L2 : Lower gastrointestinal tract pathology : sporadic and familiar cancer - histology and genetics Flashcards
- Reviewing anatomy and histology of the large bowe, Explaining the different polyps of the bowel, Describing benign and malignant tumours of the bowel, Understanding the pathogenesis of sporadic and familiar bowel tumours
what are we referring to when we talk about the colon
the Cecum, ascending (right) colon, transverse colon, descending (left) colon, sigmoid colon and rectum
which part of the bowel is predominantly involved with water absorption from the faecal material and consolidating the stools.
the large intestine
what happens when the large intestines doesn’t function properly (e.g. partly or completely removed for a number of issues )
The stools are very fluid which can result in dehydration
what is a stoma and when is it needed
a small opening in the abdomen that is used to remove body waste (faeces and urine) into a collection bag. used when the bowels are no longer functional. PEople with stoma can suffer from dehydration as their stools are liquidy
Where are most tumours / colorectal adenocarcinomas found?
on the left side of the large bowel e.g. descending, sigmoid colon and rectum
what percentage of carcinomas are found in the ascenidng colon (right side of the bowel)
around 30%
What is the percentage of colon cancers found in 1. the transverse colon, 2. descending colon, 3. sigmoid colon and 3. Rectum
- Transverse colom = 10%
- Descendig colon = 15%
- sigmoid colon = 25%
- Rectum = 20%
which side of the large intestine is larger and what does this mean for the tumour
the right side is larger which means that the tumour can reach a larger size before it becomes symptomatic ( won’t be obstructing the flow of the stool as much and the stools are more fluid on the side as well)
what happens when the tumour is on the left side of the bowel
there will be changes in bowel habits, obstructive symptoms, changes in colour and bleeding, which allows for earlier detection from warning signs.
what is one of the most common symptoms with a tumour on the left side of the bowel
anaemia from small, persistent bleeding over a long period of time (rather than symptoms from obstruction, you will get symptoms from persistent bleeding)
what is the dirstribution and incidence for colorectal cancer world wide like
colorectal cancer is common all around the world and in different ethnicities but with fewer cases being seen in the content of Africa (although this may change in the future)
What is looked for in stool samples for indicators of colorectal adenocarcinomas?
blood
why aren’t neoplastic cells looked for in cancer screening programmes
because blood traces in stools are a better indicator ( easiest possible type of screening)
what might be a reason for fewer cases in Africa
younger population (disease where the larger majority of patients are older) and underreporting
why isn’t bowel cancer necessarily found early on despite having lots of screening kits offered to high risk people
because there isn’t much uptake (this is unfortunate because the earlier you spot the precursors of the malignant tumour, the better the treatment outcome
why is the incidence of colorectal cancer potentially increasing worldwide
risk factors that associated with colorectal cancer in Western countries are becoming more common in places where the incidence was usually lower e.g. obsesty and diet
histology of the large bowel
- mucosa / glandular layer of epithelium which is arranged into a vili-type structure with finger-like projections which expand into the surface of the bowel.
- submucosa made from connective tissue which is composed of vascular and neuronal structures.
- muscularis exterma (rim) which is the muscular layer which contract to move the stools along the bowel.
- serosa
What does it mean if the tumour is limited to below the muscularis external layer
there is less chances of it metastasing (as soon as it breaks the barrier into the submucosa, there is higher metastatic potential because the submucosa is linked to the lymphatics )
incidence of disease definition
The number of new cases of a condition in a population over a specific time period
what are the two different layers of smooth muscle in the Muscularis externa
inner circular (encircle the bowel wall) and outer longitudinal muscle ( run along the length of the bowel wall). the way these two muscles are arranged in the small and large intestines varry in the small and large intestine.
distribution of disease definition
the spread of a condition across a population.
