Bowel cancer - Pathology and the screening process

Question 1

Where does bowel cancer have a high incidence?

Answer 1

High incidence in western world; low incidence in Asia and Central Africa

Bowel cancer affects men and women equally

Question 2

Risk factors for bowel cancer

Answer 2

• Migration from a low risk population to a high risk population
• Foods rich in red meat and fat increase risk of bowel cancer
• Longstanding ulcerative colitis
• Crohn’s disease - to a lesser extent than UC
• Presence of adenoma in the large bowel
• Previous history of bowel cancer surgery
• Family history of bowel cancer
• Old age

Question 3

What factors reduce the risk of bowel cancer?

Answer 3

Physical activity and low BMI are associated with low risk of cancer

Foods rich in veg, fruit and fibre

Question 4

How do foods rich in veg, fruit and fibre reduce the risk of bowel cancer?

Answer 4

Increase in faecal bulk and reduces transit time

Question 5

How does high fibre diet reduce bowel cancer?

Answer 5

• Increases formation of short chain fatty acids which promote healthy gut microbes which induce differentiation, arrest growth of cells and cause apoptosis
• By increasing stool bulk, thereby reducing stool transit time –> potential carcinogens in the stool have a shorter contact with the bowel mucosa
• By reducing secondary bile acid formation which are potentially carcinogenic

Question 6

What is a polyp?

Answer 6

Polyp is a protrusion into a hollow viscus, can be benign adenoma or malignant

Question 7

What is an adenoma?

Answer 7

Pre-cancerous lesions

Question 8

What type of epithelium do adenomas consist of?

Answer 8

Dysplastic epithelium

Question 9

What type of feature is low grade dysplasia?

Answer 9

Early precancerous feature

Question 10

What type of feature is high grade dysplasia?

Answer 10

Advanced precancerous feature, high risk of invasion if not removed

Question 11

What are pathological features of polyps?

Answer 11

Hyperplastic, tubular adenoma, villous adenoma, tubulovillous adenoma

Question 12

What is hyerplasia in polyps?

Answer 12

More goblet cells than normal mucosa; has a lace-like pattern

Question 13

What is familial adenomatus polyposis?

Answer 13

• Hundreds to thousands of polyps in large bowel, 500-2500

- Minimum of 100 polyps required to make diagnosis of FAP

Question 14

Why are the polyps called adenomas?

Answer 14

Polyps are dysplastic

Question 15

Where does FAP increase the risk of cancer?

Answer 15

Duodenum

Question 16

What is the defective gene in FAP?

Answer 16

Chr 5q21

Question 17

What is the defective gene in FAP also called?

Answer 17

Adenomatous polyposis coli (APC)

Question 18

What is the first hit in FAP?

Answer 18

Patients acquire the first abnormal gene in utero as germ cell mutation

Question 19

What is the second hit in FAP?

Answer 19

To develop polyps they acquire the second genetic abnormality in the somatic cells

Question 20

What is the two hit hypothesis to develop FAP?

Answer 20

Patient is born with a single genetic abnormal(first hit) and acquires the second genetic abnormality(second hit) after birth

Question 21

What does the two hit hypothesis explain?

Answer 21

Explains hereditary retinoblastoma, cancer of the eye in children and is applicable to most cancers

Question 22

What is loss of heterozygosity?

Answer 22

• With one copy of the abnormal gene, the cells are heterozygous
• The loss of the second set of normal genetic material during the ‘second hit’ is termed loss of heterozygosity and cells will acquire two identical copies of abnormal genes
• Cells acquire more genetic abnormalities to progress with adenoma-carcinoma sequence after the second hit

Question 23

Describe step 1 of the adenoma-carcinoma process

Answer 23

Normal mucosa - Inherited or acquired mutations(1st hit) loss of APC 5q21

Question 24

Describe step 2 of the adenoma-carcinoma process

Answer 24

Hyperproliferative epithelium - Methylation abnormalities(2nd hit) Loss of APC 5q21

Question 25

Describe step 3 of the adenoma-carcinoma process

Answer 25

Early adenoma - Mutation K-R AS gene 12p12

Question 26

Describe step 4 of the adenoma-carcinoma process

Answer 26

Intermediate adenoma - Loss of tumour suppressor gene SMAD2 and 4 18q21

Question 27

Describe step 5 of the adenoma-carcinoma process

Answer 27

Late adenoma - Loss of tumour suppressor gene p53 17p13

Question 28

Describe step 6 of the adenoma-carcinoma process

Answer 28

Invasive cancer - Telomerase activity to maintain immortality

Question 29

What is hereditary non-polyposis colorectal cancer/lynch syndrome?

Answer 29

Familial cancer affecting predominantly the caecum and right colon, before the age of 50

Question 30

What is lynch syndrome also associated with?

Answer 30

Endometrial, ovarian, small bowel and cancer of the urinary tract

Question 31

Genetics of HNPCC/lynch syndrome

Answer 31

- Errors due to mismatch in the DNA causes expansion and contractions of these repeat nucleotides causing microsatellite instability - Defective copy of the mismatch repair gene in utero is inherited in first hit and acquire the second copy during life(second hit) and develop cancer

Question 32

What are four examples of mismatch genes involved in pathogenesis in HNPCC?

Answer 32

- MSH2(2p16) and MLH1(3p21) - 30% of the HNPCC | - PMS1 and PMS2

Question 33

What is the amsterdam criteria for assessing for HNPCC?

Answer 33

- Three or more relatives with HNPCC-associated cancer - One affected patient should be a first-degree relative of the other two - Two or more successive generations should be affected - Cancer in one or more affected relatives should be diagnosed before the age of 50 years - Familial adenomatous polyposis should be excluded in any cases of colorectal cancer - Tumours should be verified by pathological examination

Question 34

Symptoms of bowel cancer

Answer 34

- Can be detected during screening - Change in bowel habit, constipation alternating with diarrhoea due to obstructive cancer - Bleeding from rectum - Anaemia especially with cancers of the caecum