Colorectal Cancer

Summary

Epidemiology

• Second most common cancer in the Western World (behind lung cancer)
• 50% of cases will result in death
• Relatively rare in Africa, Asia and South America
• Peak incidence in the 7^th decade

Aetiology

• Family history
• Age
• Diet rich in fat and meat, and low in fibre – associated with a Western Lifestyle
• IBD – due to high cell trunover
• Diabetes
• Atherosclerotic disease
• Age and family history are the two best predictors for colorectal cancer

Benign Disease

Clinical features and diagnosis

• Often asymptomatic, usually only found incidentally
• Rectal bleeding (rare)
• Hypokalaemia (very rare)

Management

• Endoscopic mucosal resection (EMR) – removal of polyps by colonoscopy. Upon discovery of one or more polyps, colonoscopy, and subsequent EMR is advisable, whereby all visible lesions should be removed. This should be followed by lifelong surveillance (every 3-5 years up to the age of 75) to check for the development of more polyps and / or colorectal cancer.
• 50% of patients will develop further polyps.

Pathology: Adenoma to Carcinoma

• A minimum of three separate genetic defects have to occur:
  • Onocgene activation (k-ras, c-myc) – associated with small adenomas becoming big adenomas.
  • Loss / mutation of tumour suppressor genes
  • Loss / suppression of genes involved with DNA repair path ways E.g., genes involved in the inhibition of apoptosis may become over-expressed
• It will take 8-10 cell replications on average for an adenoma to become a carcinoma.
• The mutations can occur in any order!
• Many of the genes associated with colorectal cancer are found in two specific locations: 5q & 18q – . Loss of herterzygositiy (LOH) in these regions is common during the formation of colorectal cancer, and some recognised genetic defects (e.g. FAP) are caused by LOH in these regions.
• Over 90% of colorectal carcinomas show 2 or more of the above mutations, 40% show three or more. It is the number of mutations, and not the order that affects the development of cancer.

Malignant Disease

General Presentation

• Iron Deficiency Anaemia
• Weight loss
• Malaise
• Vague abdominal pain
• Faecal occult blood loss
• Palpable mass (e.g. in right iliac fossa, left flank etc)
• Obstruction
• Altered bowel habit
• Tenesmus (desire to defecate)
• Rectal bleeding
• Anal and perianal pain
• Faecal incontinence
• Recurrent UTI – due to fistulation to the bladder
• Sister Mary Joseph Nodule – this is a lymph node that can be felt at the umbilicus and is a sign of metastatic spread
• Ascites – high in protein – due to local peritoneal cavity spread

• Palpable rectal mass (any age)
• Iron deficiency anaemia in men of any age
• Iron deficiency anaemia in non-menstruating women of any age
• Rectal bleeding and change of bowel habit for more than six weeks in patients over 40
• Rectal bleeding for 6 weeks or more in anybody over 50
• Anybody with a palpable rectal mass

Spread

• Usually occurs locally through the bowel wall, and to local lymph nodes
• Spread to the liver is relatively common

Investigations

• Faecal Occult blood
  • Guaiac test – for Hb breakdown products. 98% specific, but only 40-80% sensitive
  • Antibody test – uses antibodies that bind to human blood to test for the presence of blood.
• Routine biochemisty – U+E’s, FBC, LFT’s, CRP, ESR
• Colonoscopy – Investigation of choice!
• Barium enema – in cases where colonoscopy cannot be performed
• USS/CT – can asses bowel wall thickness as well as looking for metastatic spread

Staging

• Stage A – the tumour is confined to the mucosa – 5- year survival rate is 90%
• Stage B – the tumour has spread through all the layers of the mucosa to the serosa. There are no lymph nodes metastasis. The 5-year survival rate is 60%
• Stage C – the same as stage B, but there is lymph node involvement. Survival is about 30%.
• C1 – there is local lymph node involvement
• C2 – there is distant lymph node involvement
• C2 caries a worse prognosis than C1
• Stage D – this category was not originally included, but later added to refer to disease with wide spread metastatic involvement.

