Lung cancer

Notes

Introduction

Lung cancer is a common malignant tumour, with around 48,000 cases diagnosed in the UK each year.

It is the third most common malignancy in the UK and is the leading cause of cancer-related death. Smoking is the most important aetiological factor, implicated in upwards of 80% of cases.

It is categorised by the underlying cell type: 

  • Small-cell (SCLC)
  • Non-small cell lung cancer (NSCLC):
    • Adenocarcinoma
    • Squamous cell carcinoma
    • Large cell

Management depends on the subtype, stage at diagnosis and patient co-morbidities. Broadly the options include chemotherapy, radiotherapy and surgical resection.

Lung cancer statistics

Aetiology

Smoking is by far the most important aetiological factor. Exposure to other environmental agents may also increase the risk of developing lung cancer.

Smoking

Tobacco smoking is thought to be the cause of lung cancer in 80-90% of cases. Differences in gender mean women are somewhat less susceptible.

The effects of smoking remain long after cessation. The relative risk remains around two times that of a non-smoker at 30 years post cessation.

Exposure

Asbestos, a fibrous building material, is perhaps the best-known carcinogen aside from tobacco. Unfortunately, Britain spent years as one of the largest importers of the material. Despite its use being illegal for decades in the UK, cases of asbestos-related disease are still seen as many of its effects appear after a lag.

Though more strongly associated with mesothelioma, asbestos is linked with adenocarcinoma of the lung. Tobacco and asbestos exposure act synergistically increasing the risk of cancer multiple times.

Radon gas, released from naturally occurring uranium, is a recognised cause of lung cancer.

Pathophysiology

Lung cancers are divided by the cell type responsible, two broad categories exist, non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). 

Types of lung cancer (small cell vs non small cell)

Non-small cell lung cancer

Non-small cell lung cancer account for around 85% of lung cancers. Changing trends in incidence is a reflection of the timing of countries smoking epidemics.

1. Adenocarcinoma

Adenocarcinoma is now the most common form of lung cancer (around 38%). It is a cancer of the mucus-secreting cells.

Its incidence relative to other forms of lung cancer has shown an increase. It also appears proportionally more in non-smokers than squamous cell carcinoma. Smoking and asbestos exposure are both risk factors.

Adenocarcinoma tends to occur in lung peripheries.

2. Squamous cell

Squamous cell carcinoma is the second most common form of lung cancer (around 20%). Occurring in central parts of lungs, it often presents with pneumonia secondary to an obstructed bronchus.

Smoking is the most common cause. Metastases tend to occur late and histopathology shows keratin.

3. Large cell

These are undifferentiated neoplasms accounting for around 5% of lung cancers. They tend to metastasise early.

Small cell lung cancer

Account for around 15% of lung cancers. Considered separately due its fast doubling time, aggressive nature and early metastasis. SCLC is a cancer of the APUD cells, a neuroendocrine cell found in the lungs. It occurs almost exclusively in smokers.

It has an extremely poor prognosis, by the time of diagnosis curative therapy is rarely possible. SCLCs are commonly associated with paraneoplastic syndromes.

Clinical features

Lung cancer is frequently asymptomatic. When symptomatic, cough, malaise and weight loss predominate.

It may also present with haemoptysis, features of superior vena cava obstruction (SVCO) or a paraneoplastic syndrome. A higher index of suspicion is necessary for patients with a history of smoking.

Symptoms

  • Fever
  • Malaise
  • Nausea
  • Cough
  • Haemoptysis 
  • Hoarseness
  • Weight loss

Signs

  • Lymphadenopathy 
  • Stridor
  • Wheeze
  • Clubbing
  • Hypertrophic pulmonary osteoarthropathy (HPOA)
  • Signs of pleural effusion (exudative):
    • Dull (‘stony dull') percussion
    • Reduced vocal fremitus
    • Reduced breath sounds

Clinical features of lung cancer

Superior vena cava obstruction

A tumour may cause compression of the superior vena cava. This causes engorgement of vessels in the neck and face, shortness of breath and a ‘fullness’ of the head. 

