Colorectal Pathology Flashcards
What are the main functions of the large intestine
Water absorption from faecal material
Consolidating stool
Why do patients with a stoma experience dehydration
The large intestine’s function of reabsorbing water is bypassed, leading to increased water loss through stool
Where are most colorectal tumours found
Descending colon, sigmoid and rectum
Colorectal adenocarcinoma is the most common type
Why do right sided colon tumours grow larger before symptoms appear
- The ascending colon has a larger diameter
- Stool is looser, so tumours dont block flow easily
- Common symptom: anemia due to slow, persistent bleeding
How do left-sided colon tumours present
Obstructive symptoms appear earlier
Bowl habit changes, bleeding, and stool color changes
What is the first test in colorectal cancer
Checking for traces of blood in the stool
Not looking for cancer cells directly
Early detection improves treatment success
What are the layers of the large intestine
1) Epithelium: single-layered, finger-like villi for large surface area for absorption
2) Sub-mucosa: Connective tissue with blood vessels and nerves
3) Muscularis Externa: Two smooth muscles layers for movements:
- Circular muscle
- Longitudinal
How are cells in the large intestine renewed
The more immature cells are at the bottom of the crypt – those are the ones that are actively able to regenerate and then the cells that are found near the top are more differentiated and more mature to function for their specific job. This epithelium undergoes constant turnover so new cells are being generated and old cells are being disposed of.
Why is tumour depth important in prognosis
Mucosal tumours: easier to treat , low metastasis risk
Submucosal tumours: Higher invasion and metastasis risk
Why is colorectal cancer increasing in low-risk countries
Obesity
Diet high in processed foods and red meat
What are the three main pathways of colorectal cancer development
1) chromosomal instability (CIN)
2) Micro-satellite instability (MSI)
3) Serrated neoplasia Pathway
What is CIN
Most common colorectal cancer pathway
Involves chromosomal abnormalities like deletions and amplifications
A condition characterized by an increased rate of changes in the structure or number of chromosomes, leading to abnormalities like aneuploidy and structural rearrangements during cell division.
Key mutations:
- APC (early event) - Wnt signalling activation
- KRAS, PIK3CA, TP53 mutations
What drives CIN
1) Defects in chromosomal segregation (control sister chromatid separation)
2) Disordered cell senescence, induced by telomere shortening and culminating in genomic reorganisation
3) Dysfunctional DNA damage-response machinery
4) Loss of heterozygosity at a tumour suppressor gene.
What does the loss of APC lead to
1) Nuclear translocation of Beta-catenin
2) Nuclear β-Catenin → Activation of the Wnt Signaling Pathway – constitutive activation of oncogenes:
- MYC (cell proliferation)
- Cyclin D1 gene (CCND1) (pushes cell cycle forward)
3) β-Catenin Activation → Upregulation of VEGF Genes
4) β-Catenin Activation → Upregulation of PPAR-δ (PPARD) Gene - important for cell proliferation, survival, and metabolism.
What is MSI
15% of colorectal cancers
Common in lynch syndrome
A genetic instability in cancer cells characterised by changes in the number of repeated DNA bases due to impaired DNA mismatch repair, leading to hypermutation
What is the genetic abnormality that is present in serrated neoplastic pathway
Activating the V600E in BRAF, a mitogen-activated protein kinase pathway, causing constitutive activation of the mitogen-activated protein kinase-ERK pathway and uncontrolled cell division
What is a serrated adenoma
Sawtooth serrations of the epithelium and abundant mucin, similar to hyperplastic polyps
Basal crypt dilation with mucous retention
Lateral spread of crypt bases (commonly described as boot shaped or anchor shaped crypts)
What is serrated neoplastic pathway
Driven by BRAF mutation.
Progression from serrated polyps (sessile serrated adenomas, traditional serrated adenomas) to cancer.
Leads to two tumour types:
- MSI-high tumours:
Due to MMR (Mismatch Repair) deficiency. - MSS tumours:
With TP53 mutation, Wnt pathway activation, TGF-β signaling, and EMT (Epithelial-Mesenchymal Transition).
→ Alternative pathway to colorectal cancer, distinct from the conventional adenoma-carcinoma sequence
What are the common risk factors for colorectal carcinoma
- old age
- obesity and physical inactivity
- Alcohol and smoking
- Inflammatory bowel disease
- Family history
Which genetic syndromes increase colorectal cancer risk
- Familial Adenomatous Polyposis (FAP): due to the APC mutation
- Lynch syndrome (HNPCC): due to mutations in MMR (MLH1 and MSH2)
- Peutz-Jeghers Syndrome: due to STK11 gene mutation
How does diet impact colorectal cancer risk
Increased risk:
- Low fibre, high refined carbs, high red meat
- Low fibre prolongs transmit time (toxic oxidative by-products are in longer contact with colonic mucosa) and alters bacterial flora
- Beef increases bile acid production, which can turn carcinogenic
Decreased risk:
- High fibre, fotate, calcium and NSAIDs
What is a polyp
A growth of epithelial or mesenchymal origin
Can be benign or malignant
- 95% of colorectal adenocarcinomas arise from polyps
What are the different types of polyps
1) Inflammatory - Pseudopolyps, lymphoid polyps
2) Hamartomatous - Juvenile polyps, Peutz-Jeghers polyps
3) Neoplastic (Epithelial) - Adenomas, adenocarcinomas
4) Neoplastic (Mesenchymal) - Lipomas, Leiomyomas
How do adenomas develop
1) When mechanisms controlling DNA repair and cell proliferation are altered, in a tissue with constant epithelial renewal (loss of surface cells from the intestinal mucosa, replacement from proliferating cells in the crypt base)
2) As mutant cells move upwards, the predictable process of differentiation and apoptosis is disrupted and discrete adenomas form
3) Over time, adenomatous polyps increase in size, develop increasingly dysplastic features, and can eventually acquire invasive potential
