U10W5: Colorectal cancer Flashcards
What are some of the biological risk factors for colorectal cancer?
Age - longer time to accumulate mutations
Family history - genetic diseases such as FAP and Lynch syndrome
Inflammatory Bowel Disease
Previous Cancer - genomic instability
Diabetes - abnormally high insulin and abnormally high blood glucose - plentiful glucose for cancer cell growth
Gallstones - long term inflammation
Acromegaly - elevated growth hormones increase proliferation
Benign polyps in bowel - increase proliferation, higher chance of genomic instability
H.pylori infection - CagA cancer causing
What are some of the lifestyle risks for colorectal cancer?
Diet of high red and processed meat - breakdown of heme in gut releases N-nitroso chemicals that damage the bowel
Diet of very little fibre - fibre helps expel carcinogens in faeces
Overweight or obese - abnormal metabolites and inflammation promotion, increased levels on insulin
Low levels of exercise
Smoking tobacco - carcinogens, free radicals damage DNA.
Alcohol - acetaldehyde damages DNA
Radiation - such as UV in suntan.
How common is colorectal cancer?
4th most common cancer
Apprx 43,000 people are diagnosed a year
What is FAP? How does it increase the risk of colorectal cancer?
Mutation in APC - loss of function of TSG - on chromosome 5q21
Autosomal dominant pattern
Leads to a loss of
- phosphorylation and ubiquitination of Beta Catenin - so becomes free to act as Transcription factor
- Activation of Myc transcription factors
- initiate proliferative signals even in the absence of Wnt ligand.
results in large number of polyps int he distal colon, each has a small risk of becoming cancerous but the combined risk is high.
How does Lynch syndrome increase the risk of colorectal cancer?
Many genetic mutations are involved
MLH1, MSH2, MSG6, PMS2 -these are responsible for DNA mismatch repair
EPCAM - indirectly inactivate MSH2
Autosomal dominant
Results in small number of polyps in the proximal colon each has a high risk of becoming cancerous
What are the typical symptoms of colorectal cancer - specific to this?
Anaemia leading to fatigue
Abdominal mass
Unexplained weight loss and Abdominal pain - from obstruction
Rectal bleeding
Unexplained weight loss - cachexia (consumption of glucose by cancer cells) and tumour competing for nutrients, promotes gluconeogenesis
Change in bowel habit
Occult blood in faeces
Rectal mass
What are the general symptoms of cancer?
Unexplained weight loss
Appetite loss
Deep vein thrombosis (urogenital, breast, colorectal or lung)
Bleeding
Lumps
Bloating
Fatigue
Pain
What are the stool changes associated with colorectal cancer? Why does this happen?
Change is bowel habits - vary from constipation to diahorrea
Constipation - narrowed lumen as tumour grows into lumen (most common in descending colon napkin ring constriction)
Diahorrea - only liquid pass through narrowed lumen
Tenesmus - rectal tumour,activate stretch receptors and pressure in rectum
Blood - angiogenesis in tumour, new capillaries are fragile and easily burst
Mucus - tumour secreted- enhanced goblet cell function
Narrow ribbon like - narrowed lumen
What causes bright red blood in the rectal bleeding?
Normally from lower down near the rectum
Sign - colorectal cancer, anal fissures, colon polyps, crohns disease, diverticulitis, hemorrhoid, ulcerative colitis
What are the causes of dark brown blood in the faeces?
Upper GIT bleed
Crohns disease, eosophageal cancer, eosophageal carcies, eosophagitis, gastritis, GERD, liver cancer, pancreatic cancer, peptic ulcers, stomach cancer
How can you differentiate the cause of GI bleeds?
Rectal exam - hemorrhoids, anal tumour, anal fissures etc
Colonscopy - IBD, polpys, colorectal cancer
Endoscopy etc
CT scan, MRI, X-ray - identify tumours and collections of fluid
Angiography - make GIT blood vessels easier to see
Radiomuclide scan - radioactive highlight of rbcs in scan
What are hemorrhoids? Cause and clinical presentation
Cause: prolonged constipation - lack of fibre in the diet.
Same as piles
Swollen veins in the anus and lower rectum
Internal and external haemorrhoids are separated by the pectinate line.
Internal: painless bleeding during bowel movements, may prolapse which causes pain and irritation, stain when passing stool.
External: pain or discomfort, itching or irritation, swelling around the anus, bleeding
Can become thrombosed
What is diverticula/ diverticulitis? Cause and clinical presentation
Formation of diverticula – small pouch like protrusions in bowel wall (SC most likely) - areas not covered by Tenai coli.
