creation date: 2025-11-17 15:18
tags: Pathologies
Colorectal Cancer
Background
Definitions
Colorectal cancer refers to cancers of the colon and the rectum and is highly prevalent worldwide.
Colorectal cancer accounts for ~8% of all newly diagnosed cancers.
Etiology and Risk Factors
70% of cases are sporadic and thus occur by chance. In 20-25% of cases, patients have a strong colon cancer family history but with no identifiable inherited mutation. In 3-5% of cases, inherited genetic mutations (eg. HNPCC and FAP) result in colon cancer.
Several risk factors exist for developing colon cancer:
- Age (median age of diagnosis >65)
- Family history
- Inherited colon cancer mutations
- History of adenomas
- History of inflammatory bowel disease (IBD)
- Environmental factors such as:
- Alcohol consumption
- Cigarette smoking
- Obesity
- Diet rich in processed red meat
- Insulin resistance
- History of prior radiation
- Immunosuppression
Pathogenesis
Colon cancer manifests as a result of the transition from normal colonic epithelium to cancerous growth. This involves the accumulation of genetic changes over time which leads to carcinoma.
Carcinogenesis
There is 3 main genetic pathways in which colon cancer develops which overlap.
Chromosomal instability (CIN)
This is classically described as the classical adenoma-carcinoma pathway. A mutation gain disrupts the balance between oncogene and tumour suppressors resulting in carcinogenesis. Common mutations include APC, KRAS, and TP53.
APC is the most common (60% of colon cancers) and disrupt growth regulation, apoptosis, and cell differentiation.
Mismatch repair (MMR)
This pathway is characterized by MLH1, MSH2, MSH6, or PMS2 gene mutations. These mutations result in DNA replication errors to accumulate. Microsatellite instability (MSI) may be associated with MMR mutations.
CpG island methylator phenotype (CIMP)
CIMP is implicated in 15% of colon cancers. It is characterized by CpG island hypermethylation. This typically results in serrated polyps rather than classical adenomas.
CIMP pathway mutations may also be further categorized into subtypes.
Types
Colon adenocarcinoma is the predominant type, making up >90% of colon cancers.
The remainder is made of up:
- Neuroendocrine tumours
- Gastrointestinal stromal tumours
- Lymphomas
Clinical Presentation
Signs & Symptoms
Early stage colon cancer is often asymptomatic and only diagnosed with screening.
In many cases of colorectal cancer, diagnosis is made after the onset of symptoms. Presenting symptoms in order of prevalence include:
- Change in bowel habits
- Rectal bleeding
- Rectal mass
- Abdominal mass
- Iron deficiency anemia
- Abdominal pain
It should be noted that in early-onset colorectal cancer (age <50), hematochezia and abdominal pain were the most common presenting symptoms.
Findings may manifest differently depending on the location of the tumour. Certain symptoms are more frequently seen with specific locations:
- Bowel habit changes - left-sided
- Hematochezia - rectosigmoid
- Iron deficiency anemia - right-sided
- Abdominal pain - all sites
- Tenesmus, rectal pain, diminished caliber of stool - rectal
- Obstructive symptoms - cancer encircles bowel
Metastatic disease may present if the cancer spreads. This can occur by lymphatic or hematogenous dissemination. The most common metastatic sutes are:
- Regional lymph nodes
- Liver (most common first site of hematogenous spread due to portal drainage)
- Lungs
- Peritoneum
Atypical presentations include:
- Local invasion or contained perforation causing malignant fistula
- Fever due to abscesses from perforated colon cancer
- Extra-abdominal infections cause by colonic anaerobic organisms
History & Physical Exam
Owing to screening, most colorectal cancers are caught during asymptomatic phase. As such, history and physical generally is less helpful.
In cases of symptomatic suspicion, history should elicit the manifestations of colon cancer. Physical should focus on signs of metastatic disease including an abdominal and rectal exam.
Diagnosis
Criteria
Diagnosis of colorectal cancer is made by histology of malignant colonic tissue. This is obtained by biopsy during colonoscopy or surgical specimen.
Staging
A number of features of the tumour is reported by pathology:
- Specimen integrity
- Histologic subtype
- Histologic grade (degree of gland formation)
- Tumour extent (degree of invasion into colonic wall)
- Angiolymphatic invasion
- Perineural invasion
- Tumour budding (presence of malignant cells at the tumour edge)
Findings can be used in addition to further workup to stage the colon cancer using the TNM system which can then be used to categorize into Stage I-IV.
Work-up
If colonoscopy is not an option or if a colonoscopy was unable to be completed in its entirety due to obstruction, CT colonography has acceptable sensitivity to support a diagnosis. However, colonoscopy and biopsy remains the gold standard.
Following diagnosis, staging aided by evaluation of the extent of disease:
- Physical examination (esp. for ascites, hepatomegaly, lymphadenopathy)
- CT abdomen and pelvis
- Chest imaging
In general, laboratory studies serve no diagnostic role other than as a routine test. This may include:
- CBC (for anemia)
- Liver function tests
- Tumour markers - serum carcinoembryonic antigen (CEA) may be useful for prognosis
Screening
A number of screening tests are available for the detection of asymptomatic colorectal cancer and precancerous lesions. Ranging from non-invasive stool tests to invasive procedures.
In Ontario, the screening test for average risk individuals consist of the fecal immunochemical test (FIT). This is indicated for patients with no first-degree relative with colorectal cancer aged 50-74 years old. It is recommended a FIT is performed every 2 years.
In some cases, a flexible sigmoidoscopy may be used for patients with average risk.
For patients who are at higher risk (has ≥1 first-degree relative with colorectal cancer) or patients with a positive FIT, a colonoscopy is indicated. Colonoscopies are recommended every 10 years but the interval for screening may decrease based on findings on previous colonoscopies (eg. adenoma).
Differential
Diagnoses for colonic mass includes both benign and malignant diseases and require biopsy and histology to differentiate:
- Kapsoi sarcoma
- Lymphoma
- Neuroendocrine tumours
- GI stromal tumours
- Metastases from another primary (most commonly ovarian)
Red Flags / Complications
Management
Surgical Resection
For localized disease (colon wall and/or regional nodes), surgery is the only curative modality. This consists of:
- Complete removal of tumour, major vascular pedicle, and lymphatic drainage basin of affected segment of colon
- Restoration of bowel continuity using primary anastomosis
Adjuvant Systemic Therapy
For patients who have undergone potentially curative resection, chemotherapy may be considered to eradicate micrometastases and thus reducing likelihood of recurrence.
This has been shown to be effective for stage III disease but remaints controversial for stage II disease.
Postoperative radiation therapy is not typically used for resected colon cancer but can be effective for transmural and node-positive rectal cancer.
Prevention
A number of factors are considered protective against colon cancer:
- Physical activity
- Diets rich in fruits vegetables, fibre, resistant starch, fish
- Supplementation with folate, folic acid, pyridoxine, calcium, vitamin D, magnesium
- Garlic
- Coffee
- Medications (aspirin, NSAIDs, HRT in postmenopause, statins, bisphosphonates, angiotensin inhibitors)