Oncology - Bowel cancer

Question 1

What colon polyps are non neoplastic?

Answer 1

There are 3 types of hamartomatous (or non neoplastic) polyps:

1) Hyperplastic polyps
- most common type in adults
- majority in the sigmoid colon
- NO malignant potential or polyposis syndrome
- histologically have a saw tooth appearance

2) Juvenile (retention) polyps
- most common type in children
- located in the rectum (sometimes prolapse out of the rectum and bleed)
- solitary polyp: smooth surface with enlarged cystic spaces on cut section
- NO malignant potential

3) Peutz-Jeghers polyposis (PJP)
- autosomal dominant
- hamartomatous polyps predominate in the small bowel (less common in stomach and colon)
- buccal mucosa and skin pigmentation
- increased risk (>50%) for colorectal, breast and gynaecologic cancers

Question 2

What conditions are juvenile polyps associated with?

Answer 2

Juvenile polyposis - autosomal dominant but can be non hereditary. Syndrome caused by mutation in the SMAD4 gene which encodes an intracellular signalling protein in the TGF beta pathway.

Cronkhite - Canada syndrome - nonhereditarry polyposis syndrome; polyps plus ectodermal abnormalities in the nails.

Question 3

What are neoplastic polyps?

Answer 3

A GI polyp is a mass that protrudes into the bowel lumen. They can be non neoplastic or neoplastic.

Neoplastic polyps are called adenomas. They are premalignant dysplastic colonic polyps that increase in incidence with age and show equal sex incidence.

Question 4

What is the most common type of neoplastic polyp?

Answer 4

Tubular adenoma (adenomatous polyp) is the most common type of neoplastic polyp (60%).
Most often located in the sigmoid colon.
Macroscopically they are a stalked polyp:
- looks like a mushroom
- sections show complex branching of glands (adenomatous change) arranged in tubules

Question 5

What is a villous adenoma?

Answer 5

Another example of neoplastic polyps accounting for 10% of cases. They are sessile (have no stalk) with primarily a villous component (finger like processes). They are most often found in rectosigmoid junction.

These tumours secrete a protein and potassium rich mucus. Thus, large tumours can produce hypoalbuminaemia and hypokalaemia.

Villous adenomas contain foci of carcinoma more often than tubular adenomas.

Question 6

What is a tubulovillous adenoma?

Answer 6

These are the second most common type of neoplastic polyp accounting for 20-30% of cases. They are usually stalked polyps with both tubular and villous features.

Question 7

What is the pathogenesis of adenocarcinoma of the colon?

Answer 7

Neoplastic polyps arise because of alterations in crypt epithelial homeostasis. This includes (1) diminished apoptosis, (2) persistent cell replication and (3) failure to mature and differentiate as the epithelial cells migrate towards the surface. Normally, DNA synthesis ceases when cells reach the upper third of the crypts, after which they mature, migrate and become senescent. Adenomas represent disruption of this sequence. Mitotic figures are initially visible not only along the entire length of the crypt but also to the mucosal surface. As the lesion progresses, cell proliferation exceeds the rate of apoptosis and cells begin to accumulate in the upper crypts.

Question 8

Name some risk factors for malignancy in adenomatous polyps

Answer 8

1) Size is the most important factor, >2cm (40% risk of malignancy)
2) Multiple polyps
3) Polyps with increased villous component
- villous adenomas have a 30-40% risk of malignancy

Question 9

What is FAP?

Answer 9

Also called adenomatous polyposis coli (APC) FAP is an autosomal dominant conditions, in which ALL patients develop tubular adenomas and cancer (100% penetrance).

Polyps begin to develop between 10 and 20 years of age. It is caused by an inactivating mutation in the APC suppressor gene on the long arm of chromosome 5. Most cases are familial, but 30-50% reflect new mutations.

Question 10

What are the clinical findings of FAP?

Answer 10

FAP is characterised by hundreds of adenomas carpeting the colorectal mucosa, sometimes throughout its length but especially in the rectosigmoid region. Malignant transformation usually occurs between 35 and 40 years of age. Prophylactic colectomy is recommended, but some patients may also have adenomas in the small intestine and stomach. It is associated with congenital hypertrophy of the retinal pigment epithelium and desmoid tumours.

