9th January 2024

Lung Cancers

Background

Lung cancers are usually divided into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). This distinction is particularly important for prognostication. Patients with SCLC often develop symptoms at a much later stage of disease, and treatment is usually limited to a palliative approach.

NSCLCs form the majority of lung cancers, and these are usually divided into adenocarcinomas, squamous cell carcinomas and large cell carcinomas. 

In primary lung cancers, carcinomatous changes occur directly in the lung parenchyma, whilst in secondary lung cancers, there is metastatic spread to the lungs. The term lung cancer also encompasses mesothelioma, which is cancer of the pleura.

Epidemiology

Lung cancers are the second-most common type of malignancy worldwide but are the leading cause of cancer-related mortality. In the UK, there are around 48,500 cases of lung cancer annually and around 34,800 lung cancer-related deaths. The greatest risk factor for lung cancer is smoking, followed by radon exposure and (often) occupational exposure to certain chemicals and substances, including beryllium, silica, and asbestos.

Pathophysiology

The exact mechanism by which lung cancer occurs is not completely understood. Carcinogen exposure can deactivate tumour suppressor genes (such as p53) or activate oncogenes (such as c-myc), resulting in an abnormal cell cycle. Increased exposure results in increased cell dysplasia. Smoking cessation has been shown to reduce the incidence of lung cancer, with a reduction of up to 90 percent, dependent on the time and length of cessation.

The type of lung cancer depends on which cells are involved; for example, adenocarcinoma is a cancer of glandular cells which produce mucus, whereas squamous cell carcinoma affects squamous cells which line the airways.

Lung adenocarcinomas are the commonest type of lung cancer. They are often peripherally located and are highly associated with smoking. However, amongst individuals who have never smoked, it is the commonest form of lung cancer. Squamous cell carcinomas are usually centrally located, for example close to a main bronchus. They are also closely linked to smoking. Large cell carcinomas are so-called due to the large nuclei observed under microscopy. Around 80% of lung cancers are NSCLCs.

SCLCs account for around 20% of lung cancers. These cancers are more aggressive than NSCLCs. Many patients presenting with symptoms already have metastatic spread. They have the worst prognosis of all the lung cancer subtypes.

References

• Cancer Research UK, (https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/lung-cancer, accessed October 2022)
• Cancer Research UK, (https://www.cancerresearchuk.org/about-cancer/lung-cancer/stages-types-grades/types, accessed October 2022)
• Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020 (https://gco.iarc.fr/today, accessed October 2022)
• Peto R. Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case-control studies. BMJ. 2000;321(7257):323–9. 
• Siddiqui F, Vaqar S, Siddiqui AH. Lung Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 (https://www.ncbi.nlm.nih.gov/books/NBK482357, accessed October 2022)

Presentation

Lung cancers can present with symptoms related directly to the airways (for example, a cough or haemoptysis) or with systemic features of cancer, including an unexplained loss of weight, fevers and night sweats. The features of lung cancer can also be secondary to paraneoplastic syndromes such as Lambert-Eaton Myasthenic Syndrome (see below). Metastatic spread can also produce specific clinical features related to the organ involved.

Respiratory

Common symptoms include: 

• Cough, which may be productive of sputum
• Haemoptysis
• Chest pain, which may be pleuritic
• Dyspnoea
• Hoarseness of voice

Dyspnoea may be related to obstruction of the airways, reduced capacity of the lung parenchyma, or from phrenic nerve involvement. An exudative pleural effusion can occur, which is usually unilateral. 

The recurrent laryngeal nerve can be compressed by a tumour if in the apex, causing a hoarse voice as part of Horner’s syndrome. A tumour which grows from the apex of the lung is called a Pancoast tumour. Other features of Horner’s include miosis, partial ptosis, anhidrosis and a thoracic outlet syndrome, with pain and weakness in the ipsilateral upper limb. 

Superior vena cava (SVC) syndrome may result from compression of the SVC by a tumour. This results in facial oedema, venous distension observed in the chest and upper limbs, along with dyspnoea and a headache. Pemberton’s sign can be seen in SVC syndrome, where elevation of both arms for around one minute causes/worsens facial oedema.

Extra-Respiratory

The extra-respiratory clinical features of lung cancer are largely related to metastasis to the relevant organ system.

