Small/ Large Bowel Cancer

Question 1

Most common small intestine tumours?

Answer 1

Adenocarcinoma - 50% (usually duodenal)
Lymphoma (non- Hodkin’s normally)
Carcinoid (10%)

Other: Lipomas, Stromal tumours

Question 2

Risk factors for small bowel adenocarcinoma/ lymphoma?

Answer 2

Coeliac disease
Crohn’s disease
Immuno-proliferative small bowel disease (plasma cells in upper small bowel, in poor ppl with poor hygiene areas around Mediterranean and South America/ Asia, treat with tetracyclines)

Question 3

Treatment of small bowl adenocarcinoma/ lymphoma

Answer 3

Surgery + ChemoRadio

Question 4

What are carcinoid tumours?

Answer 4

• originate from enterochromaffin cells (APUD cells) of the intestine
• usually in terminal ileum or appendix (10% of these present with appendicitis)
• can cause carcinoid syndrome

Question 5

What percent of carcinoid tumours cause carcinoid syndrome?

Answer 5

5%

And only when there are liver mets

Question 6

Presentation of carcinoid syndrome?

Answer 6

bluish-red face/ neck flushing (can lead to permanent changes with telangiectases)

abdominal pain + watery diarrhoea.

Cardiac abnormalities (50%)
- pulmonary stenosis or tricuspid incompetence

Liver enlargement

Question 7

Pathophys of carcinoid syndrome?

Answer 7

the tumours secrete a variety of biologically active amines and peptides:
- serotonin -> diarrhoea
- bradykinin, tachykinins -> one of these leads to flushing
- histamine
- prostaglandins

Question 8

Tests for carcinoid syndrome?

Answer 8

• Ultrasound: liver mets
• Urine: 5-hydroxyindoleacetic acid (5-HIAA) - major metabolite of 5-HT
• Serum chromogranin A (not 100% of cases)

Question 9

Management of carcinoid syndrome?

Answer 9

octreotide and lanreotide: somatostatin analogues that inhibit the release of gut hormones.

Question 10

Peutz-Jeghers Syndrome

Answer 10

Autosomal dominant (STK11

mucocutaenous pigmentation
- circum-oral (95%)
- hands (70%) and feet (60%)

GI polyps
- generally in small bowel
- can bleed or cause obstruction or intussusception (50%)

Question 11

Management for Peutz-Jeghers Syndrome?

Answer 11

polypectomy (endoscopically)

Try to avoid bowel resection if able.

Increased screening for non GI cancers (uterine, ovarian, cervical, breast, testicular cancer)

Question 12

Risk factors for CRC?

Answer 12

IBD
Previous abdomino-pelvic radiation
Obesity
Diabetes/ insulin resistance
Meat consumption (processed meats and red meats in particular)
Low fibre

Question 13

Who is eligible for CRC screening in Aus?

Answer 13

second yearly test for those 50-74 years of age

Paricipation 40%

Question 14

Portion of CRC secondary to familial syndromes?

Answer 14

~ 5%

• Polyposis syndromes (FAP, MUTYH-associated polyposis) - each < 1% CRC
• Lynch syndrome (3% CRC)

Question 15

Gener responsible for familial adenomatous polyposis?

Answer 15

Adenomatous Polyposis Coli (APC) gene

on chromasome 5

Question 16

Gene(s) responsible for Lynch syndrome?

Answer 16

MLH1 (can be sporadic also due to promotor methylation – more common);
MSH2, MSH6
PMS2

I think MLH 3 also

Question 17

Pathophys of Lynch syndrome, and treatment implications

Answer 17

Unable to form mismatch repair complexes -> lots of tandem repeats (microsatellite instability) -> abnormal promoter regions of DNA

Leads to neoantigens -> good for immunotherapy (checkpoint inhibitors)

More likely to have R sided CRC

Question 18

What is Turcot’s syndrome?

Answer 18

FAP or Lynch syndrome with brain tumours

Question 19

Diagnostic criteria for Lynch syndrome?

Answer 19

Modified Amsterdam criteria
• One individual diagnosed with CRC (or extracolonic Lynch tumours) before age 50 years
• Two affected generations
• Three affected relatives, one a first-degree relative of the other two

• FAP excluded
• Tumours verified by pathological examination

OR

Bethesda guidelines
• CRC diagnosed in patient who is younger than 50 years
• Presence of synchronous, metachronous CRC, or other Lynch tumours, irrespective of age
• CRC with the MSI-H histology diagnosed in a patient who is younger than 60 years
• CRC diagnosed in one or more first-degree relative with a Lynch-related tumour, with one of the cancers being diagnosed under the age 50 years
• CRC diagnosed in two or more first- or second-degree relatives with Lynch-related tumours, irrespective of age

Question 20

Inherited syndrome(s) -> hamartomatous polyps?

Answer 20

1. Juvenile Polyps: most in colon in kids/ teenager.
2. Peutz-Jeghers syndrome
3. PTEN hamartoma-tumour syndrome
   - caused by germline Phosphatase and Tensin Homologue (PTEN) mutations

Question 21

Pathophys of FAP (Familial Adenomatous Polyposis)?

Answer 21

Autosomal dominant

germinline mutaiton to APC gene on chromosome 5 (over 825 mutations identified)

Penetrance ~ 100%

hundred to thousand of polyps through colon (polyps by 16yo, CRC 39yo on overage)

Question 22

Attenuated FAP

Answer 22

later presentaiton than FAP (44yo)
fewer polyps (<100)
More likely right sided polyps

Question 23

MYH associated polyposis

Answer 23

MUTY homologue-associated polyposis (MYH-AP)

autosomal recessive

Colorectal adenomas and polyps

MYH is a base-excision-repair gene that corrects oxidative DNA damage.

May account for 7-8% of familial FAP phenotype without a APC mutation identified

Question 24

Main genetic pathways leading to CRC (2)

Answer 24

CIN (Chromosomal Instability)
- APC gene defect -> mutations to tumour suppressor genes

CIMP (CpG Island methylator pathway)
- via serrated neoplasia pathway
- initiating genes of BRAF or KRAS -> epigenetic silencing tumour suppressor or mismatch repair
(KRAS mutations -> respond to EGFRi such as cetuximab or panitumab)

MSI (Micro-satellite instability)
- defects in mismatch repair genes related to Lynch syndrome

Question 25

General management of CRC

Answer 25

Surgery

Adjuvant Chemo (5-FU/ capecitabine and oxaliplatin)
( can measure circulating tumour DNA (ctDNA) to see who would benefit from)

RAS/RAF wildtype: EGFR directed therapy (cetuximab, panitumimab)

Radiotherapy: not helpful (except rectal Cx)

Question 26

Monitoring post CRC treatment

Answer 26

CEA

CT CAP annually for three years

C’scope (3 years, 5 years)

Question 27

Pattern of mets in CRC

Answer 27

Generally:
- liver (56%), lung (5%), peritoneum

Rectal: not to liver (skips portal system)

Question 28

Right vs left CRC

Answer 28

R: worse prognosis, more immune active, more BRAF mutations (bad),