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Cancer 13: Colorectal Cancer Flashcards

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1
Q

How common is colorectal cancer

A

4th most common overall

Major in developed country

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2
Q

How deadly is colorectal cancer

A

2nd leading cause of cancer death overall, behind lung cancer

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3
Q

Function of the colon

A

Extract water from faeces (electrolyte balance)

Faecal reservoir (evolutionary advantage)

Bacterial digestion of vitamins (B and K)

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4
Q

Where does colon start and end

A

Colon cancer involves anything from the caecum, all the way round to where the mucosa becomes squamous mucosa at the anus.

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5
Q

Why is the colon vulerable to cancer

A

The bowel cells have an enormous turnover: 2-5 million cells die per minute in the colon

Proliferation renders cells very vulnerable – a problem with the genetics may result in cancer

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6
Q

What is the epithelium type in the colon

A

Columnar epithelium with goblet cells

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7
Q

Outline the structure of the epithelium in the large intestine

PLEASE NOTE THERE ARE NO VILLI IN THE LARGE INTESTINE, JUST SHORT MICROVILLI

A

Crypt of lieberkuhn (gland)

Enterocytes and goblet cells are abundant.

Abundant crypts

Stem cells are found in the crypts.

NO VILLI

Enterocytes have short, irregular microvilli for salt absorption

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8
Q

Normal structure of the gut

A 
Epithelium 
Lamina propriae 
Muscaris mucosae 
Submucosa 
Circular muscle 
Longitudinal muscle 
Serosa 
Mesothelium
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9
Q

How is water absorbed in the large intestine

A

Water is absorbed as it passively follows the electrolytes, resulting in more solid gut contents)

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10
Q

Distribution of gobet cells in the large intestine

A

Increase distally

These cells dominate the crypts

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11
Q

Which cells that are present in the small intestine are not present in large

A

Paneth cells

Enteroendocrine cells also rare

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12
Q

What cell types contained in the crypts or large intestine

A

Enterocytes,

Goblet cells,

Stem cells

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13
Q

Which part of the crypt proliferates

A

The bottom, where there are stem cells.

Nearer the surface of the gut, the cells differentiate

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14
Q

What is the overal consequence of APC mutation

A

Prevents cell loss

==> mutation

Look at Peter’s lecture

Essentially, at the adhesion junction between cells, if there is cell-cell contact, then beta catenin will not accumulate in the cell.
In addition, APC rapidly degrades beta catenin.

If b-catenin levels begin to increase, then they can bid to LEF1, and this can go into the nucleus to induce proliferation.

APC mutation means accumulation of beta-catenin and thus proliferation (and prevention of cell loss?)

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15
Q

What are the general protective mechanisms to eliminate genetically defective cells

A

Natural loss
DNA monitors
Repair enzymes

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16
Q

Define polpy

A

any projection from a mucosal surface into a hollow viscus may be hyperplastic, neoplastic, inflammatory, hamartomatous

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17
Q

What are the types of colonic polyp

A 
Metaplastic/Hyperplastic
Adenomas
Juvenile
Peutz Jeghers
Lipomas 
Others (essentially any circumscribed intramucosal lesions)
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18
Q

Define adenoma

A

benign neoplasm of the mucosal epithelial cells GLANDULAR

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19
Q

Outline hyperplastic adenomas

A

Very common

90% of all LI polyps

Often multiple

No malignant potential

15% with k-ras mutation

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20
Q

What is the size of hyperplastic polyp

A

<0.5cm

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21
Q

What are the types of colonic adenoma

Which is more worrying

A

Tubular
Villous
Tubulovillous (mixed)

Villous more worrying

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22
Q

Other than microscopically, how else can polyps be classified

T/f… all pedunculated polps are villous. All sessile polyps are tubular

A

Pedunculated or sessile

F… peduncated can be tubular/villous, and sessile can be either too

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23
Q

Microscopic structure of tubular adenomas

A

Columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity

Increased proliferative activity

Reduced differentiation

Complexity/disorganisation of architecture

(showing dysplasia)

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24
Q

Micriscopic structure of villous adenomas

A

Mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity

Exophytic, frond-like extensions

Rarely may have hypersecretory function and result in excess mucus discharge and hypokalemia