• Bone
  • Features of hypercalcaemia include polydipsia, confusion, renal stones, bony pain, constipation and weakness. 
  • Severe hypercalcaemia can be associated with cardiac arrhythmias, including ventricular fibrillation.
• Adrenal
  • Abdominal pain
  • Adrenal insufficiency, causing lethargy, weight loss, fatigue, nausea, and vomiting. This can lead to an adrenal crisis, with features including profound hypotension, hyperkalaemia and hyponatraemia, hypoglycemia and syncope. This is a medical emergency.
  • Intra-abdominal haemorrhage 
• Brain
  • Headache
  • Vomiting
  • Visual field loss
  • Hemiparesis
  • Cranial nerve deficit
  • Seizures
• Liver
  • Abdominal pain due to stretching of the liver capsule
  • Peripheral oedema
  • Jaundice
  • Ascites
  • Itching

Paraneoplastic

Some types of lung cancers are associated with particular paraneoplastic syndromes. 

• Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH)
  • Associated with SCLC. The increased production of ADH causes hyponatraemia, which can result in numerous symptoms, from nausea and vomiting to seizures and coma.
• Lambert-Eaton Myasthenic Syndrome (LEMS)
  • Regarded as an autoimmune disorder associated with SCLC, LEMS is a condition in which antibodies target voltage-gated calcium channels, causing widespread weakness. Largely affecting the lower limbs, it can also lead to weakness of ocular muscles and muscles of respiration, leading to ophthalmoplegia and respiratory failure, respectively. 
• Dermatomyositis
  • Heliotropic rash, Gottron’s papules and proximal myopathy
• Hypertrophic Pulmonary Osteoarthropathy (HPO)
  • Associated with nail clubbing, periostitis and arthropathy of the long bones of the limbs
• Cushing syndrome
  • Associated with SCLC, this condition has many features, including weight gain associated with typical facies and dorsocervical fat pad, hirsutism, hypertension, diabetes mellitus, hypernatraemia and hypokalaemia, oligo/amenorrhoea, impotence and osteoporosis.
• Hypercalcaemia secondary to PTH-related protein (PTHrP)

References

• Siddiqui F, Vaqar S, Siddiqui AH. Lung Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 (https://www.ncbi.nlm.nih.gov/books/NBK482357, accessed October 2022)
• UpToDate [Internet]. Uptodate.com. 2022 [cited 10 October 2022]. Available from: https://www.uptodate.com/contents/clinical-manifestations-of-lung-cancer 

Diagnosis

Lung cancer should be investigated in any individual who has chest X-ray findings suggestive of lung cancer, or anyone who is aged over 40 with unexplained haemoptysis. 

A chest X-ray is also required in:

• Patients over the age of 40 who have recurrent chest infections, nail clubbing, supraclavicular lymphadenopathy or persistent cervical lymphadenopathy or thrombocytosis
• Patients with a history of smoking who develop a cough, fatigue, dyspnoea, chest pain, weight loss or loss of appetite

Patients who develop an unprovoked deep vein thrombosis (DVT) should have a thorough history taken, and if suspicious for lung cancer, this should be investigated.

Investigations

Blood tests

Blood tests alone are not diagnostic of lung cancer but are useful in ruling out other conditions. 

• FBC, CRP (with differential and platelet count)
• U&Es
• Bone Profile
  • Bone metastasis can result in hypercalcaemia
• LFTs
  • If there is liver metastasis, then LFTs can be deranged. ALP can be elevated in bone metastasis. 
• GGT
  • If ALP is elevated but GGT is normal, bone metastasis should be considered.

Imaging

Chest radiographs are the first-line imaging modality and are used to identify any large lesions. A pleural effusion may be present. In addition, it is helpful to have a baseline radiograph with which future scans can be compared. 

If the chest X-ray is suspicious of lung cancer, then chest computed tomography (CT) with contrast enhancement is used within 72 hours if arranged by primary care or 24 hours if an inpatient. The CT scan covers the neck, chest, abdomen and pelvis to assess for any possible metastasis.

CT imaging allows staging of the lung cancer, and for this, the TNM staging system is used. This staging is used to determine if there is curative intent, and if so, a PET CT is organised.

CT brain imaging is also used if patients have neurological symptoms or if there is treatment considered with curative intent. If metastases are found, MRI imaging is used.

X-ray imaging of joints/bones can be considered if there is suspicion of bone metastasis. 

TNM Staging

The TNM system looks at the tumour size, lymph node involvement and metastasis. The ‘T’ in the system is often followed with a suffix numeral and letter, for example, T1b, T2a. This helps categorise the physical size of the tumour. 

