Introduction
The commonest malignant tumour found in the lungs is a metastasis from another primary cancer. In fact, metastatic neoplasms to the lungs are more common than primary lung cancer. Based on clinicopathological data, the lungs are involved by metastatic disease in one third to half of all malignant lesions. It is therefore critical to find out whether the lesion in the lung is a primary lung cancer or metastasis. A biopsy is mandatory to make such distinction. Routine histopathology with the assistance of appropriate immunohistochemistry is able to distinguish primary lung cancer from a metastasis from a different primary tumour in a majority of cases. The common primary cancers metastasising to the lungs are breast, kidney, uterus, melanoma, colorectal, testes and thyroid.
Primary lung cancer
About 95% of primary lung cancers are carcinoma of the bronchus, about 2% are alveolar tumours and 3% are benign or less invasive malignant tumours.
Prognosis of primary lung cancer is very poor. The 5-year relative survival for lung cancer in Australia is about 15%.
There was an increase in 5-year relative survival for lung cancer from 8.7% for the period 1982-1987 to 14.1% for 2006-2010.
Epidemiology
Lung cancer has been the most common cancer in the world for several decades. An estimated 1.61 million people across the world were diagnosed with lung cancer in 2008, accounting for 13% of the total. More than half (55%) of the cases occurred in the developing world. Lung cancer is the fifth most commonly diagnosed cancer in Australia. About 9% of all new cancers in Australia are lung cancers. In 2009, there were 10,193 new cases of lung cancer diagnosed. In 2010, lung cancer was the commonest cause of cancer death, accounting for 19% of all cancer deaths. The mortality rate from lung cancer in Australia is significantly lower than the rates for North America, Northern Europe and East Asia. In 2010 in Australia, 3,165 people died of lung cancer and 2,864 peopel died of breast cancer. Peak incidence of lung cancer is in 60-70 year age group and is often diagnosed in ex-smokers. Highest incidence is in low socio-economic group due to high prevalence of smoking in this group.
Aetiology
Smoking is responsible for over 90% of lung cancers. Tobacco smokes contains over 60 known carcinogens. Passive smoking increases the risk of lung cancer by 1.5 fold and possibly accounts for about 5% of lung cancers. Other risk factors include exposure to arsenic, radon, radiation, iron oxide, chromium, petroleum products and possibly coal mining.
Types of lung cancer
There are 2 broad categories of lung cancer:
- Small-cell lung cancer
- SCLC accounts for about 20% of all lung cancers. It has a very aggressive behaviour and is considered a “systemic” disease at diagnosis. It develops in 3-5 years and has a doubling time of 30 days. Up to 15 % of patients with limited stage SCLC will have long-term survival. The commonest location of SCLC is around the hilum and central areas of the lungs. SCLC is most frequently associated with several para-neoplastic syndromes.
- Small cell carcinomas arise from neuroendocrine cells and secrete many different polypeptides. Some of the polypeptides have an auto feedback loop which induces further tumour growth. Often the initial presentation of patients with SCLC is with a paraneoplastic syndrome, such as Cushing’s syndrome or Addison’s disease.
- SCLC is extremely aggressive and spreads very early. Surgery does not play a part in most cases. Although SCLC responds extremely well and quickly to chemotherapy and radiation therapy, even those patients who respond usually relapse within 12 months.
- Non-small cell lung cancer
- Non-small cell lung cancer has 3 broad categories of histology. In non-small cell lung cancer histology is now considered very important as treatment choices vary significantly between the various histologies. Genetic changes include activation of oncogenes including EGFR, K-Ras, Myc and EML4-ALK, whereas a number of tumour suppressor genes, e.g., 3p, 9p, p16, 13q, 17P and P53, may be switched off in certain lung cancers.
- Adenocarcinoma: Now the most common non-small cell lung cancer and is the dominant lung cancer amongst females. Non-smokers with lung cancer most often have adenocarcinoma. Approximately 40% of all lung cancers would be adenocarcinoma.
- Adenocarcinomas are typically slow growing and take over 15 years to develop with a tumour doubling time in excess of 200 days. Adenocarcinomas are more often found peripherally and therefore often present late with distant metastases present at time of diagnosis in most patients.
- Adenocarcinomas arise from mucous cells in the bronchial epithelium. Adenocarcinoma involves mediastinal lymph nodes and he pleura and spreads to bone and brain. Adenocarcinomas are sometimes confused with mesothelioma and are most likely to cause pleural effusions.
- Squamous cell: Incidence is declining and now accounts for approximately 25% of all lung cancers. There are various subtypes, with some differences in presentation, behaviour and treatments. Squamous cell cancers are somewhat more aggressive than adenocarcinoma and take 8 or more years to develop. With doubling time in excess of 100 years, squamous cell carcinomas usually cause bronchial obstruction leading to infections. Up to 10% of squamous cell carcinomas may have cavitation. The cavitation occurs due to central necrosis of tumour mass due to rapid growth of lung cancer. These cavitating lesions are often labelled as abscess or TB cavity
- Large cell carcinoma: The least common variety accounts for about 10% of all lung cancer and is more undifferentiated with clear cell and giant cell variants. These are considered variants of adenocarcinoma and squamous cell carcinoma but because of poorly differentiated histology cannot be ascribed either. Large cell carcinomas metastasise early and have poor prognosis.
