6. Respiratory Pathology Flashcards
Outline the epidemiology of lung cancer
3rd most common cause of death in UK
Mortality rate 40,000 per annum
The 5 year survival rate is 5.5%
80% die within 1 year of diagnosis
Causative factor: tobacco, radon, asbestos
Carcinogens in tobacco smoke:
o Specific lung carcinogens: polonium-210, nickel compounds, cadmium compounds
o Tumour promoters: volatile phenols
o Co-carcinogens: pyrene, methylpyrenes, flubranthene etc
Outline smoking as a risk factor for lung cancer
Smoking stimulates chromosomal translocation & oncogenic fusion protein via k-ras and Erb B2, and inhibits the natural G1 arrest and apoptosis that occurs following a mutation via p-RB, p53 and box genes
There has been an overall decrease in prevalence of both male and female smokers since 1950, although the peak occurs for all ages in the 1970s
There is an overall increase in mortality of both the male and the female population, but peaks in mortality correspond to the time lag following smoking peaks
There is also an increased risk of lung cancer in passive smokers, which increases in correlation to an increased number of years spent with the smoker
The cumulative risk of death from lung cancer decreases for each 10 years earlier the smoker quit, but is greatest for patients who continue to smoke, and least for non-smokers
Outline the clinical features of lung cancer
Haemoptysis (coughing of blood originating from the respiratory tract below the level of the larynx)
Unexplained/persistent (> 3 weeks) cough, chest/shoulder pain, chest signs, dyspnoea (breathlessness), hoarseness, finger clubbing –> urgent referral for a chest x-ray
NB: fingernail clubbing is seen as an increase in the sponginess of the nail bed, with a change in the superior surface of the finger from a concave to a convex surface
Also may be asymptomatic; incidental finding of a mass on a chest X-ray
Outline the pathogenesis of lung cancer
Multistep theory of tumour development; as with the development of other tumours lung cancers arise as a consequence of accumulation of mutations of genes which regulate cell proliferation, invasion, angiogenesis and senescence
The pathway is different for different tumour types
A precursor lesion of some of the major lung cancer types are recognised
Atypical adenomatous hyperplasia as a precursor of adenocarcinoma
However as yet no precursor for small cell carcinoma has been identified
Specific genes mutated at different stages of development
Genes and Lung cancer; increasing recognized that polymorphisms in certain genes affect the risk of
developing lung cancer and may help explain why some smokers do not develop lung cancer
Familial lung cancers are rare, but epidemiological evidence of increased risk for first degree relatives of young age, non-smoking cases
Susceptibility genes; nicotine addiction, chemical modification of carcinogens –> polymorphisms in
cytochrome p450 enzymes and glutathione S transferases which play a role in eliminating carcinogens
Outline the pathway for squamous cell carcinomas
Normal epithelium –> hyperplasia –> squamous metaplasia –> dysplasia –> carcinoma in situ –> invasive carcinoma
Outline benign lung tumours
Benign lung tumours do not metastasise; they can cause local complications (e.g. airway obstruction, e.g. chondroma)
Outline malignant lung tumours
Malignant lung tumours have the potential to metastasise, but variable clinical behaviour from relatively indolent to aggressive; the most common are epithelial tumours
Outline squamous cell carcinomas
Squamous cell carcinoma: 25-40% of lung cancer, strong association with smoking, mainly central arising from bronchial epithelium, distant spread is later than seen in adenocarcinoma:
o Histology – shows evidence of squamous differentiation (keratinisation, desmosomes), variety of sub-types
Malignant
Outline adenocarcinomas
Adenocarcinoma: 25-40% of lung cancer, incidence increasing, most common type in non-smokers and females, often peripheral:
o Atypical adenomatous hyperplasia – proliferation of atypical cells lining the alveolar walls seen; they increase in size and eventually can become invasive
o Cytology; mucin vacuoles seen
o Histology; extrathoracic metastases common and seen early, evidence of glandular differentiation
seen with mucin secreting
o Molecular pathways; precursor may be type 2 pneumocyte/clara cell:
- In a non-smoker, EGFR mutation/amplification
- In a smoker, K ras mutation with DNA methylation of p53 occurs
Large cell carcinoma: poorly differentiation tumour composed of large cells with no histological evidence of
glandular or squamous differentiation
Electron microscopy shows evidence of some differentiation, suggesting they are probably very poorly differentiated adeno/squamous cell carcinoma; poor prognosis
Malignant
Outline small cell carcinomas
Small cell carcinoma; 20-25% of lung cancer, very strong association with smoking, very aggressive behaviour; 80% present with advanced disease and paraneoplastic syndromes
Malignant
Outline lung cancer cell types
May be small cell or non-small cell cancer
Types include:
o Squamous cell carcinoma
o Small cell carcinoma
o Adenocarcinoma
o Large cell carcinoma
o Adenosquamous carcinoma
o Carcinoid
o Bronchial gland carcinomas
o Other
Outline the importance of the histological tumour type