Tx- The imaging modality could not assess the primary tumour, or it can’t be seen

T0 – There is no sign of cancer

T1 – Cancer is contained within the lung and is less than 3cm

T2 – Cancer involves the ipsilateral main bronchus or visceral pleura, or there is ipsilateral atelectasis. The lesion is between 3cm and 5cm. 

T3 – Cancer involves the chest wall, parietal pleura, phrenic nerve or pericardium. If there is more than one tumour in the same lobe, this is also classed as T3. The lesion is between 5cm and 7cm.

T4 – Cancer involves the mediastinum, diaphragm, heart, great vessels, recurrent laryngeal nerve, carina, trachea, oesophagus, spine, or another tumour is in a different lobe of the ipsilateral lung. The lesion is greater than 7cm.


Nx – Lymph nodes could not be assessed

N0 – Regional lymph nodes not involved

N1 – Ipsilateral peribronchial and/or ipsilateral hilar node involvement

N2 – Ipsilateral mediastinal and/or subcarinal lymph node involvement.

N3 – Contralateral mediastinal/hilar, ipsilateral or contralateral scalene/supraclavicular node involvement


M0 – No distant metastasis

M1 – Distant metastasis present

Tissue Sampling – Bronchoscopy, EBUS, Tracheostomy, Pleural Aspiration

A biopsy of the suspected cancer should be obtained if possible. Depending on the location of the lesion, endobronchial ultrasound (EBUS), CT-guided biopsy or bronchoscopy could be used to obtain the tissue sample.

The tissue is sent for histology and molecular profiling. This allows visualisation of the type of tumour (e.g. SCLC) and facilitates targeted chemotherapy if certain mutations are present.

• For paratracheal or peri-bronchial lung lesions, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is used. 
• For central lesions, if the patient has known metastasis and thus node sampling isn’t needed, bronchoscopy should be used.
• For peripheral lesions, image-guided biopsy should be used, for example, CT-guided biopsy.
• In patients who have negative EBUS tissue sampling but clinical suspicion of nodal involvement is high, mediastinoscopy can be considered.
• For enlarged or PET-CT positive intrathoracic lymph nodes, EBUS-TBNA or EBUS-fine needle aspiration (EBUS-FNA) should be used.
• In patients who decline invasive testing or those with central masses should have sputum sent off for cytology. 
• To make an accurate diagnosis, tissue sampling of the lesion is required, but in patients with advanced disease who are very unwell, the diagnosis is sometimes presumed from imaging alone.

Pulmonary Function Tests / Cardiopulmonary Exercise Testing

All patients who are being considered for treatment with curative intent should have spirometry and TLCO testing. Surgery should be offered to patients if the FEV1 is normal and cardiopulmonary exercise testing shows a VO2 max of 15ml/kg/minute. Patients with FEV1 or TLCO <30% should only be considered for surgery after discussions about the risk of dyspnoea and other complications.

The FEV1 value is important in determining a patient’s suitability for surgery. An FEV1 of < 1.5 is contraindication for a lobectomy, whilst an FEV1 is a contraindication for a pneumonectomy.

References

• Suspected cancer: recognition and referral – NICE guideline [NG12] https://www.nice.org.uk/guidance/ng12/chapter/Recommendations-organised-by-site-of-cancer#lung-and-pleural-cancers (accessed October 2022)
• UpToDate [Internet]. Uptodate.com. 2022 [cited 10 October 2022]. Available from:  https://www.uptodate.com/contents/overview-of-the-initial-evaluation-diagnosis-and-staging-of-patients-with-suspected-lung-cancer
• Lababede O, Meziane MA. The Eighth Edition of TNM Staging of Lung Cancer: Reference Chart and Diagrams. The Oncologist. 2018 Apr 12;23(7):844–8.

Management

The treatment of lung cancer includes numerous modalities, from palliative care to immunotherapy and surgery. An important point of note is whether the lung cancer is a SCLC or NSCLC. Treatment is usually limited to a palliative approach in SCLC, whereas a curative approach may be taken in NSCLC.

Smoking cessation services should be offered to all patients. Stop-smoking services offer support and medical therapy, including Varenicline, Bupropion and nicotine-replacement therapy. 

Patients are assigned a McMillan specialist cancer nurse at the lung cancer clinic. This nurse becomes the patient’s point of call for support, advice, and access to palliative care. The patient is treated with a multidisciplinary team (MDT) approach. Respiratory physicians, thoracic surgeons, radiologists, specialist nurses and the patient are involved in the decision-making process.

