Week 4/5 - D - Polyps, Bowel Screening (scope, F.O.B), Adenomas, H.N.P.C.C/F.A.P/Peutz-Jeghers, Colorectal adenocarcinoma

Question 1

What is a polyp? Does a polyp indicate benign or malignant?

Answer 1

A polyp is a protrusion above an epithelial surface (it is a tumour, a swellin) Visualisation of a polyp does not tell you what caused it or if it is benign or malignant - need to investigate

Question 2

What are the symptoms of a polyp?

Answer 2

Colorectal polyps are not usually associated with symptoms.[2] When they occur, symptoms include bloody stools; changes in frequency or consistency of stools, such as a week or more of constipation or diarrhoea;[3] and fatigue arising from blood loss

Question 3

As polyps are normally asymptomatic, they are most commonly an incidental finding What has the NHS introduced to look for and remove any small growths called polyps?

Answer 3

Bowel scope screening is a new test for people aged 55 where a thin, flexible tube with a camera at the end is used to look inside your bowel One-off test where patient receives a flexible sigmoidoscopy

Question 4

Other than the one-off flexible sigmoidoscopy screening at 55,what is the other form of colorectal cancer screening that is carried out by the NHS?

Answer 4

NHS has a national screening programme offering screening every 2 years to all men and women aged 50 to 74 years in Scotland. The well known bowel cancer screening programme * Also known as Faecal Immunochemical Test (FIT) a type of faecal occult blood (FOB) test which uses antibodies that specifically recognise human haemoglobin (Hb) - it used to detect, and can quantify, the amount of human blood in a single stool sample * patients with abnormal results are offered acolonoscopy

Question 5

Colorectal polyps are projections arising from the colonic mucosal surface that may be neoplastic or non-neoplastic What are the differential diagnoses of a colonic polyp? How are you able to diagnose the different types?

Answer 5

Colorectal polyps can broadly be classified as follows: hyperplastic, neoplastic (adenomatous & malignant), hamartomatous and, inflammatory. Need to biopsy the polyp and perform histopathology

Question 6

What are the different appearances of a polyp?

Answer 6

Polyps are either pedunculated (attached to the intestinal wall by a stalk) or sessile (grow directly from the wall and are flat)

Question 7

What is an adenoma of the colon? Why is it a risk?

Answer 7

An adenoma is a tumor of glandular tissue, that has not (yet) gained the properties of a cancer. It risk progression to colon carcinoma as it is pre-malignant

Question 8

MOST cancers arise from multiple mutations and a good example of this is the stepwise accumulation of mutations involved in colorectal cancer What mutation occurs in normal cells that can lead to hyperproliferation causing the development of a small adenoma?

Answer 8

The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. (adenomatous polyposis coli) - this is normally a tumour suppressor gene however mutations prevent this function APC mutation causes the hyperproliferation of the normal colonic epithelium to form a small adenoma

Question 9

Once an APC mutation leads to the development of a small adenoma, what cause this to become a large adenoma? Which mutation is then involved leading o the development of a carcinoma from the large adenoma?

Answer 9

Small adenoma develops commonly from an APC (tumour suppressor gene) mutation Large adenoma then develops from a K-ras (proto-oncogene) mutation Adenocarcinoma develops from a p53 (tumour suppressor gene) mutation

Question 10

What is a hyperplastic polyp? Are hyperplastic polyps dysplastic or do they contain malignant potential?

Answer 10

Hyperplastic polyps are usually asymptomatic outpouches of the gut wall They are not dysplastic and do not have any malignant potential - this is confirmed via biopsy

Question 11

What are inflammatory causes of polyp formation?

Answer 11

Inflammatory causes of polyp formation include ulcerative colitis and crohn’s disease

Question 12

What are different hereditary syndromes that increase the risk of colorectal polyp formation and subsequent cancer formation? (give three examples)

Answer 12

* Hereditary non-polyposis colorectal cancer (HNPCC) aka Lynch syndrome * Familial adenomatous polyposis (FAP) * Peutz-Jeghers syndrome

Question 13

What causes HNPCC? What is the inheritance? How many polyps are there usually in this condition?

Answer 13

HNPCC is an autosomal dominant condition due to mutations in mismatch repair genes (defects in DNA mismatch repair which leads to microsatellite instability) There are usually few polyps in this condition (< 100 )

Question 14

Lifetime risk of colorectal cancer is up to 80% in patients with Lynch syndrome Which genes are most commonly mutated in HNPCC? What other types of cancer are the risks increased due to this condition?

Answer 14

Increased risk of other Lynch cancers - endometrial carcinoma, gastric carcinoma, ovarian carcinoma In HNPCC the mismatch repair genes most commonly implicated include; MLH1 MSH2 and these occur in up to 70% of people with HNPCC.