Treatment

• 80% of patients will have surgery
• Resection is the treatment of choice for Dukes A-C
• Radio and chemotherapies may be used as adjuvants in Dukes B-C, and as palliative treatments in Dukes D
• Surgery
  • You should remove 2cm either side of the tumour (5cm in all directions in the rectum)
  • Can be a laparotomy or laparoscopy
  • Anastomosis is usually, although not always made afterwards

Genetic Disorders associated with Colorectal Cancer

• Accounts for 1% of cases, prevalence is 1 in 10 000
• Autosomal dominant
• Patients inherit a ‘bad copy’ of the APC gene on chromosome 5. They have one remaining ‘good copy’ of the gene, which is still liable to mutation, and when it does, polyposis results
• 90% of these patients will develop bowel cancer

• Autosomal dominant
• Average onset of cancer is in the mid-forties
• Despite the name, polyps are often still present
• Also increase the risk of cancer in the small bowel, stomach, and other regions

Epidemiology

• It is the second most common cancer in the western world, behind lung cancer.
• ½ of all people who get colon cancer will die from it
  • This outcome is much better than from other solid tumours such as lung cancer and gastric cancer. This is because of advanced staging and management techniques which now mean that a complete resection of the rectum and anus is now quite rare.
• Rectal cancers are twice as common in men
• Right sided cancers are more common on women.  For the rest of the large bowel incidence is pretty much equal in both men and women.
• Colorectal cancer is relatively rare in Asia, Africa and South America.
• Lifetime risk for colorectal cancer – 1 in 18 for men, 1 in 28 for women.
• Peak incidence is in the 7^th decade of life.
• Once metastatic disease has been diagnosed, patients have on average about 6 months to live.
• Scotland is the most common place in the world for this disease to occur.
• It is more common in urban populations than rural ones, and this probably reflects lifestyle choices in these places. It is also more common in poorer populations.
• Age and family history are the two best predictors for colorectal cancer.

Aeitiology

• A diet rich in fat and meat, and low in fibre is a predisposing factor. Dietary fibre increases the bulk of the stool in most people by retaining water, and thus reducing the transit time of faeces in the colon. This reduces the time any potential carcinogen is in cotact with the colonic mucosa.
  • Fibre also alters the intestinal flora compilation as well as absorbing toxins, thus again reducing the chance of a carcinogen spending lots of time in contact with the large bowel wall
• A few minor dietary constituents may also reduce the risk of colorectal cancer. These include β-carotene, and vitamins C & E.
• Inflammatory bowel disease may also be a pre-disposing factor due to the high cell turnover rate.
• Diabetes
• Atherosclerotic disease
• Family history – this is an extremely important pre-determining factor for CRC. It is estimated that 10-30% of CRC has some sort of hereditary component, although the exact genetic cause of these has not yet been identified. Note below the risks of CRC with various family histories
  • None – 1/50
  • 1^st degree relative – 1/17
  • 1^st degree relative, and you are over 45 – 1/10
  • Two 1^st degree relatives – 1/6
  • Dominant pedigree (FAP, HNPCC) – ½ 

Benign Disease

Clinical features and diagnosis

• Most adenomas are asymptomatic and have no signs. Unless there is a family history, or extensive bleeding from the rectum, then diagnosis will only usually be made as a result of a screening program or ‘incidental’ colonoscopy or barium enema – usually for symptoms like unexplained anaemia or slight rectal bleeding.
• A rare finding may hypokalaemia. Polyps often secrete mucous, which contains a large amount of potassium. If there is an especially large adenomatous polyp, it may result in hypokalaemia.

Management

• Endoscopic mucosal resection (EMR) – this is a technique to remove polyps by colonoscopy. Upon discover of one or more polyps, colonoscopy, and subsequent EMR is advisable, whereby all visible lesions should be removed.
• The patient should then be given regular and lifelong surveillance (every 3-5 years up to the age of 75) to check for the development of more polyps and / or colorectal cancer.
• 50% of patients will develop further polyps.

Pathology: Adenoma to Carcinoma

Colorectal cancer is an adenocarcinoma – i.e. it develops from the mucosal lining of the colon. The adenoma will arise from glandular cells of the mucosa. Adenoma is the benign form of the disease.
It is thought that all carcinomas of the large bowel arise from adenomas.
Polyps of less than 1cm diameter are rarely malignant, however they still have the potential to become so. Polyps over 2cm have a 5-10% chance of being malignant.
Usually, the lesion will be a polyp with a stalk, however sometimes it can be a flat lesion – these are known as sessile lesions.
There can be multiple polyps or perhaps just even one. In genetic polyp causing conditions there can be hundreds if not thousands of polyps.
Progression – The adenoma-carcinoma sequence

• Colorectal cancer has the most thoroughly understood disease progression
• There are three recognised genetic defects that have to occur:
• Onocgene activation (k-ras, c-myc)
• Loss / mutation of tumour suppressor genes
• Loss / suppression of genes involved with DNA repair path ways.
• On average, an adenoma will take 8-10 years to turn into carcinoma. Small adenomas are present in 1/3 people. A primary colonic carcinoma is present in 1/30 people. Metastatic colon cancer is present in 1/60 people.