what is the distribution of colorectal cancer like world wide
It is more commonly found in Western countries and in different ethnicities. the incidence data appears to be better in Africa (but this may change in the future)
what is changing about the age range associated with colorectal cancer
being found in younger patients without any germline mutation ( before it was typically found in people aged 60-70) because of increased obsesity and consumption of a diet which is more linked with colorectal cancer
What type of disease is colorectal cancer
a heterogeneous disease (has multiple causes, symptoms and severity levels)
how does colorectal cancer develop
through the accumulation of genetic and epigenetic alterations / mutations
pathways that when mutated can incease the chance of colorectal carinoma
- pathwways of chromosome instability (CIN)
- microsatellite instability (MSI)
- serrated neoplasia
(some overlap and new pathways continue to be recognised)
which pathway is the most common
the CIN pathway ( chromosome instability) with an incidence of 65-70% of sporadic colorectal tumours
what are some risk factors for colorectal carcinoma
- older age (unmodifiable)
- obesity (becoming more of a prevalent cause of cancer and many different types e.g also breast, endometrail carcinoma…)
- physical inactivity
- alcohol consumption
- inflammatory bowel disease (whilst this can be treated it can’t be completely cured)
- family history of colorectal neoplasia
- polyposis syndromes ( can result in earlier onset e.g. familial adenomatous polyposis)
- adenomas of the bowel
what are polyposis syndromes
conditions that cause polyps in the gastrointestinal tract
what are some examples of polyposis syndromes
- familial adenomatois polypsos and variants (APC gene)
- lynch syndrome and variants (MLH1, MSH2, MSH6 and PMS2 genes - disfunction in the missmatch repair system and it is linked to many types of cancers e.g. gynaecological cancer)
- juvenile polypsosis (SMAD4, PTEN genes)
- Peutz-Jeghers syndrome (STK11 gene)
what are some dietry risk factors for colorectal carcinoma
- low vegetable fibre (prolongs the transit time which increases the toxin contact with the colorectal mucosa and alters the bacterial flora)
- high refined carbohydrates
- Increased beef consumption (enhances synthesis of bile acids by the liver which can be converted into carcinogens by the bile acids
- decreased vitamins A/C/E
- ultra processed foods
What is an inescabable ( one of the most important) risk factor in the development of a carcinoma?
an adenocarcinoma
what are polyps and which one has the highest risk of becoming cnacerous
polyps are abnormal growth on the colon lining, and while benign some in particular e.g. adenomatous (and serrated) polyps have a higher risk of becoming cancerous if not removed…… 95% of colorectal adenocarcinomas arise from polyps
what is an adenomatous polyps
benign epithelial tumour formed from glandular structures of the bowel which is the most common growth found in the lining of the colon / rectum , making up about 70% of all colon polyps (can become malignant if left unattended)
what are risk factors for adenomatous polyps
- obesity
- smoking
- oestrogen hormone replacement therapy
- alcohol
- age (starts developing around the age of 50/60)
(more or less the same as before)
*poyposis syndromes - dietry risk factors
how long does it take for an adenomatous polyps to potentially develop into cancer
10-15 years
What is a factor which always leads to adenomatous polyps
presence of an adenoma
is colorectal carcinoma a multifactoral disease?
YEs - not just one specific factor causing it ( unless it is a genetic mutation) but many factors all increasing the risk and playing a role in its development
What is an adenoma
a benign tumour formed from glandular structures in epithelial tissue.
what are some factors that can decrease the risk of adenomatous polyps
- anti inflammatory drugs
- aspirin
- diet high in folate, calcium or fibre
what is the general definition for a polyp
protuberant (mushroom like) growth of epithelial or mesenchymal origin (most common), benign or malignant. usually ASYMTOMATIC
what are some types of polyps
- Inflammatory (pseudopolyps and benign lymphoid polyps)
- Hamartomatous (juvenile polyps and Peutz-Jegher)
- Neoplastic (epithelial) (adenoma and adenocarcinoma)
- Neoplastic (mesenchymal - fats and smooth muscle) (lipoma and leiomyoma)
- other (hyperplastic)
what is a hamartomatous polyp made from
formed from benign tissue which has accumulated in a specific area (not necessarily going to be metastatic or malignant but could be an indication of a condition e.g. juvenile polp or Peutz-Jegher syndrome)
hamartomatous polyps morpholoy
benign tumour like lesion which made up of 2+ differentiated tissue elements, normally present in the organ
Juvenile polyps (hamartomatous polyp) arises in what age and from what mutation
in paediatrics (age 8), 30% of which is due to a germline mutation in the SMAD4 gene. (80% of the time these polyps are found in the rectum)
what is the role of SMAD4
transcription factor and tumour suppressor that plays a key role in regulating cell growth and division through the TGF-B pathway) (found on 18q21-22)
Peutz-Jegher (hamartomatous polyp) presentation
causes pigmentation of oral mucosa, lips, palms and genitalia, and causes polyps to form in different areas e.g. small and large bowel, stomach, lungs and bladder
when do adenomas develop (Neoplastic polyps)
when mechanisms controlling DNA repair and cell proliferation are altered in a tissue with constant epithelial renewal. This means that as mutant cells move up and differentiate, the process of apoptosis is disrupted. This allos for adenomas to form, increase in size, and accumulate dysplastic features (eventually with invasive potential) over time.