Question 15

Which side of the colon is affected by HNPCC polyps? How are the HNPCC polyps expected to look histologically?

Answer 15

In the colon the tumours are more likely to be right sided, histologically they are more likely to be mucinous and have dense lymphocytic infiltrates. Often cause a Crohn’s like inflammatory response

Question 16

What causes familial adenomatous polyposis? What is the inheritance? How many polyps are there ususally in this condition?

Answer 16

FAP is an autosomal dominant condition cause by mutations in the APC tumour suppressor gene It causes multiple colorectal adenomas to form >100 (gene penetrance approaches 100% by 50 years)

Question 17

What other cancers are FAP associated with? What is the difference in age of onset between HNPCC and FAP?

Answer 17

APC mutations have been linked to certain other cancers such as thyroid cancer. HNPCC tends to present later usually around 50 FAP tends to have an earlier onset usally in 20s

Question 18

Peutz-Jeghers syndrome was the other genetic cause of potential colorectal cancer formation What is the inheritance? What type of polyps are formed in this disease and where?

Answer 18

Peutz–Jeghers syndrome is an autosomal dominant genetic disorder It is characterized by the development of hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa

Question 19

What are hamartamous polyps? (need to define a hamartoma first)

Answer 19

A hamartoma is a benign tumour-like malformation made up of an abnormal mixture of cells and tissues found in areas of the body where growth occurs. Hamartomatous polyps, are disorganized growth of tissues of the intestinal tract

Question 20

What is the mutation involved in Peutz-Jeghr’s syndrome? Which cancers does it increase the risk of?

Answer 20

Peutz_jeghers syndrome is caused by a mutation in STK11 (a tumour suppressor gene) The syndrome increases the risk of colorectal cancers, risk of GI cancers, and risk of breast cancers

Question 21

COLORECTAL CANCER Colorectal cancer is the third most common cancer in the UK and the 2nd most common cause of UK cancer deaths What type of carcinoma is it usually? What age group does it tend to affect?

Answer 21

Colorectal cancer tends to be adenocarcinoma 3/4 of cases occur in people aged over 65

Question 22

Which side of the colon are more common for colorectal cancers to occur? What do the majority of colorectal cancers arise from?

Answer 22

25% of colorectal cancers arise in the right side More than 50% of colorectal cancers arise in the left side There are different symptoms for the different sides affected It is is accepted that the majority of colonic cancers arise from pre-existing adenomatous polyps

Question 23

The majority of colorectal cancers occur in people with no genetic risk We have already identified genetic predisposition

• * Hereditary non-polyposis colorectal cancer
• * Familial adenomatous polyposis
• * Peutz-Jeghers syndrome

What are other risk factors for colorectal cancer?

Answer 23

• * Diet
• * Low intake of fibre in the diet
• * High intake of red and processed meat
• * High fat intake
• * High sugar intake
• High alcohol intake
• Smoking
• Obesity
• Lack of physical exercise
• Inflammatory bowel disease (UC > Crohn’s)

Question 24

Colorectal cancer can present from screening as discussed previously (Faecult occult blood test (50-74 - every 2 years) or bowel scope screening (55))

• Or via symptoms indicating potential colon problems

What are the symptoms of right sided colorectal cancer? What are the symptoms of right sided colorectal cancer?

Answer 24

Right sided

• * Anaemia (iron deficinecy anaemia)
• * Weight loss
• * Abdominal pain (often colicky), potential mass in abdomen
• * (obstruction is less likely)

Left sided

• * Blood/mucus PR
• * Altered bowel habit or obstruction
• * Tenesmus (feeling of needing to evacuate bowels although they are empty)
• * Mass PR

Question 25

What are questions to ask in a patient you are suspecting of colorectal cancer?

Answer 25

Any recent change in bowel habit Any bleeding from the back massage - dark, bright red, mixed with stool/separate Any recent weight loss Any abdo pain Have you noticed a swelling in your abdomen? Any family history of bowel problems? Any previous operations?

Question 26

In a patient presenting with abdominal pain and indicative signs of colorectal cancer, what less-invasive investigation can be carried out to look for potntial masses or polyps?

Answer 26

CT colonography can be carried out - less invasive low radiation scan obtains an interior view of the colon (the large intestine) that is otherwise only seen with a more invasive procedure where an endoscope is inserted If polyps or masses are seen, the patient will require an endoscopy

Question 27

What are the investigations carried out when suspecting colorectal cancer?

