Cancer as a disease- colorectal cancer Flashcards
Where does colorectal cancer in terms of the most common cancer?
4th
Where does colorectal cancer come in terms of leading cause of cancer death?
2nd
What is the function of the colon?
Extraction of water from the faeces (electrolyte balance)
Faecal reservoir (evolutionary advantage)
Bacterial digestion for vitamins (vitamin B and K)
What is the mucosa like in a normal large bowel?
Folded but smooth
What types of cancer are cancers in the colon?
Adenocarcinomas (glandular epithelium)
What is the normal life of a cell in the colon?
They divide in crypts where stem cells are found and then they are shunted up to the top of the villus where they are shed
What is the turnover of colonic epithelium?
2-5 million cells die per minute in the colon
What does the high rate of cell proliferation mean?
Cells are vulnerable
What does the APC gene do?
Reduces the risk of mistakes during replication
What protective mechanisms are there to eliminate genetically defective cells?
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 etc
What is an adenoma?
Benign neoplasm of mucosal epithelial cells
What different types of colonic polyps are there?
Metaplastic/hyperplastic
Adenomas
Juvenile, Peutz jeghers and lipomas
How common are hyperplastic polyps?
Very- 90% of all colonic polyps
What size are hyperplastic polyps?
<0.5cm
How malignant are hyperplastic polyps?
No malignant potential- 15% have K-ras mutations
What types of colonic adenoma are there?
Tubular- 90% (>75% tubular)
Tubulovillous- 10% (25-50% villous)
Villous- (>50% villous)
What type of colonic adenoma is worse?
The more villous it is, the worse it is
What different shapes of adenoma are there?
Pedunculate- on a stalk and look a bit like a tree
Sessile adenomas are flat and raised
What is the microscopic structure of tubular adenoma like?
Columnar cells with nuclear enlargement, elongation, multi-layering and loss of polarity
What is the proliferative activity and differentiation of tubular adenomas like?
Increased proliferative activity
Reduced differentiation
What is the microscopic structure of villous adenoma like?
Mucinous cell with nuclear enlargement, elongation, multi-layering and loss of polarity
Exophytic and may have hyper secretory function and result in excess mucus discharge and hypokalaemia
What does exophytic mean?
Frond-like extension
What is dysplasia?
Abnormal growth of cells with some features of cancer- indefinite
What condition increases number of polyps?
Familial adenomatous polyposis (FAP)
What causes FAP?
5q21 gene mutation and site of mutation determines clinical variants (classic, attenuated, Gardner and Turcot etc)
What do a lot of FAP patients have as treatment?
Prophylactic colectomy
What percentage of adults have colonic adenomas at the age of 50?
25%
What percentage of adenomas become cancerous if left?
5%
How does the size of polyps affect the risk of cancer?
Larger polyps have a higher risk than small ones
For how long are cancers at a curable stage?
2 years
By how long do adenomas normally precede cancer?
15 years- endoscopic removal of polyps decreases incidence of sub sequential colorectal cancer
What genes when damaged can lead to adenoma carcinoma?
APC, K-ras, Smads, p53 and telomerase activation
What are microsatellites?
Repeat sequences that are prone to misalignment- some are in coding sequences of genes with inhibit growth or apoptosis
What are mis-match repair genes?
Recessive genes requiring two hits (MSH2, MLH1 etc)- without this there is a very elevated risk of cancer
In what conditions is their a genetic predisposition to colorectal cancer?
FAP- inactivation of APC tumour suppressor genes
HNPCC (hereditary non-polyposis colorectal cancer)- micro satellite instability (defects in DNA repair)
How many cases of colorectal cancer are there per year in the UK?
35000
What percentage of cancer deaths are due to colonic cancer?
10%
What is the normal age of people with colonic cancer?
50-80
What is the prevalence of colonic cancer like in terms of different countries?
High in USA, eastern Europe and Australia
Low in Japan, Mexico and Africa
What dietary factors increase risk of colonic cancer?
High fat
Low fibre
High red meat
Refined carbohydrates
What effect does cooking at high temperatures have?
It can alter the chemical structure and produce chemicals that can cause mutagenesis
Why does folate deficiency increase risk of colorectal cancer?
It is an important co-enzyme for nucleotide synthesis and DNA methylation
Why does MTHFR deficiency increase risk of colorectal cancer?
Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation) - this leads to mutation
Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation- this can have gene activating and silencing effects
What is the clinical presentation of colorectal cancer?
Main features: Change in bowel habit Per rectal bleeding Unexplained iron deficiency anaemia Other features: Per rectal mucus Bloating Cramps (colic) Constitutional (weight loss, fatigue)
Why is colorectal cancer commonly missed?
Doctors and patients tend to rationalise the symptoms as signs of getting old, piles or IBS
What macroscopic features of colorectal carcinoma are there?
Small carcinomas may be present within larger polypoid adenomas (pedunculate or sessile)
What is the distribution of colon cancer like throughout the colon?
Caecum/ascending colon- 22%
Transverse colon- 11%
Descending colon- 6%
Rectosigmoid- 55%
What types of carcinomas are there?
Most are adenocarcinomas:
- Mucous carcinomas
- Signet ring cell
Neuroendocrine (very rare)
What is grading based on?
Proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina
What is the differentiation of colorectal carcinomas like?
10% are well differentiated
70% are moderately differentiated
20% are poorly differentiated
What is the Dukes classification system?
Dukes A- Growth limited to wall (muscular propria) and nodes negative
Dukes B- Growth beyond muscular propria and nodes negative
Dukes C1- Nodes positive and apical lymph node negative
Dukes C2- Apical lymph node positive
What is the apical lymph node?
Highest lymph node that has been removed- if positive, it means that cancer could have spread even further in lymphatics
What clinical features affect prognosis?
Improves: Diagnosis of asymptomatic patients Rectal bleeding as presenting symptom Either: Location Diminishes: Bowel obstruction Age < 30 Preoperative serum CEA (carcinoembryonic antigen) Distant metastases
What pathological features affect prognosis?
Depth of bowel wall penetration Number of regional lymph nodes involved Degree of differentiation Diminished prognosis: Mucinous or signet ring cell Venous invasion Lymphatic invasion Perineurial invasion Improves prognosis: Local inflammation and immunologic reaction
Who is screened for colorectal cancer?
Previous adenoma
1st degree relative affected by colorectal cancer before age of 45
2 affected first degree relatives
Evidence of dominant familial cancer trait including colorectal, uterine and other cancers
Ulcerative colitis and crown’s disease
Hereditable cancer families
What is the definition of screening?
The practice of investigating apparently healthy individuals with the object of detecting unrecognised disease or people with exceptionally high risk of developing disease and of intervening in ways that will prevent occurrence of disease or improve prognosis when it develops
What do the NHS look for when screening for colon cancer?
Faecal occult blood (FOB)
From 55 years onwards what do the NHS do in terms of screening?
Send a FOB test kit
What do the NHS do if there is faecal occult blood?
An endoscopy
55-60 yr olds- sigmoidoscopy
Older- full colonoscopy