Diverticulitis – when outgrowths become inflamed
Increased pressure in colon – presses on mucosa and submucosa bubble out through weak spots.
Weaken and burst blood vessels in the wall – leading to bleeding.
Bacteria and food can live in pouches causing infection. - lead to abscess
Can cause bowel obstruction, peritonitis if ruptures and fistulae.
Painless blood in faeces.
Often incidental diagnosis.
What are the treatments for diverticular disease?
Surgery to remove affected part of bowel
Bulk forming laxatives (increase feacal mass to stimulate peristalsis)
Should AVOID stimulate laxatives
What are the treatments for acute diverticulitis?
Oral co-amoxiclav
Anagesia (avpid NSAIDs and opiates)
Nill by mouth or clear liquids only
Follow up in 2 days to review symptoms
Patients with severe symptoms should be admitted to hospital and treated as other abdominal infections or sepsis patients.
What are the symptoms of acute diverticulitis?
Pain and tenderness in the left illiac fossa
Fever
Diarrhoea
Nausea and vomiting
Rectal bleeding
Palpable abdominal mass
Raised inflammatory markers
What are some common complications of diverticula?
Perforation
Peritonitis
Peridiverticula disease
Large haemorrhage requiring blood transfusions
Fistula
Ileus /obstruction
What are some risk factors for diverticulosis?
Increased age
Low fibre diets
Obesity - changes in gut microbiome can exaggerate diverticulosis symptoms
NSAIDs - increased risk of diverticular haemorrhage
What are the major types of polyp?
Pedunculated polyps - head attached by stalk to mucosa
Sessile polyps - relatively flat base attached to colon wall
Flat polyps - height less than one half of diameter
Depressed polyps - more likely high grade dysplasia
What types of polyps are considered to not have malignant potential?
Hyperplastic polyps - normal cellular components and architecture but increased proliferation, no dysplasia and characteristic serrated pattern
Hamartomas - tissue elements normally found there but growing in disorganised mass
Inflammatory pseduopolyps - IBD ulcerations with islands of healing/healed mucosa between
What types of polyps have malignant potential?
Adenomatous polyps
Serrated polyps ( traditional serrated protuberant growth and vilifrom projections sessile serrated serrations extend to crypt base and diated L or inverted T shaped crypts)
What are the different types of adenomatous polyps?
- Tubular adenomas - branching adenomatous in tubular shape, >75% glandular
- Villous adenoma - long extending glands from surface to centre >75% villous
- Tubulocvillous adenomas - mixture of both structures
What type of polyp has the highest malignant potential?
Tubulovillous adenoma
What are the risk factors in a polyp for malignant potential?
Villous histology
Increasing polyp size
High grade dysplasia
What are the histological features of dysplasia in the colon?
Hyperchromatic nuclei
Pseudostratified
Loss of goblet cells
What are the structural features of the villous?
Tubulovillous adenoma
tubulo on the left
Vilous on the right
What are some possible histological features of a polyp in the colon?
Increased mucin aand goblet cells
Hyperplastic with pseudostratified epithelium
Hyperchromatic
High grade dysplasia - poorly defined cell borders and poor representation of original cell structure, basal cells replace epithelium , mitotic cells present closer to the epithelium surface.
What are the histological features of Grad 1 tumour in colon?
Nuclei are uniform in size and shape
Low mitotic activity
Well-formed glandular structures - resembling normal tissue
Minimal abnormalities
Typically confined to the mucosa or with slight extension into the submucosa
What are the histological features of grade 2 colorectal tumours?
Variation in nucleus shape and colour as variation in chromatin
Increased mitotic activity
Glandular structures are somewhat displaced
Some tissue disorganization and dismoplasma (connective tissue growth)
Some clear abnormalities
Extend into submucosa or muscularis
What are the histological features of grade 3 colorectal tumours?
High grade cancer
Nuclei are very different in size and shape and are often hyperchromatic
High mitotic activity
Disrupted glandular structures or absence of recognisable glands
Architecture is highly distorted
Desmosplasia
Lumen of cell may contain necrotic depbris
Muscularis is fully involved and may be extension in adjacent structures
What is the difference between staging and grading of cancer?
Grade - degree of dysplasia/differentiation in the tumour itself (more histological)
Staging - more focused on tumour size, location and spread
How do tumours develop from a polyp, to an adenoma to a carcinoma?
Common pathway
1.Normal epithelium and glandular tissue
2. Loss of APC gene - small adenoma/polyp
3. Oncogenic mutation is Ras gene - large adenoma/polyp
4. Mutation or loss of function in p53 - invasive and malignant colon cancer or adenocarcinoma
What if the Colorectal Cancer Screening test?
