Respiratory Pathology Flashcards
Carcinogens in Tobacco Smoke
What is Mutational Compensation?
Mutational Compensation
Our cells want to become immortal but there are certain house-keeping genes which induce apoptosis so that the cell don’t go out of control
Viral oncogenes in combination with smoking make these cells become more proliferative
Trends in Smoking Prevalence and Mortality
There has been a steady decline in smoking prevalence among men over the years
The peak prevalence for women was about 15 years later
This is translated to the mortality we see with lung cancer
Mortality in men is declining over time
Mortality in women continued to peak and then started declining now
No matter how long you have been smoking, it is always beneficial to stop smoking
Name a clincal feature of lung cancer?
Name 6 things that are persistant (more than 3 weeks) when a patient has lung cancer?
CXR=Urgent chest X-ray
Haemoptysis- most important one
What are the requirement for a finger nail to be clubbed?
Nail bed should be less than 180 degrees
If it is greater than 180 degrees then that could be a sign of lung cancer
What are the two ways lung cancers are catagorised?
What does the T staging tell you about a tumour?
List 3 things that T staging is based on?
If the tumour spreads to the lymph nodes in the neck then there is ………….. staging
Surgery is not practical if the cancer has spread to the lymph nodes
A …………… ……………. ……………….. can be used to sample a few cells which are then looked at by pathologists
Staging - TNM Classification
Tumour, Nodes, Metastases
The location of the tumour is also indicated in T staging
If the tumour is closer to the mediastinum or the chest wall then it has a HIGHER T STAGING irrespective of its size
So T staging is based on location, size and proximity to other organs
If the tumour spreads to the lymph nodes in the neck then there is higher staging
Surgery is not practical if the cancer has spread to the lymph nodes
A fine needle aspiration can be used to sample a few cells which are then looked at by pathologists
What happes to the staging if a cancer has spread to the lymph nodes?
TNM- N for Lymph Nodes
If the tumour spreads to the lymph nodes in the neck then there is higher staging
Metastasis
Much of the M staging will be evident from looking at scans
There could be a lot of tumour in the lymph nodes near the superior vena cava which could lead to the patients getting a throbbing head and a build up of pressure in the superior venous system
Name a complication of lung cancer that can cause edema of the face, neck and upper chest and state how the lung cancer does this?
The lung cancer grows and presses on the superior vena cava
How does a PET scan work and what is the patient given and what does he have to do for 4 hours prior to the scan?
Why are the kidneys prominant in the scan?
PET Scans
Patients fast for 4 hours and are then given radiolabelled glucose
The lung as a whole is not very active but the tumour is very metabolically active and hence show up very clearly
The kidneys are naturally very metabolically active
What area is sampled first in a patient with a lung cancer?
The area with the highest staging
Trans Thoracic CT scan
- Establish Diagnosis
- Establish Staging
- Establish Treatment Plan
What is treatment for Small cell lung cancer based on?
Name 2 features of Small cell cancers and what does its treatment involve?
If they are very debilitated, they might be given ……………… ………………….
If the tumour disappears, you give ………………… ………………. …………………….
Giving aggressive treatment to someone who is already very debilitated could kill them
Algorithm for Small Cell Lung Cancer
Diagnose —> Stage —> Treat
Treatment is based on the cell type of the tumour, the extent of the tumour (TNM), how fit the patient is (are there co-morbidities, are they fit for surgery)
Small Cell Lung cancer usually grows rapidly and metastasise early - treatment involves chemotherapy and radiotherapy
If they are very debilitated, they might be given palliative radiotherapy
If the tumour disappears, you give prophylactic brain radiotherapy
Giving aggressive treatment to someone who is already very debilitated could kill them
Algorithm for Local Non-Small Cell Lung Cancer
If it is localised, then the best treatment is ……………..
5 year survival is around 70%
Algorithm for Local Non-Small Cell Lung Cancer
If it is localised, then the best treatment is surgery
5 year survival is around 70%
Lung cancer can arise in any of those compartments.
Those tumours of the commonest type are ………………. …………. …………………..
In the periphery of the lung around the peripheral airways and the alveolar spaces you tend to get a ………………… tumour or an …………… carcinoma.