three main architectures for adenomas (neoplastic polyps)
- Tubular adenoma (less than 20%) - closley packed structure which is most simple and similar to normal structure
- Tubular-villous adenoma (20-80%)
- Villous adenoma ( more than 80% - predominantely villous elements and is the most complex structure.
On top of this adenomas can be pedonculated and sessile
why are the most dysplastic changes typically found in villous adenomas
because they tend to have been there for longer which gives them more time to aquire a bigger conformation.
what is the sturcture like for a pedunculated polyps
stalk with a head on top
what is the structure like for a sessile polyps
a flat polyps with a broader base
how does the polyps being pedonuclated or sessile affect how it is removed
pedonuclated polyps are quite easy to manage / remove as you just cut it at the stalk, whilst removing a sessile polyps with a broad base can be difficult to remove endoscopically.
what is the predominant cause of blood in stools when people come into the GP in a panic
haemorroids in the lower bowels which is very minimal and not much cause for concern.
what do you run tests to search for in the stool
occult / hidden blood
where should mitosis take place in the normal colorectal mucosa
at the bottom of the crypt ( if you see mitosis occuring further up this can be a cause for concern - not fully differentiated)
what marks the transition from normal to hyperproliferative epithelium / adenoma carcinoma
sequential alterations in key growth regulatory genes (there are associations between specific genetic alterations with advancing histologic features
what does APC gene stand for
adenomatous polypsosis coli gene
what do mutations in the adenomatous polyposis coli (APC) gene give rise to ( in adenoma-carcinoma)
gives rise to traditional adenomas
what do mutations in the BRAF oncogene generate ( in adenoma-carcinoma)
generates serrated polyps respectively
what are the three pathways that lead to adenoma carcinoma and what are they linked to
- Chromosomal instability pathway - linked to APC loss (early Adenoa) , K-ras and other oncogene dysregulation (late adenoma) and TP53 inactivation (Cancer)
- Microsatellite instability (MSI) pathway - linked to APC loss and failure of MMR genes (Adenoma) as well as TGFB and BAX mutations (Cancer)
- Serrated pathway - linked to a BRAF mutation and DNA methylation (serrated adenoma) as well as TP53, p16 inactivation and methylation / mutation of other genes ( cancer)
what is a serrated adenoma
a type of precancerous polyp in the colon or rectum that appears saw-toothed under a microscope and can potentially progress to cancer if not removed but can be easily mistaken / overlooked because it doesnt form massive lesions (BRAF mutations are often found in serrated carcinoma)
which gene is modified in patients with familiar adenomatous polyposis
APC ( in the name - adenomatous polypsosis coli gene)
what do MMR genes do
DNA repair genes that help maintain genomic stability
TP53 function
P53 is a protein that regulates DNA repair and cell division, and is involved in apoptosis, cell cycle arrest or senescence by either producing BAX, p21 or p16 respectively
Why is TP53 mutation important in cancer diagnosis?
Some tumours are defined by TP53 mutations and its timing varies ( with it being a mutation early on in the tumour or later on –> although this can be confusing)
What happens if TP53 is mutated early on vs later in cancer development?
