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Canc > Cancer 13: Colorectal Cancer > Flashcards

Cancer 13: Colorectal Cancer Flashcards

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
Q

What might be seen on adenoma microscope

A

Early stages of DNA going bad

Bigger nuclei
No longer single layer of cells (pseustratified or stratified)
Darker
Disordered architechture

Pink good, purple bad

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26
Q

What is dysplasia

A

Bad growth

Abnormal growth of cells with some features of cancer

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27
Q

How is dysplasia classified

A

Subjective analysis

Indefinite, low grade and high grade

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28
Q

Do we include appendix when talking about colon cancer

A

No

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29
Q

What could increase risk of dysplasia

A

It is associated with lesions e.g. in ulcerative collitis due to inflammation

These are called DYSPLASIA- ASSOCIATED LESIONS

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30
Q

Which mutation occurs in FAP

A

5q21 gene mutation

Site of mutation determines variant

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31
Q

What is treatment for FAP

A

Many have colectomy

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32
Q

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

A

25%

5%

Big adnomatous polyps most likely to turn into cancer

10 year lead time

Cancers curable until 2 years

33
Q

T/F most colorectal cancers arise from polyps

A

T

34
Q

In what proportion of CRC patients can residual polyp be seen

A

10-30%

35
Q

Adenomas precede cancers by how long

A

10-15 years

36
Q

How can the risk of CRC be reduced

A

Endoscopic removal of adenomatous polyps

37
Q

What are the 2 overall genetic pathways involved in CRC

A
  1. Adenoma/carcinoma sequence.

E.g. the APC gene. damaged in people with FAP. Also can be damaged in other members of population

  1. Microsatellite instability
38
Q

Genes involved in the adenoma carcinoma sequence pathway

A

APC, K ras, Smads, p53, telomerase activation

they get adenomas before carcinoma

39
Q

What is a microsatellite instability

A

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
Q

What happens if the microsatellites in mismatch repair genes are damaged

A

If the mismatch repair genes are damaged (microsatellite instability), DNA cannot be repaired

41
Q

Is 1 or 2 hits needed in lynch synfrome

A

2 hits needed (recessive genes)

42
Q

Outline the adenoma-carcinoma sequence

A

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
Q

For colon cancer, state the different genes at each part of the adenoma-carcinoa seuqnece

A

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
Q

Give an example of a disdease for each of the two genetic pathways relevant to CRC

A
  1. Adenoma-carcinoma sequence: APC. Inactivation of APC TSG.
  2. Microsatellite instability: HNPCC (Lynch’s)
45
Q

Outline the normal action of beta catenin at the bottom of the crpts and at the top

A

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
Q

Outline the action of beta-catenin in APC- crypts

A

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
Q

Age range for colon cancer

A

Ages range 50-80. Sporadic rarely < 30

48
Q

Where is colon cancer high and low

A

High in US, Eastern Europe, Australia

Low in Japan, Mexico, Africa

49
Q

What features of diet affect colonic carcinoma ris

A

Dietary Factors; High Fat, Low Fibre, High Red meat, Refined carbohydrates

50
Q

How can chemicals in food affect cancer

A

Can contain carcinogens

Also anti-cancer agents (anti-oxidants)

Heat modifies chemicals further

Bacteria modifies food residues

51
Q

Give an example of a carcinogenc food type

A

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
Q

Which dietary deficiency can cause cancer

A

FOLATES in CRC:
Coenzyme for nucleotide synthesis and DNA methylation

Folate is a protector of cells (destroyed by overcooking)

53
Q

What is the impact of MTHFR deficiency

A

Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation)

–> mutations

54
Q

What is the impact of decreased methionine synthesis

A

Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation

–> gene activation and silencing

55
Q

Give examples of anticancer food elemtns

A

Vitamin C - ROS scavenger
Vitamin E - ROS scavenger
Isothiocyanates (cruciferous veg)
Polyphenols (green tea, fruit juice)

56
Q

How do polyphenolds work to reduce cancer

A

Activates MAPK, which

Regulates Phase2 detoxifying enzymes as well as other genes (e.g.glut-S transferase) and reduce DNA oxidation

57
Q

How could garlic affect cancer

and what about green tea

A

Garlic: Garlic associated apoptosis
(Ajoene, allicin)

Green tea: EGCG-induced telomerase activity! (and is also a polyphenol)

58
Q

Clinical presentation of CRC

A
  • Change in bowel habit
  • Bleeding PR
  • Unexplained Fe deficiency anaemia

Mucus PR
Bloating
Cramps (‘colic’)
Constitutional (weight loss, fatigue)

59
Q

When is bleeding PR and unexplained Fe deficiency most commonly seen

A

Bleeding PR- left sided CRC

Fe deficiency anaemia- right sided CRC

60
Q

Outline the macroscopic deatures of CRC

A

Small carcinomas may be present within larger polypoid adenomas, pedunculated or sessile

61
Q

Distribution of colon cancer

A

Caecum/Ascending Colon 22%

Transverse Colon 11%

Descending Colon 6%

Rectosigmoid 55%

More on the sides less in the middle

62
Q

What are the types of carcinoma in the colon

A

Adenocarcinomas (Grade 1-3)
Mucinous carcinomas
Signet ring cell
Neuroendocrine

63
Q

What does colon cancer grading refer to

A

proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina

64
Q

What are the proportions fo each grading category in patients with CRC

A

~ 10% well differentiated
~ 70% moderately differentiated
~ 20% poorly differentiated

65
Q

Outine the duke classification

A

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
Q

What deermines CRC prognosis

A

Grade is how well differentiated

Dukes (pioneering of staging of tumor… refers to how far it has spread)

Thus affects treatment

67
Q

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

A

Good

Good

Bad
Bad

Colon better than rectum
Left colon better than right

Bad

Bad (very bad)

68
Q

Pathological factors affecting prognosis

A

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
Q

When would screeniing occur

A

High risk

Population

70
Q

Outline high risk colon cancer screening

A

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
Q

Population screening for colon cancer

A

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
Q

Criteria for screening colon cancer

A

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
Q

How does cancer screening occur

A

Stool test

74
Q

What are the 3 cancer screening

A

Cervical cancer, CRC and breast

75
Q

What do you want to rule out in the first instance with new onset rectal bleeding

A

Colorectal malignancy must be excluded

76
Q

Are hyperplastic adenomas to do with cancer

A

no

77
Q

Is having a high serum CEA good or bad prognosis wise in CRC

A

BAD (carcinoembryonic antigen is a tumour associated antigen)

78
Q

Treatment for colon cancer

A

Depending on stage, surgery+ medication

5-FU + leucovorin (folinic acid)

79
Q

What is the CRC cancer screenig

A

Faecal occult blood (FOB)… if +ve, then between 55-60–> sigmoidoscopy, between 60-75–> colonoscopy

Canc (16 decks)

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