Answer 27

Colorectal cancer diagnosis is performed by sampling of areas of the colon suspicious for possible tumor development, typically during colonoscopy or sigmoidoscopy, depending on the location of the lesion. It is confirmed by microscopical examination of a tissue sample.

Question 28

Colorectal cancer will then be histologically confirmed What is carried out for staging?

Answer 28

Their entire colon should have been evaluated with colonoscopy or CT colonography. CT chest/abdo/pelvis is carried out to stage the spread of cancer MRI usually required for staging if rectal cancers have spread

Question 29

What are the routes of spread in colorectal cancer?

Answer 29

Local spread to the mesorectum (fat surrounding the rectum), preitoneum Lymphatic spread to mesenteric nodes Haematogenous spread to liver, lung, bone

Question 30

Treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy and targeted therapy - usually depends on the staging What is the TNM staging of colorectal cancer? (clue same as for oeseophagus and gastric cancer)

Answer 30

Tis- carcinoma in situ T1 - invading submucosa T2 - invading muscularis propria (externa) T3 - invading serosa (adventitia) T4 - invasion of adjacent structures N0 - no node spread N1-3 - regional node mets M0 - no mets M1 - distant mets

Question 31

Primary treatment in most cases of colon cancer is surgical - colon/rectum removed and sent to pathology for staging What is the main surgery carried out to treat colon cancers?

Answer 31

Laproscopic surgery is the type of surgery carried out in the treatment of colon cancers

Question 32

Which type of laproscopic surgery is carried out if the tumour is in * Caecum, ascending or proximal transverse colon * Distal transverse or descending colon * Sigmoid colon

Answer 32

Caecum, ascending colon or proximal transverse colon - right hemicolectomy Distal transverse or descending colon - left hemicolectomy Sigmoid colon - sigmoid colectomy

Question 33

Which type of laproscopic surgery is carried out if the tumour is in Low sigmoid or high rectal Low in rectum

Answer 33

Low sigmoid or high rectal - anterior resection Low in rectum - abdominal-perineal resection (APR) - involves the formation of a permanent colostomy and removal of rectum and anus

Question 34

What is carried out in patients presenting as an emergency due to obstruction or perforation?

Answer 34

In the emergency setting where the bowel has perforated the risk of an anastomosis is much greater, particularly when the anastomosis is colon-colon. In this situation an end colostomy is often safer and can be reversed later. A proctosigmoidectomy or Hartmann’s procedure is the surgical resection of the rectosigmoid colon with closure of the anorectal stump and formation of an end colostomy.

Question 35

What is the management of advanced stage colorectal cancer? (if still aiming at curative intent) * if cancer hasnt had distal mets * if cancer has had distal mets to liver and lung

Answer 35

Surgical cancer resection + chemotherapy (ie stage 3 disease TxN1Mo Surical cancer, liver and lung resection + chemotherapy (ie stage 4 disease TxNxM1)

Question 36

What is the chemotherapy regimen used for advanced colorectal cancers? (FOLFOX or FOLFIRI regiment is standard)

Answer 36

Folinic Fluorouracil acid Oxaliplatin

or

Folinic Fluorouracil acid Irinotecan

These are the standard chemotherapy regimen used first line in advanced colorectal cancers

Question 37

How do you choose between FOLFOX and FOLFIRI?

(there is a chemotherapy regiment called FOLFIRINOX - this has the best treatment results but few patients can tolerate the stress and side effects off the 4 drugs in combination

(FOL – folinic acid (also called leucovorin, calcium folinate or FA) F – fluorouracil (also called 5FU) Irin – irinotecan. Ox – oxaliplatin)

Answer 37

Oxaloplatin causes very severe peripheral neuropathy and therefore is not ususally used if the patient is expected to have longer to live - better for stopping disease progression though

Irinotecan has less of a side effect profile so used for when the patient has a longer life expectancy

• Often patient started on FolFOx to achieve remission and then FolFIri for maintenance chemotherapy

Question 38

Palliation for colorectal cancer usually requires radiotherapy and chemotherapy as well as what else to prevent the tumour obstruction the bowel?

Answer 38

Stenting or bypassing may be carried out to preserve bowel function in palliative care

Question 39

Biological therapies improve survival when added to chemotherapy in advanced disease which is not curable What is usually considered first line to add to the chemotherapy in the treatment of advanced colorectal cancer? (it is an anti-VEGF antibody) Give an example of a drug used in the treatment of K-ras wild type metastic colorectal cancer?

Answer 39

Bevacuzimab (anti-vascular endothelial growth factor antibody) improves survival when added to combination chemo in advanced disease Cetuximab and panitumumab (anti- epidermal growth factor receptor) are used in the treatment of K-ras wild type metastatic colorectal cancer