If it is mutated earlier on this leads to a more aggressive and therapy resistant tumour. Whilst if TP53 is mutated later on, the tumour typically progresses to an invasive carcinoma at this stage
will all adenomas head in the direction of an adenocarcinoma
no as the host response can keep it under bay sometimes
what sort of mutations do you find in patients with APC mutations e.g. lynch syndrome
- an accumulation of B-catenin in the nuclei (usually found in the cytoplasm but enters the nuclei when it is made in excess) which interfers with the WNT signalling responsible for regulating epithalial proliferation. this activates oncogenes e.g. MYC,CCND1,VEGF and the peroxisome prliferator activated receptor delta (PPARdelta) gene
- leads to adenoma and low grade dysplasia - accumulation of mutations in other genes e.g. KRAS and SMAD4
- signs of miss match repair (MMR) deficiency might appear - dysregulation in TP53
- invasive fearures appear in the later stages
- overall you would start seeing the adenoma progress and eventually become malignany
What is BRAF responsible for?
The BRAF gene provides instructions for a protein that plays a crucial role in cell growth and division, specifically through the RAS/MAPK signaling pathway, and mutations in this gene can lead to uncontrolled cell growth
what sort of mutations do you find in patients with a BRAF mutation
- BRAF
- methylation of tumour suppressor genes
- invasion
what sort of adenoma is formed from a BRAF mutation
a serrated adenoma which is more difficult to spot ( smaller)
what does the CIN pathway stand for
The chromosomal instability pathway
what is the most common mutation in the CIN pathway
Loss of APC activity ( this results in nuclear translocation of B-catenin and activation of the Wnt signalling pathway with activation of oncogenes e.g. MYC, CCND1 VEGF and PPARdelta genes)
what are the observed chromosomal changes in carcinomas caused by the CIN pathway ( chromosome instability)
somatic copy number alteration - aneuploidy, deletions, insertions, amplifications or loss of heterozygosity
What drives the CIN (Chromosome Instability) pathway?
defects in chromosomal segregation ( control sister chromatid separtion), disrupted cell senescence (aging from telomere shortening) and genomic reorganisation, dysfunctional DNA damage-response and loss of heterozygosity (LOH) at a tumour suppressor genes
what is the issue with p53 and finding the cause of cancer
in some cancers the P53 is the early stage mutation, whilst in others it is the later stage mutation which makes it harder to identify and means that the right diagnosis can be missed which is required for treatment
what is the incidence of the MSI pathway ( hypermutable pathway)
15% of sporadic colorectal tumours and all colorectal tumours associated with Lynch syndrome (this is the most common hereditary colon cancer syndrome caused by germline mutations in DNA MMR genes)
what are the genetic abnormalities associated with the MSI pathway ( hypermutable pathway)
often there are motations in somatic DNA base pairs, DNA MMR genes (MLH1, MSH2, MSH6, PMS2) or EPCAM ( protein that regulates MSH2) which causes instability within microsatellite regions. errors accumulate which means DNA polymerase can;t bind to the repeating genome sequences as well
what gives the hypermutation phenotype in the MSI pathway ( hypermutable pathway)
the fact that inadequate number of bases can result in frameshift mutations that can truncate or produce a non functional protein. Usually MMR genes will recognise mistakes in mismatch repairs and perform DNA excision repair before the daughter strand replicates, although in tumour cells with the MSI phenotype, MMR is disfunctional allowing them to replicate and accumulate mutations
why is it so important to identify patients with a hypermutation phenotype tumour
because these patients tend to respond better to treatments and 35-50% of MSI tumours are caused by APC mutations which allows for a better understanding of what treatment is needed
what is the rarest type of tumour
the serrated neoplasia pathway
what is the incidence of the serrated neoplasia pathway
15% of colorectal carcinomas
Serrated neoplasia pathway development and appearance
they develop within of 3-5 years (which is faster than those from the APC pathway and means the recommended surveillance perioid needs to be closer) and are believed to arise from the serrated pathway. they are smaller in size and flat which makes them less obvious to see
what are the genetic abnormalities that are associated with the serrated neoplasia pathway
activating mutation in BRAF which results in the consitutuve activation of the mitogen activated kinase ERK pathway and uncontrolled cell division