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25
What might be seen on adenoma microscope
Early stages of DNA going bad Bigger nuclei No longer single layer of cells (pseustratified or stratified) Darker Disordered architechture Pink good, purple bad
26
What is dysplasia
Bad growth Abnormal growth of cells with some features of cancer
27
How is dysplasia classified
Subjective analysis Indefinite, low grade and high grade
28
Do we include appendix when talking about colon cancer
No
29
What could increase risk of dysplasia
It is associated with lesions e.g. in ulcerative collitis due to inflammation These are called DYSPLASIA- ASSOCIATED LESIONS
30
Which mutation occurs in FAP
5q21 gene mutation Site of mutation determines variant
31
What is treatment for FAP
Many have colectomy
32
With regard to normal colonic adenoma What percentage of people have adenomas at age 50 What percentage of colonic adenomas become cancer] Which colonic adenomas are most likely to turn into cancer Time between polyp and cancer
25% 5% Big adnomatous polyps most likely to turn into cancer 10 year lead time Cancers curable until 2 years
33
T/F most colorectal cancers arise from polyps
T
34
In what proportion of CRC patients can residual polyp be seen
10-30%
35
Adenomas precede cancers by how long
10-15 years
36
How can the risk of CRC be reduced
Endoscopic removal of adenomatous polyps
37
What are the 2 overall genetic pathways involved in CRC
1. Adenoma/carcinoma sequence. E.g. the APC gene. damaged in people with FAP. Also can be damaged in other members of population 2. Microsatellite instability
38
Genes involved in the adenoma carcinoma sequence pathway
APC, K ras, Smads, p53, telomerase activation they get adenomas before carcinoma
39
What is a microsatellite instability
In lynch syndrome, there are germline mutations in MSH2 or MLH1. These encode for mismatch repair genes. Basically some repeated regions of DNA (=microsatellites) are prone to misalignment. Microsatellite unstable is when tumor cells have microsatellites that differ from normal somatic tissue Some of these microsatellites are present in the coding regions of genes inhibiting growth or apoptosis (TGFbR11). If mismatch repair genes are mutated they are not as good as repairing the DNA when mutations do occur in these inherently unstable microsatellite regions.
40
What happens if the microsatellites in mismatch repair genes are damaged
If the mismatch repair genes are damaged (microsatellite instability), DNA cannot be repaired
41
Is 1 or 2 hits needed in lynch synfrome
2 hits needed (recessive genes)
42
Outline the adenoma-carcinoma sequence
NORMAL COLON (germline/somatic mutations of TSGs), first hit MUCOSA AT RISK (methylation abnormalities/inactivation of normal alleles) ADENOMAS Proto-oncogene mutation Homozygous loss of additional TSGs CARCINOMA Additional mutations Gross chromosome alterations
43
For colon cancer, state the different genes at each part of the adenoma-carcinoa seuqnece
NORMAL COLON: 1st hit (somatic/acquired), APC, Mismatch repair genes (e.g. MSH2) MUCOSA AT RISK: 2nd hit. APC/b-catenin, MSH2 ADENOMAS: k-ras, then loss of other TSGs (p53, LOH) CARCINOMA: many genes
44
Give an example of a disdease for each of the two genetic pathways relevant to CRC
1. Adenoma-carcinoma sequence: APC. Inactivation of APC TSG. 2. Microsatellite instability: HNPCC (Lynch's)
45
Outline the normal action of beta catenin at the bottom of the crpts and at the top
In the bottom of the crypt, where there is proliferating, undifferentiated progenitors, b-catenin is ON. Can bind to LEF1/Tcf and translocate to nucleus to promote proliferation This occurs due to Wnts pathway activation At the top of the crypts normally beta-catenin and the Tcf/LEF1 should be switched OFF. This is due to degradation of the beta catenin by APC (and others) leading to ubiquination. Cell cycle is arrested and cells are differentiated
46
Outline the action of beta-catenin in APC- crypts
Well the bottom of the crypt always has beta catenin ON because these are stem cells whose job it is to proliferate But normally at the top, beta catenin is switched OFF due to APC. In cells with APC/b-catenin mutations, it has a progenitor like phenotype. Aite of future polyp mutation. This relates to Dr Clark's lecture. There is increased b-catenin either due to loss of cadherin-mediated cell-cell adhesion OR inhibition of beta-catenin degradation (i.e. APC inactive)
47
Age range for colon cancer
Ages range 50-80. Sporadic rarely < 30
48
Where is colon cancer high and low
High in US, Eastern Europe, Australia | Low in Japan, Mexico, Africa
49
What features of diet affect colonic carcinoma ris
Dietary Factors; High Fat, Low Fibre, High Red meat, Refined carbohydrates
50
How can chemicals in food affect cancer
Can contain carcinogens Also anti-cancer agents (anti-oxidants) Heat modifies chemicals further Bacteria modifies food residues
51
