GI cancer SD Flashcards
how long is the colon?
aprox 1.5m
what are the 4 regions of the colon?
– Ascending
– Transverse
– Descending
– Sigmoid
what is ascending colon linked to small intestine by?
the caecum
what joins the rectum?
Sigmoid colon
what are the functions of the colon?
- Reabsorption of fluids and some solutes
– 2L of water enter the colon from the ileum
– 90% reabsorbed (mainly in ascending colon)
– Fat-soluble vitamins, e.g. vitamin K, vitamin B12, thiamine, riboflavin
– Negligible; no significant impact on nutrition - Movement of waste products for excretion
– Movement by haustral contractions
– Contraction of smooth muscle
how long does it take for waste to pass?
16 hours
what are the 4 parts that make up the histology of the colon?
1- mucosa- lamina propria, crypts, muscularis mucosae
2-submucosa
3-muscularis propria
4-serosa
what is the purpose of the 3 parts of the mucosa?
- Crypts
– Columnar colonocytes
– Goblet cells (mucus-secreting)
– Stem cells - Lamina propria
– Connective tissue that provides
support & immune defence
– Lymphocytes, lymph nodules - Muscularis mucosae
– 2 layers of smooth muscle
what is the submucosa?
– Connective tissue rich in blood and
lymph vessels
what is the purpose of the muscularis propria?
– Smooth muscle in three layers
(collectively the ‘taenia coli’)
– Contraction moves faeces through the
colon
what is the purpose of the serosa?
– Thin layer of mesothelial cells
– Positioning of the colon
what is FAP?
- Inherited mutation in the APCgene
– Formation of many polyps
how do you diagnose FAP?
Diagnosed by colonoscopy and genetic
testing
– Identification of 100+ polyps
– Sequencing of the APCgene
what are the risk factors for CRC?
- Diet
– ↑red meat, processed meats
– ↓fibre, chicken & fish - Lack of physical activity
- Obesity
- Alcohol & smoking
- Genetic predisposition
- Protective effect of aspirin
where is sporadic CRC most common?
most common in the descending colon, sigmoid colon and rectum
do tumours differ by region?
- Tumours differ by region
– Ascending/transverse vs descending/
rectal
– mutations in KRAS (sigmoid/rectum)
– BRAF (ascending/transverse)
– mutually exclusive
what is the estimate time it takes for ademona to develop into an advanced carcinoma?
17 years
how long does it take for carcinoma to progress to metastasis ?
– 1.8 years from advanced
carcinoma to metastasis
what is the histology of CRC?
- Loss of normal architecture
- Hyperchromatic (intensely stained) cells
- Invasion through submucosa
- Nucleus takes up a greater proportion of the cell
what is the staging of colorectal cancer?
TNM
- tumour T1- invades submucosa
2-invades muscularis propria
3- through muscularis to pericolorectal tissues
4-penetrates to surface of visceral peritoneum/ invades or adherent to other organs
how do we stage CRC in the UK?
duke stages A-D
how does CRC metastases to the liver?
Liver is the most commonly affected site
– Venous drainage from the colon to the liver
– Liver mets affect 50% of CRC patients
– 20% will be resectable much better
prognosis (poor without)
how do lungs metastases?
- Lungs second-most commonly affected
– 10-15% of CRC patients will develop lung mets
– Rare to have lung mets alone (<10%)
– Usually not resectable
what is the vogelstein model?
Bert Vogelstein described a molecular model by which CRC could
arise, now referred to as the ‘Vogelstein model’
– Step-wise accumulation of mutations/epigenetic changes and how
they relate to tumour development
1. APCTSG, regulates Wnt signalling Mutated in ~50%
of CRC
2. KRASOncogene, drives cell growth Mutated in ~45%
3. p53TSG, ‘guardian of the genome’ Mutated in ~40%
does ever colorectal cancer develop by vogelstein model?
– Vogelstein himself stressed this in his paper; it is an example
– Only 7% of tumours have mutations in all three of these genes
– Accumulation of mutations in key genes is more important than the
order
how deos colon cancer progress with altered genes?
