10.1 GI malignancies Flashcards
What is Barrets Oesophagus?
What type of carsinoma is it associated with?
How is it treated?
As a result of GORD the stratified squamous epithelium of the oesophagus undergoes a metaplastic change to become simple columnar (resembles epithelium of the stomach)
Associated with development of adenocarcinoma due to the stepwise accumulation of genetic abnormalities
Treatment: treatment for reflux disease
Describe the purpose of the screening programme in place for Barrets oesophagus?
The aim of the surveillance programme is to see if dysplasia is developing in Barrett’s oesophagus and to pick up early adenocarcinomas.
What are the 2 most common types of malignancy in the oesophagus?
Give 3 other types of malignant tumours that can occur in the oesophagus?
1) Adenocarcinoma carcinoma (most common)
2) Squamous cell carcinoma
Others: Lymphomas, melanomas, sarcomas
Give 4 key risk factors of adenocarcinomas and sqaumous cell carcinoma and oesophageal malignancies
BIGGEST ones are:
Adenocarcinoma: Gastro oeophageal reflux disease
Sqamous cell carcinoma: Alcohol and tobacco use
In which region of the oesophagus are squamous cell carcinomas most common?
What is their gross appearance?
Give one predisposing pathology
Location: Most common in the middle third (rare in the upper third and less frequent in lower third)
Gross appearance: Exophytic, ulcerating, infiltrating, stricture
Predisposition: dysplasia of the squamous epithelium
In which region of the oesophagus are Adenocarcinomas most common and why?
What is their gross appearance?
Give one predisposing pathology
Location: Distal third because this is where GERD most commonly affects
Gross appearance: mostly ulcerating and stricturing (less likely to exophytic)
Predisposition: Barrett’s oesophagus
What does exophytic mean and is this more likley in Sqamous cell or Adenocarcinomas?
Tending to grow outward beyond the surface epithelium from which it originates
More common in Sqamous cell carcinomas
How does oesophageal cancer present? (2)
Are there differences in presentation between the type of carcinoma and why?
Dysphagia and weight loss
Yes: Adenocarcinomas tend to present with a long history of dyspepsia, vomiting, anaemia and bleeding
Give 4 investigations for management of an oesphageal malignancy and when is each most useful
1) Endoscopy: most commonly used as first line
2) Barium swallow
3) Endoscopic Ultrasound (EUS): good for identification of small early stage tumours
4) CT and PET CTs: for staging purposes
How do we stage tumours and what is this good for?
TNM: best prognostic indicator
What can be said about the prognosis of oesophageal carcinoma if it:
1) Is an early mucosa confined tumours
2) Has invaded the muscularis propria (muscle wall)
Compare SSC and Adeno Ca
1) Early mucosa confined tumours: GOOD prognosis
* SSC = 70% and Adeno Ca = 80-100%
2) Has invaded the muscularis propria: survival rates rapidly decline
* 50% = SCC and Adeno Ca = 10-20%
Give 4 available treatments for oesophageal carcinomas and explain when they are best used
Give 3 available treatments for advanced disease/palliative care
1) oesophagectomy: good if tumour is advanced but not spread to vital structures
2) endoscopic mucosal resection (EMR) and radioablation: good for mucosa confined tumours
3) neoadjuvant chemoradio therapy: given for advanced tumours to achieve complete surgical excision
4) adjuvant chemotherapy: for metastatic disease (targeted treatments, Her2 treatment for Adeno Ca)
Advanced disease (palliative care)
- stenting to enable swallowing
- palliative brachytherapy and radiotherapy
- radiotherapy
Are gastric cancers more common in M or W?
Is there a high genetic component?
M > W
Yes there is a genetic component: associated with germline mutations of e cadherin
What is the most common site for Gastric cancer to occur?
Most common site is the cardia of the stomach
Much smaller proportions in the pyloric antrum and body
Give 2 infections highly associated with development of Gastric cancer?
