Colon cancer

Question 1

Discuss the epidemiology of colorectal cancer.

Answer 1

Major cancer in ‘developed’ countries
4th most common cancer overall
2nd leading cause of cancer death overall, behind lung cancer
Environmental (diet) and genetic factors in aetiology

Question 2

What are the functions of the colon?

Answer 2

Extraction of water from faeces (electrolyte balance)
Faecal reservoir (evolutionary advantage)
Bacterial digestion for vitamins (e.g. B and K)

Question 3

How many cells die per minute in the colon?

Answer 3

2-5 million

Question 4

What is the problem with the high turnover in the colon?

Answer 4

High proliferation rate renders cells vulnerable to mutation.

Question 5

What are the protective mechanisms usually in place to eliminate genetically defective cells?

Answer 5

Natural loss
DNA monitors
Repair enzymes

Question 6

What is a polyp?

Answer 6

Any projection from a mucosal surface into a hollow viscus, and may be hyper plastic, neoplastic, inflammatory, hamartomatous, etc.

Question 7

What is an adenoma?

Answer 7

A benign neoplasm of the mucosal epithelial cells.

Question 8

What are the types of colonic polyps?

Answer 8

Metaplastic/hyperplastic
Adenomas
Juvenile
Peutz Jeghers
Lipomas
Others (essentially any circumscribed intramucosal lesions)

Question 9

What percentage of hyperplastic polyps have a k-Ras mutation?

Answer 9

15%

Question 10

What percentage of lower intestinal polyps are hyperplastic?

Answer 10

90%

Question 11

How big are hyperplastic polyps?

Answer 11

<0.5cm

Question 12

Do hyperplastic polyps have malignant potential?

Answer 12

No

Question 13

What are the different types of colonic adenoma?

Answer 13

Tubular
Tubulovillous
Villous
May be pedunculate (tree) or sessile (carpet).

Question 14

Describe the microscopic structure of tubular adenomas.

Answer 14

Columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity.
Increased proliferative activity.
Reduced differentiation.
Complexity/disorganisation of architecture.

Question 15

Describe the microscopic structure of villous adenomas.

Answer 15

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 hypokalaemia.

Question 16

What causes adenomatous polyposis coli (APC/FAP)?

Answer 16

5q21 gene mutation

Question 17

What does the site of the mutation in FAP determine?

Answer 17

Clinical variants: classic, attenuated, Gardner, Turcot, etc.

Question 18

What percentage of adults have adenomas by the age of 50?

Answer 18

25%

5% of these become cancerous if left untreated.

Question 19

How do we know that adenoma can progress to carcinoma?

Answer 19

Most colorectal cancers arise from adenomas.
Residual adenoma in 10-30% of colorectal cancers.
Adenomas and carcinomas have similar distribution.
Adenomas usually precede cancer by 15 years.
Endoscopic removal of polyps decreases the incidence of subsequent colorectal cancer.

Question 20

What are microsatellites?

Answer 20

Repeat sequences prone to misalignment.

Some are in coding sequences of genes which inhibit growth or apoptosis, e.g. TGFbR11.

Question 21

What are mismatch repair genes?

Answer 21

Repair DNA damage, e.g. MSH2, MLH1 + 4 others.
If mismatch repair genes are damaged in microsatellite instability, cannot repair DNA.
Recessive genes requiring 2 hits.

Question 22

What are the 2 main pathways of genetic predisposition to colorectal cancer?

Answer 22

FAP- inactivation of APC tumour suppressor genes

HNPCC- microsatellite instability

Question 23

Discuss the epidemiology of colon cancer.

Answer 23

35,000 cases per year in UK
10% of cancer related deaths (16,000 per year UK)
Most common in 50-80 year olds. Sporadic rare <30y/o
High in US, Eastern Europe, Australia
Low in Japan, Mexico, Africa
Dietary factors contribute to risk: high fat, low fibre, high red meat, refined carbohydrates

Question 24

What can MTHFR (methylene tetrahydrofolate reductase) deficiency lead to?