- A small number of lung cancers have mixed histology consisting either of adenocarcinoma and squamous cell carcinoma admixed or less common a combination of small cell and non-small cell variant.
Tumours arising in the main bronchi tend to present earlier than those arising peripherally and frequently are associated with haemoptysis. About 80% of lung cancers are found in the lobar bronchi; the remainder are in larger bronchi.
Tumour spread
Lung cancer can spread to the pleura either directly or via lymphatic drainage.
Local
Lung cancers can invade the chest wall, compressing the intercostal nerves or brachial plexus causing neuropathic pain. Apical tumours in the superior sulcus can also affect the brachial plexus at C8, T1-2.
Apical tumours may also cause Pancoast syndrome that affect the first rib. Pancoast tumours affect the brachial plexus and the sympathetic ganglion. The result is Horner’s syndrome which consists of ptosis meiosis and dilatation lag. There may also be anhydrosis and enophthalmos on the affected side of the face.
Regional
The primary tumour spreads to the hilar, supraclavicular or mediastinal lymph nodes. Extensive nodal involvement could compress the oesophagus, invasion of the great vessels including superior vena cava that causes superior vena cava (SVC) syndrome. SVC syndrome causes early morning headaches, oedema of upper limbs, facial and conjunctival congestion, distension of jugular vein and veins on the chest wall. The loco-regional nodal disease may also cause phrenic or left recurrent nerve palsy causing a hoarse voice.
Distant
Through haematogenous route lung cancers often spread to the adrenal gland, brain, liver, bone and lungs. Brain metastases can cause focal neurological symptoms including headaches, seizures and sometimes personality change. Metastases to adrenal are almost never symptomatic and are found during routine staging procedures or at autopsy. Bone metastases cause pain and if spinal involvement is present may lead to spinal cord compression.
Even a very small primary lung cancer can cause widespread distant metastases, especially small-cell lung cancer.
Non-metastatic manifestations
Endocrine complications: Syndrome of inappropriate ADH secretion presents itself with hyponatraemia. Treatment of SIADH is fluid restriction rather than saline administration. Cushing’s syndrome is caused by ectopic ACTH secretion. The clinical features are similar to Cushing’s syndrome caused by other causes but in lung cancer often there is concomitant MSH production leading to skin pigmentation. Excessive secretion of parathormone related protein leads to hypercalcaemia. Hypercalcaemia may also occur as a consequence of lytic bone metastases. Almost all the endocrine and non-endocrine paraneoplastic syndromes are frequently seen in SCLC; hypercalcaemia or PTHrP secretion is rare in SCLC.
- Paraneoplastic syndromes
- Paraneoplastic syndrome is a non-endocrine, non-metastatic complication of lung cancer. Paraneoplastic syndrome can present themselves years before, at the time of, or subsequent to the diagnosis of lung cancer.
- Neurological complications
- Polyneuropathy: Caused by antibodies formed against the myelin sheath.
- Lambert-Eaton myasthenic syndrome: Caused by an autoimmune reaction in which antibodies are formed against presynaptic voltage gated calcium channels in the neuromuscular junction. The most frequent consequence is muscle weakness of limbs.
- Cerebellar degeneration: This is an autoimmune reaction targeted against Purkinje cells of cerebellum. Neurological symptoms present insidiously and progress rapidly to a severely disabled state. Clinical findings include cerebellar ataxia, dysarthria, vertigo, diplopia, nystagmus and emesis.
- Hypertrophic pulmonary osteoarthropathy
- HPOA is the combination of finger clubbing and thickening of periosteum and synovium of the long bones of upper and lower extremities. It is most often seen in non-small cell lung cancer and is rarely seen in SCLC. There will be joint stiffness, severe pain in the wrists and ankles, and sometimes also gynaecomastia. On X-ray there will be proliferative periostitis at the ends of the long bones, which have an ‘onion skin’ appearance.
Presentation of lung cancer
- Respiratory symptoms of persistent dry cough, haemoptysis, wheezing, “recurrent” pneumonia or dyspnoea.
- Worsening of pre-existing COPD
- Feeling of fullness in the chest or even severe pain
- Change in character of smoker’s cough and pattern of dyspnoea
- Occasionally stridor or wheeze
- Systemic symptoms of weight loss, fevers, clubbing or fatigue
- Symptoms from local compression: chest pain, bone pain, SVC obstruction, and dysphagia.
Examination
More often than not physical examination is normal. There may be unilateral pleural effusion or signs of consolidation or collapse of a lobe of the lung. Other findings may include enlarged supraclavicular nodes, recurrent laryngeal nerve paralysis, SVC syndrome and HPOA.