Give 6 other risk factors
Infection with Helicobacter Pylori or EBV
Other risk factors:
- pernicious anaemia and autoimmune gastritis
- gastric ulcers
- previous gastric surgery
- diet (low fruit and veg + high salt or smoked foods)
- smoking
- genetic factors
Why can smoked food increase risk of cancer?
Smoked food contain N-nitroso compounds and benzopyrene which both act as both an initiator and promoter
Why cancer is said to be “multistep and multifactorial” what do that mean?
Multifactorial means that there are a variety of factors that increase/decrease your risk of developing cancer eg:
- Intrinsic factors: age, gender, herditary
- Extrinsin factors: high BMI, fruit and veg intake, physical activity, tobacco and alcohol use, environmental factors (chemicals, radiation, viruses)
Multistep means that multiple mutations are required in enough cells before it can become fully malignant
- Initiator + progression occur through exposure to multiple promoters = fullt malignant neoplasm
Describe how normal mucosa progressing to chronic gastritis can eventually lead to development of a Carcinoma?
Process is multistep and multifactoral
Describe how helicobacter pylori can lead to development of carcinoma
Helicobacter pylori causes chronic inflammation of the mucosal lining which can lead to intestinal metaplasia of the stomach.
This can then progress to dysplasia and then neoplasia
CagA ***
Give 3 common macrscopic features of Gastric cancer
1) Fungating
2) Ulcerating
3) Infiltrative (eg. linitis plastica)
Give 2 microscopic features of a gastric adenocarcinoma and state an infection that commonly causes each
1) Intestinal variable degree of gland formation (commonly associated with H pylori)
2) Diffuse single cells and small groups, signet ring cells- linitis plastica (common in younger age group and EBV infection)
What is linitis plastica and what type of cancer usually causes this?
What is the macroscopic appearance described as and explain what microcopic feature causes this?
Linitis plastica is a type of adenocarcinoma
Macroscopic: there is little mucosal lesion seen, tumour infiltrates entire area resulting in entire stomach becoming thickened which is seen on both radiology and endoscopy
- Reffered to as a “Leather bottled stomach”
Microscopic: this leather bottled appearance is due to the presence of signet ring cells. These are single cells containing lots of mucin in the centre, which pushes the nuclei to the peripheries causing it to adapt a ring like appearance
Give 3 common presentations of gastric cancer and 3 common investigations
Clinical features: symptoms often vague
- epigastric pain
- vomiting
- weight loss
Investigations
- endoscopy
- biopsy
- barium studies
What is meant by “early gastric cancer” vs “advanced gastric cancer”?
Early: confined to mucosa/sub-mucosa (good prognosis)
Advanced: further spread (5 year survival = 10% but with curative surgery 50%)
Give 4 ways in which gastric cancer can spread
1) direct extension to adjacent organs (pancreas, liver, spleen, transverse colon, greater omentum)
2) Lymphatic spread is usually to regional lymph nodes
* can occasionally present later in the left supraclavicular lymph node (Virchow’s node)
3) Haematogenous spread most commonly to liver
* can also spread to lung peritoneum, adrenals, ovary
4) Transcoelomic spread within the abdominal cavity, often to the peritoneum and ovaries (Krukenberg tumours)
Give 3 treatments for gastric cancers
1) surgery
2) chemotherapy
3) Herceptin (for individuals that are Her2 positive)
What is the most common type of GI lymphoma?
Which infection is it strongly associated with it?
How do can we treat and compare prognosis to gastric cancer
Gastric Lymphoma: tumour of the lymphocytes
Usually a low-grade lesion and has a strong association with H. pylori. Hence, eradication of H. pylori genrally leads to regression of tumour
Rarley but occasionally tumour may be deeply infiltrating low grade or high grade lymphomas which require treatment with chemotherapy and radiotherapy
Prognosis much better than gastric cancer
How common are GI Stromal tumours and are they more likley to be benign or metastatic?
Where do they most commonly occur and what cell type do these metaplasias arise from?
What gene is expressed that can be used as a cancer marker?
How is it treated?
