Colorectal cancer Flashcards
What types of colorectal neoplasia exist?
Benign: adenoma
Malignant: adenocarcinoma
What types of colorectal polyps exist?
Inflammatory
Hamartomatous (occur as a result of faulty development)
Metaplastic
Neoplastic (i.e. adenoma)
what do oncogenes do
a) when normal
b) when mutated
a) promote cell growth and division
b) When mutated cause excess cell growth and division (gain of function)
What do tumour suppressor genes do
a) when normal
b) when mutated?
a) suppress cell growth and division
b) allow cell growth and division (loss of function)
What are the genetic/epigenetic abnormalities involved in the adenoma-carcinoma sequence of colorectal cancer?
Activation of oncogenes
Loss or mutation of tumour suppression genes
Defective genes of the DNA repair pathway leading to genomic instability
Which oncogenes are most frequently altered in colorectal cancer?
What do these alterations cause to occur?
KRAS
c-MYC
Point mutations in KRAS:
Can lead to EGFR (epidermal growth factor receptor) independent activation of the MAPK (mitogen-activated protein kinases) pathway inducing cell proliferation, preventing apoptosis, and promoting invasion, metastasis and neovascularisation.
Overexpression of c-MYC:
a feature of most colorectal cancers
it encodes a nuclear phosphoprotein that is required for DNA synthesis
increased expression may be followed by increased cellular proliferation
What may contribute oncogene activation?
Age related hypomethylation
Which tumour suppression genes are altered in colorectal cancer?
Point mutations in APC (adenomatous polyposis coli) gene MCC (mutated in colorectal cancer) DCC (deleted in colorectal cancer) TP53 (gene product is p53) Deletions in NME1
What alteration occurs in the APC gene, and what is the effect?
Point mutations.
Subsequent deletion of the accompanying normal allele results in the complete loss of the tumour suppressor function, leading to colorectal cancer.
What alteration occurs in the MCC gene and what is its effect?
MCC- mutated in colorectal cancer
The gene product is involved in cell cycle control
What alteration occurs in the DCC gene and what is its effect?
DCC- deleted in colorectal cancer
Involved in the control of apoptosis
What is the product of the TP53 gene and what does it do?
The product is p53.
This is a nuclear protein that can hold the cell cycle at the G1/S checkpoint and allow time for succesful DNA repair, or initiate apoptosis if the DNA damage is irrepairable.
What alteration may occur to the NME1 gene and what is the result?
Deletions
May facilitate metastasis
What factors contribute to the development of colorectal cancer?
Inherited genetic factors
Long-standing ulcerative colitis
Environmental factors:
Mostly dietary, e.g. high fibre diet is protective
Where do colorectal cancers occur?
Why is this of clinical importance?
50% in the rectum
30% in the sigmoid colon
The rest are equally distributed in the caecum, ascending, transverse and descending colon
This is important because about 50% of colorectal cancers can be reached with a finger and 80% with the sigmoidoscope.
What are the different types of macroscopic appearances of colorectal cancer?
Ulcerative
Polypoidal
Annular/stenosing
What type of cancers are the majority of the ones in the rectum?
How do they present?
Ulcerative.
They usually present with rectal bleeding.
Where are annular/stenosing type cancers mostly seen?
What do they cause?
The descending colon and sigmoid.
They usually precede obstruction relatively early because of the narrowing of the lumen and the solid consistency of the faeces at this site.
Where are polypoid cancers more common?
What do they cause?
The right colon
They tend to cause recurrent occult bleeding and the patient develops iron-deficiency anaemia. These tumours are more likely to be advanced at the time of presentation.
How are adenomas classified histologically?
Tubular - 75%
Villous - 10%
Tubulovillous- intermediate in pattern- 15%
What do tubular adenomas look like macroscopically?
Small- usually less than 10mm in diameter
Resemble a raspberry
Most are pedunculated (have a stalk)
A minority have a broad base ( are sessile)
What is the microscopic appearance of tubular adenomas?
Numerous elongated and branching crypts lined by mucous secreting epithelium showing varying degrees of dysplasia
What do villous adenomas look like macroscopically?
They are usually sessile
Often are over 20mm in diameter
Some extend over a wide area as a thick, carpet-like growth
What is the microscopic appearance of villous adenomas?
Elongated villi in a papillary growth pattern
The villi are lined by columnar epithelium showing dyplasia
How are adenocarcinomas classified histologically?
Well differentiated
Moderately differentiated
Poorly differentiated
How are adenocarcinomas staged pathologically?
