Lung Cancer

Introduction

• 95% of lung cancers are carcinoma of the bronchus
• 2% are alveolar tumours
• 3% are benign or less invasive malignant tumours.

Smoking as a risk factor

Relative smoking risk:

Never Smoked	1%
Smoker	43%
Ex-Smoker (after 10 years)	2-10%
Exposure to asbestos	5%
Smoker and exposed to asbestos	90%

After 10 years of stopping the risk is greatly reduced, but it never reaches that of non-smokers

Types of tumour

For the provision of treatment, tumours are divided into small cell carcinoma and non-small cell carcinoma. However, there are actually four types of bronchial carcinoma:

Cell type	Development time*	Survival	Common Location
Small cell 20-30% of cases	3 years – doubles in 30 days	Around 5%	Around the hilum / central
Adenoma 30% of cases	15 years – doubles in 200 days		More often found peripherally – therefore present late because they less likely to cause obstruction symptoms
Squamous cell carcinoma 35% of cases	8 years
Large Cell 15% of cases	?		Centrally

*this is the time from the initial malignant change to presentation

A good tip – tumours arising in a main bronchus tend to present earlier than those arising in a small bronchus – because they will cause far greater symptoms at an early stage.

80% of tumours are in the lobar bronchi – the rest are in larger bronchi.

Squamous cell carcinoma

• Usually present as obstructive lesions of the bronchus leading to infection.
• Occasionally cavitates (10% at presentation) – this will occur when the central part of the tumour undergoes necrosis. On x-ray this may have the appearances of an abscess, or a TB cavity, but on CT, you will clearly be able to see the jagged edge of the cavity, and possible infiltration of other structures (such as the pleura) and thus the cavity can be differentiated.

• These images show the presence of a cavity caused by lung cancer. Note how on the X-ray it is not possible to tell whether it is an abscess or a cancer (the border’s definition cannot be easily seen) but on the CT there is obviously a jagged border – indicating cancer. The cancer is also likely to have a thicker wall than a cavity caused by infection. Cavities are more likely to be infective if the cavity has appeared quickly. A smooth border and the presence of fluid make it more likely to be an abscess.
• Local spread is common, but metastasis are normally late (but frequent)
• Often causes hypercalcaemia – by bone destruction or production of PTH analogues.

Adenocarcinoma

• Arises from mucous cells in the bronchial epithelium
• Commonly invades the mediastinal lymph nodes and the pleura, and spreads to the brain and bones
• Does not usually cavitate
• Can cause excessive mucous secretion
• Proportionally more common in non-smokers, women and in the Far East
  • i.e. these are the least likely to be related to smoking
• May sometimes be confused with mesothelioma
• Most likely to cause pleural effusion (as are mesotheliomas)

Large cell carcinomas

• These are basically just less well differentiated versions of adenocarcinomas and squamous cell carcinoma – i.e. squamous cell and adenocarcinomas have a longer time to develop before presentation, they will present as large cell carcinomas.
• They metastasise early
• Associated with poor prognosis

Bronchoalveolar cell carcinoma

• These are very rare
• It is a variation of adenocarcinoma
• they account for 1-2% of all lung carcinoma
• they will present as a single nodule, or many small nodular lesions
• occasionally they cause production of huge amounts of mucous (which will be coughed up as sputum)
• may appear like consolidation on the CXR
• Causes ‘bronchorrhoea’ – diarrhoea of the bronchus – produces huge amounts of white sputum!

Small cell carcinoma

aka oat cell carcinoma
Arise from endocrine cells (Kulchitsky cells). These are APUD cells, and as a result, these tumours will secrete many poly-peptides. Some of these polypeptides will cause auto-feedback to induce further cell growth. They can also cause various presentations such as Addison’s and Cushing’s disease.
Small cell carcinoma spreads very early and is almost always inoperable at presentation. These tumours do respond to chemotherapy, but the prognosis is generally poor.
APUD cells – there are two types:

• Open – secrete products in response to luminal contents, as well as nervous and hormonal stimuli
• Closed – have no luminal receptors, and just respond to nervous and hormonal stimuli.