These are UNcommon (GIST) and often unpredictable, can be benign or malignant (depends on site, size, mitoses, other necrosis)
Most common site is the stomach, derived from interstitial cells of Cajal. These tumours express the C-kit gene (CD117) which can be used as a cancer marker on histological examination.
Specific targeted treatment using Imatinib
If a GIST is detected in the SI what can be said about it?
GIST tumours can also occur in the SI and if they occur here there is a higher risk of malignancy
How common are small intestine tumours and are they more likley to benign or metastatic?
What type are they most likley to be?
Small intestine tumours are rare and can be either benign OR metastatic
Lymphomas and neuroendocrine tumours are more common in the SI compared to adenocarcinomas
What is a neuroendocrine tumour?
Neuroendocrine tumors are neoplasms that arise from cells of the endocrine(hormonal) and nervous systems. This means they can secrete substances such as hormones
They most commonly occur in the small intestine and are often known as carcinoid tumors
These are usually Incidental findings during evaluation of non specific symptoms (eg. during apendicitis) Hence, the symptoms produced are dependant on location, size and other tumour specific factors
Describe the 4 most common locations of a neuroendocrine tumour
What is their classification based on?
1) small intestine (38%)
2) rectum(34%)
3) colon( 16%)
4) stomach(10%)
Rare in the oesophagus and anus.
Their classification based on tumour biology: tumour size, tumour site, proliferation rate
Describe the various presentations of a neuroendocrine and why
1) symptoms due to local mass effect
* if tumour grows it can produce obstruction, resulting in obstructive symptoms
2) symptoms due to substances secreted by tumour (eg. hormones)
* most commonly present as abdominal pain, diarrhoea, flushing
3) symptoms as a result of tumour fibrosis
* substances secreted can lead to fibrosis of surrounding tissue, which can cause obstructive symptoms
4) primary tumour can be silent and present later with metastasis (carcinoid syndrome)
- symptoms relating to where tumour has metastisised
- This is the most common cause of symtoms produced
What is Carcinoid syndrome?
Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors (neuroendocrine tumour of the SI)
The syndrome includes flushing and diarrhea, and occasioanlly heart failure, vomiting and bronchoconstriction.
In neuroendocrine tumours why is it more likly to only produce symptoms once metastisis has occured?
During the primary stage, when substances are secreted by the tumour in the SI they directly enter the liver through the portal vein. Here they are converted into metabolites which are inactive and do not produce symptoms. Hence, often do not produce symptoms
However, if the tumour metastasises to other parts of the body, in particular to the liver itself the substances get secreted directly into the systemic circulation (these are still active substances) which is why symptoms may only appear at this time
What is treatment of a neuroendocrine tumour?
- SURVEILLANCE
- Endoscopic removal
- Surgery
- If hepatic metastasis: resection, radiofrequency ablation/chemoembolisation
Why may cytotoxic chemotherapy not be effective in neuroendocrine tumours?
Because most of these tumours have a very low proliferation rate-cytotoxic chemotherapy may not be effective
What does the “adenoma-carcinoma sequence” show and how was it illustrated?
What phase of cancer evolution is this?
The AC sequence shows that most malignant tumours require alterations affecting a combination of multiple TS genes and proto-oncogenes.
It was illustrated by colon carcinoma, which usually starts as a colonic adenoma, from which arises a carcinoma.
This steady accumulation of multiple mutations is called cancer progression
Cancer evolves by what 3 steps?
1) Initiation
2) promotion
3) progression
Define an Adenoma and an Adenocarcinoma
Adenomas: benign pre-malignant tumours (have the potential to become malignant)
Adenocarcinoma: invasive carcinoma that is malignant
What is the most common invasive carcinoma of the large intestine?
