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A 65-year-old male presented to his GP with a cough persistent over the preceding four weeks. He was an ex-smoker of five years with a forty pack-year history. He denied dyspnoea, chest pain, haemoptysis or weight loss. He had no significant medical history, took no regular medications and worked as a mechanic. On examination there was no evidence of cachexia or digital clubbing. Auscultation of his chest revealed right lower zone crackles.
Based on the persistent cough and focal examination findings, he was referred for an urgent chest x-ray, which identified an opacity in the right lower zone. The report was sent to the GP, who completed an online referral to the rapid-access lung clinic. The patient was seen in this clinic eight days later. Pulmonary function testing (PFTs) on day of clinic confirmed GOLD stage A chronic obstructive airways disease. A CT thorax and upper abdomen performed the following day showed a right lower lobe mass measuring 3.5cm with distal atelectasis and small volume right hilar adenopathy. There were no enlarged mediastinal nodes, pleural disease or distant metastases.
Based on the suspicion of malignant localised hilar lymph node involvement by suspected lung cancer, he proceeded to endobronchial ultrasound (EBUS). This confirmed enlarged lymph nodes at the subcarinal and the right hilar regions. Transbronchial needle aspiration (TBNA) was performed at the subcarinal region first. An onsite cytologist reviewed the samples. The presence of lymph node tissue was confirmed but no evidence of malignancy was seen. The right hilar nodes were then aspirated and were found to contain malignant cells. Further samples were taken to ensure an adequate volume of tissue was available for analysis. The patient was discharged well post-procedure.
Subsequent PET-CT scan confirmed increased FDG activity in the right lower lobe lesion and right hilum without evidence of other nodal involvement or metastatic disease. Final cytological analysis and immunohistochemistry testing of EBUS specimens confirmed squamous cell lung cancer. The imaging and pathology were reviewed at the multidisciplinary meeting the following week and the tumour was staged as TIIaN1M0. On basis of preserved performance status (ECOG 0) and PFTs, a recommendation to proceed to right lower lobectomy by video-assisted thoracoscopic surgery (VATS) was made.
The patient was admitted for surgery shortly thereafter and had an uneventful post-operative course. Following re-discussion at the multidisciplinary team meeting, final staging was confirmed as stage IIa squamous cell lung carcinoma. Surgical margins were clear and he was referred for medical oncology opinion regarding suitability for adjuvant platinum-based doublet chemotherapy.
Lung cancer accounted for 20 per cent of cancer related deaths in Ireland in 2010 and is the leading cause of cancer mortality, according to the National Cancer Registry Ireland (NCRI) (see Figure 1). The average annual incidence from 2008 to 2010 was 60/100,000 males and 36.9/100,000 females, which represents a decrease in incidence of 0.7 per cent per year for males, but an increase of 2.2 per cent per year for females from 1994 to 2010. Mortality has also decreased by 1.9 per cent per year for males but increased by 0.5 per cent per year for females. Smoking is implicated as the principal causative factor for approximately 90 per cent of cases; other risk factors include family history and exposure to radon and asbestos.
Although survival from lung cancer has improved over the past decade, overall five-year survival was estimated at only 13 per cent as of 2010. This is principally because over 75 per cent of patients have locally advanced or disseminated disease at diagnosis and few treatment options may be available (see Figure 2). Even earliest stage cancers (stage IA) have a five-year survival of only approximately 70 per cent, and survival beyond two years with advanced disease is uncommon. A recent North American screening trial has shown a reduction in lung cancer-specific mortality using annual low-dose CT scanning though confirmatory data from similar European studies is awaited.
In order to improve survival, earlier diagnosis remains key. In this regard, the National Cancer Control Programme (NCCP) established eight rapid access lung cancer clinics (RALCs) in Ireland. This pathway allows suspect lung cancer cases to be fast-tracked and thus diagnosed sooner, potentially at an earlier, more treatable stage. Nearly 40 per cent of new lung cancers are now diagnosed at these clinics and attendances at RALCs are increasing annually.
Typical symptoms of lung cancer include cough, chest pain, haemoptysis, hoarseness and unexplained weight loss. The HSE has provided online guidelines for physicians and advise that indications for an urgent referral for chest x-ray include symptoms such as a persistent cough for more than three weeks, alteration in character/severity of cough, haemoptysis, unexplained weight loss, bone pain or neurological symptoms, and signs on examination such as clubbing, lymphadenopathy, focal chest signs or hepatomegaly. Less common signs include unilateral partial ptosis, indicative of Horner’s syndrome and ‘Pemberton’s sign’ (facial flushing after elevation of patients’ arms, indicative of superior vena cava (SVC) obstruction).
Guidelines recommend that chest x-ray reports be made available to GPs within one week. If there is a suspicious finding the radiologist may refer directly to the RALC or request the referring doctor to do so. A referral should be made to the RALC despite a normal chest x-ray result if clinical findings are highly suspicious (eg, the presence of haemoptysis) in an at-risk patient.
A CT thorax and upper abdomen is indicated to further evaluate patients with an abnormal chest x-ray and/or highly suspicious clinical presentation. This is evaluated for the presence of a mass, mediastinal/hilar lymphadenopathy and evidence of metastatic disease. Radiological staging of the disease is documented in accordance with the latest TNM staging guidelines (TNM 7, see Figure 3).
PET scanning uses uptake of fluorodeoxyglucose (18F) to identify increased metabolic activity, as is commonly seen in malignancy. Some cancers however, for example adenocarcinoma with lepidic pattern (formerly known as bronchoalveolar carcinoma), may appear ‘cold’ on PET. Infection will also be ‘hot’ on PET and is an important differential for regions of increased FDG activity. Consolidation surrounding tumours is important to recognise in order to avoid upstaging the disease based on size.