You can also get primary small cell carcinoma in the oesophagus, stomach and cervix.

Spread

The tumour may spread to the pleura, either directly, or by lymphatic drainage.

Local

• They can also spread to the chest wall, damaging the intercostal nerves, or even the brachial plexus and causing severe pain. This is caused by tumours in the apex of the lung (called superior sulcus tumours), and they can affect the lower part of the brachial plexus – C8, T1 and T2 – and this will cause severe pain in the shoulder and down the inner surface of the arm. There is also weakness of the hand. This is known as Pancoast’s tumour. And the pain this causes is known as pancoast’s syndrome.
  • This can lead to loss of the first rib – the tumour just eats it up!
  • Any apical tumour is a Pancoast’s tumour
• The sympathetic ganglion may also be involved – and if this is damaged it can result in Horner’s syndrome.
  • Horner’s syndrome – this results from damage to the sympathetic nervous system. In this particular case it results from damage to the sympathetic chain at or above the stellate ganglion. These ganglia are on the outside of the thoracic vertebrae – so it would have to be a central posterior tumour that would cause this.
• Clinical features of Horner’s Syndrome  include a drooping eyelid (ptosis) resulting from improper innervation of the superior tarsal muscle, ‘upside-down’ ptosis, miosis (constricted pupil) and dilation lag.
• There may also be anhydrosis (decreased sweating) and enophthalmosis (an impression that the eye has sunk in) on the affected side of the face. There may also be dilation of blood vessels on the affected side, resulting in flushing, and a blood shot eye.   
  • The primary tumour, or lymph nodes metastasis can spread to the mediastinum and invade or compress the heart, oesophagus, superior vena cava (causing early morning headache, oedema of the upper limbs, facial congestion and distension of the jugular vein and veins on the chest), trachea, and phrenic or left recurrent laryngeal nerves. In the case of the left recurrent laryngeal nerve the tumours invade the Hilar area.

Nodal – supraclavicular and mediastinal lymph nodes can be affected

Blood borne – mets to the liver, bone adrenal glands, skin and brain. Mets in the brain can cause change in personality, epilepsy, or a focal neurological lesion. The deposits in the adrenal glands are rarely symptomatic, but often found on post mortem.

• Bony mets are particularly painful, and can cause pathological fractures. They can also result in spinal cord compression, which may require emergency surgery.

Even a very small primary tumour can result in wide-spread metastasis. This is especially true of small cell carcinomas.  
 

Non-metastatic manifestations of bronchial carcinoma

Endocrine complications – ~10% of all cases (usually small cell carcinoma)

• Inappropriate ADH secretion – this can cause hyponatreamia – be careful! – this hyponatraemia is not caused by lack of sodium – but by ‘dilation’ of body fluids, due to excess secretion of ADH – not enough water is being secreted.
  • So by denying the patient fluids, you can bring the sodium back to normal!
• Ectopic ACTH secretion – causing Cushing’s syndrome – will produce symptoms similar to those on steroids – and these patients (unlike those just on steroids) will be very heavily pigmented.
• Hypercalcemia – due to the secretion of parathyroid hormone related peptides (PTH). This mostly occurs with squamous cell cancer.
• Endocrine disturbances are typically associated with small cell carcinoma

Paraneoplastic syndromes

The definition of a paraneoplastic syndrome is a non-endocrine, non-metastatic complication.
These can present several years before the tumour itself presents. They are generally rare – e.g. in comparison to local and metastatic spread.