The mutations can occur at any time and in any order, but are associated with specific effects:

• K-Ras – oncogene – this is often associated with small adenomas becoming big adenomas. The mutation is only present in 10% of adenomas whose diameter is less than 1cm. However, the mutation is present in 40% of polyps of 1-2cm size, and 50% in full blown colorectal cancer.  It is thought that this gene is mutated by eating red meat. These mutations are usually point mutations, and the protein produced is no longer able to hydrolyse GTP to GDP. This results in over emphasised signalling for cell division.
• C-myc – oncogene – over expression of this gene is a feature of most colorectal cancers. This genes encodes a protein that is required for DNA synthesis – increased expression is associated with increased cell proliferation.
• APC – tumour suppressor gene – found on 5q
• DCC – deleted in colorectal cancer. Found on 18q. It is related to cell adhesion.
• MCC – mutated in colorectal cancer. Found on 5q
• C-yes
• Bcl-2 – this is a very important inhibitor of apoptosis. It may become over-expressed.
• P53- mutations to this occur in more than 75% of carcinomas.
• 5q & 18q – these are common locations on the chromosome for many of the genes above. Loss of herterzygositiy (LOH) in these regions is common during the formation of colorectal cancer.

Over 90% of colorectal carcinomas show 2 or more of the above mutations, 40% show three or more. It is the number of mutations, and not the order that affects the development of cancer.

Malignant Disease

Presentation

• About 50% of cancers occur at the retrosigmoid junction or in the rectum.
• There can sometimes be an ascites high in protein. This is produced by local spread into the peritoneal cavity.
• Sister Mary Joseph Nodule – this is a lymph node that can be felt at the umbilicus and is a sign of metastatic spread.
• Liver metastases are relatively common but probably asymptomatic at first. Later they can cause slight pain and hepatomegaly, and late on they may lead to jaundice.
• Lung metastasis can produce a persistent cough.
• You may also get spread to bone marrow, producing leucoerythroblastic anaemia.

• Often asymptomatic but may present with iron deficiency anaemia, and other vague symptoms such as weight loss and malaise.
• Vague abdominal pain
• Faecal occult blood loss
• Palpable right iliac fossa mass
• Acute appendicitis – this may rarely occur due to caecal tumour blocking off the entrance to the appendix
• Distal ileal obstruction (rare)-  shows advanced disease – the faecal matter entering the caecum is normally liquid – and it takes a massive blockage to prevent liquid getting through!

• By the time the stool reaches this region it is often hard as most of the water has been absorbed. As a result, obstruction may be a symptom in this form of the disease. The diagnosis may be confused with diverticular disease or IBS.
• Alteration of bowel habit – often alternating between constipation and diarrhoea.
• There may or may not be any pain. If pain is present it is often colicky.
• Desire to defecate (tenesmus) and distension
• Palpable mass in the left side of the abdomen.
• There may often be mucus visible in the stools, but visible blood is rare (only about 10% of cases)

• Rectal bleeding – This is a particularly common finding. The blood may be dark and mixed with the stool, but it can also be lighter coloured and completely separate from the stool.
• Changes in bowel habit – could be more frequent and there may also be lots of mucus and diarrhoea.
• Continuous urge to defecate – caused by the presence of a large tumour in the bowel which gives a continuous feeling of fullness. This is known as tenesmus
• Anal and perineal pain. May at first be associated with the urge to defecate, but can later become constant. This occurs with a low rectal cancer that invades the anal sphincters.
• There may also be faecal incontinence caused by a cancer invading the anal sphincter, and back pain caused by involvement of the sacral plexus.
• Infiltration of the urinary tract, leading to urinary tract infections, possible fistulas, and even renal failure.