Question 11

What is Gardner’s syndrome?

Answer 11

This is a variant of APC with additional findings including benign osteomas and desmoid tumours.

Question 12

What is Turcot’s syndrome?

Answer 12

Autosomal recessive (AR) polyposis syndrome with the additional finding of malignant brain tumours (e.g. astrocytoma and medulloblastoma).

Question 13

How should patients with known polyps be followed up?

Answer 13

Isolated polyps seldom give symptoms unless large and distal. It is important to risk stratify patients to ensure they get appropriate colonoscopy.

1) Low risk = 1-2 adenomas <1 cm
- No follow up or repeat colonscopy at 5 years

2) Medium risk = 3-4 small adenomas or 1 large adenoma >1 cm
- Re-scope at 3 years

3) High risk = more than 5 small adenomas or 3 large adenomas >1 cm
- Re-scope at 1 year

Question 14

How common is colon cancer?

Answer 14

Second most common cancer related death in adults.
Third most common cancer in men and women.
Incidence rates have been decreasing
- increase in screening (e.g. faecal occult blood test, colonoscopy)

Peak incidence in the 7th decade.

Question 15

What are the risk factors for developing colon cancer?

Answer 15

1) Age >50 years
2) Cigarette smoking
3) Obesity, physical inactivity, heavy alcohol intake
4) Hereditary polyposis syndrome
5) Hereditary non polyposis colon cancer
6) Family cancer syndrome
7) First degree relative with colon cancer
8) Inflammatory bowel disease
- UC > CD
9) Diet
- low fibre diet, increased saturated fats, reduced veg intake

Question 16

What is the aetiology of colorectal cancer?

Answer 16

Most cancers of the colon and rectum arise in adenomatous polyps, thus factors related to development of adenomatous polyps may lead to colorectal cancer as well.

Carcinogenesis of colorectal cancer occurs via the adenocarcinoma-carcinoma sequence. Sequence specific genetic abnormalities result in the transition from normal colonic mucosa to invasive carcinoma; genes involved include APC, KRAS, p53 and Bax.

Question 17

When does loss of APC occur in the carcinogenesis of colorectal cancer?

Answer 17

Loss of APC is an EARLY event. APC accounts for 80% of sporadic colon cancers, whereas mutations in mismatch repair genes accounts for 15% of sporadic colon cancers. Germline mutations in APC lead to FAP.

Normal APC suppresses beta catenin. Mutant APC allows beta catenin to accumulate in the nucleus, where it acts as a transcription factor to activate key proliferation genes.

Question 18

Loss of p53 in the carcinogenesis of colorectal cancer occurs….

Answer 18

LATE. In the most common form of adenocarcinoma of the colon, mutation in p53 participates in the transition from adenoma to carcinoma and is a late event in the pathway.

Question 19

What is the role of mismatch repair genes in the carcinogenesis of colorectal cancer?

Answer 19

Somatic mutations in mismatch repair genes account for 15% of sporadic colorectal cancer. DNA repair is impaired leading to deficient correction of spontaneous replication errors, particularly in simple repetitive sequences (microsatellites). MMR deficiencies can occur through 2 main mechanisms:

1) In hereditary Warthin-Lynch syndrome (HNPCC) a germline mutation in one of the MMR genes is followed by a loss of heterozygocity later on in life
2) In a sporadic form, hypermethylation of the promotor of the MLH1 gene, encoding the MMR protein inactivates transcription of the gene

Question 20

Where is colon cancer most commonly found?

Answer 20

Descending colon
Rectosigmoid and rectum
Cecum and ascending colon
Transverse colon

Question 21

What are the clinical features of colon cancer?