Answer 24

Disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation), leading to mutations.

Question 25

What are folates important in colorectal cancer?

Answer 25

Coenzyme for nucleotide synthesis and DNA methylation.

Question 26

What can decreased methionine synthesis lead to?

Answer 26

Genomic hypomethylation and focal hypermethylation, leading to gene activation and silencing.

Question 27

Why is food important in colorectal cancer?

Answer 27

``` Contains 5000-10,000 bioactive chemicals Contains carcinogens Also contains anti-cancer agents Heat modifies chemicals further Bacteria modify food residues ```

Question 28

Name some anti-cancer food elements.

Answer 28

Vitamin C and E (ROS scavengers) Isothiocyanates (cruciferous veg) Polyphenols (green tea, fruit juice)- activate MAPK; regulate phase 2 detoxifying enzymes as well as other genes (e.g. glut-S transferase) and reduce DNA oxidation

Question 29

What is the clinical presentation of colorectal cancer?

Answer 29

``` Change in bowel habit Bleeding PR Unexplained iron deficiency anaemia Mucus PR Bloating Cramps ('colic') Constitutional (weight loss, fatigue) Patients rationalise these symptoms as 'getting old, piles or irritable bowel', and so do doctors. ```

Question 30

What is the distribution of cancers around the bowel?

Answer 30

Caecum/ascending colon = 22% Transverse colon = 11% Descending colon = 6% Rectosigmoid = 55%

Question 31

What are the types of carcinoma that exist in the large bowel, and which is most common?

Answer 31

Adenocarcinomas grade 1-3 (most common, from glands) Mucinous carcinomas Signet ring cell Neuroendocrine

Question 32

How are colonic carcinomas graded?

Answer 32

Proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina. 10% are well-differentiated 70% are moderately differentiated. 20% are poorly differentiated.

Question 33

How are colonic carcinomas staged?

Answer 33

Dukes classification. Dukes A: growth limited to wall; nodes negative Dukes B: growth beyond muscular propria; nodes negative Dukes C1: nodes positive; apical lymph node negative Dukes C2: apical lymph node positive

Question 34

What clinical features affect prognosis in colon cancer?

Answer 34

Diagnosis in asymptomatic patients → ?improved prognosis Rectal bleeding as presenting symptom → improved prognosis Bowel obstruction/proliferation → diminished prognosis Tumor location: ?colon better than rectum ?left colon better than right colon Age <30 → diminished prognosis Preoperative serum CEA → diminished prognosis with high CEA level Distant metastases → markedly diminished prognosis

Question 35

What are the pathological features affecting prognosis in colon cancer?

Answer 35

Depth of bowel wall penetration → increased penetration diminishes prognosis Number of regional lymph nodes involved → 1-4 nodes better than >4 nodes Degree of differentiation → well > poorly differentiated Mucinous (colloid) or signet ring cell → diminished prognosis Venous invasion → diminished prognosis Lymphatic invasion → diminished prognosis Perineural invasion → diminished prognosis Local inflammation and immunologic reaction → improved prognosis

Question 36

What are the criteria for screening for high risk colon cancer?

Answer 36

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 Heritable cancer families (include other sites)

Question 37

What is screening?

Answer 37

The practice of 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.

Question 38

Why is colon cancer screened for?

Answer 38

Important condition in respect to the seriousness and/or frequency Natural history of disease known Test is simple and accessible to patient Test is sensitive and selective Screening population has equal access to screening procedure Cost effective

Question 39

Why must the natural history of the disease be known for it to be screened for?

Answer 39

To identify where screening can take place | To enable the effects of any intervention to be assessed

Question 40

How is colon cancer screened for?

Answer 40

Faecal occult blood (FOB) | Colonoscopy/sigmoidoscopy if positive.

Question 41

If a 76-year-old man presents with new onset rectal bleeding to the GP, what must be excluded in the first instance?

Answer 41

Colorectal malignancy.