• Palpable rectal mass (any age)
• Iron deficiency anaemia in men of any age
• Iron deficiency anaemia in non-menstruating women of any age
• Rectal bleeding and change of bowel habit for more than six weeks in patients over 40
• Rectal bleeding for 6 weeks or more in anybody over 50
• Anybody with a palpable rectal mass

Incidence

Spread

• Spread normally occurs through the bowel wall. Often rectal cancers will infiltrate pelvic viscera and side walls. Lymphatic spread is common at presentation, and spread can also reach the liver through systemic and portal venous systems. Spread to the lungs is rare.
• Tumour staging at the time of presentation is the most important factor in determining prognosis.
• The site of the cancer can have an effect on overall patient outcome. Rectal cancers often have a better outcome than colonic ones because they are detected earlier. However, there is a higher risk of recurrence in rectal cancers due to the fact it is harder to remove all the tissue you need to.
• Generally, right sided tumours have a better prognosis then left sided ones, even if they are both staged at the same level.

Investigations

Faecal Occult blood

• Guaiac test – This will detect about 40-80% of asymptomatic colocrectal cancer, particularly if the cancer is left sided. It tests for a breakdown product of haemoglobin. Dietary restrictions are necessary to prevent a false positive result. This means for 3 days prior to the test the patient should not eat red meat, melons, things high in vitamin C or take NSAID’s. The test is 98% specific.
• Antibody test –this uses labelled antibodies to human blood and checks if they bind. This can detect up to 80% of asymptomatic cancer. In particular, it will pick up 70% of adenomas larger than 1cm. However, it has lower specificity.

In general the faecal occult blood tests are used for screening and not as an investigation. A positive result will require a full investigation of the entire colon and rectum.
Routine biochemistry – i.e. U+E’s, FBC, LFT’s, CRP.
Colonoscopy – this gives a very detailed view of the whole colon. It has two major benefits – any suspicious lesions can be biopsied; and many polyps can be removed during the procedure. Its major disadvantage is in that it is invasive, and also carries a slight risk of perforation. It also requires sedation.

• Rigid Sigmoidoscopy – this is useful because it allows examination of the bowel without any prior bowel preparation. The mucosa, mucous, faeces and blood are all examined in their natural state
• Flexible sigmoidoscopy – this allows examination of the rectum, sigmoid colon, and most of the descending colon with relative comfort for the patient.

Barium Enema – provides good anatomical information about large lesions in the colon however, it often misses small lesions and abnormalities that will be picked up by colonoscopy. Many lesions picked up by barium enema will need further analysis by colonoscopy anyway. A sigmoidoscopy is always needed with a barium enema because the barium study provides very poor visualisation of the rectum.

• In most centres, a colonoscopy is the first line investigation, and barium enema is only used if the colonoscopy was incomplete due to anatomical or pathological abnormalities.

Endo-rectal ultrasound – this is very useful for assessing the level of penetration of the tumour into the bowel wall. It can also identify enlarged lymph nodes, but cannot always say whether the nodes show metastatic spread or not. It can be performed as an outpatient procedure without any sedation or bowel preparation. The test is useful in pinning down the area that needs to be resected.
USS / CT – both of these may be used to locate any intra-abdominal metastasis, although CT is far more accurate. However, neither of these tests is used regularly as they are both reasonably expensive and have not been shown to improve outcome. Pre-operative CT is sometimes used in patients where distant metastasis are suspected.
MRI – this is sometimes used to assess the extent of spread of rectal cancer.
Intra-operative hepatic ultrasound – often used during the surgery to assess spread to the liver. It helps in planning the extent of any liver resection.
Carcinoembryonic antigen – CEA – this is a non-specific antigen found circulating in the blood that is raised in cases of colorectal cancer. Screening for this has not had any noticeable impact on outcomes, and its major use is after a resection, a raised CEA can indicate recurrence.

Staging

• Stage A – the tumour is confined to the mucosa – 5- year survival rate is 90%
• Stage B – the tumour has spread through all the layers of the mucosa to the serosa. There are no lymph nodes metastasis. The 5-year survival rate is 60%
• Stage C – the same as stage B, but there is lymph node involvement. Survival is about 30%.
• C1 – there is local lymph node involvement
• C2 – there is distant lymph node involvement
• C2 caries a worse prognosis than C1
• Stage D – this category was not originally included, but later added to refer to disease with wide spread metastatic involvement.