Unless comorbidities or performance status preclude further investigations, a tissue diagnosis is essential to guide treatment decisions. In general the aim is to obtain the highest yield for histological diagnosis and staging, with the least invasive test for the patient. For example, where a lung mass and liver lesion are present, positive histological samples from a liver biopsy will upstage the patient to stage IV, removing requirement to sample the lung lesion.
If there is a mass present on CT without evidence of distant disease, the location will determine whether or not it is amenable to bronchoscopic biopsy or requires a CT-guided transthoracic needle biopsy.
Figure 3: TNM7 staging of lung cancer
An airway inspection is commonly performed in the investigation of chronic cough, haemoptysis and when there is a visible lesion on CT that is likely to be amenable to endobronchial biopsy. Lesions in more distal airways can be sampled using transbronchial biopsies under fluoroscopic guidance. For bronchoscopic biopsies, aspirin can usually be continued but other anti-platelet agents are ordinarily discontinued for at least five days, INR should be less than 1.4 and novel anticoagulants should be held for two days in those with normal renal function. Bronchial washings and brushings can also be taken at time of biopsies for cytological examination.
Endobronchial ultrasound consists of a specialised bronchoscopy with an ultrasound probe on the tip of the endoscope that permits assessment of location, size and consistency of mediastinal/hilar lymph nodes. A needle is passed under ultrasound guidance through the airway wall into the node and a fine needle aspirate is taken. Where possible, rapid onsite evaluation (ROSE) is performed by an experienced cytopathologist in the bronchoscopy suite.
CT-guided transthoracic needle biopsy
When a lesion is peripheral, it may be preferable to obtain tissue percutaneously with CT-guidance. This is performed by a radiologist who uses a mapping CT to identify the direction of the biopsy needle and then advances the needle under image-guidance into the lesion. Pitfalls with this method can include sampling areas of necrosis within lesions that contain no viable malignant cells. Potential complications include pneumothorax and parenchymal haemorrhage. Extensive emphysematous change, common in lung cancer patients, increases the risk of pneumothorax and may be a contraindication in some cases.
The histological differentiation nomenclature between types of lung cancer has undergone refinements in recent years. Firstly the tumour tissue is defined as small cell carcinoma or non-small cell carcinoma. Non-small cell carcinomas are then subdivided into adenocarcinoma, adenocarcinoma with lepidic content, squamous cell carcinoma, large cell carcinoma and non-small cell carcinoma not otherwise specified, depending on morphological appearance and immunohistochemistry.
Recent advances in genetic testing have identified a number of mutations in lung cancer cell types, which may provide greater treatment options for patients. Mutations in the epidermal growth factor receptor (EGFR) are seen in approximately 10 per cent of adenocarcinomas and when present indicate a likely response to oral chemotherapeutic agents called tyrosine kinase inhibitors. When ALK mutations are present, targeted therapy such as crizotinib or ceritinib are potential treatment options. As these mutations are mutually exclusive, testing for ALK is only performed when in patients with EGFR wild type.
Once a potential lung cancer is identified, the patient’s case is listed for discussion at a multidisciplinary team meeting, attended ordinarily by respiratory physicians, (cardio) thoracic surgeons, medical and radiation oncologists, radiologists and pathologists. The data collected is reviewed and a management plan is agreed.
Cancer directed therapy
The management of lung cancer depends on the stage at diagnosis, histological subtype, lung function reserve, taking into account the patient’s wishes, performance status and comorbidities. Surgical cure is possible in stage I disease. Stage II cancers are technically resectable but usually require adjuvant chemotherapy. In those patients with localised disease but competing comorbidities or severe lung function impairment, ablative radiation therapy strategies (eg, stereotactic body radiation therapy) should be discussed as options. In fit patients, stage IIIA cancers may be amenable to potentially curative combined chemoradiotherapy.
Operable tumours are treated by VATS lobectomy in preference to open lobectomy where possible. Less commonly, pneumonectomy is performed but is associated with higher risk. Neoadjuvant chemotherapy may potentially downstage patients to allow for a lobectomy but pneumonectomy following chemotherapy has resulted in poor outcomes in large studies and is not recommended.
Some tumours are classified as a more advanced stage because of their location close to the carina. In certain circumstances these tumours can be treated with a ‘sleeve lobectomy’ where the portion of the right or left main bronchus involved is removed and the remaining lobar bronchus is anastomosed to the hilum.
For patients with stage IIIB and IV disease, treatment with palliative platinum-based doublet chemotherapy improves survival and quality-of-life in patients with adequate performance status. Those harbouring an actional mutation should be considered for targeted therapy. Patients with unresectable cancer causing airway obstruction and distal lobar collapse may benefit from bronchoscopic debulking and/or stenting procedures to open airways and improve symptoms. Malignant pleural effusions can be managed either by talc pleurodesis after fluid removal or, in suitable patients, by means of indwelling pleural catheter drainage that can be managed in an outpatient setting in order to prevent recurrence.
Palliative care service involvement early is essential in order to help alleviate symptoms and provide for appropriate end-of-life care.
Survival in lung cancer has improved over the past decade but unfortunately remains low. Early diagnosis improves outcomes and the establishment of RALC clinics in Ireland allows more rapid assessment and management of patients. Smoking cessation is a fundamental aspect of lung cancer prevention and should be addressed at every opportunity. Increased awareness and better diagnostics and treatments will hopefully improve outcomes in the future.
References available on request