CasaD - Colorectal Cancer Flashcards
Cancer Epidemology?
MAJOR cancer of the developed world
• 4th most common world-wide
Causative factors of colorectal cancer?
Environment (diet)
&
Genetic factors
Function of the colon?
Extraction of water from faeces
• electrolyte balance
Faecal reservoir
• evolutionary advantage
Bacterial digestion for vitamin
• e.g. B & K
Anatomy of the colorectal?
Smooth folded mucosa
• w. THICK muscle layer
Cancer type = adenocarcinoma (glandular)
Cells divide in the crypts of Lieberkuhn
• and are shunted UP
Explain how Turnover causes the development of colorectal cancer
Turnover:
• 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
What normal protective mechanisms does the colorectal have in regards to turnover?
Normal protective mechanisms include: – natural loss – DNA monitors & – repair enzymes
Define polyp
Polyp = any projection from a mucosal surface into a hollow viscus
& may be:
hyperplastic, neoplastic, inflammatory, hamartomatous etc.
Define adenoma
A benign neoplasm of the mucosal epithelial cells
What different colonic polyp types can there be
Polyp types include:
• Metaplastic /hyperplastic
- Adenomas
- Juvenile, Peutz Jeghers, lipomas, others – (don’t need to know much about these)
Explain 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 colonic adenoma types?
Tubular
– 90% adenomas (>75% tubular)
Tubulovillous
– 10% adenoma (25-50% villous)
Villous
– (>50% villous).
Other
– flat, serrated
The more villous, the worse
Relationship with colorectal cancer and villous?
The MORE villous = the WORSE
Anatomy of the 2 types of adenoma?
Adenomas on a stalk
• pedunculated
Flat & raised adenoma
• sessile
BOTH can be tubular, villour etc.
Tubular microstructure of adenomas?
COLUMNAR cells with:
• nuclear enlargement
• elongation
• multi-layering and loss of polarity
Proliferation increases
Reduced differentiation
Complexity/disorganisation of architecture
Villous microstructure of 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.
Define dysplasia
Abnormal growth of cells with SOME features of cancer
(i.e. UC leads to dysplasia)
Indefinite
• has both HIGH & LOW-grade
APC?
Adenomatous Polyposis
Explain APC
APC/FAP (familial adenomatous polyposis)
o 5q21 gene mutation
o Site of mutation determines clinical variants
– i.e. classic, attenuated, Gardner, Turcot
o Many patients of FAP have a prophylactic colectomy
Epidemology of colonic adenomas?
25% of adults have adenomas at age 50 –> 5% become cancers if left.
• adenomas precede carcinomas by about 15 years
Larger polyps have a greater chance of becoming cancerous than smaller polyps.
Cancers stay at a curable stage for about 2 years.
Progression from adenoma to carcinoma?
Most colorectal cancers arise from adenomas
• with 10-30% of CRCs having a residual adenoma
Endoscopic removal of polyps DECREASES the incidence of subsequent CRC
Genetic pathways in colorectal cancer?
•
(1) Adenoma Carcinoma Sequence
(2) Microsatellite Instability
Explain (1) in genetic pathways in Colorectal Cancer
Adenoma Carcinoma Sequence
- APC = best known genes that is damaged
- Others = K-Ras, Smads, p53, telomerase activation
Explain (2) in genetic pathways in Colorectal Cancer
Microsatellite Instability
Microsatellites are repeat sequences prone to misalignment
• some microsatellites are in coding sequences of genes which inhibit growth or apoptosis
Mismatch repair genes
• are recessive genes requiring 2 hits (loss of this greatly increases chances of CRC)
• HNPCC – Hereditary Non-Polyposis Colorectal Cancer – germ-line mutations
2 main pathways for genetic predisposition for colorectal cancer?
FAP
• inactivation of APC TSG
HNPCC
• microsatellite instability
Dietary factors that predispose to colonic carcinoma?
High fat
Low fibre
High red meat
Refined carbohydrates
High oC cooking can modify chemicals further in the food
• induce mutagenic chemicals
Explain HCAs
Heterocyclic Amines
These include PhIP
• PhIP is oxidised
• turns into N-OH-PhIP + deoxyguanosine
• This then turns MUTAGENESIS
Explain 2 specific dietary deficiencies that can lead to colorectal cancer
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 & silencing effects
Food can also have anti-carcinogenic elements - what are these?
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 = thus reduce DNA oxidation – EGCG-induced telomerase activity – Garlic associated apoptosis
Clinical presentation of colorectal cancer?
Change in bowel habit
Pre-rectal bleeding
– Patients & doctors rationalise these symptoms as getting old!
Unexplained iron deficient anaemia
Other
– mucus pre-rectal production, bloating, cramps (“colic”), weight loss and fatigue
Macroscopic features of colorectal cancer?
Small carcinomas may present w. larger polypoid adenomas
• pedunculated OR sessile
Distribution of colon cancer around the colon?
Caecum/ascending colon
- 22%
Transverse colon
- 11%
Descending colon
- 6%
Recto-sigmoid
- 55%
Microscopic features of carcinomas?
Almost all are adenocarcinomas:
Mucinous carcinoma
Signet ring cell carcinoma
Neuroendocrine carcinoma (rare).
How is colorectal cancer graded?
Defined by the proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina:
o 10% = well differentiated
o 70% = moderately differentiated
o 20% = poorly differentiated.
Explain the Dukes Classification
Dukes A
• growth limited to mucosa/submusoca
• 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 A –> C2.
Clinical features affecting 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
Pathological features affecting 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
Treatment options for colorectal cancer?
Grade 1
• surgery
Grade 2
• surgery
• 5FU
Grade 3
• surgery
• 5FU/Leucovorin
Grade 4
• surgery
• metastatectomy/ chemo/ palliative RT
Screeing prerequisities for those at HIGH RISK for Colon Cancer?
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
NHS screening for colon cancer?
They look for FOB – Faecal Occult Blood.
• from 55+, a FOB test kit is send to people
If positive, an endoscopy is performed
• 55-60yo = sigmoidoscopy
• 60+ = full colonoscopy
A 76 year old man presents with new onset rectal bleeding to the GP:
A/ Haemorrhoids must be excluded in the first instance
B/ Factor 5 leiden abnormalities are the likely cause
C/ The GP should reassure and send the patient home
D/ Colorectal malignancy must be excluded in the first instance
E/ Crohn’s disease must be excluded in the first instance
D
With respect to the aetiology of colorectal adenocarcinoma:
A/ Many carcinomas are derived from adenomas
B/ Adenomas are invasive tumours
C/ Ulcerative colitis is the underlying cause in many cases
D/ Many carcinomas are derived from hyperplastic polyps
E/ Angiodysplasia is the underlying cause in many cases
A