Treatment

• About 80% of colorectal cancer patients will undergo surgery, but less than 50% will survive to 5 years.
• Resection of the tumour is the primary treatment in Duke’s stage A-C. This may be accompanied by adjuvant therapy in stages B & C. The adjuvant therapy usually involves radiotherapy, as chemotherapy is generally not effective. There is some evidence that 5-flurouracil may be of benefit.
• In cases where the disease is so advanced surgery cannot be attempted, then radiotherapy and chemotherapy may be given, with the latter being more effective.

Surgery

• It is necessary to remove the tumour and some surrounding tissue to ensure all malignant tissue has been removed. The normal cut-off point is 2cm either side of the main tumour. Only about 3% of tumours have spread further than this. Most of these cases are Duke’s stage C with large metastatic involvement. In these cases, up to 15cm of bowel on either side of the tumour may be removed along with associated lymph nodes.
• Rectal cancer is slightly different. Usually surgeons like to remove 5cm either side, although 2cm may be acceptable. It is also important to remember in these cases that spread is just as likely laterally as it is longitudinally, and thus surrounding connective tissue within a radius of 5cm should also be removed.
• Usually an anastomosis is made where the bowel has been resected
• Surgery can be laparoscopic or laparotomic. Certain tumours lend themselves to the different techniques, for example, tumours in the transverse colon and distal rectum are difficult to perform laparoscopic ally.
• There are benefits to laparoscopic surgery, such as shorter stay in hospital, less chance of adhesions, quicker return to normal life, and smaller scars. However, the procedure is much more difficult to perform by the surgeon.
• Preparation for surgery – proper preparation can reduce both wound and anastomotic sepsis. Usually, the day before the operation, a preparation such as Golytely, Fleet phosphosoda or picolax is given. These are basically just laxatives that clear out faecal debris before the operation.
  • In patients with bowel obstruction, a longer course of 2-3 days may be necessary.
  • Prophylactic antibioticsare given to reduce the risk of wound infection and intra-abdominal sepsis. Usually they are just given for 24 hours immediately after the operation. If they are given for longer, they just encourage resistant organisms and can lead to increased risk of pseudomembranous colitis.
  • Thrombo-embolus – this is an important risk to take into account, particularly considering the risk factors associated with this and colorectal cancer.

Genetic Disorders

Familial Adenomatous polyposis (FAP)

• About 1% of CRC can be attributed to FAP. It is present in about 1/10 000 people and is autosomal dominant.
• The condition results from an inherited mutation of gene APC on the long arm of chromosome 5, followed by the acquired mutation of the ‘good copy’ of the APC gene.
• These patients will have hundreds, if not thousands of polyps extending the length of the colon.
• These patients may often suffer from iron deficiency anaemia, due to bleeding of the many polyps they have.
• More than 90% of people with FAP will develop bowel cancer.

Hereditary non-polyposis colorectal cancer (HNPCC)

• This is a hereditary from of colorectal cancer where the cancer is most commonly found in the ascending colon.
• The average age of onset of colon cancer is in the mid-forties.
• It is autosomal dominant.
• The name is a little confusing in that often polyps are still present.
• This condition also increases the risk of small bowel, stomach, endometrial and a variety of other cancers.

Prevention and screening for genetic conditions

• General prevention involves the promotion of a high-fibre, low fat diet.
• Screening is often given for those at particularly high risk – which basically means those diagnosed with FAP or HNPCC.
• NSAID’s and aspirin may play a role in prevention, although the evidence is debateable.
• Faecal occult blood (FOB) screening has been advocated by some, and randomised control trials have shown it to reduce mortality by 15-33%. However, as the test has low-sensitivity, it results in a large number of unnecessary colonoscopies. For example, one study found that of the people who appeared positive, 12% had malignant disease and 17% had adenomas.
• In the USA, a ‘once only procedure’ of a flexible sigmoidoscopy is now recommended for all people aged between 55-65. This has been shown to reduce CRC mortality by 33%. A trail of this method has been undertaken in the UK and the results are positive, although as of yet, it is not a country wide program.
• Colonoscopy is THE test for CRC. But it is pretty expensive; and it requires sedation and bowel preparation as well as a whole team of professionals on hand. There is also the risk of perforation. These factors mean that colonoscopy is not used as a main stream method of screening.
• Virtual colonoscopy may play a role in the future. It is a form of CT scan, that produces a computerised visualisation of the colon, but it cannot pick out the same level of detail as a real colonoscopy. Genetic testing may also be something used in years to come.
• Currently there is an FOB trial running in the UK, and the hope that some sort of screening will be rolled out nationwide on the NHS within the next few years.

References

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