Then the development of tumours occurs via 2 different routes
1. route which converges with the MIS pathway where a mutation in the MMR gene results in the MSI high phenotype
2. route which involves the acquisation of a TP53 mutation and activation of oncogenic pathways e.g. Wnt signaling, TGFB signaling and epithelial to mesenchumal transition (results in MSS tumours rather than MSI)
serrated adenoma appearance under a microscope
sawtooth serrated epithelium with lots of mucin ( similar to hyperplastic polyps)
characteristics of serrated adenoma
It can spread laterally within the crypt base (which means it tends to spread rather than cause vertical growth)
colorectal adenocarcinoma spread around the world
it is the most common gastrointestinal tumour in the USA, whilst it is less common in Africa, Asia and parts of South America
what percentage of the US population are affected by colorectal adenocarcinoma in their lifetime and who does it mostly affect
5% of US population will be affected especially in men. it is the most common cause of cancer-related death in nonsmokers and peaks in those aged 60-80 (less than 20% of cases are in those over 50 (although this is becoming more common) and it rarely occurs in patients younger than 40 exceptif they have a predisposing syndrome)
what ages are bowel cancer screenings offered to?
to everyone aged 54 to 74 every 2 years.
different degrees of cellular atypia in colorectal adenocarcinoma
- well or moderately differentiated adenocarcinoma with gland-forming carcinoma with marked desmoplasia
-the glands often don’t produce that much mucin anymore and often filled with necrotic debris in both primary and metastatic sites - inflammatory cells and scattered neuroendocrine cells are common intramural venous invasion that may be easier to identify
what possible treatment is being used for colorectal adenocarcinomas
immunotherapy which uses the body’s immune system to target and destroy cancer cells. In colorectal cancer, immune checkpoint inhibitors, like those targeting the PD-L1 pathway, are common so can be used as a target. only issue is that there are many side effects that come with this and would be based on the concept of the immune system fighting against the cancer
proportion of colorectal adenocarcinomas that fall under the grading of
1. well differentiated
2. moderately differentiated
3. poorly differentiated
- well differentiated : 15-20% of all carcinomas
- Moderalty differentiated : 60-70% of all carcinomas
- poorly differentiated : 15-20% of all carcinomas
how are the colorectal adenocarcinomas graded
through looking at histology slides one can see how differentiated the cells are, and then how far the tumour has spread can be analysed (both inside and outside of the bowel depending on how much tissue is collected). the size of the lymph nodes around the bowel is also another obvious predictor of the tumours behavior
screening methods used to identify tumours
- Faecal occult bloods (many other reasons why there could be blood in the stool which would give a false positives)
- colonoscopy to see if we find a specific lesion after a positive test
- Flexible sigmoidoscopy
- Genetic testing (MMR testing to identify immunohistochemistry
what are some reasons for why you could find blood in the stool
by having an inflammatory bowel disease, Diverticular disease, infections, ischemic changes of the bowel…..
what is the concern when dealing with conditions such as lynch syndrome
these patients typically have many polyps - do you remove all of them or the entire bowel….
how many genetic abnormalities cause lyncg syndorme
dominant autosomal condition which causes abnormalities in 4 mismatch repair genes ( microsatelite instability)
what is used to test if someone has lynch syndrome
genetic tests
Familial adenomatous polyposis (FAP)
A relatively rare disease that accorus in ~1:8000 individuals. It causes the entire colon to be coated with polyps (1000s) over time and without intervention will eventually result in the development of colon cancer.
what causes Familial adenomatous polyposis (FAP)
mutations in the APC gene (adenomatous polyposis coli), a tumour suppressor gene involved in cell cycle control and downregulation of B-catenin through the Wnt signaling pathway
how long does it take for someone with familial adenomatous polyposis (FAP) to have their entire colon coated and for at least one to become an adenocarcinoma
it will take 15 years for them to develop and then by their mid 20s / 30s at least one will be an adenocarcinoma (might have to have their bowel removed and get a stoma inserted)