Some patients are found to have advanced disease and cannot be offered curative treatment, or they do not have the capacity to undergo the recommended treatment. Such patients can be managed with a purely palliative approach.

Pleural effusions can be managed with pleural aspirations or a pleural drain. Talc pleurodesis is used after drainage to prevent re-accumulation of the effusion. Palliative radiotherapy and/or endobronchial stents can be offered as required to minimise respiratory distress.

Brain metastases are treated with dexamethasone, and the dose is slowly weaned down to the lowest therapeutic dose in an attempt to reduce corticosteroid side effects. 

Bone metastases are treated with radiotherapy and analgesia. 

NSCLC

In NSCLC, where curative intent may be suitable, a lobectomy can be offered. This is commonly done via video-assisted thoracoscopic surgery (VATS), a minimally invasive technique similar to laparoscopic surgery in the abdomen. The benefits of VATS procedures over open surgery include reduced length of hospital stay, fewer post-operative complications and reduced time needing chest drains. More extensive surgery, including a pneumonectomy or bi-lobectomy, can be offered if clear margins are needed and cannot be confidently gained from a VATS procedure.

For patients in whom surgical intervention cannot be offered or it is declined, radical radiotherapy or chemotherapy can be offered. The survival benefits must be weighed up against the toxic side effects of the therapies. Patients with a good performance status should be offered adjuvant chemotherapy. Chemotherapy and immunotherapy regimens are selected based on particular mutations found in the NSCLC.

SCLC

SCLC is usually treated with chemo- and radiotherapy, but if at an early stage with no lymphatic or metastatic spread, surgery can be considered. Novel treatments can be offered to patients as part of clinical trials. 

Asbestos-related lung disease

The mesothelium is a protective lining of various organs, and depending on the organ, it can be called the pleura, peritoneum, pericardium or tunica vaginalis. It can, therefore, lead to symptoms related to these different organ systems. Asbestos exposure can cause benign or malignant disease within the mesothelium – benign changes are often inconsequential, but mesothelioma is an incurable cancer.

Asbestosis is a form of basal lung fibrosis. It is caused by inhalation of asbestos fibres, and disease occurs many years after exposure. A chest X-ray may be entirely normal, so a high-resolution CT chest is necessary to visualise the lung parenchyma. Pulmonary function tests show a restrictive deficit, and these investigations, alongside a strong exposure history is usually enough to make a diagnosis. A lung or pleural biopsy is rarely needed.

Pleural effusions, plaques and thickening can occur as asbestos-related lung disease. The pleural effusions can resolve spontaneously, and plaques/thickening may be found with a chest X-ray. Pleural plaques are not known to cause any symptoms and do not lead to mesothelioma, so patients with these X-ray or CT findings can be reassured and discharged. Pleural thickening can lead to respiratory symptoms.

Mesothelioma is malignant change of the mesothelium (in this case, we are limiting the topic to the pleura). The exact mechanism is unknown but is suspected to be due to lymphatic spread of asbestos fibres to the pleura. The diagnosis of mesothelioma is made with a biopsy, often as a VATS procedure. If a pleural effusion is present, then this can also be drained.

Treatment of asbestos-related lung disease is largely based around symptomatic relief. For example, treatment of a pleural effusion would involve insertion of a chest drain until dry, and then using talc pleurodesis. Conservative measures such as smoking cessation services, vaccinations and supplemental oxygen can be offered.

Patients with mesothelioma are offered palliative chemo- and radiotherapy, as well as palliative surgical therapy. Only around 45% of patients survive mesothelioma 1 year after the diagnosis is made. 

Since asbestos-related lung disease is related to occupational exposure, patients have a legal claim to compensation. Pleural plaques are an exception because they are not known to cause any symptoms.

References

• Guerrera Francesco, Anne Olland, Enrico Ruffini and Pierre-Emmanuel Falcoz. “Vats lobectomy vs. open lobectomy for early-stage lung cancer: An endless question—are we close to a definite answer?” Journal of Thoracic Disease 11, no. 12 (2019): 5616–5618. 
• Lung cancer: diagnosis and management – NICE guideline [NG122] https://www.nice.org.uk/guidance/ng122/chapter/Treatment (accessed October 2022)
• UpToDate [Internet]. Uptodate.com. 2022 [cited 10 October 2022]. Available from:  https://www.uptodate.com/contents/overview-of-the-initial-treatment-and-prognosis-of-lung-cancer