See our SVCO notes for more information.

Pancoast tumour

This is a tumour of the pulmonary apex. Their location means local spread may affect:

  • Brachial plexus
  • Cervical sympathetic trunk and the stellate ganglion
  • Subclavian vein

Pancoast tumours are known to cause:

  • Horner’s syndrome
  • Pain in the shoulder that radiates into the arm and hand
  • Atrophy of muscles of the upper limb
  • Oedema of the upper limb

Metastasis

Metastasis may cause a variety of clinical features:

  • Bone: bone pain, raised ALP
  • Brain: focal and non-focal neurology
  • Liver: abnormal LFTs
  • Adrenal glands: though a common site of metastasis, normally asymptomatic

Paraneoplastic syndromes

Paraneoplastic syndromes refer to remote effects of tumours unrelated to mass effect, invasion or metastasis.

Hypercalcaemia

Hypercalcaemia may occur in lung cancers due to:

  • Bony metastasis
  • Tumour secretion of:
    • Parathyroid hormone-related protein (PTHrP) 
    • Calcitriol 

Clinical manifestations of hypercalcaemia are often remembered by “stones, bones, groans, thrones, and psychiatric moans”. This refers to renal calculi, bone pain, abdominal pain, polyuria and signs of altered mental status. Hypercalcaemia is common in lung carcinoma, seen in approximately 50% of patients with squamous cell carcinoma, 20% of adenocarcinoma and 15% of small cell carcinoma.

See our Hypercalcaemia notes for more details.

SIADH

The syndrome of inappropriate anti-diuretic hormone is seen in around 10% of patients with SCLC. Symptoms are those of hyponatraemia and in extreme cases, cerebral oedema may occur.

See our SIADH notes for more details.

Cushing’s syndrome

Cushing’s syndrome is caused by exposure to high levels of glucocorticoids. In rare cases, lung cancers produce ectopic ACTH driving an increase in glucocorticoids.

See our Cushing's syndrome notes for more details.

Lambert-Eaton syndrome

This syndrome is caused by antibodies to voltage-gated calcium channels. It is seen in 1-3% of SCLC. It is characterised by both proximal and ocular muscle weakness.

Hypertrophic osteoarthropathy 

This syndrome is characterised by clubbing and periostitis. It features a symmetrical, painful arthropathy affecting the distal joints.

Referral guidance

Patients with suspected lung cancer require two-week wait referral for further review.

NICE guidelines NG 12: Suspected cancer: recognition and referral offer advice on referral for suspected malignancy. They advise two-week wait referral in patients with:

  • Suggestive CXR findings
  • Unexplained haemoptysis and aged over 40

Patients with evidence of SVCO or stridor require urgent referral and emergency admission to hospital for further review.

Consider urgent CXR (within 2 weeks) in those aged over 40 with:

  • Persistent or recurrent chest infection
  • Clubbing
  • Supraclavicular lymphadenopathy or persistent cervical lymphadenopathy
  • Chest signs indicative of lung cancer
  • Thrombocytosis 

Consider urgent CXR (within 2 weeks) in those aged over 40 with two of the following or have ever smoked and have one of the following:

  • Cough
  • Fatigue
  • Shortness of breath
  • Chest pain
  • Weight loss
  • Appetite loss

Investigations & diagnosis

Investigations look for evidence of a primary lung cancer, this involves imaging and tissue sampling.

It is necessary to identify the cell type, the extent of invasion, nodal involvement and any metastasis.

Bedside

  • Observations
  • Blood pressure
  • Lung function tests

Bloods

  • FBC
  • U&Es
  • LFTs

Imaging

  • CXR
  • CT scan
  • PET-CT
  • Bronchoscopy 

Lung cancer on CXR

Large left sided parahilar mass suspicious for lung cancer

Image courtesy of Assoc Prof Frank Gaillard and Radiopaedia

Special tests

Tissue biopsy:

  • Obtained via endoscopy, video-assisted thoracoscopic surgery (VATS), mediastinoscopy.
  • Obtained from the tumour, lymph node or metastasis.