• Neurological complications – 2-16% of cases
  • Polyneuropathy – caused by antibodies against the myelin sheath – the damage is irreversible. It can present with virtually any neurological symptom.
  • Cerebellar degeneration – and other encephalopathies.
  • Lambert-Eaton Syndrome – essentially myasthenia gravis secondary to lung carcinoma. Other muscular condition may also occur.
• Vascular and haematological complications – rare
  • Thrombophlebitis migrans
  • Anaemia – can be microcytic or normocytic
• HPOA – Hypertrophic pulmonary osteoarthropathy – this occurs in 3% of cases (mostly small cell and adenoma). There will be joint stiffness, and severe pain in the wrists and ankles, sometimes also gynaecomastia. On x-ray there will be proliferative periostitis at the ends of the long bones, which have an ‘onion skin’ appearance. This is also associated with finger clubbing where cancer is the cause. It is thought to be caused by a blood borne factor released by the tumour – when patients have the primary tumour removed the pain goes away!
• Finger clubbing! 30% of cases– caused by non-small cell carcinoma. This is thought to be a result of ecptopic hormone production, which occurs in approx. 10% of cases, although other clinical manifestations are rare.
• Carcinoid syndrome – This presents with hepatomegaly, flushing and diahrroea – Diagnosed using 24 hour urine 5-HIAA tests.

Presentation of Bronchial carcinoma

• Many patients have co-existing COPD
• Pain – patient may initially describe the feeling as a ‘fullness’ in the chest. Later, it may develop to a severe persistent pain.
• Cough is usually the earliest symptom. Often it is dry, but they may be purulent sputum if there is associated infection; often the infection is a result of bronchial obstruction.
  • A change in character of a ‘smokers cough’ may be a telltale sign, particularly if it associated with other respiratory symptoms.
• Haemoptysis is common with tumours arising in central bronchi. Occasionally, these tumours may invade large blood vessels which can cause a massive haemoptysis that can be fatal.
  • Typically, smokers may present with bronchial carcinoma with several episodes of small amounts of haemoptysis. This should always be investigated!
    • A single episode, particularly in the background of infection need not be investigated.
  • Haemoptysis – may present as just the taste of blood in the back of the mouth – particularly in the morning.
• Pneumonia – if this is recurrent at the same site, or is slow to respond to treatment, then this is suggestive of bronchial carcinoma. Tumours the block the bronchi prevent the proper functioning of the mucociliary escalator, and thus bacteria are retained behind the blockage.
• Shortness of breath will generally only occur if there is obstruction of a large bronchi
• Stridor may be present if there is a large tumour either in the trachea, or in one of the large bronchi. It will tend to be monophonic. Stridor tends to be present when there is an obstruction above the main carina.
  • Monophonic and polyphonic wheeze – monophonic wheeze indicates there is only one obstruction – this is an ominous sign as the most probable cause is a carcinoma. Polyphonic wheeze is more suggestive of many airway blockages.
  • Stridor is often audible by the naked ear
• Pleuritic chest pain – this is chest pain that may be present all the time, but is far more pronounced on movement of the lungs. This indicates invasion of the pleura.
• Hoarseness of the voice – this suggests there is left laryngeal involvement, particularly if there is also a bovine (sounds like a cow?!) cough. If this involvement is present, then the tumour is inoperable.

Mortality rates for lung cancer are the same as ten years ago. This is due to the fact that lung cancer presents so late.

Nature of Presentation

• Typically, respiratory symptoms that do not respond to other standard treatments (e.g. cough that doesn’t respond to antibiotics)
• Persistent symptoms
• Change in nature of chronic ‘smoker’s cough’
• History of smoking!
• Isolated incidences of haemoptysis
• Weight loss
• Decreased appetite – as a result of the inflammatory reaction that the tumour induces – particularly TNF that is released
• HPOA
• Hoarseness of voice – involvement of the vocal chords of left recurrent laryngeal nerves
• Pancoasts’ tumour

Examination

This is usually normal, unless there is significant bronchial obstruction, or the tumour has spread (e.g. to pleura; pleuritic pain, supraclavicular nodes; palpable or mediastinum).
Tumours in large bronchi may cause collapse of the lung, or obstructive emphysema.

• There may be absent breath sounds and dullness to percussion at the lung base in cases where there is phrenic involvement – as this will cause unilateral raising of the diaphragm.
• Involvement of the pleura may not only cause pleuritic chest pain, but also a pleural rub, and signs of pleural effusion.
• You should always check the axillary lymph nodes when you suspect lung cancer, because they can metastasise to here early!

Screening programs have been tried in USA, but none have been proven to improve outcome. CT screening programs may be useful in the future.