Answer 21

Left sided cancers:

• tend to obstruct: bowel diameter is smaller than right colon, lesions have an annular, “napkin ring” appearance
• change in bowel habits lasting longer than 4 weeks: constipation and diarrhoea with or without bleeding, bright red blood coats the stool
• strep bovis endocarditis

Right sided cancers:

• tend to bleed: bowel diameter is greater than left colon, tumours are more polypoid in appearance
• blood is mixed with stool
• iron deficiency is more common than in left sided cancers

Other features include

• Tenesmus
• Palpable mass
• Weight loss

Question 22

What symptoms warrant an urgent 2 week referral for suspected colon cancer?

Answer 22

Patients >40 years with unexplained weight loss AND abdominal pain
Patients >50 years with unexplained rectal bleeding
Patients >60 with iron deficiency anaemia OR a change in bowel habit
Tests show occult blood in faeces

Question 23

What features should make you consider an urgent 2 week referral for suspected colon cancer?

Answer 23

An urgent referral should be “considered” if:

• there is an abdominal or rectal mass
• there is an unexplained anal mass or ulceration
• patients <50 years with rectal bleeding AND any of the following unexplained findings
  a) abdominal pain
  b) change in bowel habit
  c) weight loss
  d) iron deficiency anaemia

Question 24

What is the bowel cancer screening programme?

Answer 24

Screening methods include annual faecal occult blood test, flexible sigmoidoscopy every 5 years, annual FOBT + sigmoidoscopy every 5 years.

FOBT kits are sent out to all asymptomatic individuals over the age of 60 every 2 years. Patients over the age of 74 may request screening.

FOBT should also be offered to:

• patients > 50 years with unexplained abdominal pain OR weight loss
• patients < 60 years with change in bowel habits OR iron deficiency anaemia
• patients >60 years with anaemia even in the absence of iron deficiency

Abnormal FOBT is offered an appointment with a nurse specialist and colonoscopy is offered.

Question 25

How is bowel cancer staged?

Answer 25

2 staging systems are used:

1) TNM classification system - Tumour, Nodes, Metastasis (staging CT)
2) Dukes staging - looks at spread of cancer

Dukes A = tumour confined to the mucosa (90% 5 year survival)
Dukes B = tumour invading the bowel wall (70%)
Dukes C = lymph node metastases (45%)
Dukes D = distant metastases (6%)(20% if resectable)

It is important that patients receive a full colonoscopy to determine the spread of cancer within the colon.

Question 26

How is colon cancer treated?

Answer 26

Most patients with colon cancer are treated with surgery. Resectional surgery is the ONLY option for cure in patients with colon cancer. The lymphatic drainage of the tumour follows the arterial supply and therefore most tumours resections are tailored around the resection of particular lymphatic chains. This may not be appropriate for some patients, for example HNPCC patients who may do better with a panproctocolectomy rather than segmental resection.

The next step is to decide on restoration or continuity. For an anastomosis to heal key technical factors include adequate blood supply, mucosal apposition and no tissue tension. Surrounding sepsis, an unstable patient or an inexperienced surgeon may compromise this, and it may be safer to construct an end stoma rather than an anastomosis.

Question 27

What procedure is best to resect a tumour of the cecum, ascending and proximal transverse colon?

Answer 27

Right hemi-colectomy followed by an ileo-colic anastomosis. The patient will have an ileostomy if a restoration is not possible.

Question 28

What procedure would best remove a tumour of the distal transverse or descending colon?

Answer 28

A left hemi-colectomy would be the best option in this case with a colon-colon anastomosis, or colostomy if unsuitable.

Question 29

What procedure would best remove a tumour in the sigmoid colon?

Answer 29

High anterior resection with a colo-rectal anastomosis.

Question 30

How would an obstructing colon cancer be managed?

Answer 30

If this was present in the right or transverse colon a resection and a primary anastomosis would be performed.

If this was a left sided lesion then a Hartmann’s procedure is performed. This involves resection of the sigmoid colon and a proximal end colostomy (LIF) + oversewing the distal bowel and reversal in 4-6 months. .

Question 31

What is the prognosis of colorectal cancer?

Answer 31

Overall prognosis depends on stage of disease. Average 5 year survival rate is 65%. Carcinoembryonic antigen (CEA) can be used to detect recurrence.