Cytology:

  • From aspirates, washings, pleural fluids.
  • Obtained from the tumour, lymph node or metastasis.

Squamous cell carcinoma on histology

Cytology showing non-small cell carcinoma of the lung

Image courtesy of Ed Uthman

TNM staging

Staging helps guide management as well as providing prognostic information

NSCLC is staged using the tumour node metastasis (TMN) staging system (based upon IASLC 8th Edition Lung Cancer TNM staging guidelines). SCLC may also be staged this way, though the VALSG staging system may be used instead/in conjunction with it.

Tumour

  • TX: Primary tumour cannot be assessed or tumour proven by presence of malignant cells in sputum or bronchial washings but not visualised by imaging or bronchoscopy
  • T0: No evidence of a primary tumour
  • Tis: Carcinoma in situ 
  • T1: Tumour measuring 3 cm or less in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)
  • T2: Tumour > 3 cm but ≤ 5 cm or tumour with any of the following features:
    • Involves the main bronchus regardless of distance from the carina but without the involvement of the carina
    • Invades visceral pleura
    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region involving part or all of the lung
  • T3: Tumour > 5 cm but ≤ 7 cm in greatest dimension or associated with separate tumour nodule(s) in the same lobe as the primary tumour or directly invades any of the following structure:
    • Chest wall (including the parietal pleura and superior sulcus)
    • Phrenic nerve
    • Parietal pericardium
  • T4: Tumour > 7 cm in greatest dimension or associated with separate tumour nodule(s) in a different ipsilateral lobe than that of the primary tumour or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body or carina)

Node

  • Nx: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
  • N2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
  • N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

Metastasis

  • M0: no distant metastasis
  • M1: distant metastasis present

VALSG staging

SCLC may be staged in a more simple two stage system named VALSG staging. It is felt this better reflects the limited opportunities for treatment with curative intent.

Limited disease: tumour not spread beyond hemithorax, regional nodes that may be treated with single radiotherapy field.

Extensive disease: tumour spread beyond hemithorax or extensively through the hemithorax, distant metastasis, malignant effusions or contralateral hilar/supraclavicular involvement.

Management

Management is guided primarily by the cancers cell type, staging and the patients performance status. 

All smokers should be encouraged to stop. Below is a broad look at the treatment options. The reality is that management is complex and based upon multiple factors beyond the scope of this note.

NSCLC

Surgical:

  • Utilised in stage I and II disease, typically in the form of a lobectomy.
  • Lymph node sampling during the operation offers prognostic information.

Chemotherapy:

  • May be used in combination with surgery as:
    • Neo-adjuvant: prior to surgery
    • Adjuvant: following surgery 
  • May be offered in those with more extensive disease in which surgery is not appropriate.
  • Third generation chemotherapeutics and platinum agents often used.

Radiotherapy:

  • Often a palliative treatment, to improve symptoms and survival.
  • Radical (with curative intent) radiotherapy may be used in early disease.

SCLC

Surgical:

  • Only an option in early disease, appropriate in <5% of cases.
  • In T1/2 N0 disease surgery with curative intent may be utilised.

Chemotherapy:

  • Typically utilises platinum-based combination therapy.

Radiotherapy:

  • Mostly used for palliative relief.

Prognosis

Lung cancer is the leading cause of cancer-related death in the UK.

In the UK the overall survival is (figures from Cancer Research UK):

  • One-year survival: 40.6%
  • Five-year survival: 16.2%

Prognosis is highly dependent on age and stage at time of diagnosis. Almost half survive 5-years if aged 15-39 whilst just 5 in 100 of those over 80 survive that long. When diagnosed at the earliest stage 88% survive one-year or more compared with 19% diagnosed at the latest stage.

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