Who is it offered to?
Available to all 60-74 year olds, can be requested if older.(expanding to make available from 50yrs)
Sent a faecal immunochemical test to collect a small sample of faeces and send it to a lab
Positive results - indicates presence of human Hb and further testing recommended
Negatove result - no human Hb detected, no need for further testing but screening should be repeated at normal interval.
What is the difference in how gFOBT and FIT work to identify blood in the stool?
gFOBT: Guiac reagent and H202 (hydrogen peroxidase)
React in the presence of heme
Guiac is oxidised
resulting product is blue in colour
FIT: antibodies against human Hb, exposed to stool mixture** (positive result detected by enzyme reaction??)
What are the clinical investigations that may be used when a patient presents with a change in bowel habit?
Colonoscopy
Barium Enema
Rectal exam
Fecal Occult Blood test
Urine dipstick
Full blood test - inflammatory markers and pathogen antigens
What is the preparation for a barium enema?
Light diet - few days before test, low fibre foods only such as clear soups
Take laxatives
Drink plenty of fluids - encourage stool movements and prevent dehydration
How does fibre relate to constipation and diahorrea?
Insoluble fibre, coarse fibre - cause diahorrea
Soluble fibre and fine fibre - cause constipation
What is the difference between Hematemesis, melena and hematochezia?
Haematemesis - Blood in vomit
Melena - black stool due to GI bleeding (upper GI)
Hematochezia - fresh red blood passage in the stool
In relation to dietary restrictions what might a person need to stop in order to have a colonoscopy?
In the week before: Meds containing iron - coats GIT makes harder to see
Aspirin - risk of GI bleed
Meds containing codein phosphate and loperamide - cause constipation
2 days before: reduce meal size, no fibre, no red coloured food or liquids, no alcohol
Day of: stop taking bulk forming laxatives.
Should not eat from 9am day before until after procedure
In relation to dietary restrictions what should a person start doing before their colonoscopy?
2 days before: drink plenty of fluids - aim for 2L a day
1 day before: drink clear fluids only after a light breakfast before 9am
Take a bowel prep solution
What are the different options for bowel prep solutions?
Sodium picosulphate (picolax)
Klean Prep
Moviprep
What is the mechanism of action of picolax?
Is a stimulant laxative - cleanse colon to allow better view in a colonoscopy
Contains sodium picosulphate - is hydrolysed by colonic bacterial enzyme sulfatase into active compound BHPM.
This acts directly on colonic mucosa to stimulate eneteric nervous system hence peristalsis and increase secretion of water.
Inhibits absorption of water and electrolytes
So increases intestinal content and peristalis leading to defecation
Picolax also contains magnesium citrate which acts as an osmotic laxative - to increase water secretion into the bowel lumen.
What method is normally used for bowel cleansing?
Is appointment in the morning recommends: original Senna tables with water, 1st sachet of picolax and 2nd sacchet of picolax the day before roughly 2.5 hours apart
Is appointment in the morning:
Senna tables, with water and first picolax is taken the evening before and second picolax is taken early morning of
What sedation/pain relief if offered in colonscopy? Why?
May be offered sedation
More commonly to have Entonox (gas and air)
In complicated or prolonged investigations may be put under general anaesthetic but this is very rare.
Why might a CT scan be used in colorectal cancer?
Investigate for location of tumours and metastasis. (used to calculate TNM score)
Very good for observing bone and soft tissue differences
Is cheaper and faster (5 mins)
However, can be insensitive to small masses.
Also may be used for CT colonoscopy which is minimally invasive (takes images from many angles and combines to produce an image of the bowel)
Why might an MRI be used in colorectal cancer diagnosis/treatment?
Identify size, location and metastasis of a tumour
Excellenet, very high detail on soft tissue
Is more expensive
Takes longer (15 minutes to 2 hours) depending on the quality of image desired
What clinical roles might be involved in CRC diagnosis, treatment and management?
Specialist screening practitioner
Gastroenterologist
MDT (radiologist, radiographer, oncologist, etc)
Specialist nurse
Surgeon
What is the role of the specialist screening practitioner?
Give patients information to enable them to make appropriate choices for investigation and screening tests - informed consent
Will assess the suitability of patients for investigation
Arrange procedures and follow ups
Record the outcomes of procedures and explain results to patient.
See patients if they receive a positive colorectal cancer screening test
What is the role of a gastroeneterlogist?
Diagnose, manage and treat gastrointesinal (stomach and intestine) and hepatological diseases (liver, pancreas and billary system)
What is the role of the specialist colorectal cancer nurse?