Using the Dukes’ and or TNM classification system
Dukes:
A- the tumour is confined to the submucosa or muscle layer
B- the tumour has spread through the muscle layer but does not yet involve the lymph nodes
C- Any tumour involving lymph nodes irrespective of extent of direct spread
D- distant metastases
TNM: T- tumour T1- submucosa only T2- into muscle T3- Through muscle T4- Adjacent structures (including peritoneum)
N- nodes
N0- no lymph node involvement
N1- 3 or less lymph nodes involved
N2- more than 3 nodes involved
M- metastasis
M0- no distant metastases
M1- distant metastases
Where does colorectal cancer spread to locally?
Adjacent structures
Where does colorectal cancer spread to via the lymphatic system?
Pericolic nodes
Perivascular noes
Where does colorectal cancer spread to via the blood?
Liver
Lungs
List protective and causative lifestyle factors of colorectal cancer.
Say which of these are most important
Protective:
Vegetables
Fibre
Exercise- most important protective factor
Causative: Red and processed meat- only dietary factor proven to be causative Smoking Alcohol Obesity- most causative factor
Suggest a reason for why exercise is protective against colorectal cancer.
AMP kinase increases muscle glucose uptake and decreases cell turnover.
AMP kinase is activated by the tumour suppressor gene LKB1, and is also activated by exercise.
If LKB1 is mutated or lost, there is increased cell turnover. This effect is increased if the patient also does not do exercise.
What are the most important genes in autosomal dominant inherited colorectal cancer?
Describe the conditions they cause.
Mutation in APC (adenomatous polyposis coli) gene
Causes FAP (familial adenomatous polyposis
A rare disease carried by either parent.
Numerous adenomas develop at early age, mainly in the large intestine, but also in the small bowel, and consequently undergo malignant change, with an almost inevitable progression to adenocarcinoma by the age of 35.
This causes 1-3% of all colorectal cancers.
Mutation in DNA mismatch repair gene.
The defects in these genes and the ensuing replication errors are manigest as “microsatellite instability”.
Alterations in two mismatch repair genes, hMLH1 and hMSH2, have been identified in most kindreds with hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome).
Only one or two adenomas develop but they rapidly turn malignant.
Cause 5-10% of all colorectal cancers.
Name conditions that predispose to colorectal cancer
Adenomatous polyps
Ulcerative colitis
Crohn’s disease
What symptoms are caused by colorectal cancer in the rectum?
Rectal bleeding
Tenesmus
What symptoms are caused by colorectal caner in the left colon?
Pain
Change of bowel habit- loose stools- solid faeces build up behind the tumour and only liquid stools can get through
Rectal bleeding
What symptoms are caused by colorectal cancer in the right colon?
Anaemia
What the general clinical findings of colorectal cancer?
Anaemia
Cachexia
Lymphadenopathy
What are abdominal clinical findings of colorectal cancer?
Mass
Hepatomegaly
Distension
What are rectal clinical findings of colorectal cancer?
Mass
Blood
What investigations are used to diagnose colorectal cancer?
Barium enema
CT colography
Sigmoidoscopy
Colonoscopy (gold standard)
What test is used in screening for colorectal cancer?
What percentage of colorectal cancers does it detect?
Faecel occult blood test
It detects about 70% of colorectal cancers
It is sent to everyone in the UK between the ages of 50 and 74 every 2 years
What investigations are used to help stage colorectal cancer?
Lungs: CXR or CT
Liver: Ultrasound or CT
Primary rectal cancer: CT or MRI
What are the emergency presentations of colorectal cancer?
Obstruction: Distension Constipation Pain Vomiting
Bleeding
Perforation
How is an obstruction treated?
Colostomy alone
Resection + colostomy
Stenting
What is the treatment for colorectal cancer?
Surgery- the only curative cancer
Radiotherapy- next in line- not curative
Chemotherapy- not curative
What types of surgery are used to remove colonic cancer?
right hemicolectomy extended right hemicolectomy transverse colectomy left hemicolectomy sigmoid colectomy subtotal colectomy
What types of surgery are used to remove rectal cancer?
Abdomino-perineal excision: the whole rectum and anal canal is removed.
The patient requires a colostomy.
Anterior resection:
Part of the rectum is taken out and the sigmoid colon is taken down and joined to the distal rectum.
How can radiotherapy be used in the treatment of colorectal cancer?
Adjuvant
Pre- or post-operative
Reduces local recurrence after rectal excision
Palliative
Inoperable primary rectal cancer
Recurrent rectal cancer
How is chemotherapy used in colorectal cancer?
5-fluorouracil (5-FU)
Adjuvant for Stage C
5-10% absolute improvement in survival
For advanced disease
median survival advantage of ~5 months
new drugs – oxaliplatin, irinotecan
Biological agents – cetuximab, bemab