Investigations
- CXR and if any abnormalities on chest x-ray then a CT scan of the chest. A normal CXR does not mean any further investigation in the presence of persistent symptoms in a smoker over the age of 40. CXR will only demonstrate approximately 60% of lung cancers, as the remainder are too central to be seen on lung fields.
- CT Scans of chest and upper abdomen: The soft tissue windows will demonstrate any hilar, mediastinal or subcarinal nodes. Also liver and adrenal metastases can be visualised. Lung windows may show other nodules, which may be metastases. Bone windows may show any possible bony metastases. See PET scan below. MRI scans play little or no part in the diagnosis of lung cancer.
- Sputum cytology if available.
- In all cases of haemoptysis and in most cases of “central” lung cancer a fibre-optic bronchoscopy with brushings, washings and biopsies as appropriate. Use of endobronchial ultrasound guided biopsy of central lymph nodes in experienced hands may be another method of obtaining cytological confirmation of lung cancer. Mediastinoscopy may still have a role in staging lung cancer but is nowadays being increasingly supplanted by PET/CT scans.
- CT guided percutaneous biopsy of peripheral lesions, not within reach of a bronchoscope.
- Once a diagnosis of lung cancer is made a PET/CT scan may give information about distant spread of lung cancer.
- Standard haematology and biochemistry particularly looking at serum calcium and sodium levels as well as any hepatic or renal dysfunction.
Staging and treatment of lung cancer
Treatment depends on a number of factors including the precise histology, extent of disease and performance status of the patient. Patients being considered for radical surgery must have adequate respiratory function.
- Small-cell lung cancer
- Limited stage, when the tumour is confined to one hemithorax, Extensive stage when there are distant metastases or presence of pleural effusion.
- Non-small cell lung cancer: Staged using TNM system as below:
- Tumour size:
- T1 < or = to 3cm
- T2 > 3cm
- T3 = local extension (parietal pleura, chest wall or within 2cm of carina)
- T4 = spread to great vessels, trachea, mediastinum, or oesophagus (un-resectable)
- Lymph Node
- N0 = no involvement
- N1 = hilar nodes
- N2 = mediastinal nodes
- N3 = contralateral nodes or ipsilateral supraclavicular (unresectable)
- Metastases
- M0 = none
- M1 = presence (unresectable)
- Stage IA - T1 N0 M0
- Stage IB - T2 N0 M0 (T > 3cm)
- Stage IIA - T1 N1 M0
- Stage IIB - T2 N1 M0; T3 N0 M0
- Stage IIIA - T3 N1 M0; T1-3 N2 M0
- Stage IIIB - Any T N3 M0; T4 Any N M0
- Stage IV - Any T Any N M1
Prognosis and treatment of lung cancer
- Small-cell lung cancer
- Small cell lung cancer is considered a systemic disease at the outset even if the staging shows limited stage disease. Most of the patients are likely to have micrometastases.
- Five-year survival is approximately 15% with treatment, however symptom control and short-term disease response is seen in excess of 85% of patients.
- Limited stage untreated life expectancy is 12-16 weeks and with treatment life span can be extended to beyond 12 months.
- Extensive stage life expectancy is about 8-10 weeks and with treatment life can be extended to about 8 months.
- Mainstay of treatment is chemotherapy with a platinum and etoposide doublet. In patients with limited stage disease, radiation therapy to the site of primary tumour is also strongly recommended. Patients with limited stage small-cell lung cancer who seem to achieve a complete response to chemoradiotherapy, may be offered prophylactic cranial irradiation to prevent CNS recurrence due to the fact that chemotherapy does not penetrate blood brain barrier and CNS recurrences are common.
- Non-small cell lung cancer
- Surgery 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. The types of surgical procedures depend on the extent and the location of disease as well as other factors like age, pulmonary reserve and other co-morbidities. Lobectomy and pneumonectomy are most frequent procedures but in some cases a segmental resection can be done.
- Stage I: Following surgery, 70% patients will survive 5 years.
- Stage II: Following surgery only 40-50% patients will survive 5 years, as many patients have micrometastases undetectable by routine staging including PET scans. Benefits from adjuvant chemotherapy are modest at about 5%.
- Stage IIIA: Often considered inoperable has a 5-year survival of <25% following surgery. Mainstay of treatment these days is combined chemoradiotherapy given synchronously rather than sequentially.
- Stage IIIB or IV: Untreated, only 5-10% will be alive at 12 months. With chemotherapy, over 20% will survive beyond 12 months. Benefits from chemotherapy are only observed in patients with performance status of WHO grade 0 or 1. Patients with performance status of grade 2 or more should not be offered chemotherapy. There is no role for single agent chemotherapy. Many targeted therapies are being considered depending on presence or absence of certain growth or promoting genes and histopathology plays a critical role in determining appropriate and targeted therapy for NSCLC. Involvement of palliative care teams at an early stage is very important in management of patients with Stages IIIb or IV.