Investigations

X-ray

• Symptomatic tumours will usually be visible on x-ray
• Asymptomatic tumours can be seen on x-ray if they are greater than 1cm in diameter.
• Lateral views may be useful to assess areas of the lung behind the heart and in the hilar region.
• A small number of tumours are confined to central airways and not visible on x-ray because of the heart. These tumours however will be seen on bronchoscopy and CT.
• A normal chest x-ray should not be a sign to deter further investigation, especially in smokers over the age of 40. In many cases of isolated haemoptysis the chest x-ray is normal.
• 70% of lung cancers present with a mass:
  • Virtually all small cell carcinomas and squamous cells will present as a visible mass
  • Adenocarcinomas, tend to occur more around the periphery of the lung than other tumours.
• Bronchial carcinoma can appear as a round shadow on an x-ray. It typically has a jagged edge, although this may not be distinguishable. It may also appear as a cavity.
• Bronchial carcinoma can not only spread to mediastinal lymph nodes, but it may also spread to the lymphatic channels. This causes lymphangitis carcinomatosa  which will cause dyspnoea and may causing a streaky shadowing on the x-ray. This is usually unilateral. If it is bilateral that it is more likely to be due to lung mets from other primaries, usually one from below the diaphragm, e.g. in the stomach or colon.
• Basically, you are looking for:

• Peripheral circular opacities
• Hilar enlargement
• Lung collapse
• Consolidation
• Pleural effusion
• Bony secondaries
• If you do see anything on x-ray – take a lateral x-ray! – if possible – try to compare with a previous x-ray

CT

• This is particularly useful for looking at disease in the mediastinum.
• It can also detect masses that are too small to be seen on CXR (<1cm diameter)
• A normal CT of nodes before surgery excludes the need for mediastinoscopy and node biopsy.
• Staging CT should include the liver, adrenals and brain to check for mets
• A staging CT of the chest:
  • Looks at the chin to the kidneys (so includes adrenals and liver)
  • Must do one with contrast and without – contrast shows whether it is a lesion or just a blood vessel.
• This is only about 60% accurate for mets – it doesn’t always pick up nodes if they are less than 10mm

PET

• It is also useful for staging – where the f-deoxyglucose PET scan is employed.
• No point in doing a PET if you don’t plan to operate! Basically it just tells you if it has spread – thus if it is suitable for surgery.
  • You would normally do a staging CT first – if this is clear, then you use a PET to look for more distant spread. If it all looks clear, then you can operate.
• This is about 90% accurate for mets
• On the PET results you look at the SUV value – the higher this is, the more likely the lesion is to be metastatic spread (scale is about 1-9)

Bronchoscopy

• This is most useful to obtain cytology and biopsy. Tumours that involve the first 2cm on either main bronchus are inoperable. You may also see:
  • Widening of the angle of the carina – this suggests involvement of the mediastinal lymph nodes; either due to metastasis or they may be reactive. You can biopsy them on bronchoscopy by passing a needle through the bronchial wall.
  • Cytology – this is the study of cells that are no longer in their natural environmental structure – e.g. cell obtained from a bronchial washing. Histology is the study of both the cells, and the natural structure in which they are found.
• Only really useful for tumours in an area about 10cm square around the hilum:

Percutaneous aspiration and biopsy – CT guided biopsy

• This is useful for peripheral lesions that cannot be seen by bronchoscopy. It is done through the chest wall and usually guided by x-ray or CT.
• This is able to reach 75% of peripheral lesions that cannot be reached by bronchoscopy.
• The chance of pneumothorax is very high (anywhere between 1-25% – thus the patient has to be fit enough to survive one of these if you are going to do this on them. Twice as many patients will require a chest drain as receive a pneumothorax)
• Haemoptysis will also occur in about 5% of patients
• This is useful if positive, but if negative is pretty useless (i.e. it could just means you missed the part of the lesion you wanted)

Other investigations

• FBC – for detection of anaemia
• LFT’s – to check for liver involvement
• Biochemistry – hypercalcaemia, hyponatraemia
  • Increased Ca2+ – this will occur as a result of bone metastasis. May also be a result of secretion of parathyroid hormone.
  • Decreased sodium – this will occur as a result of adrenal involvement (Addisonianism).

