Lung Cancer

Lung cancer is the most common cause of cancer-related mortality in the world.  It is responsible for the deaths of one in every ten people who die in their 60s in the industrialized countries. 90% of lung cancer cases are directly caused by smoking and lung cancer is the reason why smokers live, on average, ten years less than non-smokers.

Main types of lung cancer

Primary lung cancers develop in the epithelial cells that form the lining of the lung and there are two main types: small cell lung carcinoma (SCLC) and non-SCLC (NSCLC). There are three types of NSCLC (squamous cell carcinoma, adenocarcinoma and large cell carcinoma). Squamous cell cancer is the most common but all three behave similarly including  in their response to treatment.

SCLC usually develops in the bronchi at the centre of the lung. SCLC accounts for 20% of all lung tumours and is almost always caused by smoking. The cells involved are small and mainly localizes to midlevel bronchioles. Despite a generally good initial response to chemotherapy, it has a particularly poor prognosis, because of early extra thoracic dissemination and frequent disease relapse.

The major form of NSCLC, squamous carcinoma, begins when ciliated epithelial cells (cilia are tentacles used to waft detritus out of the airway) are lost from the lining of the airways and some of the underlying columnar cells begin to grow abnormally and change to a flatter shape (squamous cells).  This leads to ‘carcinoma in situ’, an abnormal growth that has not invaded adjacent tissues.  When this acquires invasive capacity and spreads within the lung and then to other organs it has become a malignant lung cancer. Squamous cell carcinoma is highly associated with tobacco smoking and is the most common type of lung cancer in men.

Adenocarcinoma is the most common form of NSCLC in both women and non-smokers. It develops mostly from the junction between the terminal bronchiole and the alveolus, termed ‘bronchoalveolar duct junction’, the source of mucus.

Large cell carcinoma, less common than the other two forms of NSCLC, forms near the surface of the lungs and comprises a class of rather poorly differentiated and less aggressive tumours. The most frequent subtype is large cell neuroendocrine carcinoma.

New cases/year World 2008: 1,607,000 [males: 1,092,000, females: 515,000];USA 2011 (est): 221,130; UK 2008: 40,800
Deaths/year World 2004: 1,375,000 [males: 948,000, females: 427,000];USA 2011 (est): 156,940; UK 2008: 35,260
Risk factors Male, over 60 years of age, living in an industrialised area.Smoking causes over 90% of lung cancers.

In addition to asbestos, exposure through working conditions to any of the following has been shown to carry an increased risk: arsenic, chromium, iron oxide, coal and petroleum products and radiation.

A family history of lung cancer in a first degree relative doubles the risk.

Symptoms None in the earliest stages: as the cancer develops can cause cough, haemoptysis (coughing up blood), chest pain, weight loss, breathlessness and tiredness.
Classification As shown above, there are two main categories of lung cancer, SCLC and NSCLC.  SCLC is classified as Limited (confined to chest) or Extensive (metastatic). Three main sub-types NSCLC have similar prognoses and treatment strategies.
Staging TNM tumour staging system is used.
Major gene mutations SCLC: Most tumours have inactivated P53 and RB1. Activating mutations commonly occur in MYC, PIK3CA, EGFR and KRAS. Whole genome sequencing has identified a set of mutations that commonly arise from carcinogens in tobacco smoke.NSCLC: EGFR, MET and PIK3CA are often mutated: the EML4-ALK fusion protein is present in about 5% of tumours.
Treatment SCLC: The disease has usually metastasised by time of diagnosis: for this reason <1% of patients receive surgery.  Only treatment is chemotherapy (etoposide + cisplatin or carboplatin) combined with radiation therapy. Pravastatin is in Phase III trials for SCLC.NSCLC: Surgery if the disease is sufficiently localised (less than 10% of cases). Chemotherapy and radiation therapy.  Drugs in use: cisplatin, carboplatin, docetaxel, gemcitabine, paclitaxel, pemetrexed, irinotecan, vinorelbine. Erlotinib is one of the most promising targeted therapies: patients with EGFR mutation show up to 18 month increased survival.  Gefitinib also effective. Drug resistance invariably develops. Novel anti-EGFR drugs are in development. Crizotinib, an inhibitor of ALK, appears promising.
Side effects Etoposide, cisplatin, carboplatin, docetaxel, gemcitabine, paclitaxel, pemetrexed, irinotecan and vinorelbine generally suppress the immune system and in particular can cause neutropenia (low white cell count). Other side effects can include nausea, hair loss and, for cisplatin, loss of hearing. Erlotinib associated with itchy, acne-like rash that covers head and chest.
Prognosis SCLC: There is usually a good initial response to chemotherapy but this is often rapidly followed by relapse.  2-year survival rate <15%.  Overall 5-year survival rate 5 to 10%.NSCLC: The five year survival rate for Stage IA (T1N0M0) is 73%, IB (T2N0M0) 55%, IIA (T1N1M0 40%, IIB (T2N1M0 or T3N0M0) 40%, IIIA (T1-3N2M0 or T3N1M0 10-35%, IIIB (Any T4 or any N3M0 5%, IV (Any M1) <5%.

In addition to SCLC and NSCLC there are several much rarer forms of cancer that can affect the lung:

Mesothelioma: a rare cancer of mesothelial cells that cover most internal organs. Approximately 70% arise in the pleura (the membrane that surrounds the lung), the majority as a result of chronic inflammation caused by exposure to asbestos, the risk being 500 times higher from blue asbestos than that from white asbestos.  The average time for this disease to develop is between 30 and 40 years after exposure.  With the cessation of the use of asbestos the incidence of mesothelioma is expected to decline from the estimate of 3,000 UK cases in 2015.  Smoking alone does not appear to cause mesothelioma but it greatly increases the risk due to asbestos. The main symptoms are breathlessness and chest pain.  Surgery is an option only in rare cases where the tumour is very localised.  Radiotherapy may reduce tumour size. The most effective chemotherapy is pemetrexed + cisplatin or carboplatin; vinorelbine, gemcitabine and raltitrexed may also be used.  The average survival time from diagnosis is 11 to 14 months.

Carcinoid: a rare (<2.5% of all lung tumours) and less malignant form of small cell carcinoma that arises most frequently in the gastrointestinal tract.

Classic or typical bronchial carcinoid tumours develop in the relatively young and women are 10 times more likely to be affected than men.  They are the least aggressive of lung tumours: fewer than 3% metastasise beyond the regional lymph nodes and they are treatable by surgery with a 94% 5-year survival rate.

Atypical bronchial carcinoid tumours are more aggressive than typical carcinoids and mainly occur in older men.  About one third metastasise to distant sites, a capacity reflected in a 57% 5-year survival rate.

Large cell neuroendocrine carcinoma (LCNEC) of the lung, so named because the cells of the tumour are at least three times the size of SCLC. LCNEC patients may be treated by surgery but the 5-year survival rate is similar to that of SCLC.

Tracheal cancer (i.e. of the windpipe) is rare (0.1% of all cancers, <1% of lung cancers).  There are two main forms, squamous cell carcinoma (developing from cells lining the airway) and adenoid cystic carcinoma (developing from glandular tissue).  Treatment is by surgery followed by radiotherapy and chemotherapy (cisplatin or carboplatin).

For further information on lung cancer consult the British Thoracic Society.