Lung cancer can arise in any of those compartments.
Those tumours of the commonest type are squamous cell carcinomas
In the periphery of the lung around the peripheral airways and the alveolar spaces you tend to get a glandular tumour or an adeno carcinoma.
List causes of lung cancer in non smokers?
ASBESTOS EXPOSURE
Radiation
Genetic Predisposition- Familial Lung Cancers
Heavy Metals (Chromates, arsenic, Nickel)
Development of Carcinoma
Multistep accumalation of mutations resulting in: name 4 things
List 2 features of benign tumors and give an example of one in the lung?
List one feature of malignant lung tumours and what is the commonest type?
Squamous cell carcinomas tend to arise in the airways in a multistep pattern of development.
When the airways are repeatidly exposed to irratents like smoke or carcinogens. it responds by ………
Why is this a problem?
Squamous cell carcinomas tend to arise in the airways in a multistep pattern of development.
When the airways are repeatidly exposed to irratents like smoke or carcinogens. it responds by changing from a less resisliant epithilium type to a more resillient epithelium type. It chaneges fom a cilitaed epitheium ot a squamous epithilum ( same one that lines your skin).
The problem is that there is no mucos or cilia cells so the carcinogens accumulate and therefore mutations accumulate- cancer.
Adenocarcinoma Development
Define adenoma?
Atypical adenomatous hyperplasia- Poliferation of atypical cells lining the ……………. ………….. Increase in size and can eventually become …………..
Adenoma is a benign tumor of glandular tissue
Atypical adenomatous hyperplasia- Poliferation of atypical cells lining the alveolar walls. Increase in size and can eventually become invasive.
Incidence of Non-Small Cell Carcinoma
Incidence of squamous cell carcinoma is …………………..
Incidence of adenocarcinoma is ………………………
Adenocarcinoma is the most common form of lung cancer among NON-SMOKERS
So as incidence of smoking decreases, the proportion of lung cancer that is attributed to adenocarcinoma increases
This could also be due to a change in the type of cigarettes smoked - years ago, the cigarettes had a large amount of tar so people couldn’t breathe it in as deeply
Squamous cell carcinomas tend to arise near the …………………..
Adenocarcinoma tends to arise in the ………………………..
Incidence of Non-Small Cell Carcinoma
Incidence of squamous cell carcinoma is decreasing
Incidence of adenocarcinoma is INCREASING
Adenocarcinoma is the most common form of lung cancer among NON-SMOKERS
So as incidence of smoking decreases, the proportion of lung cancer that is attributed to adenocarcinoma increases
This could also be due to a change in the type of cigarettes smoked - years ago, the cigarettes had a large amount of tar so people couldn’t breathe it in as deeply
Squamous cell carcinomas tend to arise near the mediastinum
Adenocarcinoma tends to arise in the periphery
Development of Carcinoma
Multistep pathway changes from:
Metaplasia
Dysplasia
Carcinoma in situ
Invasive carcinoma
NOTE: a precursor lesion has not been identified for small cell carcinoma
Associated with the accumulation of mutations
There are different pathways for different types of tumours
Some of the early stages are reversible e.g. if you have early stage dysplasia
Cytology of Adenocarcinoma
What do glandular epithelium often produce?
Decribe the cytology of an adenocarcinoma?
