Cancer as a Disease: Colorectal Cancer Flashcards
What is the function of the colon?
- extraction of water from faeces - elctrolyte balance
- faecal reservoir
- bacterial digestion for vitamin production
Describe the anatomy of the colon
- Smooth folded mucosa with a thick muscle layer
- Cancer type = adenocarcinoma (glandular)
- Cells divide in the crypts (stem cells) and are shunted up
Describe the turnover of the colon
2-5m cells per minute die in the colon -> high proliferation rate (cells are vulnerable to mutation)
APC mutation PREVENTS cell loss and causes cell proliferation
- Normal protective mechanisms include – natural loss, DNA monitors & repair enzymes
What is a polyp?
any projection from a mucosal surface into a hollow viscus, and may be hyperplastic/neoplastic/inflammatory/hamartomatous.
What are examples of polyp types?
- Metaplastic/hyperplastic
- Adenomas
- Juvenile, Peutz Jeghers, lipomas
What is an adenoma?
benign neoplasm of the mucosa
What are hyperplastic polyps?
- Very common growths <0.5cm
- Constitute 90% of all colon polyps
- Often come in multiples
- They have NO malignant potential but 15% have a K-Ras mutation
What are the different types of colonic adenomas?
- Tubular – 90% adenomas (>75% tubular)
- Tubulovillous – 10% adenoma (25-50% villous)
- Villous – (>50% villous)
- Other – flat, serrated.
*The more villous, the worse
Describe the anatomy of the adenoma
Adenomas on a stalk – pedunculated
Flat and raised adenoma – sessile
Can both be tubular, villous
Describe the microstructure of tubular adenomas?
- Columnar cells with nuclear enlargement, elongation and multi-layering and loss of polarity
- Proliferation
- Reduced differentiation
- Complexity/ disorganisation of architecture
Describe the microstructure of villous adenomas?
- Mucinous cells with nuclear enlargement, elongation, multi-layering and loss of polarity
- Exophytic – front-like extensions
- Rarely, may hyper-secrete resulting in excess mucus discharge and hypokalaemia
What is APC?
Adenomatous Polyposis Coli
- Dysplasia
- Familial Adenomatous Polyposis (FAP):
> 5q21 gene mutation.
> Site of mutation determines clinical variants – i.e. classic, attenuated, Gardner, Turcot
- Many patients of FAP have a prophylactic colectomy
What is dysplasia?
abnormal growth of cells with same features of cancer
What are the main pathways to CRC?
- FAP – inactivation of APC TSG
- HNPCC – microsatellite instability
What are microsatellites?
repeat sequences prone to misalignment
Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis.
How can dietary factors predispose to colonic carcinoma?
high fat, low fibre, high red meat, refined carbohydrates
High temperature cooking can modify chemicals further in food and induce mutagenic chemicals
Heterocyclic Amines (HCAs) include PhIP - PhIP (is oxidised) -> N-OH-PhIP + deoxyguanosine -> mutagenesis
Dietary deficiencies:
- Folates:
- Folates are co-enzymes needed for nucleotide synthesis and DNA methylation - MTHFR – Methylenetetrahydrofolate Reductase:
- Deficiency leads to disruption in DNA synthesis causing DNA instability -> mutation
- Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation -> gene activating and silencing effects
How can food have anti carconogenic elements?
- Vitamin C and E – ROS scavengers
- Isothiocyanates – cruciferous vegetables
- Polyphenols – green tea and fruit juice
> Can activate MAPK pathways -> regulating phase 2 metabolisms to detoxify enzymes as well as other genes and thus reduce DNA oxidation
> EGCG-induced telomerase activity
> Garlic associated apoptosis
How does CRC present?
- Change in bowel habit
- Pre-rectal bleeding
- Unexplained iron deficient anaemia
- Other – mucus pre-rectal production, bloating, cramps (“colic”), weight loss and fatigue
*Patients & doctors rationalise these symptoms as getting old!
What are the macroscopic features of CRC?
Small carcinomas may be present within larger polypoid adenomas (pedunculated or sessile)
What are the microscopic features of CRC?
Almost all are adenocarcinomas
- Mucinous carcinoma
- Signet ring cell carcinoma
- Neuroendocrine carcinoma (rare)
Describe the distribution of colon cancer
- Caecum/ascending colon 22%
- Transverse colon 11%
- Descending colon 6%
- Recto-sigmoid 55%
How is CRC defined?
by the proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina
- 10% -> Well differentiated
- 70% -> Moderately differentiated
- 20% -> Poorly differentiated
What is Dukes classification?
- Dukes A - growth limited to wall, nodes negative
- Dukes B - growth beyond Muscularis propria, nodes negative
- Dukes C1 - nodes positive, apical lymph node negative
- Dukes C2 - apical lymph nodes (LN) positive
> Apical lymph nodes – highest lymph node to have been removed. If +ve, chance of spread to lymph
*The scale has a worse prognosis as you go down AC2
What clinical features affect prognosis?
- Diagnosis of asymptomatic patients = +ve
- Rectal bleeding as presenting symptom = +ve
- Bowel obstruction = -ve
- Tumour location = ±ve
- Age <30 = -ve
- Preoperative serum CEA (high) = -ve
- Distant metastasis = -ve
What are the pathological features that affect prognosis?
- Decreased bowel wall penetration = +ve
- Decreased regional LN involvement = +ve
- Poor differentiation = -ve
- Mucinous/signed ring cell type = -ve
- Venous invasion = -ve
- Lymphatic invasion = -ve
- Peri-neural invasion = -ve
- Local inflammation and immunologic reaction = +ve
What are the prequisites for CRC screening?
- Previous adenoma
- 1st degree relative affected by CRC before age 45
- Two affected 1st degree relatives
- Evidence of dominant familial cancer trait
- UC and Crohn’s disease
- Heritable cancer families
What are the criteria for screening?
- Condition should be important in respect to the seriousness and/or frequency
- Natural history of the disease must be known – to identify where/if screening and intervention takes place
- Test must be simple, acceptable, sensitive, selective and cost-effective
- Screening population should have equal access to the screening procedure
What dot hey look for in NHS screening for colon cancer?
for FOB – Faecal Occult Blood
*From 55+, a FOB test kit is send to people
What happens if FOB is positive?
endoscopy is performed:
- 55-60yo = sigmoidoscopy
- 60+ = full colonoscopy