APC – loss of function (TSG)
RAS – gain of function (Oncogene) – MAPK signals and cell cycle
p53 – loss of function (TSG)
TGF-β– loss of function (Growth Suppressor)
how do you screen for colorectal cancer?
Faecal Occult Blood Test
* Measure of blood (haem) in stool – frequent in CRC
how is the faecal occult blood stool test done?
Hydrogen peroxide developer solution applied
* Detects pseudoperoxidase activity of haemoglobin
* Limitations
– Red meat (+ve), Cauliflower (+ve), uncooked
vegetables (+ve), Haemorrhoids (+ve)
– High vitamin C (-ve)
how are positive faecal tests followed up?
sigmoidoscopy
what is the gold standard screening approach to screening?
colonoscopy- detects polyps, adenomas and tumours
what is the diet before a colonsocopy?
Patients required to undergo a strict diet for up to three days in advance (low fibre, only clear liquids) and bowel prep using laxatives
how often is colonscopy screening recommended?
every 5-10 years
what are the different types of endoscopy?
lexible sigmoidoscopy- covers the descending colon
colonoscopy- provides full coverage
what is flexible sigmoidoscopy?
Similar to colonoscopy in enabling removal of polyps/adenomas and taking
biopsies
* Covers only the descending colon
– However, this is where most sporadic CRC tumours originate
– Therefore provides coverage of 70-80% of CRC cases
– Colonoscopy is preferred for colitis-associated CRC, for example
what is the benefit of flexible sigmoidoscopy?
- No sedation required
- Reduces costs and shorter duration (10mins vs 30mins + recovery time)
what is the main treatment stratigies for colorectal cancers?
remove the tumour and chemotherapy to
reduce the risk of metastases
when does adjuvant therapy begin with colorectal cancer?
Adjuvant therapy normally begins ~6 weeks after surgery
– Timing depends upon post-operative wound healing and patient
age/frailty
how does 5 FU work in GI cancer?
Thymidylate synthase inhibitor
Stops production of thymidine no thymidine
for DNA replication cell death
how does leucovorin work in GI cancer?
Reduced form of folic acid Enhances 5-FU activity (stabilised 5-FU/thymidylate synthase complex)
what is the purpose of oxaliplatin?
Platinum-based compound
Creates platinum-based DNA adducts blocks
DNA replication cytotoxic; beneficial with
Stage III tumours and beyond
what is the purpose of capecitabine?
Thymidylate synthase inhibitor
Converted to 5-FU in the body; may offer
improved tolerability and reduced non-tumour
cytotoxicity
what is the purpose of irinotecan?
Topoisomerase inhibitor Prevents DNA replication cytotoxic
what are the CRC key signalling and targeted therapies?
- EGFR Inhibitors
– Target EGFR (epidermal growth factor receptor) that promotes tumour growth - VEGFR Inhibitors
– Target VEGF (vascular endothelial growth factor) that promotes growth of neovasculature - Immunotherapy
– Target PD-1, which is expressed on tumours to block immune response
– PD-1 inhibition increases immune response to the tumour
– Generally given to patients who are not responding to chemotherapy
what role does EGFR play in crc?
- EGFR Activation stimulates
multiple downstream pathways - These drive cellular proliferation
and promote cell survival (anti-
apoptosis)
what happens when there is mutation in pathways in CRC?
activates the pathways
irrespective of EGFR activity
– KRAS: ~40% of tumours
– BRAF: ~10%
– PI3K: 25%
– PTEN: <10%
what can patients who are wild type patients recieve?
Cetuximab / Panitumumab - EGFR MAb’s
what happens if there is mutant RAS?
therapy ineffective
what are someVEGF MabS?
- Bevacizumab (Avastin®), Aflibercept (Zaltrap®), Ramucirumab (Cyramza®),
Regorafenib (Stivarga®).
when may immunotherapy be used?
A subset of metastatic CRC patients will have genetic alterations that prevent
cells from repairing damaged DNA = High rates of DNA mutations.
– mismatch repair deficiency (dMMR)
– high microsatellite instability (MSI-H).
– Some of these mutations may lead to the production of
abnormal antigens that can be targeted by immune cells