Cytology of Adenocarcinoma
It’s an adenocarcinoma so it has to show some evidence of glandular differentiation
Glandular epithelium often produces MUCIN
The blue around the outside - you can see BIG atypical nuclei and the rest of the cytoplasm is filled with mucin globule
Molecular Pathways in Adenocarcinoma
There are TWO pathways, one is associated with smoking and the other with non-smoking:
Smoker = …………. mutation (DNA methylation + p53)
Non-Smoker = ………… mutation/amplification (Epidermal Growth Factor Receptor)
It is important to determine whether the adenocarcinoma involves a K ras mutation or an EGFR mutation
If the patient has a ……………….. mutation then they ARE NOT going to respond to targeted therapy (like Tarceva)
If it is an ……………. mutation, you need to see whether it is a responder mutation or a resistance mutation
Some patients with responder mutation with quite advanced disease (metastasis and large tumour) can show almost complete regression with these targeted therapies
So, there is a group of patients who respond really well to the targeted therapies and pathologists must identify these patients
Molecular Pathways in Adenocarcinoma
There are TWO pathways, one is associated with smoking and the other with non-smoking:
Smoker = K ras mutation (DNA methylation + p53)
Non-Smoker = EGFR mutation/amplification (Epidermal Growth Factor Receptor)
It is important to determine whether the adenocarcinoma involves a K ras mutation or an EGFR mutation
If the patient has a K ras mutation then they ARE NOT going to respond to targeted therapy (like Tarceva)
If it is an EGFR mutation, you need to see whether it is a responder mutation or a resistance mutation
Some patients with responder mutation with quite advanced disease (metastasis and large tumour) can show almost complete regression with these targeted therapies
So, there is a group of patients who respond really well to the targeted therapies and pathologists must identify these patients
Progression of Atypical Adenomatous Hyperplasia
In the left hand image, you can see the large white circle is a respiratory bronchiole and to the right of that you can see the alveolar walls are thickened and are lined by atypical cells
Over time some of these cells will grow larger and LARGER but they are NOT invasive yet
At some point, the cells will mutate and be able to form enzymes that break down the stroma
Breaking down the stroma forms fibrous scars and is accompanied by INFLAMMATION
Once the adenocarcinoma has become invasive, it has potential to spread around the body
The invasive tumour can break down the elastin in the basement membrane and form the pink fibrous stroma
Adenocarcinoma Development
Forms from ………………… epithelium
Tend to develop in the ………………… and are increasing in incidence because of deeper inhalation of cigarette smoke and because it is more common in non-smokers
The precursor lesion is ………………….. ……………………….. …………………..
………………….. ……………………….. ………………….. = proliferation of atypical cells lining the alveolar walls. Increases in size and can eventually become invasive
Adenocarcinoma Development
Forms from glandular epithelium
Tend to develop in the periphery and are increasing in incidence because of deeper inhalation of cigarette smoke and because it is more common in non-smokers
The precursor lesion is ATYPICAL ADENOMATOUS HYPERPLASIA
Atypical Adenomatous Hyperplasia = proliferation of atypical cells lining the alveolar walls. Increases in size and can eventually become invasive
Cytology of Squamous Cell Carcinoma
The irregular cells have:
List two
Cytology of Squamous Cell Carcinoma
The irregular cells have:
Large Nuclei
Keratin in the cytoplasm
Small Cell Carcinoma
Cytology of Small Cell Carcinoma
THIS IS THE WORST FORM OF LUNG CANCER
Small cell lung cancer consists of, as the name suggests, small cells
On the left is a normal ciliated cell and the cells in the middle are the small cell carcinoma cells - they are basically just nuclei with a small amount of cytoplasm
The small cell carcinoma cells look a bit like lymphocytes
Histology of Small Cell Carcinoma
20-25% of all lung cancer
Often central near the ……………………
Very close association with ………………………
80% of cases present with advanced disease
Although very …………………………. - there is an awful prognosis
Have a lot of …………………… ………………….
MIDDLE IMAGE: you can see the small cell carcinoma with lots of mitoses
Because they divide so fast, the tumour often outgrows its blood supply and becomes necrotic
Very rare in non-smokers
Histology of Small Cell Carcinoma
20-25% of all lung cancer
Often central near the bronchi
Very close association with SMOKING
80% of cases present with advanced disease
Although very chemosensitive - there is an awful prognosis
Have a lot of paraneoplastic syndromes
MIDDLE IMAGE: you can see the small cell carcinoma with lots of mitoses
Because they divide so fast, the tumour often outgrows its blood supply and becomes necrotic
Very rare in non-smokers
Importance of Histological Tumour Type
Small Cell Lung Carcinoma
Survival 2-4 months untreated
Survival 10-20 months with current treatment
………………………. (surgery is very rare as it has usually spread by the time it’s identified)
Non-Small Cell Lung Carcinoma
Early Stage 1: 60% 5 year survival
Late Stage 4: 5% 5 year survival
20-30% have early stage tumours suitable for surgical resection
Less ………………………….