Other cytology

• Sputum and pleural fluid – you need to make sure you send at least 20ml of each
• Cytology is generally not very accurate – because there is a very high false negative rate.

Mediastinoscopy

• Just put a cut just above the sternal notch and stick a camera down – helps to see in the mediastinum because you can’t see this very well on x-ray – checks for nodes in cases of peripheral tumours
• You can get to post tracheal lymph nodes best.
• PET has reduced the need for this procedure – it used to be done in all patients – now its only done in cases where they can’t decide if there is spread or not
• Presence of any mediastinal disease is a contraindication for surgery
• The procedure itself requires general anaesthetic, and thus many patients aren’t fit for it.

Two questions to ask:

• Has it spread?
• Is the patient fit for surgery? (must have FEV 0.7)

Staging, Treatment and Prognosis

For lung cancer, you want to know the type of tumour, the location of the tumour, and the performance status to be able to know what treatment to give. As is the case for many conditions, treatment is best planned by the Multi-disciplinary-Team.
Prognosis is poor. As a general rule:

• 20% of cases will survive to 12 months
• 6% will survive to 5 years

Staging

Non-small cell carcinoma is staged using the TNM system (see below). Small cell is generally very aggressive, and is staged as either limited or extensive.
TNM staging is used for non-small cell carcinoma:

Primary Tumour

Nodes

Size significant lymph nodes – these are any lymph nodes above 1cm diameter.

Stage    

Management

Only about 15-20% of cancers are suitable for surgery at presentation

Operable tumours are the ones that tend to be asymptomatic and are discovered incidentally. Usually, lung cancer presents with a complication; e.g. pleural effusion, metastatic pain.
Surgery as a treatment option is typically rare.

Treatment options in more detail
Small cell carcinoma
These have nearly always metastasised by the time of recognition. Chemotherapy may be of some use; the regimens currently recommended are:

• Cyclophosphamide + doxorubicin + vincristine + etoposide, or
• Cisplatin + radiotherapy if the disease is limited

5 year survival is only 10% with treatment. Mean survival is just 2-3 months after diagnosis.

Chemotherapy

Is now a day patient treatment. Common treatment is Gemcitabine and Carboplantin. There are extensive side-effects, and although chemotherapy can prolong life, many patients opt not to undergo treatment, due to the reduced quality of life during this period.

Treatment regimen
Day one – Bolus
Day 14 – Blood tests:

• Neutrophil count is likely to be reduced (these are the fastest reproducing cells) – these cells have a life expectancy of about 8 hours.
• People feel really ill from day 12-14
• Nausea only lasts the first day or so
• On day 21, the next round of treatment is given
• People tend to have 4 cycles. – so basically the total amount of treatment is 12 weeks.
• During the 3^rd week of each cycle, you may have blood transfusions and other treatments that help you to recover before the next cycle. the final week of a cycle is a kind of recovery week, allowing you to feel a bit better before the next cycle.

Performance status – assessment for chemotherapy
This is a WHO classification and it is scored 0-4. The fitter you are the lower the number!

• 0 – fit and active
• 1 – fit and active but unable to work
  • E.g. someone who is able to live around the house ok, but not able to do their normal manual labour job
• 2 – not working, but able to be up and about for 50% of the day. Able to self care
• 3 – able to self care, but up and active for less than 50% of the day (i.e. sits in a chair for at least 50% of their waking hours)
• 4 – bed bound – probably hospitalised / cared for

Chemotherapy is only available for those in 0-2, and under the age of 80.

Brain Metastasis and survival
In cases involving brain mets the survival drops to 1-2 months. Prognosis is determined by the brain mets, and no longer by the primary tumour.

Clinical trials
These don’t usually involve new drugs – they are just basically new combinations of old drugs.

Non-small cell carcinoma
Surgical excision is the treatment of choice for tumours at the periphery with no metastatic spread. However, only 5-10% of cases are suitable for resection, and 70% of these will survive to 5 years.

