Colorectal Polyps and Neoplasms Flashcards
Rectal bleeding is bright red blood passed around or with the stool. It is extremely common and becomes more so with age.
Give a differential diagnosis for a patient with rectal bleeding
- haemorrhoids
- colorectal polyps or cancer
- anal fissures
- anal fistula
- IBD - crohn’s and UC
- diverticulitis
- trauma
- coagulopathies
- angiodysplasia
- anorectal varices
- proctitis
- intussusception
Constipation refers to bowels which open infrequently, and the faeces are hard and often cause pain during defacation.
Give a differential diagnosis for constipation
- general: pregnancy, inadequate fibre/diet, dehydration
- metabolic/endocrine: DM, hypercalcaemia, hypothyroidism, porphyria
- functional: dyschezia, IBS
- drugs: opiates, aspirin, anticholinergics, ca-ch blockers, antidepressants
- adynamic bowel: spinal cord lesions, Parkinson’s, Hirschprung’s, senility, myxoedema
- GI: obstruction, colonic disease (carcinoma, diverticular), aganglionisis, anal fissure, prolapsed piles
- defecatory disorders: rectal prolapse/intussusceptions, rectocoele, pelvic floor dysfunction, megarectum
What are adenomatous polyps?
- colorectal adenomas dervied from epithelial cells lining in mucosa
- v common, incidence increases w age
- at 60 years they are found in approx 20% of population
- adenomas may be sporadic or familial
- familal adenomas occur in syndromes such as FAP
If a patient is found to have a polyp, does that mean they have cancer?
- from naked-eye appearance: mass projecting from mucosal surface
- term ‘polyp’ tells us nothing about its biological behaviour
- may be benign, premalignant or malignant
What is meant by the following terms to describe a polyp?
- pedunculated
- sessile
- tubular
- villous
- tubulovillous
- pedunculated - attached to the normal mucosa by a stalk
- sessile - atttached to normal mucosa by broad base
- tubular - composed of tubular structures when looked at down microscope
- villous - composed of finger-like projections when looked at down microscope
- tubulovillous - contains mixture of tubular + villous architectures
Polyps are predominantly asymptomatic. However what are some clinical features that might be mentioned by a patient with polyps?
- rectal bleeding
- mucus discharges
- tenesmus
- changes in bowel habits, particularly urgency
- signs of anaemia
- fatigue
- sessile villous adenomas present with profuse diarrhoea and hypokalaemia
Many polyps are picked up incidentally when imaging is performed for other reasons
Are colorectal adenomas cancerous?
- no - they are dysplastic by definition
- pre-malignant, so left untreated may progress to adenocarcinoma
- in the GI tract, dyplasia is graded as low or high
Majority of adenomas will not progress to adenocarcinoma during a person’s lifetime. What are features associatd with a greater risk of progression?
- high grade dysplasia (rather than low grade)
- increasing size
- histological type (villous is higher risk than tubular)
Why is the term ‘adenoma’ in the GI tract confusing?
- in most contexts, an adenoma is a benign tumour of glandular epithelium which does not have the potential to become cancer (ie. adenomas are not premalignant)
- however in GI tract, term ‘adenoma’ is used for premalignant lesions
- by definition adenomas in GI tract are dysplastic (premalignant)
About 70% of colorectal cancers arise as a result of a (3) stepwise progression. What is this progression?
normal mucosa -> adenoma -> invasive adenocarcinoma
What is the progession to invasive adenocarcinoma due to?
accumulation of mutations in a number of critical growth-regulating genes:
- inappropriate activation of proto-oncogenes (eg. K-ras, c-myc)
- inactivation of tumour suppressor genes (eg. APC, TP53) - remember that both copies of tumour suppressor genes must be inactivated (‘two-hit’ hypothesis) since if only one allele for the gene is damaged, the second can still produce the correct protein
the exact order in which these mutations are acquired may very; it is the accumulation of mutations rather than their occurrence in a specific order which is most critical
Hence, use examples of genes to describe the process occurring from normal colon to carcinoma
What are the two pathways for developing colorectal cancers?
- 70%: chromosomal instability pathway (=adenoma-carcinoma pathway)
- 30%: microsatellite instability (MSI) pathway (= serrated pathway)
The large majority of pts who develop colorectal cancer through the adenoma-carcinoma pathway do so by acquiring sporadic mutations during life. These pts do not have a familial syndrome.
A small minority of pts who develop colorectal cancer through the adenoma-carcinoma pathway have a germline mutation in what gene?
- APC gene
- these pts have familial adenomatous polyposis
What is familial adenomatous polyposis?
- have germline mutation in one allele of APC gene
- other allele is normal
- FAP is a familial syndrome, inherited (autosomal dominant)
- although de novo germline mutations may account for up to 25% of cases
- affects 1 in 10,000
How/why do patients with FAP develop cancer?
- by following adenoma-carcinoma pathway sequence
- however, bc they have a germline mutation in the APC gene, every single cell in the body has the mutation (ie. every cell is already one step further along the pathway than in non-FAP patients)
- they develop hundreds of adenomatous polyps throughout the large intestine during their teens + 20s - t_he risk of development of an adenocarcinoma in one of these polyps is almost 100%_ by the age of about 40
- prophylactic panproctocolectomy is usually advised in these pts
FAP is thought to account for less than 1% of colorectal cancers (it is less common than Lynch syndrome). What is the mean age of developing colorectal cancer in FAP patients?
- 39 - compared to 70 in sporadic cases
FAP confers an increased risk of developing small intestinal adenomas/carcinomas - where, in particular?
- ampulla of Vater
What extra-intestinal manifestations is FAP associated with?
- desmoid tumours (locally aggressive tumor that does not metastasize)
- thyroid carcinomas
- osteomas (non-cancerous bony growths)
- congenital hypertrophy of the retinal pigmented epithelium
Fairly recently it has been recognised that ~30% cancers arise from an alternative pathway. What is this pathway?
- Microsatellite instability pathway (=serrated pathway)
- cancers arise from serrated polyps (also termed serrated “lesions”)
- called serrated as they have a serrated appearance microscopically
These serrated polyps may acquire sporadic mutations in a number of key genes, such as?
- activation of BRAF (an oncogene)
- silencing of mismatch repair genes (eg. MLH1, MSH2) due to hypermethylation of promotors. This results in microsatellite instability (MSI) - insertion or deletion of nucleotides within repeated sequences of DNA.
the accumulation of these mutations may lead to development of carcinoma
What is Lynch syndrome?
- familial syndrome, inherited (autosomal dominant)
- up to 5% of cases may be due to de novo mutations
- have germline mutation in one allele of a DNA mismatch repair gene
- other allele is normal
- a ‘second hit’ (eg. promotor methylation, second mutation) is present in the genome of tumours in patients with LS
Lynch syndrome: The order of frequency for germline mutation in the DNA mismatch repair gene is: MSH6 (most common), MSH2, MLH1, PMS2. What are the mismatch repair genes responsible for?
- recognising + repairing mistakes in DNA transcription
- which occur particualrly in areas of repeat DNA sequences (microsatellites) where DNA polymerases have a tendency to ‘slip’, either inserting extra or removing repeats.
- in the case of mononucleotide and dinucleotide repeat sequences this often leads to a frameshift mutation, resulting in a shortened non-functional protein
What cancers are patients with Lynch syndrome at risk of developing?
- Colorectal
- Endometrial - in women with LS, this is more common than colorectal cancer + it is more often the first (sentinel) cancer they develop
- Stomach
- Pancreatic
- Small bowel
- Ureter
- Renal pelvic
- Ovarian