Question 32

What is HNPCC?

Answer 32

HNPCC, or Warthin-Lynch syndrome is an autosomal dominant inherited disease that accounts for 3-5% of all colorectal cancers. It is characterised by:

1) Onset of colorectal cancer at a young age
2) Few adenomas (hence non “nonpolyposis”)
3) High frequency of carcinomas proximal to the splenic flexure (70%)
4) Multiple synchronous or metachronous colorectal cancers and
5) Extracolonic cancers including endometrial and ovarian cancers; adenocarcinomas of the stomach; small intestine and hepatobiliary tract and TCC of the renal pelvis and ureter.

Question 33

What is the pathogenesis of HNPCC?

Answer 33

HNPCC is caused by a germline mutation followed by a second somatic mutation in DNA mismatch repair genes, most commonly hMSH2 on chromosome 2. These mutations lead to widespread genomic instability particularly in simple repetitive sequences (microsatellites) which are particularly prone to replication errors.

Question 34

When is chemotherapy given for colorectal cancer?

Answer 34

Neo-adjuvant chemotherapy is given BEFORE surgery to downsize the tumour.

Adjuvant chemotherapy is given AFTER surgery to maximise the patients chances of cure.

Palliative chemotherapy is given when the patient cannot be cured or to delay or reverse cancer related symptoms.

Question 35

What chemotherapeutic agents are commonly given in colorectal cancer?

Answer 35

5-FU:

• adjuvant or metastatic as combination regime
• Thymidylate syntahase inhibitor (antimetabolite)
• capecitabine - oral 5-FU pro drug

Oxaliplatin:

• given in combination with 5-FU
• platinum based compound, inhibits DNA synthesis

Irinotecan:

• used in first line metastatic disease
• interacts with topoisomerase I to inhibit DNA replication and transcription

There is a survival benefit to giving 2/3 chemotherapeutic drugs + targeted/ biologic agent.

Question 36

What biologic agents can be used for colorectal cancer?

Answer 36

VEGFR inhibitors (e.g. bevacizumab)

• “starves” the tumour by disrupting its blood supply
• given along with chemotherapy

EGFR inhibitors (e.g. cetuximab, and Panitumumab)

• monoclonal antibody
• binds to EGFR expressed on cells

Question 37

How long are patients with colorectal cancer followed up?

Answer 37

Serial CEA blood tests are performed to check for recurrence.

Colonoscopy one year after removal of the cancer. Surveillance colonoscopy every 5 years to identify new polyps or cancers.

Question 38

What is the surgical treatment of rectal cancer?

Answer 38

Tumours located in the rectum can be surgically resected with either an anterior resection or an abdomino-perineal excision of rectum (APER). The technical aspects governing the choice between these two procedures can be complex to appreciate and the main point to appreciate for the exam is that involvement of the sphincter complex or very low tumours require APER. In the rectum a 2cm distal clearance margin is required and this may also impact on the procedure chosen. In addition to excision of the rectal tube an integral part of the procedure is a meticulous dissection of the mesorectal fat and lymph nodes (total mesorectal excision/ TME).

Question 39

Can patients with rectal cancer be offered neo-adjuvant radiotherapy?

Answer 39

Because the rectum is an extraperitoneal structure (until you remove it that is!) it is possible to irradiate it, something which cannot be offered for colonic tumours. This has a major impact in rectal cancer treatment and many patients will be offered neoadjuvent radiotherapy (both long and short course) prior to resectional surgery. Patients with T1 and 2 /N0 disease on imaging do not require irradiation and should proceed straight to surgery. Patients with T4 disease will typically have long course chemo radiotherapy. Those with T3 , N0 tumours may be offered short course radiotherapy prior to surgery. Patients presenting with large bowel obstruction from rectal cancer should not undergo resectional surgery without staging as primary treatment (very different from colonic cancer). This is because rectal surgery is more technically demanding, the anastomotic leak rate is higher and the danger of a positive resection margin in an unstaged patient is high. Therefore patients with obstructing rectal cancer should have a defunctioning loop colostomy.