Small-cell lung carcinoma have a survival of 2-4 months if untreated, with only 10-20 months treated with current therapy; treatment is usually chemoradiotherapy as too spread for surgery
In contrast, non-small cell lung carcinoma have a 60% 5 year survival rate after early stage detection, are often suitable for surgical resection and are less chemosensitive
Outline lung cancer diagnosis
Role of the pathologist - Confirm diagnosis, determine histological type of tumour, determine tumour stage, determine molecular pathology
Cytology - Study of cells; look for malignant cells shed in sputum, or washed/brushed off airways at bronchoscopy, pleural fluid, endoscopic fine needle aspiration of an tumour/enlarged lymph node
Histology - Study of tissues: Biopsy tumour at bronchoscopy or via percutaneous CT guidance, mediastinoscopy/lymph node biopsy for staging
Special techniques - Gene profiling
Summarise lung cancer staging
All patients should have cross sectional imaging with a CT scan of the thorax, liver and adrenals for staging purposes
Selected patients may require additional investigations such as a bone scan, or positron emmision tomography (PET scan)
Staging is classified according to TNM status (tumour, lymph nodes, and metastases)
State the different classes of breast cancer classification
T:
- T1
- T2
- T3
- T4
N:
- N0
- N1
- N2
- N3
M:
- M0
- M1
Outline the ‘T’ classification of lung cancer
[T - Primary tumour]
T1 - tumour =3cm diameter without invasion more proximal than lobar bronchus
T2 - tumour >3cm diameter ,or, a tumour of any size with the following: invades visceral pleura, atelectasis of less than entire lung, proximal extent at least 2cm from carina (last cartilage ring before trachea divides into bronchi)
T3 - tumour of any size with any of the following:
o Invasion of chest wall
o Involvement of diaphragm, mediastinal pleura, or pericardium
o Atelectasis involving entire lung
o Proximal entent within 2cm of carina
T4 - tumour of any size with any of the following:
o Invasion of the mediastinum
o Invasion of heart or great vessels
o Invasion of the trachea or oesophagus
o Invasion of vertebral body or carina
o Presence of malignant pleural or pericardial effusion (excess fluid accumulation)
o Satellite tumour nodule(s) within same lobe as primary tumour
Define atelectasis
Atelectasis is a complete or partial collapse of a lung or lobe of a lung; develops when the tiny air sacs (alveoli) within the lung become deflated
It’s a breathing (respiratory) complication after surgery.
Outline the ‘N’ classification of lung cancer
[N - Nodal involvement]
N0 - no regional node involvement
N1 - metastasis to ipsilateral hilar and/or ipsilateral peribronchial nodes
N2 - metastasis to ipsilateral mediastinal and/or subcarinal nodes
N3 - metastasis to contralateral mediastinal or hilar nodes OR ipsilateral or contralateral scalene or
supraclavicular nodes
Lymph nodes include:
anterior carinal, posterior carinal, right paratracheal, left paratracheal, right main
bronchus, left main bronchus, right upper hilar, subcarinal, right lower hilar, sub-sub carinal, left hilar
Outline the ‘M’ classification of lung cancer
M0 – distant metastasis absent
M1 – distant metastasis present (includes metastatic tumour nodules in a different lobe from the primary
tumour)
Metastasis may include: brain, bone, hepatic, superior vena caval obstruction
Summarise treatment options for lung cancers
The choice of treatment is based on three key factors:
o Histological cell type
o The stage of the lung cancer
o Performance status of the patient
Outline molecular therapeutics
Molecular changes in lung cancer provide prognostic data and therapeutic data (predicted response to conventional chemotherapy and targets for novel drugs)
Predictors of response to conventional chemotherapy - ‘Excision Repair cross-complimentation group 1 protein (ERCCG1)’ - in advanced stage non-small cell lung carcinoma, if ERCCG1 positive then there is a poor response to cisplatin-based chemotherapy
Outline cisplatin
isplatin is a chemotherapy medication used to treat a number of cancers
Cisplatin is administered intravenously as short-term infusion in normal saline for treatment of solid malignancies
Cisplatin interferes with DNA replication, which kills the fastest proliferating cells, which in theory are carcinogenic
Outline the targets of lung cancer treatment
Targets of Treatment – EGFR (epidermal growth factor receptor):
- In healthy cells, membrane receptor tyrosine kinase regulates angiogenesis, proliferation, apoptosis and
migration - In non-small cell lung carcinoma, mutation/amplification occurs, and this is the target of tyrosine kinase inhibitors which can be used as a treatment
Outline the treatment of small cell lung cancer
Small cell lung cancers are rapidly growing tumours, which are highly responsive to chemotherapy and radiotherapy
However, there is the early development of metastases and most patients present with extensive disease
A number of cytotoxic agents are active in small cell lung cancer; combination chemotherapy including cisplatin would be considered conventional treatment
The combination of cisplatin and etoposide is thought to be more superior to other commonly used regimes such as cyclophosphamide, doxorubicin, and vincristine
Sequential regimes of chemotherapy with cycling between agents have failed to show significant advantages and preclude the use of alternative agents for disease relapse
What is etoposide?
