6. Respiratory Pathology

Question 1

Outline the epidemiology of lung cancer

Answer 1

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

Question 2

Outline smoking as a risk factor for lung cancer

Answer 2

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

Question 3

Outline the clinical features of lung cancer

Answer 3

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

Question 4

Outline the pathogenesis of lung cancer

Answer 4

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

Question 5

Outline the pathway for squamous cell carcinomas

Answer 5

Normal epithelium –> hyperplasia –> squamous metaplasia –> dysplasia –> carcinoma in situ –> invasive carcinoma

Question 6

Outline benign lung tumours

Answer 6

Benign lung tumours do not metastasise; they can cause local complications (e.g. airway obstruction, e.g. chondroma)

Question 7

Outline malignant lung tumours

Answer 7

Malignant lung tumours have the potential to metastasise, but variable clinical behaviour from relatively indolent to aggressive; the most common are epithelial tumours

Question 8

Outline squamous cell carcinomas

Answer 8

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

Question 9

Outline adenocarcinomas

Answer 9

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

Question 10

Outline small cell carcinomas

Answer 10

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

Question 11

Outline lung cancer cell types

Answer 11

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

Question 12

Outline the importance of the histological tumour type

Answer 12

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

Question 13

Outline lung cancer diagnosis

Answer 13

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

Question 14

Summarise lung cancer staging

Answer 14

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)

Question 15

State the different classes of breast cancer classification

Answer 15

T:

• T1
• T2
• T3
• T4

N:

• N0
• N1
• N2
• N3

M:

• M0
• M1

Question 16

Outline the ‘T’ classification of lung cancer

Answer 16

[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

Question 17

Define atelectasis

Answer 17

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.

Question 18

Outline the ‘N’ classification of lung cancer

Answer 18

[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

Question 19

Outline the ‘M’ classification of lung cancer

Answer 19

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

Question 20

Summarise treatment options for lung cancers

Answer 20

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

Question 21

Outline molecular therapeutics

Answer 21

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

Question 22

Outline cisplatin

Answer 22

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

Question 23

Outline the targets of lung cancer treatment

Answer 23

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

Question 24

Outline the treatment of small cell lung cancer

Answer 24

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

Question 25

What is etoposide?

Answer 25

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

Question 26

Outline the treatment of non-small cell lung cancer

Answer 26

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

Question 27

What are the 2 classes of lung cancer complications?

Answer 27

Local

Systemic

Question 28

Outline some local complications of lung cancer

Answer 28

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

Question 29

Define pleura

Answer 29

Each of a pair of serous membranes lining the thorax and enveloping the lungs in humans and other mammals

Question 30

Briefly outline Horner’s syndrome

Answer 30

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)

Question 31

Outline pleural effusions

Answer 31

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’

Question 32

Define dysphagia

Answer 32

Dysphagia is the medical term for the symptom of difficulty in swallowing

Question 33

Outline prognosis/survival for lung cancer

Answer 33

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

Question 34

Outline malignant pleural tumours (mesothelioma)

Answer 34

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

Question 35

Outline COPD

Answer 35

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

Question 36

Outline asthma

Answer 36

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

Question 37

Outline bronchitis

Answer 37

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

Question 38

Outline emphysema

Answer 38

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

Question 39

Define aetiology

Answer 39

The cause, set of causes, or manner of causation of a disease or condition

Question 40

Define sputum

Answer 40

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