Importance of Histological Tumour Type
Small Cell Lung Carcinoma
Survival 2-4 months untreated
Survival 10-20 months with current treatment
Chemoradiotherapy (surgery is very rare as it has usually spread by the time it’s identified)
Non-Small Cell Lung Carcinoma
Early Stage 1: 60% 5 year survival
Late Stage 4: 5% 5 year survival
20-30% have early stage tumours suitable for surgical resection
Less chemosensitive
New data suggests that it is becoming increasingly important to SUB-TYPE non-small cell carcinoma for treatment
Some adenocarcinomas respond well to anti-EGFR drugs (e.g. Tarceva)
In contrast, some patients with squamous cell carcinoma develop fatal haemorrhage with Bevacizumab
Targets of Treatment - EGFR (Epidermal Growth Factor Receptor)
EGFR sits on the surface of cells and signals a variety of downstream pathways that make the cell divide
You can get mutation or amplification of EGFR, mainly in adenocarcinoma (predominantly among non-smokers)
EGFR is a type of membrane receptor TYROSINE KINASE
It regulates angiogenesis, proliferation, apoptosis and migration
EGFR is the target of a TYROSINE KINASE INHIBITOR
TNM Staging System
This is a measure of how advanced the tumour is
The TNM staging is used to determine prognosis and operability
Tumour staging can be clinical, radiological or PATHOLOGICAL (latter is most accurate - gold standard)
Symptoms, signs and complications of Lung Cancer
Local Effects of Bronchogenic Carcinoma
If you have a proximal tumour then it is likely to be squamous cell carcinoma or small cell carcinoma
A proximal tumour could cause BRONCHIAL OBSTRUCTION which could lead to:
Collapse of the distal lung
Leads to shortness of breath
Impaired drainage of the bronchus
Chest infection - pneumonia, abscess
INVASION OF LOCAL STRUCTURES:
Invasion of local airways and vessels
Haemoptysis, cough
Invasion around large vessels
Superior vena cava syndrome - venous congestion of the head and arm oedema and ultimately circulatory collapse
Oesophagus
Dysphagia (difficulty swallowing)
Chest Wall
Pain
Nerves
Horner’s Syndrome (characterised by miosis (constricted pupil) and ptosis (weak, droopy eyelid) due to effect of tumour on the sympathetic nervous system
EXTENSION THROUGH PLEURA OR PERICARDIUM
Pleuritis or pericarditis with effusions
Breathlessness
Cardiac compromise (effusion can affect cardiac function)
DIFFUSE LYMPHATIC SPREAD WITHIN LUNG
Shortness of breath
Very poor prognostic features
Systemic Effects of Bronchogenic Carcinoma
Physical effects of metastatic spread:
Brain (fits)
Skin (lumps)
Liver (liver pain, deranges liver function tests)
Bone (bone pain, fracture)
Paraneoplastic Syndrome = systemic effect of tumour due to abnormal expression by tumour cells of factors (e.g. hormones) NOT normally expressed by the tissue from which the tumour arose
Paraneoplastic Syndromes
Endocrine
Anti-diuretic hormone (ADH)
You can get syndrome of inappropriate ADH (SIADH) causing hyponatremia (especially in small cell carcinoma)
Adrenocorticotropic Hormone (ACTH)
Cushing’s Syndrome (especially in small cell carcinoma)
Parathyroid hormone-related peptides
Hypercalcaemia (especially squamous cell carcinoma)
Others:
Calcitonin –> Hypocalcaemia
Gonadotrophins –> Gynaecomastia
Serotonin –> Carcinoid Syndrome (especially CARCINOID tumours; rarely small cell carcinoma)
Non-Endocrine
Haematologic/Coagulation defects
Skin
Muscular
Miscellaneous
Read Laz notes
Malignant Pleural Tumours - Mesothelioma
Aetiology - ASBESTOS exposure
There is currently a peak in mesothelioma incidence
It is essentially FATAL
There is a long lag time - tumour develops decades after exposure
More common in males (3:1)
Usually occurs in people 50-70 years old
Commonly present with shortness of breath, chest pain
Awful prognosis