Give an example of a carcinogenc food type
HCAs (heterocyclic amines) can form when meat is cooked, and the creatinine and AAs in the meal react (only with heat) E.G PhIP is a HCA made from creatinine and phenylalanine If oxidised, the resulting N-OH-PhIP can react with deoxyguanosine and cause mutagenesis
52
Which dietary deficiency can cause cancer
FOLATES in CRC: Coenzyme for nucleotide synthesis and DNA methylation Folate is a protector of cells (destroyed by overcooking)
53
What is the impact of MTHFR deficiency
Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation) --> mutations
54
What is the impact of decreased methionine synthesis
Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation --> gene activation and silencing
55
Give examples of anticancer food elemtns
Vitamin C - ROS scavenger Vitamin E - ROS scavenger Isothiocyanates (cruciferous veg) Polyphenols (green tea, fruit juice)
56
How do polyphenolds work to reduce cancer
Activates MAPK, which Regulates Phase2 detoxifying enzymes as well as other genes (e.g.glut-S transferase) and reduce DNA oxidation
57
How could garlic affect cancer and what about green tea
Garlic: Garlic associated apoptosis (Ajoene, allicin) Green tea: EGCG-induced telomerase activity! (and is also a polyphenol)
58
Clinical presentation of CRC
- Change in bowel habit - Bleeding PR - Unexplained Fe deficiency anaemia Mucus PR Bloating Cramps (‘colic’) Constitutional (weight loss, fatigue)
59
When is bleeding PR and unexplained Fe deficiency most commonly seen
Bleeding PR- left sided CRC Fe deficiency anaemia- right sided CRC
60
Outline the macroscopic deatures of CRC
Small carcinomas may be present within larger polypoid adenomas, pedunculated or sessile
61
Distribution of colon cancer
Caecum/Ascending Colon 22% Transverse Colon 11% Descending Colon 6% Rectosigmoid 55% More on the sides less in the middle
62
What are the types of carcinoma in the colon
Adenocarcinomas (Grade 1-3) Mucinous carcinomas Signet ring cell Neuroendocrine
63
What does colon cancer grading refer to
proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina
64
What are the proportions fo each grading category in patients with CRC
~ 10% well differentiated ~ 70% moderately differentiated ~ 20% poorly differentiated
65
Outine the duke classification
HOW FAR IT HAS GONE THROUGH Dukes A - growth limited to wall - nodes negative Dukes B - growth beyond musc propria - nodes negative Dukes C1 - nodes positive - apical LN negative Dukes C2 - apical LN positive
66
What deermines CRC prognosis
Grade is how well differentiated Dukes (pioneering of staging of tumor... refers to how far it has spread) Thus affects treatment
67
Outline the effect of following on prognosis: Diagnosis in asymptomatic patients Rectal bleeding as presenting symptoms Bowel obstruction/perforation Tumour location Age <30 Distant metastases
Good Good Bad Bad Colon better than rectum Left colon better than right Bad Bad (very bad)
68
Pathological factors affecting prognosis
Bad prognosis: Depth of bowel penetration Number of lymph nodes Defree of differentiation Mucinour of signet ring cell (bad) Venous invasion Lympathic invasion Perineuroal invasion Improved prognosis: local inflammation and immunologic reaction
69
When would screeniing occur
High risk Population
70
Outline high risk colon cancer screening
Previous adenoma 1st Degree relative affected by colorectal cancer before the age of 45 2 affected first degree relatives evidence of dominant familial cancer trait including colorectal, uterine, and other cancers UC and Crohn’s disease Hereditable cancer families (include other sites)
71
Population screening for colon cancer
investigating apparently healthy individuals with the object of detecting unrecognised disease or people with an exceptionally high risk of developing disease, and of intervening in ways that will prevent the occurrence of disease or improve the prognosis when it develops.
72
Criteria for screening colon cancer
Importance of the disease:- condition should be important in respect to the seriousness and/or frequency The natural history of the disease must be known in order to:1. To identify where screening can take place2. To enable the effects of any intervention to be assessed
73
How does cancer screening occur
Stool test
74
What are the 3 cancer screening
Cervical cancer, CRC and breast
75
What do you want to rule out in the first instance with new onset rectal bleeding
Colorectal malignancy must be excluded
76
Are hyperplastic adenomas to do with cancer
no
77
Is having a high serum CEA good or bad prognosis wise in CRC
BAD (carcinoembryonic antigen is a tumour associated antigen)
78
Treatment for colon cancer
Depending on stage, surgery+ medication 5-FU + leucovorin (folinic acid)
79
What is the CRC cancer screenig
Faecal occult blood (FOB)... if +ve, then between 55-60--> sigmoidoscopy, between 60-75--> colonoscopy

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