Flashcards in Oncology - Bowel cancer Deck (39):
What colon polyps are non neoplastic?
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
What conditions are juvenile polyps associated with?
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.
What are neoplastic polyps?
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.
What is the most common type of neoplastic polyp?
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
What is a villous adenoma?
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.
What is a tubulovillous adenoma?
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.
What is the pathogenesis of adenocarcinoma of the colon?
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.
Name some risk factors for malignancy in adenomatous polyps
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
What is FAP?
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.
What are the clinical findings of FAP?
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.
What is Gardner's syndrome?
This is a variant of APC with additional findings including benign osteomas and desmoid tumours.
What is Turcot's syndrome?
Autosomal recessive (AR) polyposis syndrome with the additional finding of malignant brain tumours (e.g. astrocytoma and medulloblastoma).
How should patients with known polyps be followed up?
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
How common is colon cancer?
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.
What are the risk factors for developing colon cancer?
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
- low fibre diet, increased saturated fats, reduced veg intake
What is the aetiology of colorectal cancer?
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.
When does loss of APC occur in the carcinogenesis of colorectal cancer?
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.
Loss of p53 in the carcinogenesis of colorectal cancer occurs....
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.
What is the role of mismatch repair genes in the carcinogenesis of colorectal cancer?
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
Where is colon cancer most commonly found?
Rectosigmoid and rectum
Cecum and ascending colon
What are the clinical features of colon cancer?
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
- Palpable mass
- Weight loss
What symptoms warrant an urgent 2 week referral for suspected colon cancer?
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
What features should make you consider an urgent 2 week referral for suspected colon cancer?
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
What is the bowel cancer screening programme?
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.
How is bowel cancer staged?
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.
How is colon cancer treated?
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.
What procedure is best to resect a tumour of the cecum, ascending and proximal transverse colon?
Right hemi-colectomy followed by an ileo-colic anastomosis. The patient will have an ileostomy if a restoration is not possible.
What procedure would best remove a tumour of the distal transverse or descending colon?
A left hemi-colectomy would be the best option in this case with a colon-colon anastomosis, or colostomy if unsuitable.
What procedure would best remove a tumour in the sigmoid colon?
High anterior resection with a colo-rectal anastomosis.
How would an obstructing colon cancer be managed?
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. .
What is the prognosis of colorectal cancer?
Overall prognosis depends on stage of disease. Average 5 year survival rate is 65%. Carcinoembryonic antigen (CEA) can be used to detect recurrence.
What is HNPCC?
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.
What is the pathogenesis of HNPCC?
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.
When is chemotherapy given for colorectal cancer?
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.
What chemotherapeutic agents are commonly given in colorectal cancer?
- adjuvant or metastatic as combination regime
- Thymidylate syntahase inhibitor (antimetabolite)
- capecitabine - oral 5-FU pro drug
- given in combination with 5-FU
- platinum based compound, inhibits DNA synthesis
- 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.
What biologic agents can be used for colorectal cancer?
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
How long are patients with colorectal cancer followed up?
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.
What is the surgical treatment of rectal cancer?
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).