevacizumab (added to 1st-line chemotherapy)
      • Ramucirumab (2nd-line treatment) 
      • VEGF trap or aflibercept (2nd-line treatment) 
    • Anti-EGFR (epidermal growth factor receptor) (added to chemotherapy in stage IV tumors with specific mutations): cetuximab, panitumumab 
    • BRAF inhibitor (for metastatic CRC that progressed with prior chemotherapy): encorafenib
    • Immune checkpoint inhibitors (for MSI-H or deficient mismatch repair (dMMR) CRC): pembrolizumab, nivolumab
    • Multi-targeted kinase inhibitor (for metastatic, refractory CRC after progression on standard regimens): regorafenib
    • Trifluridine/tipiracil (refractory CRC after progression on standard regimens) 

Follow-up

Carcinoembryonic antigen:

  • Monitored for 5 years after the completion of treatment (every 6 months). 
  • Serial values after surgery/treatment: 
    • Elevation of CEA should be retested.
    • When confirmed, testing may include CT scan, positron emission tomography (PET), and/or colonoscopy looking for disease recurrence.

Colonoscopy:

  • Within a few months after surgical resection, then 1 year after surgery
  • Every 3–5 years thereafter

Imaging:

  • Annual CT scan (chest and abdomen) for at least 3 years
  • Annual CT scan (pelvis) for rectal cancer if pelvic radiation was not given

Familial Colon Cancer Syndromes

Familial adenomatous polyposis

  • Autosomal dominant
  • Occurs due to a mutation in the APC gene
  • Hundreds of colorectal adenomas develop (seen in colonoscopy) by age 15 years.
  • Risk of CRC: 100%, often detected by age 40 years
  • Screening for cancer: colonoscopy starting at 10–15 years of age
  • Treatment: prophylactic colectomy (proctocolectomy or total colectomy), usually by age 20
  • Indications for colectomy in FAP: 
    • Elective
    • Suspected CRC
    • Presence of colonic dysplasia or neoplasia 
    • Significant increase in polyp number during screening

Hereditary non-polyposis colorectal cancer/Lynch syndrome

  • Autosomal dominant
  • Occurs due to mutation of 1 of the DNA mismatch repair genes (MSH2, MSH6, MLH1) resulting in MSI, or the EPCAM gene.
  • Risks of CRC: 75%
  • At-risk individuals who meet the Amsterdam II criteria (“3-2-1 rule”):
    • 3 or more relatives with CRC, 1 of whom must be a first-degree relative of the other 2
    • Involvement of 2 or more generations
    • At least 1 cancer must have been diagnosed < 50 years of age.
    • FAP has been excluded.
    • Tumors verified by pathologic examination
  • Confirmatory test: DNA sequencing
  • CRC screening: annual screening colonoscopy at 20–25 years of age
  • Management: 
    • Surveillance generally preferred
    • Aspirin (may reduce risk of CRC)
    • Surgery if surveillance not feasible/confirmed mutations/when advanced adenoma/CRC found

Peutz-Jeghers syndrome

  • Autosomal dominant
  • STK11 mutation
  • Development of hamartomas of the small and large intestines
  • Associated with hyperpigmentation of the mouth, hands, and feet
  • Risk of developing CRC: 40%
  • Malignancies:
    • Gastrointestinal (GI) malignancies (stomach, small bowel, and colon) develop in 40%–60% of cases.
    • Breast cancer in 30%–50% of cases
    • Nonintestinal organs (gonads, pancreas)

Differential Diagnosis

  • IBD: also presents with changes in bowel habits, abdominal pain, and weight loss, but colonoscopy findings and extraintestinal manifestations of IBD help differentiate this disease from CRC. Fecal calprotectin is a highly sensitive test for intestinal inflammation that can be used to distinguish IBD.
  • Hemorrhoids: also presents with blood per rectum and changes in bowel habits. Hemorrhoids may cause rectal pain and can be identified on physical exam or anoscopic exam. Bleeding per rectum in a patient > 50 years of age with hemorrhoids still needs to be investigated for CRC.
  • Diverticular disease: diverticulosis is the presence of sac-like protrusions in the colon. Complications include diverticular bleeding and diverticulitis, which also present with blood per rectum and changes in bowel habits. Colonoscopic findings differentiate diverticular disease from CRC.
  • Small bowel neoplasms: also present with blood in stool and obstructive symptoms. To differentiate these neoplasms from CRC, upper and lower endoscopy may be required.
  • Neuroendocrine tumors: affect the right colon in the majority of cases. These lesions have characteristic symptoms of carcinoid syndrome (diarrhea, flushing, and wheezing).

References

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