Provide individualised care
Provide support, advice and written information before and after diagnosis
Liase with patient GP and other members of the healthcare team.
Ensures the patients views and wishes are heard at MDT meetings
What is the normal mechanism of Wnt signalling?
Wnt is secreted by stromal cells at the bottom of colonic crypts
Acts locally on intestinal stem cells
Binds to frizzle transmembrane receptor and recruits co-receptor LRP5/6
Results in activation of Dishevelled protein
This acts on the destruction complex
What is the role of the destruction complex is normal active Wnt signalling?
Activated Dishevelled recruits axin to the receptor complex
This causes a loss of structure in the diestruction complex so falls apart
releases Beta catentin - transloactes to the nucleus and functions as a transcription factor
Causes the expression of genes needed for cell proliferation such as c-Myc
What happens to the destruction complex normally in the absence of Wnt signalling?
Axin not recruited
Destruction comples remains intact
GSK3 phosphorylates beta catenin so it is targeted for degradation via ubiquitination
Unable to act as transcription factor, so genes required for cell proliferation are not expressed
In colorectal cancer what is the mutation affecting the destruction complex?
What are its effects?
APC is inactivated (often is a non-sense mutation forming truncated proteins)
APC inactivation deregulates the destruction complex
No longer binds to beta catenin
Beta catenin is not degraded and is released from the destruction complex
Is free to function as a transcription factor, activating cellular proliferation genes such as c-myc
This occurs even in the absence of Wnt signalling.
What is neoadjuvant radiotherapy and chemotherapy?
Why is it used?
Used to decrease the size of a tumour before surgery (main treatment)
Can help shrink metastasis, ensure better functional outcome after surgery as less tissue needs to be removed
Reduce the risk of local reoccurence
Chemotherapy - uses drugs, commonly 5-fluuroracil (inhibits thymidilate synthase)
Radiatherapy - uses high energy rays, cause oxidative stress damaged DNA or may damage plasma membrane leading to cell death
What are the different types of colorectal surgery and when are they used?
Local resection - most common, used for small early stage cancers - use a colonscope to identify polyp, cutting instrument then passed down to remove cancer and surrounding normal border - then passed to histpathologist
Colectomy - removal of all (total) or part of (partial) the bowel. Ends of bowel may be joined together to form an anastomosis or may be brought outside the body to form a stoma.
What are some new treatments being considered for colorectal cancer?
Radiofrequency ablation - thin, needle like probe, release radiofrequency waves to heat tumour and destroy cancerous cells
Cryoablation: probe attached to argon gas to freeze abnormal cells.
What are the different surgical methods of carrying out a colectomy?
open surgery: large incision made down abdomen
Laproscopic surgery: key hole surgery, small incisions made to pass surgical instruments with camera through
Robotic surgery: new technique to advance key hole surgery
What are the side effects of radiotherapy?
Fatigue
Weakness
Nausea and vomitting
Diarrhoea
Sore skin (around site e.g rectum)
Passing more urine (bladder may shrink due to radiotherapy)
What are some side effects of chemotherapy?
Nausea
Weight loss
Fatgiue
Easy bleeding and blood loss
Diarrhoea
Constipation
Hair loss
Lower resistance to infection
What are some side effects/complications of surgery for colorectal cancer?
Anastomotic leak - where the two ends of bowel have been joined together
Bowel not functioning - risk of nervous damage or fragment peristalsis
INfection
Blood clots
Leakage
What factors influence what treatment a patient with colorectal cancer will receive?
Size, type and stage of cacner
Location in colon, rectum or both
Metastasis of cancer
Genetic changes in cancer
Age and general health of patient
Other medical conditions
Other medications that patient is on
Patient preference
Risk benefit of all types of treatment
What is a stoma and a colostomy bag?
Stoma - opening in the abdmone connected to either the urinary or the digestive system
Allos passage of waste out of the body
Pink and red in appearance, may bleed slightly especially in the beginning but this is normal
Attached to a colostomy bag to collect waste.
What are the three different types of stoma?
Colostomy - opening in large intestine
Ileostomy - opening in the small intestine
Urostomy - bypass the bladder, often connect ureters to a section of small intestine then out the abdominal wall
Compare colostomy and ileostomy.
Colostomy - easier to manage, reduced skin excoriation, harder to reverse, likely permanent, thicker effluent, left illiac fossa location
Ileostomy - harder to manage, skin irrtation (more pancreatic enzymes), reversible, temporarily, liquid effluent located in right iliac fossa.
What is the difference between an end stoma and a loop stoma?