Adenocarcinoma
Give 2 genetic conditions that predispose one to developing adenomas and state why
Explain each condition inlcuding its inherritance
Both cause predisposition to development of Adenomas
1) Familial adenomatous polyposis
- many adenomatous polyps form mainly in the epithelium of the large intestine
- autosomal dominant
- mutation on chromosome 5
2) Gardner’s syndrome (also known as familial colorectal polyposis)
- subtype of FAP
- autosomal dominant
- characterized by the presence of multiple polyps in the colon together AND tumors of the bone and soft tisse
How are Adenomas classified and give the 3 types
Classified based on the presence of villi
More villi on adenoma = greater the risk of becoming an adenocarcinoma
Three types on histology:
1) Tubular adenoma
2) Tubulovillous adenoma (>20% villous)
3) Villous adenoma (> 80% villous)
give 4 factors that determine the risk of an adenoma developing into malignancy (adenocarsinoma)
Detection of these factors is useful for what?
1) Type
2) Dysplasia
* increases risk to 27% if high grade dysplasia
3) Polyp size
* polyps>20mm = higher incidence of invasive carcinomas 35% to 53%
4) Number of polyps
Detection of these lesions form the basis of colorectal screening
What are the 2 main bowel cancer screeing programes in the UK?
Who are they eligible to and what specific test is used?
1) Bowel cancer screening program
- 70-75 year old women
- Faecal occult blood *FIT(Faecal Immunochemical testing)
2) Bowel scope screening programme (subset of above)
- 55 year olds
- Flexible sigmoidoscopy that examines the L side of colon
Describe the incidence, distribution between sexes and disease progressionn of colorectal adenocarcinomas
Incidence highest in elderly (>70 =300/100,000)
Same incidence between male and females (rectal carcinomas slightly more common in men)
disease has slow progression, not often diagnosed until disease has spread to lymph nodes or elsewhere
Give 6 factors that increase risk of colorectal adenocarsinoma
1) age (peak 60-70)
2) polyposis syndromes
3) UC and Crohn’s
4) low residue diet and low transit time
5) high fat intake
6) genetic predisposition
Give 2 reason why a HIGH fibre diet may decreas the risk of colorectal adenocarcinomas
1) Increased sterol bulk and decreased transit time reduces the time of exposure of the mucosa to carcinogens.
2) certain fibres may bind carcinogens and therefore protect the mucosa
What are the 3 investigations you would do for a colorectal adenocarcinoma
1) Blood tests: check for anaemia!!
- FBC
- Liver function tests
- CEA
2) Colonic examination
- colonoscopy with biopsy
- CT Colonography
- Barium enema
3) Radiology
- CT chest/abdo/pelvis
- PET evaluation of suspicious lesions on CT
- MRI to stage rectal cancer and decide management options
What is CEA in a blood test for Colorectal Adenocarcinoma?
CEA (carcinoembryonic antigen) is a tumour marker used to monitor a disease after it has been diagnosed and treated (disease progression). Not often used for primary diagnosis
In colorectal screen why is Flexible sigmoidoscopy only used to examine the LEFT side?
What other “easy” examination can therfore also detect a larger % of colorectal cancers?
Left side of the colon consists of the descending and sigmoid colon
- 50% of cancers occur in the rectum
- 30% in the sigmoid colon
Hence, 80% of cancers can be detected by only examining the Left side
50% of cancers (rectum) can also be identified by a rectal exam (using finger)
Describe the various presentations of colorectal carcinomas in the following sites and explain why
1) Rectal lesions
2) Left sided lesions
3) right sided tumours
1) Rectal lesions are often ulcerated and present as rectal bleeding
2) Left sided lesions are usually stenosing lesions which present with obstruction
* also alteration of bowel habit and colicky abdominal pain are common presentations relatively early
3) Right sided tumours are often polypoidal and fungating. These present as anaemia due to recurrent occult bleeding are often late presentation
Why do Right sided colorectal tumours often present late?