Etoposide is a chemotherapy medication used for the treatments of a number of types of cancer
It is used by mouth or injection into a vein
Outline the treatment of non-small cell lung cancer
In non-small cell lung cancer surgery should be considered in all patients with Stage 1, Stage 2, resectable Stage 3 disease with appropriate cardiovascular reserve
In patients with unresectable Stage 3 disease, multi-modality treatment may offer better survival but most regimes require further assessment
The role of neoadjuvant chemotherapy followed by surgery is currently under exploration
A reasonable approach in the meantime would be for patients to be offered at least three cycles of chemotherapy with sequential or concomitant radiotherapy
In patients with advanced disease combination chemotherapy for palliation should be considered in those with a reasonable performance status
In all other patients best supportive care, and where appropriate, treatment with palliative radiotherapy
What are the 2 classes of lung cancer complications?
Local
Systemic
Outline some local complications of lung cancer
o Bronchial obstruction (collapse of lung –> shortness of breath, or impaired drainage of bronchus –> chest infection)
o Local invasion of local airways (causing haemoptysis), large vessels (SVC syndrome –> circulatory
collapse), oesophagus (–> dysphagia), chest wall ( –> pain) and nerves (Horner’s syndrome)
o Extension through the pleura/pericardium (with effusions –> dyspnoea and cardiac compromise)
o Diffuse lymphatic spread within lung –> shortness of breath; this is a very poor prognostic feature
Define pleura
Each of a pair of serous membranes lining the thorax and enveloping the lungs in humans and other mammals
Briefly outline Horner’s syndrome
Horner’s syndrome is a combination of symptoms that arises when a group of nerves known as the sympathetic trunk is damaged
Symptoms include a persistently small pupil (mitosis) and drooping of the upper eyelids (ptosis)
Outline pleural effusions
A pleural effusion is excess fluid that accumulates in the pleural cavity, the fluid-filled space that surrounds the lungs
This excess can impair breathing by limiting the expansion of the lungs
Various kinds of pleural effusion, depending on the nature of the fluid and what caused its entry into the pleural space, are hydrothorax (serous fluid), hemothorax (blood), urinothorax (urine), chylothorax (chyle), or pyothorax (pus)
A pneumothorax is the accumulation of air in the pleural space, and is commonly called a ‘collapsed lung’
Define dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing
Outline prognosis/survival for lung cancer
Survival rates are related to suitability for surgery, which is considered for stage I, II, III and some IIIa patients
This highlights the need for early detection
There is usually a 5% overall surgical risk and 10% risk of major complication
Adenocarcinomas have a longer survival rate than squamous, small cell and undifferentiated malignancies; small cell malignancies have the earliest deaths on average
Outline malignant pleural tumours (mesothelioma)
Aetiology – asbestos exposure
Responsible for <1% cancer deaths, but incidence increases
Fatal
Medico-legal implications of diagnosis; compensation for occupational hazards; most patients have a history of asbestos exposure, but the tumour usually develops decades after the exposure
Incidence in males is 3x females
Presents with dyspnoea and chest pain
Outline COPD
Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long-term breathing problems and poor airflow
The main symptoms include shortness of breath and cough with sputum production
COPD is a progressive disease, meaning it typically worsens over time
Causes include smoking, air pollution, occupational exposures, genetics, exacerbations, other causes, etc.
Symptoms include coughing and shortness of breath
Outline asthma
Assthma is a common long-term inflammatory disease of the airways of the lungs
It is characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm
Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath
Asthma is thought to be caused by a combination of genetic and environmental factors
There is no cure for asthma
Symptoms can be prevented by avoiding triggers, such as allergens and irritants, and by the use of inhaled corticosteroids
Outline bronchitis
Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs
Symptoms include coughing up mucus, wheezing, shortness of breath, and chest discomfort
Bronchitis is divided into two types: acute and chronic
Acute bronchitis is also known as a ‘chest cold’
In more than 90% of cases the cause is a viral infection
Risk factors include exposure to tobacco smoke, dust, and other air pollution
Outline emphysema
Emphysema is a type of COPD, in the same way that chronic bronchitis is
Tobacco smoking is the most common cause of COPD, with factors such as air pollution and genetics playing a smaller role
While COPD was previously divided into emphysema and chronic bronchitis, emphysema is only a description of lung changes rather than a disease itself, and chronic bronchitis is simply a descriptor of symptoms that may or may not occur with COPD
Define aetiology
The cause, set of causes, or manner of causation of a disease or condition
Define sputum
A mixture of saliva and mucus coughed up from the respiratory tract, typically as a result of infection or other disease and often examined microscopically to aid medical diagnosis