• Surgery is not appropriate for those over 65, as the operative mortality exceeds the survival rate.
• Adjuvant chemotherapy has been shown to be beneficial. It can down-stage a tumour before treatment, and may be given with treatment as well, where it can improve 5-year survival.
• In Europe – resection rate is about 20%
• In UK – resection rate is only 13%
• The survival rate is greater in Europe than in the UK.

Radiotherapy – this can be given if surgery is declined, or in cases where surgery is not suitable. Poor lung function is a contraindication for this type of treatment. It can be curative in selected patients, typically those with slow-growing squamous carcinoma.

• Radiation pneumonitis will develop in 10-15% of cases – this is defined as an acute infiltrate that is confined to the area treated with radiotherapy, and occurs within 3 months of therapy. Pneumonitis is a very general term, just referring to inflammation of the lung tissue. It is often successfully treated with steroids.
• Radical radiotherapy – this can be done on cancers that are in a 6x6x6cm cube. On selected patients, this has a cure rate of about 60%.
  • Adjuvant chemotherapy improves outcomes.
• Radiotherapy for symptom relief – suitable targets for this include; bone pain, haemoptysis, and SVC obstruction.

Palliative care
This is a very important part of treatment. Involvement of specialised practitioners at an early stage (e.g. MacMillan nurse), often with the family can help plan and provide for the future. As the patient nears the end of their life, they will still often attend outpatients appointments at hospital, but these are unlikely to alter previous treatment regimens. Patients may plan to where they would prefer to spend the last hours of their life (e.g. at home, or in a hospice), and good planning, with social and medical support can avoid stressful and unnecessary acute hospital admission when the patient’s health deteriorates.

Mesothelioma and asbestosis

Asbestos is a naturally occurring fibre, which is relatively inert, as well as being fireproof, and a good insulator. In developed countries it was used widely to insulate buildings during the mid 20^th Century.
Several types of asbestos fibre exist, varying by the quality of the individual fibres. These types exists in three colours – white, blue and brown. Blue is the most dangerous clinically. Its fibres are up to 50mm long, but only 1-2nanometres wide. Very rarely, other similar sized fibres – such as in volcanic expulsions, can cause mesothelioma.

• Asbestos fibres are easily inhaled, but then become lodged in the lung. The properties of the fibres means they are particularly difficult to destruction by normal body mechanisms (e.g. enzymatic destruction).
• You are at most risk of inhaling the fibres if you have worked cutting and breaking up sheets of asbestos
• Use of asbestos in the UK is now prohibited (except in certain cases). As a result, cases should decline in the future, but there is still a risk for workers in the construction industry, particularly those involved with the demolition of old buildings that used asbestos.
• It takes 20-40 years between inhalation of fibres and development of mesothelioma.
• Smoking and asbestos fibres have a synergistic effect – thus the risk of bronchial carcinoma when having worked with asbestos and having smoked is greater than the sum of the two individual risks.

Asbestosis
This is fibrosis of the lung tissue secondary to exposure to asbestos.. Is a progressive condition that will present 5-10 years after exposure. Causes severe reduction in lung function and progressive dyspnoea. Restrictive pattern. There may also be finger clubbing, and bilateral end-inspiratory crackles.

• X-ray findings – dark streaks, honeycomb appearance (honeycomb lung)

There is no curative treatment, although steroids are often prescribed (little evidence for their use).

Mesothelioma
Can result from only light exposure to asbestos fibres. Is progressive and patients will have a restrictive pattern on pulmonary function tests. Often presents with pleural effusion, and progressive dyspnoea.  There may also be chest wall pain and ascites due to abdominal involvement.
The tumour will begin as pleuritic nodules, which gradually grow and extend around the whole surface of the lung, and even into the fissures, hence the chest wall pain. Intercostal nerves and hilar lymph nodes may be invaded.

The median survival is around 2-years from presentation.
The number of cases has been steadily rising since the early 1980’s, and is now around 1000 per year in the UK.

There is no treatment.

References

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