The right side (ascending and transverse colon) is more distensible and the fluid nature of the faeces means obstruction is less likley to occur, hence present late when severity increases causing problems
Give 2 macroscopic features of a colorectal adenocarcinoma
60-70% recto-sigmoid
1) fungating (esp right side)
2) ostenotic (esp left side)
Give 4 prognostic indicators for a colorectal adenocarcinoma
1) grading
2) staging (TNM and Dukes staging)
3) Extramural vascular venous permeation
4) CRM (Circumferential resection margin involvement in rectal tumours)
Give 2 microscopic features of a colorectal adenocarcinoma
1) mucinous type would be seen as high mucin production of the right side + microsastellite instability
2) signet ring cell type
What is a Mucinous adenocacinoma?
Mucinous AC is a specific variant of Adenocarsinomas
They have high levels of mucin production (seen microscopically) and are RIGHT sided tumours. These are usually associated with microsastellite instability
Define grading and state what anaplastic means
Grading is the degree of differentiation, how much the tumour resembles the normal parent mucosa/epithelium under a microscope
A benign neoplasm has cells that closely resemble the parent tissue, well differentiated (low grade)
Malignant neoplasms range from well to poorly differentiated (high grade)
Cells with no resemblance to any tissue are called anaplastic
Give 3 routes of colorectal adenocarcinoma spread include specific organs/nodes involved
1) direct through bowel wall to adjacent organs eg. bladder
2) via lymphatics to mesenteric lymph nodes
3) via blood stream to liver, lung etc…
What is used to stage colorectal adenocarcinomas and give the 4 stage
Duke’s staging: no longer used in UK as it is not compatible with latest TNM staging
A: confined to bowel wall
B: through wall, lymph nodes clear
C: lymph nodes involved
C1/C2 highest node clear/involved
Describe the T stages of colorectal cancer
How the tumour has extended through the mucosa
T1: goes into submucosa
T2: into the muscle (muscularis propria)
T3: beyond muscle layer (into subserosa)
T4: breached serosal layer of colon
What is meant by “circumferential resection margin” in rectal tumours
The CMR is the margin of non-tumorous tissue around a tumor that has been surgically removed. These are examined microscopically by a pathologist to ensure the margin is free from tumor cells
Most of the colon is covered by peritoneum, it is only the rectum that is not. Instead the rectum is surrounded by fat
In order to ensure the tumour was sucsessfully removed the surgeon must resect all/large amount of fat. If he is able to do this:
- it was a good quality surgery
- there is less chance of CRM involvement
- there is less chance of local recurrence
Give 4 ways you would treat a colorectal adenocarcinoma?
1) Surgical resection with curative intent
- +/- Neoadjuvant therapy in rectal tumours
- post operative chemoradiotherapy
2) Palliative:
- Stenting in obstructive tumours
- palliative chemotherapy and surgery
3) Metatstectomy-liver and lung resections
4) Targeted therapy
GIve 2 examples of targeted therapy/personalised medicine for a colorectal adenocarcinom
If patient has metastatic colorectal adenocarcinoma, the oncologist will test for:
1) Kras gene
- “wild type Kras” may respond to EGFR treatment which will avoid unnecessary chemo
- mutated form of Kras does not respond to EGFR inhibitors so requires other treatment
2) Mistmatch repair genes
* helps to determine whether the patient has a microsatellite instability
Give an example of an EGFR inhibitor and state when it may be used
Cetuximab, may be used in metastaic colorectal adenocarcinoma if the patient has the “wild type Kras”
What is a microsatellite instability in colorectal carcinomas?
Microsatellite instability (MSI) is a frequent phenotype caused by the loss of DNA mismatch repair proteins (MMR)
Important to know for treatment and prognosis of disease
What does is a patient has MSI CRC what does this mean and what is its significance? (3)
MSI CRC =microsatellite instability due to loss of MMR proteins
Significance:
1) Pronostic: all MSI CRC patients unusually have better prognosis BUT only in pT3N0 stage
2) Predictibe: MSI CRC do NOT respond to 5FU based chemotherapy
3) Identification of Lynch syndrome
- endoscopic surveillance
- LS patients at at a high risk of second primary cancers eg. endometrial /ovarian/gastric/renal and bladder tumours
- LS patients relatives benefit from testing