End stoma - one bowel opening - when other section of bowel has been removed completely or stitched shut (e,g no distal bowel remains in body)
Loop stoma - when a loop of the bowel is pulled outside the body then cut a proximal and distal bowel section remain, two ends used to make stoma
What are some common indications of a colostomy or ileostomy?
Bowel cancer
Chrons disease
Diverticulitis
Bowel incontinence
Hisrchsprung disease
Obestruction
Bowel polyps
Megacolon
Why might no further treatment be needed in a cancer patients journey?
Complete Cancer remission achieved - no signs or symptoms or detectable signs of cancer.
Recommend continue monitoring and observing the patient
If this is true for five years some doctors might say you are cured.
What are some triggers to seek consultations/medical advice?
Symptom perception - high risk illness
Sanctioning of either Timing - if still ill on monday then ill go or Social pressure - such as such made me come
Occurence of an interpersonal crisis (no longer able to cope
Interference with social or personal activities
Interference with vocational or physical activity
What are some barriers to consultation?
Lack of time
Lack of access to healthcare service
Embarrassment or stigma around health conditions
Lack of knowledge around own health and symptoms
Fear of outcome
Fear or dislike of interaction with medical staff - often associated with a poor previous experience.
What are the four different types of stigma that exist?
Discrediting
Discreditable
Enacted
Felt
What is discrediting stigma?
How might this relate to a stoma?
Stigma that is based on a clearly known or visible condition
For example - worried people will think they are unhygienic because of stoma bag
What is discreditable stigma?
Stimga against something that can be concealable e.g sexual orientation, hidden disability
Stigma against patients with cancer, assume tired or smoker etc
What is enacted stigma?
How does this relate to a stoma?
The experience of unfair treatment by others.
E.g not being invited to friends pool party because they don’t want to see your stoma bag.
What is felt stigma?
How does this relate to a stoma?
The expectation of discrimination that prevents people from talking about their experience and stops them from seeking help
Often feel shame about themselves
How should doctors approach difficult and embarrassing topics with a patient?
Do not be embarrassed or nervous yourself - emotion transfer
Signpost in conversation - make the patient aware and let them prepare for more personal questions
Reflect patients own language - e,g bum, backpassage, rear end etc
Gain an understanding of what the patient already knows and expects to find out
Use a suitable location and atmosphere - e.g quite room, no interruption, maintain eye contact.
Offer suitable support - e.g opportunity to ask questions, provide more resources (website or paper)
What are some of the biological/clincal effects of living with a stoma bag?
Inability to control gas - due to loss or distrubance to GIT bacteria
Foul smell
Parastromal hernia ( intestines push through muscle around the atoma resulting in a noticeable bulge around the skin)
Stoma prolapse - may require further surgery
Stoma blockage - blockage from food, should call GP or stoma nurse immediately, or call 111 is there’s a risk colon could burst
Rectal discharge - mucus from rectum is bowel still intact
Skin problems - irritated, sore, infected
Leakage - try different bags
What are some of the psychosocial complications of having a stoma bag?
Unable to particpate in certain sports - swimming and weight lifting due to risk of damage to stoma orconcern that people may see it
Difficulties in sex life/intimacy
Change in body image
Depression and anxiety
Low self esteem
Loss of independence - need help changing bag or first, or unable to be away from bathroom/home for long.
Diet restrictions - tend to follow normal diet - some people may avoid too much fibre, alcohol or spicy foods to avoid diahorrea.
What are the psychosocial impacts of living with cancer and thinking it might kill you?
Depression, anxiety
Low self esteem
Change in body image
Strain of relationships
Lack of hope in health, disengage in treatment
Lack of interest in everyday activity
Some people see a new meaning of life - clarifies what is important to them and decide to reach out to old friends and family.
The grief of a future that they do not get to have.
What is the mechanism of cachexia in cancer patients?
Increased energy expenditure - from inflammation demand, tumour metabolism, cytokines may also increase basal metabolic rate leading to futile cycling
Decreased energy intake - nausea, vomiting, bowel habit changes/pain, fatigue
Leads to a negative energy balance that promotes muscle catabolism over anabolism causing weight loss.
How is a polyp removed in a colposcopy polypectomy?
Colonscope inserted up rectum used to identify polyp
Solution usually sodium hyaluronate is injected into submucosal layer under lesion to elevate it - less likely to remove underlying health tissue
1. Endscopic mural resection - remove polyp using a snare .
2. Endoscopic submucosal dissection - submucosa and overlying removed using a needle knife
Mrgins will be examined histologically to ensure no cancerous close to edge - that may indicate same cancer cells remain so risk of spread
